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Sample records for brain inos expressing

  1. Prodigiosin inhibits gp91{sup phox} and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia

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    Chang, Chia-Che [Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan (China); Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan (China); Wang, Yea-Hwey [Department of Nursing, College of Medicine and Nursing, Hungkuang University, Taichung, Taiwan (China); Chern, Chang-Ming [Division of Neurovascular Disease, Neurological Institute, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Liou, Kuo-Tong [Department of Chinese Martial Arts, Chinese Culture University, Taipei, Taiwan (China); Hou, Yu-Chang [Department of Chinese Medicine, Taoyuan General Hospital, Department of Health, Taiwan (China); Department of Nursing, Yuanpei University, Hsinchu, Taiwan (China); Department of Bioscience Technology, Chuan-Yuan Christian University, Taoyuan, Taiwan (China); Peng, Yu-Ta [Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China); Shen, Yuh-Chiang, E-mail: yuhcs@nricm.edu.tw [National Research Institute of Chinese Medicine, Taipei, Taiwan (China); Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China)

    2011-11-15

    This study aimed to explore the mechanisms by which prodigiosin protects against hypoxia-induced oxidative/nitrosative brain injury induced by middle cerebral artery occlusion/reperfusion (MCAo/r) injury in mice. Hypoxia in vitro was modeled using oxygen-glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone MCAo/r injury with prodigiosin (10 and 100 {mu}g/kg, i.v.) at 1 h after hypoxia ameliorated MCAo/r-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. MCAo/r induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (gp91{sup phox}), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b leukocytes due to breakdown of blood-brain barrier (BBB) by activation of nuclear factor-kappa B (NF-{kappa}B). All these changes were significantly diminished by prodigiosin. In BV-2 cells, OGD induced ROS and nitric oxide production by up-regulating gp91{sup phox} and iNOS via activation of the NF-{kappa}B pathway, and these changes were suppressed by prodigiosin. In conclusion, our results indicate that prodigiosin reduces gp91{sup phox} and iNOS expression possibly by impairing NF-{kappa}B activation. This compromises the activation of microglial and/or inflammatory cells, which then, in turn, mediates prodigiosin's protective effect in the MCAo/r mice. -- Highlights: Black-Right-Pointing-Pointer Prodigiosin ameliorated brain infarction and deficits. Black-Right-Pointing-Pointer Prodigiosin protected against hypoxia/reperfusion-induced brain injury. Black-Right-Pointing-Pointer Prodigiosin diminished oxidative/nitrosativestress and leukocytes infiltration. Black-Right-Pointing-Pointer Prodigiosin reduced BBB breakdown. Black

  2. Expression of Inducible Nitric Oxide Synthase (iNOS) in Microglia of the Developing Quail Retina

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    Sierra, Ana; Navascués, Julio; Cuadros, Miguel A.; Calvente, Ruth; Martín-Oliva, David; Ferrer-Martín, Rosa M.; Martín-Estebané, María; Carrasco, María-Carmen; Marín-Teva, José L.

    2014-01-01

    Inducible nitric oxide synthase (iNOS), which produce large amounts of nitric oxide (NO), is induced in macrophages and microglia in response to inflammatory mediators such as LPS and cytokines. Although iNOS is mainly expressed by microglia that become activated in different pathological and experimental situations, it was recently reported that undifferentiated amoeboid microglia can also express iNOS during normal development. The aim of this study was to investigate the pattern of iNOS expression in microglial cells during normal development and after their activation with LPS by using the quail retina as model. iNOS expression was analyzed by iNOS immunolabeling, western-blot, and RT-PCR. NO production was determined by using DAR-4M AM, a reliable fluorescent indicator of subcellular NO production by iNOS. Embryonic, postnatal, and adult in situ quail retinas were used to analyze the pattern of iNOS expression in microglial cells during normal development. iNOS expression and NO production in LPS-treated microglial cells were investigated by an in vitro approach based on organotypic cultures of E8 retinas, in which microglial cell behavior is similar to that of the in situ retina, as previously demonstrated in our laboratory. We show here that amoeboid microglia in the quail retina express iNOS during normal development. This expression is stronger in microglial cells migrating tangentially in the vitreal part of the retina and is downregulated, albeit maintained, when microglia differentiate and become ramified. LPS treatment of retina explants also induces changes in the morphology of amoeboid microglia compatible with their activation, increasing their lysosomal compartment and upregulating iNOS expression with a concomitant production of NO. Taken together, our findings demonstrate that immature microglial cells express iNOS during normal development, suggesting a certain degree of activation. Furthermore, LPS treatment induces overactivation of amoeboid

  3. REDUCED NITRIC OXIDE PRODUCTION AND INOS MRNA EXPRESSION IN IFN-G STIMULATED CHICKEN MACROPHAGES TRANSFECTED WITH INOS SIRNAS

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    Utilizing RNA interference technology with siRNA in the HD-11 macrophage cell line, we determined how the inhibition or knock-down of the iNOS (inducible nitric oxide synthase) gene affected IFN-y' induced macrophage production of nitric oxide (NO) and mRNA expression of genes involved in this biolo...

  4. The Expression and Correlation of iNOS and p53 in Oral Squamous Cell Carcinoma

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    Lan Yang

    2015-01-01

    Full Text Available Oral squamous cell carcinoma (OSCC is the most prevalent form of oral cancer. Inducible nitric oxide synthase (iNOS and p53 are associated with a variety of human cancers, but their expression and interaction in OSCC have not been fully explored. In this study, we investigated the expression of iNOS and p53 in OSCC and their correlation with tumor development and prognosis. In addition, we explored the interaction of iNOS and p53 in OSCC. The expression of iNOS and p53 in OSCC was investigated using immunohistochemical method and their interaction was studied using RNAi technique. Our results showed that the expression of both iNOS and p53 was significantly correlated with tumor stages and pathological grade of OSCC (P<0.05. In contrast, there was no correlation between iNOS and p53 expression and lymph node metastasis (P<0.05. The OSCC survival rate was negatively associated with iNOS expression, but not with p53. A significant increase in the expression of the p53 was observed when iNOS expression was knocked down. The immunoexpression of iNOS is correlated with tumorigenesis and prognosis of OSCC and may serve as a prognostic marker.

  5. Glycochenodeoxycholate (GCDC) inhibits cytokine induced iNOS expression in rat hepatocytes.

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    Bucher, Brian T; Feng, Xuesheng; Jeyabalan, Geetha; Zhang, Baochun; Shao, Lifang; Guo, Zhong; Geller, David A

    2007-03-01

    Although the accumulation of hydrophobic bile acid (e.g., glycine conjugated chenodeoxycholic acid, GCDC) is considered to be an important factor contributing to cholestatic liver dysfunction, its pathogenesis is poorly understood. The purpose of this study was to examine the effect of the bile salt GCDC on the regulation of iNOS expression, a key immune modulator during liver inflammation. GCDC significantly decreased cytokine-stimulated iNOS promoter activity, and both iNOS mRNA and protein expression. GCDC decreased iNOS promoter activity by preventing IkappaB degradation and inhibiting NF-kappaB DNA-binding activity. To explore the role of iNOS in bile salt induced apoptosis, we also examined the effect of NO on caspase-3 activity. GCDC strongly induced caspase-3 activity, and this increase was abrogated by both exogenous NO exposure and endogenous NO synthesis. Furthermore, adenoviral iNOS (AdiNOS) pre-treatment decreased acute cholestatic-induced liver injury in a rat bile duct ligation model. These findings indicate a novel signaling pathway where potentially toxic bile salts down-regulate hepatic iNOS expression. This blockade of the iNOS mediated antiapoptotic phenotype may have important implications in certain liver disorders.

  6. SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells.

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    Redd, Priscilla S; Ibrahim, Mohammed L; Klement, John D; Sharman, Sarah K; Paschall, Amy V; Yang, Dafeng; Nayak-Kapoor, Asha; Liu, Kebin

    2017-06-01

    Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T-cell receptor and STAT1, thus inhibiting T-cell activation and the antitumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b(+)Gr1(-) and immature CD11b(+)Gr1(+) myeloid cells in vivo Strikingly, although IRF8 was silenced in tumor-induced MDSCs, iNOS expression was significantly elevated in tumor-induced MDSCs, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathologic conditions. Furthermore, tumor-induced MDSCs exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B-H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions. Cancer Res; 77(11); 2834-43. ©2017 AACR. ©2017 American Association for Cancer Research.

  7. Expression of beta-catenin, COX-2 and iNOS in colorectal cancer: relevance of COX-2 adn iNOS inhibitors for treatment in Malaysia.

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    Hong, Seok Kwan; Gul, Yunus A; Ithnin, Hairuszah; Talib, Arni; Seow, Heng Fong

    2004-01-01

    Promising new pharmacological agents and gene therapy targeting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) could modulate treatment of colorectal cancer in the future. The aim of this study was to elucidate the expression fo beta-catenin and teh presence of COX-2 and iNOS in colorectal cancer specimens in Malaysia. This is a useful prelude to future studies investigating interventions directed towards COX-2 adn iNOS. A cross-section study using retrospective data over a 2-year period (1999-2000) involved 101 archival, formalin-fixed, paraffin-embedded tissue samples of colorectal cancers that were surgically resected in a tertiary referral. COX-2 production was detected in adjacent normal tissue in 34 sample (33.7%) and in tumour tissue in 60 samples (59.4%). More tumours expressed iNOS (82/101, 81.2%) than COX-2. No iNOS expression was detected in adjacent normal tissue. Intense beta-catenin immunoreactivity at the cell-to-cell border. Poorly differentiated tumours had significantly lower total beta-catenin (p = 0.009) and COX-2 scores (p = 0.031). No significant relationships were established between pathological stage and beta-catenin, COX-2 and iNOS scores. the accumulation of beta-catenin does not seem to be sufficient to activate pathways that lead to increased COX-2 and iNOS expression. A high proportion of colorectal cancers were found to express COX-2 and a significant number produced iNOS, suggesting that their inhibitors may be potentially useful as chemotherapeutic agents in the management of colorectal cancer.

  8. Inorganic Polyphosphate Suppresses Lipopolysaccharide-Induced Inducible Nitric Oxide Synthase (iNOS) Expression in Macrophages

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    Harada, Kana; Shiba, Toshikazu; Doi, Kazuya; Morita, Koji; Kubo, Takayasu; Makihara, Yusuke; Piattelli, Adriano; Akagawa, Yasumasa

    2013-01-01

    In response to infection, macrophages produce a series of inflammatory mediators, including nitric oxide (NO), to eliminate pathogens. The production of these molecules is tightly regulated via various mechanisms, as excessive responses are often detrimental to host tissues. Here, we report that inorganic polyphosphate [poly(P)], a linear polymer of orthophosphate ubiquitously found in mammalian cells, suppresses inducible nitric oxide synthase (iNOS) expression induced by lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, in mouse peritoneal macrophages. Poly(P) with longer chains is more potent than those with shorter chains in suppressing LPS-induced iNOS expression. In addition, poly(P) decreased LPS-induced NO release. Moreover, poly(P) suppressed iNOS mRNA expression induced by LPS stimulation, thereby indicating that poly(P) reduces LPS-induced iNOS expression by down-regulation at the mRNA level. In contrast, poly(P) did not affect the LPS-induced release of TNF, another inflammatory mediator. Poly(P) may serve as a regulatory factor of innate immunity by modulating iNOS expression in macrophages. PMID:24040305

  9. Increased intracellular Ca2+ decreases cisplatin resistance by regulating iNOS expression in human ovarian cancer cells.

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    Yu, Yang; Xie, Qi; Liu, Weimin; Guo, Yuting; Xu, Na; Xu, Lu; Liu, Shibing; Li, Songyan; Xu, Ye; Sun, Liankun

    2017-02-01

    Previous studies have reported that intracellular Ca2+ signals and inducible nitric oxide synthase (iNOS) are involved in cell apoptosis. However, the role of iNOS in cisplatin resistance in ovarian cancer remains unclear. Here, we demonstrate that SKOV3/DDP ovarian cancer cells were more resistant to cisplatin than were SKOV3 ovarian cancer cells. The expression of intracellular Ca2+ and iNOS was more strongly induced by cisplatin in SKOV3 cells than in SKOV3/DDP cells. TAT-conjugated IP3R-derived peptide (TAT-IDPS) increased cisplatin-induced iNOS expression and apoptosis in SKOV3/DDP cells. 2-Aminoethoxydiphenyl borate (2-APB) decreased cisplatin-induced iNOS expression and apoptosis in SKOV3 cells. Thus, iNOS induction may be a valuable strategy for improving the anti-tumor efficacy of cisplatin in ovarian cancer. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  10. NITRIC OXIDE PRODUCTION AND iNOS mRNA EXPRESSION IN IFN-8-STIMULATED CHICKEN MACROPHAGES TRANSFECTED WITH iNOS siRNAs

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    Utilizing RNA interference technology with siRNA in the HD-11 macrophage cell line, we determined how the knock-down of the iNOS (inducible nitric oxide synthase) gene affected IFN-' induced macrophage production of nitric oxide (NO) and mRNA expression of genes involved in this biological pathway i...

  11. Identification of hamster inducible nitric oxide synthase (iNOS) promoter sequences that influence basal and inducible iNOS expression.

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    Saldarriaga, Omar A; Travi, Bruno L; Choudhury, Goutam Ghosh; Melby, Peter C

    2012-07-01

    IFN-γ/LPS-activated hamster (Mesocricetus auratus) macrophages express significantly less iNOS (NOS2) than activated mouse macrophages, which contributes to the hamster's susceptibility to intracellular pathogens. We determined a mechanism responsible for differences in iNOS promoter activity in hamsters and mice. The HtPP (1.2 kb) showed low basal and inducible promoter activity when compared with the mouse, and sequences within a 100-bp region (-233 to -133) of the mouse and hamster promoters influenced this activity. Moreover, within this 100 bp, we identified a smaller region (44 bp) in the mouse promoter, which recovered basal promoter activity when swapped into the hamster promoter. The mouse homolog (100-bp region) contained a cis-element for NF-IL-6 (-153/-142), which was absent in the hamster counterpart. EMSA and supershift assays revealed that the hamster sequence did not support the binding of NF-IL-6. Introduction of a functional NF-IL-6 binding sequence into the hamster promoter or its alteration in the mouse promoter revealed the critical importance of this transcription factor for full iNOS promoter activity. Furthermore, the binding of NF-IL-6 to the iNOS promoter (-153/-142) in vivo was increased in mouse cells but was reduced in hamster cells after IFN-γ/LPS stimulation. Differences in the activity of the iNOS promoters were evident in mouse and hamster cells, so they were not merely a result of species-specific differences in transcription factors. Thus, we have identified unique DNA sequences and a critical transcription factor, NF-IL-6, which contribute to the overall basal and inducible expression of hamster iNOS.

  12. Chronic moderate alcohol consumption induces iNOS expression in the penis: An immunohistochemical study.

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    Gonca, Süheyla; Yazir, Yusufhan; Göçmez, Semil Selcan; Dalçik, Ekim Nur; Utkan, Tijen; Dalçik, Hakki

    2014-01-01

    To investigate the effect of moderate alcohol consumption on metabolic alterations, inducible nitric oxide synthase (iNOS), immunohistochemical distribution, and morphological damage to penile erectile tissue in rats. Male Wistar albino rats were divided into 2 groups. Group 1 rats (control group, n = 8) received tap water ad libitum, and group 2 rats (n = 8) were fed with 20% ethanol. Increasing levels of alcohol were given to the rats over 12 weeks. Immunohistochemistry was then performed using the avidin-biotin-peroxidase technique on 5-pm thickness tissue sections. Stained sections were examined by imaging microscope. Alcohol consumption resulted in a significant increase in iNOS immunoreactivity in the penile erectile tissue. Increased iNOS expression was determined in the tunica albuginea, cavernosal smooth muscle cells, trabeculae of connective tissue, arterioles, and the urethral epithelium. Moreover, chronic alcohol consumption resulted in decreasing serum testosterone and high density lipoprotein (HDL) levels with increasing cholesterol and triglyceride levels. Chronic moderate alcohol consumption can affect penile erectile tissue by increasing iNOS immunoreactivity and induce histopathological damage such as penile fibrosis. These abnormalities are also related to the defense mechanism against morphological damage.

  13. SOD1 suppresses maternal hyperglycemia-increased iNOS expression and consequent nitrosative stress in diabetic embryopathy.

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    Weng, Hongbo; Li, Xuezheng; Reece, E Albert; Yang, Peixin

    2012-05-01

    Hyperglycemia induces oxidative stress and increases inducible nitric oxide synthase (iNOS) expression. We hypothesized that oxidative stress is responsible for hyperglycemia-induced iNOS expression. iNOS-luciferase activities, nitrosylated protein, and lipid peroxidation markers 4-hydroxynonenal and malondialdehyde were determined in parietal yolk sac-2 cells exposed to 5 mmol/L glucose or high glucose (25 mmol/L) with or without copper zinc superoxide dismutase 1 (SOD1) treatment. Levels of iNOS protein and messenger RNA, nitrosylated protein, and cleaved caspase-3 and -8 were assessed in wild-type embryos and SOD1-overexpressing embryos from nondiabetic and diabetic dams. SOD1 treatment diminished high glucose-induced oxidative stress, as evidenced by 4-hydroxynonenal and malondialdehyde reductions, and it blocked high glucose-increased iNOS expression, iNOS-luciferase activities, and nitrosylated protein. In vivo SOD1 overexpression suppressed hyperglycemia-increased iNOS expression and nitrosylated protein, and it blocked caspase-3 and -8 cleavage. We conclude that oxidative stress induces iNOS expression, nitrosative stress, and apoptosis in diabetic embryopathy. Copyright © 2012 Mosby, Inc. All rights reserved.

  14. Acute toxication of deltamethrin results in activation of iNOS, 8-OHdG and up-regulation of caspase 3, iNOS gene expression in common carp (Cyprinus carpio L.).

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    Arslan, Harun; Altun, Serdar; Özdemir, Selçuk

    2017-06-01

    Deltamethrin is a widely used synthetic pyrethroid pesticide that protects agricultural yields, including crops, fruits, and vegetables from insect-pests. It is known that deltamethrin toxication leads to metabolic disorders and has detrimental effects on the brain and liver in different organisms. However, the harmful effects of deltamethrin toxication on aquatic animals remain unclear. In the present study, we aimed to evaluate the adverse effects of deltamethrin toxication by performing a histopathological examination, an immunofluorescence assay, and a qRT-PCR on common carp. We observed that a low-dose (0.04μM) and a high-dose (0.08μM) of deltamethrin exposure caused lamellar cells hyperplasia and inflammatory cells infiltration in the gills, hyperemia, diffuse hydropic degenerations and focal necrosis in the hepatocytes, necrotic changes in the neurons, and also induced activation of inducible Nitric Oxide Synthase (iNOS) and 8-hydroxy-2-deoxyguanosine (8-OHdG) in the gills, liver, and brain depending on the exposure time (24h, 48h, 72h and 96h). In addition, deltamethrin toxication caused the up-regulation of caspase-3 and the inducible Nitric Oxide Synthase (iNOS) of the gene expression depending on the dose (0.04μM and 0.08μM) and the exposure time in the brain (p<0.05, p<0.01, p<0.001). Our results indicated that long-term deltamethrin exposure could lead to inflammation, oxidative stress, DNA damage, and apoptosis on the different organs in common carp. Thus, deltamethrin toxication is dangerous for common carp populations, and the usage of deltamethrin should be controlled and restricted in agricultural areas. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Inhibitory effects of Euterpe oleracea Mart. on nitric oxide production and iNOS expression.

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    Matheus, Maria Eline; de Oliveira Fernandes, Sidnei Bessa; Silveira, Cristiane Silva; Rodrigues, Verônica Pinto; de Sousa Menezes, Fabio; Fernandes, Patricia Dias

    2006-09-19

    The palm Euterpe oleracea is a plant of great economic value in Brazil. Although the heart of palm extracted from its trunk is considered a delicacy the world over, its fruits are popular only among Brazilians. In some poor regions of Brazil, there are reports on the popular use of its juice in the treatment of several disorders, mainly those of oxidative onset as cardiovascular ones. Because of its wide utilization; because there are very few scientific studies of this species, and to discover if its use in folk medicine for problems related with oxidation is in fact justifiable, we decided, in this study, to evaluate the effects of Euterpe oleracea flowers, fruits and spikes fractions on: nitric oxide (NO) production, NO scavenger capacity, and on the expression of inducible nitric oxide synthase enzyme, as well. Results showed that the fractions obtained from fruits were the most potent in inhibiting NO production, followed by those from flowers and spikes. Only in high doses, did some fractions reduce cell viability. Reduction on NO production was not due to NO scavenger activity. These results were accompanied by inhibition of iNOS expression. The more pronounced effect was observed in the fractions in which the concentration of cyanidin-3-O-glucoside and cyanidin-3-O-rhamnoside were higher. To sum up, our results indicate that fractions from Euterpe oleracea inhibits NO production by reducing the levels of inducible nitric oxide synthase expression.

  16. Inhibitory effect of di-catechol rooperol on VCAM-1 and iNOS expression in cytokine-stimulated endothelium.

    Science.gov (United States)

    Bereta, J; Bereta, M; Allison, A C; Kruger, P B; Koj, A

    1997-01-01

    Induced expression of vascular cell adhesion molecule-1 (VCAM-1) and of nitric oxide synthase (iNOS) is believed to play a role in the pathogenesis of atherosclerosis, asthma, as well as other inflammatory disorders. In the current study we examined the effect of the di-catechol rooperol [(E)-1,5-bis (3',4'-dihydroxyphenyl) pent-4-en-1-yne] on the process of microvascular endothelial cell (MME) activation by TNF-alpha and IFN-gamma. We show that rooperol decreases VCAM-1 and iNOS mRNA levels in cytokine-activated MME with subsequent inhibition of VCAM-1 membrane expression as measured by adhesion of P815 cells to MME monolayers, and NO production, as reflected in the nitrite concentration in culture medium. The properties of rooperol now described suggest that rooperol may be an anti-inflammatory agent useful in the treatment of several inflammatory disorders.

  17. TNF-α expression, not iNOS expression, is correlated with NF-κB ...

    African Journals Online (AJOL)

    Previous studies have shown that pro-inflammatory cytokines were involved in the genesis and persistence of neuropathic pain. Nuclear factor kappa B (NF-κB) plays a crucial role in regulating proinflammatory cytokine gene expression. In this study, we examined the hypothesis that NF-κB would regulate the expression of ...

  18. iNOS expression and biosynthesis of nitric oxide metabolites in the course of tumor growth of different histogenesis

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    V. P. Deryagina

    2016-01-01

    Full Text Available The dynamics of the production of nitric oxide (NO metabolites: nitrites, nitrates, volatile nitrosamines and iNOS expression was studied in mice with subcutaneous transplanted, spontaneous and chemical- induced tumors. Tumor growth was accompanied by increased production of nitrites + nitrates in tumors or their release with urine that not dependent on tumor histotype. The total concentration of nitrites and nitrates in tumors reached micromolar levels characteristic of nitrosative stress. The ability of peritoneal macrophages + monocytes to generates nitrites was suppressed at the stage of intensive growth of the Lewis lung carcinoma, which may indicate a decrease in the cytotoxic properties of immune cells. The possibility of formation in the Erlich carcinoma of volative N-nitrosodimethylamine and N-nitrosodiethylamine compounds with pronounced carcinogenic properties was demonstrated. A positive expression of iNOS was revealed in some areas of lung carcinoma at all investigated time points using the immunohistochemical method. The lungs metastases were not stain or weakly stained. This may indicate selection of the cells with a low activity of iNOS migrating in the lungs.

  19. Chronic moderate alcohol consumption induces iNOS expression in the penis: An immunohistochemical study

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    GONCA, Süheyla; YAZIR, Yusufhan; GÖÇMEZ, Semil Selcan; DALÇIK, Ekim Nur; Utkan, Tijen; DALÇIK, Hakkı

    2014-01-01

    To investigate the effect of moderate alcohol consumption on metabolic alterations, inducible nitric oxide synthase (iNOS), immunohistochemical distribution, and morphological damage to penile erectile tissue in rats. Materials and methods: Male Wistar albino rats were divided into 2 groups. Group 1 rats (control group, n = 8) received tap water ad libitum, and group 2 rats (n = 8) were fed with 20% ethanol. Increasing levels of alcohol were given to the rats over 12 weeks. Immunohistochemi...

  20. Echinocystic Acid Inhibits IL-1β-Induced COX-2 and iNOS Expression in Human Osteoarthritis Chondrocytes.

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    Ma, Zhiqiang; Wang, Yanlong; Piao, Taikui; Liu, Jianyu

    2016-04-01

    Echinocystic acid (EA), a pentacyclic triterpene isolated from the fruits of Gleditsia sinensis Lam, displays a range of pharmacological activities including anti-inflammatory and antioxidant effects. However, the effect of EA on IL-1β-stimulated osteoarthritis chondrocyte has not been reported. The purpose of this study was to assess the effects of EA on IL-1β-stimulated human osteoarthritis chondrocyte. Chondrocytes were stimulated with IL-1β in the absence or presence of EA. NO and PGE2 production were measured by Griess reagent and ELISA. The expression of COX-2, iNOS, nuclear factor-κB (NF-κB), inhibitory kappa B (IκBα), c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK) were detected by Western blot analysis. The results showed that EA suppressed IL-1β-induced collagenase-3 (MMP-13), NO, and PGE2 production in a dose-dependent manner. IL-1β up-regulated the expression of COX-2 and iNOS, and the increase was inhibited by EA. Furthermore, IL-1β-induced NF-κB and mitogen-activated protein kinase (MAPK) activation were inhibited by EA. In conclusion, EA effectively attenuated IL-1β-induced inflammatory response in osteoarthritis chondrocyte which suggesting that EA may be a potential agent in the treatment of osteoarthritis.

  1. Effect of Progesterone Therapy on TNF-α and iNOS Gene Expression in Spinal Cord Injury Model

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    Akram Farahabadi

    2016-06-01

    Full Text Available Spinal cord injury (SCI as a destructive crash result in neurons degeneration. The SCI lead to the onset of biochemical and molecular cascades such as inflammation that in turn has a key role in neurodegeneration development. The previous studies demonstrated the role of TNF-α and iNOS genes in intensifying the process after SCI. As a consequence, these genes overexpression intensify the inflammation and neuron degeneration process. In the present study, 32 male Wistar rats were chased and divided into four groups of eight. The SCI were induced in three groups and another group used as a sham. The progesterone hormone used as a therapeutic agent in rats with SCI. The results showed that injection of 10 μg/kg/12h progesterone hormone reduced the TNF-α and iNOS gene expression significantly and confirmed the role of progesterone in the reduction of inflammation. Also, the numbers of intact neurons in progesterone group were higher than other groups that demonstrated the protective effects of progesterone on neuron death. The BBB test was performed and demonstrated that progesterone is an effective factor to the improvement of locomotor response. These results of the study confirmed the anti-inflammatory activity of progesterone hormone and suggested that it can be used as a therapeutic factor for SCI.

  2. 4-dimethylamino-3',4'-dimethoxychalcone downregulates iNOS expression and exerts anti-inflammatory effects.

    Science.gov (United States)

    Herencia, F; Ferrándiz, M L; Ubeda, A; Guillén, I; Dominguez, J N; Charris, J E; Lobo, G M; Alcaraz, M J

    2001-01-01

    Reactive oxygen and nitrogen species contribute to the pathophysiology of inflammatory conditions. We have studied the effects of a novel superoxide scavenger, 4-dimethylamino-3', 4'-dimethoxychalcone (CH11) in macrophages and in vivo. CH11 has been shown to inhibit the chemiluminescence induced by zymosan in mouse peritoneal macrophages and the cytotoxic effects of superoxide. In the same cells, the modulation by superoxide of nitric oxide (NO) production in response to zymosan was investigated. CH11 was more effective than the membrane-permeable scavenger Tiron for inhibition of inducible nitric oxide synthase (iNOS) protein expression and nitrite production. We have shown that CH11 inhibited chemiluminescence in vivo, as well as cell migration, and eicosanoid and tumor necrosis factor-alpha (TNF-alpha) levels in the mouse air pouch injected with zymosan. This chalcone derivative also exerted anti-inflammatory effects in the carrageenan paw oedema.

  3. Organ-specific and differential requirement of TYK2 and IFNAR1 for LPS-induced iNOS expression in vivo.

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    Painz, Ronald; Walter, Ingrid; Kolbe, Thomas; Rigler, Doris; Vogl, Claus; Steinborn, Ralf; Rülicke, Thomas; Helmreich, Magdalena; Karaghiosoff, Marina; Müller, Mathias

    2007-01-01

    Lipopolysaccharide (LPS) is an integral structural component of the outer membrane of Gram-negative bacteria and the principal active agent in the pathogenesis of endotoxin shock. LPS is a potent inducer of a variety of cytokines and inflammatory agents that lead to a profound alteration of gene expression patterns in cells and organs. The gene coding for the inducible nitric oxide synthase (iNOS) is highly responsive to LPS in vitro and in vivo and accounts for the production of nitric oxide (NO). The Janus kinase (JAK) family member tyrosine kinase 2 (TYK2) is a constituent of the interferon (IFN) type I response pathway and an important effector in the progression of endotoxin shock. Macrophages deficient for IFNalphabeta receptor chain 1 (IFNAR1) or TYK2 were shown to have an impaired LPS-induced iNOS expression. Here we determined the contribution of IFNAR1 and TYK2 to iNOS expression in vivo in a lethal LPS challenge model. TYK2 and IFNAR1 were found to be crucial for the LPS-induced iNOS mRNA and protein expression in spleen and lung that could be attributed to the Mac3-positive population. In liver LPS-induced iNOS mRNA expression was only partially impaired in TYK2-deficient mice and was unimpaired in IFNAR1-deficient mice, indicating organ specificity. TYK2(-/-) and IFNAR1(-/-) mice also differ with respect to IFNgamma production upon LPS challenge in that TYK2(-/-) mice show a defect while IFNAR1(-/-) mice do not. Our data suggest that iNOS is induced through IFNAR1 and TYK2 in Mac3-positive cells which are the main source of iNOS in spleen and lung. The LPS-induced iNOS expression in liver is independent of IFNAR1 and partially dependent on TYK2, which is most likely due to the lack of IFNgamma production in the absence of TYK2.

  4. Evaluation of INOS, ICAM-1, and VCAM-1 gene expression: A study of adult T cell leukemia malignancy associated with HTLV-1.

    Science.gov (United States)

    Jafarian, Mahdokht; Mozhgani, Sayed-Hamidreza; Patrad, Elham; Vaziri, Hamidreza; Rezaee, Seyed Abdolrahim; Akbarin, Mohammad Mehdi; Norouzi, Mehdi

    2017-04-01

    The main aim of this study was to evaluate the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and inducible nitric oxide synthase (iNOS) as host factors, and proviral load as the viral parameter, in adult T-cell leukemia/lymphoma (ATLL) individuals and healthy carrier (HC(s)) groups. Peripheral blood mononuclear cells (PBMC) from ATLL patients (n = 17) and HC subjects (as the control group, n = 17) were evaluated using real-time PCR to determine the levels of HTLV-1 proviral load and mRNA expression of ICAM, VCAM-1, and iNOS. ICAM-1 was significantly lower in ATLL patients than in control subjects. Although the expression of VCAM-1 was higher in ATLL individuals, there was no significant difference between the studied groups. In addition, no iNOS expression was found in ATLL patients, when compared to the HCs subjects, while ATLL patients demonstrated a higher level of proviral load when compared to the control group. Considering the importance of ICAM-1 in facilitating immune recognition of infected cells, it is posited that reduction of ICAM-1 expression is a unique strategy for circumventing appropriate immune responses that are mediated by different accessory proteins. Additionally, as the viral regulatory protein Tax and the NF-κB pathway play pivotal roles in expression of iNOS, lack of the latter in ATLL patients may be related to the level of Tax expression, disruption of the NF-κB pathway, or the occurrence of epigenetical mechanisms in the human iNOS promoter. Further studies are recommended to gain a better understanding of the interaction between host and viral factors in HTLV-1 pathogenesis and to identify a possible therapeutic target for ATLL.

  5. Effect of sildenafil citrate on interleukin-1β-induced nitric oxide synthesis and iNOS expression in SW982 cells

    Science.gov (United States)

    Kim, Kyung-Ok; Park, Shin-Young; Han, Chang-Woo; Chung, Hyun Kee; Ryu, Dae-Hyun

    2008-01-01

    The purpose of this study was to identify the effect of sildenafil citrate on IL-1β-induced nitric oxide (NO) synthesis and iNOS expression in human synovial sarcoma SW982 cells. IL-1β stimulated the cells to generate NO in both dose- and time-dependent manners. The IL-1β-induced NO synthesis was inhibited by guanylate cyclase (GC) inhibitor, LY83583. When the cells were treated with 8-bromo-cGMP, a hydrolyzable analog of cGMP, NO synthesis was increased upto 5-fold without IL-1β treatment suggesting that cGMP is an essential component for increasing the NO synthesis. Synoviocytes and chondrocytes contain strong cGMP phosphodiesterase (PDE) activity, which has biochemical features of PDE5. When SW982 cells were pretreated with sildenafil citrate (Viagra), a PDE5 specific inhibitor, sildenafil citrate significantly inhibited IL-1β-induced NO synthesis and iNOS expressions. From this result, we noticed that PDE5 activity is required for IL-1β-induced NO synthesis and iNOS expressions in human synovial sarcoma cells, and sildenafil citrate may be able to suppress an inflammatory reaction of synovium through inhibition of NO synthesis and iNOS expression by cytokines. PMID:18587266

  6. Imidacloprid exposure cause the histopathological changes, activation of TNF-α, iNOS, 8-OHdG biomarkers, and alteration of caspase 3, iNOS, CYP1A, MT1 gene expression levels in common carp (Cyprinus carpio L.).

    Science.gov (United States)

    Özdemir, Selçuk; Altun, Serdar; Arslan, Harun

    2018-01-01

    Imidacloprid (IMI) is a neonicotinoid that is widely used for the protection of crops and carnivores from insects and parasites, respectively. It is well known that imidacloprid exposure has a harmful effect on several organisms. However, there is little information about imidacloprid toxicity in aquatic animals, particularly fish. Thus, in the current study, we assessed the histopathological changes; activation of iNOS, 8-OHdG and TNF-α; and expression levels of caspase 3, iNOS, CYP1A and MT1 genes in the common carp exposed to imidacloprid. For this purpose, fish were exposed to either a low dose (140 mg/L) or a high dose (280 mg/L) of imidacloprid for 24 h, 48 h, 72 h and 96 h. After IMI exposure, we detected hyperplasia of secondary lamellar cells and mucous cell hyperplasia in the gills, as well as hydropic degeneration in hepatocytes and necrosis in the liver. Moreover, 8-OHdG, iNOS and TNF-α activation was found particularly in the gills and liver but also moderately in the brain. Transcriptional analysis showed that caspase 3 expression was altered low dose and high doses of IMI for 72 h and 96 h exposure (p  0.05) except with low and high doses of IMI for 96 h (p < 0.05), and lastly, MT1 gene expression was up-regulated only in the brain with low doses of IMI for 96 h and high doses of IMI for 48 h, 72 h and 96 h exposure (p < 0.05, p < 0.01). Our results indicated that acute IMI exposure moderately induce apoptosis in the brain but caused severe histopathological lesions, inflammation, and oxidative stress in the gills, liver, and brain of the common carp.

  7. Inhibited Production of iNOS by Murine J774 Macrophages Occurs via a phoP-Regulated Differential Expression of NFκB and AP-1

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    Scott D. Hulme

    2012-01-01

    Full Text Available Background. There are no reported data to explain how Salmonella suppress nitrite ion production in macrophages or whether this phenomenon is unique to typhoidal or non-typhoidal serovars. The aims of this study were, therefore, to investigate these phenomena. Methods. We measured survival of S. typhimurium 14028 and its phoP mutant in murine J774 macrophages, cultured with or without interferon gamma. We compared expression of inducible nitric oxide synthase (iNOS mRNA and protein, and nitrite ion production and also examined binding of nuclear factor B (NFB and activator protein 1 (AP-1 to macrophage DNA. Results. S. typhimurium 14028 inhibited binding of NFB and AP-1 to DNA in murine J774. A macrophages via an intact phoP regulon. This correlated with increased survival and reduced iNOS expression. Suppression of NFB activity was ameliorated in macrophages cultured with IFN-γ and this correlated with increased expression of iNOS mRNA and nitrite ion production, although IFN-γ had no effect on AP-1/DNA interaction. We show, that with one exception, suppression of iNOS is unique to typhoidal serovars. Conclusion. S. typhimurium inhibit NFB and AP-1 interaction with macrophage DNA via the PhoP regulon, this reduces nitrite ion production and is principally associated with typhoidal serovars.

  8. Agastache rugosa leaf extract inhibits the iNOS expression in ROS 17/2.8 cells activated with TNF-alpha and IL-1beta.

    Science.gov (United States)

    Oh, Hwa Min; Kang, Young Jin; Kim, Sun Hee; Lee, Young Soo; Park, Min Kyu; Heo, Ja Myung; Sun, Jin ji; Kim, Hyo Jung; Kang, Eun Sil; Kim, Hye Jung; Seo, Han Geuk; Lee, Jae Heun; Yun-Choi, Hye Sook; Chang, Ki Churl

    2005-03-01

    It has been suggested that nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) may act as a mediator of cytokine-induced effects on bone turn-over. NO is also recognized as an important factor in bone remodeling, i.e., participating in osteoblast apoptosis in an arthritic joint. The components of Agastache rugosa are known to have many pharmacological activities. In the present study, we investigated the effects of Agastache rugosa leaf extract (ELAR) on NO production and the iNOS expression in ROS 17/2.8 cells activated by a mixture of inflammatory cytokines including TNF-alpha and IL-1beta. A preincubation with ELAR significantly and concentration-dependently reduced the expression of iNOS protein in ROS 17/2.8 cells activated with the cytokine mixture. Consequently, the NO production was also significantly reduced by ELAR with an IC50 of 0.75 mg/mL. The inhibitory mechanism of iNOS induction by ELAR prevented the activation and translocation of NF-kappaB (p65) to the nucleus from the cytosol fraction. Furthermore, ELAR concentration-dependently reduced the cellular toxicity induced by sodium nitroprusside, an NO-donor. These results suggest that ELAR may be beneficial in NO-mediated inflammatory conditions such as osteoporosis.

  9. Role of iNOS and eNOS expression in a group of Egyptian diabetic and nondiabetic nephropathy patients

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    Mayssa I. Aly

    2013-01-01

    Conclusion The presence of iNOS is associated with tubular damage resulting in renal failure. The upregulation of NO in diabetes mellitus type 2 may explain the endothelial dysfunction that is associated with almost all diabetic complications.

  10. Quercetin modulates iNOS, eNOS and NOSTRIN expressions and attenuates oxidative stress in warm hepatic ischemia-reperfusion injury in rats

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    Mohamed Abd-Elbaset

    2015-09-01

    Full Text Available The pathogenesis of hepatic ischemia/reperfusion (I/R is mediated through the generation of oxidative and nitrosative stress-induced cell injury. Hence, the present study was designed to evaluate the hepatoprotective effect of quercetin (QR compared to N-acetylcysteine (NAC against hepatic I/R injury in rats and to assess iNOS, eNOS and NOSTRIN protein expressions, as a possible mechanism of its hepatoprotective effect. Hepatic ischemia was surgically performed by occlusion of hepatic pedicle (hepatic artery, portal vein, bile duct that supplies the left and medial lobes (approximately 70% of the total liver mass, for 30 min with a vascular clamp followed by releasing the clamp and the liver was reperfused for 30 min. QR-pretreatment increased eNOS protein expression with simultaneous decrease in iNOS and NOSTRIN protein expressions. It also decreased serum aspartate aminotransferase (AST, alanine aminotransferases (ALT and hepatic myeloperoxidase (MPO activities. In addition, it restored the depleted content of reduced glutathione (GSH and decreased malondialdehyde (MDA and nitric oxide (NO levels. A notable finding is that QR alleviated I/R-induced histopathological changes. Therefore, the present study illustrates the hepatoprotective effect of quercetin compared to N-acetylcysteine against ischemia/reperfusion-induced liver injury by inhibiting oxidative stress and by modulating iNOS, eNOS and NOSTRIN protein expressions.

  11. [Effect of triptolide on iNOS and SP expressions in spinal dorsal horn and dorsal root ganglion of rats with adjuvant arthritis].

    Science.gov (United States)

    Chen, Wei; Zhang, Xu-Dong; Lu, Zhuo-Hui; Wei, Deng-Ming

    2014-05-01

    To observe the analgesic effect of triptolide (TP) of high, middle and low doses on rats with adjuvant arthritis (AA), and the expressions of inducible nitric oxide synthase (iNOS) and substance P (SP) in spinal dorsal horn and dorsal root ganglion (DRG) of corresponding sections, in order to discuss the possible mechanism for the analgesic effect of TP on rats with adjuvant arthritis. Fifty SD rats were selected and randomly divided into the normal group (group A), the model group (group B), and TP low (group C), middle (group D), high (group E) dose groups. Except for the group A, all of the remaining groups were injected with 0.1 mL of Freund's complete adjuvant through their right rear toes to establish the model. At 14 d after the model establishment, rats in C, D and E groups were intraperitoneally injected with different doses of TP (0.1 mg x kg(-1) for the group C, 0.2 mg x kg(-1) for the group D, 0.4 mg x kg(-1) for the group E) once a day for 9 days. Then the 50% mechanical withdraw threshold (MWT) was determined. And the expressions of iNOS and SP in lumbar5 (L5) spinal dorsal horn and DRG were detected with the immunohistochemical method. The 50% MWT of rats in the group B was significantly lower than that of the group A (P effect relationship. The immunohistochemical results indicated that the iNOS and SP expressions significantly increased in the group B (P effect relationship. TP shows a good analgesic effect on AA, and could inhibit the iNOS and SP expressions in spinal dorsal horn and DRG in rats with adjuvant arthritis, which may be one of action mechanisms for the analgesic effect of TP.

  12. Eupatolide inhibits lipopolysaccharide-induced COX-2 and iNOS expression in RAW264.7 cells by inducing proteasomal degradation of TRAF6.

    Science.gov (United States)

    Lee, Jongkyu; Tae, Nara; Lee, Jung Joon; Kim, Taeho; Lee, Jeong-Hyung

    2010-06-25

    Inula britannica is a traditional medicinal plant used to treat bronchitis, digestive disorders, and inflammation in Eastern Asia. Here, we identified eupatolide, a sesquiterpene lactone from I. britannica, as an inhibitor of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Eupatolide inhibited the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) as well as iNOS and COX-2 protein expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Eupatolide dose-dependently decreased the mRNA levels and the promoter activities of COX-2 and iNOS in LPS-stimulated RAW264.7 cells. Moreover, eupatolide significantly suppressed the LPS-induced expression of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) reporter genes. Pretreatment of eupatolide inhibited LPS-induced phosphorylation and degradation of I kappaB alpha, and phosphorylation of RelA/p65 on Ser-536 as well as the activation of mitogen-activated protein kinases (MAPKs) and Akt in LPS-stimulated RAW264.7 cells. Eupatolide induced proteasomal degradation of tumor necrosis factor receptor-associated factor-6 (TRAF6), and subsequently inhibited LPS-induced TRAF6 polyubiquitination. These results suggest that eupatolide blocks LPS-induced COX-2 and iNOS expression at the transcriptional level through inhibiting the signaling pathways such as NF-kappaB and MAPKs via proteasomal degradation of TRAF6. Taken together, eupatolide may be a novel anti-inflammatory agent that induces proteasomal degradation of TRAF6, and a valuable compound for modulating inflammatory conditions. (c) 2010 Elsevier B.V. All rights reserved.

  13. Inhibitory Effect of Inflexinol on Nitric Oxide Generation and iNOS Expression via Inhibition of NF-κB Activation

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    Jae Woong Lee

    2007-01-01

    Full Text Available Inflexinol, an ent-kaurane diterpenoid, was isolated from the leaves of Isodon excisus. Many diterpenoids isolated from the genus Isodon (Labiatae have antitumor and antiinflammatory activities. We investigated the antiinflammatory effect of inflexinol in RAW 264.7 cells and astrocytes. As a result, we found that inflexinol (1, 5, 10 μM suppressed the expression of inducible nitric oxide synthase (iNOS and cyclooxygenase-2 (COX-2 as well as the production of nitric oxide (NO in LPS-stimulated RAW 264.7 cells and astrocytes. Consistent with the inhibitory effect on iNOS and COX-2 expression, inflexinol also inhibited transcriptional and DNA binding activity of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into nucleus. These results suggest that inflexinol inhibits iNOS and COX-2 expression through inhibition of NF-κB activation, thereby inhibits generation of inflammatory mediators in RAW 264.7 cells and astrocytes, and may be useful for treatment of inflammatory diseases.

  14. High BMI levels associate with reduced mRNA expression of IL10 and increased mRNA expression of iNOS (NOS2) in human frontal cortex

    DEFF Research Database (Denmark)

    Lauridsen, J K; Olesen, R H; Vendelbo, J

    2017-01-01

    analysis was performed with BMI as variable on data on IL10, IL1β, IL6, PTGS2 (COX2) and NOS2 (iNOS). Increasing BMI is associated with a decrease in the mRNA expression of IL10 (P=0.014) and an increase in the expression of NOS2 (iNOS; P=0.040). Expressions of IL10 and NOS2 (iNOS) were negatively...... correlated (PIL10 was mostly affected by individuals with BMI ⩾40. Multiple linear regression analyses with BMI, age, sex and race as variables were performed in order to identify potential confounders. In conclusion, increasing BMI could affect the IL10-mediated anti...

  15. Arsenic affects inflammatory cytokine expression in Gallus gallus brain tissues.

    Science.gov (United States)

    Sun, Xiao; He, Ying; Guo, Ying; Li, Siwen; Zhao, Hongjing; Wang, Yu; Zhang, Jingyu; Xing, Mingwei

    2017-06-05

    The heavy metal arsenic is widely distributed in nature and posses a serious threat to organism's health. However, little is known about the arsenic-induced inflammatory response in the brain tissues of birds and the relationship and mechanism of the inflammatory response. The purpose of this study was to explore the effects of dietary arsenic on the expression of inflammatory cytokines in the brains of Gallus gallus. Seventy-two 1-day-old male Hy-line chickens were divided into a control group, a low arsenic trioxide (As2O3)-treated (7.5 mg/kg) group, a middle As2O3-treated (15 mg/kg) group, and a high As2O3-treated (30 mg/kg) group. Arsenic exposure caused obvious ultrastructural changes. The mRNA levels of the transcription factor nuclear factor-κB (NF-κB) and of pro-inflammatory cytokines, including inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and prostaglandin E synthase (PTGEs), in chicken brain tissues (cerebrum, cerebellum, thalamus, brainstem and myelencephalon) on days 30, 60 and 90, respectively, were measured by real-time PCR. The protein expression of iNOS was detected by western blot. The results showed that after being treated with As2O3, the levels of inflammatory-related factor NF-κB and pro-inflammatory cytokines in chicken brain tissues increased (P Arsenic exposure in the chickens triggered host defence and induced an inflammatory response by regulating the expression of inflammatory-related genes in the cerebrum, cerebellum, thalamus, brainstem and myelencephalon. These data form a foundation for further research on arsenic-induced neurotoxicity in Gallus gallus.

  16. Arctigenin inhibits lipopolysaccharide-induced iNOS expression in RAW264.7 cells through suppressing JAK-STAT signal pathway.

    Science.gov (United States)

    Kou, Xianjuan; Qi, Shimei; Dai, Wuxing; Luo, Lan; Yin, Zhimin

    2011-08-01

    Arctigenin has been demonstrated to have an anti-inflammatory function, but the precise mechanisms of its action remain to be fully defined. In the present study, we determined the effects of arctigenin on lipopolysaccharide (LPS)-induced production of proinflammatory mediators and the underlying mechanisms involved in RAW264.7 cells. Our results indicated that arctigenin exerted its anti-inflammatory effect by inhibiting ROS-dependent STAT signaling through its antioxidant activity. Arctigenin also significantly reduced the phosphorylation of STAT1 and STAT 3 as well as JAK2 in LPS-stimulated RAW264.7 cells. The inhibitions of STAT1 and STAT 3 by arctigenin prevented their translocation to the nucleus and consequently inhibited expression of iNOS, thereby suppressing the expression of inflammation-associated genes, such as IL-1β, IL-6 and MCP-1, whose promoters contain STAT-binding elements. However, COX-2 expression was slightly inhibited at higher drug concentrations (50 μM). Our data demonstrate that arctigenin inhibits iNOS expression via suppressing JAK-STAT signaling pathway in macrophages. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

  17. The expression of genes encoding for COX-2, MPO, iNOS, and sPLA2-IIA in patients with recurrent depressive disorder.

    Science.gov (United States)

    Gałecki, Piotr; Gałecka, Elżbieta; Maes, Michael; Chamielec, Marcelina; Orzechowska, Agata; Bobińska, Kinga; Lewiński, Andrzej; Szemraj, Janusz

    2012-05-01

    There is evidence that inflammation, oxidative and nitrosative stress (IO&NS) play a role in the pathophysiology of depression. There are also data indicating altered inflammatory gene expression in depressive disorder and that genetic variants of IO&NS genes are associated with increased risk of the disease in question. The aim of this study was to explore mRNA expression of four IO&NS genes PTGS2, MPO, NOS2A, and PLA2G2A coding respectively: cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and secretory phospholipase A2 type IIA (sPLA2-IIA). Expression of the mRNA was determined using quantitative real-time PCR, in peripheral blood cells of patients with recurrent depressive disorder (rDD) and normal controls. The mRNA expressions of the genes encoding for COX-2, MPO, iNOS and sPLA2-IIA were significantly increased in the peripheral blood cells of depressed patients versus controls. Patients were treated with antidepressants. Our results indicate and may confirm the role of peripheral IO&NS pathways in the pathophysiology of depression. The results represent a promising way to investigate biological markers of depression. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Development of Antisense Therapeutic and Imaging Agents to Detect and Suppress Inducible Nitric Oxide Synthase (iNOS) Expression in Acute Lung Injury (ALI)

    Science.gov (United States)

    Shen, Yuefei

    This dissertation focuses on the development and investigation of antisense imaging and therapeutic agents, combined with nanotechnology, to detect and suppress inducible nitric oxide synthase (iNOS) expression for the diagnosis and treatment of acute lung injury (ALI). To achieve this goal, several efforts were made. The first effort was the identification and characterization of high binding affinity antisense peptide nucleic acids (PNAs) and shell-crosslinked knedel-like nanoparticle (SCK)-PNA conjugates to the iNOS mRNA. Antisense binding sites on the iNOS mRNA were first mapped by a procedure for rapidly generating a library of antisense accessible sites on native mRNAs (MASL) which involves reverse transcription of whole cell mRNA extracts with a random oligodeoxynucleotide primer followed by mRNA-specific PCR. Antisense PNAs against the antisense accessible sites were accordingly synthesized and characterized. The second effort was the investigation of cationic shell crosslinked knedel-like nanoparticle (cSCK)-mediated siRNA delivery to suppress iNOS expression for the treatment of ALI. siRNA with its unique gene-specific properties could serve as a promising therapeutic agent, however success in this area has been challenged by a lack of efficient biocompatible transfection agents. cSCK with its nanometer size and positive charge previously showed efficient cellular delivery of phosphorothioate ODNs (oligodeoxynucleotides), plasmid DNA and PNA. Herein, cSCK showed good siRNA binding and facilitated efficient siRNA transfection in HeLa, a mouse macrophage cell line and other human cell lines. cSCK led to greater silencing efficiency than Lipofectamine 2000 in HeLa cells as determined by the viability following transfection with cytotoxic and non-cytotoxic siRNAs, as well in 293T and HEK cells, and was comparable in BEAS-2B and MCF10a cells. The third effort was the preparation of an iNOS imaging probe through electrostatic complexation between a radiolabeled

  19. Immunohistochemical characterization of mononuclear cells and MHC II expression in the brain of horses with experimental chronic Trypanosoma evansi infection Caracterização imunoistoquímica de células mononucleares e expressão de CMH II no sistema nervoso central de eqüinos com infecção crônica experimental por Trypanosoma evansi

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    Karen R. Lemos

    2007-12-01

    Full Text Available An histochemical and immunohistochemical study was carried out to evaluate the mechanisms of immune response of horses experimentally infected by Trypanosoma evansi. For this purpose the HE histochemical stain and the avidin biotin peroxidase method were used. To determine the presence and immunoreactivity of immune cells we used anti-major histocompatibility complex II antibodies. Cellular infiltration fenotype was characterized with the aid of anti-CD3 antibody for T lymphocytes and by anti-BLA 36 antibodies for B lymphocytes. Macrophages were marked with an antibody against myeloid/histyocites antigen (clone Mac387. Lesions in the CNS of experimentally infected horses were those of a wide spread non suppurative encephalomyelitis and meningomyelitis. The severity of lesions varied in different parts of the nervous system, reflecting an irregular distribution of inflammatory vascular changes. Lymphoid perivascular cuffs and meningeal infiltrations were of predominantly composed of T and B cells. The parasite, T. evansi, was not identified in these horses tissues.Este estudo objetivou caracterizar a resposta imune celular no sistema nervoso central (SNC de eqüinos com infecção crônica experimental por Trypanosoma evansi. Para este propósito, foram utilizados os métodos histoquímicos (HE e imunoistoquímicos do complexo avidina-biotina peroxidase (ABC. O fenótipo do infiltrado celular foi caracterizado com o auxílio de anticorpos anti - CD3, para linfócitos T e antiBLA36 para linfócitos B. Os macrófagos foram marcados com anticorpo antiantígenos da linhagem mielóide/histiócitos (Clone Mac387. A lesão no sistema nervoso central (SNC dos eqüinos infectados com T. evansi foi caracterizada como meningoencefalite e meningomielite não supurativa. A gravidade das lesões variou em diferentes segmentos do SNC, refletindo distribuição irregular das alterações vasculares. A distribuição de células T e B e antígenos do complexo

  20. Atorvastatin Attenuates Bleomycin-Induced Pulmonary Fibrosis via Suppressing iNOS Expression and the CTGF (CCN2/ERK Signaling Pathway

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    Bo Zhu

    2013-12-01

    Full Text Available Pulmonary fibrosis is a progressive and fatal lung disorder with high mortality rate. To date, despite the fact that extensive research trials are ongoing, pulmonary fibrosis continues to have a poor response to available medical therapy. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known for its broad pharmacological activities, remains a remedy against multiple diseases. The present study investigated the antifibrotic potential of atorvastatin against bleomycin-induced lung fibrosis and to further explore the possible underlying mechanisms. Our results showed that atorvastatin administration significantly ameliorated the bleomycin mediated histological alterations and blocked collagen deposition with parallel reduction in the hydroxyproline level. Atorvastatin reduced malondialdehyde (MDA level and lung indices. Atorvastatin also markedly decreased the expression of inducible nitric oxide synthase (iNOS in lung tissues and, thus, prevented nitric oxide (NO release in response to bleomycin challenge. Furthermore, atorvastatin exhibited target down-regulation of connective tissue growth factor (CTGF (CCN2 and phosphorylation extracellular regulated protein kinases (p-ERK expression. Taken together, atorvastatin significantly ameliorated bleomycin-induced pulmonary fibrosis in rats, via the inhibition of iNOS expression and the CTGF (CCN2/ERK signaling pathway. The present study provides evidence that atorvastatin may be a potential therapeutic reagent for the treatment of lung fibrosis.

  1. Human umbilical cord expresses several vasoactive peptides involved in the local regulation of vascular tone: protein and gene expression of Orphanin, Oxytocin, ANP, eNOS and iNOS

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    Aldo Gerbino

    2011-07-01

    Full Text Available Full-term human umbilical cord contains three blood vessels: two arteries coiled around a vein and surrounded by Wharton’s jelly, a mucous tissue with few mesenchymal stromal cells and abundant extracellular matrix. Umbilical vessels lack innervations, thus endothelial cells must play a role in the control of blood flow. The aim of this study was to investigate in human umbilical cord the expression of five peptides that could be involved in the regulation of vascular tone: Orphanin FQ, Oxytocin, Atrial Natriuretic Peptide (ANP, endothelial Nitric Oxide Synthase (eNOS and inducible Nitric Oxide Synthase (iNOS. The expression of these molecules in full-term human umbilical cord was investigated through immunohistochemistry and RT-PCR. Immunoreactivity for Orphanin FQ was detected in Wharton’s jelly, vessel musculature and endothelium; Oxytocin, ANP and eNOS were expressed by the umbilical epithelium, Wharton’s jelly and endothelium, whereas iNOS only by endothelial cells. RT-PCR analysis showed transcriptional expression of Oxytocin, ANP and eNOS mRNAs. The presence of Orphanin, Oxytocin, ANP, eNOS and iNOS proteins was identified in the human umbilical cord. mRNA expression for Oxytocin, ANP and eNOS suggest that these molecules are synthesized by umbilical cord cells themselves. The expression of these vasoactive molecules could be part of a general mechanism locally regulating vascular tone. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 2, pp. 211–218

  2. Human umbilical cord expresses several vasoactive peptides involved in the local regulation of vascular tone: protein and gene expression of Orphanin, Oxytocin, ANP, eNOS and iNOS.

    Science.gov (United States)

    Mauro, Annamaria; Buscemi, Maria; Provenzano, Salvatore; Gerbino, Aldo

    2011-01-01

    Full-term human umbilical cord contains three blood vessels: two arteries coiled around a vein and surrounded by Wharton's jelly, a mucous tissue with few mesenchymal stromal cells and abundant extracellular matrix. Umbilical vessels lack innervations, thus endothelial cells must play a role in the control of blood flow. The aim of this study was to investigate in human umbilical cord the expression of five peptides that could be involved in the regulation of vascular tone: Orphanin FQ, Oxytocin, Atrial Natriuretic Peptide (ANP), endothelial Nitric Oxide Synthase (eNOS) and inducible Nitric Oxide Synthase (iNOS). The expression of these molecules in full-term human umbilical cord was investigated through immunohistochemistry and RT-PCR. Immunoreactivity for Orphanin FQ was detected in Wharton's jelly, vessel musculature and endothelium; Oxytocin, ANP and eNOS were expressed by the umbilical epithelium, Wharton's jelly and endothelium, whereas iNOS only by endothelial cells. RT-PCR analysis showed transcriptional expression of Oxytocin, ANP and eNOS mRNAs. The presence of Orphanin, Oxytocin, ANP, eNOS and iNOS proteins was identified in the human umbilical cord. mRNA expression for Oxytocin, ANP and eNOS suggest that these molecules are synthesized by umbilical cord cells themselves. The expression of these vasoactive molecules could be part of a general mechanism locally regulating vascular tone.

  3. Stimulatory effect of ouabain on VCAM-1 and iNOS expression in murine endothelial cells: involvement of NF-kappa B.

    Science.gov (United States)

    Bereta, J; Cohen, M C; Bereta, M

    1995-12-11

    Endothelial cells play a pivotal role in the development of atherosclerosis. An 'activated' phenotype of these cells is manifested by signal transduction-dependent expression of genes encoding cytokines, pro- and anticoagulant factors, and cell adhesion molecules. In the current study we examined the effect of ouabain, an inhibitor of Na+/K(+)-ATPase, on the process of endothelial cell activation. We demonstrated that ouabain was able to stimulate VCAM-1 expression and potentiate the effect of IFN-gamma on this process. Moreover, ouabain provided a complementary signal for either TNF or IFN-gamma in inducing iNOS expression. Our data also show, for the first time, that inhibition of Na+/K(+)-ATPase led to activation of the transcription factor, NF-kappa B, which may provide an explanation for the effects of ouabain on endothelial cells.

  4. In vivo expression profiles of cytokine and iNOS mRNAs in rats infected with Eimeria separata.

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    Shi, M Q; Hirzmann, J; Dafa'alla, T H; Zahner, H

    2001-05-22

    Studies on cytokine (IFN-gamma, IL-2, IL-4, IL-5, IL-10) and inducible NO-synthase (iNOS) gene transcription in mesenteric lymph nodes (MLN) and the caecum wall were performed 0, 48, and 72h after primary and challenge infections of rats with Eimeria separata using RT-PCR. The amount of IFN-gamma mRNA was elevated in MLN and caeca 72h after primary and 48-72h after challenge infection when compared with uninfected controls. Increased amounts of IL-2 mRNA were only found in MLN of infected rats 72h post-infection (p.i.). In case of IL-10, infections did not affect the amount of mRNA in MLN, but led to markedly increased levels in the caecum wall of both infected groups 48 and 72h p.i. Levels of IL-4 mRNA remained unchanged after infections and IL-5 gene transcripts were undetectable. Amounts of iNOS mRNA (not investigated in MLN) were found strongly enhanced 48 and 72h p.i. in the caecum walls of all infected animals when compared with naive controls. The data are discussed in regard of the cellular source of the cytokines and their immunological role.

  5. Oral concentrated grape juice suppresses expression of NF-kappa B, TNF-α and iNOS in experimentally induced colorectal carcinogenesis in Wistar rats.

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    Campanholo, Vanessa Maria de Lima Pazine; Silva, Roseane Mendes; Silva, Tiago Donizetti; Neto, Ricardo Artigiani; Paiotti, Ana Paula Ribeiro; Ribeiro, Daniel Araki; Forones, Nora Manoukian

    2015-01-01

    The aim of this study was to evaluate the effects of grape juice on colon carcinogenesis induced by azoxymethane (AOM) and expression of NF-kB, iNOS and TNF- α. Forty male Wistar rats were divided into 7 groups: G1, control; G2, 15 mg/kg AOM; G3, 1% grape juice 2 weeks before AOM; G4, 2% grape juice 2 weeks before AOM; G5, 1% grape juice 4 weeks after AOM; G6, 2% grape juice 4 weeks after AOM; G7, 2% grape juice without AOM. Histological changes and aberrant crypt foci (ACF) were studied, while RNA expression of NF- kB, TNF- and iNOS was evaluated by qPCR. The number of ACF was higher in G2, and G4 presented a smaller number of crypts per focus than G5 (p=0.009) and G6. Small ACF (1-3) were more frequent in G4 compared to G2, G5 and G6 (p=0.009, p=0.009 and p=0.041, respectively). RNA expression of NF-kB was lower in G3 and G4 compared to G2 (p=0.004 and p=0.002, respectively). A positive correlation was observed between TNF- α and NF-kB gene expression (p=0.002). In conclusion, the administration of 2% grape juice before AOM reduced the crypt multiplicity, attenuating carcinogenesis. Lower expression of NF-kB was observed in animals exposed to grape juice for a longer period of time, regardless of concentration.

  6. Association of Inorganics Accumulation with the Activation of NF-κB Signaling Pathway and the iNOS Expression of Lung Tissue in Xuanwei Lung Cancer Patients

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    Jiapeng YANG

    2016-01-01

    Full Text Available Background and objective Indoor air pollution induces asthma, leads to chronic obstructive pulmonary disease, and may promote lung cancer. Our previous studies found that the accumulation of inorganic particulate matter that is due to indoor air pollution can lead to damage to alveolar cells and activation of signaling pathway, and ultimately provoke tumorigenesis. The aim of this study is to explore the accumulation of inorganics and activation of nuclear factor κB (NF-κB-inducible nitric oxide synthase (iNOS signaling pathway of lung tissue in Xuanwei lung cancer patients. Methods From December 2013 to November 2014, 48 cases Xuanwei patients with lung cancer who underwent surgical treatment from the Third Affiliated Hospital of Kunming Medical University were enrolled in this study and compared with lung cancer patients from other regions. The ultrastructure of postoperative specimens was observed by transmission electron microscopy (TEM to explore the occurrence of inorganic particles. Serum cytokines were analyzed. Then, the expression levels of NF-κB-p65 protein and iNOS protein in postoperative specimens was explored by immunohistochemistry and Western blot. Finally, 8-OHdG accumulation in lung cancer tissues and urine was measured. Results A large number of nanoscale inorganics were observed in alveolar type II cells and macrophages located in adjacent tissues of lung cancer with Xuanwei patients. Silicon (Si content was found in inorganic elemental analysis. The serum interleukin (IL-1β levels (31.50±19.16 pg/mL of Xuanwei lung-cancer patients were remarkably higher than those from other regions (11.33±6.94 pg/mL (P<0.01, with statistically significant difference. The pathological tissues of Xuanwei lung-cancer patients express NF-κB-p65, and iNOS expression were significantly higher than those of patients from non-Xuanwei regions. No significant difference was found between cancerous and normal adjacent tissues. Xuanwei lung

  7. Tetramethylpyrazine attenuates TNF-α-induced iNOS expression in human endothelial cells: Involvement of Syk-mediated activation of PI3K-IKK-IκB signaling pathways

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    Zheng, Zhen; Li, Zhiliang; Chen, Song; Pan, Jieyi; Ma, Xiaochun, E-mail: zjoever@gmail.com

    2013-08-15

    Endothelial cells produce nitric oxide (NO) by activation of constitutive nitric oxide synthase (NOS) and transcription of inducible NO synthase (iNOS). We explored the effect of tetramethylpyrazine (TMP), a compound derived from chuanxiong, on tumor necrosis factor (TNF)-α-induced iNOS in human umbilical vein endothelial cells (HUVECs) and explored the signal pathways involved by using RT-PCR and Western blot. TMP suppressed TNF-α-induced expression of iNOS by inhibiting IκB kinase (IKK) phosphorylation, IκB degradation and nuclear factor κB (NF-κB) nuclear translocation, which were required for NO gene transcription. Exposure to wortmannin abrogated IKK/IκB/NF-κB-mediated iNOS expression, suggesting activation of such a signal pathway might be phosphoinositide-3-kinase (PI3K) dependent. Spleen tyrosine kinase (Syk) inhibitor piceatannol significantly inhibited NO production. Furthermore, piceatannol obviously suppressed TNF-α-induced IκB phosphorylation and the downstream NF-κB activation, suggesting that Syk is an upstream key regulator in the activation of PI3K/IKK/IκB-mediated signaling. TMP significantly inhibited TNF-α-induced phosphorylation of Syk and PI3K. Our data indicate that TMP might repress iNOS expression, at least in part, through its inhibitory effect of Syk-mediated PI3K phosphorylation in TNF-α-stimulated HUVECs. -- Highlights: •TMP suppressed TNF-α-induced expression of iNOS by inhibiting IKK/IκB/NF-κB pathway. •PI3K inhibitor wortmannin abrogated IKK/IκB/NF-κB-mediated iNOS expression. •Syk inhibitor piceatannol repressed PI3K/IKK/IκB mediated NO production. •Syk is an upstream regulator in the activation of PI3K/IKK/IκB-mediated signaling. •TMP might repress iNOS expression through Syk-mediated PI3K pathway.

  8. Halicephalobus gingivalis (H.deletrix in the brain of a horse Halicephalobus gingivalis (H.deletrix no cérebro de um eqüino

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    Rosemeri de Oliveira Vasconcelos

    2007-08-01

    Full Text Available A 10-year-old Mangalarga gelding with rhabditiform nematode infection in the brain is described. Clinical signs were limited to circling and right side paralysis. Histological examination of the brain revealed marked gliosis and discreet edema. The perivascular mononuclear inflammatory infiltrate was composed of few layers of lymphocytes, plasmocytes and macrophages and rare eosinophils. The presence of rhabditiform nematodes was associated with the infiltrate. Areas of malacia associated with the parasites and parasite tracks with axonal spheroids were also seen close to the vessels and to the etiological agent and were more evident in the white matter. In the meninges there was moderate inflammatory infiltrate associated with perivascular parasites. The identification of the nematode was based on the histological examination of the cerebral fragments.Um eqüino macho, com 10 anos, Mangalarga, apresentou uma infecção por um nematódeo rabditiforme no cérebro. Os sinais clínicos limitaram-se ao fato de o animal andar em círculos e apresentar paralisia do lado direito. O exame histológico do cérebro revelou acentuada gliose e discreto edema intersticial. O infiltrado inflamatório mononuclear perivascular era composto por poucas camadas de linfócitos, plasmócitos, macrófagos e raros eosinófilos, associados aos nematódeos rabditiformes. Áreas de malácia e trajetos com esferóides axonais são vistos ao redor de vasos e do agente etiológico, sendo mais evidentes na substância branca. Nas meninges, o infiltrado inflamatório foi moderado e associado a parasitas perivasculares. A identificação do nematódeo foi baseada no exame histológico do cérebro do cavalo.

  9. Edaravone attenuates hippocampal damage in an infant mouse model of pneumococcal meningitis by reducing HMGB1 and iNOS expression via the Nrf2/HO-1 pathway

    Science.gov (United States)

    Li, Zheng; Ma, Qian-qian; Yan, Yan; Xu, Feng-dan; Zhang, Xiao-ying; Zhou, Wei-qin; Feng, Zhi-chun

    2016-01-01

    ), nor it affected the protein levels of HMGB1 and iNOS in the hippocampus of the mice with mild meningitis. Conclusion: Edaravone produces neuroprotective actions in a mouse model of pneumococcal meningitis by reducing neuronal apoptosis and HMGB1 and iNOS expression in the hippocampus via the Nrf2/HO-1 pathway. Thus, edaravone may be a promising agent for the treatment of bacterial meningitis. PMID:27569388

  10. Extractable and non-extractable polyphenols from blueberries modulate LPS-induced expression of iNOS and COX-2 in RAW264.7 macrophages via the NF-κB signalling pathway.

    Science.gov (United States)

    Cheng, Anwei; Han, Caijing; Fang, Xixiu; Sun, Jinyue; Chen, Xiangyan; Wan, Fachun

    2016-08-01

    Plant polyphenols are rich in blueberries that have a wide range of properties beneficial to human health. There are two types, according to the solubility of polyphenols, which were defined as extractable polyphenols (EPP) and non-extractable polyphenols (NEPP), respectively. At present, in most of reports, 'total polyphenol' refers only to EPP excluding NEPP. In this paper, the effects of EPP and NEPP on lipopolysaccharides (LPS) induced production of nitric oxide (NO) and gene expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 cells via nuclear factor-κB (NF-κB) signalling pathway were compared. The results showed that EPP and NEPP from blueberries significantly inhibited the LPS-induced production of NO and gene expression of iNOS and COX-2 in cells. The constitutive level of p65 sub-unit of NF-κB was obviously detected after the treatments with EPP or NEPP. By contrast, the level of phosphorylated p65 (P-p65) was strongly inhibited by EPP or NEPP. EPP had a stronger inhibition on the gene expression of iNOS and COX-2 than that of NEPP. These findings of inhibition of iNOS and COX-2 mRNA expression through the suppression of NF-κB suggest that EPP and ENPP from blueberries have significant anti-inflammatory effect and may be a potential medicine. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

  11. The tissue microlocalisation and cellular expression of CD163, VEGF, HLA-DR, iNOS, and MRP 8/14 is correlated to clinical outcome in NSCLC.

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    Ohri, Chandra M; Shikotra, Aarti; Green, Ruth H; Waller, David A; Bradding, Peter

    2011-01-01

    We have previously investigated the microlocalisation of M1 and M2 macrophages in NSCLC. This study investigated the non-macrophage (NM) expression of proteins associated with M1 and M2 macrophages in NSCLC. Using immunohistochemistry, CD68(+) macrophages and proteins associated with either a cytotoxic M1 phenotype (HLA-DR, iNOS, and MRP 8/14), or a non-cytotoxic M2 phenotype (CD163 and VEGF) were identified. NM expression of the markers was analysed in the islets and stroma of surgically resected tumours from 20 patients with extended survival (ES) (median 92.7 months) and 20 patients with poor survival (PS) (median 7.7 months). The NM expression of NM-HLA-DR (pMRP 8/14 (p = 0.02) was increased in ES compared to PS patients in the tumour islets. The tumour islet expression of NM-VEGF, was decreased in ES compared to PS patients (pMRP 8/14 (p = 0.01) expression in the stroma of ES patients compared with PS patients. The 5-year survival for patients with above and below median NM expression of the markers in the islets was 74.9% versus 4.7% (NM-HLA-DR pMRP 8/14 p = 0.04), as opposed to 34.1% versus 44.4% (NM-CD163 p = 0.41) and 19.4% versus 59.0% (NM-VEGF p = 0.001). Cell proteins associated with M1 and M2 macrophages are also expressed by other cell types in the tumour islets and stroma of patients with NSCLC. Their tissue and cellular microlocalisation is associated with important differences in clinical outcome.

  12. Dietary blue pigments derived from genipin, attenuate inflammation by inhibiting LPS-induced iNOS and COX-2 expression via the NF-κB inactivation.

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    Qiang-Song Wang

    Full Text Available The edible blue pigments produced by gardenia fruits have been used as value-added colorants for foods in East Asia for 20 years. However, the biological activity of the blue pigments derived from genipin has not been reported.The anti-inflammatory effect of blue pigments was studied in lipopolysaccharide (LPS stimulated RAW 264.7 macrophage in vitro. The secretions of nitric oxide (NO and prostaglandin E(2 (PGE(2 were inhibited in concentration-dependent manner by blue pigments. Real-time reverse-transcription polymerase chain reaction (Real-time RT-PCR analyses demonstrated that the mRNA expression of inducible nitric oxide synthase (iNOS, cyclooxygenase-2 (COX-2, interleukin (IL-6, and tumor necrosis factor alpha (TNF-α was inhibited, moreover, ELISA results showed that the productions of IL-6 and TNF-α were inhibited. Cell-based ELISA revealed the COX-2 protein expression was inhibited. The proteome profiler array showed that 12 cytokines and chemokines involved in the inflammatory process were down-regulated by blue pigments. Blue pigments inhibited the nuclear transcription factor kappa-B (NF-κB activation induced by LPS, and this was associated with decreasing the DNA-binding activity of p65 and p50. Furthermore, blue pigments suppressed the degradation of inhibitor of κB (IκB α, Inhibitor of NF-κB Kinase (IKK α, IKK-β, and phosphorylation of IκB-α. The anti-inflammatory effect of blue pigments in vivo was studied in carrageenan-induced paw edema and LPS-injecting ICR mice. Finally, blue pigments significantly inhibited paw swelling and reduced plasma TNF-α and IL-6 production in vivo.These results suggest that the anti-inflammatory properties of blue pigments might be the results from the inhibition of iNOS, COX-2, IL-6, IL-1β, and TNF-α expression through the down-regulation of NF-κB activation, which will provide strong scientific evidence for the edible blue pigments to be developed as a new health-enhancing nutritional

  13. CXCL12 expression in hematopoietic tissues of mice exposed to sublethal dose of ionizing radiation in the presence od iNOS inhibitor

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    Perez Vieira, Daniel [Instituto de Pesquisas Energeticas e Nucleares (IPEN), Sao Paulo, SP (Brazil). Lab. de Biologia Molecular; Hermida, Felipe Pessoa de Melo; Andrade Junior, Heitor Franco de [Instituto de Medicina Tropical de Sao Paulo, SP (Brazil). Lab. de Protozoologia

    2005-07-01

    Full text of publication follows: We study the production of CXCL12, a stem cell homing chemokine, in spleen and bone marrow of mice exposed at LD50% of {gamma}-radiation, w/wo a iNOS blocker, aminoguanidine, to test if inflammatory nitric oxide is involved in necrotic processes of stem cell death after ionizing radiation exposure. Groups of 10 male 6-week old C57Bl/6j mice were killed at specific time points after a 8Gy dose irradiation ({sup 60}Co source; 4,22kGy/h dose rate) and spleen and bone marrow samples were immersed and stored in TriZOL for total mRNA extraction. RT-PCR assays were performed to determine the production of CXCL12 as compared to murine {beta}-actin at days 2nd, 5th, 7th, 9th and 15th days after radiation in a semiquantitative way. PCR was performed after cDNA synthesis using Oligo-dT primers and specific primers for CXCL12 and {beta}-actin. Artificial optical density was determined in silver-stained PAGE resolved specific amplification products of CXCL12, using amplification of murine {beta}-actin as standard, and measurements obtained by the Image J freeware. CXCL12 production in spleen samples reached its maximum at 5th day after radiation exposure in animals not treated with aminoguanidine, but this peak was extended to at 7th day in treated animals. Non treated animals presented a decrease of CXCL12 expression up to 15th day of experiment, and aminoguanidine treated animals showed sustained increase of expression levels between 9th and 15th days. In bone marrow samples, the main difference among the two different experimental groups was a maintenance of CXCL12 mRNA expression between 7th and 9th days, persisting until the end of the experiment. Our data demonstrates that the effect of aminoguanidine appears to sustain the CXCL12 mRNA synthesis in hematopoietic tissues of irradiated mice, providing some evidences that the axis iNOS -NO - inflammation must be involved in stem cell death, aside to the direct radiation effect, suggesting

  14. Cox-2 Inhibition Protects against Hypoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis via Akt-Dependent Enhancement of iNOS Expression

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    Lei Pang

    2016-01-01

    Full Text Available The present study explored the potential causal link between ischemia-driven cyclooxygenase-2 (COX-2 expression and enhanced apoptosis during myocardial ischemia/reperfusion (I/R by using H9C2 cardiomyocytes and primary rat cardiomyocytes subjected to hypoxia/reoxygenation (H/R. The results showed that H/R resulted in higher COX-2 expression than that of controls, which was prevented by pretreatment with Helenalin (NFκB specific inhibitor. Furthermore, pretreatment with NS398 (COX-2 specific inhibitor significantly attenuated H/R-induced cell injury [lower lactate dehydrogenase (LDH leakage and enhanced cell viability] and apoptosis (higher Bcl2 expression and lower level of cleaved caspases-3 and TUNEL-positive cells in cardiomyocytes. The amelioration of posthypoxic apoptotic cell death was paralleled by significant attenuation of H/R-induced increases in proinflammatory cytokines [interleukin 6 (IL6 and tumor necrosis factor (TNFα] and reactive oxygen species (ROS production and by higher protein expression of phosphorylated Akt and inducible nitric oxide synthase (iNOS and enhanced nitric oxide production. Moreover, the application of LY294002 (Akt-specific inhibitor or 1400W (iNOS-selective inhibitor cancelled the cellular protective effects of NS398. Findings from the current study suggest that activation of NFκB during cardiomyocyte H/R induces the expression of COX-2 and that higher COX-2 expression during H/R exacerbates cardiomyocyte H/R injury via mechanisms that involve cross talks among inflammation, ROS, and Akt/iNOS/NO signaling.

  15. Effect of dietary lipid on the growth, fatty acid composition and Δ5 Fads expression of abalone ( Haliotis discus hannai Ino) hepatopancreas

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    Li, Mingzhu; Mai, Kangsen; Ai, Qinghui; He, Gen; Xu, Wei; Zhang, Wenbing; Zhang, Yanjiao; Zhou, Huihui; Liufu, Zhiguo

    2015-04-01

    This study investigated the effect of dietary lipid on the growth, fatty acid composition and Δ5 fatty acyl desaturase genes ( Fads) expression of juvenile abalone ( Haliotis discus hannai Ino) hepatopancreas. Six purified diets were formulated to contain tripalmitin (TP), olive oil (OO, 72.87% 18:1n-9), grape seed oil (GO, 68.67% 18:2n-6), linseed oil (LO, 70.48% 18:3n-3), ARA oil (AO, 41.81% ARA) or EPA oil (EO, 44.09% EPA and 23.67% DAH). No significant difference in survival rate was observed among abalone fed with different diets. Weight gain rate ( WGR) and daily growth rate of shell length ( DGR SL) were significantly increased in abalone fed with diets containing OO, AO and EO, but decreased in abalone fed with LO diet ( P Fads in hepatopancreas of abalone was enhanced by high concentration of 18:3n-3 and suppressed by dietary LC-PUFAs; however it was not affected by dietary high concentration of 18:1n-9 or 18:2n-6. These results provided valuable information for understanding the synthesis of LC-PUFAs and nutritional regulation of Δ5 Fads expression in abalone.

  16. Assessment of the effect of diode laser therapy on incisional wound healing and expression of iNOS and eNOS on rat oral tissue

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    Parichehr Ghalayani

    2013-01-01

    Conclusion: Histological findings showed that diode laser needs several repeated irradiations for the acceleration of wound healing. The iNOS amount showed that increases are associated with better healing.

  17. Upregulation of ICAM-1 Expression on J774.2 Macrophages by Endotoxin Involves Activation of NF-κB but not Protein Tyrosine Kinase: Comparison to Induction of iNOS

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    Hartmut Ruetten

    1999-01-01

    Full Text Available This study compares the signal transduction pathway which leads to the upregulation of intercellular adhesion molecule-1 (ICAM-1 expression with that of the increase in the expression of inducible nitric oxide synthase (iNOS protein and activity caused by endotoxin in cultured J774.2 macrophages. Treatment of J774.2 cells with lipopolysaccharide E. coli (LPS induced a concentration-dependent increase in the expression of ICAM-1 on the cell surface within 4 h and an increase in iNOS protein and activity at 24 h. The upregulation of ICAM-1 expression on J774.2 macrophages caused by LPS was significantly inhibited by pretreatment of the cells with inhibitors of the activation of the nuclear transcription factor NF-κB, such as L-1-tosylamido-2-phenylethylchloromethyl ketone (TPCK, pyrrolidine dithiocarbamate (PDTC, rotenone or calpain inhibitor I, but not by the tyrosine kinase inhibitors, tyrphostin AG126 or genistein. In contrast, genistein or tyrphostin AG126 also prevented the induction of iNOS protein and activity in J774.2 macrophages elicited by LPS. Thus, the increase in the expression of ICAM-1 on J774.2 macrophages by endotoxin involves the activation of NFκB, but not of protein tyrosine kinase.

  18. The tissue microlocalisation and cellular expression of CD163, VEGF, HLA-DR, iNOS, and MRP 8/14 is correlated to clinical outcome in NSCLC.

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    Chandra M Ohri

    Full Text Available BACKGROUND: We have previously investigated the microlocalisation of M1 and M2 macrophages in NSCLC. This study investigated the non-macrophage (NM expression of proteins associated with M1 and M2 macrophages in NSCLC. METHODS: Using immunohistochemistry, CD68(+ macrophages and proteins associated with either a cytotoxic M1 phenotype (HLA-DR, iNOS, and MRP 8/14, or a non-cytotoxic M2 phenotype (CD163 and VEGF were identified. NM expression of the markers was analysed in the islets and stroma of surgically resected tumours from 20 patients with extended survival (ES (median 92.7 months and 20 patients with poor survival (PS (median 7.7 months. RESULTS: The NM expression of NM-HLA-DR (p<0.001, NM-iNOS (p = 0.02 and NM-MRP 8/14 (p = 0.02 was increased in ES compared to PS patients in the tumour islets. The tumour islet expression of NM-VEGF, was decreased in ES compared to PS patients (p<0.001. There was more NM-CD163 expression (p = 0.04 but less NM-iNOS (p = 0.002 and MRP 8/14 (p = 0.01 expression in the stroma of ES patients compared with PS patients. The 5-year survival for patients with above and below median NM expression of the markers in the islets was 74.9% versus 4.7% (NM-HLA-DR p<0.001, 65.0% versus 14.6% (NM-iNOS p = 0.003, and 54.3% versus 22.2% (NM-MRP 8/14 p = 0.04, as opposed to 34.1% versus 44.4% (NM-CD163 p = 0.41 and 19.4% versus 59.0% (NM-VEGF p = 0.001. CONCLUSIONS: Cell proteins associated with M1 and M2 macrophages are also expressed by other cell types in the tumour islets and stroma of patients with NSCLC. Their tissue and cellular microlocalisation is associated with important differences in clinical outcome.

  19. mRNA expression and localization of bNOS, eNOS and iNOS in human cervix at preterm and term labour

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    Byström Birgitta

    2005-08-01

    Full Text Available Abstract Background Preterm birth is the primary cause of the neonatal mortality and morbidity. There will be no preterm birth without a cervical softening. Nitric oxide (NO is shown to be a mediator of term cervical ripening. The aim of this study was to investigate mRNA expression of the three isomers of NO synthases (NOS and to identify them by immunohistochemistry in the human cervix at preterm birth compared to term. Methods The three isomers of NOS- inducible (iNOS, endothelial (eNOS and neuronal (bNOS – were investigated in the human cervix. The expression of mRNA was determined using Real-Time Multiplex RT-PCR. The localisation of synthases in the cervical tissue was analysed using immunohistochemistry. Cervical biopsies were obtained from 4 groups of women without clinical signs of infection: preterm (PTL, term labour (TL, preterm not in labour (PTnotL and term not in labour (TnotL patients. One-Way ANOVA, Kruskal-Wallis, Student t-test or Mann-Whitney test were applied as appropriate to determine statistically significant differences among the groups. Results Patients in preterm labour had significantly (p Conclusion The mRNA levels were higher in the preterm labour group compared to the women at term labour. The significant increase of the eNOS mRNA expression, from the unripe to the favourable cervical state during labour, may indicate a role of eNOS and supports the role of NO in the cervical ripening process. All the three synthases were identified by immunohistochemistry in all the groups of study.

  20. Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration

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    Brown Guy C

    2005-09-01

    Full Text Available Abstract Background Inflammation-activated glia are seen in many CNS pathologies and may kill neurons through the release of cytotoxic mediators, such as nitric oxide from inducible NO synthase (iNOS, and possibly superoxide from NADPH oxidase (NOX. We set out to determine the relative role of these species in inducing neuronal death, and to test the dual-key hypothesis that the production of both species simultaneously is required for significant neuronal death. Methods Primary co-cultures of cerebellar granule neurons and glia from rats were used to investigate the effect of NO (from iNOS, following lipopolysaccharide (LPS and/or cytokine addition or superoxide/hydrogen peroxide (from NOX, following phorbol 12-myristate 13-acetate (PMA, ATP analogue (BzATP, interleukin-1β (IL-1β or arachidonic acid (AA addition on neuronal survival. Results Induction of glial iNOS caused little neuronal death. Similarly, activation of NOX alone resulted in little or no neuronal death. However, if NOX was activated (by PMA or BzATP in the presence of iNOS (induced by LPS and interferon-γ then substantial delayed neuronal death occurred over 48 hours, which was prevented by inhibitors of iNOS (1400W, NOX (apocynin or a peroxynitrite decomposer (FeTPPS. Neurons and glia were also found to stain positive for nitrotyrosine (a putative marker of peroxynitrite only when both iNOS and NOX were simultaneously active. If NOX was activated by weak stimulators (IL-1β, AA or the fibrillogenic prion peptide PrP106-126 in the presence of iNOS, it caused microglial proliferation and delayed neurodegeneration over 6 days, which was prevented by iNOS or NOX inhibitors, a peroxynitrite decomposer or a NMDA-receptor antagonist (MK-801. Conclusion These results suggest a dual-key mechanism, whereby glial iNOS or microglial NOX activation alone is relatively benign, but if activated simultaneously are synergistic in killing neurons, through generating peroxynitrite. This

  1. Dietary ascorbic acid modulates the expression profile of stress protein genes in hepatopancreas of adult Pacific abalone Haliotis discus hannai Ino.

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    Wu, Chenglong; Wang, Jia; Xu, Wei; Zhang, Wenbing; Mai, Kangsen

    2014-12-01

    This study was conducted to investigate the effects of dietary ascorbic acid (AA) on transcriptional expression patterns of antioxidant proteins, heat shock proteins (HSP) and nuclear factor kappa B (NF-κB) in the hepatopancreas of Pacific abalone Haliotis discus hannai Ino (initial average length: 84.36 ± 0.24 mm) using real-time quantitative PCR assays. L-ascorbyl-2-molyphosphate (LAMP) was added to the basal diet to formulate four experimental diets containing 0.0, 70.3, 829.8 and 4967.5 mg AA equivalent kg(-1) diets, respectively. Each diet was fed to triplicate groups of adult abalone in acrylic tanks (200 L) in a flow-through seawater system. Each tank was stocked with 15 abalone. Animals were fed once daily (17:00) to apparent satiation for 24 weeks. The results showed that the dietary AA (70.3 mg kg(-1)) could significantly up-regulate the expression levels of Cu/Zn superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), feritin (FT) and heat shock protein 26 (HSP26) in the hepatopancreas of abalone in this treatment compared to the controls. However, the expression levels of Mn-SOD, glutathione peroxidase (GPX), thioredoxin peroxidase (TPx), selenium-binding protein (SEBP), HSP70 and HSP90 were significantly down-regulated. Compared with those in the group with 70.3 mg kg(-1) dietary AA, the expression levels of CAT, GST and HSP26 were decreased in abalone fed with very high dietary AA (4967.5 mg kg(-1)). In addition, significant up-regulations of expression levels of Mn-SOD, GPX, TPx, SEBP, FT, HSP70, HSP90 and NF-κB were observed in abalone fed with apparently excessive dietary AA (829.8 and 4967.5 mg kg(-1)) as compared to those fed 70.3 mg kg(-1) dietary AA. These findings showed that dietary AA influenced the expression levels of antioxidant proteins, heat shock proteins and NF-κB in the hepatopancreas of abalone at transcriptional level. Levels of dietary AA that appeared adequate (70.3 mg kg(-1)) reduced the oxidative stress

  2. Rheosmin, a naturally occurring phenolic compound inhibits LPS-induced iNOS and COX-2 expression in RAW264.7 cells by blocking NF-kappaB activation pathway.

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    Jeong, Jin Boo; Jeong, Hyung Jin

    2010-01-01

    Inflammation is part of the host defense mechanism against harmful matters and injury; however, aberrant inflammation is associated to the development of chronic disease such as cancer. Raspberry ketone is a natural phenolic compound. It is used in perfumery, in cosmetics, and as a food additive to impart a fruity odor. In this study, we evaluated whether rheosmin, a phenolic compound isolated from pine needles regulates the expression of iNOS and COX-2 protein in LPS-stimulated RAW264.7 cells. Rheosmin dose-dependently inhibited NO and PGE(2) production and also blocked LPS-induced iNOS and COX-2 expression. Rheosmin potently inhibited the translocation of NF-kappaB p65 into the nucleus by IkappaB degradation following IkappaB-alpha phosphorylation. This result shows that rheosmin inhibits NF-kappaB activation. In conclusion, our results suggest that rheosmin inhibits LPS-induced iNOS and COX-2 expression in RAW264.7 cells by blocking NF-kappaB activation pathway. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  3. Multi-walled carbon nanotubes induce COX-2 and iNOS expression via MAP Kinase-dependent and -independent mechanisms in mouse RAW264.7 macrophages

    Directory of Open Access Journals (Sweden)

    Lee Jong

    2012-05-01

    Full Text Available Abstract Background Carbon nanotubes (CNTs are engineered graphene cylinders with numerous applications in engineering, electronics and medicine. However, CNTs cause inflammation and fibrosis in the rodent lung, suggesting a potential human health risk. We hypothesized that multi-walled CNTs (MWCNTs induce two key inflammatory enzymes in macrophages, cyclooxygenase-2 (COX-2 and inducible nitric oxide synthase (iNOS, through activation of extracellular signal-regulated kinases (ERK1,2. Methods RAW264.7 macrophages were exposed to MWCNTs or carbon black nanoparticles (CBNPs over a range of doses and time course. Uptake and subcellular localization of MWCNTs was visualized by transmission electron microscopy (TEM. Protein levels of COX-2, iNOS, and ERK1,2 (total ERK and phosphorylated ERK were measured by Western blot analysis. Prostaglandin-E2 (PGE2 and nitric oxide (NO levels in cell supernatants were measured by ELISA and Greiss assay, respectively. Results MWCNTs, but not CBNPs, induced COX-2 and iNOS in a time- and dose-dependent manner. COX-2 and iNOS induction by MWCNTs correlated with increased PGE2 and NO production, respectively. MWCNTs caused ERK1,2 activation and inhibition of ERK1,2 (U0126 blocked MWCNT induction of COX-2 and PGE2 production, but did not reduce the induction of iNOS. Inhibition of iNOS (L-NAME did not affect ERK1,2 activation, nor did L-NAME significantly decrease COX-2 induction by MWCNT. Nickel nanoparticles (NiNPs, which are present in MWCNTs as a residual catalyst, also induced COX-2 via ERK-1,2. However, a comparison of COX-2 induction by MWCNTs containing 4.5 and 1.8% Ni did not show a significant difference in ability to induce COX-2, indicating that characteristics of MWCNTs in addition to Ni content contribute to COX-2 induction. Conclusion This study identifies COX-2 and subsequent PGE2 production, along with iNOS induction and NO production, as inflammatory mediators involved in the macrophage response to

  4. Anti-Inflammatory Effects of Flavonoids: Genistein, Kaempferol, Quercetin, and Daidzein Inhibit STAT-1 and NF-κB Activations, Whereas Flavone, Isorhamnetin, Naringenin, and Pelargonidin Inhibit only NF-κB Activation along with Their Inhibitory Effect on iNOS Expression and NO Production in Activated Macrophages

    Directory of Open Access Journals (Sweden)

    Mari Hämäläinen

    2007-01-01

    The present study characterises the effects and mechanisms of naturally occurring phenolic compounds on iNOS expression and NO production in activated macrophages. The results partially explain the pharmacological efficacy of flavonoids as anti-inflammatory compounds.

  5. Ginsenoside Rd inhibits the expressions of iNOS and COX-2 by suppressing NF-κB in LPS-stimulated RAW264.7 cells and mouse liver.

    Science.gov (United States)

    Kim, Dae Hyun; Chung, Jae Heun; Yoon, Ji Sung; Ha, Young Mi; Bae, Sungjin; Lee, Eun Kyeong; Jung, Kyung Jin; Kim, Min Sun; Kim, You Jung; Kim, Mi Kyung; Chung, Hae Young

    2013-03-01

    Ginsenoside Rd is a primary constituent of the ginseng rhizome and has been shown to participate in the regulation of diabetes and in tumor formation. Reports also show that ginsenoside Rd exerts anti-oxidative effects by activating anti-oxidant enzymes. Treatment with ginsenoside Rd decreased nitric oxide and prostaglandin E2 (PGE2) in lipopolysaccharides (LPS)-challenged RAW264.7 cells and in ICR mouse livers (5 mg/kg LPS; LPS + ginsenoside Rd [2, 10, and 50 mg/kg]). Furthermore, these decreases were associated with the down-regulations of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and of nuclear factor (NF)-κB activity in vitro and in vivo. Our results indicate that ginsenoside Rd treatment decreases; 1) nitric oxide production (40% inhibition); 2) PGE2 synthesis (69% to 93% inhibition); 3) NF-κB activity; and 4) the NF-κB-regulated expressions of iNOS and COX-2. Taken together, our results suggest that the anti-inflammatory effects of ginsenoside Rd are due to the down-regulation of NF-κB and the consequent expressional suppressions of iNOS and COX-2.

  6. India-Based Neutrino Observatory (INO)

    Indian Academy of Sciences (India)

    India-Based Neutrino Observatory (INO) · Atmospheric neutrinos – India connection · INO Collaboration · INO Project components · ICAL: The physics goals ... Synergy with other experiments: CPV · Human Resource development & Training · INO Outreach Activities · Why India should be interested in a project like INO ?

  7. Modulation of ENaC, CFTR, and iNOS expression in bronchial epithelial cells after stimulation with Staphylococcus epidermidis (94B080) and Staphylococcus aureus (90B083).

    Science.gov (United States)

    Hussain, Rashida; Oliynyk, Igor; Roomans, Godfried M; Björkqvist, Maria

    2013-09-01

    Bacteria affect the respiratory epithelium, which is covered by airway surface liquid (ASL) and mucus. Ion concentrations in the ASL are determined by the cystic fibrosis transmembrane conductance regulator (CFTR) and the epithelial Na(+) channel (ENaC). Neonatal sepsis is a major risk factor for subsequent pulmonary disease in preterm newborns. Predominating are coagulase-negative staphylococci (e.g., Staphylococccus epidermidis and Staphylococccus aureus). The aim of this study was to investigate modulation of CFTR, ENaC, mucins, proinflammatory cytokines, and inducible nitric oxide synthase (iNOS) in respiratory epithelial cells after S. epidermidis 94B080 and S. aureus 90B083 exposure. Bronchial epithelial cells were incubated with S. epidermidis 94B080 and S. aureus 90B083 (neonatal blood isolates) for 1-36 h. Expression of CFTR, ENaC, iNOS, and mucins was analyzed by real-time PCR and Western blotting. Release of cytokines was analyzed by ELISA, and production of NO by the Griess assay. Expression of CFTR significantly decreased after 36 h incubation with S. epidermidis and more prominently with S. aureus, whereas S. epidermidis caused a significant increase in the expression of β- and γ-ENaC. Expression of iNOS increased, but NO was not detected. Both staphylococci caused a decrease in the intracellular Ca(2+) concentration. S. aureus induced increased secretion of IL-6, IL-8, and transforming nuclear factor (TNF)-α in a time-dependent manner as compared with S. epidermidis. In conclusion, expression of ENaC, CFTR, and iNOS is modulated by exposure to S. aureus 90B083 and S. epidermidis 94B080. S. aureus is more potent in causing release of IL-6, IL-8, and TNF-α by bronchial epithelial cells as compared with S. epidermidis. The mRNA expression for the mucus proteins MUC2, MUC5AC, and MUC5B could not be measured, neither in the presence nor in the absence of bacteria. © 2013 APMIS. Published by John Wiley & Sons Ltd.

  8. Spontaneous expression of inducible nitric oxide synthase in the hypothalamus and other brain regions of aging rats.

    Science.gov (United States)

    Vernet, D; Bonavera, J J; Swerdloff, R S; Gonzalez-Cadavid, N F; Wang, C

    1998-07-01

    Our laboratory has demonstrated that aging in Brown-Norway rats is associated with decreased LH pulse amplitude and reduced GnRH and LH responsiveness to excitatory amino acids (EAA), presumably through the NMDA receptor (NMDAR). Nitric oxide (NO) is a neurotransmitter postulated to be involved in hypothalamic synaptic events required for normal GnRH regulation through the activation of neuronal nitric oxide synthase (nNOS). Paradoxically, excessive stimulation of nNOS by NMDAR or the expression of inducible nitric oxide synthase (iNOS) can lead to supraphysiological levels of NO acting as effector of apoptosis with resultant decreased regional neuronal function. The aims of this study were to determine: 1) whether aging in the preoptic area/medial basal hypothalamus is associated with altered NO synthesis; 2) the possible roles of the NMDAR/nNOS cascade and iNOS in this process; and 3) whether alterations in the levels of NOS isoforms are specific to this region of the brain. Brown Norway male rats (N = 5) at ages 1 (immature), 3 (adult), and 24 (old) months, were used for measuring NMDARs in hypothalamic membranes by the binding of a (3H)-NMDAR ligand. Another series of the same age groups of rats (N = 9) were used to determine by Western blot the contents of NMDAR, nNOS, and iNOS in the hypothalamus, and only iNOS in the frontal and parietal cortex, and cerebellum. NOS activity was measured in the hypothalamus by the arginine/citrulline assay. A significant decrease of NMDA analog binding was found in the hypothalamus from old rats as compared with adult (-66%) and immature animals (-57%), accompanied by a reduction in NMDAR content (-34% and -46%, respectively). NOS activity in the hypothalamus was 67% and 100% higher in old rats as compared with the other two groups, although no significant differences were observed in nNOS content. However, hypothalamic iNOS increased 3.8- and 7.6-fold in old rats, as compared with adult and immature, respectively. This

  9. The effect of doxazosin and sildenafil citrate combination on bladder tissue contractility, alpha adrenergic receptor, and iNOS subtype expression in a male rat model of partially bladder outlet obstruction.

    Science.gov (United States)

    Gumrah, Abdulkadir; Tanidir, Yiloren; Tinay, Ilker; Ozyurek, Mustafa; Tarcan, Tufan

    2017-08-01

    Our aim was to investigate the effects of doxazosin, sildenafil, and their combination on bladder tissue contractility and adrenergic receptor (AR) and inducible nitric oxide synthase (iNOS) expression utilizing a male rat model of partial urethral obstruction (PUO). Thirty male Sprague Dawley rats were divided into five groups. Except the SHAM group, all animals in remaining four groups underwent surgery for PUO. No further treatment was given to the first group (NT group). Remaining three groups received 6 weeks of treatment with 20 mg/kg doxazosin (D group), 20 mg/kg sildenafil (S group), 20 mg/kg doxazosin, and 20 mg/kg sildenafil combination (DS group), respectively via oral gavage. Then, bladder strips were harvested from each animal for isometric tension studies and for real time polymerase chain reaction studies of both AR subtypes and iNOS mRNA. Contractile responses to carbachol and electrical field stimulation at various concentrations/frequencies showed a significant increase after PUO. Any treatment helped to normalize these increased responses. Alpha 1a and 1d AR subtype expressions were found to be down- and up-regulated, respectively, in every group with PUO, compared to SHAM group. iNOS expression was similar in D and NT groups and significantly increased in S and DS groups. Contractile changes of rat bladder tissue due to PUO were prevented by sildenafil or doxazosin alone or in combination where combination treatment did not provide any additional advantage. Further studies are needed to clarify the role of phosphodiesterase inhibitors and combination treatment in the treatment of LUTS. © 2016 Wiley Periodicals, Inc.

  10. Preliminary phytochemical analysis and evaluation of antioxidant, cytotoxic and inhibition of lipopolysaccaride - induced NOS (iNOS) expression in BALB/c mice liver by Ziziphus oenoplia Mill. fruit.

    Science.gov (United States)

    Thirugnanasampandan, Ramaraj; Ramya, Gunasekar; Bhuvaneswari, Gunasekaran; Aravindh, Srinivasan; Vaishnavi, Suresh; Gogulramnath, Madhusudhanan

    2017-03-09

    Ziziphus oenoplia Mill. is an ethnomedicinal plant and its fruit has been traditionally used by Puliar tribes of Anamalai Hills, Tamil Nadu, India to treat various ailments. Phytochemical analysis, antioxidant, cytotoxic and inducible nitric oxide synthase (iNOS) gene downregulation activities of Z. oenoplia fruit (ZOF) were studied. To explore bioactive compounds present in the ripened fruits, high-performance thin-layer chromatography (HPTLC) and gas chromatography/mass spectrometry (GC-MS) analysis were done. Free radical scavenging, hepatoprotective, inhibition of iNOS gene expression and cytotoxic activities of ethanol extract of fruit were also studied. Total flavonoid content of ZOFwas estimated as 69 µg/mg catechin equivalent. HPTLC densitogram confirmed the presence of quercetin and GC-MS analysis showed a total of 16 compounds of 87.66 % with quinic acid as a major compound which accounted for 22.29 %. Free radical-scavenging activity of ethanolic fruit extract was ranged from 160.12 to 650.23 µg/mL. An amount of 1.5 µg lipopolysaccharide (LPS)- induced severe inflammation in BALB/c mice liver, followed by treatment with ethanolic fruit extract of 100 µg concentration, exhibited significant hepatoprotection and reverse transcriptase polymerase (RT-PCR) analysis showed downregulation of iNOS gene expression in hepatocytes at transcriptional level. ZOF also showed significant cytotoxicity and propidium iodide staining confirmed the induction of apoptosis in cervical cancer cells (HeLa). Findings of the present study prove that ZOF is a rich source of bioactive compounds with a wide range of pharmacological activities. Hence, consumption of this wild edible fruit will be a cost-effective and easily available natural nutritional source for health protection.

  11. Ruminant brain ribonucleases: expression and evolution.

    Science.gov (United States)

    Zhao, W; Confalone, E; Breukelman, H J; Sasso, M P; Jekel, P A; Hodge, E; Furia, A; Beintema, J J

    2001-05-05

    Molecular evolutionary analyses of mammalian ribonucleases have shown that gene duplication events giving rise to three paralogous genes occurred in ruminant ancestors. One of these genes encodes a ribonuclease identified in bovine brain. A peculiar feature of this enzyme and orthologous sequences in other ruminants are C-terminal extensions consisting of 17-27 amino acid residues. Evidence was obtained by Western blot analysis for the presence of brain-type ribonucleases in brain tissue not only of ox, but also of sheep, roe deer and chevrotain (Tragulus javanicus), a member of the earliest diverged taxon of the ruminants. The C-terminal extension of brain-type ribonuclease from giraffe deviates much in sequence from orthologues in other ruminants, due to a change of reading frame. However, the gene encodes a functional enzyme, which could be expressed in heterologous systems. The messenger RNA of bovine brain ribonuclease is not only expressed at a high level in brain tissue but also in lactating mammary gland. The enzyme was isolated and identified from this latter tissue, but was not present in bovine milk, although pancreatic ribonucleases A and B could be isolated from both sources. This suggests different ways of secretion of the two enzyme types, possibly related to structural differences. The sequence of the brain-type RNase from chevrotain suggests that the C-terminal extensions of ruminant brain-type ribonucleases originate from deletions in the ancestral DNA (including a region with stop codons), followed by insertion of a 5-8-fold repeated hexanucleotide sequence, coding for a proline-rich polypeptide.

  12. Protection by neuroglobin expression in brain pathologies

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    Eliana Baez

    2016-09-01

    Full Text Available Astrocytes play an important role in physiological, metabolic and structural functions and, when impaired, they can be involved in various pathologies including Alzheimer, focal ischemic stroke and traumatic brain injury. These disorders involve an imbalance in the blood flow and nutrients such as glucose and lactacte, leading to biochemical and molecular changes that cause neuronal damage, which is followed by loss of cognitive and motor functions. Previous studies have shown that astrocytes are more resilient than neurons during brain insults as a consequence of their more effective antioxidant systems, transporters and enzymes, which made them less susceptible to excitotoxicity. In addition, astrocytes synthesize and release different protective molecules for neurons, including neuroglobin, a member of the globin family of proteins. After brain injury neuroglobin expression is induced in astrocytes. Since neuroglobin promotes neuronal survival, its increased expression in astrocytes after brain injury may represent an endogenous neuroprotective mechanism. Here, we review the role of neuroglobin in the CNS, its relationship with different pathologies, and the role of different factors that regulate its expression in astrocytes.

  13. The heme oxygenase-1 inducer THI-56 negatively regulates iNOS expression and HMGB1 release in LPS-activated RAW 264.7 cells and CLP-induced septic mice.

    Science.gov (United States)

    Park, Eun Jung; Jang, Hwa Jin; Tsoyi, Konstantin; Kim, Young Min; Park, Sang Won; Kim, Hye Jung; Lee, Jae Heun; Chang, Ki Churl

    2013-01-01

    The nuclear DNA binding protein high mobility group box 1 (HMGB1) has recently been suggested to act as a late mediator of septic shock. The effect of ((S)-6,7-dihydroxy-1-(4-hydroxynaphthylmethyl)-1,2,3,4-tetrahydroisoquinoline alkaloid, also known as THI-56, in an experimental model of sepsis was investigated. THI-56 exhibited potent anti-inflammatory properties in response to LPS in RAW 264.7 cells. In particular, THI-56 significantly inhibited the expression of inducible nitric oxide synthase (iNOS) and the release of HMGB1 in activated macrophages. THI-56 activated NE-F2-regulated factor 2 (Nrf-2)/heme oxygenase 1 (HO-1). The specific knockdown of the HO-1 gene by HO-1 siRNA significantly reversed the inhibitory effects of THI-56 on iNOS expression and HMGB1 release in LPS-stimulated macrophages. Importantly, THI-56 administration protected animals from death induced by either a lethal dose of LPS or cecal ligation and puncture (CLP). Furthermore, the ALT, AST, BUN, creatinine, and HMGB1 levels in the blood were significantly increased in CLP-induced septic mice, and the administration of THI-56 reduced these levels in a concentration-dependent and zinc protoporphyrin IX (ZnPPIX)-sensitive manner. In addition, the administration of THI-56 significantly ameliorated not only lung damage but also macrophage infiltration in the livers of CLP-induced septic mice, and these effects were also abrogated in the presence of ZnPPIX. Thus, we conclude that THI-56 significantly attenuates the proinflammatory response induced by LPS and reduces organ damage in a CLP-induced sepsis model through the upregulation of Nrf-2/HO-1.

  14. [The expression of GFAP after brain concussion in rats].

    Science.gov (United States)

    Zhang, Chun-Bing; Li, Yong-Hong

    2006-04-01

    To study the expression of GFAP and pathologic changes after rats brain concussion, so that to provide evidence on brain concussion for forensic identification. Forty-five SD rats were divided into 3, 6, 12, 24 h and 2, 4, 7, 10 d and normal control groups in terms of different wounding time after brain concussion model established, and the expression of GFAP after rats brain concussion were then observed by using SP immunohistochemical method. In normal control brain, low-level GFAP expressions could be observed. After six hours' brain concussion, GFAP positive cells increased obviously. The trend reached to the peak at 7d, partly declined at 10d, then decreased gradually. Brain concussion induced the expression of GFAP. The detection of GFAP could be useful for diagnosis of brain concussion on forensic pathology, and could be a reference index for timing of injury after brain concussion.

  15. Positive selection on gene expression in the human brain

    DEFF Research Database (Denmark)

    Khaitovich, Philipp; Tang, Kun; Franz, Henriette

    2006-01-01

    Recent work has shown that the expression levels of genes transcribed in the brains of humans and chimpanzees have changed less than those of genes transcribed in other tissues [1] . However, when gene expression changes are mapped onto the evolutionary lineage in which they occurred, the brain...... shows more changes than other tissues in the human lineage compared to the chimpanzee lineage [1] , [2] and [3] . There are two possible explanations for this: either positive selection drove more gene expression changes to fixation in the human brain than in the chimpanzee brain, or genes expressed...... in the brain experienced less purifying selection in humans than in chimpanzees, i.e. gene expression in the human brain is functionally less constrained. The first scenario would be supported if genes that changed their expression in the brain in the human lineage showed more selective sweeps than other genes...

  16. [Expression of c-myc protein on rats' brains after brain concussion].

    Science.gov (United States)

    Fang, Wei-Hua; Wang, Dong-Liang; Wang, Feng

    2006-10-15

    To study the changes of expression of c-myc protein on rats' brains after brain concussion. sixty rats were randomly divided into brain concussion groups and control group. The expression of c-myc protein was microscopically observed by immunohistochemical method. No expression of c-myc protein in control group were observed. However, positive expression of c-myc protein in some neurons was seen at 20 min after brain concussion, and reach to the peak at 8h after brain concussion and then decreased gradually. These findings suggest that the detection of c-myc protein could be an index of diagnosis of brain concussion.

  17. Expression and regulation of brain metallothionein.

    Science.gov (United States)

    Ebadi, M; Iversen, P L; Hao, R; Cerutis, D R; Rojas, P; Happe, H K; Murrin, L C; Pfeiffer, R F

    1995-07-01

    Many, but not all, zinc-containing neurons in the brain are a subclass of the glutamatergic neurons, and they are found predominantly in the telencephalon. These neurons store zinc in their presynaptic terminals and release it by a calcium-dependent mechanism. These "vesicular" pools of zinc are viewed as endogenous modulators of ligand- and voltage-gated ion channels. Metallothioneins (MTs) are low molecular weight zinc-binding proteins consisting of 25-30% cysteine, with no aromatic amino acids or disulfide bonds. The areas of the brain containing high contents of zinc such as the retina, the pineal gland, and the hippocampus synthesize unique isoforms of MT on a continuous basis. The four MT isoforms are thought to provide the neurons and glial elements with mechanisms to distribute, donate, and sequester zinc at presynaptic terminals; or buffer the excess zinc at synaptic junctions. In this cause, glutathione disulfide may participate in releasing zinc from MT. A similar nucleotide and amino acid sequence has made it difficult to obtain cDNA probes and antibodies capable of distinguishing indisputably among MT isoforms. MT-I and MT-II isoforms are found in the brain and in the peripheral tissues; MT-III isoform, possessing an additional seven amino acids, is expressed mostly in the brain and to a very minute extent in the intestine and pancreas; whereas MT-IV isoform is found in tissues containing stratified squamous epithelial cells. Since MTs are expressed in neurons that sequester zinc in their synaptic vesicles, the regulation of the expression of MT isoforms is extremely important in terms of maintaining the steady-state level of zinc and controlling redox potentials. The concentration of zinc has been shown to be altered in an extensive number of disorders of the central nervous system, including alcoholism. Alzheimer-type dementia, amyotrophic lateral sclerosis, Down's syndrome, epilepsy, Friedreich's ataxia, Guillaine-Barré syndrome, hepatic

  18. Nitric oxide synthase expression and apoptotic cell death in brains of AIDS and AIDS dementia patients

    NARCIS (Netherlands)

    Vincent, V. A.; de Groot, C. J.; Lucassen, P. J.; Portegies, P.; Troost, D.; Tilders, F. J.; van Dam, A. M.

    1999-01-01

    To determine the occurrence and cellular localization of inducible nitric oxide synthase (iNOS), NOS activity and its association with cell death in brains of AIDS and AIDS dementia complex (ADC) patients. Post-mortem cerebral cortex tissue of eight AIDS patients, eight ADC patients and eight

  19. Recombinant TgHSP70 Immunization Protects against Toxoplasma gondii Brain Cyst Formation by Enhancing Inducible Nitric Oxide Expression

    Directory of Open Access Journals (Sweden)

    Neide M. Silva

    2017-04-01

    Full Text Available Toxoplasma gondii is known to cause congenital infection in humans and animals and severe disease in immunocompromised individuals; consequently development of vaccines against the parasite is highly necessary. Under stress conditions, T. gondii expresses the highly immunogenic heat shock protein 70 (TgHSP70. Here, we assessed the protective efficacy of rTgHSP70 immunization combined with Alum in oral ME-49 T. gondii infection and the mechanisms involved on it. It was observed that immunized mice with rTgHSP70 or rTgHSP70 adsorbed in Alum presented a significantly reduced number of cysts in the brain that was associated with increased iNOS+ cell numbers in the organ, irrespective the use of the adjuvant. Indeed, ex vivo experiments showed that peritoneal macrophages pre-stimulated with rTgHSP70 presented increased NO production and enhanced parasite killing, and the protein was able to directly stimulate B cells toward antibody producing profile. In addition, rTgHSP70 immunization leads to high specific antibody titters systemically and a mixed IgG1/IgG2a response, with predominance of IgG1 production. Nonetheless, it was observed that the pretreatment of the parasite with rTgHSP70 immune sera was not able to control T. gondii internalization and replication by NIH fibroblast neither peritoneal murine macrophages, nor anti-rTgHSP70 antibodies were able to kill T. gondii by complement-mediated lysis, suggesting that these mechanisms are not crucial to resistance. Interestingly, when in combination with Alum, rTgHSP70 immunization was able to reduce inflammation in the brain of infected mice and in parallel anti-rTgHSP70 immune complexes in the serum. In conclusion, immunization with rTgHSP70 induces massive amounts of iNOS expression and reduced brain parasitism, suggesting that iNOS expression and consequently NO production in the brain is a protective mechanism induced by TgHSP70 immunization, therefore rTgHSP70 can be a good candidate for

  20. Long-term fenofibrate treatment impaired glucose-stimulated insulin secretion and up-regulated pancreatic NF-kappa B and iNOS expression in monosodium glutamate-induced obese rats: Is that a latent disadvantage?

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    Liu Shuai-nan

    2011-10-01

    Full Text Available Abstract Background Fenofibrate, a PPAR alpha agonist, has been widely used in clinics as lipid-regulating agent. PPAR alpha is known to be expressed in many organs including pancreatic beta cells and regulate genes involved in fatty acid metabolism. Some reports based on cell lines or animals have provided evidences that PPAR alpha agonists may affect (increased or suppressed beta cell insulin secretion, and several studies are producing interesting but still debated results. Methods In this research, we investigated the long term effects of fenofibrate on beta cell function in a metabolic syndrome animal model, monosodium glutamate (MSG induced obese rats. Obese MSG rats were administered by gavage with fenofibrate at a dose of 100 mg/kg for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed to evaluate glucose metabolism and insulin sensitivity. We have used the hyperglycemic clamp technique to evaluate the capacity of beta cell insulin secretion. This technique provides an unbiased approach to understand the beta cell function in vivo. The changes of gene and protein expression in the pancreas and islets were also analyzed by Real-Time-PCR, Western blot and immunostaining. Results Fenofibrate reduced the plasma lipid levels within a few days, and showed no beneficial effects on glucose homeostasis or insulin sensitivity in obese MSG rats. But the animals treated with fenofibrate exhibited significantly decreased fasting plasma insulin and impaired insulin secretory response to glucose stimulation. Further studies confirmed that fenofibrate increased MDA level and decreased total ATPase activity in pancreatic mitochondrion, accompanied by the upregulation of iNOS and NF-kappa B and TNF alpha expression in pancreatic islets of obese MSG rats. Conclusions Long-term fenofibrate treatment disrupted beta cell function, and impaired glucose-stimulated insulin secretion in obese MSG rats, perhaps to some extent associated

  1. Differential Expression of Nitric Oxide Synthase Isoforms nNOS and iNOS in Patients with Non-Segmental Generalized Vitiligo

    Directory of Open Access Journals (Sweden)

    Mario Vaccaro

    2017-11-01

    Full Text Available Nitric oxide (NO is involved in several biological processes, but its role in human melanogenesis is still not well understood. Exposure to UVA and UVB induces nitric oxide production in keratinocytes and melanocytes through the activation of constitutive nitric oxide synthase, increasing tyrosinase activity and melanin synthesis, whereas inducible nitric oxide synthase over expression might be involved in hypopigmentary disorders. The aim of this study was to evaluate whether inducible nitric oxide synthase and neuronal nitric oxide synthase expression were modified in vitiligo skin compared to healthy controls. Skin biopsies were obtained from inflammatory/lesional and white/lesional skin in 12 patients with active, non-segmental vitiligo; site-matched biopsies of normal skin from eight patients were used as controls. Nitric oxide synthase isoforms expression was evaluated by confocal laser scanning microscopy and Western Blot analysis. Inducible nitric oxide synthase expression was significantly increased in inflammatory/lesional skin compared to healthy skin; melanocytes showed a moderate neuronal nitric oxide synthase expression in white/lesional skin, demonstrating that metabolic function still goes on. The obtained data demonstrated that vitiligo lesions were characterized by modifications of nitric oxide synthase isoforms, thus confirming the hypothesis that nitric oxide imbalance is involved in vitiligo and supporting the idea that nitric oxide synthase inhibitors might be used as a possible therapeutic approach for the management of vitiligo.

  2. Differential Expression of Nitric Oxide Synthase Isoforms nNOS and iNOS in Patients with Non-Segmental Generalized Vitiligo.

    Science.gov (United States)

    Vaccaro, Mario; Irrera, Natasha; Cutroneo, Giuseppina; Rizzo, Giuseppina; Vaccaro, Federico; Anastasi, Giuseppe P; Borgia, Francesco; Cannavò, Serafinella P; Altavilla, Domenica; Squadrito, Francesco

    2017-11-26

    Nitric oxide (NO) is involved in several biological processes, but its role in human melanogenesis is still not well understood. Exposure to UVA and UVB induces nitric oxide production in keratinocytes and melanocytes through the activation of constitutive nitric oxide synthase, increasing tyrosinase activity and melanin synthesis, whereas inducible nitric oxide synthase over expression might be involved in hypopigmentary disorders. The aim of this study was to evaluate whether inducible nitric oxide synthase and neuronal nitric oxide synthase expression were modified in vitiligo skin compared to healthy controls. Skin biopsies were obtained from inflammatory/lesional and white/lesional skin in 12 patients with active, non-segmental vitiligo; site-matched biopsies of normal skin from eight patients were used as controls. Nitric oxide synthase isoforms expression was evaluated by confocal laser scanning microscopy and Western Blot analysis. Inducible nitric oxide synthase expression was significantly increased in inflammatory/lesional skin compared to healthy skin; melanocytes showed a moderate neuronal nitric oxide synthase expression in white/lesional skin, demonstrating that metabolic function still goes on. The obtained data demonstrated that vitiligo lesions were characterized by modifications of nitric oxide synthase isoforms, thus confirming the hypothesis that nitric oxide imbalance is involved in vitiligo and supporting the idea that nitric oxide synthase inhibitors might be used as a possible therapeutic approach for the management of vitiligo.

  3. Expression of iron-related genes in human brain and brain tumors

    Directory of Open Access Journals (Sweden)

    Britton Robert S

    2009-04-01

    Full Text Available Abstract Background Defective iron homeostasis may be involved in the development of some diseases within the central nervous system. Although the expression of genes involved in normal iron balance has been intensively studied in other tissues, little is known about their expression in the brain. We investigated the mRNA levels of hepcidin (HAMP, HFE, neogenin (NEO1, transferrin receptor 1 (TFRC, transferrin receptor 2 (TFR2, and hemojuvelin (HFE2 in normal human brain, brain tumors, and astrocytoma cell lines. The specimens included 5 normal brain tissue samples, 4 meningiomas, one medulloblastoma, 3 oligodendrocytic gliomas, 2 oligoastrocytic gliomas, 8 astrocytic gliomas, and 3 astrocytoma cell lines. Results Except for hemojuvelin, all genes studied had detectable levels of mRNA. In most tumor types, the pattern of gene expression was diverse. Notable findings include high expression of transferrin receptor 1 in the hippocampus and medulla oblongata compared to other brain regions, low expression of HFE in normal brain with elevated HFE expression in meningiomas, and absence of hepcidin mRNA in astrocytoma cell lines despite expression in normal brain and tumor specimens. Conclusion These results indicate that several iron-related genes are expressed in normal brain, and that their expression may be dysregulated in brain tumors.

  4. Increased vascular expression of iNOS at day but not at night in asthmatic subjects with increased nocturnal airway obstruction

    NARCIS (Netherlands)

    ten Hacken, NHT; Postma, DS; Drok, G; Smith, M; Kraan, J; Timens, W

    Nitric oxide production by endothelial cells may have important consequences for the development of airway inflammation as well as for airway obstruction. The present study investigated whether the expression of vascular inducible nitric oxide synthase (MOS) and endothelial nitric oxide synthase

  5. Oleifolioside A, a New Active Compound, Attenuates LPS-Stimulated iNOS and COX-2 Expression through the Downregulation of NF-κB and MAPK Activities in RAW 264.7 Macrophages

    Directory of Open Access Journals (Sweden)

    Hai Yang Yu

    2012-01-01

    Full Text Available Oleifolioside A, a new triterpenoid compound isolated from Dendropanax morbifera Leveille (D. morbifera, was shown in this study to have potent inhibitory effects on lipopolysaccharide (LPS-stimulated nitric oxide (NO and prostaglandin E2 (PGE2 production in RAW 264.7 macrophages. Consistent with these findings, oleifolioside A was further shown to suppress the expression of LPS-stimulated inducible nitric oxide synthase (iNOS and cyclooxigenase-2 (COX-2 in a dose-dependent manner at both the protein and mRNA levels and to significantly inhibit the DNA-binding activity and transcriptional activity of NF-κB in response to LPS. These results were found to be associated with the inhibition of the degradation and phosphorylation of IκB-α and subsequent translocation of the NF-κB p65 subunit to the nucleus. Inhibition of NF-κB activation by oleifolioside A was also shown to be mediated through the prevention of p38 MAPK and ERK1/2 phosphorylation. Taken together, our results suggest that oleifolioside A has the potential to be a novel anti-inflammatory agent capable of targeting both the NF-κB and MAPK signaling pathways.

  6. Leaves of Raphanus sativus L. Shows Anti-Inflammatory Activity in LPS-Stimulated Macrophages via Suppression of COX-2 and iNOS Expression

    Science.gov (United States)

    Park, Hye-Jin; Song, Minjung

    2017-01-01

    Raphanus sativus L. (RS) is a cruciferous vegetable that is widely consumed in Korea. The anticancer activity of leaves of RS (RSL) extract has been investigated; however, no studies focused on its anti-inflammatory effects. Therefore, the aim of the current study was to evaluate the anti-inflammatory effects of RSL extract. In brief, RSL powder was fractionated into n-hexane, chloroform, ethyl acetate, n-butanol, and water-soluble fractions. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells were treated with each fraction for initial screening. It was found that the chloroform fraction significantly inhibited nitric oxide release in LPS-stimulated RAW264.7 cells with a half maximal inhibitory concentration value of 196 μg/mL. In addition, the mRNA and protein expression levels of inducible nitric oxide synthase, measured using reverse transcriptase-polymerase chain reaction and western blotting, respectively, were reduced in a concentration-dependent manner. Moreover, the inflammatory cyclooxygenase-2 enzyme expression decreased. Furthermore, the expression of nuclear factor-kappa B (NF-κB), the key regulator of the transcriptional activation of the inflammatory cytokine genes, was reduced by the RSL chloroform fraction. Therefore, the results of our study suggest that RSL exhibits anti-inflammatory effects in LPS-stimulated macrophages via NF-κB inactivation. PMID:28401088

  7. Leaves ofRaphanus sativusL. Shows Anti-Inflammatory Activity in LPS-Stimulated Macrophages via Suppression of COX-2 and iNOS Expression.

    Science.gov (United States)

    Park, Hye-Jin; Song, Minjung

    2017-03-01

    Raphanus sativus L. (RS) is a cruciferous vegetable that is widely consumed in Korea. The anticancer activity of leaves of RS (RSL) extract has been investigated; however, no studies focused on its anti-inflammatory effects. Therefore, the aim of the current study was to evaluate the anti-inflammatory effects of RSL extract. In brief, RSL powder was fractionated into n -hexane, chloroform, ethyl acetate, n -butanol, and water-soluble fractions. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells were treated with each fraction for initial screening. It was found that the chloroform fraction significantly inhibited nitric oxide release in LPS-stimulated RAW264.7 cells with a half maximal inhibitory concentration value of 196 μg/mL. In addition, the mRNA and protein expression levels of inducible nitric oxide synthase, measured using reverse transcriptase-polymerase chain reaction and western blotting, respectively, were reduced in a concentration-dependent manner. Moreover, the inflammatory cyclooxygenase-2 enzyme expression decreased. Furthermore, the expression of nuclear factor-kappa B (NF-κB), the key regulator of the transcriptional activation of the inflammatory cytokine genes, was reduced by the RSL chloroform fraction. Therefore, the results of our study suggest that RSL exhibits anti-inflammatory effects in LPS-stimulated macrophages via NF-κB inactivation.

  8. Conservation of regional gene expression in mouse and human brain.

    Directory of Open Access Journals (Sweden)

    Andrew D Strand

    2007-04-01

    Full Text Available Many neurodegenerative diseases have a hallmark regional and cellular pathology. Gene expression analysis of healthy tissues may provide clues to the differences that distinguish resistant and sensitive tissues and cell types. Comparative analysis of gene expression in healthy mouse and human brain provides a framework to explore the ability of mice to model diseases of the human brain. It may also aid in understanding brain evolution and the basis for higher order cognitive abilities. Here we compare gene expression profiles of human motor cortex, caudate nucleus, and cerebellum to one another and identify genes that are more highly expressed in one region relative to another. We separately perform identical analysis on corresponding brain regions from mice. Within each species, we find that the different brain regions have distinctly different expression profiles. Contrasting between the two species shows that regionally enriched genes in one species are generally regionally enriched genes in the other species. Thus, even when considering thousands of genes, the expression ratios in two regions from one species are significantly correlated with expression ratios in the other species. Finally, genes whose expression is higher in one area of the brain relative to the other areas, in other words genes with patterned expression, tend to have greater conservation of nucleotide sequence than more widely expressed genes. Together these observations suggest that region-specific genes have been conserved in the mammalian brain at both the sequence and gene expression levels. Given the general similarity between patterns of gene expression in healthy human and mouse brains, we believe it is reasonable to expect a high degree of concordance between microarray phenotypes of human neurodegenerative diseases and their mouse models. Finally, these data on very divergent species provide context for studies in more closely related species that address

  9. MAP kinase phosphatase-2 plays a key role in the control of infection with Toxoplasma gondii by modulating iNOS and arginase-1 activities in mice.

    Directory of Open Access Journals (Sweden)

    Stuart Woods

    2013-08-01

    Full Text Available The dual specific phosphatase, MAP kinase phosphatase-2 (MKP-2 has recently been demonstrated to negatively regulate macrophage arginase-1 expression, while at the same time to positively regulate iNOS expression. Consequently, MKP-2 is likely to play a significant role in the host interplay with intracellular pathogens. Here we demonstrate that MKP-2(-/- mice on the C57BL/6 background have enhanced susceptibility compared with wild-type counterparts following infection with type-2 strains of Toxoplasma gondii as measured by increased parasite multiplication during acute infection, increased mortality from day 12 post-infection onwards and increased parasite burdens in the brain, day 30 post-infection. MKP-2(-/- mice did not, however, demonstrate defective type-1 responses compared with MKP-2(+/+ mice following infection although they did display significantly reduced serum nitrite levels and enhanced tissue arginase-1 expression. Early resistance to T. gondii in MKP-2(+/+, but not MKP-2(-/-, mice was nitric oxide (NO dependent as infected MKP-2(+/+, but not MKP-2(-/- mice succumbed within 10 days post-infection with increased parasite burdens following treatment with the iNOS inhibitor L-NAME. Conversely, treatment of infected MKP-2(-/- but not MKP-2(+/+ mice with nor-NOHA increased parasite burdens indicating a protective role for arginase-1 in MKP-2(-/- mice. In vitro studies using tachyzoite-infected bone marrow derived macrophages and selective inhibition of arginase-1 and iNOS activities confirmed that both iNOS and arginase-1 contributed to inhibiting parasite replication. However, the effects of arginase-1 were transient and ultimately the role of iNOS was paramount in facilitating long-term inhibition of parasite multiplication within macrophages.

  10. [Effects of Tongluo Xingnao effervescent tablets on blood rheology, iNOS, VEGF and LDH-5 in MID rats].

    Science.gov (United States)

    Ren, Xiang-Yi; Hu, Yong; Wei, Jiang-Ping; Fu, Wen-Jun; Xu, Shi-Jun; Wang, Yong-Yan

    2016-03-01

    The study was to explore effects of Tongluo Xingnao effervescent tablets on the blood rheology, iNOS, VEGF and LDH-5 in multi-infarct dementia(MID) model rats. Establish MID model rats were induced by microthrombosis, from which 50 successful model rats were randomly divided into five groups, such as the model control group, the dihydroergotoxine mesylate tablets(hydergine) group(0.7 mg•kg⁻¹), Tongluo Xingnao effervescent tablets high-dose, medium-dose and low-dose groups(7.56, 3.78, 1.89 g•kg⁻¹). Another ten rats in the sham group were randomly selected as the parallel control group. Each group was orally administered with drugs for 90 days. The learning and memory ability was evaluated with the Morris water maze test, while the whole blood viscosity and the erythrocyte aggregation index derived from abdominal aorta were measured in different shear rates. In addition, the levels of VEGF and iNOS in the serum were determined by ELISA kits. The expression of LDH-5 in hippocampus of rats was measured with immunohistochemistry and image quantitative analysis. The result showed that Tongluo Xingnao effervescent tablets notably decreased the escape latency of MID model rats, increased times of entering into the escape platform and prolonged retention time in medium ring, meanwhile the whole blood viscosity in MID model rats was also notably reduced in four shear rates, i.e. 1, 5, 30, 200 S⁻¹, erythrocyte aggregation index, serum VEGF and iNOS, and average optical density value of LDH-5, with a statistically significant differences compared with the model control group (Peffervescent tablets could improve the ability of learning and memory of MID model rats and the blood rheology, reduce the level of iNOS, VEGF and the expression of LDH-5, and then improved the brain energy supply. Copyright© by the Chinese Pharmaceutical Association.

  11. India-based Neutrino Observatory (INO)

    Indian Academy of Sciences (India)

    The INO Collaboration includes several institutes and universities in India and has been funded by the Department of Atomic Energy (DAE), India for the feasi- bility study. This study includes possible location(s) for INO, physics issues and associated choice of detector; subsequent detector R&D, and detailed physics sim-.

  12. Genes differentially expressed in medulloblastoma and fetal brain

    NARCIS (Netherlands)

    Michiels, E. M.; Oussoren, E.; van Groenigen, M.; Pauws, E.; Bossuyt, P. M.; Voûte, P. A.; Baas, F.

    1999-01-01

    Serial analysis of gene expression (SAGE) was used to identify genes that might be involved in the development or growth of medulloblastoma, a childhood brain tumor. Sequence tags from medulloblastoma (10229) and fetal brain (10692) were determined. The distributions of sequence tags in each

  13. Chemical clearing and dehydration of GFP expressing mouse brains

    National Research Council Canada - National Science Library

    Becker, Klaus; Jährling, Nina; Saghafi, Saiedeh; Weiler, Reto; Dodt, Hans-Ulrich

    2012-01-01

    ...) can be applied as a more GFP-friendly clearing medium. Clearing with dibenzyl ether provides improved tissue transparency and strikingly improved fluorescence intensity in GFP expressing mouse brains and other samples as mouse spinal cords, or embryos...

  14. Relationships between gene expression and brain wiring in the adult rodent brain.

    Directory of Open Access Journals (Sweden)

    Leon French

    2011-01-01

    Full Text Available We studied the global relationship between gene expression and neuroanatomical connectivity in the adult rodent brain. We utilized a large data set of the rat brain "connectome" from the Brain Architecture Management System (942 brain regions and over 5000 connections and used statistical approaches to relate the data to the gene expression signatures of 17,530 genes in 142 anatomical regions from the Allen Brain Atlas. Our analysis shows that adult gene expression signatures have a statistically significant relationship to connectivity. In particular, brain regions that have similar expression profiles tend to have similar connectivity profiles, and this effect is not entirely attributable to spatial correlations. In addition, brain regions which are connected have more similar expression patterns. Using a simple optimization approach, we identified a set of genes most correlated with neuroanatomical connectivity, and find that this set is enriched for genes involved in neuronal development and axon guidance. A number of the genes have been implicated in neurodevelopmental disorders such as autistic spectrum disorder. Our results have the potential to shed light on the role of gene expression patterns in influencing neuronal activity and connectivity, with potential applications to our understanding of brain disorders. Supplementary data are available at http://www.chibi.ubc.ca/ABAMS.

  15. Anti-inflammatory potential of an ethyl acetate fraction isolated from Justicia gendarussa roots through inhibition of iNOS and COX-2 expression via NF-κB pathway.

    Science.gov (United States)

    Kumar, Kavitha S; Vijayan, Viji; Bhaskar, Shobha; Krishnan, Kripa; Shalini, V; Helen, A

    2012-01-01

    Justicia gendarussa Burm.f. (J. gendarussa) is a plant used as traditional medicine in different parts of India and China to treat inflammatory disorders like rheumatoid arthritis. But its mechanism of anti-inflammatory action is still unclear. Hence in this context, the objective of our study is to reveal the mechanism of anti-inflammatory activity of J. gendarussa which would form an additional proof to the traditional knowledge of this plant. The anti-inflammatory function and mechanism(s) of action was studied in an ethyl acetate fraction isolated from methanolic extract of J. gendarussa roots (EJG). Anti-inflammatory studies were conducted on rats using partitioned fractions isolated from methanolic extract of J. gendarussa roots. In carrageenan-induced rat paw edema, ethyl acetate fraction brought about 80% and 93% edema inhibition at 3rd and 5th hour at a dose of 50 mg/kg, when compared to other extracts and Voveran. We investigated whether EJG inhibits the release of cycloxygenase (COX), 5-lipoxygenase (5-LOX), interleukin-6 (IL-6) and nuclear factor kappa B (NF-κB) in LPS stimulated human peripheral blood mononuclear cells (hPBMCs). Results shows that EJG dose dependently inhibited LPS-activated COX, 5-LOX, IL-6, and NF-κB in hPBMCs. EJG also reduced LPS induced levels of iNOS and COX-2 mRNA expression in hPBMCs. This study provides an insight into the probable mechanism(s) underlying the anti-inflammatory activity of EJG and therefore, we report the first confirmation of the anti-inflammatory potential of this traditionally employed herbal medicine in vitro. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. On Expression Patterns and Developmental Origin of Human Brain Regions.

    Science.gov (United States)

    Kirsch, Lior; Chechik, Gal

    2016-08-01

    Anatomical substructures of the human brain have characteristic cell-types, connectivity and local circuitry, which are reflected in area-specific transcriptome signatures, but the principles governing area-specific transcription and their relation to brain development are still being studied. In adult rodents, areal transcriptome patterns agree with the embryonic origin of brain regions, but the processes and genes that preserve an embryonic signature in regional expression profiles were not quantified. Furthermore, it is not clear how embryonic-origin signatures of adult-brain expression interplay with changes in expression patterns during development. Here we first quantify which genes have regional expression-patterns related to the developmental origin of brain regions, using genome-wide mRNA expression from post-mortem adult human brains. We find that almost all human genes (92%) exhibit an expression pattern that agrees with developmental brain-region ontology, but that this agreement changes at multiple phases during development. Agreement is particularly strong in neuron-specific genes, but also in genes that are not spatially correlated with neuron-specific or glia-specific markers. Surprisingly, agreement is also stronger in early-evolved genes. We further find that pairs of similar genes having high agreement to developmental region ontology tend to be more strongly correlated or anti-correlated, and that the strength of spatial correlation changes more strongly in gene pairs with stronger embryonic signatures. These results suggest that transcription regulation of most genes in the adult human brain is spatially tuned in a way that changes through life, but in agreement with development-determined brain regions.

  17. On Expression Patterns and Developmental Origin of Human Brain Regions.

    Directory of Open Access Journals (Sweden)

    Lior Kirsch

    2016-08-01

    Full Text Available Anatomical substructures of the human brain have characteristic cell-types, connectivity and local circuitry, which are reflected in area-specific transcriptome signatures, but the principles governing area-specific transcription and their relation to brain development are still being studied. In adult rodents, areal transcriptome patterns agree with the embryonic origin of brain regions, but the processes and genes that preserve an embryonic signature in regional expression profiles were not quantified. Furthermore, it is not clear how embryonic-origin signatures of adult-brain expression interplay with changes in expression patterns during development. Here we first quantify which genes have regional expression-patterns related to the developmental origin of brain regions, using genome-wide mRNA expression from post-mortem adult human brains. We find that almost all human genes (92% exhibit an expression pattern that agrees with developmental brain-region ontology, but that this agreement changes at multiple phases during development. Agreement is particularly strong in neuron-specific genes, but also in genes that are not spatially correlated with neuron-specific or glia-specific markers. Surprisingly, agreement is also stronger in early-evolved genes. We further find that pairs of similar genes having high agreement to developmental region ontology tend to be more strongly correlated or anti-correlated, and that the strength of spatial correlation changes more strongly in gene pairs with stronger embryonic signatures. These results suggest that transcription regulation of most genes in the adult human brain is spatially tuned in a way that changes through life, but in agreement with development-determined brain regions.

  18. Metal ion toxins and brain aquaporin-4 expression: an overview

    Directory of Open Access Journals (Sweden)

    Adriana eXimenes-Da-Silva

    2016-06-01

    Full Text Available Metal ions such as iron, zinc, and manganese are essential to metabolic functions, protein synthesis, neurotransmission, and antioxidant neuroprotective mechanisms. Conversely, non-essential metals such as mercury and lead are sources of human intoxication due to occupational activities or environmental contamination. Essential or non-essential metal accumulation in the central nervous system (CNS results in changes in blood-brain barrier (BBB permeability, as well as triggering microglia activation and astrocyte reactivity and changing water transport through the cells, which could result in brain swelling. Aquaporin-4 is the main water channel in the CNS, is expressed in astrocyte foot processes in brain capillaries and along the circumventricular epithelium in the ventricles, and has important physiological functions in maintaining brain osmotic homeostasis and supporting brain excitability through regulation of the extracellular space. Some evidence has pointed to a role of AQP4 during metal intoxication in the brain, where it may act in a dual form as a neuroprotector or a mediator of the development of oxidative stress in neurons and astrocytes, resulting in brain swelling and neuronal damage. This mini-review presents the way some metal ions affect changes in AQP4 expression in the CNS and discuss the ways in which water transport in brain cells can be involved in brain damage.

  19. Ruminant brain ribonucleases : expression and evolution

    NARCIS (Netherlands)

    Zhao, W; Confalone, E; Breukelman, HJ; Sasso, MP; Jekel, PA; Hodge, E; Furia, A; Beintema, JJ

    2001-01-01

    Molecular evolutionary analyses of mammalian ribonucleases have shown that gene duplication events giving rise to three paralogous genes occurred in ruminant ancestors. One of these genes encodes a ribonuclease identified in bovine brain. A peculiar feature of this enzyme and orthologous sequences

  20. MicroRNA expression profiling of the porcine developing brain.

    Directory of Open Access Journals (Sweden)

    Agnieszka Podolska

    Full Text Available BACKGROUND: MicroRNAs are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level and play an important role in the control of developmental and physiological processes. In particular, the developing brain contains an impressive diversity of microRNAs. Most microRNA expression profiling studies have been performed in human or rodents and relatively limited knowledge exists in other mammalian species. The domestic pig is considered to be an excellent, alternate, large mammal model for human-related neurological studies, due to its similarity in both brain development and the growth curve when compared to humans. Considering these similarities, studies examining microRNA expression during porcine brain development could potentially be used to predict the expression profile and role of microRNAs in the human brain. METHODOLOGY/PRINCIPAL FINDINGS: MicroRNA expression profiling by use of microRNA microarrays and qPCR was performed on the porcine developing brain. Our results show that microRNA expression is regulated in a developmentally stage-specific, as well as a tissue-specific manner. Numerous developmental stage or tissue-specific microRNAs including, miR-17, miR-18a, miR-29c, miR-106a, miR-135a and b, miR-221 and miR-222 were found by microarray analysis. Expression profiles of selected candidates were confirmed by qPCR. CONCLUSIONS/SIGNIFICANCE: The differential expression of specific microRNAs in fetal versus postnatal samples suggests that they likely play an important role in the regulation of developmental and physiological processes during brain development. The data presented here supports the notion that microRNAs act as post-transcriptional switches which may regulate gene expression when required.

  1. Automated gene expression pattern annotation in the mouse brain.

    Science.gov (United States)

    Yang, Tao; Zhao, Xinlin; Lin, Binbin; Zeng, Tao; Ji, Shuiwang; Ye, Jieping

    2015-01-01

    Brain tumor is a fatal central nervous system disease that occurs in around 250,000 people each year globally and it is the second cause of cancer in children. It has been widely acknowledged that genetic factor is one of the significant risk factors for brain cancer. Thus, accurate descriptions of the locations of where the relative genes are active and how these genes express are critical for understanding the pathogenesis of brain tumor and for early detection. The Allen Developing Mouse Brain Atlas is a project on gene expression over the course of mouse brain development stages. Utilizing mouse models allows us to use a relatively homogeneous system to reveal the genetic risk factor of brain cancer. In the Allen atlas, about 435,000 high-resolution spatiotemporal in situ hybridization images have been generated for approximately 2,100 genes and currently the expression patterns over specific brain regions are manually annotated by experts, which does not scale with the continuously expanding collection of images. In this paper, we present an efficient computational approach to perform automated gene expression pattern annotation on brain images. First, the gene expression information in the brain images is captured by invariant features extracted from local image patches. Next, we adopt an augmented sparse coding method, called Stochastic Coordinate Coding, to construct high-level representations. Different pooling methods are then applied to generate gene-level features. To discriminate gene expression patterns at specific brain regions, we employ supervised learning methods to build accurate models for both binary-class and multi-class cases. Random undersampling and majority voting strategies are utilized to deal with the inherently imbalanced class distribution within each annotation task in order to further improve predictive performance. In addition, we propose a novel structure-based multi-label classification approach, which makes use of label

  2. Correlation of inducible nitric oxide synthase (iNOS) inhibition with TNF-α, caspase-1, FasL and TLR-3 in pathogenesis of rabies in mouse model.

    Science.gov (United States)

    Madhu, B P; Singh, K P; Saminathan, M; Singh, R; Tiwari, A K; Manjunatha, V; Harish, C; Manjunathareddy, G B

    2016-02-01

    The role of inflammatory cytokines such as interleukin-1α/β (IL-1α/β), IL-6, IL-10, tumour necrosis factor-alpha (TNF-α), interferons, nitric oxide (NO) and inducible nitric oxide synthase (iNOS) in pathogenesis of rabies is being actively pursued. Presently, levels of certain immune molecules in pathogenesis of rabies in mice have been investigated. CVS strain of rabies infection resulted in early increase in iNOS, TNF-α, caspase-1, Fas ligand (FasL) and toll-like receptor-3 (TLR-3) mRNA levels in brain, and nitric oxide levels in serum. The severity of clinical signs and microscopic lesions largely correlated with NO levels. Aminoguanidine (AG; iNOS inhibitor) decreased NO production with delay in development of clinical signs and increase in survival time. Prolonged survival time correlated with reduced viral load evident by real-time PCR, reduced fluorescent signals of rabies antigen in brain and reduced immunohistochemistry signals in neuronal cytoplasm. These parameters suggested that nitric oxide did influence the rabies virus replication. Inhibition of iNOS by AG administration led to decreased expression of TNF-α, caspase-1, FasL and TLR-3 mRNA levels suggesting that increase in NO levels in rabies virus infection possibly contributed to development of disease through inflammation, apoptosis and immune-evasive mechanisms.

  3. Prolyl carboxypeptidase mRNA expression in the mouse brain.

    Science.gov (United States)

    Jeong, Jin Kwon; Diano, Sabrina

    2014-01-13

    Prolyl carboxypeptidase (PRCP), a serine protease, is widely expressed in the body including liver, lung, kidney and brain, with a variety of known substrates such as plasma prekallikrein, bradykinin, angiotensins II and III, and α-MSH, suggesting its role in the processing of tissue-specific substrates. In the brain, PRCP has been shown to inactivate hypothalamic α-MSH, thus modulating melanocortin signaling in the control of energy metabolism. While its expression pattern has been reported in the hypothalamus, little is known on the distribution of PRCP throughout the mouse brain. This study was undertaken to determine PRCP expression in the mouse brain. Radioactive in situ hybridization was performed to determine endogenous PRCP mRNA expression. In addition, using a gene-trap mouse model for PRCP deletion, X-gal staining was performed to further determine PRCP distribution. Results from both approaches showed that PRCP gene is broadly expressed in the brain. © 2013 Published by Elsevier B.V.

  4. Aberrant expression of long noncoding RNAs in autistic brain.

    Science.gov (United States)

    Ziats, Mark N; Rennert, Owen M

    2013-03-01

    The autism spectrum disorders (ASD) have a significant hereditary component, but the implicated genetic loci are heterogeneous and complex. Consequently, there is a gap in understanding how diverse genomic aberrations all result in one clinical ASD phenotype. Gene expression studies from autism brain tissue have demonstrated that aberrantly expressed protein-coding genes may converge onto common molecular pathways, potentially reconciling the strong heritability and shared clinical phenotypes with the genomic heterogeneity of the disorder. However, the regulation of gene expression is extremely complex and governed by many mechanisms, including noncoding RNAs. Yet no study in ASD brain tissue has assessed for changes in regulatory long noncoding RNAs (lncRNAs), which represent a large proportion of the human transcriptome, and actively modulate mRNA expression. To assess if aberrant expression of lncRNAs may play a role in the molecular pathogenesis of ASD, we profiled over 33,000 annotated lncRNAs and 30,000 mRNA transcripts from postmortem brain tissue of autistic and control prefrontal cortex and cerebellum by microarray. We detected over 200 differentially expressed lncRNAs in ASD, which were enriched for genomic regions containing genes related to neurodevelopment and psychiatric disease. Additionally, comparison of differences in expression of mRNAs between prefrontal cortex and cerebellum within individual donors showed ASD brains had more transcriptional homogeneity. Moreover, this was also true of the lncRNA transcriptome. Our results suggest that further investigation of lncRNA expression in autistic brain may further elucidate the molecular pathogenesis of this disorder.

  5. Comparative gene expression analysis of murine retina and brain.

    Science.gov (United States)

    Hackam, Abigail S; Qian, Jiang; Liu, Dongmei; Gunatilaka, Tushara; Farkas, Ronald H; Chowers, Itay; Kageyama, Masaaki; Parmigiani, Giovanni; Zack, Donald J

    2004-08-31

    Several high-throughput studies have described gene expression in the central nervous system (CNS), and recently there has been increasing interest in analyzing how gene expression compares in different regions of the CNS. As the retina is often used as a model system to study CNS development and function, we compared retina and brain gene expression using microarray analyses. Mouse retina, brain and liver RNA was hybridized to a custom cDNA microarray containing 5,376 genes and ESTs, and the data from the quantified scanned images were analyzed using Bioconductor and SAM. Preferential retina expression was confirmed by real-time PCR. The cellular distribution of genes newly identified as retina enriched genes was determined by immunohistochemistry. Using stringent statistical analyses we identified 733 genes that were preferentially expressed in retina and 389 in brain. The retina-liver hybridizations identified an additional 837 retina enriched genes. The cellular distribution in the retina was determined for two genes that had not previously been reported to be expressed in the retina, the transcription regulatory proteins EWS and PCPB1. Both proteins were found primarily in the inner nuclear layer. Finally, a comparison of the microarray data to publicly available SAGE and EST library databases demonstrated only limited overlap of the sets of retina enriched genes identified by the different methodologies. The preferential retinal expression of a subset of genes from the microarray, which were not identified as differentially expressed by other methods, was confirmed by quantitative PCR. The finding of differences in the groups of identified retina enriched genes from the various profiling techniques supports the use of multiple approaches to obtain a more complete description of retinal gene expression. Characterization of gene expression profiles of retina and brain may facilitate the understanding of the processes that underlie differences between the retina

  6. MicroRNA expression profiling of the porcine developing brain

    DEFF Research Database (Denmark)

    Podolska, Agnieszka; Kaczkowski, Bogumil; Busk, Peter Kamp

    2011-01-01

    MicroRNAs are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level and play an important role in the control of developmental and physiological processes. In particular, the developing brain contains an impressive diversity of microRNAs. Most micro......RNA expression profiling studies have been performed in human or rodents and relatively limited knowledge exists in other mammalian species. The domestic pig is considered to be an excellent, alternate, large mammal model for human-related neurological studies, due to its similarity in both brain development...

  7. Reelin expression in brain endothelial cells: an electron microscopy study.

    Science.gov (United States)

    Perez-Costas, Emma; Fenton, Erin Y; Caruncho, Hector J

    2015-03-24

    Reelin expression and function have been extensively studied in the brain, although its expression has been also reported in other tissues including blood. This raises the possibility that reelin might be able to cross the blood-brain barrier, which could be functionally relevant. Up-to-date no studies have been conducted to assess if reelin is present in the blood-brain barrier, which is mainly constituted by tightly packed endothelial cells. In this report we assessed the expression of reelin in brain capillaries using immunocytochemistry and electron microscopy. At the light microscope, reelin immunolabeling appeared in specific endothelial cells in brain areas that presented abundant diffuse labeling for this protein (e.g., layer I of the cortex, or the stratum lacunosum moleculare of the hippocampus), while it was mostly absent from capillaries in other brain areas (e.g., deeper cortical layers, or the CA1 layer of the hippocampus). As expected, at the electron microscope reelin labeling was observed in neurons of the cortex, where most of the labeling was associated with the rough endoplasmic reticulum. Importantly, reelin was also observed in some endothelial cells located in small capillaries, which confirmed the findings obtained at the light microscope. In these cells, reelin labeling was located primarily in caveolae (i.e., vesicles of transcytosis), and associated with the plasma membrane of the luminal side of endothelial cells. In addition, some scarce labeling was observed in the nuclear membrane. The presence of reelin immunolabeling in brain endothelial cells, and particularly in caveolar vesicles within these cells, suggests that reelin and/or reelin peptides may be able to cross the blood-brain barrier, which could have important physiological, pathological, and therapeutic implications.

  8. Effects of nitric oxide synthase deficiency on a disintegrin and metalloproteinase domain-containing protein 12 expression in mouse brain samples.

    Science.gov (United States)

    Lendeckel, Uwe; Wolke, Carmen; Bernstein, Hans-Gert; Keilhoff, Gerburg

    2015-08-01

    A disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) belongs to the ADAM family of transmembrane proteins. Via proteolysis, cell adhesion, cell-cell fusion, cell-matrix interaction and membrane protein shedding, ADAM proteins are involved in normal brain development, and also in cancer genesis and progression, and in inflammation. Therefore, neurobiological research focusing on this protein is increasing. Nitric oxide (NO), which is endogenously produced by NO synthases (NOS), is associated with glial tumors. However, knock-out of NOS produces only limited antitumor effects. The present study analyzed the expression of ADAM12 in the cortex and hippocampus of C57/BL6 wild-type mice, and endothelial NOS-, neuronal NOS-(nNOS) or inducible NOS (iNOS)-deficient (-/-) mice, at different stages of development. Expression of ADAM12 was quantified using immunoblot analysis of cortical and hippocampal tissue samples from fetal, neonatal (5 days postnatal), adult (12 weeks old) or >1 year old mice. Using reverse transcription-quantitative polymerase chain reaction, ADAM12 expression was analyzed in cultured N9, OLN93, C6 and PC12 cells, representing the four main cell types in the brain, following NOS inhibition. ADAM12 expression was low in all mouse genotypes and regions of the brain, and in fetal and neonatal mice, an increase in expression was observed with increasing age. The highest levels of expression were observed in the cortex of adult mice, iNOS(-/-) mice of >1 year and wild-type mice, and in the hippocampus of adult and iNOS(-/-) mice of >1 year. By contrast, ADAM12 expression was lowest in adult nNOS(-/-) mice. Inhibition of NOS using N(ω)-Nitro-L-arginine methyl ester hydrochloride, induced ADAM12 mRNA expression in N9 and PC12 cell lines. Inhibition of NOS using L-N(6)-(1-Iminoethyl)lysine dihydrochloride, induced ADAM12 mRNA expression in N9 and C6 cell lines. No change in ADAM12 expression was observed in OLN93 cells following NOS

  9. Exploring Brain Gene Expression i Animal Models of Behaviour

    OpenAIRE

    Lindberg, Julia

    2007-01-01

    The genetic basis for behavioural traits is largely unknown. The overall aim of this thesis was to find genes with importance for behavioural traits related to fear and anxiety. Microarray analysis was used to screen expression profiles of brain regions important for emotional behaviour in dogs, wolves, foxes and mice. In a first experiment, dogs and their wild ancestors the wolves were compared. Our results suggested that directed selection for behaviour might have resulted in expression cha...

  10. Mirroring pain in the brain : emotional expression versus motor imitation

    NARCIS (Netherlands)

    Budell, Lesley; Kunz, Miriam; Jackson, Philip L; Rainville, Pierre

    2015-01-01

    Perception of pain in others via facial expressions has been shown to involve brain areas responsive to self-pain, biological motion, as well as both performed and observed motor actions. Here, we investigated the involvement of these different regions during emotional and motor mirroring of pain

  11. Neuroglobin and Cytoglobin expression in the human brain

    DEFF Research Database (Denmark)

    Hundahl, Christian Ansgar; Kelsen, Jesper; Hay-Schmidt, Anders

    2013-01-01

    Neuroglobin and Cytoglobin are new members of the heme-globin family. Both globins are primarily expressed in neurons of the brain and retina. Neuroglobin and Cytoglobin have been suggested as novel therapeutic targets in various neurodegenerative diseases based on their oxygen binding and cell p...

  12. The brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3, and induced nitric oxide synthase expressions after low-level laser therapy in an axonotmesis experimental model.

    Science.gov (United States)

    Gomes, Lessandra Esper Abdala; Dalmarco, Eduardo Monguilhott; André, Edison Sanfelice

    2012-11-01

    A robust body of evidence has shown that low-level laser therapy (LLLT) improves peripheral nerve regeneration. However, the biochemical background triggered in this process is not yet fully understood. The purpose of this study was to evaluate the mRNA expression of neurotrophic factors (brain-derived neurotrophic factor [BDNF], nerve growth factor [NGF], and neurotrophin-3, [NT-3]) and also an inflammatory marker (induced nitric oxide synthase [iNOS]) in an axonotmesis experimental model after low-level laser therapy. Thirty-six adult male Wistar rats (250-350 g) were subjected to right sciatic nerve crush injury, and 24 h later, the animals in the three different experimental groups (n=18) were irradiated on a daily basis with helium-neon laser (collimated HeNe laser, continuous emission, wavelength: 632.8 nm, power density: 0.5 mW/cm(2), irradiation time: 20 sec, energy density: 10 J/cm(2)) during 7, 14, and 21 consecutive days, respectively. The control group (n=18) underwent the same procedures, but with the equipment turned off. At the end of the experiments, animals were killed with an overdose of anesthesia to remove samples from the sciatic nerve lesion epicenter to determine the mRNA expression of BDNF, NGF, NT-3 and iNOS enzyme. Comparisons between groups showed that HeNe laser increased the mRNA expression of both BDNF and NGF factors after 14 days of LLLT, with peak expression at the 21st day. Increase in NT-3 mRNA expression was not observed. In addition, HeNe laser produced iNOS expression reduction, which played an important role in the inflammatory process. The reported data could have a relevant practical value because LLLT is a noninvasive procedure, and have revealed significant increase in neurotrophic factor expressions and inflammatory process reduction, opening the possibility of using LLLT as an important aid to nerve regeneration process.

  13. Expression of Alzheimer's disease risk genes in ischemic brain degeneration.

    Science.gov (United States)

    Ułamek-Kozioł, Marzena; Pluta, Ryszard; Januszewski, Sławomir; Kocki, Janusz; Bogucka-Kocka, Anna; Czuczwar, Stanisław J

    2016-12-01

    We review the Alzheimer-related expression of genes following brain ischemia as risk factors for late-onset of sporadic Alzheimer's disease and their role in Alzheimer's disease ischemia-reperfusion pathogenesis. More recent advances in understanding ischemic etiology of Alzheimer's disease have revealed dysregulation of Alzheimer-associated genes including amyloid protein precursor, β-secretase, presenilin 1 and 2, autophagy, mitophagy and apoptosis. We review the relationship between these genes dysregulated by brain ischemia and the cellular and neuropathological characteristics of Alzheimer's disease. Here we summarize the latest studies supporting the theory that Alzheimer-related genes play an important role in ischemic brain injury and that ischemia is a needful and leading supplier to the onset and progression of sporadic Alzheimer's disease. Although the exact molecular mechanisms of ischemic dependent neurodegenerative disease and neuronal susceptibility finally are unknown, a downregulated expression of neuronal defense genes like alfa-secretase in the ischemic brain makes the neurons less able to resist injury. The recent challenge is to find ways to raise the adaptive reserve of the brain to overcome such ischemic-associated deficits and support and/or promote neuronal survival. Understanding the mechanisms underlying the association of these genes with risk for Alzheimer's disease will provide the most meaningful targets for therapeutic development to date. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  14. FTO is expressed in neurones throughout the brain and its expression is unaltered by fasting.

    Directory of Open Access Journals (Sweden)

    James S McTaggart

    Full Text Available Single-nucleotide polymorphisms in the first intron of the ubiquitously expressed FTO gene are associated with obesity. Although the physiological functions of FTO remain unclear, food intake is often altered when Fto expression levels are manipulated. Furthermore, deletion of FTO from neurones alone has a similar effect on food intake to deletion of FTO in all tissues. These results indicate that FTO expression in the brain is particularly important. Considerable focus has been placed on the dynamic regulation of Fto mRNA expression in the hypothalamus after short-term (16-48 hour fasting, but results have been controversial. There are no studies that quantify FTO protein levels across the brain, and assess its alteration following short-term fasting. Using immunohistochemistry, we found that FTO protein is widely expressed in mouse brain, and present in the majority of neurones. Using quantitative Western blotting and RT-qPCR we show that FTO protein and mRNA levels in the hypothalamus, cerebellum and rostral brain are relatively uniform, and levels in the brain are higher than in skeletal muscles of the lower limbs. Fasting for 18 hours does not alter the expression pattern, or levels, of FTO protein and mRNA. We further show that the majority of POMC neurones, which are critically involved in food intake regulation, also express FTO, but that the percentage of FTO-positive POMC neurones is not altered by fasting. In summary, we find no evidence that Fto/FTO expression is regulated by short-term (18-hour fasting. Thus, it is unlikely that the hunger and increased post-fasting food intake caused by such food deprivation is driven by alterations in Fto/FTO expression. The widespread expression of FTO in neurones also suggests that physiological studies of this protein should not be limited to the hypothalamus.

  15. Let-7i attenuates human brain microvascular endothelial cell damage in oxygen glucose deprivation model by decreasing toll-like receptor 4 expression.

    Science.gov (United States)

    Xiang, Wei; Tian, Canhui; Peng, Shunli; Zhou, Liang; Pan, Suyue; Deng, Zhen

    2017-11-04

    The let-7 family of microRNAs (miRNAs) plays an important role on endothelial cell function. However, there have been few studies on their role under ischemic conditions. In this study, we demonstrate that let-7i, belonging to the let-7 family, rescues human brain microvascular endothelial cells (HBMECs) in an oxygen-glucose deprivation (OGD) model. Our data show that the expression of let-7 family miRNAs was downregulated after OGD. Overexpression of let-7i significantly alleviated cell death and improved survival of OGD-treated HBMECs. Let-7i also protected permeability in an in vitro blood brain barrier (BBB) model. Further, let-7i downregulated the expression of toll-like receptor 4 (TLR4), an inflammation trigger. Moreover, overexpression of let-7i decreased matrix metallopeptidase 9 (MMP9) and inducible nitric oxide synthase (iNOS) expression under OGD. Upon silencing TLR4 expression in HBMECs, the anti-inflammatory effect of let-7i was abolished. Our research suggests that let-7i promotes OGD-induced inflammation via downregulating TLR4 expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Investigation of G72 (DAOA expression in the human brain

    Directory of Open Access Journals (Sweden)

    Hirsch Steven

    2008-12-01

    Full Text Available Abstract Background Polymorphisms at the G72/G30 locus on chromosome 13q have been associated with schizophrenia or bipolar disorder in more than ten independent studies. Even though the genetic findings are very robust, the physiological role of the predicted G72 protein has thus far not been resolved. Initial reports suggested G72 as an activator of D-amino acid oxidase (DAO, supporting the glutamate dysfunction hypothesis of schizophrenia. However, these findings have subsequently not been reproduced and reports of endogenous human G72 mRNA and protein expression are extremely limited. In order to better understand the function of this putative schizophrenia susceptibility gene, we attempted to demonstrate G72 mRNA and protein expression in relevant human brain regions. Methods The expression of G72 mRNA was studied by northern blotting and semi-quantitative SYBR-Green and Taqman RT-PCR. Protein expression in human tissue lysates was investigated by western blotting using two custom-made specific anti-G72 peptide antibodies. An in-depth in silico analysis of the G72/G30 locus was performed in order to try and identify motifs or regulatory elements that provide insight to G72 mRNA expression and transcript stability. Results Despite using highly sensitive techniques, we failed to identify significant levels of G72 mRNA in a variety of human tissues (e.g. adult brain, amygdala, caudate nucleus, fetal brain, spinal cord and testis human cell lines or schizophrenia/control post mortem BA10 samples. Furthermore, using western blotting in combination with sensitive detection methods, we were also unable to detect G72 protein in a number of human brain regions (including cerebellum and amygdala, spinal cord or testis. A detailed in silico analysis provides several lines of evidence that support the apparent low or absent expression of G72. Conclusion Our results suggest that native G72 protein is not normally present in the tissues that we analysed

  17. Aging and Gene Expression in the Primate Brain

    Energy Technology Data Exchange (ETDEWEB)

    Fraser, Hunter B.; Khaitovich, Philipp; Plotkin, Joshua B.; Paabo, Svante; Eisen, Michael B.

    2005-02-18

    It is well established that gene expression levels in many organisms change during the aging process, and the advent of DNA microarrays has allowed genome-wide patterns of transcriptional changes associated with aging to be studied in both model organisms and various human tissues. Understanding the effects of aging on gene expression in the human brain is of particular interest, because of its relation to both normal and pathological neurodegeneration. Here we show that human cerebral cortex, human cerebellum, and chimpanzee cortex each undergo different patterns of age-related gene expression alterations. In humans, many more genes undergo consistent expression changes in the cortex than in the cerebellum; in chimpanzees, many genes change expression with age in cortex, but the pattern of changes in expression bears almost no resemblance to that of human cortex. These results demonstrate the diversity of aging patterns present within the human brain, as well as how rapidly genome-wide patterns of aging can evolve between species; they may also have implications for the oxidative free radical theory of aging, and help to improve our understanding of human neurodegenerative diseases.

  18. Aging and gene expression in the primate brain.

    Directory of Open Access Journals (Sweden)

    Hunter B Fraser

    2005-09-01

    Full Text Available It is well established that gene expression levels in many organisms change during the aging process, and the advent of DNA microarrays has allowed genome-wide patterns of transcriptional changes associated with aging to be studied in both model organisms and various human tissues. Understanding the effects of aging on gene expression in the human brain is of particular interest, because of its relation to both normal and pathological neurodegeneration. Here we show that human cerebral cortex, human cerebellum, and chimpanzee cortex each undergo different patterns of age-related gene expression alterations. In humans, many more genes undergo consistent expression changes in the cortex than in the cerebellum; in chimpanzees, many genes change expression with age in cortex, but the pattern of changes in expression bears almost no resemblance to that of human cortex. These results demonstrate the diversity of aging patterns present within the human brain, as well as how rapidly genome-wide patterns of aging can evolve between species; they may also have implications for the oxidative free radical theory of aging, and help to improve our understanding of human neurodegenerative diseases.

  19. NMO in pediatric patients: brain involvement and clinical expression.

    Science.gov (United States)

    Peña, Joaquín A; Ravelo, María Elena; Mora-La Cruz, Eduardo; Montiel-Nava, Cecilia

    2011-02-01

    To analyze the clinical, neuroimaging characteristics and positivity of the acquaporin water channel (NMO-IgG) in pediatric patients with neuromyelitis optica (NMO). This disorder could have a variable clinical expression. To address such variability, the term NMO spectrum has been suggested. We evaluated six pediatric patients, with a median age of 11 years at the time of the study, with the diagnosis of NMO by the Wingerchuck criteria. All the cases exhibited bilateral optic neuritis (ON). Four patients had abnormalities on brain MRI from the onset,although only three of them developed symptoms correlated to those lesions during the course of their disorder. NMO-IgG was positive in 80%. Optic neuropathy is the most impaired feature in NMO patients. Brain MRI lesions are not compatible with multiple sclerosis and positivity of the NMO-IgG are also present in NMO pediatric patients, confirming the heterogeneity in the expression of this disorder.

  20. Gene Expression Profiling during Pregnancy in Rat Brain Tissue

    Directory of Open Access Journals (Sweden)

    Phyllis E. Mann

    2014-03-01

    Full Text Available The neurophysiological changes that occur during pregnancy in the female mammal have led to the coining of the phrases “expectant brain” and “maternal brain”. Although much is known of the hormonal changes during pregnancy, alterations in neurotransmitter gene expression have not been well-studied. We examined gene expression in the ventromedial nucleus of the hypothalamus (VMH during pregnancy based on the fact that this nucleus not only modulates the physiological changes that occur during pregnancy but is also involved in the development of maternal behavior. This study was designed to identify genes that are differentially expressed between mid- and late-pregnancy in order to determine which genes may be associated with the onset and display of maternal behavior and the development of the maternal brain. A commercially available PCR array containing 84 neurotransmitter receptor and regulator genes (RT2 Profiler PCR array was used. Brains were harvested from rats on days 12 and 21 of gestation, frozen, and micropunched to obtain the VMH. Total RNA was extracted, cDNA prepared, and SYBR Green qPCR was performed. In the VMH, expression of five genes were reduced on day 21 of gestation compared to day 12 (Chrna6, Drd5, Gabrr2, Prokr2, and Ppyr1 whereas Chat, Chrm5, Drd4, Gabra5, Gabrg2, LOC289606, Nmu5r2, and Npy5r expression was elevated. Five genes were chosen to be validated in an additional experiment based on their known involvement in maternal behavior onset. This experiment confirmed that gene expression for both the CCK-A receptor and the GABAAR γ2 receptor increases at the end of pregnancy. In general, these results identify genes possibly involved in the establishment of the maternal brain in rats and indicate possible new genes to be investigated.

  1. Body language in the brain: constructing meaning from expressive movement

    Science.gov (United States)

    Tipper, Christine M.; Signorini, Giulia; Grafton, Scott T.

    2015-01-01

    This fMRI study investigated neural systems that interpret body language—the meaningful emotive expressions conveyed by body movement. Participants watched videos of performers engaged in modern dance or pantomime that conveyed specific themes such as hope, agony, lust, or exhaustion. We tested whether the meaning of an affectively laden performance was decoded in localized brain substrates as a distinct property of action separable from other superficial features, such as choreography, kinematics, performer, and low-level visual stimuli. A repetition suppression (RS) procedure was used to identify brain regions that decoded the meaningful affective state of a performer, as evidenced by decreased activity when emotive themes were repeated in successive performances. Because the theme was the only feature repeated across video clips that were otherwise entirely different, the occurrence of RS identified brain substrates that differentially coded the specific meaning of expressive performances. RS was observed bilaterally, extending anteriorly along middle and superior temporal gyri into temporal pole, medially into insula, rostrally into inferior orbitofrontal cortex, and caudally into hippocampus and amygdala. Behavioral data on a separate task indicated that interpreting themes from modern dance was more difficult than interpreting pantomime; a result that was also reflected in the fMRI data. There was greater RS in left hemisphere, suggesting that the more abstract metaphors used to express themes in dance compared to pantomime posed a greater challenge to brain substrates directly involved in decoding those themes. We propose that the meaning-sensitive temporal-orbitofrontal regions observed here comprise a superordinate functional module of a known hierarchical action observation network (AON), which is critical to the construction of meaning from expressive movement. The findings are discussed with respect to a predictive coding model of action understanding

  2. Facial Expression Recognition for Traumatic Brain Injured Patients

    DEFF Research Database (Denmark)

    Ilyas, Chaudhary Muhammad Aqdus; Nasrollahi, Kamal; Moeslund, Thomas B.

    2018-01-01

    In this paper, we investigate the issues associated with facial expression recognition of Traumatic Brain Insured (TBI) patients in a realistic scenario. These patients have restricted or limited muscle movements with reduced facial expressions along with non-cooperative behavior, impaired...... reasoning and inappropriate responses. All these factors make automatic understanding of their expressions more complex. While the existing facial expression recognition systems showed high accuracy by taking data from healthy subjects, their performance is yet to be proved for real TBI patient data...... by considering the aforementioned challenges. To deal with this, we devised scenarios for data collection from the real TBI patients, collected data which is very challenging to process, devised effective way of data preprocessing so that good quality faces can be extracted from the patients facial video...

  3. Conditional gene expression systems in the transgenic rat brain

    Directory of Open Access Journals (Sweden)

    Schönig Kai

    2012-09-01

    Full Text Available Abstract Background Turning gene expression on and off at will is one of the most powerful tools for the study of gene function in vivo. While several conditional systems were successful in invertebrates, in mice the Cre/loxP recombination system and the tet-controlled transcription activation system are predominant. Both expression systems allow for spatial and temporal control of gene activities, and, in the case of tet regulation, even for the reversible activation/inactivation of gene expression. Although the rat is the principal experimental model in biomedical research, in particular in studies of neuroscience, conditional rat transgenic systems are exceptionally rare in this species. Results We addressed this lack of technology, and established and thoroughly characterized CreERT2 and tTA transgenic rats with forebrain-specific transgene expression, controlled by the CaMKII alpha promoter. In addition, we developed new universal rat reporter lines for both transcription control systems and established inducible and efficient reporter gene expression in forebrain neurons. Conclusions We demonstrate that conditional genetic manipulations in the rat brain are both feasible and practicable and outline advantages and limitations of the Tet and Cre/loxP system in the rat brain.

  4. Mirroring pain in the brain: emotional expression versus motor imitation.

    Directory of Open Access Journals (Sweden)

    Lesley Budell

    Full Text Available Perception of pain in others via facial expressions has been shown to involve brain areas responsive to self-pain, biological motion, as well as both performed and observed motor actions. Here, we investigated the involvement of these different regions during emotional and motor mirroring of pain expressions using a two-task paradigm, and including both observation and execution of the expressions. BOLD responses were measured as subjects watched video clips showing different intensities of pain expression and, after a variable delay, either expressed the amount of pain they perceived in the clips (pain task, or imitated the facial movements (movement task. In the pain task condition, pain coding involved overlapping activation across observation and execution in the anterior cingulate cortex, supplementary motor area, inferior frontal gyrus/anterior insula, and the inferior parietal lobule, and a pain-related increase (pain vs. neutral in the anterior cingulate cortex/supplementary motor area, the right inferior frontal gyrus, and the postcentral gyrus. The 'mirroring' response was stronger in the inferior frontal gyrus and middle temporal gyrus/superior temporal sulcus during the pain task, and stronger in the inferior parietal lobule in the movement task. These results strongly suggest that while motor mirroring may contribute to the perception of pain expressions in others, interpreting these expressions in terms of pain content draws more heavily on networks involved in the perception of affective meaning.

  5. Mirroring pain in the brain: emotional expression versus motor imitation.

    Science.gov (United States)

    Budell, Lesley; Kunz, Miriam; Jackson, Philip L; Rainville, Pierre

    2015-01-01

    Perception of pain in others via facial expressions has been shown to involve brain areas responsive to self-pain, biological motion, as well as both performed and observed motor actions. Here, we investigated the involvement of these different regions during emotional and motor mirroring of pain expressions using a two-task paradigm, and including both observation and execution of the expressions. BOLD responses were measured as subjects watched video clips showing different intensities of pain expression and, after a variable delay, either expressed the amount of pain they perceived in the clips (pain task), or imitated the facial movements (movement task). In the pain task condition, pain coding involved overlapping activation across observation and execution in the anterior cingulate cortex, supplementary motor area, inferior frontal gyrus/anterior insula, and the inferior parietal lobule, and a pain-related increase (pain vs. neutral) in the anterior cingulate cortex/supplementary motor area, the right inferior frontal gyrus, and the postcentral gyrus. The 'mirroring' response was stronger in the inferior frontal gyrus and middle temporal gyrus/superior temporal sulcus during the pain task, and stronger in the inferior parietal lobule in the movement task. These results strongly suggest that while motor mirroring may contribute to the perception of pain expressions in others, interpreting these expressions in terms of pain content draws more heavily on networks involved in the perception of affective meaning.

  6. Dehydroepiandrosterone sulfate augments blood-brain barrier and tight junction protein expression in brain endothelial cells.

    Science.gov (United States)

    Papadopoulos, Dimitrios; Scheiner-Bobis, Georgios

    2017-08-01

    Tight junctions (TJ) between brain endothelial cells are essential for formation and maintenance of the blood-brain barrier (BBB). Although loss of BBB integrity is associated with several neuropathological disorders, treatments that augment or stabilise the BBB are scarce. Here we show that physiological concentrations of dehydroepiandrosterone sulfate (DHEAS) stimulate the expression of the TJ proteins zonula occludens-1 (ZO-1) and claudin-3 in the brain-derived endothelial cell line bEnd.3 and promote TJ formation between neighbouring cells, demonstrated by augmented transendothelial resistance across cell monolayers. Silencing androgen receptor expression by siRNA does not prevent DHEAS-induced stimulation of ZO-1 expression, indicating that conversion of DHEAS into testosterone is not required for its actions. Suppression of Gnα11 expression by siRNA prevents DHEAS actions, pointing towards a G-protein-coupled receptor as being a mediator of the DHEAS effects. These results are consistent with the idea that DHEAS, acting as a hormone in its own right, supports the integrity of the BBB. The current findings might help in developing new strategies for the prevention or treatment of neurological disorders associated with BBB defects. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Effekt der selektiven Hemmung der induzierbaren NO-Synthase (iNOS) in einem experimentellen Model der Pulmonalen Hypertonie

    OpenAIRE

    Krug, Christoffer

    2008-01-01

    Die Rolle der verschiedenen Stickstoffmonoxidsynthasen (NOS) in der Pathogenese der Pulmonalen Hypertonie wird kontrovers diskutiert. Insbesondere die Rolle der induzierbaren NO-Synthase (iNOS oder NOS2) ist wenig untersucht. Im Rahmen dieser Arbeit erfolgten Untersuchungen in einem etablierten experimentellen Modell der Pulmonalen Hypertonie durch Injektion des Alkaloids Monocrotalin in der Ratte. In diesem klinisch relevanten Modell der PH konnte eine signifikant erhöhte Expression der iNOS...

  8. iNOS Activity Modulates Inflammation, Angiogenesis, and Tissue Fibrosis in Polyether-Polyurethane Synthetic Implants

    Directory of Open Access Journals (Sweden)

    Puebla Cassini-Vieira

    2015-01-01

    Full Text Available There is considerable interest in implantation techniques and scaffolds for tissue engineering and, for safety and biocompatibility reasons, inflammation, angiogenesis, and fibrosis need to be determined. The contribution of inducible nitric oxide synthase (iNOS in the regulation of the foreign body reaction induced by subcutaneous implantation of a synthetic matrix was never investigated. Here, we examined the role of iNOS in angiogenesis, inflammation, and collagen deposition induced by polyether-polyurethane synthetic implants, using mice with targeted disruption of the iNOS gene (iNOS−/− and wild-type (WT mice. The hemoglobin content and number of vessels were decreased in the implants of iNOS−/− mice compared to WT mice 14 days after implantation. VEGF levels were also reduced in the implants of iNOS−/− mice. In contrast, the iNOS−/− implants exhibited an increased neutrophil and macrophage infiltration. However, no alterations were observed in levels of CXCL1 and CCL2, chemokines related to neutrophil and macrophage migration, respectively. Furthermore, the implants of iNOS−/− mice showed boosted collagen deposition. These data suggest that iNOS activity controls inflammation, angiogenesis, and fibrogenesis in polyether-polyurethane synthetic implants and that lack of iNOS expression increases foreign body reaction to implants in mice.

  9. Brain Microglia Express Steroid-Converting Enzymes in the Mouse

    Science.gov (United States)

    Gottfried-Blackmore, Andres; Sierra, Amanda; Jellinck, Peter H.; McEwen, Bruce S.; Bulloch, Karen

    2008-01-01

    In the CNS, steroid hormones play a major role in the maintenance of brain homeostasis and it’s response to injury. Since activated microglia are the pivotal immune cell involved in neurodegeneration, we investigated the possibility that microglia provide a discrete source for the metabolism of active steroid hormones. Using RT-PCR, our results showed that mouse microglia expressed mRNA for 17β-hydroxysteroid dehydrogenase type-1 and steroid 5α-reductase type-1, which are involved in the metabolism of androgens and estrogens. Microglia also expressed the peripheral benzodiazepine receptor and steroid acute regulatory protein; however, the enzymes required for de novo formation of progesterone and DHEA from cholesterol were not expressed. To test the function of these enzymes, primary microglia cultures were incubated with steroid precursors, DHEA and AD. Microglia preferentially produced delta-5 androgens (Adiol) from DHEA and 5α-reduced androgens from AD. Adiol behaved as an effective estrogen receptor agonist in neuronal cells. Activation of microglia with pro-inflammatory factors, LPS and INFγ did not affect the enzymatic properties of these proteins. However, PBR ligands reduced TNFα production signifying an immunomodulatory role for PBR. Collectively, our results suggest that microglia utilize steroid-converting enzymes and related proteins to influence inflammation and neurodegeneration within microenvironments of the brain. PMID:18329265

  10. AB224. SaRNA guided inos upregulation improves erectile function of diabetic rats

    OpenAIRE

    T. Wang; Li, M; Yuan, H; Zhan, Y; Xu, H; Wang, S; Yang, W; Liu, J; Ye, Z.; Li, LC

    2014-01-01

    Purpose Promoter targeted saRNAs mediate sequence specific up-regulation of gene expression. We explored the therapeutic effect of RNA activation mediated iNOS gene activation on improving erectile function in a rat model of diabetes mellitus. Materials and methods An optimal saRNA sequence specific for iNOS promoter was cloned into an adenoviral vector, resulting in AdU6/shiNOS and AdU6/shControl. The corresponding viruses were used to transduce cultured rat cavernous smooth muscle cells. St...

  11. Brain Gene Expression Signatures From Cerebrospinal Fluid Exosome RNA Profiling

    Science.gov (United States)

    Zanello, S. B.; Stevens, B.; Calvillo, E.; Tang, R.; Gutierrez Flores, B.; Hu, L.; Skog, J.; Bershad, E.

    2016-01-01

    While the Visual Impairment and Intracranial Pressure (VIIP) syndrome observations have focused on ocular symptoms, spaceflight has been also associated with a number of other performance and neurologic signs, such as headaches, cognitive changes, vertigo, nausea, sleep/circadian disruption and mood alterations, which, albeit likely multifactorial, can also result from elevation of intracranial pressure (ICP). We therefore hypothesize that these various symptoms are caused by disturbances in the neurophysiology of the brain structures and are correlated with molecular markers in the cerebrospinal fluid (CSF) as indicators of neurophysiological changes. Exosomes are 30-200 nm microvesicles shed into all biofluids, including blood, urine, and CSF, carrying a highly rich source of intact protein and RNA cargo. Exosomes have been identified in human CSF, and their proteome and RNA pool is a potential new reservoir for biomarker discovery in neurological disorders. The purpose of this study is to investigate changes in brain gene expression via exosome analysis in patients suffering from ICP elevation of varied severity (idiopathic intracranial hypertension -IIH), a condition which shares some of the neuroophthalmological features of VIIP, as a first step toward obtaining evidence suggesting that cognitive function and ICP levels can be correlated with biomarkers in the CSF. Our preliminary work, reported last year, validated the exosomal technology applicable to CSF analysis and demonstrated that it was possible to obtain gene expression evidence of inflammation processes in traumatic brain injury patients. We are now recruiting patients with suspected IIH requiring lumbar puncture at Baylor College of Medicine. Both CSF (5 ml) and human plasma (10 ml) are being collected in order to compare the pattern of differentially expressed genes observed in CSF and in blood. Since blood is much more accessible than CSF, we would like to determine whether plasma biomarkers for

  12. Inhibition of Lipopolysaccharide-Induced iNOS, COX- 2, and TNF ...

    African Journals Online (AJOL)

    Inhibition of Lipopolysaccharide-Induced iNOS, COX- 2, and TNF-α Expression by Aqueous Extract of Orixa Japonica in RAW 264.7 Cells via Suppression of NF- kB Activity. C-H Kang, YH Choi, I-W Choi, J-D Lee, G-Y Kim ...

  13. Inhibition of iNOS and DNA Oxidation by Methanol Extract of ...

    African Journals Online (AJOL)

    Purpose: To investigate the antioxidant properties of the methanol extract of S. tenuifolia as well as its effect on inducible nitric oxide synthase (iNOS) and cycleooxygenase-2 (COX-2) expression in lipopolysaccharides (LPS)-induced cell damage in macrophage cells. Methods: The antioxidant activities of the plant extract ...

  14. Review of terahertz technology development at INO

    Science.gov (United States)

    Dufour, Denis; Marchese, Linda; Terroux, Marc; Oulachgar, Hassane; Généreux, Francis; Doucet, Michel; Mercier, Luc; Tremblay, Bruno; Alain, Christine; Beaupré, Patrick; Blanchard, Nathalie; Bolduc, Martin; Chevalier, Claude; D'Amato, Dominic; Desroches, Yan; Duchesne, François; Gagnon, Lucie; Ilias, Samir; Jerominek, Hubert; Lagacé, François; Lambert, Julie; Lamontagne, Frédéric; Le Noc, Loïc; Martel, Anne; Pancrati, Ovidiu; Paultre, Jacques-Edmond; Pope, Tim; Provençal, Francis; Topart, Patrice; Vachon, Carl; Verreault, Sonia; Bergeron, Alain

    2015-10-01

    Over the past decade, INO has leveraged its expertise in the development of uncooled microbolometer detectors for infrared imaging to produce terahertz (THz) imaging systems. By modifying its microbolometer-based focal plane arrays to enhance absorption in the THz bands and by developing custom THz imaging lenses, INO has developed a leading-edge THz imaging system, the IRXCAM-THz-384 camera, capable of exploring novel applications in the emerging field of terahertz imaging and sensing. Using appropriate THz sources, results show that the IRXCAM-THz-384 camera is able to image a variety of concealed objects of interest for applications such as non-destructive testing and weapons detections. By using a longer wavelength (94 GHz) source, it is also capable of sensing the signatures of various objects hidden behind a drywall panel. This article, written as a review of THz research at INO over the past decade, describes the technical components that form the IRXCAM-THz-384 camera and the experimental setup used for active THz imaging. Image results for concealed weapons detection experiments, an exploration of wavelength choice on image quality, and the detection of hidden objects behind drywall are also presented.

  15. Methylxanthines and calcium-mobilizing agents inhibit the expression of cytokine-inducible nitric oxide synthase and vascular cell adhesion molecule-1 in murine microvascular endothelial cells.

    Science.gov (United States)

    Bereta, M; Bereta, J; Georgoff, I; Coffman, F D; Cohen, S; Cohen, M C

    1994-06-01

    In response to exposure to the inflammatory cytokines tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN-gamma), murine brain microvascular endothelial cells (MME) synthesize the cell surface molecule, vascular cell adhesion molecule-1 (VCAM-1), and the intracellular enzyme, inducible nitric oxide synthase (iNOS). However, iNOS synthesis requires the presence of both TNF and IFN-gamma, while VCAM-1 can be induced by either cytokine alone. We examined the induction of VCAM-1 and iNOS under a variety of conditions to better define the regulation of TNF and IFN-gamma signal transduction pathways in MME. We utilized the analysis of steady-state levels of iNOS mRNA as well as the measurement of MME-released NO-EDRF (nitric oxide as an endothelium-derived relaxing factor) activity and accumulation of nitrite in the culture medium to define iNOS expression and activity. VCAM-1 expression was determined by flow cytometric analysis. Our data indicate that low density lipoproteins inhibited cytokine-induced iNOS activity by affecting the steady-state levels of iNOS mRNA. Methylxanthines (caffeine and theophylline) as well as several calcium-mobilizing agents inhibited the expression/activity of both iNOS and VCAM-1 in MME. The effectiveness of these agents was dependent upon the degree of disruption in cell calcium homeostasis during cytokine treatment. Cells which had been pretreated with calcium-modulating drugs and then washed and allowed to return to normal calcium homeostasis showed little to no effect from these agents. In addition, our results suggest that NO produced by iNOS acts as a metabolic switch during inflammation by inhibiting oxidative phosphorylation and forcing vascular endothelial cells to temporarily utilize anaerobic energy metabolism.

  16. Human brain arteriovenous malformations express lymphatic-associated genes.

    Science.gov (United States)

    Shoemaker, Lorelei D; Fuentes, Laurel F; Santiago, Shauna M; Allen, Breanna M; Cook, Douglas J; Steinberg, Gary K; Chang, Steven D

    2014-12-01

    Brain arteriovenous malformations (AVMs) are devastating, hemorrhage-prone, cerebrovascular lesions characterized by well-defined feeding arteries, draining vein(s) and the absence of a capillary bed. The endothelial cells (ECs) that comprise AVMs exhibit a loss of arterial and venous specification. Given the role of the transcription factor COUP-TFII in vascular development, EC specification, and pathological angiogenesis, we examined human AVM tissue to determine if COUP-FTII may have a role in AVM disease biology. We examined 40 human brain AVMs by immunohistochemistry (IHC) and qRT-PCR for the expression of COUP-TFII as well as other genes involved in venous and lymphatic development, maintenance, and signaling. We also examined proliferation and EC tube formation with human umbilical ECs (HUVEC) following COUP-TFII overexpression. We report that AVMs expressed COUP-TFII, SOX18, PROX1, NFATC1, FOXC2, TBX1, LYVE1, Podoplanin, and vascular endothelial growth factor (VEGF)-C, contained Ki67-positive cells and heterogeneously expressed genes involved in Hedgehog, Notch, Wnt, and VEGF signaling pathways. Overexpression of COUP-TFII alone in vitro resulted in increased EC proliferation and dilated tubes in an EC tube formation assay in HUVEC. This suggests AVM ECs are further losing their arterial/venous specificity and acquiring a partial lymphatic molecular phenotype. There was significant correlation of gene expression with presence of clinical edema and acute hemorrhage. While the precise role of these genes in the formation, stabilization, growth and risk of hemorrhage of AVMs remains unclear, these findings have potentially important implications for patient management and treatment choice, and opens new avenues for future work on AVM disease mechanisms.

  17. Brain expressed microRNAs implicated in schizophrenia etiology.

    Directory of Open Access Journals (Sweden)

    Thomas Hansen

    Full Text Available BACKGROUND: Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. METHODOLOGY/PRINCIPAL FINDINGS: We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects, were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206 and hsa-mit-198 (mir-198 showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038, of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1 in the network have previously been associated with schizophrenia. CONCLUSIONS/SIGNIFICANCE: We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15 of targets in common, eight of which are also connected

  18. NMO in pediatric patients: brain involvement and clinical expression

    Directory of Open Access Journals (Sweden)

    Joaquín A. Peña

    2011-02-01

    Full Text Available OBJECTIVE: To analyze the clinical, neuroimaging characteristics and positivity of the acquaporin water channel (NMO-IgG in pediatric patients with neuromyelitis optica (NMO. This disorder could have a variable clinical expression. To address such variability, the term NMO spectrum has been suggested. METHOD: We evaluated six pediatric patients, with a median age of 11 years at the time of the study, with the diagnosis of NMO by the Wingerchuck criteria. RESULTS: All the cases exhibited bilateral optic neuritis (ON. Four patients had abnormalities on brain MRI from the onset,although only three of them developed symptoms correlated to those lesions during the course of their disorder. NMO-IgG was positive in 80%. CONCLUSION: Optic neuropathy is the most impaired feature in NMO patients. Brain MRI lesions are not compatible with multiple sclerosis and positivity of the NMO-IgG are also present in NMO pediatric patients, confirming the heterogeneity in the expression of this disorder.

  19. Human INO80/YY1 chromatin remodeling complex transcriptionally regulates the BRCA2- and CDKN1A-interacting protein (BCCIP in cells

    Directory of Open Access Journals (Sweden)

    Jiaming Su

    2016-08-01

    Full Text Available Abstract The BCCIP (BRCA2- and CDKN1A-interacting protein is an important cofactor for BRCA2 in tumor suppression. Although the low expression of BCCIP is observed in multiple clinically diagnosed primary tumor tissues such as ovarian cancer, renal cell carcinoma and colorectal carcinoma, the mechanism of how BCCIP is regulated in cells is still unclear. The human INO80/YY1 chromatin remodeling complex composed of 15 subunits catalyzes ATP-dependent sliding of nucleosomes along DNA. Here, we first report that BCCIP is a novel target gene of the INO80/YY1 complex by presenting a series of experimental evidence. Gene expression studies combined with siRNA knockdown data locked candidate genes including BCCIP of the INO80/YY1 complex. Silencing or over-expressing the subunits of the INO80/YY1 complex regulates the expression level of BCCIP both in mRNA and proteins in cells. Also, the functions of INO80/YY1 complex in regulating the transactivation of BCCIP were confirmed by luciferase reporter assays. Chromatin immunoprecipitation (ChIP experiments clarify the enrichment of INO80 and YY1 at +0.17 kb downstream of the BCCIP transcriptional start site. However, this enrichment is significantly inhibited by either knocking down INO80 or YY1, suggesting the existence of both INO80 and YY1 is required for recruiting the INO80/YY1 complex to BCCIP promoter region. Our findings strongly indicate that BCCIP is a potential target gene of the INO80/YY1 complex.

  20. [Expression of c-jun protein after experimental rat brain concussion].

    Science.gov (United States)

    Wang, Feng; Li, Yong-hong

    2010-02-01

    To observe e-jun protein expression after rat brain concussion and explore the forensic pathologic markers following brain concussion. Fifty-five rats were randomly divided into brain concussion group and control group. The expression of c-jun protein was observed by immunohistochemistry. There were weak positive expression of c-jun protein in control group. In brain concussion group, however, some neutrons showed positive expression of c-jun protein at 15 min after brain concussion, and reach to the peak at 3 h after brain concussion. The research results suggest that detection of c-jun protein could be a marker to determine brain concussion and estimate injury time after brain concussion.

  1. Invited Review: How sleep deprivation affects gene expression in the brain: a review of recent findings

    National Research Council Canada - National Science Library

    Chiara Cirelli

    2002-01-01

    ..., and the functional consequences of sleep loss. To determine what molecular changes occur in the brain during the sleep-waking cycle and after sleep deprivation, our laboratory is performing a systematic screening of brain gene expression in rats...

  2. Characterization of iNOS+ Neutrophil-like ring cell in tumor-bearing mice

    Directory of Open Access Journals (Sweden)

    Virtuoso Lauren P

    2012-07-01

    Full Text Available Abstract Background Myeloid-derived Suppressor Cells (MDSC have been identified as tumor-induced immature myeloid cells (IMC with potent immune suppressive activity in cancer. Whereas strict phenotypic classification of MDSC has been challenging due to the highly heterogeneous nature of cell surface marker expression, use of functional markers such as Arginase and inducible nitric oxide synthase (iNOS may represent a better categorization strategy. In this study we investigated whether iNOS could be utilized as a specific marker for the identification of a more informative homogenous MDSC subset. Methods Single-cell suspensions from tumors and other organs were prepared essentially by enzymatic digestion. Flow cytometric analysis was performed on a four-color flow cytometer. Morphology, intracellular structure and localization of iNOS+ ring cells in the tumor were determined by cytospin analysis, immunofluorescence microscopy and immunohistochemistry, respectively. For functional analysis, iNOS+ ring subset were sorted and tested in vitro cell culture experiments. Pharmacologic inhibition of iNOS was performed both in vivo and in vitro. Results The results showed that intracellular iNOS staining distinguished a granular iNOS+ SSChi CD11b+ Gr-1dim F4/80+ subset with ring-shaped nuclei (ring cells among the CD11b+ Gr-1+ cell populations found in tumors. The intensity of the ring cell infiltrate correlated with tumor size and these cells constituted the second major tumor-infiltrating leukocyte subset found in established tumors. Although phenotypic analysis demonstrated that ring cells shared characteristics with tumor-associated macrophages (TAM, morphological analysis revealed a neutrophil-like appearance as detected by cytospin and immunofluorescence microscopy analysis. The presence of distinct iNOS filled granule-like structures located next to the cell membrane suggested that iNOS was stored in pre-formed vesicles and available for rapid

  3. Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain.

    Science.gov (United States)

    Montoya, Julio Cesar; Fajardo, Dianora; Peña, Angela; Sánchez, Adalberto; Domínguez, Martha C; Satizábal, José María; García-Vallejo, Felipe

    2014-01-01

    The information of gene expression obtained from databases, have made possible the extraction and analysis of data related with several molecular processes involving not only in brain homeostasis but its disruption in some neuropathologies; principally in Down syndrome and the Alzheimer disease. To correlate the levels of transcription of 19 genes located in the Down Syndrome Critical Region (DSCR) with their expression in several substructures of normal human brain. There were obtained expression profiles of 19 DSCR genes in 42 brain substructures, from gene expression values available at the database of the human brain of the Brain Atlas of the Allen Institute for Brain Sciences", (http://human.brain-map.org/). The co-expression patterns of DSCR genes in brain were calculated by using multivariate statistical methods. Highest levels of gene expression were registered at caudate nucleus, nucleus accumbens and putamen among central areas of cerebral cortex. Increased expression levels of RCAN1 that encode by a protein involved in signal transduction process of the CNS were recorded for PCP4 that participates in the binding to calmodulin and TTC3; a protein that is associated with differentiation of neurons. That previously identified brain structures play a crucial role in the learning process, in different class of memory and in motor skills. The precise regulation of DSCR gene expression is crucial to maintain the brain homeostasis, especially in those areas with high levels of gene expression associated with a remarkable process of learning and cognition.

  4. Myoglobin Expression in Chelonia mydas Brain, Heart and Liver Tissues

    Directory of Open Access Journals (Sweden)

    RINI PUSPITANINGRUM

    2010-09-01

    Full Text Available An understanding of the underpinning physiology and biochemistry of animals is essential to properly understand the impact of anthropogenic changes and natural catastrophes upon the conservation of endangered species. An observation on the tissue location of the key respiratory protein, myoglobin, now opens up new opportunities for understanding how hypoxia tolerance impacts on diving lifestyle in turtles. The respiratory protein, myoglobin has functions other than oxygen binding which are involved in hypoxia tolerance, including metabolism of reactive oxygen species and of the vascular function by metabolism of nitric oxide. Our work aims to determine whether myoglobin expression in the green turtle exists in multiple non muscle tissues and to confirm the hypothesis that reptiles also have a distributed myoglobin expression which is linked to the hypoxia-tolerant trait. This initial work in turtle hatch Chelonia mydas confirms the presence of myoglobin transcriptin brain, heart and liver tissues. Furthermore, it will serve as a tool for completing the sequence and generating an in situ hybridization probe for verifying of cell location in expressing tissues.

  5. Myoglobin Expression in Chelonia mydas Brain, Heart and Liver Tissues

    Directory of Open Access Journals (Sweden)

    RINI PUSPITANINGRUM

    2010-09-01

    Full Text Available An understanding of the underpinning physiology and biochemistry of animals is essential to properly understand the impact of anthropogenic changes and natural catastrophes upon the conservation of endangered species. An observation on the tissue location of the key respiratory protein, myoglobin, now opens up new opportunities for understanding how hypoxia tolerance impacts on diving lifestyle in turtles. The respiratory protein, myoglobin has functions other than oxygen binding which are involved in hypoxia tolerance, including metabolism of reactive oxygen species and of the vascular function by metabolism of nitric oxide. Our work aims to determine whether myoglobin expression in the green turtle exists in multiple non muscle tissues and to confirm the hypothesis that reptiles also have a distributed myoglobin expression which is linked to the hypoxiatolerant trait. This initial work in turtle hatch Chelonia mydas confirms the presence of myoglobin transcriptin brain, heart and liver tissues. Furthermore, it will serve as a tool for completing the sequence and generating an in situ hybridization probe for verifying of cell location in expressing tissues.

  6. Expression of Nestin by Neural Cells in the Adult Rat and Human Brain

    OpenAIRE

    Hendrickson, Michael L.; Rao, Abigail J.; Demerdash, Omar N. A.; Kalil, Ronald E.

    2011-01-01

    Neurons and glial cells in the developing brain arise from neural progenitor cells (NPCs). Nestin, an intermediate filament protein, is thought to be expressed exclusively by NPCs in the normal brain, and is replaced by the expression of proteins specific for neurons or glia in differentiated cells. Nestin expressing NPCs are found in the adult brain in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus. While significant attention has b...

  7. Gender-specific gene expression in post-mortem human brain: localization to sex chromosomes.

    Science.gov (United States)

    Vawter, Marquis P; Evans, Simon; Choudary, Prabhakara; Tomita, Hiroaki; Meador-Woodruff, Jim; Molnar, Margherita; Li, Jun; Lopez, Juan F; Myers, Rick; Cox, David; Watson, Stanley J; Akil, Huda; Jones, Edward G; Bunney, William E

    2004-02-01

    Gender differences in brain development and in the prevalence of neuropsychiatric disorders such as depression have been reported. Gender differences in human brain might be related to patterns of gene expression. Microarray technology is one useful method for investigation of gene expression in brain. We investigated gene expression, cell types, and regional expression patterns of differentially expressed sex chromosome genes in brain. We profiled gene expression in male and female dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum using the Affymetrix oligonucleotide microarray platform. Differentially expressed genes between males and females on the Y chromosome (DBY, SMCY, UTY, RPS4Y, and USP9Y) and X chromosome (XIST) were confirmed using real-time PCR measurements. In situ hybridization confirmed the differential expression of gender-specific genes and neuronal expression of XIST, RPS4Y, SMCY, and UTY in three brain regions examined. The XIST gene, which silences gene expression on regions of the X chromosome, is expressed in a subset of neurons. Since a subset of neurons express gender-specific genes, neural subpopulations may exhibit a subtle sexual dimorphism at the level of differences in gene regulation and function. The distinctive pattern of neuronal expression of XIST, RPS4Y, SMCY, and UTY and other sex chromosome genes in neuronal subpopulations may possibly contribute to gender differences in prevalence noted for some neuropsychiatric disorders. Studies of the protein expression of these sex-chromosome-linked genes in brain tissue are required to address the functional consequences of the observed gene expression differences.

  8. Exploration and visualization of gene expression with neuroanatomy in the adult mouse brain

    Directory of Open Access Journals (Sweden)

    Pathak Sayan

    2008-03-01

    Full Text Available Abstract Background Spatially mapped large scale gene expression databases enable quantitative comparison of data measurements across genes, anatomy, and phenotype. In most ongoing efforts to study gene expression in the mammalian brain, significant resources are applied to the mapping and visualization of data. This paper describes the implementation and utility of Brain Explorer, a 3D visualization tool for studying in situ hybridization-based (ISH expression patterns in the Allen Brain Atlas, a genome-wide survey of 21,000 expression patterns in the C57BL6J adult mouse brain. Results Brain Explorer enables users to visualize gene expression data from the C57Bl/6J mouse brain in 3D at a resolution of 100 μm3, allowing co-display of several experiments as well as 179 reference neuro-anatomical structures. Brain Explorer also allows viewing of the original ISH images referenced from any point in a 3D data set. Anatomic and spatial homology searches can be performed from the application to find data sets with expression in specific structures and with similar expression patterns. This latter feature allows for anatomy independent queries and genome wide expression correlation studies. Conclusion These tools offer convenient access to detailed expression information in the adult mouse brain and the ability to perform data mining and visualization of gene expression and neuroanatomy in an integrated manner.

  9. Lombalgia em eqüinos

    Directory of Open Access Journals (Sweden)

    Ana Liz Garcia Alves

    2007-06-01

    Full Text Available As lombalgias, sejam elas de origem primária ou secundária, são uma causa importante para a queda de desempenho atlético em eqüinos, mas o tamanho e a biomecânica complexa dificultam o diagnóstico e tratamento desta enfermidade. Sendo assim, o conhecimento da anatomia desta região é de grande importância para a semiologia toracolombar. O diagnóstico das lombalgias se faz por meio do exame físico e dos exames complementares, representados pelos métodos de diagnóstico por imagem, tais como a radiografia, a ultra-sonografia e a termografia. As principais afecções causadoras das lombalgias nos eqüinos são o contato entre processos espinhosos, a desmite supraespinhosa, a osteoartrite dos processos articulares e lesões dos corpos e discos vertebrais. Os principais tratamentos utilizados para estas lesões são os antiinflamatórios não esteroidais, infiltrações locais, acupuntura, fisioterapia, manejo do treinamento e cirurgia.

  10. Broad integration of expression maps and co-expression networks compassing novel gene functions in the brain.

    Science.gov (United States)

    Okamura-Oho, Yuko; Shimokawa, Kazuro; Nishimura, Masaomi; Takemoto, Satoko; Sato, Akira; Furuichi, Teiichi; Yokota, Hideo

    2014-11-10

    Using a recently invented technique for gene expression mapping in the whole-anatomy context, termed transcriptome tomography, we have generated a dataset of 36,000 maps of overall gene expression in the adult-mouse brain. Here, using an informatics approach, we identified a broad co-expression network that follows an inverse power law and is rich in functional interaction and gene-ontology terms. Our framework for the integrated analysis of expression maps and graphs of co-expression networks revealed that groups of combinatorially expressed genes, which regulate cell differentiation during development, were present in the adult brain and each of these groups was associated with a discrete cell types. These groups included non-coding genes of unknown function. We found that these genes specifically linked developmentally conserved groups in the network. A previously unrecognized robust expression pattern covering the whole brain was related to the molecular anatomy of key biological processes occurring in particular areas.

  11. Brain Activity while Reading Sentences with Kanji Characters Expressing Emotions

    Science.gov (United States)

    Yuasa, Masahide; Saito, Keiichi; Mukawa, Naoki

    In this paper, we describe the brain activity associated with kanji characters expressing emotion, which are places at the end of a sentence. Japanese people use a special kanji character in brackets at the end of sentences in text messages such as those sent through e-mail and messenger tools. Such kanji characters plays a role to expresses the sender's emotion (such as fun, laughter, sadness, tears), like emoticons. It is a very simple and effective way to convey the senders' emotions and his/her thoughts to the receiver. In this research, we investigate the effects of emotional kanji characters by using an fMRI study. The experimental results show that both the right and left inferior frontal gyrus, which have been implicated on verbal and nonverbal information, were activated. We found that we detect a sentence with an emotional kanji character as the verbal and nonverval information, and a sentence with emotional kanji characters enrich communication between the sender and the reciever.

  12. Income inequality, gene expression, and brain maturation during adolescence.

    Science.gov (United States)

    Parker, Nadine; Wong, Angelita Pui-Yee; Leonard, Gabriel; Perron, Michel; Pike, Bruce; Richer, Louis; Veillette, Suzanne; Pausova, Zdenka; Paus, Tomas

    2017-08-07

    Income inequality is associated with poor health and social outcomes. Negative social comparisons and competition may involve the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in underlying some of these complex inter-relationships. Here we investigate brain maturation, indexed by age-related decreases in cortical thickness, in adolescents living in neighborhoods with differing levels of income inequality and household income. We examine whether inter-regional variations relate to those in glucocorticoid receptor (HPA) and androgen receptor (HPG) gene expression. For each sex, we used a median split of income inequality and household income (income-to-needs ratio) to create four subgroups. In female adolescents, the high-inequality low-income group displayed the greatest age-related decreases in cortical thickness. In this group, expression of glucocorticoid and androgen receptor genes explained the most variance in these age-related decreases in thickness across the cortex. We speculate that female adolescents living in high-inequality neighborhoods and low-income households may experience greater HPA and HPG activity, leading to steeper decreases in cortical thickness with age.

  13. Global gene expression profiling of healthy human brain and its application in studying neurological disorders.

    Science.gov (United States)

    Negi, Simarjeet K; Guda, Chittibabu

    2017-04-18

    Brain function is governed by precise regulation of gene expression across its anatomically distinct structures; however, the expression patterns of genes across hundreds of brain structures are not clearly understood. Here, we describe a gene expression model, which is representative of the healthy human brain transcriptome by using data from the Allen Brain Atlas. Our in-depth gene expression profiling revealed that 84% of genes are expressed in at least one of the 190 brain structures studied. Hierarchical clustering based on gene expression profiles delineated brain regions into structurally tiered spatial groups and we observed striking enrichment for region-specific processes. Further, weighted co-expression network analysis identified 19 robust modules of highly correlated genes enriched with functional associations for neurogenesis, dopamine signaling, immune regulation and behavior. Also, structural distribution maps of major neurotransmission systems in the brain were generated. Finally, we developed a supervised classification model, which achieved 84% and 81% accuracies for predicting autism- and Parkinson's-implicated genes, respectively, using our expression model as a baseline. This study represents the first use of global gene expression profiling from healthy human brain to develop a disease gene prediction model and this generic methodology can be applied to study any neurological disorder.

  14. Rate of evolution in brain-expressed genes in humans and other primates.

    Directory of Open Access Journals (Sweden)

    Hurng-Yi Wang

    2007-02-01

    Full Text Available Brain-expressed genes are known to evolve slowly in mammals. Nevertheless, since brains of higher primates have evolved rapidly, one might expect acceleration in DNA sequence evolution in their brain-expressed genes. In this study, we carried out full-length cDNA sequencing on the brain transcriptome of an Old World monkey (OWM and then conducted three-way comparisons among (i mouse, OWM, and human, and (ii OWM, chimpanzee, and human. Although brain-expressed genes indeed appear to evolve more rapidly in species with more advanced brains (apes > OWM > mouse, a similar lineage effect is observable for most other genes. The broad inclusion of genes in the reference set to represent the genomic average is therefore critical to this type of analysis. Calibrated against the genomic average, the rate of evolution among brain-expressed genes is probably lower (or at most equal in humans than in chimpanzee and OWM. Interestingly, the trend of slow evolution in coding sequence is no less pronounced among brain-specific genes, vis-à-vis brain-expressed genes in general. The human brain may thus differ from those of our close relatives in two opposite directions: (i faster evolution in gene expression, and (ii a likely slowdown in the evolution of protein sequences. Possible explanations and hypotheses are discussed.

  15. Central administration of insulin-like growth factor-I decreases depressive-like behavior and brain cytokine expression in mice

    Directory of Open Access Journals (Sweden)

    Dantzer Robert

    2011-02-01

    Full Text Available Abstract Exogenous administration of insulin-like growth factor (IGF-I has anti-depressant properties in rodent models of depression. However, nothing is known about the anti-depressant properties of IGF-I during inflammation, nor have mechanisms by which IGF-I alters behavior following activation of the innate immune system been clarified. We hypothesized that central IGF-I would diminish depressive-like behavior on a background of an inflammatory response and that it would do so by inducing expression of the brain-derived neurotrophic factor (BDNF while decreasing pro-inflammatory cytokine expression in the brain. IGF-I (1,000 ng was administered intracerebroventricularly (i.c.v. to CD-1 mice. Mice were subsequently given lipopolysaccharide i.c.v. (LPS, 10 ng. Sickness and depressive-like behaviors were assessed followed by analysis of brain steady state mRNA expression. Central LPS elicited typical transient signs of sickness of mice, including body weight loss, reduced feed intake and decreased social exploration toward a novel juvenile. Similarly, LPS increased time of immobility in the tail suspension test (TST. Pretreatment with IGF-I or antidepressants significantly decreased duration of immobility in the TST in both the absence and presence of LPS. To elucidate the mechanisms underlying the anti-depressant action of IGF-I, we quantified steady-state mRNA expression of inflammatory mediators in whole brain using real-time RT-PCR. LPS increased, whereas IGF-I decreased, expression of inflammatory markers interleukin-1ß (IL-1ß, tumor necrosis factor-(TNFα, inducible nitric oxide synthase (iNOS and glial fibrillary acidic protein (GFAP. Moreover, IGF-I increased expression of BDNF. These results indicate that IGF-I down regulates glial activation and induces expression of an endogenous growth factor that shares anti-depressant activity. These actions of IGF-I parallel its ability to diminish depressive-like behavior.

  16. The role of iNOS and PHOX in periapical bone resorption.

    Science.gov (United States)

    Silva, M J B; Sousa, L M A; Lara, V P L; Cardoso, F P; Júnior, G M; Totola, A H; Caliari, M V; Romero, O B; Silva, G A B; Ribeiro-Sobrinho, A P; Vieira, L Q

    2011-04-01

    Nitric oxide (NO) and reactive oxygen species (ROS) are key molecules in resistance to pathogens. Little is known about their role in pathogenesis of periapical lesions. To address this issue, we induced periapical lesions in mice lacking nitric oxide synthase (iNOS(-/-)) or phagocyte oxidase (PHOX(-/-)). iNOS(-/-) mice expressed higher levels of IL-1β, TNF-α, RANK, RANKL, and MCP-1 than C57BL/6 and PHOX(-/-). Apical thickening of the periodontal ligament was also greater in iNOS(-/-) compared with other groups. Interestingly, ROS production did not interfere in periapical lesion progression, but seemed to be essential for the appearance of multinucleated TRAP-positive cells. Thus, periapical lesion progression in iNOS(-/-) was associated with an imbalance of pro-inflammatory cytokines (IL-1β and TNF-α), bone-resorptive modulators (RANK and RANKL), and MCP-1. We conclude that NO, but not ROS, controls progression of bone resorption in a murine experimental model of apical periodontitis.

  17. HIF‑1 signaling pathway involving iNOS, COX‑2 and caspase‑9 mediates the neuroprotection provided by erythropoietin in the retina of chronic ocular hypertension rats.

    Science.gov (United States)

    Gui, Dongmei; Li, Yanfeng; Chen, Xiaolong; Gao, Dianwen; Yang, Yang; Li, Xun

    2015-02-01

    This study aimed to investigate the impacts of erythropoietin (EPO) on the electroretinogram b‑wave (ERG‑b), and on the mRNA and protein expression levels of hypoxia‑inducible factor‑1α (HIF‑1α), inducible nitric oxide synthase (iNOS), cyclooxygenase‑2 (COX‑2) and caspase‑9 in chronic ocular hypertension rats. Episcleral vein cauterization (EVC) was used to establish the chronic ocular hypertension rat model based on the intraocular pressure (IOP) value. ERG‑b and mRNA and protein expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9 in normal, EVC‑treated and EVC combined with EPO (EVC+EPO)‑treated rats were measured by electroretinography, RT‑PCR and western blotting, respectively. Moreover, the correlations of HIF‑1α with IOP, ERG‑b, iNOS, COX‑2 and caspase‑9 were evaluated. The mRNA and protein expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9 in EVC‑treated rats were increased significantly compared with normal rats. The peak expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9 were respectively obtained 7, 7, 7 and 14 days postoperatively. Compared with EVC‑treated rats, EPO administration weakened the mRNA and protein expression levels of HIF‑1α, iNOS, COX‑2 and caspase‑9. The mRNA expression level of HIF‑1α demonstrated a significant positive correlation with IOP and ERG‑b. HIF‑1α was positively correlated with iNOS, COX‑2 and caspase‑9 at the mRNA and protein levels. The protective effect of EPO on the retina of chronic ocular hypertension rats may be mediated by the HIF‑1 signaling pathway involving iNOS, COX‑2 and caspase‑9.

  18. [Robo1 expression in non-small cell lung cancer and its brain metastasis].

    Science.gov (United States)

    Li, Xiao-xia; Jin, Ling; Sun, Zeng-feng; Gu, Feng; Li, Wen-liang; Ma, Yong-jie

    2013-03-01

    To detect the expression of Robo1 in lung cancer tissues, adjacent non-cancerous tissues as well as lung cancer brain metastasis, and explore the correlation of Robo1 expression to lung cancer brain metastasis. SP (streptavidin-peroxidase) staining method was used to examine the Robo1 expression in specimens from 80 cases of NSCLC, 52 cases of adjacent non-cancerous tissues and 72 cases of lung cancer with single brain metastasis (without metastasis in other organs). The Robo1 expression was further examined in 17 self control cases with lung cancer tissues and their brain metastasis tissues. The results were assessed by Kaplan-Meier analysis and log-rank test. The positive expression rate of Robo1 among adjacent non-cancerous tissues, lung cancers tissues and the lung cancer brain metastasis tissues were 1.9% (1/52), 13.8% (11/80) and 40.3% (29/72), respectively, and significant differences were detected among them (P Robo1 in lung cancer tissue and their brain metastasis tissues were 17.6% and 64.7%, respectively, with a significant difference between them (P cancer brain metastasis, the median survival time of cases with positive Robo1 expression was 10 months, significantly shorter than that of cases with negative expression of Robo1 (17 months, P Robo1 was increased in sequence from the lowest in adjacent non-cancerous tissues, intermediate in the lung cancer tissues to highest in the lung cancer brain metastasis tissues. The expression of Robo1 in lung cancer brain metastasis is negatively correlated with the prognosis of patients with lung cancer brain metastasis. Robo1 may promote the genesis and progression of lung cancer and lung cancer brain metastasis as a cancer-promoting oncogene.

  19. Expression of the Otx2 homeobox gene in the developing mammalian brain: embryonic and adult expression in the pineal gland

    DEFF Research Database (Denmark)

    Rath, Martin F; Muñoz, Estela; Ganguly, Surajit

    2006-01-01

    that the level of Otx2 mRNA appears to be independent of the photoneural input to the gland. Our results are consistent with the view that pineal expression of Otx2 is required for development and we hypothesize that it plays a role in the adult in controlling the expression of the cluster of genes associated......Otx2 is a vertebrate homeobox gene, which has been found to be essential for the development of rostral brain regions and appears to play a role in the development of retinal photoreceptor cells and pinealocytes. In this study, the temporal expression pattern of Otx2 was revealed in the rat brain......, with special emphasis on the pineal gland throughout late embryonic and postnatal stages. Widespread high expression of Otx2 in the embryonic brain becomes progressively restricted in the adult to the pineal gland. Crx (cone-rod homeobox), a downstream target gene of Otx2, showed a pineal expression pattern...

  20. Aerobic glycolysis in the human brain is associated with development and neotenous gene expression

    Science.gov (United States)

    Goyal, Manu S.; Hawrylycz, Michael; Miller, Jeremy A.; Snyder, Abraham Z.; Raichle, Marcus E.

    2015-01-01

    SUMMARY Aerobic glycolysis (AG), i.e., non-oxidative metabolism of glucose despite the presence of abundant oxygen, accounts for 10–12% of glucose used by the adult human brain. AG varies regionally in the resting state. Brain AG may support synaptic growth and remodeling; however, data supporting this hypothesis are sparse. Here, we report on investigations on the role of AG in the human brain. Meta-analysis of prior brain glucose and oxygen metabolism studies demonstrates that AG increases during childhood, precisely when synaptic growth rates are highest. In resting adult humans, AG correlates with persistence of gene expression typical of infancy (transcriptional neoteny). In brain regions with the highest AG, we find increased gene expression related to synapse formation and growth. In contrast, regions high in oxidative glucose metabolism express genes related to mitochondria and synaptic transmission. Our results suggest that brain AG supports developmental processes, particularly those required for synapse formation and growth. PMID:24411938

  1. Intracerebral transplants of primary muscle cells: a potential 'platform' for transgene expression in the brain

    Science.gov (United States)

    Jiao, S.; Schultz, E.; Wolff, J. A.

    1992-01-01

    After the transplantation of rat primary muscle cells into the caudate or cortex of recipient rats, the muscle cells were able to persist for at least 6 months. Muscle cells transfected with expression plasmids prior to transplantation were able to express reporter genes in the brains for at least 2 months. These results suggest that muscle cells might be a useful 'platform' for transgene expression in the brain.

  2. Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex.

    Science.gov (United States)

    Somani, Sukrut; Robb, Gillian; Pickard, Benjamin S; Dufès, Christine

    2015-11-10

    The possibility of using gene therapy for the treatment of brain diseases such as brain cancer, Alzheimer's and Parkinson's diseases, is currently hampered by the lack of gene delivery systems able to cross the blood-brain barrier and deliver DNA to the brain following intravenous administration. On the basis that lactoferrin can effectively reach the brain by using specific receptors for crossing the blood-brain barrier, we propose to investigate if a lactoferrin-bearing generation 3-diaminobutyric polypropylenimine (DAB) dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration. In this work, we demonstrated that the conjugation of lactoferrin to the dendrimer led to an enhanced DNA uptake by 2.1-fold in bEnd.3 murine brain capillary endothelial cells compared to the unmodified dendriplex in vitro. In vivo, the intravenous administration of lactoferrin-bearing DAB dendriplex resulted in a significantly increased gene expression in the brain, by more than 6.4-fold compared to that of DAB dendriplex, while decreasing gene expression in the lung and the kidneys. Gene expression in the brain was significantly higher than in any other major organs of the body. Lactoferrin-bearing generation 3 polypropylenimine dendrimer is therefore a highly promising delivery system for systemic gene delivery to the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. brain-coX: investigating and visualising gene co-expression in seven human brain transcriptomic datasets.

    Science.gov (United States)

    Freytag, Saskia; Burgess, Rosemary; Oliver, Karen L; Bahlo, Melanie

    2017-06-08

    The pathogenesis of neurological and mental health disorders often involves multiple genes, complex interactions, as well as brain- and development-specific biological mechanisms. These characteristics make identification of disease genes for such disorders challenging, as conventional prioritisation tools are not specifically tailored to deal with the complexity of the human brain. Thus, we developed a novel web-application-brain-coX-that offers gene prioritisation with accompanying visualisations based on seven gene expression datasets in the post-mortem human brain, the largest such resource ever assembled. We tested whether our tool can correctly prioritise known genes from 37 brain-specific KEGG pathways and 17 psychiatric conditions. We achieved average sensitivity of nearly 50%, at the same time reaching a specificity of approximately 75%. We also compared brain-coX's performance to that of its main competitors, Endeavour and ToppGene, focusing on the ability to discover novel associations. Using a subset of the curated SFARI autism gene collection we show that brain-coX's prioritisations are most similar to SFARI's own curated gene classifications. brain-coX is the first prioritisation and visualisation web-tool targeted to the human brain and can be freely accessed via http://shiny.bioinf.wehi.edu.au/freytag.s/ .

  4. Analysis of spatial-temporal gene expression patterns reveals dynamics and regionalization in developing mouse brain.

    Science.gov (United States)

    Chou, Shen-Ju; Wang, Chindi; Sintupisut, Nardnisa; Niou, Zhen-Xian; Lin, Chih-Hsu; Li, Ker-Chau; Yeang, Chen-Hsiang

    2016-01-20

    Allen Brain Atlas (ABA) provides a valuable resource of spatial/temporal gene expressions in mammalian brains. Despite rich information extracted from this database, current analyses suffer from several limitations. First, most studies are either gene-centric or region-centric, thus are inadequate to capture the superposition of multiple spatial-temporal patterns. Second, standard tools of expression analysis such as matrix factorization can capture those patterns but do not explicitly incorporate spatial dependency. To overcome those limitations, we proposed a computational method to detect recurrent patterns in the spatial-temporal gene expression data of developing mouse brains. We demonstrated that regional distinction in brain development could be revealed by localized gene expression patterns. The patterns expressed in the forebrain, medullary and pontomedullary, and basal ganglia are enriched with genes involved in forebrain development, locomotory behavior, and dopamine metabolism respectively. In addition, the timing of global gene expression patterns reflects the general trends of molecular events in mouse brain development. Furthermore, we validated functional implications of the inferred patterns by showing genes sharing similar spatial-temporal expression patterns with Lhx2 exhibited differential expression in the embryonic forebrains of Lhx2 mutant mice. These analysis outcomes confirm the utility of recurrent expression patterns in studying brain development.

  5. [Robo1 expression in breast cancer and its relationship to brain metastasis].

    Science.gov (United States)

    Wang, Jing; Wang, Le; Liu, Fang-fang; Ma, Yong-jie; Fu, Li; Li, Wen-liang; Gu, Feng

    2011-06-01

    To detect the expression of Robo1 in different breast tumors and its association with the breast cancer brain metastasis. Labelled streptavidin-biotin (LSAB) staining was used to examine the Robo1 expression in specimens from 24 cases of invasive ductal carcinoma (IDC) with brain metastasis, 71 cases of IDC without brain metastasis, 22 cases of ductal carcinoma in situ (DCIS) and 23 cases of fibroadenoma. The expression pattern of Robo1 in DCIS (59.1%) and IDC (45.3%) was significantly lower than that in adenofibroma (87.0%, P Robo1 in IDC with brain metastasis (12.5%) was significantly lower than that in IDC without brain metastasis (56.3%, P Robo1 was much higher in more than 50 year-old-group (57.8%) than that in less than 50 year-old-group (34.0%) of IDC patients. The overall survival time in patients with the Robo1 negative expression was significantly shorter than those with positive expression (P Robo1 expression and the tumor size, lymph node metastasis, pathologic stage, histological grade and clinical stage (P > 0.05). The Robo1 expression correlates negatively with IDC brain metastasis, and correlates positively with the age and prognosis of IDC patients. Robo1 may be applied as a marker in evaluation of the IDC prognosis and brain metastasis.

  6. Epigenetic control of vasopressin expression is maintained by steroid hormones in the adult male rat brain

    Science.gov (United States)

    Auger, Catherine J.; Coss, Dylan; Auger, Anthony P.; Forbes-Lorman, Robin M.

    2011-01-01

    Although some DNA methylation patterns are altered by steroid hormone exposure in the developing brain, less is known about how changes in steroid hormone levels influence DNA methylation patterns in the adult brain. Steroid hormones act in the adult brain to regulate gene expression. Specifically, the expression of the socially relevant peptide vasopressin (AVP) within the bed nucleus of the stria terminalis (BST) of adult brain is dependent upon testosterone exposure. Castration dramatically reduces and testosterone replacement restores AVP expression within the BST. As decreases in mRNA expression are associated with increases in DNA promoter methylation, we explored the hypothesis that AVP expression in the adult brain is maintained through sustained epigenetic modifications of the AVP gene promoter. We find that castration of adult male rats resulted in decreased AVP mRNA expression and increased methylation of specific CpG sites within the AVP promoter in the BST. Similarly, castration significantly increased estrogen receptor α (ERα) mRNA expression and decreased ERα promoter methylation within the BST. These changes were prevented by testosterone replacement. This suggests that the DNA promoter methylation status of some steroid responsive genes in the adult brain is actively maintained by the presence of circulating steroid hormones. The maintenance of methylated or demethylated states of some genes in the adult brain by the presence of steroid hormones may play a role in the homeostatic regulation of behaviorally relevant systems. PMID:21368111

  7. Dominant expression of angiogenin in NeuN positive cells in the focal ischemic rat brain.

    Science.gov (United States)

    Huang, Li; Huang, Yining; Guo, Huailian

    2009-10-15

    Angiogenin (ANG) is a potent angiogenic factor. The purposes of this study were to observe the change of the expression level of ANG and to identify the cell types that express ANG in the focal ischemic rat brain. The rat brain ischemia-reperfusion model was produced by a 2 h occlusion of the left middle cerebral artery with a nylon thread followed by reperfusion for 1 day, 3 days, 7 days or 14 days. The expression levels of ANG in the rat brain at each time points were determined by western blotting. The co-staining of ANG with NeuN was observed using double immunofluorescent labeling combined with confocal laser scanning microscope. We found that the expression level of ANG increased significantly in the rat brain 1 day, 3 days, and 7 days after ischemia (Pbrain after ischemia. The upregulated ANG was mostly expressed by neurons.

  8. Brain death induces renal expression of heme oxygenase-1 and heat shock protein 70

    Directory of Open Access Journals (Sweden)

    van Dullemen Leon FA

    2013-01-01

    Full Text Available Abstract Background Kidneys derived from brain dead donors have lower graft survival and higher graft-function loss compared to their living donor counterpart. Heat Shock Proteins (HSP are a large family of stress proteins involved in maintaining cell homeostasis. We studied the role of stress-inducible genes Heme Oxygenase-1 (HO-1, HSP27, HSP40, and HSP70 in the kidney following a 4 hour period of brain death. Methods Brain death was induced in rats (n=6 by inflating a balloon catheter in the epidural space. Kidneys were analysed for HSPs using RT-PCR, Western blotting, and immunohistochemistry. Results RT-PCR data showed a significant increase in gene expression for HO-1 and HSP70 in kidneys of brain dead rats. Western blotting revealed a massive increase in HO-1 protein in brain dead rat kidneys. Immunohistochemistry confirmed these findings, showing extensive HO-1 protein expression in the renal cortical tubules of brain dead rats. HSP70 protein was predominantly increased in renal distal tubules of brain dead rats treated for hypotension. Conclusion Renal stress caused by brain death induces expression of the cytoprotective genes HO-1 and HSP70, but not of HSP27 and HSP40. The upregulation of these cytoprotective genes indicate that renal damage occurs during brain death, and could be part of a protective or recuperative mechanism induced by brain death-associated stress.

  9. Cholesterogenic genes expression in brain and liver of ganglioside-deficient mice.

    Science.gov (United States)

    Mlinac, Kristina; Fon Tacer, Klementina; Heffer, Marija; Rozman, Damjana; Bognar, Svjetlana Kalanj

    2012-10-01

    The aim of this study was to determine the effect of changed ganglioside profile on transcription of selected genes involved in cholesterol homeostasis. For that purpose, the expression of 11 genes related to cholesterol synthesis, regulation, and cholesterol transport was investigated in selected brain regions (frontal cortex, hippocampus, brain stem, cerebellum) and liver of St8sia1 knockout (KO) mice characterized by deficient synthesis of b- and c-series gangliosides and accumulation of a-series gangliosides. The expression of majority of the analyzed genes, as determined using quantitative real time PCR, was slightly higher in St8sia1 KO compared to wild-type (wt) controls. More prominent changes were observed in Hmgr, Cyp51, and Cyp46 expression in brain (hippocampus and brain stem) and Srebp1a, Insig2a, and Ldlr in liver. In addition, the expression of master transcriptional regulators, Srebp1a, Srebp1c, and Insig2a, as well as transporters Ldlr and Vldlr differed between liver and brain, and within brain regions in wt animals. Cyp46 expression was expectedly brain-specific, with brain region difference in both wt and St8sia1 KO. The established change in transcriptome of cholesterogenic genes is associated to specific alteration of ganglioside composition which indicates relationship between gangliosides and regulation of cholesterol metabolism.

  10. Expression of CD44 splice variants in human primary brain tumors

    NARCIS (Netherlands)

    Kaaijk, P.; Troost, D.; Morsink, F.; Keehnen, R. M.; Leenstra, S.; Bosch, D. A.; Pals, S. T.

    1995-01-01

    Expression of CD44, particularly of certain splice variants, has been linked to tumor progression and metastatic potential in a number of different animal and human cancers. Although differential expression of CD44 standard epitopes (CD44s) in human brain tumors has been reported, the expression of

  11. Transmission of facial expressions of emotion co-evolved with their efficient decoding in the brain: behavioral and brain evidence.

    Science.gov (United States)

    Schyns, Philippe G; Petro, Lucy S; Smith, Marie L

    2009-05-20

    Competent social organisms will read the social signals of their peers. In primates, the face has evolved to transmit the organism's internal emotional state. Adaptive action suggests that the brain of the receiver has co-evolved to efficiently decode expression signals. Here, we review and integrate the evidence for this hypothesis. With a computational approach, we co-examined facial expressions as signals for data transmission and the brain as receiver and decoder of these signals. First, we show in a model observer that facial expressions form a lowly correlated signal set. Second, using time-resolved EEG data, we show how the brain uses spatial frequency information impinging on the retina to decorrelate expression categories. Between 140 to 200 ms following stimulus onset, independently in the left and right hemispheres, an information processing mechanism starts locally with encoding the eye, irrespective of expression, followed by a zooming out to processing the entire face, followed by a zooming back in to diagnostic features (e.g. the opened eyes in "fear", the mouth in "happy"). A model categorizer demonstrates that at 200 ms, the left and right brain have represented enough information to predict behavioral categorization performance.

  12. Differential Expression of Sirtuin Family Members in the Developing, Adult, and Aged Rat Brain

    Directory of Open Access Journals (Sweden)

    Elena eSidorova-Darmos

    2014-12-01

    Full Text Available The sirtuins are NAD+-dependent protein deacetylases and/or ADP-ribosyltransferases that play roles in metabolic homeostasis, stress response and potentially aging. This enzyme family resides in different subcellular compartments, and acts on a number of different targets in the nucleus, cytoplasm and in the mitochondria. Despite their recognized ability to regulate metabolic processes, the roles played by specific sirtuins in the brain - the most energy demanding tissue in the body - remains less well investigated and understood. In the present study, we examined the regional mRNA and protein expression patterns of individual sirtuin family members in the developing, adult, and aged rat brain. Our results show that while each sirtuin is expressed in the brain at each of these different stages, they display unique spatial and temporal expression patterns within the brain. Further, for specific members of the family, the protein expression profile did not coincide with their respective mRNA expression profile. Moreover, using primary cultures enriched for neurons and astrocytes respectively, we found that specific sirtuin members display preferential neural lineage expression. Collectively, these results provide the first composite illustration that sirtuin family members display differential expression patterns in the brain, and provide evidence that specific sirtuins could potentially be targeted to achieve cell-type selective effects within the brain.

  13. [Construction and expression of recombinant adeno-associated virus expressing brain-derived neurotrophic factor].

    Science.gov (United States)

    Li, Huiming; Qiu, Wei; Wang, Feng; Wei, Fang; Chen, Xiafang; Wu, Xiaobing; Huang, Qian

    2008-02-01

    A fusion gene called Ig-BDNF, in which brain-derived neurotrophic factor cDNA fused to the 3' end of signal peptide of Ig coding sequence, was constructed by PCR, digested and subcloned into shuttle plasmid pSNAV to obtain a recombinant plasmid pSNAV-Ig-BDNF. Then the plasmid encoding fusion protein was transfected into 293 cell lines and the stably transfected clones were selected with neomycin. AAV1 containing Ig-BDNF fusion gene vectors were obtained by super-infection by Herpes virus. The resultant adeno-associated virus vectors AAV-Ig-BDNF were confirmed by PCR, Western blotting and a sandwich enzyme-linked immunosorbent assay (ELISA) after infection of 293 cell lines. The results indicated that AAV-Ig-BDNF contained the target gene, and infected cells and produced the fusion protein into the supernatant. The content of BDNF in medium per 5x104 cells over a 24 h incubation period reached 1000 pg/mL. With the help of non-replicative adenovirus during AAV-Ig-BDNF infection, the expression of BDNF increased 7-8 fold, and the enhancement of BDNF gene expression was observed in a concentration-dependent manner. These results suggested that a functional AAV-Ig-BDNF was successfully constructed and it offers basis for further study for gene therapy of neural degeneration diseases.

  14. Lymphatic endothelial cells efferent to inflamed joints produce iNOS and inhibit lymphatic vessel contraction and drainage in TNF-induced arthritis in mice.

    Science.gov (United States)

    Liang, Qianqian; Ju, Yawen; Chen, Yan; Wang, Wensheng; Li, Jinlong; Zhang, Li; Xu, Hao; Wood, Ronald W; Schwarz, Edward M; Boyce, Brendan F; Wang, Yongjun; Xing, Lianping

    2016-03-12

    In this study, we sought to determine the cellular source of inducible nitric oxide synthase (iNOS) induced in lymphatic endothelial cells (LECs) in response to tumor necrosis factor (TNF), the effects of iNOS on lymphatic smooth muscle cell (LSMC) function and on the development of arthritis in TNF-transgenic (TNF-Tg) mice, and whether iNOS inhibitors improve lymphatic function and reduce joint destruction in inflammatory erosive arthritis. We used quantitative polymerase chain reactions, immunohistochemistry, histology, and near-infrared imaging to examine (1) iNOS expression in podoplanin + LECs and lymphatic vessels from wild-type (WT) and TNF-Tg mice, (2) iNOS induction by TNF in WT LECs, (3) the effects of iNOS inhibitors on expression of functional muscle genes in LSMCs, and (4) the effects of iNOS inhibitors on lymphatic vessel contraction and drainage, as well as the severity of arthritis, in TNF-Tg mice. LECs from TNF-Tg mice had eight fold higher iNOS messenger RNA levels than WT cells, and iNOS expression was confirmed immunohistochemically in podoplanin + LECs in lymphatic vessels from inflamed joints. TNF (0.1 ng/ml) increased iNOS levels 40-fold in LECs. LSMCs cocultured with LECs pretreated with TNF had reduced expression of functional muscle genes. This reduction was prevented by ferulic acid, which blocked nitric oxide production. Local injection of L-N(6)-(1-iminoethyl)lysine 5-tetrazole-amide into inflamed paws of TNF-Tg mice resulted in recovery of lymphatic vessel contractions and drainage. Treatment of TNF-Tg mice with ferulic acid reduced synovial inflammation as well as cartilage and bone erosion, and it also restored lymphatic contraction and drainage. iNOS is produced primarily by LECs in lymphatic vessel efferent from inflamed joints of TNF-Tg mice in response to TNF and inhibits LSMC contraction and lymph drainage. Ferulic acid represents a potential new therapy to restore lymphatic function and thus improve inflammatory

  15. Expression of nestin by neural cells in the adult rat and human brain.

    Science.gov (United States)

    Hendrickson, Michael L; Rao, Abigail J; Demerdash, Omar N A; Kalil, Ronald E

    2011-04-07

    Neurons and glial cells in the developing brain arise from neural progenitor cells (NPCs). Nestin, an intermediate filament protein, is thought to be expressed exclusively by NPCs in the normal brain, and is replaced by the expression of proteins specific for neurons or glia in differentiated cells. Nestin expressing NPCs are found in the adult brain in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus. While significant attention has been paid to studying NPCs in the SVZ and SGZ in the adult brain, relatively little attention has been paid to determining whether nestin-expressing neural cells (NECs) exist outside of the SVZ and SGZ. We therefore stained sections immunocytochemically from the adult rat and human brain for NECs, observed four distinct classes of these cells, and present here the first comprehensive report on these cells. Class I cells are among the smallest neural cells in the brain and are widely distributed. Class II cells are located in the walls of the aqueduct and third ventricle. Class IV cells are found throughout the forebrain and typically reside immediately adjacent to a neuron. Class III cells are observed only in the basal forebrain and closely related areas such as the hippocampus and corpus striatum. Class III cells resemble neurons structurally and co-express markers associated exclusively with neurons. Cell proliferation experiments demonstrate that Class III cells are not recently born. Instead, these cells appear to be mature neurons in the adult brain that express nestin. Neurons that express nestin are not supposed to exist in the brain at any stage of development. That these unique neurons are found only in brain regions involved in higher order cognitive function suggests that they may be remodeling their cytoskeleton in supporting the neural plasticity required for these functions.

  16. Analysis of Gene Expression Profiles in the Human Brain Stem, Cerebellum and Cerebral Cortex.

    Directory of Open Access Journals (Sweden)

    Lei Chen

    Full Text Available The human brain is one of the most mysterious tissues in the body. Our knowledge of the human brain is limited due to the complexity of its structure and the microscopic nature of connections between brain regions and other tissues in the body. In this study, we analyzed the gene expression profiles of three brain regions-the brain stem, cerebellum and cerebral cortex-to identify genes that are differentially expressed among these different brain regions in humans and to obtain a list of robust, region-specific, differentially expressed genes by comparing the expression signatures from different individuals. Feature selection methods, specifically minimum redundancy maximum relevance and incremental feature selection, were employed to analyze the gene expression profiles. Sequential minimal optimization, a machine-learning algorithm, was employed to examine the utility of selected genes. We also performed a literature search, and we discuss the experimental evidence for the important physiological functions of several highly ranked genes, including NR2E1, DAO, and LRRC7, and we give our analyses on a gene (TFAP2B that have not been investigated or experimentally validated. As a whole, the results of our study will improve our ability to predict and understand genes related to brain regionalization and function.

  17. Comparison of regional gene expression differences in the brains of the domestic dog and human

    OpenAIRE

    Kennerly Erin; Thomson Susanne; Olby Natasha; Breen Matthew; Gibson Greg

    2004-01-01

    Abstract Comparison of the expression profiles of 2,721 genes in the cerebellum, cortex and pituitary gland of three American Staffordshire terriers, one beagle and one fox hound revealed regional expression differences in the brain but failed to reveal marked differences among breeds, or even individual dogs. Approximately 85 per cent (42 of 49 orthologue comparisons) of the regional differences in the dog are similar to those that differentiate the analogous human brain regions. A smaller p...

  18. Analysis of spatial-temporal gene expression patterns reveals dynamics and regionalization in developing mouse brain

    OpenAIRE

    Shen-Ju Chou; Chindi Wang; Nardnisa Sintupisut; Zhen-Xian Niou; Chih-Hsu Lin; Ker-Chau Li; Chen-Hsiang Yeang

    2016-01-01

    Allen Brain Atlas (ABA) provides a valuable resource of spatial/temporal gene expressions in mammalian brains. Despite rich information extracted from this database, current analyses suffer from several limitations. First, most studies are either gene-centric or region-centric, thus are inadequate to capture the superposition of multiple spatial-temporal patterns. Second, standard tools of expression analysis such as matrix factorization can capture those patterns but do not explicitly incorp...

  19. Fresh Frozen Plasma Modulates Brain Gene Expression in a Swine Model of Traumatic Brain Injury and Shock

    DEFF Research Database (Denmark)

    Sillesen, Martin; Bambakidis, Ted; Dekker, Simone E

    2017-01-01

    analysis revealed an upregulation of genes involved in metabolic and platelet signaling, as well as collagen formation and downregulation of inflammation. CONCLUSIONS: Fresh frozen plasma resuscitation in this model was associated with downregulation of inflammatory pathway genes and expression of gene...... clusters mapping to increased metabolic and platelet signaling, which, in turn, was reversely associated with brain swelling....

  20. A regulatory toolbox of MiniPromoters to drive selective expression in the brain

    Science.gov (United States)

    Portales-Casamar, Elodie; Swanson, Douglas J.; Liu, Li; de Leeuw, Charles N.; Banks, Kathleen G.; Ho Sui, Shannan J.; Fulton, Debra L.; Ali, Johar; Amirabbasi, Mahsa; Arenillas, David J.; Babyak, Nazar; Black, Sonia F.; Bonaguro, Russell J.; Brauer, Erich; Candido, Tara R.; Castellarin, Mauro; Chen, Jing; Chen, Ying; Cheng, Jason C. Y.; Chopra, Vik; Docking, T. Roderick; Dreolini, Lisa; D'Souza, Cletus A.; Flynn, Erin K.; Glenn, Randy; Hatakka, Kristi; Hearty, Taryn G.; Imanian, Behzad; Jiang, Steven; Khorasan-zadeh, Shadi; Komljenovic, Ivana; Laprise, Stéphanie; Liao, Nancy Y.; Lim, Jonathan S.; Lithwick, Stuart; Liu, Flora; Liu, Jun; Lu, Meifen; McConechy, Melissa; McLeod, Andrea J.; Milisavljevic, Marko; Mis, Jacek; O'Connor, Katie; Palma, Betty; Palmquist, Diana L.; Schmouth, Jean-François; Swanson, Magdalena I.; Tam, Bonny; Ticoll, Amy; Turner, Jenna L.; Varhol, Richard; Vermeulen, Jenny; Watkins, Russell F.; Wilson, Gary; Wong, Bibiana K. Y.; Wong, Siaw H.; Wong, Tony Y. T.; Yang, George S.; Ypsilanti, Athena R.; Jones, Steven J. M.; Holt, Robert A.; Goldowitz, Daniel; Wasserman, Wyeth W.; Simpson, Elizabeth M.

    2010-01-01

    The Pleiades Promoter Project integrates genomewide bioinformatics with large-scale knockin mouse production and histological examination of expression patterns to develop MiniPromoters and related tools designed to study and treat the brain by directed gene expression. Genes with brain expression patterns of interest are subjected to bioinformatic analysis to delineate candidate regulatory regions, which are then incorporated into a panel of compact human MiniPromoters to drive expression to brain regions and cell types of interest. Using single-copy, homologous-recombination “knockins” in embryonic stem cells, each MiniPromoter reporter is integrated immediately 5′ of the Hprt locus in the mouse genome. MiniPromoter expression profiles are characterized in differentiation assays of the transgenic cells or in mouse brains following transgenic mouse production. Histological examination of adult brains, eyes, and spinal cords for reporter gene activity is coupled to costaining with cell-type–specific markers to define expression. The publicly available Pleiades MiniPromoter Project is a key resource to facilitate research on brain development and therapies. PMID:20807748

  1. The circadian deadenylase Nocturnin is necessary for stabilization of the iNOS mRNA in mice.

    Directory of Open Access Journals (Sweden)

    Shuang Niu

    Full Text Available Nocturnin is a member of the CCR4 deadenylase family, and its expression is under circadian control with peak levels at night. Because it can remove poly(A tails from mRNAs, it is presumed to play a role in post-transcriptional control of circadian gene expression, but its target mRNAs are not known. Here we demonstrate that Nocturnin expression is acutely induced by the endotoxin lipopolysaccharide (LPS. Mouse embryo fibroblasts (MEFs lacking Nocturnin exhibit normal patterns of acute induction of TNFα and iNOS mRNAs during the first three hours following LPS treatment, but by 24 hours, while TNFα mRNA levels are indistinguishable from WT cells, iNOS message is significantly reduced 20-fold. Accordingly, analysis of the stability of the mRNAs showed that loss of Nocturnin causes a significant decrease in the half-life of the iNOS mRNA (t(1/2 = 3.3 hours in Nocturnin knockout MEFs vs. 12.4 hours in wild type MEFs, while having no effect on the TNFα message. Furthermore, mice lacking Nocturnin lose the normal nighttime peak of hepatic iNOS mRNA, and have improved survival following LPS injection. These data suggest that Nocturnin has a novel stabilizing activity that plays an important role in the circadian response to inflammatory signals.

  2. Human speech- and reading-related genes display partially overlapping expression patterns in the marmoset brain.

    Science.gov (United States)

    Kato, Masaki; Okanoya, Kazuo; Koike, Taku; Sasaki, Erika; Okano, Hideyuki; Watanabe, Shigeru; Iriki, Atsushi

    2014-06-01

    Language is a characteristic feature of human communication. Several familial language impairments have been identified, and candidate genes for language impairments already isolated. Studies comparing expression patterns of these genes in human brain are necessary to further understanding of these genes. However, it is difficult to examine gene expression in human brain. In this study, we used a non-human primate (common marmoset; Callithrix jacchus) as a biological model of the human brain to investigate expression patterns of human speech- and reading-related genes. Expression patterns of speech disorder- (FoxP2, FoxP1, CNTNAP2, and CMIP) and dyslexia- (ROBO1, DCDC2, and KIAA0319) related genes were analyzed. We found the genes displayed overlapping expression patterns in the ocular, auditory, and motor systems. Our results enhance understanding of the molecular mechanisms underlying language impairments. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Disease association and inter-connectivity analysis of human brain specific co-expressed functional modules.

    Science.gov (United States)

    Oh, Kimin; Hwang, Taeho; Cha, Kihoon; Yi, Gwan-Su

    2015-12-16

    In the recent studies, it is suggested that the analysis of transcriptomic change of functional modules instead of individual genes would be more effective for system-wide identification of cellular functions. This could also provide a new possibility for the better understanding of difference between human and chimpanzee. In this study, we analyzed to find molecular characteristics of human brain functions from the difference of transcriptome between human and chimpanzee's brain using the functional module-centric co-expression analysis. We performed analysis of brain disease association and systems-level connectivity of species-specific co-expressed functional modules. Throughout the analyses, we found human-specific functional modules and significant overlap between their genes in known brain disease genes, suggesting that human brain disorder could be mediated by the perturbation of modular activities emerged in human brain specialization. In addition, the human-specific modules having neurobiological functions exhibited higher networking than other functional modules. This finding suggests that the expression of neural functions are more connected than other functions, and the resulting high-order brain functions could be identified as a result of consolidated inter-modular gene activities. Our result also showed that the functional module based transcriptome analysis has a potential to expand molecular understanding of high-order complex functions like cognitive abilities and brain disorders.

  4. Gene expression changes in female zebrafish (Danio rerio) brain in response to acute exposure to methylmercury

    Science.gov (United States)

    Richter, Catherine A.; Garcia-Reyero, Natàlia; Martyniuk, Chris; Knoebl, Iris; Pope, Marie; Wright-Osment, Maureen K.; Denslow, Nancy D.; Tillitt, Donald E.

    2011-01-01

    Methylmercury (MeHg) is a potent neurotoxicant and endocrine disruptor that accumulates in aquatic systems. Previous studies have shown suppression of hormone levels in both male and female fish, suggesting effects on gonadotropin regulation in the brain. The gene expression profile in adult female zebrafish whole brain induced by acute (96 h) MeHg exposure was investigated. Fish were exposed by injection to 0 or 0.5(mu or u)g MeHg/g. Gene expression changes in the brain were examined using a 22,000-feature zebrafish microarray. At a significance level of pfemale brain. Future studies will compare the gene expression profile induced in response to MeHg with that induced by other toxicants and will investigate responsive genes as potential biomarkers of MeHg exposure.

  5. Identification and expression analysis of nervous wreck, which is preferentially expressed in the brain of the male silkworm moth, Bombyx mori

    OpenAIRE

    Kiya, Taketoshi; Iwami, Masafumi

    2011-01-01

    Sexually dimorphic neural circuits are essential for reproductive behaviour. The molecular basis of sexual dimorphism in the silkworm moth (Bombyx mori) brain, however, is unclear. We conducted cDNA subtraction screening and identified nervous wreck (Bmnwk), a synaptic growth regulatory gene, whose expression is higher in the male brain than in the female brain of the silkworm. Bmnwk was preferentially expressed in the brain at the late pupae and adult stages. In situ hybridization revealed t...

  6. Brain expressed microRNAs implicated in schizophrenia etiology

    DEFF Research Database (Denmark)

    Hansen, Thomas; Olsen, Line; Lindow, Morten

    2007-01-01

    Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors...

  7. Exclusive neuronal expression of SUCLA2 in the human brain

    DEFF Research Database (Denmark)

    Dobolyi, Arpád; Ostergaard, Elsebet; Bagó, Attila G

    2015-01-01

    SUCLA2 encodes the ATP-forming β subunit (A-SUCL-β) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology asso...

  8. Infants' Emerging Sensitivity to Emotional Body Expressions: Insights from Asymmetrical Frontal Brain Activity

    Science.gov (United States)

    Missana, Manuela; Grossmann, Tobias

    2015-01-01

    Sensitive responding to others' emotional body expressions is an essential social skill in humans. Using event-related brain potentials, it has recently been shown that the ability to discriminate between emotional body expressions develops between 4 and 8 months of age. However, it is not clear whether the perception of emotional body expressions…

  9. Regulation of expression of atrial and brain natriuretic peptide, biomarkers for heart development and disease

    NARCIS (Netherlands)

    Sergeeva, Irina A.; Christoffels, Vincent M.

    2013-01-01

    The mammalian heart expresses two closely related natriuretic peptide (NP) hormones, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). The excretion of the NPs and the expression of their genes strongly respond to a variety of cardiovascular disorders. NPs act to increase

  10. Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development

    DEFF Research Database (Denmark)

    Venø, Morten T; Hansen, Thomas B; Venø, Susanne T

    2015-01-01

    BACKGROUND: Recently, thousands of circular RNAs (circRNAs) have been discovered in various tissues and cell types from human, mouse, fruit fly and nematodes. However, expression of circRNAs across mammalian brain development has never been examined. RESULTS: Here we profile the expression of circ...

  11. Differential gene expression in brain tissues of aggressive and non-aggressive dogs

    Directory of Open Access Journals (Sweden)

    Tverdal Aage

    2010-06-01

    Full Text Available Abstract Background Canine behavioural problems, in particular aggression, are important reasons for euthanasia of otherwise healthy dogs. Aggressive behaviour in dogs also represents an animal welfare problem and a public threat. Elucidating the genetic background of adverse behaviour can provide valuable information to breeding programs and aid the development of drugs aimed at treating undesirable behaviour. With the intentions of identifying gene-specific expression in particular brain parts and comparing brains of aggressive and non-aggressive dogs, we studied amygdala, frontal cortex, hypothalamus and parietal cortex, as these tissues are reported to be involved in emotional reactions, including aggression. Based on quantitative real-time PCR (qRT-PCR in 20 brains, obtained from 11 dogs euthanised because of aggressive behaviour and nine non-aggressive dogs, we studied expression of nine genes identified in an initial screening by subtraction hybridisation. Results This study describes differential expression of the UBE2V2 and ZNF227 genes in brains of aggressive and non-aggressive dogs. It also reports differential expression for eight of the studied genes across four different brain tissues (amygdala, frontal cortex, hypothalamus, and parietal cortex. Sex differences in transcription levels were detected for five of the nine studied genes. Conclusions The study showed significant differences in gene expression between brain compartments for most of the investigated genes. Increased expression of two genes was associated with the aggression phenotype. Although the UBE2V2 and ZNF227 genes have no known function in regulation of aggressive behaviour, this study contributes to preliminary data of differential gene expression in the canine brain and provides new information to be further explored.

  12. Netrin-1 expression is an independent prognostic factor for poor patient survival in brain metastases.

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    Patrick N Harter

    Full Text Available The multifunctional molecule netrin-1 is upregulated in various malignancies and has recently been presented as a major general player in tumorigenesis leading to tumor progression and maintenance in various animal models. However, there is still a lack of clinico-epidemiological data related to netrin-1 expression. Therefore, the aim of our study was to elucidate the association of netrin-1 expression and patient survival in brain metastases since those constitute one of the most limiting factors for patient prognosis. We investigated 104 brain metastases cases for netrin-1 expression using in-situ hybridization and immunohistochemistry with regard to clinical parameters such as patient survival and MRI data. Our data show that netrin-1 is strongly upregulated in most cancer subtypes. Univariate analyses revealed netrin-1 expression as a significant factor associated with poor patient survival in the total cohort of brain metastasis patients and in sub-entities such as non-small cell lung carcinomas. Interestingly, many cancer samples showed a strong nuclear netrin-1 signal which was recently linked to a truncated netrin-1 variant that enhances tumor growth. Nuclear netrin-1 expression was associated with poor patient survival in univariate as well as in multivariate analyses. Our data indicate both total and nuclear netrin-1 expression as prognostic factors in brain metastases patients in contrast to other prognostic markers in oncology such as patient age, number of brain metastases or Ki67 proliferation index. Therefore, nuclear netrin-1 expression constitutes one of the first reported molecular biomarkers for patient survival in brain metastases. Furthermore, netrin-1 may constitute a promising target for future anti-cancer treatment approaches in brain metastases.

  13. Air pollution and brain damage.

    Science.gov (United States)

    Calderón-Garcidueñas, Lilian; Azzarelli, Biagio; Acuna, Hilda; Garcia, Raquel; Gambling, Todd M; Osnaya, Norma; Monroy, Sylvia; DEL Tizapantzi, Maria Rosario; Carson, Johnny L; Villarreal-Calderon, Anna; Rewcastle, Barry

    2002-01-01

    Exposure to complex mixtures of air pollutants produces inflammation in the upper and lower respiratory tract. Because the nasal cavity is a common portal of entry, respiratory and olfactory epithelia are vulnerable targets for toxicological damage. This study has evaluated, by light and electron microscopy and immunohistochemical expression of nuclear factor-kappa beta (NF-kappaB) and inducible nitric oxide synthase (iNOS), the olfactory and respiratory nasal mucosae, olfactory bulb, and cortical and subcortical structures from 32 healthy mongrel canine residents in Southwest Metropolitan Mexico City (SWMMC), a highly polluted urban region. Findings were compared to those in 8 dogs from Tlaxcala, a less polluted, control city. In SWMMC dogs, expression of nuclear neuronal NF-kappaB and iNOS in cortical endothelial cells occurred at ages 2 and 4 weeks; subsequent damage included alterations of the blood-brain barrier (BBB), degenerating cortical neurons, apoptotic glial white matter cells, deposition of apolipoprotein E (apoE)-positive lipid droplets in smooth muscle cells and pericytes, nonneuritic plaques, and neurofibrillary tangles. Persistent pulmonary inflammation and deteriorating olfactory and respiratory barriers may play a role in the neuropathology observed in the brains of these highly exposed canines. Neurodegenerative disorders such as Alzheimer's may begin early in life with air pollutants playing a crucial role.

  14. Expression of the homeobox genes OTX2 and OTX1 in the early developing human brain

    DEFF Research Database (Denmark)

    Larsen, Karen B; Lutterodt, Melissa C; Møllgård, Kjeld

    2010-01-01

    protein was found in the subcommissural organ, pineal gland, and cerebellum. The early expression of OTX2 and OTX1 in proliferative cell layers of the human fetal brain supports the concept that these homeobox genes are important in neuronal cell development and differentiation: OTX1 primarily......In rodents, the Otx2 gene is expressed in the diencephalon, mesencephalon, and cerebellum and is crucial for the development of these brain regions. Together with Otx1, Otx2 is known to cooperate with other genes to develop the caudal forebrain and, further, Otx1 is also involved in differentiation...... of young neurons of the deeper cortical layers. We have studied the spatial and temporal expression of the two homeobox genes OTX2 and OTX1 in human fetal brains from 7 to 14 weeks postconception by in situ hybridization and immunohistochemistry. OTX2 was expressed in the diencephalon, mesencephalon...

  15. Income inequality, gene expression, and brain maturation during adolescence

    OpenAIRE

    Parker, Nadine; Wong, Angelita Pui-Yee; Leonard, Gabriel; Perron, Michel; Pike, G Bruce; Richer, Louis; Veillette, Suzanne; Pausova, Zdenka; Paus, Tomas

    2017-01-01

    Income inequality is associated with poor health and social outcomes. Negative social comparisons and competition may involve the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in underlying some of these complex inter-relationships. Here we investigate brain maturation, indexed by age-related decreases in cortical thickness, in adolescents living in neighborhoods with differing levels of income inequality and household income. We examine whether inter-regi...

  16. Human brain arteriovenous malformations express lymphatic-associated genes

    OpenAIRE

    Shoemaker, Lorelei D.; Fuentes, Laurel F; Santiago, Shauna M; Allen, Breanna M; Cook, Douglas J.; Steinberg, Gary K.; Chang, Steven D.

    2014-01-01

    Objective Brain arteriovenous malformations (AVMs) are devastating, hemorrhage-prone, cerebrovascular lesions characterized by well-defined feeding arteries, draining vein(s) and the absence of a capillary bed. The endothelial cells (ECs) that comprise AVMs exhibit a loss of arterial and venous specification. Given the role of the transcription factor COUP-TFII in vascular development, EC specification, and pathological angiogenesis, we examined human AVM tissue to determine if COUP-FTII may ...

  17. Gene expression in the rodent brain is associated with its regional connectivity.

    Directory of Open Access Journals (Sweden)

    Lior Wolf

    2011-05-01

    Full Text Available The putative link between gene expression of brain regions and their neural connectivity patterns is a fundamental question in neuroscience. Here this question is addressed in the first large scale study of a prototypical mammalian rodent brain, using a combination of rat brain regional connectivity data with gene expression of the mouse brain. Remarkably, even though this study uses data from two different rodent species (due to the data limitations, we still find that the connectivity of the majority of brain regions is highly predictable from their gene expression levels-the outgoing (incoming connectivity is successfully predicted for 73% (56% of brain regions, with an overall fairly marked accuracy level of 0.79 (0.83. Many genes are found to play a part in predicting both the incoming and outgoing connectivity (241 out of the 500 top selected genes, p-value<1e-5. Reassuringly, the genes previously known from the literature to be involved in axon guidance do carry significant information about regional brain connectivity. Surveying the genes known to be associated with the pathogenesis of several brain disorders, we find that those associated with schizophrenia, autism and attention deficit disorder are the most highly enriched in the connectivity-related genes identified here. Finally, we find that the profile of functional annotation groups that are associated with regional connectivity in the rodent is significantly correlated with the annotation profile of genes previously found to determine neural connectivity in C. elegans (Pearson correlation of 0.24, p<1e-6 for the outgoing connections and 0.27, p<1e-5 for the incoming. Overall, the association between connectivity and gene expression in a specific extant rodent species' brain is likely to be even stronger than found here, given the limitations of current data.

  18. Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent brain.

    Directory of Open Access Journals (Sweden)

    Melissa A Fowler

    2007-06-01

    Full Text Available The canonical transient receptor potential (TRPC channels are a family of non-selective cation channels that are activated by increases in intracellular Ca(2+ and G(q/phospholipase C-coupled receptors. We used quantitative real-time PCR, in situ hybridization, immunoblots and patch-clamp recording from several brain regions to examine the expression of the predominant TRPC channels in the rodent brain. Quantitative real-time PCR of the seven TRPC channels in the rodent brain revealed that TRPC4 and TRPC5 channels were the predominant TRPC subtypes in the adult rat brain. In situ hybridization histochemistry and immunoblotting further resolved a dense corticolimbic expression of the TRPC4 and TRPC5 channels. Total protein expression of HIP TRPC4 and 5 proteins increased throughout development and peaked late in adulthood (6-9 weeks. In adults, TRPC4 expression was high throughout the frontal cortex, lateral septum (LS, pyramidal cell layer of the hippocampus (HIP, dentate gyrus (DG, and ventral subiculum (vSUB. TRPC5 was highly expressed in the frontal cortex, pyramidal cell layer of the HIP, DG, and hypothalamus. Detailed examination of frontal cortical layer mRNA expression indicated TRPC4 mRNA is distributed throughout layers 2-6 of the prefrontal cortex (PFC, motor cortex (MCx, and somatosensory cortex (SCx. TRPC5 mRNA expression was concentrated specifically in the deep layers 5/6 and superficial layers 2/3 of the PFC and anterior cingulate. Patch-clamp recording indicated a strong metabotropic glutamate-activated cation current-mediated depolarization that was dependent on intracellular Ca(2+and inhibited by protein kinase C in brain regions associated with dense TRPC4 or 5 expression and absent in regions lacking TRPC4 and 5 expression. Overall, the dense corticolimbic expression pattern suggests that these Gq/PLC coupled nonselective cation channels may be involved in learning, memory, and goal-directed behaviors.

  19. The Ketogenic Diet Suppresses the Cathepsin E Expression Induced by Kainic Acid in the Rat Brain

    Science.gov (United States)

    Jeong, Hyun Jeong; Kim, Hojeong; Kim, Yoon-Kyoung; Park, Sang-Kyu; Kang, Dong-Won

    2010-01-01

    Purpose The ketogenic diet has long been used to treat epilepsy, but its mechanism is not yet clearly understood. To explore the potential mechanism, we analyzed the changes in gene expression induced by the ketogenic diet in the rat kainic acid (KA) epilepsy model. Materials and Methods KA-administered rats were fed the ketogenic diet or a normal diet for 4 weeks, and microarray analysis was performed with their brain tissues. The effects of the ketogenic diet on cathepsin E messenger ribonucleic acid (mRNA) expression were analyzed in KA-administered and normal saline-administered groups with semi-quantitative and real-time reverse transcription polymerase chain reaction (RT-PCR). Brain tissues were dissected into 8 regions to compare differential effects of the ketogenic diet on cathepsin E mRNA expression. Immunohistochemistry with an anti-cathepsin E antibody was performed on slides of hippocampus obtained from whole brain paraffin blocks. Results The microarray data and subsequent RT-PCR experiments showed that KA increased the mRNA expression of cathepsin E, known to be related to neuronal cell death, in most brain areas except the brain stem, and these increases of cathepsin E mRNA expression were suppressed by the ketogenic diet. The expression of cathepsin E mRNA in the control group, however, was not significantly affected by the ketogenic diet. The change in cathepsin E mRNA expression was greatest in the hippocampus. The protein level of cathepsin E in the hippocampus of KA-administered rat was elevated in immunohistochemistry and the ketogenic diet suppressed this increase. Conclusion Our results showed that KA administration increased cathepsin E expression in the rat brain and its increase was suppressed by the ketogenic diet. PMID:20635438

  20. Chronological changes in microRNA expression in the developing human brain.

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    Michael P Moreau

    Full Text Available MicroRNAs (miRNAs are endogenously expressed noncoding RNA molecules that are believed to regulate multiple neurobiological processes. Expression studies have revealed distinct temporal expression patterns in the developing rodent and porcine brain, but comprehensive profiling in the developing human brain has not been previously reported.We performed microarray and TaqMan-based expression analysis of all annotated mature miRNAs (miRBase 10.0 as well as 373 novel, predicted miRNAs. Expression levels were measured in 48 post-mortem brain tissue samples, representing gestational ages 14-24 weeks, as well as early postnatal and adult time points.Expression levels of 312 miRNAs changed significantly between at least two of the broad age categories, defined as fetal, young, and adult.We have constructed a miRNA expression atlas of the developing human brain, and we propose a classification scheme to guide future studies of neurobiological function.

  1. C/EBPβ Isoforms Expression in the Rat Brain during the Estrous Cycle

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    Valeria Hansberg-Pastor

    2015-01-01

    Full Text Available The CCAAT/enhancer-binding protein beta (C/EBPβ is a transcription factor expressed in different areas of the brain that regulates the expression of several genes involved in cell differentiation and proliferation. This protein has three isoforms (LAP1, LAP2, and LIP with different transcription activation potential. The role of female sex hormones in the expression pattern of C/EBPβ isoforms in the rat brain has not yet been described. In this study we demonstrate by western blot that the expression of the three C/EBPβ isoforms changes in different brain areas during the estrous cycle. In the cerebellum, LAP2 content diminished on diestrus and proestrus and LIP content diminished on proestrus and estrus days. In the prefrontal cortex, LIP content was higher on proestrus and estrus days. In the hippocampus, LAP isoforms presented a switch on diestrus day, since LAP1 content was the highest while that of LAP2 was the lowest. The LAP2 isoform was the most abundant one in all the three brain areas. The LAP/LIP ratio changed throughout the cycle and was tissue specific. These results suggest that C/EBPβ isoforms expression changes in a tissue-specific manner in the rat brain due to the changes in sex steroid hormone levels presented during the estrous cycle.

  2. CXCL12, CXCR4 and CXCR7 expression in brain metastases.

    Science.gov (United States)

    Salmaggi, Andrea; Maderna, Emanuela; Calatozzolo, Chiara; Gaviani, Paola; Canazza, Alessandra; Milanesi, Ida; Silvani, Antonio; DiMeco, Francesco; Carbone, Antonino; Pollo, Bianca

    2009-09-01

    Brain metastases occur in about 25% of patients who die of cancer. The most common sources of brain metastases in adults are lung, breast, kidney, colorectal cancer and melanoma. The chemokine/receptor system CXCL12/CXCR4 plays a key role in multiple biological functions; among these, homing of neoplastic cells from the primary site to the target and metastasis progression. Recently, an alternative CXCL12 receptor CXCR7 has been discovered. The aim of our study was to investigate the expression of CXCL12 and its receptors CXCR4 and CXCR7 by immunohistochemistry in 56 patients with metastatic brain disease from different non-CNS primary tumors and evaluate their prognostic relevance as well as that of other patient/treatment-related features on patient survival. CXCL12 showed an expression in tumor cells and in tumor vessels; CXCR7 was expressed by tumor and endothelial cells (both within the tumor and in the adjacent brain tissue), while CXCR4 showed a positivity in all samples with a nuclear pattern. Among the investigated immunohistochemical parameters, only CXCL12 expression in tumor endothelial cells showed a statistically significant correlation with shorter survival (p = 0.04 log-rank), perhaps identifying more aggressive tumors. Thus, this is the first study evaluating at the same time the expression of CXCL12 and its two receptors in a cohort of brain metastases.

  3. Brain alpha- and beta-globin expression after intracerebral hemorrhage

    OpenAIRE

    He, Yangdong; Hua, Ya; Lee, Jin-Yul; Liu, Wenquan; Keep, Richard F; Wang, Michael M.; Xi, Guohua

    2010-01-01

    Our recent study has demonstrated that hemoglobin (Hb) is present in cerebral neurons and neuronal Hb is inducible after cerebral ischemia. In the present study, we examined the effects of intracerebral hemorrhage (ICH) on the mRNA levels of the α-globin (HbA) and the β-globin (HbB) components of Hb and Hb protein in the brain in vivo and in vitro. In vivo, male Sprague-Dawley rats received either a needle insertion (sham) or an infusion of autologous whole blood into the basal ganglia and we...

  4. Brain expressed microRNAs implicated in schizophrenia etiology

    DEFF Research Database (Denmark)

    Hansen, Thomas; Olsen, Line; Lindow, Morten

    2007-01-01

    Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors....... Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation....

  5. Expression of novel Alzheimer's disease risk genes in control and Alzheimer's disease brains.

    Directory of Open Access Journals (Sweden)

    Celeste M Karch

    Full Text Available Late onset Alzheimer's disease (LOAD etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR, with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.

  6. Evolutionary and Expression Analyses Show Co-option of khdrbs Genes for Origin of Vertebrate Brain

    OpenAIRE

    Su Wang; Su Wang; Qingyun Yang; Qingyun Yang; Ziyue Wang; Ziyue Wang; Shuoqi Feng; Shuoqi Feng; Hongyan Li; Hongyan Li; Dongrui Ji; Dongrui Ji; Shicui Zhang; Shicui Zhang

    2018-01-01

    Genes generated by whole genome duplications (WGD) can be co-opted by changing their regulation process or altering their coding proteins, which has been shown contributable to the emergence of vertebrate morphological novelties such as vertebrate cartilage. Mouse khdrbs genes, differing from its invertebrate orthologs, were mainly expressed in brain, hinting that khdrbs gene family as a member of genetic toolkit may be linked to vertebrate brain development. However, the evolutionary relatio...

  7. Circadian clock gene expression in brain regions of Alzheimer 's disease patients and control subjects.

    Science.gov (United States)

    Cermakian, Nicolas; Lamont, Elaine Waddington; Boudreau, Philippe; Boivin, Diane B

    2011-04-01

    Circadian oscillators have been observed throughout the rodent brain. In the human brain, rhythmic expression of clock genes has been reported only in the pineal gland, and little is known about their expression in other regions. The investigators sought to determine whether clock gene expression could be detected and whether it varies as a function of time of day in the bed nucleus of the stria terminalis (BNST) and cingulate cortex, areas known to be involved in decision making and motivated behaviors, as well as in the pineal gland, in the brains of Alzheimer's disease (AD) patients and aged controls. Relative expression levels of PERIOD1 (PER1 ), PERIOD2 (PER2), and Brain and muscle Arnt-like protein-1 (BMAL1) were detected by quantitative PCR in all 3 brain regions. A harmonic regression model revealed significant 24-h rhythms of PER1 in the BNST of AD subjects. A significant rhythm of PER2 was found in the cingulate cortex and BNST of control subjects and in all 3 regions of AD patients. In controls, BMAL1 did not show a diurnal rhythm in the cingulate cortex but significantly varied with time of death in the pineal and BNST and in all 3 regions for AD patients. Notable differences in the phase of clock gene rhythms and phase relationships between genes and regions were observed in the brains of AD compared to those of controls. These results indicate the presence of multiple circadian oscillators in the human brain and suggest altered synchronization among these oscillators in the brain of AD patients. © 2011 Sage Publications

  8. Impaired social brain network for processing dynamic facial expressions in autism spectrum disorders

    Science.gov (United States)

    2012-01-01

    Background Impairment of social interaction via facial expressions represents a core clinical feature of autism spectrum disorders (ASD). However, the neural correlates of this dysfunction remain unidentified. Because this dysfunction is manifested in real-life situations, we hypothesized that the observation of dynamic, compared with static, facial expressions would reveal abnormal brain functioning in individuals with ASD. We presented dynamic and static facial expressions of fear and happiness to individuals with high-functioning ASD and to age- and sex-matched typically developing controls and recorded their brain activities using functional magnetic resonance imaging (fMRI). Result Regional analysis revealed reduced activation of several brain regions in the ASD group compared with controls in response to dynamic versus static facial expressions, including the middle temporal gyrus (MTG), fusiform gyrus, amygdala, medial prefrontal cortex, and inferior frontal gyrus (IFG). Dynamic causal modeling analyses revealed that bi-directional effective connectivity involving the primary visual cortex–MTG–IFG circuit was enhanced in response to dynamic as compared with static facial expressions in the control group. Group comparisons revealed that all these modulatory effects were weaker in the ASD group than in the control group. Conclusions These results suggest that weak activity and connectivity of the social brain network underlie the impairment in social interaction involving dynamic facial expressions in individuals with ASD. PMID:22889284

  9. Brain SERT Expression of Male Rats Is Reduced by Aging and Increased by Testosterone Restitution

    Science.gov (United States)

    Herrera-Pérez, José Jaime; Fernández-Guasti, Alonso; Martínez-Mota, Lucía

    2013-01-01

    In preclinical and clinical studies aging has been associated with a deteriorated response to antidepressant treatment. We hypothesize that such impairment is explained by an age-related decrease in brain serotonin transporter (SERT) expression associated with low testosterone (T) levels. The objectives of this study were to establish (1) if brain SERT expression is reduced by aging and (2) if the SERT expression in middle-aged rats is increased by T-restitution. Intact young rats (3–5 months) and gonad-intact middle-aged rats with or without T-restitution were used. The identification of the brain SERT expression was done by immunofluorescence in prefrontal cortex, lateral septum, hippocampus, and raphe nuclei. An age-dependent reduction of SERT expression was observed in all brain regions examined, while T-restitution recovered the SERT expression only in the dorsal raphe of middle-aged rats. This last action seems relevant since dorsal raphe plays an important role in the antidepressant action of selective serotonin reuptake inhibitors. All data suggest that this mechanism accounts for the T-replacement usefulness to improve the response to antidepressants in the aged population. PMID:26317087

  10. Brain SERT Expression of Male Rats Is Reduced by Aging and Increased by Testosterone Restitution

    Directory of Open Access Journals (Sweden)

    José Jaime Herrera-Pérez

    2013-01-01

    Full Text Available In preclinical and clinical studies aging has been associated with a deteriorated response to antidepressant treatment. We hypothesize that such impairment is explained by an age-related decrease in brain serotonin transporter (SERT expression associated with low testosterone (T levels. The objectives of this study were to establish (1 if brain SERT expression is reduced by aging and (2 if the SERT expression in middle-aged rats is increased by T-restitution. Intact young rats (3–5 months and gonad-intact middle-aged rats with or without T-restitution were used. The identification of the brain SERT expression was done by immunofluorescence in prefrontal cortex, lateral septum, hippocampus, and raphe nuclei. An age-dependent reduction of SERT expression was observed in all brain regions examined, while T-restitution recovered the SERT expression only in the dorsal raphe of middle-aged rats. This last action seems relevant since dorsal raphe plays an important role in the antidepressant action of selective serotonin reuptake inhibitors. All data suggest that this mechanism accounts for the T-replacement usefulness to improve the response to antidepressants in the aged population.

  11. Expression and localization of claudins-3 and -12 in transformed human brain endothelium

    Directory of Open Access Journals (Sweden)

    Schrade Anja

    2012-02-01

    Full Text Available Abstract Background The aim of this study was to characterize the hCMEC/D3 cell line, an in vitro model of the human Blood Brain Barrier (BBB for the expression of brain endothelial specific claudins-3 and -12. Findings hCMEC/D3 cells express claudins-3 and -12. Claudin-3 is distinctly localized to the TJ whereas claudin -12 is observed in the perinuclear region and completely absent from TJs. We show that the expression of both proteins is lost in cell passage numbers where the BBB properties are no longer fully conserved. Expression and localization of claudin-3 is not modulated by simvastatin shown to improve barrier function in vitro and also recommended for routine hCMEC/D3 culture. Conclusions These results support conservation of claudin-3 and -12 expression in the hCMEC/D3 cell line and make claudin-3 a potential marker for BBB characteristics in vitro.

  12. Evaluation of miR-362 Expression in Astrocytoma of Human Brain Tumors

    Science.gov (United States)

    Kheirollahi, Majid; Moodi, Mahdiye; Ashouri, Saeideh; Nikpour, Parvaneh; Kazemi, Mohammad

    2017-01-01

    Background: Patients affected by gliomas have a poor prognosis. Astrocytoma is a subtype of glioma. Identification of biomarkers could be an effective way to an early diagnosis of tumor or to distinguish more aggressive tumors that need more intensive therapy. In this study, we investigated whether the expression of miR-362 was increased or decreased in patients with different grades of astrocytoma. Materials and Methods: miR-362 expression was compared in 25 patients with astrocytoma with that of 4 normal nonneoplastic brain tissues. Results: In all tumor tissues, the expression of miR-362 was significantly decreased relative to its expression in normal brain tissues. However, there was no significant difference between miR-362 expressions in high and low grades of astrocytoma. Conclusions: In conclusion, miR-362 showed a down-regulation pattern in astrocytoma tissues that was different from the pattern obtained from previously published microarray studies. PMID:29142892

  13. Astrocyte-targeted expression of IL-6 protects the CNS against a focal brain injury

    DEFF Research Database (Denmark)

    Penkowa, Milena; Giralt, Mercedes; Lago, Natalia

    2003-01-01

    The effect of CNS-targeted IL-6 gene expression has been thoroughly investigated in the otherwise nonperturbed brain but not following brain injury. Here we examined the impact of astrocyte-targeted IL-6 production in a traumatic brain injury (cryolesion) model using GFAP-IL6 transgenic mice....... This study demonstrated that transgenic IL-6 production significantly increased wound healing following the cryolesion. Thus, at 20 days postlesion (dpl) the GFAP-IL6 mice showed almost complete wound healing compared to litter mate nontransgenic controls. It seems likely that a reduced inflammatory response...... neuropathological insult such as following traumatic injury, a clear neuroprotective role is evident....

  14. Expression of Zinc Finger Protein 804A (ZNF804A) in the brain

    DEFF Research Database (Denmark)

    Benedikz, Eirikur

    Schizophrenia is a severe psychiatric disorder with lifetime prevalence between 0.5 and 1%. The disease is characterized by delusions, hallucinations, altered cognition, emotional reactivity and disorganized behavior. Research increasingly suggests that schizophrenia is a subtle disorder of brain...... of ZNF804A in different brain regions and at different ages in rats using qPCR. Our results show that expression of ZNF804A is developmentally regulated and increases significantly in the brain of embryonic day 18 rats (the developmental equivalent of a 9 week old human fetus). In cortex and cerebellum...... the mRNA levels of ZNF804A are high around birth and then decrease to the adult level. The expression of ZNF804A is also developmentally regulated in the hippocampus, but after decreasing from the postnatal levels, the expression increases again in the adult. These results suggest that ZNF804A plays...

  15. Gene expression changes with age in skin, adipose tissue, blood and brain.

    Science.gov (United States)

    Glass, Daniel; Viñuela, Ana; Davies, Matthew N; Ramasamy, Adaikalavan; Parts, Leopold; Knowles, David; Brown, Andrew A; Hedman, Asa K; Small, Kerrin S; Buil, Alfonso; Grundberg, Elin; Nica, Alexandra C; Di Meglio, Paola; Nestle, Frank O; Ryten, Mina; Durbin, Richard; McCarthy, Mark I; Deloukas, Panagiotis; Dermitzakis, Emmanouil T; Weale, Michael E; Bataille, Veronique; Spector, Tim D

    2013-07-26

    Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age. Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues. Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.

  16. Categorical Representation of Facial Expressions in the Infant Brain

    Science.gov (United States)

    Leppanen, Jukka M.; Richmond, Jenny; Vogel-Farley, Vanessa K.; Moulson, Margaret C.; Nelson, Charles A.

    2009-01-01

    Categorical perception, demonstrated as reduced discrimination of within-category relative to between-category differences in stimuli, has been found in a variety of perceptual domains in adults. To examine the development of categorical perception in the domain of facial expression processing, we used behavioral and event-related potential (ERP)…

  17. MicroRNAs show mutually exclusive expression patterns in the brain of adult male rats

    DEFF Research Database (Denmark)

    Olsen, Line; Klausen, Mikkel; Helboe, Lone

    2009-01-01

    BACKGROUND: The brain is a major site of microRNA (miRNA) gene expression, but the spatial expression patterns of miRNAs within the brain have not yet been fully covered. METHODOLOGY/PRINCIPAL FINDINGS: We have characterized the regional expression profiles of miRNAs in five distinct regions...... of the adult rat brain: amygdala, cerebellum, hippocampus, hypothalamus and substantia nigra. Microarray profiling uncovered 48 miRNAs displaying more than three-fold enrichment between two or more brain regions. Notably, we found reciprocal expression profiles for a subset of the miRNAs predominantly found...... (> ten times) in either the cerebellum (miR-206 and miR-497) or the forebrain regions (miR-132, miR-212, miR-221 and miR-222). CONCLUSIONS/SIGNIFICANCE: The results indicate that some miRNAs could be important for area-specific functions in the brain. Our data, combined with previous studies in mice...

  18. Homocysteine homeostasis and betaine-homocysteine S-methyltransferase expression in the brain of hibernating bats.

    Directory of Open Access Journals (Sweden)

    Yijian Zhang

    Full Text Available Elevated homocysteine is an important risk factor that increases cerebrovascular and neurodegenerative disease morbidity. In mammals, B vitamin supplementation can reduce homocysteine levels. Whether, and how, hibernating mammals, that essentially stop ingesting B vitamins, maintain homocysteine metabolism and avoid cerebrovascular impacts and neurodegeneration remain unclear. Here, we compare homocysteine levels in the brains of torpid bats, active bats and rats to identify the molecules involved in homocysteine homeostasis. We found that homocysteine does not elevate in torpid brains, despite declining vitamin B levels. At low levels of vitamin B6 and B12, we found no change in total expression level of the two main enzymes involved in homocysteine metabolism (methionine synthase and cystathionine β-synthase, but a 1.85-fold increase in the expression of the coenzyme-independent betaine-homocysteine S-methyltransferase (BHMT. BHMT expression was observed in the amygdala of basal ganglia and the cerebral cortex where BHMT levels were clearly elevated during torpor. This is the first report of BHMT protein expression in the brain and suggests that BHMT modulates homocysteine in the brains of hibernating bats. BHMT may have a neuroprotective role in the brains of hibernating mammals and further research on this system could expand our biomedical understanding of certain cerebrovascular and neurodegenerative disease processes.

  19. Brain CD47 Expression in a Swine Model of Intracerebral Hemorrhage

    OpenAIRE

    Zhou, Xiang; Xie, Qing; Xi, Guohua; Keep, Richard F.; Hua, Ya

    2014-01-01

    CD47 contributes to neuronal death, inflammation and angiogenesis after brain ischemia. The role of CD47 in intracerebral hemorrhage (ICH) has not been investigated and the current study examined brain CD47 expression in a pig ICH model. Pigs received a blood injection or needle insertion into the right frontal lobe and were euthanized at different times to examine CD47 expression. Pigs were also treated with an iron chelator, deferoxamine, (50 mg/kg, i.m.) or vehicle and killed at day-3 to e...

  20. Disruption of the blood-brain interface in neonatal rat neocortex induces a transient expression of metallothionein in reactive astrocytes

    DEFF Research Database (Denmark)

    Penkowa, M; Moos, T

    1995-01-01

    rats were subjected to a localized freeze lesion of the neocortex of the right temporal cortex. This lesion results in a disrupted blood-brain interface, leading to extravasation of plasma proteins. From 16 h, reactive astrocytosis, defined as an increase in the number and size of cells expressing GFAP......Exposure of the adult rat brain parenchyma to zinc induces an increase in the intracerebral expression of the metal-binding protein, metallothionein, which is normally confined to astrocytes, ependymal cells, choroid plexus epithelial cells, and brain endothelial cells. Metallothionein is expressed...... only in diminutive amounts in astrocytes of the neonatal rat brain, which could imply that neonatal rats are devoid of the capacity to detoxify free metals released from a brain wound. In order to examine the influence of a brain injury on the expression of metallothionein in the neonatal brain, PO...

  1. Singing-driven gene expression in the developing songbird brain.

    Science.gov (United States)

    Johnson, Frank; Whitney, Osceola

    2005-10-15

    Neural and behavioral development arises from an integration of genetic and environmental influences, yet specifying the nature of this interaction remains a primary problem in neuroscience. Here, we review molecular and behavioral studies that focus on the role of singing-driven gene expression during neural and vocal development in the male zebra finch (Taeniopygia guttata), a songbird that learns a species-typical vocal pattern during juvenile development by imitating an adult male tutor. A primary aim of our lab has been to identify naturally-occurring environmental influences that shape the propensity to sing. This ethological approach underlies our theoretical perspective, which is to integrate the significance of singing-driven gene expression into a broader ecological context.

  2. Singing-driven gene expression in the developing songbird brain

    OpenAIRE

    Johnson, Frank; Whitney, Osceola

    2005-01-01

    Neural and behavioral development arises from an integration of genetic and environmental influences, yet specifying the nature of this interaction remains a primary problem in neuroscience. Here, we review molecular and behavioral studies that focus on the role of singing-driven gene expression during neural and vocal development in the male zebra finch (Taeniopygia guttata), a songbird that learns a species-typical vocal pattern during juvenile development by imitating an adult male tutor. ...

  3. Fear across the senses: brain responses to music, vocalizations and facial expressions.

    Science.gov (United States)

    Aubé, William; Angulo-Perkins, Arafat; Peretz, Isabelle; Concha, Luis; Armony, Jorge L

    2015-03-01

    Intrinsic emotional expressions such as those communicated by faces and vocalizations have been shown to engage specific brain regions, such as the amygdala. Although music constitutes another powerful means to express emotions, the neural substrates involved in its processing remain poorly understood. In particular, it is unknown whether brain regions typically associated with processing 'biologically relevant' emotional expressions are also recruited by emotional music. To address this question, we conducted an event-related functional magnetic resonance imaging study in 47 healthy volunteers in which we directly compared responses to basic emotions (fear, sadness and happiness, as well as neutral) expressed through faces, non-linguistic vocalizations and short novel musical excerpts. Our results confirmed the importance of fear in emotional communication, as revealed by significant blood oxygen level-dependent signal increased in a cluster within the posterior amygdala and anterior hippocampus, as well as in the posterior insula across all three domains. Moreover, subject-specific amygdala responses to fearful music and vocalizations were correlated, consistent with the proposal that the brain circuitry involved in the processing of musical emotions might be shared with the one that have evolved for vocalizations. Overall, our results show that processing of fear expressed through music, engages some of the same brain areas known to be crucial for detecting and evaluating threat-related information. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  4. Fear across the senses: brain responses to music, vocalizations and facial expressions

    Science.gov (United States)

    Angulo-Perkins, Arafat; Peretz, Isabelle; Concha, Luis; Armony, Jorge L.

    2015-01-01

    Intrinsic emotional expressions such as those communicated by faces and vocalizations have been shown to engage specific brain regions, such as the amygdala. Although music constitutes another powerful means to express emotions, the neural substrates involved in its processing remain poorly understood. In particular, it is unknown whether brain regions typically associated with processing ‘biologically relevant’ emotional expressions are also recruited by emotional music. To address this question, we conducted an event-related functional magnetic resonance imaging study in 47 healthy volunteers in which we directly compared responses to basic emotions (fear, sadness and happiness, as well as neutral) expressed through faces, non-linguistic vocalizations and short novel musical excerpts. Our results confirmed the importance of fear in emotional communication, as revealed by significant blood oxygen level-dependent signal increased in a cluster within the posterior amygdala and anterior hippocampus, as well as in the posterior insula across all three domains. Moreover, subject-specific amygdala responses to fearful music and vocalizations were correlated, consistent with the proposal that the brain circuitry involved in the processing of musical emotions might be shared with the one that have evolved for vocalizations. Overall, our results show that processing of fear expressed through music, engages some of the same brain areas known to be crucial for detecting and evaluating threat-related information. PMID:24795437

  5. Gene expression of the TGF-beta family in rat brain infected with Borna disease virus.

    Science.gov (United States)

    Nishino, Yoshii; Ooishi, Ryo; Kurokawa, Sachiko; Fujino, Kan; Murakami, Masaru; Madarame, Hiroo; Hashimoto, Osamu; Sugiyama, Kazutoshi; Funaba, Masayuki

    2009-01-01

    CRNP5, a variant of Borna disease virus (BDV), has stronger pathogenesis in rats than the related variant CRP3, although only 4 amino acids in the whole genome are different. As a first step to clarify the differential pathogenesis between the variants, the present study focused on examining the expression of the transforming growth factor (TGF)-beta family in the brain of rats infected with BDV. The main results were as follows. (1) BDV infection, irrespective of the variant, up-regulates TGF-beta1 expression in the brain, (2) the expressions of signal receptors for TGF-beta1 are also increased, (3) the expression of brain inhibin/activin betaE is up-regulated by BDV infection, and (4) the expression of brain inhibin/activin betaC tends to be higher in rats exhibiting severe Borna disease. These results indicate that members of the TGF-beta family are involved in neuronal disorders induced by BDV infection in a ligand-dependent manner. In particular, up-regulation of inhibin/activin betaC may be a key event responsible for induction of the stronger pathogenesis of the CRNP5 variant of BDV.

  6. T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression.

    Science.gov (United States)

    Mustafa, Dana A M; Pedrosa, Rute M S M; Smid, Marcel; van der Weiden, Marcel; de Weerd, Vanja; Nigg, Alex L; Berrevoets, Cor; Zeneyedpour, Lona; Priego, Neibla; Valiente, Manuel; Luider, Theo M; Debets, Reno; Martens, John W M; Foekens, John A; Sieuwerts, Anieta M; Kros, Johan M

    2018-01-19

    The discovery of genes and molecular pathways involved in the formation of brain metastasis would direct the development of therapeutic strategies to prevent this deadly complication of cancer. By comparing gene expression profiles of Estrogen Receptor negative (ER-) primary breast tumors between patients who developed metastasis to brain and to organs other than brain, we found that T lymphocytes promote the formation of brain metastases. To functionally test the ability of T cells to promote brain metastasis, we used an in vitro blood-brain barrier (BBB) model. By co-culturing T lymphocytes with breast cancer cells, we confirmed that T cells increase the ability of breast cancer cells to cross the BBB. Proteomics analysis of the tumor cells revealed Guanylate-Binding Protein 1 (GBP1) as a key T lymphocyte-induced protein that enables breast cancer cells to cross the BBB. The GBP1 gene appeared to be up-regulated in breast cancer of patients who developed brain metastasis. Silencing of GBP1 reduced the ability of breast cancer cells to cross the in vitro BBB model. In addition, the findings were confirmed in vivo in an immunocompetent syngeneic mouse model. Co-culturing of ErbB2 tumor cells with activated T cells induced a significant increase in Gbp1 expression by the cancer cells. Intracardial inoculation of the co-cultured tumor cells resulted in preferential seeding to brain. Moreover, intracerebral outgrowth of the tumor cells was demonstrated. The findings point to a role of T cells in the formation of brain metastases in ER- breast cancers, and provide potential targets for intervention to prevent the development of cerebral metastases.

  7. Early expression of hypocretin/orexin in the chick embryo brain.

    Directory of Open Access Journals (Sweden)

    Kyle E Godden

    Full Text Available Hypocretin/Orexin (H/O neuropeptides are released by a discrete group of neurons in the vertebrate hypothalamus which play a pivotal role in the maintenance of waking behavior and brain state control. Previous studies have indicated that the H/O neuronal development differs between mammals and fish; H/O peptide-expressing cells are detectable during the earliest stages of brain morphogenesis in fish, but only towards the end of brain morphogenesis (by ∼ 85% of embryonic development in rats. The developmental emergence of H/O neurons has never been previously described in birds. With the goal of determining whether the chick developmental pattern was more similar to that of mammals or of fish, we investigated the emergence of H/O-expressing cells in the brain of chick embryos of different ages using immunohistochemistry. Post-natal chick brains were included in order to compare the spatial distribution of H/O cells with that of other vertebrates. We found that H/O-expressing cells appear to originate from two separate places in the region of the diencephalic proliferative zone. These developing cells express the H/O neuropeptide at a comparatively early age relative to rodents (already visible at 14% of the way through fetal development, thus bearing a closer resemblance to fish. The H/O-expressing cell population proliferates to a large number of cells by a relatively early embryonic age. As previously suggested, the distribution of H/O neurons is intermediate between that of mammalian and non-mammalian vertebrates. This work suggests that, in addition to its roles in developed brains, the H/O peptide may play an important role in the early embryonic development of non-mammalian vertebrates.

  8. A Comparison of Brain Gene Expression Levels in Domesticated and Wild Animals

    Science.gov (United States)

    Albert, Frank W.; Somel, Mehmet; Carneiro, Miguel; Aximu-Petri, Ayinuer; Halbwax, Michel; Thalmann, Olaf; Blanco-Aguiar, Jose A.; Trut, Lyudmila; Villafuerte, Rafael; Ferrand, Nuno; Kaiser, Sylvia; Jensen, Per; Pääbo, Svante

    2012-01-01

    Domestication has led to similar changes in morphology and behavior in several animal species, raising the question whether similarities between different domestication events also exist at the molecular level. We used mRNA sequencing to analyze genome-wide gene expression patterns in brain frontal cortex in three pairs of domesticated and wild species (dogs and wolves, pigs and wild boars, and domesticated and wild rabbits). We compared the expression differences with those between domesticated guinea pigs and a distant wild relative (Cavia aperea) as well as between two lines of rats selected for tameness or aggression towards humans. There were few gene expression differences between domesticated and wild dogs, pigs, and rabbits (30–75 genes (less than 1%) of expressed genes were differentially expressed), while guinea pigs and C. aperea differed more strongly. Almost no overlap was found between the genes with differential expression in the different domestication events. In addition, joint analyses of all domesticated and wild samples provided only suggestive evidence for the existence of a small group of genes that changed their expression in a similar fashion in different domesticated species. The most extreme of these shared expression changes include up-regulation in domesticates of SOX6 and PROM1, two modulators of brain development. There was almost no overlap between gene expression in domesticated animals and the tame and aggressive rats. However, two of the genes with the strongest expression differences between the rats (DLL3 and DHDH) were located in a genomic region associated with tameness and aggression, suggesting a role in influencing tameness. In summary, the majority of brain gene expression changes in domesticated animals are specific to the given domestication event, suggesting that the causative variants of behavioral domestication traits may likewise be different. PMID:23028369

  9. A comparison of brain gene expression levels in domesticated and wild animals.

    Directory of Open Access Journals (Sweden)

    Frank W Albert

    2012-09-01

    Full Text Available Domestication has led to similar changes in morphology and behavior in several animal species, raising the question whether similarities between different domestication events also exist at the molecular level. We used mRNA sequencing to analyze genome-wide gene expression patterns in brain frontal cortex in three pairs of domesticated and wild species (dogs and wolves, pigs and wild boars, and domesticated and wild rabbits. We compared the expression differences with those between domesticated guinea pigs and a distant wild relative (Cavia aperea as well as between two lines of rats selected for tameness or aggression towards humans. There were few gene expression differences between domesticated and wild dogs, pigs, and rabbits (30-75 genes (less than 1% of expressed genes were differentially expressed, while guinea pigs and C. aperea differed more strongly. Almost no overlap was found between the genes with differential expression in the different domestication events. In addition, joint analyses of all domesticated and wild samples provided only suggestive evidence for the existence of a small group of genes that changed their expression in a similar fashion in different domesticated species. The most extreme of these shared expression changes include up-regulation in domesticates of SOX6 and PROM1, two modulators of brain development. There was almost no overlap between gene expression in domesticated animals and the tame and aggressive rats. However, two of the genes with the strongest expression differences between the rats (DLL3 and DHDH were located in a genomic region associated with tameness and aggression, suggesting a role in influencing tameness. In summary, the majority of brain gene expression changes in domesticated animals are specific to the given domestication event, suggesting that the causative variants of behavioral domestication traits may likewise be different.

  10. Notch receptor expression in neurogenic regions of the adult zebrafish brain.

    Directory of Open Access Journals (Sweden)

    Vanessa de Oliveira-Carlos

    Full Text Available The adult zebrash brain has a remarkable constitutive neurogenic capacity. The regulation and maintenance of its adult neurogenic niches are poorly understood. In mammals, Notch signaling is involved in stem cell maintenance both in embryonic and adult CNS. To better understand how Notch signaling is involved in stem cell maintenance during adult neurogenesis in zebrafish we analysed Notch receptor expression in five neurogenic zones of the adult zebrafish brain. Combining proliferation and glial markers we identified several subsets of Notch receptor expressing cells. We found that 90 [Formula: see text] of proliferating radial glia express notch1a, notch1b and notch3. In contrast, the proliferating non-glial populations of the dorsal telencephalon and hypothalamus rarely express notch3 and about half express notch1a/1b. In the non-proliferating radial glia notch3 is the predominant receptor throughout the brain. In the ventral telencephalon and in the mitotic area of the optic tectum, where cells have neuroepithelial properties, notch1a/1b/3 are expressed in most proliferating cells. However, in the cerebellar niche, although progenitors also have neuroepithelial properties, only notch1a/1b are expressed in a high number of PCNA [Formula: see text] cells. In this region notch3 expression is mostly in Bergmann glia and at low levels in few PCNA [Formula: see text] cells. Additionally, we found that in the proliferation zone of the ventral telencephalon, Notch receptors display an apical high to basal low gradient of expression. Notch receptors are also expressed in subpopulations of oligodendrocytes, neurons and endothelial cells. We suggest that the partial regional heterogeneity observed for Notch expression in progenitor cells might be related to the cellular diversity present in each of these neurogenic niches.

  11. Astrocyte cultures derived from human brain tissue express angiotensinogen mRNA

    Energy Technology Data Exchange (ETDEWEB)

    Milsted, A.; Barna, B.P.; Ransohoff, R.M.; Brosnihan, K.B.; Ferrario, C.M. (Cleveland Clinic Foundation, OH (USA))

    1990-08-01

    The authors have identified human cultured cell lines that are useful for studying angiotensinogen gene expression and its regulation in the central nervous system. A model cell system of human central nervous system origin expressing angiotensinogen has not previously been available. Expression of angiotensinogen mRNA appears to be a basal property of noninduced human astrocytes, since astrocytic cell lines derived from human glioblastomas or nonneoplastic human brain tissue invariably produced angiotensinogen mRNA. In situ hybridization histochemistry revealed that angiotensinogen mRNA production was not limited to a subpopulation of astrocytes because >99% of cells in these cultures contained angiotensinogen mRNA. These cell lines will be useful in studies of the molecular mechanisms controlling angiotensin synthesis and the role of biologically active angiotensin in the human brain by allowing the authors to examine regulation of expression of the renin-angiotensin system in human astrocyte cultures.

  12. [Expression of CaMK II delta in cerebral cortex following traumatic brain injury].

    Science.gov (United States)

    Pan, Hong; Zhang, Jing-Jing; Xu, Dong-Dong; Gu, Zhen-Yong; Tao, Lu-Yang; Zhang, Ming-Yang

    2014-06-01

    To observe the time-course expression of calcium-calmodulin dependent protein kinase II delta (CaMK II delta) in cerebral cortex after traumatic brain injury (TBI). The TBI rat model was established. The expression of CaMK II delta in cerebral cortex around injured area was tested by Western blotting and immunohistochemical staining. Western blotting revealed expression of CaMK II delta in normal rat brain cortex. It gradually increased after TBI, peaked after 3 days, and then returned to normal level. The result of immunohistochemical staining was consistent with that of Western blotting. The expression of CaMK II delta around injured area after TBI increased initially and then decreased. It could be used as a new indicator for wound age determination following TBI.

  13. Why India should be interested in a project like INO ?

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Why India should be interested in a project like INO ? Excitement of carrying out front ranking research in the exciting area of neutrino physics. Will address a key question in neutrino physics- Neutrino mass ordering. Help us to pick up the correct theory beyond ...

  14. Inclusion of GENIE as neutrino event generator for INO ICAL

    Indian Academy of Sciences (India)

    physics experiment in the INO cavern. Its main goal is the determination of sign of 2–3 mass-squared difference, Δ m 32 2 ( = m 3 2 − m 2 2 ) in the presence of matter effects, apart from the precise measurement of other neutrino parameters. Like all ...

  15. Astrocytes cultured from specific brain regions differ in their expression of adrenergic binding sites.

    Science.gov (United States)

    Ernsberger, P; Iacovitti, L; Reis, D J

    1990-05-28

    We sought to characterize regional heterogeneity of astrocytes using adrenergic receptor sites as cellular markers. Primary cultures made from 6 regions of neonatal rat brain consisted almost exclusively of astrocytes. Membranes from astrocytes cultured 1-3 weeks were prepared for radioligand binding assays of beta- and alpha 2-adrenergic sites using the ligands [3H]dihydroalprenolol and [3H]p-aminoclonidine, respectively. Receptor expression was not affected by time in culture. Astrocytes from different brain regions varied up to 3-fold with respect to number but not affinity for both classes of adrenergic binding site with a rank order of cerebral cortex = superior colliculus greater than hippocampus = ventral midbrain greater than or equal to caudate nucleus greater than or equal to hypothalamus. Binding to beta- and alpha 2-adrenergic receptors was positively correlated across brain regions. Astrocytic receptor binding in each region did not correspond to total receptor levels assessed by quantitative autoradiography. We conclude that: (a) astrocytes are markedly heterogeneous between major brain regions with respect to expression of adrenergic binding sites; (b) regional variations in the density of adrenergic binding sites in brain reflect, in part, local specialization of astrocytes; and (c) a substantial proportion of the adrenergic binding sites in some brain regions may be on astrocytes.

  16. Expression of manganese superoxide dismutase in rat blood, heart and brain during induced systemic hypoxia

    Directory of Open Access Journals (Sweden)

    Septelia I. Wanandi

    2011-02-01

    Full Text Available Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to  determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2 for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1 and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21, MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can  possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

  17. Regional differences in gene expression and promoter usage in aged human brains

    KAUST Repository

    Pardo, Luba M.

    2013-02-19

    To characterize the promoterome of caudate and putamen regions (striatum), frontal and temporal cortices, and hippocampi from aged human brains, we used high-throughput cap analysis of gene expression to profile the transcription start sites and to quantify the differences in gene expression across the 5 brain regions. We also analyzed the extent to which methylation influenced the observed expression profiles. We sequenced more than 71 million cap analysis of gene expression tags corresponding to 70,202 promoter regions and 16,888 genes. More than 7000 transcripts were differentially expressed, mainly because of differential alternative promoter usage. Unexpectedly, 7% of differentially expressed genes were neurodevelopmental transcription factors. Functional pathway analysis on the differentially expressed genes revealed an overrepresentation of several signaling pathways (e.g., fibroblast growth factor and wnt signaling) in hippocampus and striatum. We also found that although 73% of methylation signals mapped within genes, the influence of methylation on the expression profile was small. Our study underscores alternative promoter usage as an important mechanism for determining the regional differences in gene expression at old age.

  18. Differential expression of human homeodomain TGIFLX in brain tumor cell lines.

    Directory of Open Access Journals (Sweden)

    Reza Raoofian

    2013-12-01

    Full Text Available Glioblastoma is the most common and the most lethal primary brain cancer. This malignancy is highly locally invasive, rarely metastatic and resistant to current therapies. Little is known about the distinct molecular biology of glioblastoma multiforme (GBM in terms of initiation and progression. So far, several molecular mechanisms have been suggested to implicate in GBM development. Homeodomain (HD transcription factors play central roles in the expression of genomic information in all known eukaryotes. The TGIFX homeobox gene was originally discovered in human adult testes. Our previous study showed implications of TGIFLX in prostate cancer and azoospermia, although the molecular mechanism by which TGIFLX acts is unknown. Moreover, studies reported that HD proteins are involved in normal and abnormal brain developments. We examined the expression pattern of TGIFLX in different human brain tumor cell lines including U87MG, A172, Daoy and 1321N1. Interestingly, real time RT-PCR and western blot analysis revealed a high level of TGIFLX expression in A172 cells but not in the other cell lines. We subsequently cloned the entire coding sequence of TGIFLX gene into the pEGFP-N1 vector, eukaryotic expression vector encoding eGFP, and transfected into the U-87 MG cell line. The TGIFLX-GFP expression was confirmed by real time RT-PCR and UV-microscopic analysis. Upon transfection into U87 cells, fusion protein TGIFLX-GFP was found to locate mainly in the nucleus. This is the first report to determine the nuclear localization of TGIFLX and evaluation of its expression level between different brain tumor cell lines. Our data also suggest that TGIFLX gene dysregulation could be involved in the pathogenesis of some human brain tumors.

  19. Aging shapes the population-mean and -dispersion of gene expression in human brains

    Directory of Open Access Journals (Sweden)

    Candice Brinkmeyer-Langford

    2016-08-01

    Full Text Available Human aging is associated with cognitive decline and an increased risk of neurodegenerative disease. Our objective for this study was to evaluate potential relationships between age and variation in gene expression across different regions of the brain. We analyzed the Genotype-Tissue Expression (GTEx data from 54 and 101 tissue samples across 13 brain regions in post-mortem donors of European descent aged between 20 and 70 years at death. After accounting for the effects of covariates and hidden confounding factors, we identified 1,446 protein-coding genes whose expression in one or more brain regions is correlated with chronological age at a false discovery rate of 5%. These genes are involved in various biological processes including apoptosis, mRNA splicing, amino acid biosynthesis, and neurotransmitter transport. The distribution of these genes among brain regions is uneven, suggesting variable regional responses to aging. We also found that the aging response of many genes, e.g., TP37 and C1QA, depends on individuals’ genotypic backgrounds. Finally, using dispersion-specific analysis, we identified genes such as IL7R, MS4A4E, and TERF1/TERF2 whose expressions are differentially dispersed by aging, i.e., variances differ between age groups. Our results demonstrate that age-related gene expression is brain region-specific, genotype-dependent, and associated with both mean and dispersion changes. Our findings provide a foundation for more sophisticated gene expression modeling in the studies of age-related neurodegenerative diseases.

  20. HO1 and Wnt expression is independently regulated in female mice brains following permanent ischemic brain injury.

    Science.gov (United States)

    Tulsulkar, Jatin; Ward, Alicia; Shah, Zahoor A

    2017-05-01

    A gender difference in stroke is observed throughout epidemiologic studies, pathophysiology, treatment and outcomes. We investigated the neuroprotective role of hemeoxygenase (HO) enzyme, which catabolizes free heme to bilirubin, carbon monoxide and biliverdin in the female brain after permanent ischemia. We have previously reported in male mice that genetic deletion of HO1 exacerbates the brain damage after permanent ischemia, and the mechanism of neuroprotection is dependent on the HO1/Wnt pathway; however, the role of HO1/Wnt mediated neuroprotection in the female brain is yet to be investigated. We subjected ovary intact female mice, HO1(-/-) intact, HO1 inhibitor tin mesoporphyrin (SnMP) treated intact and/or ovariectomized female mice to permanent ischemia (pMCAO), and the animals were sacrificed after 7days. The SnMP treatment for 7days significantly reduced the HO1 enzyme activity as compared to that of vehicle treated group. Infarct volume analysis showed significantly lower infarct in intact, HO1(-/-) intact, and SnMP treated group as compared to the OVX group, suggesting the role of estrogen in neuroprotection. However, there were no differences in infarct volume observed between the intact, HO1(-/-) and SnMP treated group, suggesting a sexually dimorphic role of HO1 neuroprotection. Western blot analysis on intact and SnMP-treated groups subjected to pMCAO suggested no significant differences in Wnt expression. Together, these results suggest that HO1 neuroprotection is sexually dimorphic and Wnt expression is independently regulated in the female brain following permanent ischemia. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. EPA or DHA enhanced oxidative stress and aging protein expression in brain of d-galactose treated mice.

    Science.gov (United States)

    Hsu, Yuan-Man; Yin, Mei-Chin

    2016-06-01

    Effects of eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6) upon fatty acid composition, oxidative and inflammatory factors and aging proteins in brain of d-galactose (DG) treated aging mice were examined. Each fatty acid at 7 mg/kg BW/week was supplied for 8 weeks. Brain aging was induced by DG treatment (100 mg/kg body weight) via daily subcutaneous injection for 8 weeks. DG, EPA and DHA treatments changed brain fatty acid composition. DG down-regulated brain Bcl-2 expression and up-regulated Bax expression. Compared with DG groups, EPA and DHA further enhanced Bax expression. DG decreased glutathione content, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production, the intake of EPA or DHA caused greater ROS and GSSG formation. DG treatments up-regulated the protein expression of p47(phox) and gp91(phox), and the intake of EPA or DHA led to greater p47(phox) and gp91(phox) expression. DG increased brain prostaglandin E2 (PGE2) levels, and cyclooxygenase (COX)-2 expression and activity, the intake of EPA or DHA reduced brain COX-2 activity and PGE2 formation. DG enhanced brain p53, p16 and p21 expression. EPA and DHA intake led to greater p21 expression, and EPA only caused greater p53 and p16 expression. These findings suggest that these two PUFAs have toxic effects toward aging brain.

  2. Killing of Brain Tumor Cells by Hypoxia-Responsive Element Mediated Expression of BAX

    Directory of Open Access Journals (Sweden)

    Hangjun Ruan

    1999-11-01

    Full Text Available The presence of radioresistant hypoxic cells in human brain tumors limits the overall effectiveness of conventional fractionated radiation therapy. Tumor-specific therapies that target hypoxic cells are clearly needed. We have investigated the expression of suicide genes under hypoxia by a hypoxia-responsive element (HRE, which can be activated through hypoxia-inducible factor-1 (HIF-1. We transfected plasmids containing multiple copies of HIRE into U-87 MG and U-251 MG-NCI human brain tumor cells and tested their ability to induce LacZ gene expression under anoxia. Gene expression under anoxia versus oxia was increased about 12-fold for U-87 MG cells and about fourfold for U-251 MG-NCI cells. At intermediate hypoxic conditions, increased LacZ gene expression in U-87 MG cells was induced by the plasmid that contained three HREs, but not by the plasmid with two HREs. Lastly, when we placed a suicide gene BAX under the control of HREs, cells transfected with the BAX plasmids were preferentially killed through apoptosis under anoxia. Our studies demonstrate that HRE-regulated gene expression is active in brain tumor cells, and that the amount of increased gene expression obtained is dependent on the cell line, the HIRE copy number, and the degree of hypoxia.

  3. Misregulated E-cadherin expression associated with an aggressive brain tumor phenotype.

    Directory of Open Access Journals (Sweden)

    Laura J Lewis-Tuffin

    Full Text Available BACKGROUND: Cadherins are essential components of the adherens junction complexes that mediate cell-cell adhesion and regulate cell motility. During tissue morphogenesis, changes in cadherin expression (known as cadherin switching are a common mechanism for altering cell fate. Cadherin switching is also common during epithelial tumor progression, where it is thought to promote tumor invasion and metastasis. E-cadherin is the predominant cadherin expressed in epithelial tissues, but its expression is very limited in normal brain. METHODOLOGY/PRINCIPAL FINDINGS: We identified E-cadherin expression in a retrospective series of glioblastomas exhibiting epithelial or pseudoepithelial differentiation. Unlike in epithelial tissues, E-cadherin expression in gliomas correlated with an unfavorable clinical outcome. Western blotting of two panels of human GBM cell lines propagated either as xenografts in nude mice or grown under conventional cell culture conditions confirmed that E-cadherin expression is rare. However, a small number of xenograft lines did express E-cadherin, its expression correlating with increased invasiveness when the cells were implanted orthotopically in mouse brain. In the conventionally cultured SF767 glioma cell line, E-cadherin expression was localized throughout the plasma membrane rather than being restricted to areas of cell-cell contact. ShRNA knockdown of E-cadherin in these cells resulted in decreased proliferation and migration in vitro. CONCLUSIONS/SIGNIFICANCE: Our data shows an unexpected correlation between the abnormal expression of E-cadherin in a subset of GBM tumor cells and the growth and migration of this aggressive brain tumor subtype.

  4. Evidence of a bigenomic regulation of mitochondrial gene expression by thyroid hormone during rat brain development

    Energy Technology Data Exchange (ETDEWEB)

    Sinha, Rohit Anthony; Pathak, Amrita; Mohan, Vishwa; Babu, Satish; Pal, Amit; Khare, Drirh [Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014 (India); Godbole, Madan M., E-mail: madangodbole@yahoo.co.in [Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014 (India)

    2010-07-02

    Hypothyroidism during early mammalian brain development is associated with decreased expression of various mitochondrial encoded genes along with evidence for mitochondrial dysfunction. However, in-spite of the similarities between neurological disorders caused by perinatal hypothyroidism and those caused by various genetic mitochondrial defects we still do not know as to how thyroid hormone (TH) regulates mitochondrial transcription during development and whether this regulation by TH is nuclear mediated or through mitochondrial TH receptors? We here in rat cerebellum show that hypothyroidism causes reduction in expression of nuclear encoded genes controlling mitochondrial biogenesis like PGC-1{alpha}, NRF-1{alpha} and Tfam. Also, we for the first time demonstrate a mitochondrial localization of thyroid hormone receptor (mTR) isoform in developing brain capable of binding a TH response element (DR2) present in D-loop region of mitochondrial DNA. These results thus indicate an integrated nuclear-mitochondrial cross talk in regulation of mitochondrial transcription by TH during brain development.

  5. Comparison of regional gene expression differences in the brains of the domestic dog and human

    Directory of Open Access Journals (Sweden)

    Kennerly Erin

    2004-11-01

    Full Text Available Abstract Comparison of the expression profiles of 2,721 genes in the cerebellum, cortex and pituitary gland of three American Staffordshire terriers, one beagle and one fox hound revealed regional expression differences in the brain but failed to reveal marked differences among breeds, or even individual dogs. Approximately 85 per cent (42 of 49 orthologue comparisons of the regional differences in the dog are similar to those that differentiate the analogous human brain regions. A smaller percentage of human differences were replicated in the dog, particularly in the cortex, which may generally be evolving more rapidly than other brain regions in mammals. This study lays the foundation for detailed analysis of the population structure of transcriptional variation as it relates to cognitive and neurological phenotypes in the domestic dog.

  6. Vascular endothelial growth factor and vascular endothelial growth factor receptor-2 expression in mdx mouse brain.

    Science.gov (United States)

    Nico, Beatrice; Corsi, Patrizia; Vacca, Angelo; Roncali, Luisa; Ribatti, Domenico

    2002-10-25

    Recent data have demonstrated that vascular endothelial growth factor (VEGF) is expressed by subsets of neurons, coincident with angiogenesis within its developing cerebral cortex. In this study, with the aim of elucidating the mechanisms of vascular involvement during brain impairment in Duchenne muscular distrophy (DMD), we have correlated the vascular density with VEGF and VEGF receptor-2 (VEGFR-2) expression in the brain cortex of normal and mdx mouse, an animal model with a genetic defect in a region homologous with the human DMD gene. Results showed that in mdx mouse, tissue area occupied by microvessels positive to factor VIII related antigen and VEGFR-2 increased in parallel to the tissue area occupied by neurons positive to VEGF. Our data suggest that increased vascularity in the brain of mdx mouse may be due, at least in part, to proliferation of endothelial cells in response to VEGF secreted by neuronal cells.

  7. A novel brain receptor is expressed in a distinct population of olfactory sensory neurons

    NARCIS (Netherlands)

    Conzelmann, S; Levai, O; Bode, B; Eisel, U; Raming, K; Breer, H; Strotmann, J

    2000-01-01

    Three novel G-protein-coupled receptor genes related to the previously described RA1c gene have been isolated from the mouse genome. Expression of these genes has been detected in distinct areas of the brain and also in the olfactory epithelium of the nose. Developmental studies revealed a

  8. Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier.

    Science.gov (United States)

    Osgood, Doreen; Miller, Miles C; Messier, Arthur A; Gonzalez, Liliana; Silverberg, Gerald D

    2017-09-01

    Decreased clearance of potentially toxic metabolites, due to aging changes, likely plays a significant role in the accumulation of amyloid-beta (Aβ) peptides and other macromolecules in the brain of the elderly and in the patients with Alzheimer's disease (AD). Aging is the single most important risk factor for AD development. Aβ transport receptor proteins expressed at the blood-brain barrier are significantly altered with age: the efflux transporters lipoprotein receptor-related protein 1 and P-glycoprotein are reduced, whereas the influx transporter receptor for advanced glycation end products is increased. These receptors play an important role in maintaining brain biochemical homeostasis. We now report that, in a rat model of aging, gene transcription is altered in aging, as measured by Aβ receptor gene messenger RNA (mRNA) at 3, 6, 9, 12, 15, 20, 30, and 36 months. Gene mRNA expression from isolated cerebral microvessels was measured by quantitative polymerase chain reaction. Lipoprotein receptor-related protein 1 and P-glycoprotein mRNA were significantly reduced in aging, and receptor for advanced glycation end products was increased, in parallel with the changes seen in receptor protein expression. Transcriptional changes appear to play a role in aging alterations in blood-brain barrier receptor expression and Aβ accumulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Gene × Smoking Interactions on Human Brain Gene Expression: Finding Common Mechanisms in Adolescents and Adults

    Science.gov (United States)

    Wolock, Samuel L.; Yates, Andrew; Petrill, Stephen A.; Bohland, Jason W.; Blair, Clancy; Li, Ning; Machiraju, Raghu; Huang, Kun; Bartlett, Christopher W.

    2013-01-01

    Background: Numerous studies have examined gene × environment interactions (G × E) in cognitive and behavioral domains. However, these studies have been limited in that they have not been able to directly assess differential patterns of gene expression in the human brain. Here, we assessed G × E interactions using two publically available datasets…

  10. RESEARCH NOTE Study of bantam miRNA expression in brain ...

    Indian Academy of Sciences (India)

    Navya

    RESEARCH NOTE. Study of bantam miRNA expression in brain tumour resulted due to loss of polarity modules in Drosophila melanogaster. ANIMESH BANERJEE and JAGAT K ROY*. Banaras Hindu University, Varanasi, UP INDIA. For correspondence. E-mail: jkroy@bhu.ac.in. Introduction: Tumorigenesisinvolves a ...

  11. Expressive Electronic Journal Writing: Freedom of Communication for Survivors of Acquired Brain Injury

    Science.gov (United States)

    Fraas, Michael; Balz, Magdalen A.

    2008-01-01

    In addition to the impaired ability to effectively communicate, adults with acquired brain injury (ABI) also experience high incidences of depression, social isolation, and decreased quality of life. Expressive writing programs have been shown to be effective in alleviating these concomitant impairments in other populations including incarcerated…

  12. Chronic alcohol consumption increases the expression of uncoupling protein-2 and -4 in the brain.

    Science.gov (United States)

    Graw, Jan A; von Haefen, Clarissa; Poyraz, Deniz; Möbius, Nadine; Sifringer, Marco; Spies, Claudia D

    2013-10-01

    Chronic alcohol consumption leads to oxidative stress in a variety of cells, especially in brain cells because they have a reduced oxidative metabolism of alcohol. Uncoupling proteins (UCPs) are anion channels of the inner mitochondrial membrane, which can decouple internal respiration. "Mild uncoupling" of the mitochondrial respiratory chain leads to a reduced production of free radicals (reactive oxygen species) and a reduction in oxidative cell stress. The extent to which chronic alcohol consumption regulates UCP-2 and -4 in the brain is still unknown. We examined the effects of a 12-week 5% alcohol diet in the brain of male Wistar rats (n = 34). Cerebral gene and protein expression of UCP-2, -4, as well as Bcl-2, and the release of cytochrome c out of the mitochondria were detected by real-time polymerase chain reaction and Western blot analysis. The percentage of degenerated cells was determined by Fluoro-Jade B staining of brain slices. Brains of rats with a chronic alcohol diet showed an increased gene and protein expression of UCP-2 and -4. The expression of the antiapoptotic protein Bcl-2 in the brain of the alcohol-treated animals was decreased significantly, whereas cytochrome c release from mitochondria was increased. In addition increased neurodegeneration could be demonstrated in the alcohol-treated animals. Chronic alcohol consumption leads to a cerebral induction of UCP-2 and -4 with a simultaneous decrease in the antiapoptotic protein Bcl-2, cytochrome c release from mitochondria and increased neurodegeneration. This study reveals a compensatory effect of UCP-2 and -4 in the brain during chronic alcohol consumption. Copyright © 2013 by the Research Society on Alcoholism.

  13. Age-related changes of the nitric oxide system in the rat brain.

    Science.gov (United States)

    Siles, Eva; Martínez-Lara, Esther; Cañuelo, Ana; Sánchez, Marta; Hernández, Raquel; López-Ramos, Juan Carlos; Del Moral, María Luisa; Esteban, Francisco José; Blanco, Santos; Pedrosa, Juan Angel; Rodrigo, José; Peinado, María Angeles

    2002-11-29

    This work examines the age-related changes of the NO pathway in the central nervous system (CNS), analyzing nitric oxide synthase (NOS) isoform expression, the level of nitrotyrosine-modified proteins, and the NOS activity in the cerebral cortex, decorticated brain (basal ganglia, thalamus, hypothalamus, tegtum and tegmentum) and cerebellum of young, adult and aged rats. Our data demonstrate that the different NOS isoforms are not uniformly expressed across the CNS. In this sense, the nNOS and eNOS isoenzymes are expressed mainly in the cerebellum and decorticated brain, respectively, while the iNOS isoenzyme shows the highest level in cerebellum. Concerning age, in the cerebral cortex nNOS significantly increased its expression only in adult animals; meanwhile, in the cerebellum the eNOS expression decreased whereas iNOS increased in adult and aged rats. No age-related changes in any isoform were found in decorticated brain. NOS activity, determined by nitrate plus nitrite quantification, registered the highest levels in the cerebellum, where the significant increase detected with aging was probably related to iNOS activity. The number of nitrotyrosine-modified immunoreactive bands differed among regions; thus, the highest number was detected in the decorticated brain while the cerebellum showed the least number of bands. Finally, bulk protein nitration increased in cerebral cortex only in adult animal. No changes were found in the decorticated brain, and the decrease detected in the cerebellum of aged animals was not significant. According to these results, the NO pathway is differently modified with age in the three CNS regions analyzed. Copyright 2002 Elsevier Science B.V.

  14. Brain expression genome-wide association study (eGWAS identifies human disease-associated variants.

    Directory of Open Access Journals (Sweden)

    Fanggeng Zou

    Full Text Available Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202 and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197. We conducted an expression genome-wide association study (eGWAS using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs significant in both ADs and non-ADs (q<0.05, p=7.70 × 10(-5-1.67 × 10(-82. Of these, 2,089 were also significant in the temporal cortex (p=1.85 × 10(-5-1.70 × 10(-141. The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6. We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6 of significant cisSNPs with suggestive AD-risk association (p<10(-3 in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings

  15. ino Reinart : ma usun väärtuspõhise poliitika olemasolusse / Väino Reinart

    Index Scriptorium Estoniae

    Reinart, Väino, 1962-

    2007-01-01

    Värske Eesti suursaadik Ameerika Ühendriikides Väino Reinart väljendab oma intervjuus seisukohta, et Ameerika viib maailmaareenil ellu inimlikele väärtustele tuginevat poliitikat ja et salatehingute sõlmimine on jäänud diplomaatia ajalukku. Lisa: Curriculum Vitae

  16. Identification and expression analysis of nervous wreck, which is preferentially expressed in the brain of the male silkworm moth, Bombyx mori.

    Science.gov (United States)

    Kiya, Taketoshi; Iwami, M

    2011-10-01

    Sexually dimorphic neural circuits are essential for reproductive behaviour. The molecular basis of sexual dimorphism in the silkworm moth (Bombyx mori) brain, however, is unclear. We conducted cDNA subtraction screening and identified nervous wreck (Bmnwk), a synaptic growth regulatory gene, whose expression is higher in the male brain than in the female brain of the silkworm. Bmnwk was preferentially expressed in the brain at the late pupae and adult stages. In situ hybridization revealed that Bmnwk is highly expressed in the optic lobe of the male moth brain. These findings suggest that Bmnwk has a role in the development and/or maintenance of the optic lobe in the male silkworm brain. © 2011 The Authors. Insect Molecular Biology © 2011 The Royal Entomological Society.

  17. Expressive writing in people with traumatic brain injury and learning disability.

    Science.gov (United States)

    Wheeler, Lisa; Nickerson, Sherry; Long, Kayla; Silver, Rebecca

    2014-01-01

    There is a dearth of systematic studies of expressive writing disorder (EWD) in persons with Traumatic Brain Injury (TBI). It is unclear if TBI survivors' written expression differs significantly from that experienced by persons with learning disabilities. It is also unclear which cognitive or neuropsychological variables predict problems with expressive writing (EW) or the EWD. This study investigated the EW skill, and the EWD in adults with mild traumatic brain injuries (TBI) relative to those with learning disabilities (LD). It also determined which of several cognitive variables predicted EW and EWD. Principle Component Analysis (PCA) of writing samples from 28 LD participants and 28 TBI survivors revealed four components of expressive writing skills: Reading Ease, Sentence Fluency, Grammar and Spelling, and Paragraph Fluency. There were no significant differences between the LD and TBI groups on any of the expressive writing components. Several neuropsychological variables predicted skills of written expression. The best predictors included measures of spatial perception, verbal IQ, working memory, and visual memory. TBI survivors and persons with LD do not differ markedly in terms of expressive writing skill. Measures of spatial perception, visual memory, verbal intelligence, and working memory predict writing skill in both groups. Several therapeutic interventions are suggested that are specifically designed to improve deficits in expressive writing skills in individuals with TBI and LD.

  18. The retinal pigment epithelium (RPE) induces FasL and reduces iNOS and Cox2 in primary monocytes.

    Science.gov (United States)

    Hettich, Christin; Wilker, Sebastian; Mentlein, Rolf; Lucius, Ralph; Roider, Johann; Klettner, Alexa

    2014-11-01

    Retinal pigment epithelium (RPE) cells may alter the phenotype of monocytes by soluble factors that may be influenced by stimulation of the RPE. Since RPE cells carry the toll-like receptor-3 (TLR3) that detects and reacts to viral infection through binding of dsRNA we investigated the effects of RPE cells with or without TLR3 stimulation on blood-derived monocytes with respect to regulation of pro-/anti-inflammatory cytokines, anti-angiogenic factors and migratory properties. Primary RPE cells were prepared from porcine eyes; monocytes were prepared from porcine blood. TLR3 activation was induced by polyinosinic:polycytidylic acid (Poly I:C). RPE cells were stimulated with Poly I:C in different concentrations for 24 hours and a cell culture supernatant was applied to the monocytes. Expression of CD14 and Fas ligand (FasL) was determined via flow cytometry. The expression of IL-6, IL-1ß, TNFα, Cox2, iNOS and IL-10 was determined via quantitative RT-PCR. Migration was determined using Boyden chamber experiments. The supernatant of RPE cells, irrespective of TLR3 activation, induced FasL expression in the monocytes. Expression of iNOS and Cox2 was reduced by RPE cells and the reduction of Cox2 but not if iNOS was lost under TLR3 activation. No induction of IL-6, IL-1ß, IL-10 or TNFα by the RPE was seen. TLR3-activated RPE cells induced monocyte migration. RPE cells induce an upregulation of FasL and a downregulation of iNOS and Cox2 without upregulating inflammatory cytokines, possibly inducing an anti-angiogenic phenotype in the monocytes. This phenotype is still upheld after challenging RPE cells with dsRNA, mimicking a viral infection.

  19. Further statistical analysis for genome-wide expression evolution in primate brain/liver/fibroblast tissue

    Directory of Open Access Journals (Sweden)

    Gu Jianying

    2004-05-01

    Full Text Available Abstract In spite of only a 1-2 per cent genomic DNA sequence difference, humans and chimpanzees differ considerably in behaviour and cognition. Affymetrix microarray technology provides a novel approach to addressing a long-term debate on whether the difference between humans and chimpanzees results from the alteration of gene expressions. Here, we used several statistical methods (distance method, two-sample t-tests, regularised t-tests, ANOVA and bootstrapping to detect the differential expression pattern between humans and great apes. Our analysis shows that the pattern we observed before is robust against various statistical methods; that is, the pronounced expression changes occurred on the human lineage after the split from chimpanzees, and that the dramatic brain expression alterations in humans may be mainly driven by a set of genes with increased expression (up-regulated rather than decreased expression (down-regulated.

  20. Effect of Boric Acid Supplementation on the Expression of BDNF in African Ostrich Chick Brain.

    Science.gov (United States)

    Tang, Juan; Zheng, Xing-ting; Xiao, Ke; Wang, Kun-lun; Wang, Jing; Wang, Yun-xiao; Wang, Ke; Wang, Wei; Lu, Shun; Yang, Ke-li; Sun, Peng-Peng; Khaliq, Haseeb; Zhong, Juming; Peng, Ke-Mei

    2016-03-01

    The degree of brain development can be expressed by the levels of brain brain-derived neurotrophic factor (BDNF). BDNF plays an irreplaceable role in the process of neuronal development, protection, and restoration. The aim of the present study was to evaluate the effects of boric acid supplementation in water on the ostrich chick neuronal development. One-day-old healthy animals were supplemented with boron in drinking water at various concentrations, and the potential effects of boric acid on brain development were tested by a series of experiments. The histological changes in brain were observed by hematoxylin and eosin (HE) staining and Nissl staining. Expression of BDNF was analyzed by immunohistochemistry, quantitative real-time PCR (QRT-PCR), and enzyme linked immunosorbent assay (ELISA). Apoptosis was evaluated with Dutp-biotin nick end labeling (TUNEL) reaction, and caspase-3 was detected with QRT-PCR. The results were as follows: (1) under the light microscope, the neuron structure was well developed with abundance of neurites and intact cell morphology when animals were fed with less than 160 mg/L of boric acid (groups II, III, IV). Adversely, when boric acid doses were higher than 320 mg/L(groups V, VI), the high-dose boric acid neuron structure was damaged with less neurites, particularly at 640 mg/L; (2) the quantity of BDNF expression in groups II, III, and IV was increased while it was decreased in groups V and VI when compared with that in group I; (3) TUNEL reaction and the caspase-3 mRNA level showed that the amount of cell apoptosis in group II, group III, and group IV were decreased, but increased in group V and group VI significantly. These results indicated that appropriate supplementation of boric acid, especially at 160 mg/L, could promote ostrich chicks' brain development by promoting the BDNF expression and reducing cell apoptosis. Conversely, high dose of boric acid particularly in 640 mg/L would damage the neuron structure of

  1. Dominant Negative Effects of a Non-conducting TREK1 Splice Variant Expressed in Brain*

    OpenAIRE

    Veale, Emma L; Rees, Kathryn A.; Mathie, Alistair; Trapp, Stefan

    2010-01-01

    Two-pore domain potassium (K2P) channels modulate neuronal excitability throughout the entire CNS. The stretch-activated channel TREK1 (K2P2.1) is expressed widely in brain and has been linked to depression, neuroprotection, pain perception, and epilepsy. Little, however, is known about the regulation of TREK1 expression on the transcriptional and translational level or about its trafficking to the plasma membrane. Here we have used PCR techniques to identify a splice variant of TREK1 express...

  2. Personality Trait and Facial Expression Filter-Based Brain-Computer Interface

    Directory of Open Access Journals (Sweden)

    Seongah Chin

    2013-02-01

    Full Text Available In this paper, we present technical approaches that bridge the gap in the research related to the use of brain-computer interfaces for entertainment and facial expressions. Such facial expressions that reflect an individual's personal traits can be used to better realize artificial facial expressions in a gaming environment based on a brain-computer interface. First, an emotion extraction filter is introduced in order to classify emotions on the basis of the users' brain signals in real time. Next, a personality trait filter is defined to classify extrovert and introvert types, which manifest as five traits: very extrovert, extrovert, medium, introvert and very introvert. In addition, facial expressions derived from expression rates are obtained by an extrovert-introvert fuzzy model through its defuzzification process. Finally, we confirm this validation via an analysis of the variance of the personality trait filter, a k-fold cross validation of the emotion extraction filter, an accuracy analysis, a user study of facial synthesis and a test case game.

  3. Conscious and unconscious processing of facial expressions: evidence from two split-brain patients.

    Science.gov (United States)

    Prete, Giulia; D'Ascenzo, Stefania; Laeng, Bruno; Fabri, Mara; Foschi, Nicoletta; Tommasi, Luca

    2015-03-01

    We investigated how the brain's hemispheres process explicit and implicit facial expressions in two 'split-brain' patients (one with a complete and one with a partial anterior resection). Photographs of faces expressing positive, negative or neutral emotions were shown either centrally or bilaterally. The task consisted in judging the friendliness of each person in the photographs. Half of the photograph stimuli were 'hybrid faces', that is an amalgamation of filtered images which contained emotional information only in the low range of spatial frequency, blended to a neutral expression of the same individual in the rest of the spatial frequencies. The other half of the images contained unfiltered faces. With the hybrid faces the patients and a matched control group were more influenced in their social judgements by the emotional expression of the face shown in the left visual field (LVF). When the expressions were shown explicitly, that is without filtering, the control group and the partially callosotomized patient based their judgement on the face shown in the LVF, whereas the complete split-brain patient based his ratings mainly on the face presented in the right visual field. We conclude that the processing of implicit emotions does not require the integrity of callosal fibres and can take place within subcortical routes lateralized in the right hemisphere. © 2013 The British Psychological Society.

  4. [LINGO-1 expression of brain tissue in experimental autoimmune encephalomyelitis mouse].

    Science.gov (United States)

    Wang, Chunjuan; Guo, Shougang; Qu, Chuanqiang; Zhang, Jie; Fu, Peicai; Tang, Ronghua

    2014-04-22

    To observe the changes of LINGO-1 expression with time after onset in EAE mouse. C57/BL6 mice were completely randomly divided into EAE model group (n = 15) , adjuvant group (n = 15) and control group (n = 15) .LINGO-1 expression of brain tissue was detected on day 1, 7, 14, 21 and 30 after onset by RT-PCR and Western blot.RhoA and p-RhoA expression of brain tissue was analysed by Western blot. The LINGO-1mRNA levels in EAE model group were markedly higher than control group on day 1, 7and 14 after onset (4.63 ± 0.25, 2.72 ± 0.12, 1.98 ± 0.16, P Lingo-1 mRNA was close to control group.Expression levels of Lingo-1 protein on day 1, 7, 14, 21, 30 were higher than control group (2.11 ± 0.15, 3.15 ± 0.09, 2.45 ± 0.12, 1.89 ± 0.17, 1.21 ± 0.05, P LINGO-1 expression of brain tissue of EAE mouse upregulates and changes with time after onset, which may inhibit myelination by RhoA activation.In clinic, the antagonist of LINGO-1 for MS should be applied as soon as possible.

  5. Flexible, AAV-equipped Genetic Modules for Inducible Control of Gene Expression in Mammalian Brain

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    Godwin K Dogbevia

    2016-01-01

    Full Text Available Controlling gene expression in mammalian brain is of utmost importance to causally link the role of gene function to cell circuit dynamics under normal conditions and disease states. We have developed recombinant adeno-associated viruses equipped with tetracycline-controlled genetic switches for inducible and reversible control of gene expression in a cell type specific and brain subregion selective manner. Here, we characterize a two-virus approach to efficiently and reliably switch gene expression on and off, repetitively, both in vitro and in vivo. Our recombinant adeno-associated virus (rAAV-Tet approach is highly flexible and it has great potential for application in basic and biomedical neuroscience research and gene therapy.

  6. Oct-2 forms a complex with Oct-1 on the iNOS promoter and represses transcription by interfering with recruitment of RNA PolII by Oct-1

    Science.gov (United States)

    Bentrari, Fatima; Chantôme, Aurelie; Knights, Andrew; Jeannin, Jean-François; Pance, Alena

    2015-01-01

    Oct-1 (POU2f1) and Oct-2 (POU2f2) are members of the POU family of transcription factors. They recognize the same DNA sequence but fulfil distinct functions: Oct-1 is ubiquitous and regulates a variety of genes while Oct-2 is restricted to B-cells and neurones. Here we examine the interplay and regulatory mechanisms of these factors to control the inducible nitric oxide synthase (iNOS, NOS2). Using two breast cancer cell lines as a comparative model, we found that MCF-7 express iNOS upon cytokine stimulation while MDA-MB-231 do not. Oct-1 is present in both cell lines but MDA-MB-231also express high levels of Oct-2. Manipulation of Oct-2 expression in these cell lines demonstrates that it is directly responsible for the repression of iNOS in MDA-MB-231. In MCF-7 cells Oct-1 binds the iNOS promoter, recruits RNA PolII and triggers initiation of transcription. In MDA-MB-231 cells, both Oct-1 and Oct-2 bind the iNOS promoter, forming a higher-order complex which fails to recruit RNA PolII, and as a consequence iNOS transcription does not proceed. Unravelling the mechanisms of transcription factor activity is paramount to the understanding of gene expression patterns that determine cell behaviour. PMID:26271992

  7. Metallothionein-I overexpression alters brain inflammation and stimulates brain repair in transgenic mice with astrocyte-targeted interleukin-6 expression

    DEFF Research Database (Denmark)

    Penkowa, Milena; Camats, Jordi; Giralt, Mercedes

    2003-01-01

    Transgenic expression of IL-6 in the CNS under the control of the GFAP gene promoter, glial fibrillary acidic protein-interleukin-6 (GFAP-IL-6) mice, raises an inflammatory response and causes significant brain damage. However, the results obtained in the GFAP-IL-6 mice after a traumatic brain...

  8. Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype.

    Science.gov (United States)

    Salminen, Antero; Ojala, Johanna; Kaarniranta, Kai; Haapasalo, Annakaisa; Hiltunen, Mikko; Soininen, Hilkka

    2011-07-01

    Cellular stress increases progressively with aging in mammalian tissues. Chronic stress triggers several signaling cascades that can induce a condition called cellular senescence. Recent studies have demonstrated that senescent cells express a senescence-associated secretory phenotype (SASP). Emerging evidence indicates that the number of cells expressing biomarkers of cellular senescence increases in tissues with aging, which implies that cellular senescence is an important player in organismal aging. In the brain, the aging process is associated with degenerative changes, e.g. synaptic loss and white matter atrophy, which lead to progressive cognitive impairment. There is substantial evidence for the presence of oxidative, proteotoxic and metabolic stresses in aging brain. A low-level, chronic inflammatory process is also present in brain during aging. Astrocytes demonstrate age-related changes that resemble those of the SASP: (i) increased level of intermediate glial fibrillary acidic protein and vimentin filaments, (ii) increased expression of several cytokines and (iii) increased accumulation of proteotoxic aggregates. In addition, in vitro stress evokes a typical senescent phenotype in cultured astrocytes and, moreover, isolated astrocytes from aged brain display the proinflammatory phenotype. All of these observations indicate that astrocytes are capable of triggering the SASP and the astrocytes in aging brain display typical characteristics of cellular senescence. Bearing in mind the many functions of astrocytes, it is evident that the age-related senescence of astrocytes enhances the decline in functional capacity of the brain. We will review the astroglial changes occurring during aging and emphasize that senescent astrocytes can have an important role in age-related neuroinflammation and neuronal degeneration. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  9. Effect of Hemin on Brain Alterations and Neuroglobin Expression in Water Immersion Restraint Stressed Rats

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    Merhan Ragy

    2016-01-01

    Full Text Available In the brain, the heme oxygenase (HO system has been reported to be very active and its modulation seems to play a crucial role in the pathophysiology of neurodegenerative disorders. Hemin as HO-1 inducer has been shown to attenuate neuronal injury so the goal of this study was to assess the effect of hemin therapy on the acute stress and how it would modulate neurological outcome. Thirty male albino rats were divided into three groups: control group and stressed group with six-hour water immersion restraint stress (WIRS and stressed group, treated with hemin, in which each rat received a single intraperitoneal injection of hemin at a dose level of 50 mg/kg body weight at 12 hours before exposure to WIRS. Stress hormones, oxidative stress markers, malondialdehyde (MDA, and total antioxidant capacity (TAC were measured and expressions of neuroglobin and S100B mRNA in brain tissue were assayed. Our results revealed that hemin significantly affects brain alterations induced by acute stress and this may be through increased expression of neuroglobin and through antioxidant effect. Hemin decreased blood-brain barrier damage as it significantly decreased the expression of S100B. These results suggest that hemin may be an effective therapy for being neuroprotective against acute stress.

  10. Chitinase expression in Alzheimer's disease and non-demented brains regions.

    Science.gov (United States)

    Sanfilippo, C; Malaguarnera, L; Di Rosa, M

    2016-10-15

    Alzheimer disease is the most typical form of dementia. The causes of AD are not yet completely understood, but they include a combination of genetic, environmental and lifestyle factors that influence ja person's risk for developing the disease. New biomarkers related to these processes could be important for the diagnosis and follow-up of AD patients. The intent of this study was to weigh the expression levels of chitinases genes in brain regions of late-onset AD (LOAD) patients. We analysed three microarray datasets obtained from the NCBI in order to verify the expression levels of chitinase genes family in brain biopsies (CR, DLPFC and VC) of LOAD patients compared to healthy subjects. We also divided the sample in function of sex difference and ages. The analysis showed that all chitinases genes were modulated in LOAD brain regions compared to healthy subjects. Furthermore positively correlation was identified between chitinases gene expression and healthy age's subjects. Moreover, it has been shown that CHI3L1 and CHI3L2 were regulated differently in healthy and LOAD brain depending on the sex. It is possible to conclude that all chitinases could be considered new potential markers for LOAD disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. The Effect of Pyrroloquinoline Quinone on the Expression of WISP1 in Traumatic Brain Injury

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    Yongqi Ye

    2017-01-01

    Full Text Available WISP1, as a member of the CCN4 protein family, has cell protective effects of promoting cell proliferation and inhibiting cell apoptosis. Although some studies have confirmed that WISP1 is concerned with colon cancer and lung cancer, there is little report about the influence of WISP1 in traumatic brain injury. Here, we found that the expression of WISP1 mRNA and protein decreased at 3 d and then increased at 5 d after traumatic brain injury (TBI. Meanwhile, immunofluorescence demonstrated that there was little colocation of WISP1 with GFAP, Iba1, and WISP1 colocalized with NeuN partly. WISP1 colocalized with LC3, but there was little of colocation about WISP1 with cleaved caspase-3. Subsequent study displayed that the expression of β-catenin protein was identical to that of WISP1 after TBI. WISP1 was mainly located in cytoplasm of PC12 or SHSY5Y cells. Compared with the negative control group, WISP1 expression reduced obviously in SHSY5Y cells transfected with WISP1 si-RNA. CCK-8 assay showed that pyrroloquinoline quinone (PQQ had little influence on viability of PC12 and SHSY5Y cells. These results suggested that WISP1 played a protective role after traumatic brain injury in rats, and this effect might be relative to autophagy caused by traumatic brain injury.

  12. Allelic Specificity of Ube3a Expression in the Mouse Brain during Postnatal Development

    Science.gov (United States)

    JUDSON, MATTHEW C.; SOSA-PAGAN, JASON O.; DEL CID, WILMER A.; HAN, JI EUN; PHILPOT, BENJAMIN D.

    2014-01-01

    Genetic alterations of the maternal UBE3A allele result in Angelman syndrome (AS), a neurodevelopmental disorder characterized by severe developmental delay, lack of speech, and difficulty with movement and balance. The combined effects of maternal UBE3A mutation and cell type-specific epigenetic silencing of paternal UBE3A are hypothesized to result in a complete loss of functional UBE3A protein in neurons. However, the allelic specificity of UBE3A expression in neurons and other cell types in the brain has yet to be characterized throughout development, including the early postnatal period when AS phenotypes emerge. Here we define maternal and paternal allele-specific Ube3a protein expression throughout postnatal brain development in the mouse, a species which exhibits orthologous epigenetic silencing of paternal Ube3a in neurons and AS-like behavioral phenotypes subsequent to maternal Ube3a deletion. We find that neurons downregulate paternal Ube3a protein expression as they mature and, with the exception of neurons born from postnatal stem cell niches, do not express detectable paternal Ube3a beyond the first postnatal week. By contrast, neurons express maternal Ube3a throughout postnatal development, during which time localization of the protein becomes increasingly nuclear. Unlike neurons, astrocytes and oligodendrotyes biallelically express Ube3a. Notably, mature oligodendrocytes emerge as the predominant Ube3a-expressing glial cell type in the cortex and white matter tracts during postnatal development. These findings demonstrate the spatiotemporal characteristics of allele-specific Ube3a expression in key brain cell types, thereby improving our understanding of the developmental parameters of paternal Ube3a silencing and the cellular basis of AS. PMID:24254964

  13. MicroRNA expression and regulation in human, chimpanzee, and macaque brains.

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    Hai Yang Hu

    2011-10-01

    Full Text Available Among other factors, changes in gene expression on the human evolutionary lineage have been suggested to play an important role in the establishment of human-specific phenotypes. However, the molecular mechanisms underlying these expression changes are largely unknown. Here, we have explored the role of microRNA (miRNA in the regulation of gene expression divergence among adult humans, chimpanzees, and rhesus macaques, in two brain regions: prefrontal cortex and cerebellum. Using a combination of high-throughput sequencing, miRNA microarrays, and Q-PCR, we have shown that up to 11% of the 325 expressed miRNA diverged significantly between humans and chimpanzees and up to 31% between humans and macaques. Measuring mRNA and protein expression in human and chimpanzee brains, we found a significant inverse relationship between the miRNA and the target genes expression divergence, explaining 2%-4% of mRNA and 4%-6% of protein expression differences. Notably, miRNA showing human-specific expression localize in neurons and target genes that are involved in neural functions. Enrichment in neural functions, as well as miRNA-driven regulation on the human evolutionary lineage, was further confirmed by experimental validation of predicted miRNA targets in two neuroblastoma cell lines. Finally, we identified a signature of positive selection in the upstream region of one of the five miRNA with human-specific expression, miR-34c-5p. This suggests that miR-34c-5p expression change took place after the split of the human and the Neanderthal lineages and had adaptive significance. Taken together these results indicate that changes in miRNA expression might have contributed to evolution of human cognitive functions.

  14. Inducible nitric oxide synthase (iNOS) drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of TSC2

    Science.gov (United States)

    Lopez-Rivera, Esther; Jayaraman, Padmini; Parikh, Falguni; Davies, Michael A.; Ekmekcioglu, Suhendan; Izadmehr, Sudeh; Milton, Denái R.; Chipuk, Jerry E.; Grimm, Elizabeth A.; Estrada, Yeriel; Aguirre-Ghiso, Julio; Sikora, Andrew G.

    2014-01-01

    Melanoma is one of the cancers of fastest-rising incidence in the world. iNOS is overexpressed in melanoma and other cancers, and previous data suggest that iNOS and nitric oxide (NO) drive survival and proliferation of human melanoma cells. However, specific mechanisms through which this occurs are poorly defined. One candidate is the PI3K/AKT/mTOR pathway, which plays a major role in proliferation, angiogenesis, and metastasis of melanoma and other cancers. We used the chick embryo chorioallantoic membrane (CAM) assay to test the hypothesis that melanoma growth is regulated by iNOS-dependent mTOR pathway activation. Both pharmacologic inhibition and siRNA-mediated gene silencing of iNOS suppressed melanoma proliferation and in vivo growth on the CAM in human melanoma models. This was associated with strong downregulation of mTOR pathway activation by Western blot analysis of p-mTOR, p-P70S6K, p-S6RP, and p-4EBP1. iNOS expression and NO were associated with reversible nitrosylation of TSC2, and inhibited dimerization of TSC2 with its inhibitory partner TSC1, enhancing GTPase activity of its target Rheb, a critical activator of mTOR signaling. Immunohistochemical analysis of tumor specimens from stage III melanoma patients showed a significant correlation between iNOS expression levels and expression of mTOR pathway members. Exogenously-supplied NO was also sufficient to reverse mTOR pathway inhibition by the B-Raf inhibitor Vemurafenib. In summary, covalent modification of TSC2 by iNOS-derived NO is associated with impaired TSC2/TSC1 dimerization, mTOR pathway activation, and proliferation of human melanoma. This model is consistent with the known association of iNOS overexpression and poor prognosis in melanoma and other cancers. PMID:24398473

  15. Altered expression of BDNF, BDNF pro-peptide and their precursor proBDNF in brain and liver tissues from psychiatric disorders: rethinking the brain?liver axis

    OpenAIRE

    Yang, B; Ren, Q; Zhang, J-c; Chen, Q-X; Hashimoto, K

    2017-01-01

    Brain-derived neurotrophic factor (BDNF) has a role in the pathophysiology of psychiatric disorders. The precursor proBDNF is converted to mature BDNF and BDNF pro-peptide, the N-terminal fragment of proBDNF; however, the precise function of these proteins in psychiatric disorders is unknown. We sought to determine whether expression of these proteins is altered in the brain and peripheral tissues from patients with psychiatric disorders. We measured protein expression of proBDNF, mature BDNF...

  16. Dietary Selenium Supplementation Modulates Growth of Brain Metastatic Tumors and Changes the Expression of Adhesion Molecules in Brain Microvessels.

    Science.gov (United States)

    Wrobel, Jagoda K; Wolff, Gretchen; Xiao, Rijin; Power, Ronan F; Toborek, Michal

    2016-08-01

    Various dietary agents can modulate tumor invasiveness. The current study explored whether selenoglycoproteins (SeGPs) extracted from selenium-enriched yeast affect tumor cell homing and growth in the brain. Mice were fed diets enriched with specific SeGPs (SeGP40 or SeGP65, 1 mg/kg Se each), glycoproteins (GP40 or GP65, 0.2-0.3 mg/kg Se each) or a control diet (0.2-0.3 mg/kg Se) for 12 weeks. Then, murine Lewis lung carcinoma cells were infused into the brain circulation. Analyses were performed at early (48 h) and late stages (3 weeks) post tumor cell infusion. Imaging of tumor progression in the brain revealed that mice fed SeGP65-enriched diet displayed diminished metastatic tumor growth, fewer extravasating tumor cells and smaller metastatic lesions. While administration of tumor cells resulted in a significant upregulation of adhesion molecules in the early stage of tumor progression, overexpression of VCAM-1 (vascular call adhesion molecule-1) and ALCAM (activated leukocyte cell adhesion molecule) messenger RNA (mRNA) was diminished in SeGP65 supplemented mice. Additionally, mice fed SeGP65 showed decreased expression of acetylated NF-κB p65, 48 h post tumor cell infusion. The results indicate that tumor progression in the brain can be modulated by specific SeGPs. Selenium-containing compounds were more effective than their glycoprotein controls, implicating selenium as a potential negative regulator of metastatic process.

  17. Physical weight loading induces expression of tryptophan hydroxylase 2 in the brain stem.

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    Joon W Shim

    Full Text Available Sustaining brain serotonin is essential in mental health. Physical activities can attenuate mental problems by enhancing serotonin signaling. However, such activity is not always possible in disabled individuals or patients with dementia. Knee loading, a form of physical activity, has been found to mimic effects of voluntary exercise. Focusing on serotonergic signaling, we addressed a question: Does local mechanical loading to the skeleton elevate expression of tryptophan hydroxylase 2 (tph2 that is a rate-limiting enzyme for brain serotonin? A 5 min knee loading was applied to mice using 1 N force at 5 Hz for 1,500 cycles. A 5-min treadmill running was used as an exercise (positive control, and a 90-min tail suspension was used as a stress (negative control. Expression of tph2 was determined 30 min - 2 h in three brain regions --frontal cortex (FC, ventromedial hypothalamus (VMH, and brain stem (BS. We demonstrated for the first time that knee loading and treadmill exercise upregulated the mRNA level of tph2 in the BS, while tail suspension downregulated it. The protein level of tph2 in the BS was also upregulated by knee loading and downregulated by tail suspension. Furthermore, the downregulation of tph2 mRNA by tail suspension can be partially suppressed by pre-application of knee loading. The expression of tph2 in the FC and VMH was not significantly altered with knee loading. In this study we provided evidence that peripheral mechanical loading can activate central tph2 expression, suggesting that physical cues may mediate tph2-cathalyzed serotonergic signaling in the brain.

  18. Effect of aminoguanidine and albendazole on inducible nitric oxide synthase (iNOS activity in T. spiralis-infected mice muscles

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    Iwona Mozer-Lisewska

    2011-08-01

    Full Text Available The aim of this study was to provide evidence for the expression of iNOS in the cells of inflammatory infiltrates around larvae in skeletal muscles of T. spiralis infected mice. The BALB/c mice (n=8 divided into subgroups, received either aminoguanidine (AMG - a specific iNOS inhibitor or albendazole (ALB - an antiparasitic drug of choice in trichinellosis treatment. Control animals (n=2 in each subgroup were either uninfected and treated or uninfected and untreated. Frozen sections of hind leg muscles from mice sacrificed at various time intervals after infection were cut and subjected to immunohistochemistry, using monoclonal anti-iNOS antibody. The ALB-treated mice revealed stronger iNOS staining in the infiltrating cells around larvae than the infected and untreated animals. On the contrary, in the AMG-treated animals, the infiltrating cells did not show any specific iNOS reaction. These data confirm the specificity of iNOS staining in the cellular infiltrates around T. spiralis larvae and shed some light on the role of nitric oxide during ALB treatment in experimental trichinellosis.

  19. Crystal structure of SPSB2 in complex with a rational designed RGD-containing cyclic peptide inhibitor of SPSB2-iNOS interaction.

    Science.gov (United States)

    You, Tingting; Wang, Yuhui; Li, Kefa; Zhang, Danting; Wei, Huan; Luo, Yanhong; Li, Hua; Lu, Yongzhi; Su, Xunchen; Kuang, Zhihe

    2017-07-29

    SPRY domain-containing SOCS box protein 2 (SPSB2) is a negative regulator of inducible nitric oxide synthase (iNOS) that modulates the lifetime of iNOS and thus the levels of nitric oxide (NO) production. Inhibitors that can disrupt the endogenous SPSB2-iNOS interaction and augment NO production have potential as novel antimicrobial and anticancer drugs. In this study, we have designed a cyclic peptide (cR8), containing an RGD motif and the SPSB2 binding motif (DINNNV). ITC and chemical shift perturbation showed that cR8 binds to the iNOS binding site on SPSB2 with a Kd of 671 nM, and saturation transfer difference NMR showed that cR8 binds to αvβ3 integrin-expressing cells. Moreover, we determined the crystal structure of SPSB2 in complex with cR8, at a resolution of 1.34 Å. cR8 forms extensive hydrogen bonding with SPSB2 residues, but loss of an intramolecular hydrogen bond that is present in SPSB2-bound iNOS peptide may destabilize the bound conformation of cR8 and lead to a gentle reduction in SPSB2 binding affinity. These results serve as a useful basis for designing site-directed SPSB2 inhibitors in the future. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells.

    Science.gov (United States)

    Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi; Shah, Khalid

    2015-06-01

    Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications. © The Author (2015). Published by Oxford University Press on

  1. Elevated transcription factor specificity protein 1 in autistic brains alters the expression of autism candidate genes.

    Science.gov (United States)

    Thanseem, Ismail; Anitha, Ayyappan; Nakamura, Kazuhiko; Suda, Shiro; Iwata, Keiko; Matsuzaki, Hideo; Ohtsubo, Masafumi; Ueki, Takatoshi; Katayama, Taiichi; Iwata, Yasuhide; Suzuki, Katsuaki; Minoshima, Shinsei; Mori, Norio

    2012-03-01

    Profound changes in gene expression can result from abnormalities in the concentrations of sequence-specific transcription factors like specificity protein 1 (Sp1). Specificity protein 1 binding sites have been reported in the promoter regions of several genes implicated in autism. We hypothesize that dysfunction of Sp1 could affect the expression of multiple autism candidate genes, contributing to the heterogeneity of autism. We assessed any alterations in the expression of Sp1 and that of autism candidate genes in the postmortem brain (anterior cingulate gyrus [ACG], motor cortex, and thalamus) of autism patients (n = 8) compared with healthy control subjects (n = 13). Alterations in the expression of candidate genes upon Sp1/DNA binding inhibition with mithramycin and Sp1 silencing by RNAi were studied in SK-N-SH neuronal cells. We observed elevated expression of Sp1 in ACG of autism patients (p = .010). We also observed altered expression of several autism candidate genes. GABRB3, RELN, and HTR2A showed reduced expression, whereas CD38, ITGB3, MAOA, MECP2, OXTR, and PTEN showed elevated expression in autism. In SK-N-SH cells, OXTR, PTEN, and RELN showed reduced expression upon Sp1/DNA binding inhibition and Sp1 silencing. The RNA integrity number was not available for any of the samples. Transcription factor Sp1 is dysfunctional in the ACG of autistic brain. Consequently, the expression of potential autism candidate genes regulated by Sp1, especially OXTR and PTEN, could be affected. The diverse downstream pathways mediated by the Sp1-regulated genes, along with the environmental and intracellular signal-related regulation of Sp1, could explain the complex phenotypes associated with autism.

  2. Effects of Facial Expression and Language on Trustworthiness and Brain Activities

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    Shu Morioka

    2015-01-01

    Full Text Available Social communication uses verbal and nonverbal language. We examined the degree of trust and brain activity when verbal and facial expressions are incongruent. Fourteen healthy volunteers viewed photographs of 8 people with pleasant (smile or unpleasant expressions (disgust alone or combined with a verbal [positive/negative] expression. As an index for degree of trust, subjects were asked to offer a donation when told that the person in the photograph was troubled financially. Positive emotions and degree of trust were evaluated using the Visual Analogue Scale (VAS. Event-related potentials (ERPs were obtained at 170–240 ms after viewing the photographs. Brain activity during incongruent conditions was localized using standardized Low Resolution Brain Electromagnetic Tomography (sLORETA. VAS scores for positive × smile condition were significantly higher than those for the other conditions (p<0.05. The donation offered was significantly lower for incongruence between verbal and facial expressions, particularly for negative × smile condition. EEG showed more activity in the parietal lobe with incongruent than with congruent conditions. Incongruence [negative × smile] elicited the least positive emotion, degree of trust, and amount of offer. Our results indicate that incongruent sensory information increased activity in the parietal lobe, which may be a basis of mentalizing.

  3. Increased BDNF expression in fetal brain in the valproic acid model of autism.

    Science.gov (United States)

    Almeida, Luis E F; Roby, Clinton D; Krueger, Bruce K

    2014-03-01

    Human fetal exposure to valproic acid (VPA), a widely-used anti-epileptic and mood-stabilizing drug, leads to an increased incidence of behavioral and intellectual impairments including autism; VPA administration to pregnant rats and mice at gestational days 12.5 (E12.5) or E13.5 leads to autistic-like symptoms in the offspring and is widely used as an animal model for autism. We report here that this VPA administration protocol transiently increased both BDNF mRNA and BDNF protein levels 5-6-fold in the fetal mouse brain. VPA exposure in utero induced smaller increases in the expression of mRNA encoding the other neurotrophins, NT3 (2.5-fold) and NT4 (2-fold). Expression of the neurotrophin receptors, trkA, trkB and trkC were minimally affected, while levels of the low-affinity neurotrophin receptor, p75(NTR), doubled. Of the nine 5'-untranslated exons of the mouse BDNF gene, only expression of exons I, IV and VI was stimulated by VPA in utero. In light of the well-established role of BDNF in regulating neurogenesis and the laminar fate of postmitotic neurons in the developing cortex, an aberrant increase in BDNF expression in the fetal brain may contribute to VPA-induced cognitive disorders by altering brain development. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Sex-dependent gene expression in early brain development of chicken embryos

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    Stigson Michael

    2006-02-01

    Full Text Available Abstract Background Differentiation of the brain during development leads to sexually dimorphic adult reproductive behavior and other neural sex dimorphisms. Genetic mechanisms independent of steroid hormones produced by the gonads have recently been suggested to partly explain these dimorphisms. Results Using cDNA microarrays and real-time PCR we found gene expression differences between the male and female embryonic brain (or whole head that may be independent of morphological differentiation of the gonads. Genes located on the sex chromosomes (ZZ in males and ZW in females were common among the differentially expressed genes, several of which (WPKCI-8, HINT, MHM non-coding RNA have previously been implicated in avian sex determination. A majority of the identified genes were more highly expressed in males. Three of these genes (CDK7, CCNH and BTF2-P44 encode subunits of the transcription factor IIH complex, indicating a role for this complex in neuronal differentiation. Conclusion In conclusion, this study provides novel insights into sexually dimorphic gene expression in the embryonic chicken brain and its possible involvement in sex differentiation of the nervous system in birds.

  5. Expression weighted cell type enrichments reveal genetic and cellular nature of major brain disorders

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    Nathan Gerald Skene

    2016-01-01

    Full Text Available The cell types that trigger the primary pathology in many brain diseases remain largely unknown. One route to understanding the primary pathological cell type for a particular disease is to identify the cells expressing susceptibility genes. Although this is straightforward for monogenic conditions where the causative mutation may alter expression of a cell type specific marker, methods are required for the common polygenic disorders. We developed the Expression Weighted Cell Type Enrichment (EWCE method that uses single cell transcriptomes to generate the probability distribution associated with a gene list having an average level of expression within a cell type. Following validation, we applied EWCE to human genetic data from cases of epilepsy, Schizophrenia, Autism, Intellectual Disability, Alzheimer’s disease, Multiple Sclerosis and anxiety disorders. Genetic susceptibility primarily affected microglia in Alzheimer’s and Multiple Sclerosis; was shared between interneurons and pyramidal neurons in Autism and Schizophrenia; while intellectual disabilities and epilepsy were attributable to a range of cell-types, with the strongest enrichment in interneurons. We hypothesised that the primary cell type pathology could trigger secondary changes in other cell types and these could be detected by applying EWCE to transcriptome data from diseased tissue. In Autism, Schizophrenia and Alzheimer’s disease we find evidence of pathological changes in all of the major brain cell types. These findings give novel insight into the cellular origins and progression in common brain disorders. The methods can be applied to any tissue and disorder and have applications in validating mouse models.

  6. Immunochemical analysis of the expression of SV2C in mouse, macaque and human brain.

    Science.gov (United States)

    Dunn, Amy R; Hoffman, Carlie A; Stout, Kristen A; Ozawa, Minagi; Dhamsania, Rohan K; Miller, Gary W

    2017-12-21

    The synaptic vesicle glycoprotein 2C (SV2C) is an undercharacterized protein with enriched expression in phylogenetically old brain regions. Its precise role within the brain is unclear, though various lines of evidence suggest that SV2C is involved in the function of synaptic vesicles through the regulation of vesicular trafficking, calcium-induced exocytosis, or synaptotagmin function. SV2C has been linked to multiple neurological disorders, including Parkinson's disease and psychiatric conditions. SV2C is expressed in various cell types-primarily dopaminergic, GABAergic, and cholinergic cells. In mice, it is most highly expressed in nuclei within the basal ganglia, though it is unknown if this pattern of expression is consistent across species. Here, we use a custom SV2C-specific antiserum to describe localization within the brain of mouse, nonhuman primate, and human, including cell-type localization. We found that the immunoreactivity with this antiserum is consistent with previously-published antibodies, and confirmed localization of SV2C in the basal ganglia of rodent, rhesus macaque, and human. We observed strongest expression of SV2C in the substantia nigra, ventral tegmental area, dorsal striatum, pallidum, and nucleus accumbens of each species. Further, we demonstrate colocalization between SV2C and markers of dopaminergic, GABAergic, and cholinergic neurons within these brain regions. SV2C has been increasingly linked to dopamine and basal ganglia function. These antisera will be an important resource moving forward in our understanding of the role of SV2C in vesicle dynamics and neurological disease. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure.

    Science.gov (United States)

    Drägert, Katja; Bhattacharya, Indranil; Pellegrini, Giovanni; Seebeck, Petra; Azzi, Abdelhalim; Brown, Steven A; Georgiopoulou, Stavroula; Held, Ulrike; Blyszczuk, Przemyslaw; Arras, Margarete; Humar, Rok; Hall, Michael N; Battegay, Edouard; Haas, Elvira

    2015-08-01

    The mammalian target of rapamycin complex 2 (mTORC2) contains the essential protein RICTOR and is activated by growth factors. mTORC2 in adipose tissue contributes to the regulation of glucose and lipid metabolism. In the perivascular adipose tissue, mTORC2 ensures normal vascular reactivity by controlling expression of inflammatory molecules. To assess whether RICTOR/mTORC2 contributes to blood pressure regulation, we applied a radiotelemetry approach in control and Rictor knockout (Rictor(aP2KO)) mice generated using adipocyte protein-2 gene promoter-driven CRE recombinase expression to delete Rictor. The 24-hour mean arterial pressure was increased in Rictor(aP2KO) mice, and the physiological decline in mean arterial pressure during the dark period was impaired. In parallel, heart rate and locomotor activity were elevated during the dark period with a pattern similar to blood pressure changes. This phenotype was associated with mild cardiomyocyte hypertrophy, decreased cardiac natriuretic peptides, and their receptor expression in adipocytes. Moreover, clock gene expression was reduced or phase-shifted in perivascular adipose tissue. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus, although Rictor gene expression was also lower in brain of Rictor(aP2KO) mice. Thus, this study highlights the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes, and brain to tune physiological outcomes, such as blood pressure and locomotor activity. © 2015 American Heart Association, Inc.

  8. Gene expression profiling of brain samples from patients with Lewy body dementia.

    Science.gov (United States)

    Pietrzak, Maciej; Papp, Audrey; Curtis, Amanda; Handelman, Samuel K; Kataki, Maria; Scharre, Douglas W; Rempala, Grzegorz; Sadee, Wolfgang

    2016-10-28

    Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative disorder in the elderly. The development and progression of DLB remain unclear. In this study we used next generation sequencing to assess RNA expression profiles and cellular processes associated with DLB in the anterior cingulate cortex, a brain region affected by DLB pathology. The expression measurements were made in autopsy brain tissues from 8 DLB subjects and 10 age-matched controls using AmpliSeq technology with ion torrent sequencing. The analysis of RNA expression profiles revealed 490 differentially expressed genes, among which 367 genes were down-regulated and 123 were up-regulated. Functional enrichment analysis of genes differentially expressed in DLB indicated downregulation of genes associated with myelination, neurogenesis, and regulation of nervous system development. miRNA binding sites enriched in these mRNAs yielded a list of candidate miRNAs participating in DLB pathophysiology. Our study provides a comprehensive picture of gene expression landscape in DLB, identifying key cellular processes associated with DLB pathology. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. A new generation of MDR modulating agents with dual activity: P-gp inhibitor and iNOS inducer agents.

    Science.gov (United States)

    Colabufo, Nicola Antonio; Contino, Marialessandra; Berardi, Francesco; Perrone, Roberto; Panaro, Maria Antonietta; Cianciulli, Antonia; Mitolo, Vincenzo; Azzariti, Amalia; Quatrale, Annelisa; Paradiso, Angelo

    2011-02-01

    MultiDrug Resistance (MDR) is due to the ability of some ATPase transporters to efflux chemotherapeutic agents out from tumor cells decreasing the endocellular concentration for the pharmacological effect, causing cancer cells chemoresistance. In the present work, a set of MDR modulating agents (MC89, MC70, PB28, IG9) able to modulate transmembrane ATP-dependent transporter, P-glycoprotein (P-gp), and also to induce inducible nitric oxide synthase (iNOS) expression in a panel of tumor cell lines are presented. All selected compounds, known as potent P-gp modulating agents, stimulated nitric oxide (NO) via iNOS in U937, Caco-2 and MCF7-Adr cell lines. The results displayed a new pharmacological strategy to revert MDR and lead to develop a new class of MDR reverting agents devoid of the limits of P-gp inhibitors third generation. Copyright © 2010 Elsevier Ltd. All rights reserved.

  10. Species differences in brain gene expression profiles associated with adult behavioral maturation in honey bees

    Directory of Open Access Journals (Sweden)

    Robinson Gene E

    2007-06-01

    Full Text Available Abstract Background Honey bees are known for several striking social behaviors, including a complex pattern of behavioral maturation that gives rise to an age-related colony division of labor and a symbolic dance language, by which successful foragers communicate the location of attractive food sources to their nestmates. Our understanding of honey bees is mostly based on studies of the Western honey bee, Apis mellifera, even though there are 9–10 other members of genus Apis, showing interesting variations in social behavior relative to A. mellifera. To facilitate future in-depth genomic and molecular level comparisons of behavior across the genus, we performed a microarray analysis of brain gene expression for A. mellifera and three key species found in Asia, A. cerana, A. florea and A. dorsata. Results For each species we compared brain gene expression patterns between foragers and adult one-day-old bees on an A. mellifera cDNA microarray and calculated within-species gene expression ratios to facilitate cross-species analysis. The number of cDNA spots showing hybridization fluorescence intensities above the experimental threshold was reduced by an average of 16% in the Asian species compared to A. mellifera, but an average of 71% of genes on the microarray were available for analysis. Brain gene expression profiles between foragers and one-day-olds showed differences that are consistent with a previous study on A. mellifera and were comparable across species. Although 1772 genes showed significant differences in expression between foragers and one-day-olds, only 218 genes showed differences in forager/one-day-old expression between species (p Conclusion We conclude that the A. mellifera cDNA microarray can be used effectively for cross-species comparisons within the genus. Our results indicate that there is a widespread conservation of the molecular processes in the honey bee brain underlying behavioral maturation. Species differences in

  11. Nutritionally driven differential gene expression leads to heterochronic brain development in honeybee castes.

    Science.gov (United States)

    Moda, Lívia Maria; Vieira, Joseana; Guimarães Freire, Anna Cláudia; Bonatti, Vanessa; Bomtorin, Ana Durvalina; Barchuk, Angel Roberto; Simões, Zilá Luz Paulino

    2013-01-01

    The differential feeding regimes experienced by the queen and worker larvae of the honeybee Apis mellifera shape a complex endocrine response cascade that ultimately gives rise to differences in brain morphologies. Brain development analyzed at the morphological level from the third (L3) through fifth (L5) larval instars revealed an asynchrony between queens and workers. In the feeding phase of the last larval instar (L5F), two well-formed structures, pedunculi and calyces, are identifiable in the mushroom bodies of queens, both of which are not present in workers until a later phase (spinning phase, L5S). Genome-wide expression analyses and normalized transcript expression experiments monitoring specific genes revealed that this differential brain development starts earlier, during L3. Analyzing brains from L3 through L5S1 larvae, we identified 21 genes with caste-specific transcription patterns (e.g., APC-4, GlcAT-P, fax, kr-h1 and shot), which encode proteins that are potentially involved in the development of brain tissues through controlling the cell proliferation rate (APC4, kr-h1) and fasciculation (GlcAT-P, fax, and shot). Shot, whose expression is known to be required for axon extension and cell proliferation, was found to be transcribed at significantly higher levels in L4 queens compared with worker larvae. Moreover, the protein encoded by this gene was immunolocalized to the cytoplasm of cells near the antennal lobe neuropiles and proximal to the Kenyon cells in the brains of L4 queens. In conclusion, during the larval period, the brains of queens are larger and develop more rapidly than workers' brains, which represents a developmental heterochrony reflecting the effect of the differential feeding regime of the two castes on nervous system development. Furthermore, this differential development is characterized by caste-specific transcriptional profiles of a set of genes, thus pointing to a link between differential nutrition and differential

  12. Nutritionally Driven Differential Gene Expression Leads to Heterochronic Brain Development in Honeybee Castes

    Science.gov (United States)

    Moda, Lívia Maria; Vieira, Joseana; Guimarães Freire, Anna Cláudia; Bonatti, Vanessa; Bomtorin, Ana Durvalina; Barchuk, Angel Roberto; Simões, Zilá Luz Paulino

    2013-01-01

    The differential feeding regimes experienced by the queen and worker larvae of the honeybee Apis mellifera shape a complex endocrine response cascade that ultimately gives rise to differences in brain morphologies. Brain development analyzed at the morphological level from the third (L3) through fifth (L5) larval instars revealed an asynchrony between queens and workers. In the feeding phase of the last larval instar (L5F), two well-formed structures, pedunculi and calyces, are identifiable in the mushroom bodies of queens, both of which are not present in workers until a later phase (spinning phase, L5S). Genome-wide expression analyses and normalized transcript expression experiments monitoring specific genes revealed that this differential brain development starts earlier, during L3. Analyzing brains from L3 through L5S1 larvae, we identified 21 genes with caste-specific transcription patterns (e.g., APC-4, GlcAT-P, fax, kr-h1 and shot), which encode proteins that are potentially involved in the development of brain tissues through controlling the cell proliferation rate (APC4, kr-h1) and fasciculation (GlcAT-P, fax, and shot). Shot, whose expression is known to be required for axon extension and cell proliferation, was found to be transcribed at significantly higher levels in L4 queens compared with worker larvae. Moreover, the protein encoded by this gene was immunolocalized to the cytoplasm of cells near the antennal lobe neuropiles and proximal to the Kenyon cells in the brains of L4 queens. In conclusion, during the larval period, the brains of queens are larger and develop more rapidly than workers’ brains, which represents a developmental heterochrony reflecting the effect of the differential feeding regime of the two castes on nervous system development. Furthermore, this differential development is characterized by caste-specific transcriptional profiles of a set of genes, thus pointing to a link between differential nutrition and differential

  13. Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.

    Science.gov (United States)

    Eising, Else; Huisman, Sjoerd M H; Mahfouz, Ahmed; Vijfhuizen, Lisanne S; Anttila, Verneri; Winsvold, Bendik S; Kurth, Tobias; Ikram, M Arfan; Freilinger, Tobias; Kaprio, Jaakko; Boomsma, Dorret I; van Duijn, Cornelia M; Järvelin, Marjo-Riitta R; Zwart, John-Anker; Quaye, Lydia; Strachan, David P; Kubisch, Christian; Dichgans, Martin; Davey Smith, George; Stefansson, Kari; Palotie, Aarno; Chasman, Daniel I; Ferrari, Michel D; Terwindt, Gisela M; de Vries, Boukje; Nyholt, Dale R; Lelieveldt, Boudewijn P F; van den Maagdenberg, Arn M J M; Reinders, Marcel J T

    2016-04-01

    Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.

  14. Phosphorylation of human INO80 is involved in DNA damage tolerance

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Dai; Waki, Mayumi; Umezawa, Masaki; Aoki, Yuka [Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 (Japan); Utsugi, Takahiko [Bio Matrix Research Inc., 105 Higashifukai, Nagareyama, Chiba 275-0101 (Japan); Ohtsu, Masaya [Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 (Japan); Murakami, Yasufumi, E-mail: yasufumi@rs.noda.tus.ac.jp [Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510 (Japan); Bio Matrix Research Inc., 105 Higashifukai, Nagareyama, Chiba 275-0101 (Japan)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Depletion of hINO80 significantly reduced PCNA ubiquitination. Black-Right-Pointing-Pointer Depletion of hINO80 significantly reduced nuclear dots intensity of RAD18 after UV irradiation. Black-Right-Pointing-Pointer Western blot analyses showed phosphorylated hINO80 C-terminus. Black-Right-Pointing-Pointer Overexpression of phosphorylation mutant hINO80 reduced PCNA ubiquitination. -- Abstract: Double strand breaks (DSBs) are the most serious type of DNA damage. DSBs can be generated directly by exposure to ionizing radiation or indirectly by replication fork collapse. The DNA damage tolerance pathway, which is conserved from bacteria to humans, prevents this collapse by overcoming replication blockages. The INO80 chromatin remodeling complex plays an important role in the DNA damage response. The yeast INO80 complex participates in the DNA damage tolerance pathway. The mechanisms regulating yINO80 complex are not fully understood, but yeast INO80 complex are necessary for efficient proliferating cell nuclear antigen (PCNA) ubiquitination and for recruitment of Rad18 to replication forks. In contrast, the function of the mammalian INO80 complex in DNA damage tolerance is less clear. Here, we show that human INO80 was necessary for PCNA ubiquitination and recruitment of Rad18 to DNA damage sites. Moreover, the C-terminal region of human INO80 was phosphorylated, and overexpression of a phosphorylation-deficient mutant of human INO80 resulted in decreased ubiquitination of PCNA during DNA replication. These results suggest that the human INO80 complex, like the yeast complex, was involved in the DNA damage tolerance pathway and that phosphorylation of human INO80 was involved in the DNA damage tolerance pathway. These findings provide new insights into the DNA damage tolerance pathway in mammalian cells.

  15. Maternal zinc deficiency impairs brain nestin expression in prenatal and postnatal mice.

    Science.gov (United States)

    Wang, F D; Bian, W; Kong, L W; Zhao, F J; Guo, J S; Jing, N H

    2001-06-01

    Effects of maternal dietary zinc deficiency on prenatal and postnatal brain development were investigated in ICR strain mice. From d 1 of pregnancy (E0) until postnatal d 20 (P20), maternal mice were fed experimental diets that contained 1 mg Zn/kg/day (severe zinc deficient, SZD), 5 mg Zn/kg/day (marginal zinc deficient, MZD), 30 mg Zn/kg/day (zinc adequately supplied, ZA) or 100 mg Zn/kg/day (zinc supplemented, ZS and pair-fed, PF). Brains of offspring from these dietary groups were examined at various developmental stages for expression of nestin, an intermediate filament protein found in neural stem cells and young neurons. Immunocytochemistry showed nestin expression in neural tube 10.5 d post citrus (dpc) as well as in the cerebral cortex and neural tube from 10.5 dpc to postnatal d 10 (P10). Nestin immunoreactivities in both brain and neural tube of those zinc-supplemented control groups (ZA, ZS, PF) were stronger than those in zinc-deficient groups (SZD and MZD). Western blot analysis confirmed that nestin levels in pooled brain extracts from each of the zinc-supplemented groups (ZA, ZS, PF) were much higher than those from the zinc-deficient groups (SZD and MZD) from 10.5 dpc to P10. Immunostaining and Western blots showed no detectable nestin in any of the experimental and control group brains after P20. These observations of an association between maternal zinc deficiency and decreased nestin protein levels in brains of offspring suggest that zinc deficiency suppresses development of neural stem cells, an effect which may lead to neuroanatomical and behavioral abnormalities in adults.

  16. Perception of Emotional Facial Expressions in Amyotrophic Lateral Sclerosis (ALS) at Behavioural and Brain Metabolic Level.

    Science.gov (United States)

    Aho-Özhan, Helena E A; Keller, Jürgen; Heimrath, Johanna; Uttner, Ingo; Kassubek, Jan; Birbaumer, Niels; Ludolph, Albert C; Lulé, Dorothée

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) primarily impairs motor abilities but also affects cognition and emotional processing. We hypothesise that subjective ratings of emotional stimuli depicting social interactions and facial expressions is changed in ALS. It was found that recognition of negative emotions and ability to mentalize other's intentions is reduced. Processing of emotions in faces was investigated. A behavioural test of Ekman faces expressing six basic emotions was presented to 30 ALS patients and 29 age-, gender and education matched healthy controls. Additionally, a subgroup of 15 ALS patients that were able to lie supine in the scanner and 14 matched healthy controls viewed the Ekman faces during functional magnetic resonance imaging (fMRI). Affective state and a number of daily social contacts were measured. ALS patients recognized disgust and fear less accurately than healthy controls. In fMRI, reduced brain activity was seen in areas involved in processing of negative emotions replicating our previous results. During processing of sad faces, increased brain activity was seen in areas associated with social emotions in right inferior frontal gyrus and reduced activity in hippocampus bilaterally. No differences in brain activity were seen for any of the other emotional expressions. Inferior frontal gyrus activity for sad faces was associated with increased amount of social contacts of ALS patients. ALS patients showed decreased brain and behavioural responses in processing of disgust and fear and an altered brain response pattern for sadness. The negative consequences of neurodegenerative processes in the course of ALS might be counteracted by positive emotional activity and positive social interactions.

  17. Transcriptomics of the late gestation ovine fetal brain: modeling the co-expression of immune marker genes.

    Science.gov (United States)

    Rabaglino, Maria B; Keller-Wood, Maureen; Wood, Charles E

    2014-11-19

    Major changes in gene expression occur in the fetal brain to modulate the function of this organ postnatally. Thus, factors can alter the genomics of the fetal brain, predisposing to neurological disorders later in life. We hypothesized that the physiological dynamics of the immune system transcriptome of the fetal brain during the last stage of gestation will reveal patterns of immune function and development in the developing brain. In this study we applied weighted gene co-expression analysis of microarrays performed on ovine fetal brain samples, to model the changes in gene expression throughout the second half of gestation. Clusters of co-expressed genes that strongly increase in expression toward the first day of extra-uterine life are related to the hematopoietic lineage, while activation of immune pathways is induced after birth. Moreover, the pattern of gene expression suggests induction of tolerance mechanisms, probably necessary to protect highly produced proteins--such as myelin basic protein--from an autoimmune attack. This study provides insight into the dramatic changes in gene expression that take place in the brain during the fetal life, especially during the last stage of gestation, and suggests that the immune system may have an important role in maturation of the fetal brain, which if disrupted or altered, could have negative consequences in postnatal life.

  18. Pheromone-induced odor learning modifies Fos expression in the newborn rabbit brain.

    Science.gov (United States)

    Charra, R; Datiche, F; Gigot, V; Schaal, B; Coureaud, G

    2013-01-15

    Associative learning contributes crucially to adjust the behavior of neonates to the permanently changing environment. In the European rabbit, the mammary pheromone (MP) excreted in milk triggers sucking behavior in newborns, and additionally promotes very rapid learning of initially neutral odor cues. Such stimuli become then as active as the MP itself to elicit the orocephalic motor responses involved in suckling. In this context, the rabbit is an interesting model to address the question of brain circuits early engaged by learning and memory. Here, we evaluated the brain activation (olfactory bulb and central regions) induced in 4-day-old pups by an odorant (ethyl acetoacetate, EAA) after single pairing with the MP and its subsequent acquired ability to elicit sucking-related behavior (conditioned group) or after mere exposure to EAA alone (unconditioned group). The brain-wide mapping of c-Fos expression was used to compare neural activation patterns in both groups. Evidence of high immunostaining to odorant EAA occurred in the mitral+granule cells layer of the main olfactory bulb in pups previously exposed to EAA in association with the MP. These pups also showed higher expression of Fos in the piriform cortex, the hypothalamic lateral preoptic area and the amygdala (cortical and basal nuclei). Thus, MP-induced odor learning induces rapid brain modifications in rabbit neonates. The cerebral framework supporting the acquisition appears however different compared to the circuit involved in the processing of the MP itself. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Gene expression profiling following maternal deprivation: Involvement of the brain renin-angiotensin system

    Directory of Open Access Journals (Sweden)

    Claudia Liebl

    2009-05-01

    Full Text Available The postnatal development of the mouse is characterized by a stress hyporesponsive period (SHRP, where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differentially regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently up-regulated genes, angiotensinogen, was validated using in-situ hybridization. Angiotensinogen is the precursor of angiotensin II, the main effector of the brain renin-angiotensin system (RAS, which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor (AT(1 antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain a nd ACTH release following maternal separation. AT(1 receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and contribute to identifying signaling cascades that control stress system activity in the neonate.

  20. Expression and prognostic value of Oct-4 in astrocytic brain tumors

    DEFF Research Database (Denmark)

    Krogh Petersen, Jeanette; Jensen, Per; Sørensen, M. D.

    2016-01-01

    suggested to have promising potentials as prognostic markers in gliomas. Methodology/Principal Findings: The aim of the present study was to investigate the expression and prognostic impact of the TSC-related marker Oct-4 in astrocytic brain tumors of increasing grade. In total 114 grade II, III and IV...... astrocytic brain tumors were immunohistochemically stained for Oct-4, and the fraction and intensity of Oct-4 positive cells were determined by morphometric analysis of full tumor sections. Oct-4 was expressed in all tumors, and the Oct-4 positive cell fraction increased with tumor grade (p = 0.......045). There was no association between survival and Oct-4 positive cell fraction, neither when combining all tumor grades nor in analysis of individual grades. Oct-4 intensity was not associated with grade, but taking IDH1 status into account we found a tendency for high Oct-4 intensity to be associated with poor prognosis...

  1. Lipopolysaccharide-induced overproduction of nitric oxide and overexpression of iNOS and interleukin-1β proteins in zinc-deficient rats.

    Science.gov (United States)

    Miyazaki, Takashi; Takenaka, Tsuneo; Inoue, Tsutomu; Sato, Makiko; Miyajima, Yuka; Nodera, Makoto; Hanyu, Mayuko; Ohno, Yoichi; Shibazaki, Satomi; Suzuki, Hiromichi

    2012-03-01

    Zinc deficiency leads to decreased cellular immune responses. The overproduction of nitrogen species derived from inducible nitric oxide synthase (iNOS), its enzyme, and interleukine-1 beta (IL-1β), and inflammatory cytokine have been implicated in immune responses. The goal of this study was to investigate the effects of lipopolysaccharide (LPS)-induced changes in NO metabolites, iNOS, and IL-1β protein expression in the lungs of zinc-deficient rats. Male Sprague-Dawley rats (body weight, 100 g) were divided into two groups and were fed either a zinc-deficient diet (ZnD) or a zinc-containing diet (Cont). After 4 weeks on these diets, rats received a 10-mg/kg dose of LPS injected via the tail vein and were then maintained for an additional 72 h. To determine total NO concentrations in the blood, serum zinc concentration, iNOS protein expression, IL-1β, and iNOS immunohistochemistry, blood and lung samples were obtained at pre-LPS injection, 5, 24, and 72 h after injection. Total NO levels were significantly increased at 5, at 24, and at 72 h after LPS injection compared with pre-LPS injection level in ZnD group; significant changes in total NO levels was elevated at 5 h from at pre-LPS level but not significant changes from basal level at 24 and 72 h in the control group. Based on western blot analyses and immunohistochemistry, clear bands indicating iNOS and IL-1β protein expression and iNOS antibody-stained inflammatory cells were detected at 5 and 24 h in the ZnD group and 5 h in the Cont group, not observed at 24 and 72 h in the control group. These results suggest that zinc deficiency induces overexpression of iNOS and IL-1β proteins from inflammatory cells around the alveolar blood vessels, resulting in overproduction of total NO and persisted inflammatory response in the zinc-deficient rat lung. Taken together, overexpression of LPS-induced iNOS, overproduction of iNOS-derived NO, and overexpression of IL-1β may induce nitrosative and oxidative

  2. Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates Central Immune Signaling Pathways

    OpenAIRE

    Ziats, Mark N.; Rennert, Owen M.

    2011-01-01

    The Autism Spectrum Disorders (ASD) represent a clinically heterogeneous set of conditions with strong hereditary components. Despite substantial efforts to uncover the genetic basis of ASD, the genomic etiology appears complex and a clear understanding of the molecular mechanisms underlying Autism remains elusive. We hypothesized that focusing gene interaction networks on ASD-implicated genes that are highly expressed in the developing brain may reveal core mechanisms that are otherwise obsc...

  3. Pattern of c-Fos expression induced by tail suspension test in the mouse brain

    Directory of Open Access Journals (Sweden)

    Kentaro Hiraoka

    2017-06-01

    Full Text Available The tail suspension test (TST has been widely used as a screening assay for antidepressant drugs. However, the neural substrates underlying the stress response and antidepressant-like effect during the TST remain largely unknown despite the prevalence of this test. In the present study, we used immunohistochemistry to examine alterations in c-Fos expression as a measure of neuronal activity in the mouse brain after acute administration of the antidepressant drugs nortriptyline or escitalopram (or saline as a control with or without a subsequent TST session. We found that without the TST session, nortriptyline administration enhanced the density of c-Fos-immunoreactive cells in regions of the central extended amygdala, paraventricular hypothalamic nucleus, and relevant regions of the brain stem, whereas escitalopram did not change c-Fos expression in any region. Following the TST in the absence of antidepressant drugs, we observed a significant increase in c-Fos-positive cell density in a number of brain regions within the limbic telencephalon, hypothalamus, and brain stem. We detected a statistically significant interaction using an analysis of variance between the main effects of the drug and stress response in four regions: the infralimbic cortex, lateral septal nucleus (intermediate part, ventrolateral preoptic nucleus, and solitary nucleus. Following the TST, escitalopram but not nortriptyline increased c-Fos-positive cell density in the infralimbic cortex and ventrolateral preoptic nucleus, whereas nortriptyline but not escitalopram increased c-Fos expression in the solitary nucleus. Both antidepressants significantly increased c-Fos expression in the lateral septal nucleus (intermediate part. The present results indicate that neuronal activity increases in septo-hypothalamic regions and related structures, especially the lateral septal nucleus, following administration of drugs producing an antidepressant-like effect in mice subjected to

  4. NLRP3 Inflammasome Is Expressed and Functional in Mouse Brain Microglia but Not in Astrocytes.

    Directory of Open Access Journals (Sweden)

    Audrey Gustin

    Full Text Available Neuroinflammation is the local reaction of the brain to infection, trauma, toxic molecules or protein aggregates. The brain resident macrophages, microglia, are able to trigger an appropriate response involving secretion of cytokines and chemokines, resulting in the activation of astrocytes and recruitment of peripheral immune cells. IL-1β plays an important role in this response; yet its production and mode of action in the brain are not fully understood and its precise implication in neurodegenerative diseases needs further characterization. Our results indicate that the capacity to form a functional NLRP3 inflammasome and secretion of IL-1β is limited to the microglial compartment in the mouse brain. We were not able to observe IL-1β secretion from astrocytes, nor do they express all NLRP3 inflammasome components. Microglia were able to produce IL-1β in response to different classical inflammasome activators, such as ATP, Nigericin or Alum. Similarly, microglia secreted IL-18 and IL-1α, two other inflammasome-linked pro-inflammatory factors. Cell stimulation with α-synuclein, a neurodegenerative disease-related peptide, did not result in the release of active IL-1β by microglia, despite a weak pro-inflammatory effect. Amyloid-β peptides were able to activate the NLRP3 inflammasome in microglia and IL-1β secretion occurred in a P2X7 receptor-independent manner. Thus microglia-dependent inflammasome activation can play an important role in the brain and especially in neuroinflammatory conditions.

  5. Circulating IGF1 regulates hippocampal IGF1 levels and brain gene expression during adolescence.

    Science.gov (United States)

    Yan, Han; Mitschelen, Matthew; Bixler, Georgina V; Brucklacher, Robert M; Farley, Julie A; Han, Song; Freeman, Willard M; Sonntag, William E

    2011-10-01

    GH and its anabolic mediator, IGF1, are important not only in somatic growth but also in the regulation of brain function. Even though GH treatment has been used clinically to improve body composition and exercise capacity in adults, its influence on central nervous system function has only recently been recognized. This is also the case for children with childhood-onset GH deficiency (GHD) where GH has been used to stimulate bone growth and enhance final adult height. Circulating IGF1 is transported across the blood-brain barrier and IGF1 and its receptors are also synthesized in the brain by neurons and glial and endothelial cells. Nevertheless, the relationship between circulating IGF1 and brain IGF1 remains unclear. This study, using a GH-deficient dwarf rat model and peripheral GH replacement, investigated the effects of circulating IGF1 during adolescence on IGF1 levels in the brain. Our results demonstrated that hippocampal IGF1 protein concentrations during adolescence are highly regulated by circulating IGF1, which were reduced by GHD and restored by systematic GH replacement. Importantly, IGF1 levels in the cerebrospinal fluid were decreased by GHD but not restored by GH replacement. Furthermore, analysis of gene expression using microarrays and RT-PCR indicated that circulating IGF1 levels did not modify the transcription of Igf1 or its receptor in the hippocampus but did regulate genes that are involved in microvascular structure and function, brain development, and synaptic plasticity, which potentially support brain structures involved in cognitive function during this important developmental period.

  6. Global analysis of gene expression in the developing brain of Gtf2ird1 knockout mice.

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    Jennifer O'Leary

    Full Text Available Williams-Beuren Syndrome (WBS is a neurodevelopmental disorder caused by a hemizygous deletion of a 1.5 Mb region on chromosome 7q11.23 encompassing 26 genes. One of these genes, GTF2IRD1, codes for a putative transcription factor that is expressed throughout the brain during development. Genotype-phenotype studies in patients with atypical deletions of 7q11.23 implicate this gene in the neurological features of WBS, and Gtf2ird1 knockout mice show reduced innate fear and increased sociability, consistent with features of WBS. Multiple studies have identified in vitro target genes of GTF2IRD1, but we sought to identify in vivo targets in the mouse brain.We performed the first in vivo microarray screen for transcriptional targets of Gtf2ird1 in brain tissue from Gtf2ird1 knockout and wildtype mice at embryonic day 15.5 and at birth. Changes in gene expression in the mutant mice were moderate (0.5 to 2.5 fold and of candidate genes with altered expression verified using real-time PCR, most were located on chromosome 5, within 10 Mb of Gtf2ird1. siRNA knock-down of Gtf2ird1 in two mouse neuronal cell lines failed to identify changes in expression of any of the genes identified from the microarray and subsequent analysis showed that differences in expression of genes on chromosome 5 were the result of retention of that chromosome region from the targeted embryonic stem cell line, and so were dependent upon strain rather than Gtf2ird1 genotype. In addition, specific analysis of genes previously identified as direct in vitro targets of GTF2IRD1 failed to show altered expression.We have been unable to identify any in vivo neuronal targets of GTF2IRD1 through genome-wide expression analysis, despite widespread and robust expression of this protein in the developing rodent brain.

  7. Global analysis of gene expression in the developing brain of Gtf2ird1 knockout mice.

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    O'Leary, Jennifer; Osborne, Lucy R

    2011-01-01

    Williams-Beuren Syndrome (WBS) is a neurodevelopmental disorder caused by a hemizygous deletion of a 1.5 Mb region on chromosome 7q11.23 encompassing 26 genes. One of these genes, GTF2IRD1, codes for a putative transcription factor that is expressed throughout the brain during development. Genotype-phenotype studies in patients with atypical deletions of 7q11.23 implicate this gene in the neurological features of WBS, and Gtf2ird1 knockout mice show reduced innate fear and increased sociability, consistent with features of WBS. Multiple studies have identified in vitro target genes of GTF2IRD1, but we sought to identify in vivo targets in the mouse brain. We performed the first in vivo microarray screen for transcriptional targets of Gtf2ird1 in brain tissue from Gtf2ird1 knockout and wildtype mice at embryonic day 15.5 and at birth. Changes in gene expression in the mutant mice were moderate (0.5 to 2.5 fold) and of candidate genes with altered expression verified using real-time PCR, most were located on chromosome 5, within 10 Mb of Gtf2ird1. siRNA knock-down of Gtf2ird1 in two mouse neuronal cell lines failed to identify changes in expression of any of the genes identified from the microarray and subsequent analysis showed that differences in expression of genes on chromosome 5 were the result of retention of that chromosome region from the targeted embryonic stem cell line, and so were dependent upon strain rather than Gtf2ird1 genotype. In addition, specific analysis of genes previously identified as direct in vitro targets of GTF2IRD1 failed to show altered expression. We have been unable to identify any in vivo neuronal targets of GTF2IRD1 through genome-wide expression analysis, despite widespread and robust expression of this protein in the developing rodent brain.

  8. Brain region-specific expression of MeCP2 isoforms correlates with DNA methylation within Mecp2 regulatory elements.

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    Carl O Olson

    Full Text Available MeCP2 is a critical epigenetic regulator in brain and its abnormal expression or compromised function leads to a spectrum of neurological disorders including Rett Syndrome and autism. Altered expression of the two MeCP2 isoforms, MeCP2E1 and MeCP2E2 has been implicated in neurological complications. However, expression, regulation and functions of the two isoforms are largely uncharacterized. Previously, we showed the role of MeCP2E1 in neuronal maturation and reported MeCP2E1 as the major protein isoform in the adult mouse brain, embryonic neurons and astrocytes. Recently, we showed that DNA methylation at the regulatory elements (REs within the Mecp2 promoter and intron 1 impact the expression of Mecp2 isoforms in differentiating neural stem cells. This current study is aimed for a comparative analysis of temporal, regional and cell type-specific expression of MeCP2 isoforms in the developing and adult mouse brain. MeCP2E2 displayed a later expression onset than MeCP2E1 during mouse brain development. In the adult female and male brain hippocampus, both MeCP2 isoforms were detected in neurons, astrocytes and oligodendrocytes. Furthermore, MeCP2E1 expression was relatively uniform in different brain regions (olfactory bulb, striatum, cortex, hippocampus, thalamus, brainstem and cerebellum, whereas MeCP2E2 showed differential enrichment in these brain regions. Both MeCP2 isoforms showed relatively similar distribution in these brain regions, except for cerebellum. Lastly, a preferential correlation was observed between DNA methylation at specific CpG dinucleotides within the REs and Mecp2 isoform-specific expression in these brain regions. Taken together, we show that MeCP2 isoforms display differential expression patterns during brain development and in adult mouse brain regions. DNA methylation patterns at the Mecp2 REs may impact this differential expression of Mecp2/MeCP2 isoforms in brain regions. Our results significantly contribute

  9. Brain Region-Specific Expression of MeCP2 Isoforms Correlates with DNA Methylation within Mecp2 Regulatory Elements

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    Liyanage, Vichithra R. B.; Rastegar, Mojgan

    2014-01-01

    MeCP2 is a critical epigenetic regulator in brain and its abnormal expression or compromised function leads to a spectrum of neurological disorders including Rett Syndrome and autism. Altered expression of the two MeCP2 isoforms, MeCP2E1 and MeCP2E2 has been implicated in neurological complications. However, expression, regulation and functions of the two isoforms are largely uncharacterized. Previously, we showed the role of MeCP2E1 in neuronal maturation and reported MeCP2E1 as the major protein isoform in the adult mouse brain, embryonic neurons and astrocytes. Recently, we showed that DNA methylation at the regulatory elements (REs) within the Mecp2 promoter and intron 1 impact the expression of Mecp2 isoforms in differentiating neural stem cells. This current study is aimed for a comparative analysis of temporal, regional and cell type-specific expression of MeCP2 isoforms in the developing and adult mouse brain. MeCP2E2 displayed a later expression onset than MeCP2E1 during mouse brain development. In the adult female and male brain hippocampus, both MeCP2 isoforms were detected in neurons, astrocytes and oligodendrocytes. Furthermore, MeCP2E1 expression was relatively uniform in different brain regions (olfactory bulb, striatum, cortex, hippocampus, thalamus, brainstem and cerebellum), whereas MeCP2E2 showed differential enrichment in these brain regions. Both MeCP2 isoforms showed relatively similar distribution in these brain regions, except for cerebellum. Lastly, a preferential correlation was observed between DNA methylation at specific CpG dinucleotides within the REs and Mecp2 isoform-specific expression in these brain regions. Taken together, we show that MeCP2 isoforms display differential expression patterns during brain development and in adult mouse brain regions. DNA methylation patterns at the Mecp2 REs may impact this differential expression of Mecp2/MeCP2 isoforms in brain regions. Our results significantly contribute towards characterizing

  10. Differential aquaporin 4 expression during edema build-up and resolution phases of brain inflammation

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    2011-01-01

    Background Vasogenic edema dynamically accumulates in many brain disorders associated with brain inflammation, with the critical step of edema exacerbation feared in patient care. Water entrance through blood-brain barrier (BBB) opening is thought to have a role in edema formation. Nevertheless, the mechanisms of edema resolution remain poorly understood. Because the water channel aquaporin 4 (AQP4) provides an important route for vasogenic edema resolution, we studied the time course of AQP4 expression to better understand its potential effect in countering the exacerbation of vasogenic edema. Methods Focal inflammation was induced in the rat brain by a lysolecithin injection and was evaluated at 1, 3, 7, 14 and 20 days using a combination of in vivo MRI with apparent diffusion coefficient (ADC) measurements used as a marker of water content, and molecular and histological approaches for the quantification of AQP4 expression. Markers of active inflammation (macrophages, BBB permeability, and interleukin-1β) and markers of scarring (gliosis) were also quantified. Results This animal model of brain inflammation demonstrated two phases of edema development: an initial edema build-up phase during active inflammation that peaked after 3 days (ADC increase) was followed by an edema resolution phase that lasted from 7 to 20 days post injection (ADC decrease) and was accompanied by glial scar formation. A moderate upregulation in AQP4 was observed during the build-up phase, but a much stronger transcriptional and translational level of AQP4 expression was observed during the secondary edema resolution phase. Conclusions We conclude that a time lag in AQP4 expression occurs such that the more significant upregulation was achieved only after a delay period. This change in AQP4 expression appears to act as an important determinant in the exacerbation of edema, considering that AQP4 expression is insufficient to counter the water influx during the build-up phase, while the

  11. Increased expression of neurotrophin 4 following focal cerebral ischemia in adult rat brain with treadmill exercise.

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    Jin-Young Chung

    Full Text Available Neurotrophin 4 (NT-4 belongs to the family of neurotrophic factors, and it interacts with the tyrosine kinase B (trkB receptor. NT-4 has neuroprotective effects following cerebral ischemia. Its role might be similar to brain-derived neurotrophic factor (BDNF, because both interact with trkB. Exercise also improves neural function by increasing neurotrophic factors. However, expression profiles of NT-4 in the brain during exercise are unknown. Here, we assessed the expressions of NT-4 and its receptor, trkB, following cerebral ischemia and hypothesized that exercise changes the expressions of NT-4 and trkB. Results showed that in a permanent middle cerebral artery occlusion rat model, ischemia decreased NT-4 and trkB expression. Immunohistochemistry showed their immunoreactivities around the region of the ischemic area. Treadmill exercise changed the expression of NT-4, which increased in the contralateral hemisphere in rats with ischemic injury. TrkB also showed similar patterns to its neurotophins. The change in NT-4 suggested that exercise might have primed NT4 production so that further injury causes slightly greater increases in NT4 compared with non-exercise controls.

  12. Fto colocalizes with a satiety mediator oxytocin in the brain and upregulates oxytocin gene expression

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    Olszewski, Pawel K., E-mail: olsze005@umn.edu [Department of Neuroscience, Functional Pharmacology, Uppsala University, 75124 Uppsala (Sweden); Minnesota Obesity Center, Saint Paul, MN 55108 (United States); Fredriksson, Robert; Eriksson, Jenny D. [Department of Neuroscience, Functional Pharmacology, Uppsala University, 75124 Uppsala (Sweden); Mitra, Anaya [Department of Food Science and Nutrition, Saint Paul, MN 55108 (United States); Radomska, Katarzyna J. [Department of Neuroscience, Functional Pharmacology, Uppsala University, 75124 Uppsala (Sweden); Gosnell, Blake A. [Department of Food Science and Nutrition, Saint Paul, MN 55108 (United States); Solvang, Maria N. [Department of Neuroscience, Functional Pharmacology, Uppsala University, 75124 Uppsala (Sweden); Levine, Allen S. [Minnesota Obesity Center, Saint Paul, MN 55108 (United States); Department of Food Science and Nutrition, Saint Paul, MN 55108 (United States); Schioeth, Helgi B. [Department of Neuroscience, Functional Pharmacology, Uppsala University, 75124 Uppsala (Sweden)

    2011-05-13

    Highlights: {yields} The majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto. {yields} The level of colocalization is similar in the male and female brain. {yields} Fto overexpression in hypothalamic neurons increases oxytocin mRNA levels by 50%. {yields} Oxytocin does not affect Fto expression through negative feedback mechanisms. -- Abstract: Single nucleotide polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. Alterations in Fto expression in transgenic animals affect body weight, energy expenditure and food intake. Fto, a nuclear protein and proposed transcription co-factor, has been speculated to affect energy balance through a functional relationship with specific genes encoding feeding-related peptides. Herein, we employed double immunohistochemistry and showed that the majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto in the brain of male and female mice. We then overexpressed Fto in a murine hypothalamic cell line and, using qPCR, detected a 50% increase in the level of oxytocin mRNA. Expression levels of several other feeding-related genes, including neuropeptide Y (NPY) and Agouti-related protein (AgRP), were unaffected by the FTO transfection. Addition of 10 and 100 nmol oxytocin to the cell culture medium did not affect Fto expression in hypothalamic cells. We conclude that Fto, a proposed transcription co-factor, influences expression of the gene encoding a satiety mediator, oxytocin.

  13. Significant effects of antiretroviral therapy on global gene expression in brain tissues of patients with HIV-1-associated neurocognitive disorders.

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    Alejandra Borjabad

    2011-09-01

    Full Text Available Antiretroviral therapy (ART has reduced morbidity and mortality in HIV-1 infection; however HIV-1-associated neurocognitive disorders (HAND persist despite treatment. The reasons for the limited efficacy of ART in the brain are unknown. Here we used functional genomics to determine ART effectiveness in the brain and to identify molecular signatures of HAND under ART. We performed genome-wide microarray analysis using Affymetrix U133 Plus 2.0 Arrays, real-time PCR, and immunohistochemistry in brain tissues from seven treated and eight untreated HAND patients and six uninfected controls. We also determined brain virus burdens by real-time PCR. Treated and untreated HAND brains had distinct gene expression profiles with ART transcriptomes clustering with HIV-1-negative controls. The molecular disease profile of untreated HAND showed dysregulated expression of 1470 genes at p<0.05, with activation of antiviral and immune responses and suppression of synaptic transmission and neurogenesis. The overall brain transcriptome changes in these patients were independent of histological manifestation of HIV-1 encephalitis and brain virus burdens. Depending on treatment compliance, brain transcriptomes from patients on ART had 83% to 93% fewer dysregulated genes and significantly lower dysregulation of biological pathways compared to untreated patients, with particular improvement indicated for nervous system functions. However a core of about 100 genes remained similarly dysregulated in both treated and untreated patient brain tissues. These genes participate in adaptive immune responses, and in interferon, cell cycle, and myelin pathways. Fluctuations of cellular gene expression in the brain correlated in Pearson's formula analysis with plasma but not brain virus burden. Our results define for the first time an aberrant genome-wide brain transcriptome of untreated HAND and they suggest that antiretroviral treatment can be broadly effective in reducing

  14. Expression Profile of Genes Related to Drug Metabolism in Human Brain Tumors.

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    Pantelis Stavrinou

    Full Text Available Endogenous and exogenous compounds as well as carcinogens are metabolized and detoxified by phase I and II enzymes, the activity of which could be crucial to the inactivation and hence susceptibility to carcinogenic factors. The expression of these enzymes in human brain tumor tissue has not been investigated sufficiently. We studied the association between tumor pathology and the expression profile of seven phase I and II drug metabolizing genes (CYP1A1, CYP1B1, ALDH3A1, AOX1, GSTP1, GSTT1 and GSTM3 and some of their proteins.Using qRT-PCR and western blotting analysis the gene and protein expression in a cohort of 77 tumors were investigated. The major tumor subtypes were meningioma, astrocytoma and brain metastases, -the later all adenocarcinomas from a lung primary.Meningeal tumors showed higher expression levels for AOX1, CYP1B1, GSTM3 and GSTP1. For AOX1, GSTM and GSTP1 this could be verified on a protein level as well. A negative correlation between the WHO degree of malignancy and the strength of expression was identified on both transcriptional and translational level for AOX1, GSTM3 and GSTP1, although the results could have been biased by the prevalence of meningiomas and glioblastomas in the inevitably bipolar distribution of the WHO grades. A correlation between the gene expression and the protein product was observed for AOX1, GSTP1 and GSTM3 in astrocytomas.The various CNS tumors show different patterns of drug metabolizing gene expression. Our results suggest that the most important factor governing the expression of these enzymes is the histological subtype and to a far lesser extent the degree of malignancy itself.

  15. Effects of unexpected chords and of performer's expression on brain responses and electrodermal activity.

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    Stefan Koelsch

    Full Text Available BACKGROUND: There is lack of neuroscientific studies investigating music processing with naturalistic stimuli, and brain responses to real music are, thus, largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: This study investigates event-related brain potentials (ERPs, skin conductance responses (SCRs and heart rate (HR elicited by unexpected chords of piano sonatas as they were originally arranged by composers, and as they were played by professional pianists. From the musical excerpts played by the pianists (with emotional expression, we also created versions without variations in tempo and loudness (without musical expression to investigate effects of musical expression on ERPs and SCRs. Compared to expected chords, unexpected chords elicited an early right anterior negativity (ERAN, reflecting music-syntactic processing and an N5 (reflecting processing of meaning information in the ERPs, as well as clear changes in the SCRs (reflecting that unexpected chords also elicited emotional responses. The ERAN was not influenced by emotional expression, whereas N5 potentials elicited by chords in general (regardless of their chord function differed between the expressive and the non-expressive condition. CONCLUSIONS/SIGNIFICANCE: These results show that the neural mechanisms of music-syntactic processing operate independently of the emotional qualities of a stimulus, justifying the use of stimuli without emotional expression to investigate the cognitive processing of musical structure. Moreover, the data indicate that musical expression affects the neural mechanisms underlying the processing of musical meaning. Our data are the first to reveal influences of musical performance on ERPs and SCRs, and to show physiological responses to unexpected chords in naturalistic music.

  16. Restricted expression of Borna disease virus glycoprotein in brains of experimentally infected Lewis rats.

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    Werner-Keiss, N; Garten, W; Richt, J A; Porombka, D; Algermissen, D; Herzog, S; Baumgärtner, W; Herden, C

    2008-12-01

    Borna disease virus (BDV) induces a persistent infection in the central nervous system (CNS) accompanied by a non-purulent meningoencephalitis. BDV-infection of Lewis rats provides an important model to investigate basic principles of neurotropism, viral persistence and resulting dysfunctions. To date, the in vivo strategies of BDV to persist in the CNS are not fully understood. Viral glycoproteins are main targets of the antiviral defence implicating a controlled expression in case of persistent infections. Therefore, we analysed the expression profiles of the BDV-glycoprotein (BDV-GP) and corresponding BDV-intron II RNA in experimentally infected rat brains, focusing on their spatio-temporal occurrence, regional, cellular and intracellular locations. This was carried out by immunohistochemistry and in situ hybridization. The expression pattern of the most abundantly expressed BDV-nucleoprotein (BDV-N) served as a reference. BDV-N mRNA was detected preferentially in the cytoplasm of neurones, whereas BDV-intron II mRNA was found predominantly in the nucleus of brain cells. The genomic RNA was restricted to the nucleus. Expression of BDV-GP was significantly lower than BDV-N expression and mainly limited to cerebral cortex, hippocampus, amygdala and thalamus. BDV-GP was restricted to larger neurones; BDV-N occurred also in astrocytes, oligodendrocytes and ependymal cells. The expression profiles of BDV-GP, BDV-N and their mRNAs are significantly different, indicating that BDV-GP expression is regulated in vivo. This might be achieved by restricted nuclear export and/or maturation of BDV-intron II mRNA or limited translation as a viral mechanism to escape from the immune response and enable persistence in the CNS.

  17. In vitro anti-inflammatory effects of arctigenin, a lignan from Arctium lappa L., through inhibition on iNOS pathway.

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    Zhao, Feng; Wang, Lu; Liu, Ke

    2009-04-21

    Arctigenin, a bioactive constituent from dried seeds of Arctium lappa L. (Compositae) which has been widely used as a Traditional Chinese Medicine for dispelling wind and heat included in Chinese Pharmacophere, was found to exhibit anti-inflammatory activities but its molecular mechanism remains unknown yet. To investigate the anti-inflammatory mechanism of arctigenin. Cultured macrophage RAW 264.7 cells and THP-1 cells were used for the experiments. Griess assay was used to evaluate the inhibitory effect of arctigenin on the overproduction of nitric oxide (NO). ELISA was used to determine the level of pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). The inhibitory effect on the enzymatic activity of cyclooxygenase-2 (COX-2) was tested by colorimetric method. Western blot was used to detect the expression of inducible nitric oxide synthase (iNOS) and COX-2. Arctigenin suppressed lipopolysaccharide (LPS)-stimulated NO production and pro-inflammatory cytokines secretion, including TNF-alpha and IL-6 in a dose-dependent manner. Arctigenin also strongly inhibited the expression of iNOS and iNOS enzymatic activity, whereas the expression of COX-2 and COX-2 enzymatic activity were not affected by arctigenin. These results indicated that potent inhibition on NO, TNF-alpha and IL-6, but not COX-2 expression and COX-2 activity, might constitute the anti-inflammatory mechanism of arctigenin. Arctigenin suppressed the overproduction of NO through down-regulation of iNOS expression and iNOS enzymatic activity in LPS-stimulated macrophage.

  18. Annona muricata modulate brain-CXCL10 expression during cerebral malaria phase

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    Djamiatun, Kis; Matug, Sumia M. A.; Prasetyo, Awal; Wijayahadi, Noor; Nugroho, Djoko

    2017-02-01

    Cerebral malaria (CM) contributes in malaria mortality. People in endemic region get benefices by using A. muricata-leaf extract (AME) before qualified for receiving standard anti-malaria, because AME restrains malaria infection and modulate immune responses. CXCL10 expressed by astrocytes limit brain inflammation. Vascular leakage was found in the brain of experimental CM. Additionally, biomarker related with vascular leakage, angiopoietin-2 (Ang-2) levels increase in CM-patients. Objectives of this study were to determine the efficacy of ethanolic-AME in regulating brain-CXCL10-expression and Ang-2 levels during CM-phase. The study was post-test-only-control-group design. Thirty Swiss-mice were randomly divided in 6 groups. C+ and C- groups were PbA-inoculated and healthy-mice, respectively. X1 and X2 groups were healthy-mice treated with AME 100 and 150 mg/Kg BW/day, respectively. X3 and X4 groups were PbA-inoculated and received either dose mentioned above. CXCL10 was stained by IHC, and determined by Allred score. Plasma-Ang-2 was measured by elisa-method. Kruskal-Wallis-test showed the difference of CXCL10-expression among the studied groups (p=0.003). CXCL10-expression of C+ group was lower than healthy-mice which were C-, X1 and X2 groups (p=0.008, p=0.045, and p=0.012). CXCL10-expression of X3 was comparable to healthy mice (C-, X1 and X2), and was higher than C+ and X4 groups (p=0.012 and p=0.028). CXCL10-expression of X4 group was lower than C- and X2 groups (p=0.011 and p=0.016). Kruskal-Wallis-test showed no difference of Ang-2-levels among 6 groups (p = 0.175). The conclusion is A. muricata influences brain-CXCL10 expression during CM phase, but has no association with Ang-2 levels during CM phase.

  19. Expression pattern of thyroid hormone transporters in the postnatal mouse brain

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    Julia eMüller

    2014-06-01

    Full Text Available For a comprehensive description of the tissue-specific thyroidal state under normal as well as under pathophysiological conditions it is of utmost importance to include thyroid hormone (TH transporters in the analysis as well. The current knowledge of the cell-specific repertoire of TH transporters, however, is still rather limited, although several TH transporting proteins have been identified. Here, we describe the temporal and spatial distribution pattern of the most prominent TH transporters in the postnatal mouse brain. For that purpose, we performed radioactive in situ hybridization studies in order to analyze the cellular mRNA expression pattern of the monocarboxylate transporters Mct8 and Mct10, the L-type amino acid transporters Lat1 and Lat2 as well as the organic anion transporting peptide Oatp1c1 at different postnatal time points. Highest TH transporter expression levels in the CNS were observed at postnatal day 6 and 12, while hybridization signal intensities visibly declined after the second postnatal week. The only exception was Mct10 for which the strongest signals could be observed in white matter regions at postnatal day 21 indicating that this transporter is preferentially expressed in mature oligodendrocytes. Whereas Mct8 and Lat2 showed an overlapping neuronal mRNA expression pattern in the cerebral cortex, hippocampus and in the hypothalamus, Oatp1c1 and Lat1 specific signals were most prominent in capillary endothelial cells throughout the CNS. In the choroid plexus, expression of three transporters (Mct8, Lat2 and Oatp1c1 could be detected, whereas in other brain areas (e.g. striatum, thalamus, brain stem nuclei only one of the transporter candidates appeared to be present. Overall, our study revealed a distinct mRNA distribution pattern for each of the TH transporter candidates. Further studies will reveal to which extent these transporters contribute to the cell-specific TH uptake and efflux in the mouse CNS.

  20. Gene expression in the brain and kidney of rainbow trout in response to handling stress

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    Afanasyev Sergey

    2005-01-01

    Full Text Available Abstract Background Microarray technologies are rapidly becoming available for new species including teleost fishes. We constructed a rainbow trout cDNA microarray targeted at the identification of genes which are differentially expressed in response to environmental stressors. This platform included clones from normalized and subtracted libraries and genes selected through functional annotation. Present study focused on time-course comparisons of stress responses in the brain and kidney and the identification of a set of genes which are diagnostic for stress response. Results Fish were stressed with handling and samples were collected 1, 3 and 5 days after the first exposure. Gene expression profiles were analysed in terms of Gene Ontology categories. Stress affected different functional groups of genes in the tissues studied. Mitochondria, extracellular matrix and endopeptidases (especially collagenases were the major targets in kidney. Stress response in brain was characterized with dramatic temporal alterations. Metal ion binding proteins, glycolytic enzymes and motor proteins were induced transiently, whereas expression of genes involved in stress and immune response, cell proliferation and growth, signal transduction and apoptosis, protein biosynthesis and folding changed in a reciprocal fashion. Despite dramatic difference between tissues and time-points, we were able to identify a group of 48 genes that showed strong correlation of expression profiles (Pearson r > |0.65| in 35 microarray experiments being regulated by stress. We evaluated performance of the clone sets used for preparation of microarray. Overall, the number of differentially expressed genes was markedly higher in EST than in genes selected through Gene Ontology annotations, however 63% of stress-responsive genes were from this group. Conclusions 1. Stress responses in fish brain and kidney are different in function and time-course. 2. Identification of stress

  1. Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain.

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    Beatman, Erica L; Massey, Aaron; Shives, Katherine D; Burrack, Kristina S; Chamanian, Mastooreh; Morrison, Thomas E; Beckham, J David

    2015-12-30

    We have discovered that native, neuronal expression of alpha-synuclein (Asyn) inhibits viral infection, injury, and disease in the central nervous system (CNS). Enveloped RNA viruses, such as West Nile virus (WNV), invade the CNS and cause encephalitis, yet little is known about the innate neuron-specific inhibitors of viral infections in the CNS. Following WNV infection of primary neurons, we found that Asyn protein expression is increased. The infectious titer of WNV and Venezuelan equine encephalitis virus (VEEV) TC83 in the brains of Asyn-knockout mice exhibited a mean increase of 10(4.5) infectious viral particles compared to the titers in wild-type and heterozygote littermates. Asyn-knockout mice also exhibited significantly increased virus-induced mortality compared to Asyn heterozygote or homozygote control mice. Virus-induced Asyn localized to perinuclear, neuronal regions expressing viral envelope protein and the endoplasmic reticulum (ER)-associated trafficking protein Rab1. In Asyn-knockout primary neuronal cultures, the levels of expression of ER signaling pathways, known to support WNV replication, were significantly elevated before and during viral infection compared to those in Asyn-expressing primary neuronal cultures. We propose a model in which virus-induced Asyn localizes to ER-derived membranes, modulates virus-induced ER stress signaling, and inhibits viral replication, growth, and injury in the CNS. These data provide a novel and important functional role for the expression of native alpha-synuclein, a protein that is closely associated with the development of Parkinson's disease. Neuroinvasive viruses such as West Nile virus are able to infect neurons and cause severe disease, such as encephalitis, or infection of brain tissue. Following viral infection in the central nervous system, only select neurons are infected, implying that neurons exhibit innate resistance to viral infections. We discovered that native neuronal expression of alpha

  2. Testes and brain gene expression in precocious male and adult maturing Atlantic salmon (Salmo salar)

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    2010-01-01

    Background The male Atlantic salmon generally matures in fresh water upon returning after one or several years at sea. Some fast-growing male parr develop an alternative life strategy where they sexually mature before migrating to the oceans. These so called 'precocious' parr or 'sneakers' can successfully fertilise adult female eggs and so perpetuate their line. We have used a custom-built cDNA microarray to investigate gene expression changes occurring in the salmon gonad and brain associated with precocious maturation. The microarray has been populated with genes selected specifically for involvement in sexual maturation (precocious and adult) and in the parr-smolt transformation. Results Immature and mature parr collected from a hatchery-reared stock in January were significantly different in weight, length and condition factor. Changes in brain expression were small - never more than 2-fold on the microarray, and down-regulation of genes was much more pronounced than up-regulation. Significantly changing genes included isotocin, vasotocin, cathepsin D, anamorsin and apolipoprotein E. Much greater changes in expression were seen in the testes. Among those genes in the testis with the most significant changes in expression were anti-Mullerian hormone, collagen 1A, and zinc finger protein (Zic1), which were down-regulated in precocity and apolipoproteins E and C-1, lipoprotein lipase and anti-leukoproteinase precursor which were up-regulated in precocity. Expression changes of several genes were confirmed in individual fish by quantitative PCR and several genes (anti-Mullerian hormone, collagen 1A, beta-globin and guanine nucleotide binding protein (G protein) beta polypeptide 2-like 1 (GNB2L1) were also examined in adult maturing testes. Down-regulation of anti-Mullerian hormone was judged to be greater than 160-fold for precocious males and greater than 230-fold for November adult testes in comparison to July testes by this method. For anti-Mullerian hormone

  3. Testes and brain gene expression in precocious male and adult maturing Atlantic salmon (Salmo salar).

    Science.gov (United States)

    Guiry, Aoife; Flynn, Denis; Hubert, Sophie; O'Keeffe, Allan M; LeProvost, Olivier; White, Samantha L; Forde, Patrick F; Davoren, Pamela; Houeix, Benoit; Smith, Terry J; Cotter, Deirdre; Wilkins, Noel P; Cairns, Michael T

    2010-03-30

    The male Atlantic salmon generally matures in fresh water upon returning after one or several years at sea. Some fast-growing male parr develop an alternative life strategy where they sexually mature before migrating to the oceans. These so called 'precocious' parr or 'sneakers' can successfully fertilise adult female eggs and so perpetuate their line. We have used a custom-built cDNA microarray to investigate gene expression changes occurring in the salmon gonad and brain associated with precocious maturation. The microarray has been populated with genes selected specifically for involvement in sexual maturation (precocious and adult) and in the parr-smolt transformation. Immature and mature parr collected from a hatchery-reared stock in January were significantly different in weight, length and condition factor. Changes in brain expression were small - never more than 2-fold on the microarray, and down-regulation of genes was much more pronounced than up-regulation. Significantly changing genes included isotocin, vasotocin, cathepsin D, anamorsin and apolipoprotein E. Much greater changes in expression were seen in the testes. Among those genes in the testis with the most significant changes in expression were anti-Mullerian hormone, collagen 1A, and zinc finger protein (Zic1), which were down-regulated in precocity and apolipoproteins E and C-1, lipoprotein lipase and anti-leukoproteinase precursor which were up-regulated in precocity. Expression changes of several genes were confirmed in individual fish by quantitative PCR and several genes (anti-Mullerian hormone, collagen 1A, beta-globin and guanine nucleotide binding protein (G protein) beta polypeptide 2-like 1 (GNB2L1) were also examined in adult maturing testes. Down-regulation of anti-Mullerian hormone was judged to be greater than 160-fold for precocious males and greater than 230-fold for November adult testes in comparison to July testes by this method. For anti-Mullerian hormone and guanine

  4. Testes and brain gene expression in precocious male and adult maturing Atlantic salmon (Salmo salar

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    Houeix Benoit

    2010-03-01

    Full Text Available Abstract Background The male Atlantic salmon generally matures in fresh water upon returning after one or several years at sea. Some fast-growing male parr develop an alternative life strategy where they sexually mature before migrating to the oceans. These so called 'precocious' parr or 'sneakers' can successfully fertilise adult female eggs and so perpetuate their line. We have used a custom-built cDNA microarray to investigate gene expression changes occurring in the salmon gonad and brain associated with precocious maturation. The microarray has been populated with genes selected specifically for involvement in sexual maturation (precocious and adult and in the parr-smolt transformation. Results Immature and mature parr collected from a hatchery-reared stock in January were significantly different in weight, length and condition factor. Changes in brain expression were small - never more than 2-fold on the microarray, and down-regulation of genes was much more pronounced than up-regulation. Significantly changing genes included isotocin, vasotocin, cathepsin D, anamorsin and apolipoprotein E. Much greater changes in expression were seen in the testes. Among those genes in the testis with the most significant changes in expression were anti-Mullerian hormone, collagen 1A, and zinc finger protein (Zic1, which were down-regulated in precocity and apolipoproteins E and C-1, lipoprotein lipase and anti-leukoproteinase precursor which were up-regulated in precocity. Expression changes of several genes were confirmed in individual fish by quantitative PCR and several genes (anti-Mullerian hormone, collagen 1A, beta-globin and guanine nucleotide binding protein (G protein beta polypeptide 2-like 1 (GNB2L1 were also examined in adult maturing testes. Down-regulation of anti-Mullerian hormone was judged to be greater than 160-fold for precocious males and greater than 230-fold for November adult testes in comparison to July testes by this method. For

  5. Brain Gene Expression is Influenced by Incubation Temperature During Leopard Gecko (Eublepharis macularius) Development.

    Science.gov (United States)

    Pallotta, Maria Michela; Turano, Mimmo; Ronca, Raffaele; Mezzasalma, Marcello; Petraccioli, Agnese; Odierna, Gaetano; Capriglione, Teresa

    2017-06-01

    Sexual differentiation (SD) during development results in anatomical, metabolic, and physiological differences that involve not only the gonads, but also a variety of other biological structures, such as the brain, determining differences in morphology, behavior, and response in the breeding season. In many reptiles, whose sex is determined by egg incubation temperature, such as the leopard gecko, Eublepharis macularius, embryos incubated at different temperatures clearly differ in the volume of brain nuclei that modulate behavior. Based on the premise that "the developmental decision of gender does not flow through a single gene", we performed an analysis on E. macularius using three approaches to gain insights into the genes that may be involved in brain SD during the thermosensitive period. Using quantitative RT-PCR, we studied the expression of genes known to be involved in gonadal SD such as WNT4, SOX9, DMRT1, Erα, Erβ, GnRH, P450 aromatase, PRL, and PRL-R. Then, further genes putatively involved in sex dimorphic brain differentiation were sought by differential display (DDRT-PCR) and PCR array. Our findings indicate that embryo exposure to different sex determining temperatures induces differential expression of several genes that are involved not only in gonadal differentiation (PRL-R, Wnt4, Erα, Erβ, p450 aromatase, and DMRT1), but also in neural differentiation (TN-R, Adora2A, and ASCL1) and metabolic pathways (GP1, RPS15, and NADH12). These data suggest that the brains of SDT reptiles might be dimorphic at birth, thus behavioral experiences in postnatal development would act on a structure already committed to male or female. © 2017 Wiley Periodicals, Inc.

  6. Dominant negative effects of a non-conducting TREK1 splice variant expressed in brain.

    Science.gov (United States)

    Veale, Emma L; Rees, Kathryn A; Mathie, Alistair; Trapp, Stefan

    2010-09-17

    Two-pore domain potassium (K(2P)) channels modulate neuronal excitability throughout the entire CNS. The stretch-activated channel TREK1 (K(2P)2.1) is expressed widely in brain and has been linked to depression, neuroprotection, pain perception, and epilepsy. Little, however, is known about the regulation of TREK1 expression on the transcriptional and translational level or about its trafficking to the plasma membrane. Here we have used PCR techniques to identify a splice variant of TREK1 expressed in the brain, which encodes a heavily truncated TREK1 protein retaining a single transmembrane domain. Functional expression of this splice variant TREK1ΔEx4 in tsA201 cells in the presence or absence of wild type TREK1 revealed that TREK1ΔEx4 has no channel activity itself but reduced TREK1 whole cell current amplitude. Confocal analysis of the expression of fluorescently tagged TREK1 variants revealed that TREK1ΔEx4 is translated, but it is retained in the intracellular compartment. Additionally, TREK1ΔEx4 reduced the level of TREK1 expression in the plasma membrane. Long and short forms of TREK1 derived from alternative translation initiation are differentially affected by TREK1ΔEx4, with the short form (lacking the first 41 amino acids at its N terminus) unaffected. This differential regulatory role of TREK1ΔEx4 will alter the functional profile of TREK1 current in neurons where they are expressed. These results indicate that the N-terminal domain and first transmembrane domain of TREK1 are likely to be important for channel dimerization and trafficking to the plasma membrane.

  7. Facing mixed emotions: Analytic and holistic perception of facial emotion expressions engages separate brain networks.

    Science.gov (United States)

    Meaux, Emilie; Vuilleumier, Patrik

    2016-11-01

    The ability to decode facial emotions is of primary importance for human social interactions; yet, it is still debated how we analyze faces to determine their expression. Here we compared the processing of emotional face expressions through holistic integration and/or local analysis of visual features, and determined which brain systems mediate these distinct processes. Behavioral, physiological, and brain responses to happy and angry faces were assessed by presenting congruent global configurations of expressions (e.g., happy top+happy bottom), incongruent composite configurations (e.g., angry top+happy bottom), and isolated features (e.g. happy top only). Top and bottom parts were always from the same individual. Twenty-six healthy volunteers were scanned using fMRI while they classified the expression in either the top or the bottom face part but ignored information in the other non-target part. Results indicate that the recognition of happy and anger expressions is neither strictly holistic nor analytic Both routes were involved, but with a different role for analytic and holistic information depending on the emotion type, and different weights of local features between happy and anger expressions. Dissociable neural pathways were engaged depending on emotional face configurations. In particular, regions within the face processing network differed in their sensitivity to holistic expression information, which predominantly activated fusiform, inferior occipital areas and amygdala when internal features were congruent (i.e. template matching), whereas more local analysis of independent features preferentially engaged STS and prefrontal areas (IFG/OFC) in the context of full face configurations, but early visual areas and pulvinar when seen in isolated parts. Collectively, these findings suggest that facial emotion recognition recruits separate, but interactive dorsal and ventral routes within the face processing networks, whose engagement may be shaped by

  8. Expression of aggregative adherence to hela cells by Escherichia coli strains isolated from sick horses Expressão de aderência agregativa em células HeLa por amostras de E. coli isoladas de eqüinos doentes

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    Ana Maria Alvim Liberatore

    2007-03-01

    Full Text Available The virulence attributes of 56 Escherichia coli strains isolated from sick horses (secretions of uterine cervices; gastrointestinal and lung fragments of necropsy; diarrheic feces, and tracheal washings was examined by determining their adherence pattern to HeLa cells and searching for the presence of virulence genes of the various E. coli pathotypes. Two non-adherent strains presented astA, which encodes the enteroaggregative E. coli heat-stable toxin. Twenty-seven strains (48.2% adhered to HeLa cells, 21 (77.8% of which presented the aggregative adherence pattern (AA that characterize the Enteroaggregative E. coli pathotype (EAEC. Nine of the strains presenting AA were isolated from secretions of uterine cervix, including one carrying virulence genes of the EAEC pathotype (aggR,aap,irp2, and pic. This is the first description of the AA phenotype amongst E. coli strains from sick horses. Such strains should be further evaluated regarding their potential role in the pathogenesis of diverse equine diseases and as reservoirs of human infections.Características de virulência de 56 amostras de Escherichia coli isoladas de eqüinos doentes (secreção de colo uterino, fragmentos de necrópsia do trato gastrointestinal e de pulmões, fezes diarréicas e lavado traqueal foram examinadas para determinar o padrão de aderência em células HeLa e pesquisar a presença de genes de virulência de vários patotipos de E. coli. Duas amostras não aderentes apresentaram astA, gene que codifica a toxina termo-estável de E. coli enteroagregativa. Das vinte e sete amostras (48,2% que aderiram a células HeLa, 21 (77,8% apresentaram o padrão de aderência agregativa (AA que caracteriza o patotipo de E. coli Enteroagregativa (EAEC. Nove destas amostras que apresentaram AA foram isoladas de secreção de colo uterino, incluindo uma que apresentava genes de virulência de patotipos de EAEC (aggR,aap,irp2 e pic. Esta é a primeira descrição do fenótipo AA em

  9. Peripheral inflammation is associated with remote global gene expression changes in the brain

    Science.gov (United States)

    2014-01-01

    Background Although the central nervous system (CNS) was once considered an immunologically privileged site, in recent years it has become increasingly evident that cross talk between the immune system and the CNS does occur. As a result, patients with chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease or psoriasis, are often further burdened with neuropsychiatric symptoms, such as depression, anxiety and fatigue. Despite the recent advances in our understanding of neuroimmune communication pathways, the precise effect of peripheral immune activation on neural circuitry remains unclear. Utilizing transcriptomics in a well-characterized murine model of systemic inflammation, we have started to investigate the molecular mechanisms by which inflammation originating in the periphery can induce transcriptional modulation in the brain. Methods Several different systemic and tissue-specific models of peripheral toll-like-receptor-(TLR)-driven (lipopolysaccharide (LPS), lipoteichoic acid and Imiquimod) and sterile (tumour necrosis factor (TNF) and 12-O-tetradecanoylphorbol-13-acetate (TPA)) inflammation were induced in C57BL/6 mice. Whole brain transcriptional profiles were assessed and compared 48 hours after intraperitoneal injection of lipopolysaccharide or vehicle, using Affymetrix GeneChip microarrays. Target gene induction, identified by microarray analysis, was validated independently using qPCR. Expression of the same panel of target genes was then investigated in a number of sterile and other TLR-dependent models of peripheral inflammation. Results Microarray analysis of whole brains collected 48 hr after LPS challenge revealed increased transcription of a range of interferon-stimulated genes (ISGs) in the brain. In addition to acute LPS challenge, ISGs were induced in the brain following both chronic LPS-induced systemic inflammation and Imiquimod-induced skin inflammation. Unique to the brain, this transcriptional response is

  10. Isolating dividing neural and brain tumour cells for gene expression profiling.

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    Endaya, Berwini; Cavanagh, Brenton; Alowaidi, Faisal; Walker, Tom; de Pennington, Nicholas; Ng, Jin-Ming A; Lam, Paula Y P; Mackay-Sim, Alan; Neuzil, Jiri; Meedeniya, Adrian C B

    2016-01-15

    The characterisation of dividing brain cells is fundamental for studies ranging from developmental and stem cell biology, to brain cancers. Whilst there is extensive anatomical data on these dividing cells, limited gene transcription data is available due to technical constraints. We focally isolated dividing cells whilst conserving RNA, from culture, primary neural tissue and xenografted glioma tumours, using a thymidine analogue that enables gene transcription analysis. 5-ethynyl-2-deoxyuridine labels the replicating DNA of dividing cells. Once labelled, cultured cells and tissues were dissociated, fluorescently tagged with a revised click chemistry technique and the dividing cells isolated using fluorescence-assisted cell sorting. RNA was extracted and analysed using real time PCR. Proliferation and maturation related gene expression in neurogenic tissues was demonstrated in acutely and 3 day old labelled cells, respectively. An elevated expression of marker and pathway genes was demonstrated in the dividing cells of xenografted brain tumours, with the non-dividing cells showing relatively low levels of expression. BrdU "immune-labelling", the most frequently used protocol for detecting cell proliferation, causes complete denaturation of RNA, precluding gene transcription analysis. This EdU labelling technique, maintained cell integrity during dissociation, minimized copper exposure during labelling and used a cell isolation protocol that avoided cell lysis, thus conserving RNA. The technique conserves RNA, enabling the definition of cell proliferation-related changes in gene transcription of neural and pathological brain cells in cells harvested immediately after division, or following a period of maturation. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Neuronal over-expression of ACE2 protects brain from ischemia-induced damage.

    Science.gov (United States)

    Chen, Ji; Zhao, Yuhui; Chen, Shuzhen; Wang, Jinju; Xiao, Xiang; Ma, Xiaotang; Penchikala, Madhuri; Xia, Huijing; Lazartigues, Eric; Zhao, Bin; Chen, Yanfang

    2014-04-01

    Angiotensin (Ang) II exaggerates cerebral injury in ischemic damage. Angiotensin-converting enzyme type 2 (ACE2) converts Ang II into Ang (1-7) and thus, may protect against the effects of Ang II. We hypothesized that neuronal ACE2 over-expression decreases ischemic stroke in mice with Ang II overproduction. Human renin and angiotensinogen double transgenic (RA) mice and RA mice with neuronal over-expression of ACE2 (SARA) were used for the study. The mean arterial pressure (MAP) was calculated from telemetry-recorded blood pressure (BP). SARA mice were infused peripherally with Norepinephrine to "clamp" the BP, or intracerebroventricularly-infused with a Mas receptor antagonist (A-779). Middle cerebral artery occlusion (MCAO) surgery was performed to induce permanent focal ischemic stroke. Cerebral blood flow (CBF) and neurological function were determined. Two days after surgery, brain samples were collected for various analyses. Results showed: 1) When compared to chronically hypertensive RA mice, SARA mice had lower basal MAP, less MCAO-induced infarct volume, and increased CBF, neurological function and cerebral microvascular density in the peri-infarct area; 2) These changes in SARA mice were not altered after MAP "clamping", but partially reversed by brain infusion of A-779; 3) Ang (1-7)/Ang II ratio, angiogenic factors, endothelial nitric oxide synthase (eNOS) expression and nitric oxide production were increased, whereas, NADPH oxidase subunits and reactive oxygen species were decreased in the brain of SARA mice. ACE2 protects brain from ischemic injury via the regulation of NADPH oxidase/eNOS pathways by changing Ang (1-7)/Ang II ratio, independently of MAP changes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Dehydration triggers differential microRNA expression in Xenopus laevis brain.

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    Luu, Bryan E; Storey, Kenneth B

    2015-11-15

    African clawed frogs, Xenopus laevis, although primarily aquatic, have a high tolerance for dehydration, being capable of withstanding the loss of up to 32-35% of total water body water. Recent studies have shown that microRNAs play a role in the response to dehydration by the liver, kidney and ventral skin of X. laevis. MicroRNAs act by modulating the expression of mRNA transcripts, thereby affecting diverse biochemical pathways. In this study, 43 microRNAs were assessed in frog brains comparing control and dehydrated (31.2±0.83% of total body water lost) conditions. MicroRNAs of interest were measured using a modified protocol which employs polyadenylation of microRNAs prior to reverse transcription and qPCR. Twelve microRNAs that showed a significant decrease in expression (to 41-77% of control levels) in brains from dehydrated frogs (xla-miR-15a, -150, -181a, -191, -211, -218, -219b, -30c, -30e, -31, -34a, and -34b) were identified. Genomic analysis showed that the sequences of these dehydration-responsive microRNAs were highly conserved as compared with the comparable microRNAs of mice (91-100%). Suppression of these microRNAs implies that translation of the mRNA transcripts under their control could be enhanced in response to dehydration. Bioinformatic analysis using the DIANA miRPath program (v.2.0) predicted the top two KEGG pathways that these microRNAs collectively regulate: 1. Axon guidance, and 2. Long-term potentiation. Previous studies indicated that suppression of these microRNAs promotes neuroprotective pathways by increasing the expression of brain-derived neurotrophic factor and activating anti-apoptotic pathways. This suggests that similar actions may be triggered in X. laevis brains as a protective response to dehydration. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

  13. Dynamic, mating-induced gene expression changes in female head and brain tissues of Drosophila melanogaster

    Science.gov (United States)

    2010-01-01

    Background Drosophila melanogaster females show changes in behavior and physiology after mating that are thought to maximize the number of progeny resulting from the most recent copulation. Sperm and seminal fluid proteins induce post-mating changes in females, however, very little is known about the resulting gene expression changes in female head and central nervous system tissues that contribute to the post-mating response. Results We determined the temporal gene expression changes in female head tissues 0-2, 24, 48 and 72 hours after mating. Females from each time point had a unique post-mating gene expression response, with 72 hours post-mating having the largest number of genes with significant changes in expression. At most time points, genes expressed in the head fat body that encode products involved in metabolism showed a marked change in expression. Additional analysis of gene expression changes in dissected brain tissues 24 hours post-mating revealed changes in transcript abundance of many genes, notably, the reduced transcript abundance of genes that encode ion channels. Conclusions Substantial changes occur in the regulation of many genes in female head tissues after mating, which might underlie aspects of the female post-mating response. These results provide new insights into the physiological and metabolic changes that accompany changes in female behaviors. PMID:20925960

  14. Dynamic, mating-induced gene expression changes in female head and brain tissues of Drosophila melanogaster

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    Stirling Emma J

    2010-10-01

    Full Text Available Abstract Background Drosophila melanogaster females show changes in behavior and physiology after mating that are thought to maximize the number of progeny resulting from the most recent copulation. Sperm and seminal fluid proteins induce post-mating changes in females, however, very little is known about the resulting gene expression changes in female head and central nervous system tissues that contribute to the post-mating response. Results We determined the temporal gene expression changes in female head tissues 0-2, 24, 48 and 72 hours after mating. Females from each time point had a unique post-mating gene expression response, with 72 hours post-mating having the largest number of genes with significant changes in expression. At most time points, genes expressed in the head fat body that encode products involved in metabolism showed a marked change in expression. Additional analysis of gene expression changes in dissected brain tissues 24 hours post-mating revealed changes in transcript abundance of many genes, notably, the reduced transcript abundance of genes that encode ion channels. Conclusions Substantial changes occur in the regulation of many genes in female head tissues after mating, which might underlie aspects of the female post-mating response. These results provide new insights into the physiological and metabolic changes that accompany changes in female behaviors.

  15. Maternal separation produces alterations of forebrain brain-derived neurotrophic factor expression in differently aged rats

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    Qiong eWang

    2015-09-01

    Full Text Available Early postnatal maternal separation (MS can play an important role in the development of psychopathologies during ontogeny. In the present study, we investigated the effects of repeated MS (4 h per day from postnatal day [PND] 1–21 on the brain-derived neurotrophic factor (BDNF expression in the medial prefrontal cortex (mPFC, the nucleus accumbens (NAc and the hippocampus of male and female juvenile (PND 21, adolescent (PND 35 and young adult (PND 56 Wistar rats. The results indicated that MS increased BDNF in the CA1 and the dentate gyrus (DG of adolescent rats as well as in the DG of young adult rats. However, the expression of BDNF in the mPFC in the young adult rats was decreased by MS. Additionally, in the hippocampus, there was decreased BDNF expression with age in both the MS and socially reared rats. However, in the mPFC, the BDNF expression was increased with age in the socially reared rats; nevertheless, the BDNF expression was significantly decreased in the MS young adult rats. In the NAc, the BDNF expression was increased with age in the male NMS rats, and the young adult female MS rats had less BDNF expression than the adolescent female MS rats. The

  16. Expression of interferon gamma in the brain of cats with natural Borna disease virus infection.

    Science.gov (United States)

    Wensman, Jonas Johansson; Ilbäck, Carolina; Hjertström, Elina; Blomström, Anne-Lie; Gustavsson, Malin Hagberg; Jäderlund, Karin Hultin; Ström-Holst, Bodil; Belák, Sándor; Berg, Anna-Lena; Berg, Mikael

    2011-05-15

    Borna disease virus (BDV) is a neurotropic, negative-stranded RNA virus, which causes a non-suppurative meningoencephalomyelitis in a wide range of animals. In cats, BDV infection leads to staggering disease. In spite of a vigorous immune response the virus persists in the central nervous system (CNS) in both experimentally and naturally infected animals. Since the CNS is vulnerable to cytotoxic effects mediated via NK-cells and cytotoxic T-cells, other non-cytolytic mechanisms such as the interferon (IFN) system is favourable for viral clearance. In this study, IFN-γ expression in the brain of cats with clinical signs of staggering disease (N=12) was compared to the expression in cats with no signs of this disease (N=7) by quantitative RT-PCR. The IFN-γ expression was normalised against the expression of three reference genes (HPRT, RPS7, YWHAZ). Cats with staggering disease had significantly higher expression of IFN-γ compared to the control cats (p-value ≤ 0.001). There was no significant difference of the IFN-γ expression in BDV-positive (N=7) and -negative (N=5) cats having clinical signs of staggering disease. However, as BDV-RNA still could be detected, despite an intense IFN-γ expression, BDV needs to have mechanisms to evade this antiviral immune response of the host, to be able to persist. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Expression of Tau Pathology-Related Proteins in Different Brain Regions: A Molecular Basis of Tau Pathogenesis

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    Wen Hu

    2017-09-01

    Full Text Available Microtubule-associated protein tau is hyperphosphorylated and aggregated in affected neurons in Alzheimer disease (AD brains. The tau pathology starts from the entorhinal cortex (EC, spreads to the hippocampus and frontal and temporal cortices, and finally to all isocortex areas, but the cerebellum is spared from tau lesions. The molecular basis of differential vulnerability of different brain regions to tau pathology is not understood. In the present study, we analyzed brain regional expressions of tau and tau pathology-related proteins. We found that tau was hyperphosphorylated at multiple sites in the frontal cortex (FC, but not in the cerebellum, from AD brain. The level of tau expression in the cerebellum was about 1/4 of that seen in the frontal and temporal cortices in human brain. In the rat brain, the expression level of tau with three microtubule-binding repeats (3R-tau was comparable in the hippocampus, EC, FC, parietal-temporal cortex (PTC, occipital-temporal cortex (OTC, striatum, thalamus, olfactory bulb (OB and cerebellum. However, the expression level of 4R-tau was the highest in the EC and the lowest in the cerebellum. Tau phosphatases, kinases, microtubule-related proteins and other tau pathology-related proteins were also expressed in a region-specific manner in the rat brain. These results suggest that higher levels of tau and tau kinases in the EC and low levels of these proteins in the cerebellum may accounts for the vulnerability and resistance of these representative brain regions to the development of tau pathology, respectively. The present study provides the regional expression profiles of tau and tau pathology-related proteins in the brain, which may help understand the brain regional vulnerability to tau pathology in neurodegenerative tauopathies.

  18. Expression profiling of autism candidate genes during human brain development implicates central immune signaling pathways.

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    Mark N Ziats

    Full Text Available The Autism Spectrum Disorders (ASD represent a clinically heterogeneous set of conditions with strong hereditary components. Despite substantial efforts to uncover the genetic basis of ASD, the genomic etiology appears complex and a clear understanding of the molecular mechanisms underlying Autism remains elusive. We hypothesized that focusing gene interaction networks on ASD-implicated genes that are highly expressed in the developing brain may reveal core mechanisms that are otherwise obscured by the genomic heterogeneity of the disorder. Here we report an in silico study of the gene expression profile from ASD-implicated genes in the unaffected developing human brain. By implementing a biologically relevant approach, we identified a subset of highly expressed ASD-candidate genes from which interactome networks were derived. Strikingly, immune signaling through NFκB, Tnf, and Jnk was central to ASD networks at multiple levels of our analysis, and cell-type specific expression suggested glia--in addition to neurons--deserve consideration. This work provides integrated genomic evidence that ASD-implicated genes may converge on central cytokine signaling pathways.

  19. Expression profiling of autism candidate genes during human brain development implicates central immune signaling pathways.

    Science.gov (United States)

    Ziats, Mark N; Rennert, Owen M

    2011-01-01

    The Autism Spectrum Disorders (ASD) represent a clinically heterogeneous set of conditions with strong hereditary components. Despite substantial efforts to uncover the genetic basis of ASD, the genomic etiology appears complex and a clear understanding of the molecular mechanisms underlying Autism remains elusive. We hypothesized that focusing gene interaction networks on ASD-implicated genes that are highly expressed in the developing brain may reveal core mechanisms that are otherwise obscured by the genomic heterogeneity of the disorder. Here we report an in silico study of the gene expression profile from ASD-implicated genes in the unaffected developing human brain. By implementing a biologically relevant approach, we identified a subset of highly expressed ASD-candidate genes from which interactome networks were derived. Strikingly, immune signaling through NFκB, Tnf, and Jnk was central to ASD networks at multiple levels of our analysis, and cell-type specific expression suggested glia--in addition to neurons--deserve consideration. This work provides integrated genomic evidence that ASD-implicated genes may converge on central cytokine signaling pathways.

  20. orthodenticle/otx ortholog expression in the anterior brain and eyes of Sepia officinalis (Mollusca, Cephalopoda).

    Science.gov (United States)

    Buresi, Auxane; Baratte, Sébastien; Da Silva, Corinne; Bonnaud, Laure

    2012-01-01

    The origin of cerebral structures is a major issue in both developmental and evolutionary biology. Among Lophotrochozoans, cephalopods present both a derived nervous system and an original body plan, therefore they constitute a key model to study the evolution of nervous system and molecular processes that control the neural organization. We characterized a partial sequence of an ortholog of otx2 in Sepia officinalis embryos, a gene specific to the anterior nervous system and eye development. By in situ hybridization, we assessed the expression pattern of otx2 during S. officinalis organogenesis and we showed that otx is expressed (1) in the eyes, from early to late developmental stages as observed in other species (2) in the nervous system during late developmental stages. The otx ortholog does not appear to be required for the precocious emergence of the nervous ganglia in cephalopods and is later expressed only in the most anterior ganglia of the future brain. Finally, otx expression becomes restricted to localized part of the brain, where it could be involved in the functional specification of the central nervous system of S. officinalis. These results suggest a conserved involvement of otx in eye maturation and development of the anterior neural structures in S. officinalis. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Alternative life histories shape brain gene expression profiles in males of the same population

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    Aubin-Horth, N.; Landry, C.R.; Letcher, B.H.; Hofmann, H.A.

    2005-01-01

    Atlantic salmon (Salmo salar) undergo spectacular marine migrations before homing to spawn in natal rivers. However, males that grow fastest early in life can adopt an alternative 'sneaker' tactic by maturing earlier at greatly reduced size without leaving freshwater. While the ultimate evolutionary causes have been well studied, virtually nothing is known about the molecular bases of this developmental plasticity. We investigate the nature and extent of coordinated molecular changes that accompany such a fundamental transformation by comparing the brain transcription profiles of wild mature sneaker males to age-matched immature males (future large anadromous males) and immature females. Of the ca. 3000 genes surveyed, 15% are differentially expressed in the brains of the two male types. These genes are involved in a wide range of processes, including growth, reproduction and neural plasticity. Interestingly, despite the potential for wide variation in gene expression profiles among individuals sampled in nature, consistent patterns of gene expression were found for individuals of the same reproductive tactic. Notably, gene expression patterns in immature males were different both from immature females and sneakers, indicating that delayed maturation and sea migration by immature males, the 'default' life cycle, may actually result from an active inhibition of development into a sneaker. ?? 2005 The Royal Society.

  2. Social information changes stress hormone receptor expression in the songbird brain.

    Science.gov (United States)

    Cornelius, Jamie M; Perreau, Gillian; Bishop, Valerie R; Krause, Jesse S; Smith, Rachael; Hahn, Thomas P; Meddle, Simone L

    2018-01-01

    Social information is used by many vertebrate taxa to inform decision-making, including resource-mediated movements, yet the mechanisms whereby social information is integrated physiologically to affect such decisions remain unknown. Social information is known to influence the physiological response to food reduction in captive songbirds. Red crossbills (Loxia curvirostra) that were food reduced for several days showed significant elevations in circulating corticosterone (a "stress" hormone often responsive to food limitation) only if their neighbors were similarly food restricted. Physiological responses to glucocorticoid hormones are enacted through two receptors that may be expressed differentially in target tissues. Therefore, we investigated the influence of social information on the expression of the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA in captive red crossbill brains. Although the role of MR and GR in the response to social information may be highly complex, we specifically predicted social information from food-restricted individuals would reduce MR and GR expression in two brain regions known to regulate hypothalamic-pituitary-adrenal (HPA) activity - given that reduced receptor expression may lessen the efficacy of negative feedback and release inhibitory tone on the HPA. Our results support these predictions - offering one potential mechanism whereby social cues could increase or sustain HPA-activity during stress. The data further suggest different mechanisms by which metabolic stress versus social information influence HPA activity and behavioral outcomes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Serum after traumatic brain injury increases proliferation and supports expression of osteoblast markers in muscle cells.

    Science.gov (United States)

    Cadosch, Dieter; Toffoli, Andrew M; Gautschi, Oliver P; Frey, Sönke P; Zellweger, René; Skirving, Allan P; Filgueira, Luis

    2010-03-01

    Traumatic brain injury is associated with an increased rate of heterotopic ossification within skeletal muscle, possibly as a result of humoral factors. In this study, we investigated whether cells from skeletal muscle adopt an osteoblastic phenotype in response to serum from patients with traumatic brain injury. Serum was collected from thirteen patients with severe traumatic brain injury, fourteen patients with a long-bone fracture, and ten control subjects. Primary cultures of skeletal muscle cells isolated from patients undergoing orthopaedic surgery were performed and characterized with use of immunofluorescence microscopy, reverse transcription-polymerase chain reaction, and Western blot analysis. Proliferation and osteoblastic differentiation were assessed with use of commercial cell assays, Western blot analysis (for Osterix protein), and the Villanueva bone stain. All serum-treated cell populations expressed the osteoblast marker Osterix after one week in culture. Cells treated with serum from all study groups in mineralization medium had increased alkaline phosphatase activity and mineralized nodules within the mesenchymal cell subpopulation after three weeks in culture. Serum from patients with traumatic brain injury induced a significant increase (p = 0.02) in the rate of proliferation of primary skeletal muscle cells (1.87 [95% confidence interval, 1.66 to 2.09]) compared with the rate induced by serum from patients with a fracture (1.42 [95% confidence interval, 1.21 to 1.58]) or by serum from controls (1.35 [95% confidence interval, 1.15 to 1.54]). Human serum supports the osteoblastic differentiation of cells derived from human skeletal muscle, and serum from patients with severe traumatic brain injury accelerates proliferation of these cells. These findings suggest the early presence of humoral factors following traumatic brain injury that stimulate the expansion of mesenchymal cells and osteoprogenitors within skeletal muscle.

  4. Downregulation of CREB expression in Alzheimer's brain and in Aβ-treated rat hippocampal neurons

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    Pham Serena

    2011-08-01

    Full Text Available Abstract Background Oxidative stress plays an important role in neuronal dysfunction and neuron loss in Alzheimer's brain. Previous studies have reported downregulation of CREB-mediated transcription by oxidative stress and Aβ. The promoter for CREB itself contains cyclic AMP response elements. Therefore, we examined the expression of CREB in the hippocampal neurons of Tg2576 mice, AD post-mortem brain and in cultured rat hippocampal neurons exposed to Aβ aggregates. Results Laser Capture Microdissection of hippocampal neurons from Tg2576 mouse brain revealed decreases in the mRNA levels of CREB and its target, BDNF. Immunohistochemical analysis of Tg2576 mouse brain showed decreases in CREB levels in hippocampus and cortex. Markers of oxidative stress were detected in transgenic mouse brain and decreased CREB staining was observed in regions showing abundance of astrocytes. There was also an inverse correlation between SDS-extracted Aβ and CREB protein levels in Alzheimer's post-mortem hippocampal samples. The levels of CREB-regulated BDNF and BIRC3, a caspase inhibitor, decreased and the active cleaved form of caspase-9, a marker for the intrinsic pathway of apoptosis, was elevated in these samples. Exposure of rat primary hippocampal neurons to Aβ fibrils decreased CREB promoter activity. Decrease in CREB mRNA levels in Aβ-treated neurons was reversed by the antioxidant, N-acetyl cysteine. Overexpression of CREB by adenoviral transduction led to significant protection against Aβ-induced neuronal apoptosis. Conclusions Our findings suggest that chronic downregulation of CREB-mediated transcription results in decrease of CREB content in the hippocampal neurons of AD brain which may contribute to exacerbation of disease progression.

  5. Differential transgene expression in brain cells in vivo and in vitro from AAV-2 vectors with small transcriptional control units.

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    Kügler, S; Lingor, P; Schöll, U; Zolotukhin, S; Bähr, M

    2003-06-20

    Adeno-associated- (AAV) based vectors are promising tools for gene therapy applications in several organs, including the brain, but are limited by their small genome size. Two short promoters, the human synapsin 1 gene promoter (hSYN) and the murine cytomegalovirus immediate early promoter (mCMV), were evaluated in bicistronic AAV-2 vectors for their expression profiles in cultured primary brain cells and in the rat brain. Whereas transgene expression from the hSYN promoter was exclusively neuronal, the murine CMV promoter targeted expression mainly to astrocytes in vitro and showed weak transgene expression in vivo in retinal and cortical neurons, but strong expression in thalamic neurons. We propose that neuron specific transgene expression in combination with enhanced transgene capacity will further substantially improve AAV based vector technology.

  6. Roles of apolipoprotein E (ApoE) and inducible nitric oxide synthase (iNOS) in inflammation and apoptosis in preeclampsia pathogenesis and progression.

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    Mao, Luyi; Zhou, Qiongjie; Zhou, Shufeng; Wilbur, Rhonda R; Li, Xiaotian

    2013-01-01

    To investigate potential roles of inducible nitric oxide synthase (iNOS) and apolipoprotein (apoE) in inflammation and apoptosis promoting pathological changes in preeclampsia in pregnant mice with apoE and/or iNOS knock out. B6.129 mice were crossed to produce WT, apoE(-/-), apoE(+/-), iNOS(-/-), iNOS(+/-) and apoE(-/-)iNOS(-/-) groups. Variants were confirmed by PCR. Serum lipid parameters (triglycerides, TG; total cholesterol, TC; high density lipoprotein, HDL; and low density lipoprotein, LDL), NO levels and placental electronic microscopic ultrastructures were evaluated, and blood pressure (BP), 24-hour urine protein and pregnancy outcomes were recorded for pregnant F1 generation mice. Placental expressions of inflammatory (tumor necrosis factor-α, TNF-α; interleukin-6, IL-6; nuclear factor-κB, NF-κb) and apoptotic markers (Bcl-2 associated X protein, Bax, B-cell lymphoma/leukemia-2, Bcl-2, and Caspase-3) were evaluated via Western blot. Serum lipids, BP and 24-hour urine protein levels were shown to be significantly higher and parturition and placenta weights were lower in apoE(-/-) and apoE(-/-)iNOS(-/-) groups (papoptosis parameters, including TNF-α, IL-6, NF-κb, Bax, Bcl-2 and Caspase-3 in the apoE(-/-)iNOS(-/-) group (papoptosis parameters in the iNOS(+/-) and the apoE(+/-) groups (p>0.05) showed no differences. In addition, placenta vascular endothelial and trophoblast cell morphological changes were demonstrated in both the apoE(-/-)iNOS(-/-) and apoE(-/-) groups. Elevated lipid metabolism and inflammatory/apoptosis parameters suggest a potentially significant role of apoE in preeclampsia pathology, as well as a relationship between iNOS and preeclampsia progression.

  7. Spatial patterns of genome-wide expression profiles reflect anatomic and fiber connectivity architecture of healthy human brain.

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    Goel, Pragya; Kuceyeski, Amy; LoCastro, Eve; Raj, Ashish

    2014-08-01

    Unraveling the relationship between molecular signatures in the brain and their functional, architectonic, and anatomic correlates is an important neuroscientific goal. It is still not well understood whether the diversity demonstrated by histological studies in the human brain is reflected in the spatial patterning of whole brain transcriptional profiles. Using genome-wide maps of transcriptional distribution of the human brain by the Allen Brain Institute, we test the hypothesis that gene expression profiles are specific to anatomically described brain regions. In this work, we demonstrate that this is indeed the case by showing that gene similarity clusters appear to respect conventional basal-cortical and caudal-rostral gradients. To fully investigate the causes of this observed spatial clustering, we test a connectionist hypothesis that states that the spatial patterning of gene expression in the brain is simply reflective of the fiber tract connectivity between brain regions. We find that although gene expression and structural connectivity are not determined by each other, they do influence each other with a high statistical significance. This implies that spatial diversity of gene expressions is a result of mainly location-specific features but is influenced by neuronal connectivity, such that like cellular species preferentially connects with like cells. Copyright © 2014 Wiley Periodicals, Inc.

  8. Astrocytic and microglial response and histopathological changes in the brain of horses with experimental chronic Trypanosoma evansi infection Resposta astrocítica e microglial e alterações histopatológicas no sistema nervoso central de eqüinos infectados cronicamente com Trypanosoma evansi

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    Karen Regina Lemos

    2008-08-01

    Full Text Available This study aimed to characterize astrocytic and microglial response in the central nervous system (CNS of equines experimentally infected with T. evansi. The experimental group comprised males and females with various degrees of crossbreeding, ages between four and seven years. The animals were inoculated intravenously with 10(6 trypomastigotes of T. evansi originally isolated from a naturally infected dog. All equines inoculated with T. evansi were observed until they presented symptoms of CNS disturbance, characterized by motor incoordination of the pelvic limbs, which occurred 67 days after inoculation (DAI and 124 DAI. The animals in the control group did not present any clinical symptom and were observed up to the 125th DAI. For this purpose the HE histochemical stain and the avidin biotin peroxidase method was used. Lesions in the CNS of experimentally infected horses were those of a wide spread non suppurative meningoencephalomyelitis.The severity of lesions varied in different parts of the nervous system, reflecting an irregular distribution of inflammatory vascular changes. The infiltration of mononuclear cells was associated with anisomorphic gliosis and reactive microglia was identified. The intensity of the astrocytic response in the CNS of the equines infected by T. evansi characterizes the importance of the performance of these cells in this trypanosomiasis. The characteristic gliosis observed in the animals in this experiment suggests the ability of these cells as mediators of immune response. The parasite, T. evansi, was not identified in the nervous tissues.Este estudo objetivou caracterizar a participação astrocítica e microglial no sistema nervoso central (SNC de eqüinos experimentalmente infectados com T. evansi. O grupo experimental foi formado por machos e fêmeas com vários graus de cruzamentos e idade variando entre quatro e sete anos. Os animais foram inoculados com 10(6 tripomastigotas de T. evansi, originalmente

  9. Effects of visual deprivation during brain development on expression of AMPA receptor subunits in rat’s hippocampus

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    Sayyed Alireza Talaei

    2015-06-01

    Conclusion: Dark rearing of rats during critical period of brain development changes the relative expression and also arrangement of both AMPA receptor subunits, GluR1 and GluR2 in the hippocampus, age dependently.

  10. Transcriptome analysis of human brain tissue identifies reduced expression of complement complex C1Q Genes in Rett syndrome.

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    Lin, Peijie; Nicholls, Laura; Assareh, Hassan; Fang, Zhiming; Amos, Timothy G; Edwards, Richard J; Assareh, Amelia A; Voineagu, Irina

    2016-06-06

    MECP2, the gene mutated in the majority of Rett syndrome cases, is a transcriptional regulator that can activate or repress transcription. Although the transcription regulatory function of MECP2 has been known for over a decade, it remains unclear how transcriptional dysregulation leads to the neurodevelopmental disorder. Notably, little convergence was previously observed between the genes abnormally expressed in the brain of Rett syndrome mouse models and those identified in human studies. Here we carried out a comprehensive transcriptome analysis of human brain tissue from Rett syndrome brain using both RNA-seq and microarrays. We identified over two hundred differentially expressed genes, and identified the complement C1Q complex genes (C1QA, C1QB and C1QC) as a point of convergence between gene expression changes in human and mouse Rett syndrome brain. The results of our study support a role for alterations in the expression level of C1Q complex genes in RTT pathogenesis.

  11. Brain region-specific altered expression and association of mitochondria-related genes in autism

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    Anitha Ayyappan

    2012-11-01

    Full Text Available Abstract Background Mitochondrial dysfunction (MtD has been observed in approximately five percent of children with autism spectrum disorders (ASD. MtD could impair highly energy-dependent processes such as neurodevelopment, thereby contributing to autism. Most of the previous studies of MtD in autism have been restricted to the biomarkers of energy metabolism, while most of the genetic studies have been based on mutations in the mitochondrial DNA (mtDNA. Despite the mtDNA, most of the proteins essential for mitochondrial replication and function are encoded by the genomic DNA; so far, there have been very few studies of those genes. Therefore, we carried out a detailed study involving gene expression and genetic association studies of genes related to diverse mitochondrial functions. Methods For gene expression analysis, postmortem brain tissues (anterior cingulate gyrus (ACG, motor cortex (MC and thalamus (THL from autism patients (n=8 and controls (n=10 were obtained from the Autism Tissue Program (Princeton, NJ, USA. Quantitative real-time PCR arrays were used to quantify the expression of 84 genes related to diverse functions of mitochondria, including biogenesis, transport, translocation and apoptosis. We used the delta delta Ct (∆∆Ct method for quantification of gene expression. DNA samples from 841 Caucasian and 188 Japanese families were used in the association study of genes selected from the gene expression analysis. FBAT was used to examine genetic association with autism. Results Several genes showed brain region-specific expression alterations in autism patients compared to controls. Metaxin 2 (MTX2, neurofilament, light polypeptide (NEFL and solute carrier family 25, member 27 (SLC25A27 showed consistently reduced expression in the ACG, MC and THL of autism patients. NEFL (P = 0.038; Z-score 2.066 and SLC25A27 (P = 0.046; Z-score 1.990 showed genetic association with autism in Caucasian and Japanese samples, respectively. The

  12. Changes in Rat Brain MicroRNA Expression Profiles Following Sevoflurane and Propofol Anesthesia

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    Yu Lu

    2015-01-01

    Full Text Available Background: Sevoflurane and propofol are widely used anesthetics for surgery. Studies on the mechanisms of general anesthesia have focused on changes in protein expression properties and membrane lipid. MicroRNAs (miRNAs regulate neural function by altering protein expression. We hypothesize that sevoflurane and propofol affect miRNA expression profiles in the brain, expect to understand the mechanism of anesthetic agents. Methods: Rats were randomly assigned to a 2% sevoflurane group, 600 μg·kg − 1·min − 1 propofol group, and a control group without anesthesia (n = 4, respectively. Treatment group was under anesthesia for 6 h, and all rats breathed spontaneously with continuous monitoring of respiration and blood gases. Changes in rat cortex miRNA expression profiles were analyzed by miRNA microarrays and validated by quantitative real-time polymerase chain reaction (qRT-PCR. Differential expression of miRNA using qRT-PCR among the control, sevoflurane, and propofol groups were compared using one-way analysis of variance (ANOVA. Results: Of 677 preloaded rat miRNAs, the microarray detected the expression of 277 miRNAs in rat cortex (40.9%, of which 9 were regulated by propofol and (or sevoflurane. Expression levels of three miRNAs (rno-miR-339-3p, rno-miR-448, rno-miR-466b-1FNx01 were significantly increased following sevoflurane and six (rno-miR-339-3p, rno-miR-347, rno-miR-378FNx01, rno-miR-412FNx01, rno-miR-702-3p, and rno-miR-7a-2FNx01 following propofol. Three miRNAs (rno-miR-466b-1FNx01, rno-miR-3584-5p and rno-miR-702-3p were differentially expressed by the two anesthetic treatment groups. Conclusions: Sevoflurane and propofol anesthesia induced distinct changes in brain miRNA expression patterns, suggesting differential regulation of protein expression. Determining the targets of these differentially expressed miRNAs may help reveal both the common and agent-specific actions of anesthetics on neurological and physiological

  13. Expression of metastasis-associated protein 3 in human brain glioma related to tumor prognosis.

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    Shan, Shouqin; Hui, Guangyan; Hou, Fanggao; Shi, Hua; Zhou, Guoqing; Yan, Han; Wang, Lu; Liu, Jinfeng

    2015-10-01

    Glioma represents a disparate group of tumors characterized by high invasion ability, and therefore it is of clinical significance to identify molecular markers and therapeutic targets for better clinical management. Previously, metastasis-associated protein family (MTA) is considered to promote tumor cell invasion and metastasis of human malignancies. Recently, the newly identified MTA3 has been shown to play conflicting roles in human malignancies, while the expression pattern and potential clinical significance of MTA3 in human glioma have not been addressed yet. In the present study, we investigated the protein expression of MTA3 by immunohistochemistry assay and analyzed its association with glioma prognosis in 186 cases of patients. Results showed that MTA3 expression was decreased in glioma compared with that in normal brain (P human glioma and negatively associated with prognosis of patients, suggesting that MTA3 may play a tumor suppressor role in glioma.

  14. Gene expression in the mouse brain following early pregnancy exposure to ethanol.

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    Zhang, Christine R; Chong, Suyinn

    2016-12-01

    Exposure to alcohol during early embryonic or fetal development has been linked with a variety of adverse outcomes, the most common of which are structural and functional abnormalities of the central nervous system [1]. Behavioural and cognitive deficits reported in individuals exposed to alcohol in utero include intellectual impairment, learning and memory difficulties, diminished executive functioning, attention problems, poor motor function and hyperactivity [2]. The economic and social costs of these outcomes are substantial and profound [3], [4]. Improvement of neurobehavioural outcomes following prenatal alcohol exposure requires greater understanding of the mechanisms of alcohol-induced damage to the brain. Here we use a mouse model of relatively moderate ethanol exposure early in pregnancy and profile gene expression in the hippocampus and caudate putamen of adult male offspring. The effects of offspring sex and age on ethanol-sensitive hippocampal gene expression were also examined. All array data are available at the Gene Expression Omnibus (GEO) repository under accession number GSE87736.

  15. A high-resolution anatomical framework of the neonatal mouse brain for managing gene expression data

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    Jyl Boline

    2007-11-01

    Full Text Available This study aims to provide a high-resolution atlas and use it as an anatomical framework to localize the gene expression data for mouse brain on postnatal day 0 (P0. A color Nissl-stained volume with a resolution of 13.3×50×13.3 µm3 was constructed and co-registered to a standard anatomical space defined by an averaged geometry of C57BL/6J P0 mouse brains. A 145 anatomical structures were delineated based on the histological images. Anatomical relationships of delineated structures were established based on the hierarchical relations defined in the atlas of adult mouse brain (MacKenzie-Graham et al., 2004 so the P0 atlas can be related to the database associated with the adult atlas. The co-registered multimodal atlas as well as the original anatomical delineations is available for download at http://www.loni.ucla.edu/Atlases/. The region-specific anatomical framework based on the neonatal atlas allows for the analysis of gene activity within a high-resolution anatomical space at an early developmental stage. We demonstrated the potential application of this framework by incorporating gene expression data generated using in situ hybridization to the atlas space. By normalizing the gene expression patterns revealed by different images, experimental results from separate studies can be compared and summarized in an anatomical context. Co-displaying multiple registered datasets in the atlas space allows for 3D reconstruction of the co-expression patterns of the different genes in the atlas space, hence providing better insight into the relationship between the differentiated distribution pattern of gene products and specific anatomical systems.

  16. Seasonal and regional differences in gene expression in the brain of a hibernating mammal.

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    Christine Schwartz

    Full Text Available Mammalian hibernation presents a unique opportunity to study naturally occurring neuroprotection. Hibernating ground squirrels undergo rapid and extreme physiological changes in body temperature, oxygen consumption, and heart rate without suffering neurological damage from ischemia and reperfusion injury. Different brain regions show markedly different activity during the torpor/arousal cycle: the cerebral cortex shows activity only during the periodic returns to normothermia, while the hypothalamus is active over the entire temperature range. Therefore, region-specific neuroprotective strategies must exist to permit this compartmentalized spectrum of activity. In this study, we use the Illumina HiSeq platform to compare the transcriptomes of these two brain regions at four collection points across the hibernation season: April Active, October Active, Torpor, and IBA. In the cerebral cortex, 1,085 genes were found to be differentially expressed across collection points, while 1,063 genes were differentially expressed in the hypothalamus. Comparison of these transcripts indicates that the cerebral cortex and hypothalamus implement very different strategies during hibernation, showing less than 20% of these differentially expressed genes in common. The cerebral cortex transcriptome shows evidence of remodeling and plasticity during hibernation, including transcripts for the presynaptic cytomatrix proteins bassoon and piccolo, and extracellular matrix components, including laminins and collagens. Conversely, the hypothalamic transcriptome displays upregulation of transcripts involved in damage response signaling and protein turnover during hibernation, including the DNA damage repair gene RAD50 and ubiquitin E3 ligases UBR1 and UBR5. Additionally, the hypothalamus transcriptome also provides evidence of potential mechanisms underlying the hibernation phenotype, including feeding and satiety signaling, seasonal timing mechanisms, and fuel

  17. KCC2 expression changes in Diazepam-treated neonatal rats with hypoxia-ischaemia brain damage.

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    Ma, Jun-Yuan; Zhang, Su-Pei; Guo, Liu-Bin; Li, Yong-Mei; Li, Qiang; Wang, Sai-Qi; Liu, Hong-Min; Wang, Cong

    2014-05-14

    Hypoxia-ischaemia brain damage (HIBD) is a major type of perinatal brain injury in newborns. In this study, we investigate the short- and long-term neuroprotective effects of Diazepam on neonatal rats with HIBD and the potential mechanisms underlying its protective effects. Seven-day-old Sprague-Dawley rats were subjected to left carotid artery ligation followed by a 2-h exposure to 8% oxygen and 92% nitrogen. Diazepam was administered immediately via intraperitoneal (i.p.) injection after inducing HIBD at a dose of 10 mg kg(-1)8h(-1) for three consecutive days. Three days after HIBD, rats were decapitated, and the extent of brain injury was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Additionally, the expression of Potassium-chloride cotransporter-2 (KCC2) was analysed using real-time PCR, Western blot analysis and immunohistochemistry. Three weeks after HIBD, rats were subjected to the Morris water maze (MWM) test and the locomotor activity test to determine the long-term therapeutic effects of Diazepam. We observed that the volume of infarction in the Diazepam group was significantly less (PDiazepam rats improved significantly compared with the untreated rats (PDiazepam appears to attenuate HIBD and can efficiently improve the long-term learning and memory capabilities of the animal. A potential mechanism underlying these effects may involve preventing the decrease in KCC2 expression. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Brain Network Involved in the Recognition of Facial Expressions of Emotion in the Early Blind

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    Ryo Kitada

    2011-10-01

    Full Text Available Previous studies suggest that the brain network responsible for the recognition of facial expressions of emotion (FEEs begins to emerge early in life. However, it has been unclear whether visual experience of faces is necessary for the development of this network. Here, we conducted both psychophysical and functional magnetic-resonance imaging (fMRI experiments to test the hypothesis that the brain network underlying the recognition of FEEs is not dependent on visual experience of faces. Early-blind, late-blind and sighted subjects participated in the psychophysical experiment. Regardless of group, subjects haptically identified basic FEEs at above-chance levels, without any feedback training. In the subsequent fMRI experiment, the early-blind and sighted subjects haptically identified facemasks portraying three different FEEs and casts of three different shoe types. The sighted subjects also completed a visual task that compared the same stimuli. Within the brain regions activated by the visually-identified FEEs (relative to shoes, haptic identification of FEEs (relative to shoes by the early-blind and sighted individuals activated the posterior middle temporal gyrus adjacent to the superior temporal sulcus, the inferior frontal gyrus, and the fusiform gyrus. Collectively, these results suggest that the brain network responsible for FEE recognition can develop without any visual experience of faces.

  19. Insights into TREM2 biology by network analysis of human brain gene expression data.

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    Forabosco, Paola; Ramasamy, Adaikalavan; Trabzuni, Daniah; Walker, Robert; Smith, Colin; Bras, Jose; Levine, Adam P; Hardy, John; Pocock, Jennifer M; Guerreiro, Rita; Weale, Michael E; Ryten, Mina

    2013-12-01

    Rare variants in TREM2 cause susceptibility to late-onset Alzheimer's disease. Here we use microarray-based expression data generated from 101 neuropathologically normal individuals and covering 10 brain regions, including the hippocampus, to understand TREM2 biology in human brain. Using network analysis, we detect a highly preserved TREM2-containing module in human brain, show that it relates to microglia, and demonstrate that TREM2 is a hub gene in 5 brain regions, including the hippocampus, suggesting that it can drive module function. Using enrichment analysis we show significant overrepresentation of genes implicated in the adaptive and innate immune system. Inspection of genes with the highest connectivity to TREM2 suggests that it plays a key role in mediating changes in the microglial cytoskeleton necessary not only for phagocytosis, but also migration. Most importantly, we show that the TREM2-containing module is significantly enriched for genes genetically implicated in Alzheimer's disease, multiple sclerosis, and motor neuron disease, implying that these diseases share common pathways centered on microglia and that among the genes identified are possible new disease-relevant genes. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Role of Bioflavonoid Quercetin on Expression of Urea Cycle Enzymes, Astrocytic and Inflammatory Markers in Hyperammonemic Rats.

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    Kanimozhi, Sivamani; Subramanian, Perumal; Shanmugapriya, Sakkaravarthy; Sathishkumar, Subramanian

    2017-03-01

    This study evaluates the role of quercetin on the expression of urea cycle enzymes, astrocytic, neuronal and inflammatory markers in hyperammonemic rats. Hyperammonemia (provoked by intraperitonial injections of (ammonium chloride-100 mg/kg b.w for 56 days), showed diminished expression of urea cycle enzymes [carbamyl phosphate synthetase-1 (CPS-1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS) and arginase (ARG)] in liver and decreased expression of neuronal and astrocytic markers-glutamine synthase (GS) and phosphate activated glutaminase (PAG) in brain and increased expression of brain inflammatory markers such as interleukin 6 (IL6), inducible nitric oxide synthase (iNOS) and nuclear transcription factor kappa B (NF-κB) (by western blot analysis) and exhibited downregulated expression of soluble guanylate cyclase (sGC), glial fibrillary acidic protein (GFAP) in brain and ASS in liver investigated (by RT-PCR). Oral treatment of quercetin (50 mg/kg b.w) to hyperammonemic rats (1) increased the expression of urea cycle enzymes (CPS-1, OTC, ASS and ARG), neuronal and astrocytic markers (GS and PAG) (2) decreased the expression of IL6, iNOS and NF-κB and (3) upregulated mRNA expression of SGC, GFAP and ASS. Our results specify that quercetin's antihyperammonemic effects could be through its, anti-inflammatory, neuroprotective and hepatoprotective effects.

  1. Alcohol drinking produces brain region-selective changes in expression of inducible transcription factors.

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    Bachtell, R K; Wang, Y M; Freeman, P; Risinger, F O; Ryabinin, A E

    1999-11-20

    Mapping the effects of alcohol consumption on neural activity could provide valuable information on mechanisms of alcohol's effects on behavior. The present study sought to identify effects of alcohol consumption on expression of inducible transcription factors (ITFs) in mouse brain. C57BL/6J mice were trained to consume 10% ethanol/10% sucrose solution during a 30-min limited access period. Control animals were given access to 10% sucrose solution or water. Following the final day of the procedure, animals were sacrificed and immunohistochemical analyses were performed for three ITFs (c-Fos, FosB, and Zif268). Alcohol-consuming animals had increased ITF expression in several brain areas. Specifically, c-Fos was significantly induced in the nucleus accumbens core (AcbC), the medial posteroventral portion of the central nucleus of the amygdala (CeMPV), and the Edinger-Westphal nucleus (EW). Expression of c-Fos was significantly lower in the dentate gyrus of alcohol-consuming animals vs. sucrose-consuming animals. However, it was not significantly different from the water controls. Induction of c-Fos in AcbC, CeMPV and EW was significantly related to blood alcohol concentrations (BAC). Furthermore, FosB expression in the CeMPV and the EW was also significantly higher in the alcohol-consuming animals vs. water controls. FosB expression in the EW was significantly related to BAC. The significance of these results is two-fold. First, our experiments demonstrate that ITF mapping is an effective strategy in identifying alcohol-induced changes following voluntary consumption. Second, they suggest a relationship between ITF expression in AcbC, CeMPV and EW and the level of alcohol intoxication.

  2. Monoterpenoid-based preparations in beehives affect learning, memory, and gene expression in the bee brain.

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    Bonnafé, Elsa; Alayrangues, Julie; Hotier, Lucie; Massou, Isabelle; Renom, Allan; Souesme, Guillaume; Marty, Pierre; Allaoua, Marion; Treilhou, Michel; Armengaud, Catherine

    2017-02-01

    Bees are exposed in their environment to contaminants that can weaken the colony and contribute to bee declines. Monoterpenoid-based preparations can be introduced into hives to control the parasitic mite Varroa destructor. The long-term effects of monoterpenoids are poorly investigated. Olfactory conditioning of the proboscis extension reflex (PER) has been used to evaluate the impact of stressors on cognitive functions of the honeybee such as learning and memory. The authors tested the PER to odorants on bees after exposure to monoterpenoids in hives. Octopamine receptors, transient receptor potential-like (TRPL), and γ-aminobutyric acid channels are thought to play a critical role in the memory of food experience. Gene expression levels of Amoa1, Rdl, and trpl were evaluated in parallel in the bee brain because these genes code for the cellular targets of monoterpenoids and some pesticides and neural circuits of memory require their expression. The miticide impaired the PER to odors in the 3 wk following treatment. Short-term and long-term olfactory memories were improved months after introduction of the monoterpenoids into the beehives. Chronic exposure to the miticide had significant effects on Amoa1, Rdl, and trpl gene expressions and modified seasonal changes in the expression of these genes in the brain. The decrease of expression of these genes in winter could partly explain the improvement of memory. The present study has led to new insights into alternative treatments, especially on their effects on memory and expression of selected genes involved in this cognitive function. Environ Toxicol Chem 2017;36:337-345. © 2016 SETAC. © 2016 SETAC.

  3. Optomechanical design of TMT NFIRAOS Subsystems at INO

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    Lamontagne, Frédéric; Desnoyers, Nichola; Grenier, Martin; Cottin, Pierre; Leclerc, Mélanie; Martin, Olivier; Buteau-Vaillancourt, Louis; Boucher, Marc-André; Nash, Reston; Lardière, Olivier; Andersen, David; Atwood, Jenny; Hill, Alexis; Byrnes, Peter W. G.; Herriot, Glen; Fitzsimmons, Joeleff; Véran, Jean-Pierre

    2017-08-01

    The adaptive optics system for the Thirty Meter Telescope (TMT) is the Narrow-Field InfraRed Adaptive Optics System (NFIRAOS). Recently, INO has been involved in the optomechanical design of several subsystems of NFIRAOS, including the Instrument Selection Mirror (ISM), the NFIRAOS Beamsplitters (NBS), and the NFIRAOS Source Simulator system (NSS) comprising the Focal Plane Mask (FPM), the Laser Guide Star (LGS) sources, and the Natural Guide Star (NGS) sources. This paper presents an overview of these subsystems and the optomechanical design approaches used to meet the optical performance requirements under environmental constraints.

  4. Using inositol as a biocompatible ligand for efficient transgene expression

    Science.gov (United States)

    Zhang, Lei; Bellis, Susan L; Fan, Yiwen; Wu, Yunkun

    2015-01-01

    Transgene transfection techniques using cationic polymers such as polyethylenimines (PEIs) and PEI derivatives as gene vectors have shown efficacy, although they also have shortcomings. PEIs have decent DNA-binding capability and good cell internalization performance, but they cannot deliver gene payloads very efficiently to cell nuclei. In this study, three hyperbranched polyglycerol-polyethylenimine (PG6-PEI) polymers conjugated with myo-inositol (INO) molecules were developed. The three resulting PG6-PEI-INO polymers have an increased number of INO ligands per molecule. PG6-PEI-INO 1 had only 14 carboxymethyl INO (CMINO) units per molecule. PG6-PEI-INO 2 had approximately 130 CMINO units per molecule. PG6-PEI-INO 3 had as high as 415 CMINO units approximately. Mixing PG6-PEI-INO polymers with DNA produced compact nanocomposites. We then performed localization studies using fluorescent microscopy. As the number of conjugated inositol ligands increased in PG6-PEI-INO polymers, there was a corresponding increase in accumulation of the polymers within 293T cell nuclei. Transfection performed with spherical 293T cells yielded 82% of EGFP-positive cells when using PG6-PEI-INO 3 as the vehicle. Studies further revealed that extracellular adenosine triphosphate (eATP) can inhibit the transgene efficiency of PG6-PEI-INO polymers, as compared with PEI and PG6-PEI that were not conjugated with inositol. Our work unveiled the possibility of using inositol as an effective ligand for transgene expression. PMID:25926732

  5. Ketamine induces brain-derived neurotrophic factor expression via phosphorylation of histone deacetylase 5 in rats.

    Science.gov (United States)

    Choi, Miyeon; Lee, Seung Hoon; Park, Min Hyeop; Kim, Yong-Seok; Son, Hyeon

    2017-08-05

    Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine-mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Properties and expression of Na+/K+-ATPase α-subunit isoforms in the brain of the swamp eel, Monopterus albus, which has unusually high brain ammonia tolerance.

    Directory of Open Access Journals (Sweden)

    Xiu L Chen

    Full Text Available The swamp eel, Monopterus albus, can survive in high concentrations of ammonia (>75 mmol l(-1 and accumulate ammonia to high concentrations in its brain (4.5 µmol g(-1. Na(+/K(+-ATPase (Nka is an essential transporter in brain cells, and since NH4(+ can substitute for K(+ to activate Nka, we hypothesized that the brain of M. albus expressed multiple forms of Nka α-subunits, some of which might have high K(+ specificity. Thus, this study aimed to clone and sequence the nka α-subunits from the brain of M. albus, and to determine the effects of ammonia exposure on their mRNA expression and overall protein abundance. The effectiveness of NH4(+ to activate brain Nka from M. albus and Mus musculus was also examined by comparing their Na(+/K(+-ATPase and Na(+/NH4(+-ATPase activities over a range of K(+/NH4(+ concentrations. The full length cDNA coding sequences of three nkaα (nkaα1, nkaα3a and nkaα3b were identified in the brain of M. albus, but nkaα2 expression was undetectable. Exposure to 50 mmol l(-1 NH4Cl for 1 day or 6 days resulted in significant decreases in the mRNA expression of nkaα1, nkaα3a and nkaα3b. The overall Nka protein abundance also decreased significantly after 6 days of ammonia exposure. For M. albus, brain Na(+/NH4(+-ATPase activities were significantly lower than the Na(+/K(+-ATPase activities assayed at various NH4(+/K(+ concentrations. Furthermore, the effectiveness of NH4(+ to activate Nka from the brain of M. albus was significantly lower than that from the brain of M. musculus, which is ammonia-sensitive. Hence, the (1 lack of nkaα2 expression, (2 high K(+ specificity of K(+ binding sites of Nkaα1, Nkaα3a and Nkaα3b, and (3 down-regulation of mRNA expression of all three nkaα isoforms and the overall Nka protein abundance in response to ammonia exposure might be some of the contributing factors to the high brain ammonia tolerance in M. albus.

  7. Expression of alcoholism-relevant genes in the liver are differently correlated to different parts of the brain.

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    Wang, Lishi; Huang, Yue; Jiao, Yan; Chen, Hong; Cao, Yanhong; Bennett, Beth; Wang, Yongjun; Gu, Weikuan

    2013-01-01

    The purpose of this study is to investigate whether expression profiles of alcoholism-relevant genes in different parts of the brain are correlated differently with those in the liver. Four experiments were conducted. First, we used gene expression profiles from five parts of the brain (striatum, prefrontal cortex, nucleus accumbens, hippocampus, and cerebellum) and from liver in a population of recombinant inbred mouse strains to examine the expression association of 10 alcoholism-relevant genes. Second, we conducted the same association analysis between brain structures and the lung. Third, using five randomly selected, nonalcoholism-relevant genes, we conducted the association analysis between brain and liver. Finally, we compared the expression of 10 alcoholism-relevant genes in hippocampus and cerebellum between an alcohol preference strain and a wild-type control. We observed a difference in correlation patterns in expression levels of 10 alcoholism-relevant genes between different parts of the brain with those of liver. We then examined the association of gene expression between alcohol dehydrogenases (Adh1, Adh2, Adh5, and Adh7) and different parts of the brain. The results were similar to those of the 10 genes. Then, we found that the association of those genes between brain structures and lung was different from that of liver. Next, we found that the association patterns of five alcoholism-nonrelevant genes were different from those of 10 alcoholism-relevant genes. Finally, we found that the expression level of 10 alcohol-relevant genes is influenced more in hippocampus than in cerebellum in the alcohol preference strain. Our results show that the expression of alcoholism-relevant genes in liver is differently associated with the expression of genes in different parts of the brain. Because different structural changes in different parts of the brain in alcoholism have been reported, it is important to investigate whether those structural differences in

  8. Influence of stochastic gene expression on the cell survival rheostat after traumatic brain injury.

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    Rojo, Daniel R; Prough, Donald S; Falduto, Michael T; Boone, Deborah R; Micci, Maria-Adelaide; Kahrig, Kristen M; Crookshanks, Jeanna M; Jimenez, Arnaldo; Uchida, Tatsuo; Cowart, Jeremy C; Hawkins, Bridget E; Avila, Marcela; DeWitt, Douglas S; Hellmich, Helen L

    2011-01-01

    Experimental evidence suggests that random, spontaneous (stochastic) fluctuations in gene expression have important biological consequences, including determination of cell fate and phenotypic variation within isogenic populations. We propose that fluctuations in gene expression represent a valuable tool to explore therapeutic strategies for patients who have suffered traumatic brain injury (TBI), for which there is no effective drug therapy. We have studied the effects of TBI on the hippocampus because TBI survivors commonly suffer cognitive problems that are associated with hippocampal damage. In our previous studies we separated dying and surviving hippocampal neurons by laser capture microdissection and observed unexplainable variations in post-TBI gene expression, even though dying and surviving neurons were adjacent and morphologically identical. We hypothesized that, in hippocampal neurons that subsequently are subjected to TBI, randomly increased pre-TBI expression of genes that are associated with neuroprotection predisposes neurons to survival; conversely, randomly decreased expression of these genes predisposes neurons to death. Thus, to identify genes that are associated with endogenous neuroprotection, we performed a comparative, high-resolution transcriptome analysis of dying and surviving hippocampal neurons in rats subjected to TBI. We found that surviving hippocampal neurons express a distinct molecular signature--increased expression of networks of genes that are associated with regeneration, cellular reprogramming, development, and synaptic plasticity. In dying neurons we found decreased expression of genes in those networks. Based on these data, we propose a hypothetical model in which hippocampal neuronal survival is determined by a rheostat that adds injury-induced genomic signals to expression of pro-survival genes, which pre-TBI varies randomly and spontaneously from neuron to neuron. We suggest that pharmacotherapeutic strategies that co

  9. MHC class I protein is expressed by neurons and neural progenitors in mid-gestation mouse brain.

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    Chacon, Marcelo A; Boulanger, Lisa M

    2013-01-01

    Proteins of the major histocompatibility complex class I (MHCI) are known for their role in the vertebrate adaptive immune response, and are required for normal postnatal brain development and plasticity. However, it remains unknown if MHCI proteins are present in the mammalian brain before birth. Here, we show that MHCI proteins are widely expressed in the developing mouse central nervous system at mid-gestation (E9.5-10.5). MHCI is strongly expressed in several regions of the prenatal brain, including the neuroepithelium and olfactory placode. MHCI is expressed by neural progenitors at these ages, as identified by co-expression in cells positive for neuron-specific class III β-tubulin (Tuj1) or for Pax6, a marker of neural progenitors in the dorsal neuroepithelium. MHCI is also co-expressed with nestin, a marker of neural stem/progenitor cells, in olfactory placode, but the co-localization is less extensive in other regions. MHCI is detected in the small population of post-mitotic neurons that are present at this early stage of brain development, as identified by co-expression in cells positive for neuronal microtubule-associated protein-2 (MAP2). Thus MHCI protein is expressed during the earliest stages of neuronal differentiation in the mammalian brain. MHCI expression in neurons and neural progenitors at mid-gestation, prior to the maturation of the adaptive immune system, is consistent with MHCI performing non-immune functions in prenatal brain development. These results raise the possibility that disruption of the levels and/or patterns of MHCI expression in the prenatal brain could contribute to the pathogenesis of neurodevelopmental disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring.

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    Zaidan, Hiba; Leshem, Micah; Gaisler-Salomon, Inna

    2013-11-01

    Human and animal studies indicate that vulnerability to stress may be heritable and that changes in germline may mediate some transgenerational effects. Corticotropin releasing factor type 1 (CRF1) is a key component in the stress response. We investigated changes in CRF1 expression in brain and ova of stressed female rats and in the brain of their neonate and adult offspring. Behavioral changes in adulthood were also assessed. Adult female rats underwent chronic unpredictable stress. We extracted mature oocytes and brain regions from a subset of rats and mated the rest 2 weeks following the stress procedure. CRF1 expression was assessed using quantitative reverse-transcription polymerase chain reaction. Tests of anxiety and aversive learning were used to examine behavior of offspring in adulthood. We show that chronic unpredictable stress leads to an increase in CRF1 messenger RNA expression in frontal cortex and mature oocytes. Neonatal offspring of stressed female rats show an increase in brain CRF1 expression. In adulthood, offspring of stressed female rats show sex differences in both CRF1 messenger RNA expression and behavior. Moreover, CRF1 expression patterns in frontal cortex of female offspring depend upon both maternal and individual adverse experience. Our findings demonstrate that stress affects CRF1 expression in brain but also in ova, pointing to a possible mechanism of transgenerational transmission. In offspring, stress-induced changes are evident at birth and are thus unlikely to result from altered maternal nurturance. Finally, brain CRF1 expression in offspring depends upon gender and upon maternal and individual exposure to adverse environment. © 2013 Society of Biological Psychiatry.

  11. Cloning of a Gene Whose Expression is Increased in Scrapie and in Senile Plaques in Human Brain

    Science.gov (United States)

    Wietgrefe, S.; Zupancic, M.; Haase, A.; Chesebro, B.; Race, R.; Frey, W.; Rustan, T.; Friedman, R. L.

    1985-12-01

    A complementary DNA library was constructed from messenger RNA's extracted from the brains of mice infected with the scrapie agent. The library was differentially screened with the objectives of finding clones that might be used as markers of infection and finding clones of genes whose increased expression might be correlated with the pathological changes common to scrapie and Alzheimer's disease. A gene was identified whose expression is increased in scrapie. The complementary DNA corresponding to this gene hybridized preferentially and focally to cells in the brains of scrapie-infected animals. The cloned DNA also hybridized to the neuritic plaques found with increased frequency in brains of patients with Alzheimer's disease.

  12. Oxidative stress induces the decline of brain EPO expression in aging rats.

    Science.gov (United States)

    Li, Xu; Chen, Yubao; Shao, Siying; Tang, Qing; Chen, Weihai; Chen, Yi; Xu, Xiaoyu

    2016-10-01

    Brain Erythropoietin (EPO), an important neurotrophic factor and neuroprotective factor, was found to be associated with aging. Studies found EPO expression was significantly decreased in the hippocampus of aging rat compared with that of the youth. But mechanisms of the decline of the brain EPO during aging remain unclear. The present study utilized a d-galactose (d-gal)-induced aging model in which the inducement of aging was mainly oxidative injury, to explore underlying mechanisms for the decline of brain EPO in aging rats. d-gal-induced aging rats (2months) were simulated by subcutaneously injecting with d-gal at doses of 50mg·kg(-1), 150mg·kg(-1) and 250mg·kg(-1) daily for 8weeks while the control group received vehicle only. These groups were all compared with the aging rats (24months) which had received no other treatment. The cognitive impairment was assessed using Morris water maze (MWM) in the prepared models, and the amount of β-galactosidase, the lipid peroxidation product malondialdehyde (MDA) level and the superoxide dismutase (SOD) activity in the hippocampus was examined by assay kits. The levels of EPO, EPOR, p-JAK2 and hypoxia-inducible factor-2α (HIF-2α) in the hippocampus were detected by western blot. Additionally, the correlation coefficient between EPO/EPOR expression and MDA level was analyzed. The MWM test showed that compared to control group, the escape latency was significantly extended and the times of crossing the platform was decreased at the doses of 150mg·kg(-1) and 250mg·kg(-1) (paging rats, the expressions of EPO, EPOR, p-JAK2, and HIF-2αin the brain of d-gal-treated rats were significantly decreased (paging could result in the decline of EPO in the hippocampus and oxidative stress might be the main reason for the decline of brain EPO in aging rats, involved with the decrease of HIF-2α stability. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Maternal hypothyroidism decreases progesterone receptor expression in the cortical subplate of foetal rat brain.

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    Jahagirdar, V; Zoeller, T R; Tighe, D P; Wagner, C K

    2012-08-01

    Steroid hormones exert profound effects on the development of brain areas controlling complex cognitive function in adulthood. One class, progestins, may contribute by acting on the progestin receptor (PR), which is transiently expressed in a critical layer of developing cortex: the subplate. PR expression in the subplate coincides with the establishment of ongoing cortical connectivity and may play an important organisational role. Identification of the factor(s) that regulate the precise timing of PR expression within subplate may help elucidate the function of PR. Thyroid hormone may interact with hormone response elements within the PR gene. The present study examined the effects of maternal hypothyroidism on levels of PR immunoreactivity (PR-IR) within the foetal subplate. Pregnant rats were made hypothyroid by the administration of methimazole and potassium perchlorate in drinking water. Maternal hypothyroidism significantly decreased PR-IR within the foetal subplate. Using the incorporation of 5-bromo-2'-deoxyuridine (BrDU) during subplate cell neurogenesis (embryonic day 13.5) to determine subplate cell survival in hypothyroid animals, we found that decreases in PR-IR cannot be attributed to significant subplate cell loss but are more likely the result of altered PR expression. Gestational thyroxine replacement to hypothyroid dams prevented the decrease in PR-IR within the subplate. These results identify thyroid hormone as a potential factor in the regulation of PR expression in the developing brain. These results are consistent with the idea that endocrine cross-talk between progesterone and thyroid hormone may be one mechanism by which maternal hypothyroidism alters normal cortical development. © 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd.

  14. Coordination of gene expression of arachidonic and docosahexaenoic acid cascade enzymes during human brain development and aging.

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    Veronica H Ryan

    Full Text Available The polyunsaturated arachidonic and docosahexaenoic acids (AA and DHA participate in cell membrane synthesis during neurodevelopment, neuroplasticity, and neurotransmission throughout life. Each is metabolized via coupled enzymatic reactions within separate but interacting metabolic cascades.AA and DHA pathway genes are coordinately expressed and underlie cascade interactions during human brain development and aging.The BrainCloud database for human non-pathological prefrontal cortex gene expression was used to quantify postnatal age changes in mRNA expression of 34 genes involved in AA and DHA metabolism.Expression patterns were split into Development (0 to 20 years and Aging (21 to 78 years intervals. Expression of genes for cytosolic phospholipases A2 (cPLA2, cyclooxygenases (COX-1 and -2, and other AA cascade enzymes, correlated closely with age during Development, less so during Aging. Expression of DHA cascade enzymes was less inter-correlated in each period, but often changed in the opposite direction to expression of AA cascade genes. Except for the PLA2G4A (cPLA2 IVA and PTGS2 (COX-2 genes at 1q25, highly inter-correlated genes were at distant chromosomal loci.Coordinated age-related gene expression during the brain Development and Aging intervals likely underlies coupled changes in enzymes of the AA and DHA cascades and largely occur through distant transcriptional regulation. Healthy brain aging does not show upregulation of PLA2G4 or PTGS2 expression, which was found in Alzheimer's disease.

  15. Coordination of Gene Expression of Arachidonic and Docosahexaenoic Acid Cascade Enzymes during Human Brain Development and Aging

    Science.gov (United States)

    Ryan, Veronica H.; Primiani, Christopher T.; Rao, Jagadeesh S.; Ahn, Kwangmi; Rapoport, Stanley I.; Blanchard, Helene

    2014-01-01

    Background The polyunsaturated arachidonic and docosahexaenoic acids (AA and DHA) participate in cell membrane synthesis during neurodevelopment, neuroplasticity, and neurotransmission throughout life. Each is metabolized via coupled enzymatic reactions within separate but interacting metabolic cascades. Hypothesis AA and DHA pathway genes are coordinately expressed and underlie cascade interactions during human brain development and aging. Methods The BrainCloud database for human non-pathological prefrontal cortex gene expression was used to quantify postnatal age changes in mRNA expression of 34 genes involved in AA and DHA metabolism. Results Expression patterns were split into Development (0 to 20 years) and Aging (21 to 78 years) intervals. Expression of genes for cytosolic phospholipases A2 (cPLA2), cyclooxygenases (COX)-1 and -2, and other AA cascade enzymes, correlated closely with age during Development, less so during Aging. Expression of DHA cascade enzymes was less inter-correlated in each period, but often changed in the opposite direction to expression of AA cascade genes. Except for the PLA2G4A (cPLA2 IVA) and PTGS2 (COX-2) genes at 1q25, highly inter-correlated genes were at distant chromosomal loci. Conclusions Coordinated age-related gene expression during the brain Development and Aging intervals likely underlies coupled changes in enzymes of the AA and DHA cascades and largely occur through distant transcriptional regulation. Healthy brain aging does not show upregulation of PLA2G4 or PTGS2 expression, which was found in Alzheimer's disease. PMID:24963629

  16. Inflammation stimulates thrombopoietin (Tpo) expression in rat brain-derived microvascular endothelial cells, but suppresses Tpo in astrocytes and microglia.

    Science.gov (United States)

    Zhang, Juan; Freyer, Dorette; Rung, Olga; Im, Ae-Rie; Hoffmann, Olaf; Dame, Christof

    2010-07-01

    Thrombopoietin (Tpo) and its receptor (c-Mpl; TpoR), which primary regulate megakaryopoiesis and platelet production, are also expressed in the central nervous system (CNS). Increased Tpo concentrations are present in the cerebrospinal fluid (CSF) of some patients with bacterial or viral meningitis. Since previous data implicated a proapoptotic role of Tpo on newly generated neuronal cells, we herein elucidated the regulation of Tpo in primary rat neurons (e17), astrocytes, and microglia (p0-p3), as well as in brain-derived vascular endothelial cells of 3-week-old rats after exposure to bacterial lipopolysaccharide (LPS). LPS inhibited Tpo gene expression in astrocytes and microglia, but not in neurons, most likely due to absence of Toll-like receptor 4 in neurons. While Tpo mRNA expression recovered in astrocytes after 24 h, it remained suppressed in microglia. Furthermore, we detected Tpo mRNA expression in primary brain-derived vascular endothelial cells, which also express the TpoR. In these cells, LPS significantly up-regulated Tpo mRNA expression. TpoR mRNA and protein expression remained constitutive in all cell types. Thus, our data provide evidence for a cell-type-specific modulation of Tpo mRNA expression by inflammation in brain-derived cells. Transient down-regulation of Tpo expression in astrocytes and microglia may limit Tpo-induced neuronal cell death in inflammatory brain disorders.

  17. Expression and Prognostic Value of Oct-4 in Astrocytic Brain Tumors.

    Science.gov (United States)

    Krogh Petersen, Jeanette; Jensen, Per; Dahl Sørensen, Mia; Winther Kristensen, Bjarne

    2016-01-01

    Glioblastomas are the most frequent type of malignant primary brain tumor with a median overall survival less than 15 months. Therapy resistance of glioblastomas has been attributed to the presence of tumor initiating stem-like cells (TSCs). TSC-related markers have therefore been suggested to have promising potentials as prognostic markers in gliomas. The aim of the present study was to investigate the expression and prognostic impact of the TSC-related marker Oct-4 in astrocytic brain tumors of increasing grade. In total 114 grade II, III and IV astrocytic brain tumors were immunohistochemically stained for Oct-4, and the fraction and intensity of Oct-4 positive cells were determined by morphometric analysis of full tumor sections. Oct-4 was expressed in all tumors, and the Oct-4 positive cell fraction increased with tumor grade (p = 0.045). There was no association between survival and Oct-4 positive cell fraction, neither when combining all tumor grades nor in analysis of individual grades. Oct-4 intensity was not associated with grade, but taking IDH1 status into account we found a tendency for high Oct-4 intensity to be associated with poor prognosis in anaplastic astrocytomas. Double immunofluorescence stainings showed co-localization in the perivascular niches of Oct-4 and two other TSC markers CD133 and nestin in glioblastomas. In some areas Oct-4 was expressed independently of CD133 and nestin. In conclusion, high Oct-4 fraction was associated with tumor malignancy, but seemed to be without independent prognostic influence in glioblastomas. Identification of a potential prognostic value in anaplastic astrocytomas requires additional studies using larger patient cohorts.

  18. Expression of innate immune complement regulators on brain epithelial cells during human bacterial meningitis

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    Gasque Philippe

    2006-09-01

    Full Text Available Abstract Background In meningitis, the cerebrospinal fluid contains high levels of innate immune molecules (e.g. complement which are essential to ward off the infectious challenge and to promote the infiltration of phagocytes (neutrophils, monocytes. However, epithelial cells of either the ependymal layer, one of the established niche for adult neural stem cells, or of the choroid plexus may be extremely vulnerable to bystander attack by cytotoxic and cytolytic complement components. Methods In this study, we assessed the capacity of brain epithelial cells to express membrane-bound complement regulators (ie, CD35, CD46, CD55 and CD59 in vitro and in situ by immunostaining of control and meningitis human brain tissue sections. Results Double immunofluorescence experiments for ependymal cell markers (GFAP, S100, ZO-1, E-cadherin and complement regulators indicated that the human ependymal cell line model was strongly positive for CD55, CD59 compared to weak stainings for CD46 and CD35. In tissues, we found that CD55 was weakly expressed in control choroid plexus and ependyma but was abundantly expressed in meningitis. Anti-CD59 stained both epithelia in apical location while increased CD59 staining was solely demonstrated in inflamed choroid plexus. CD46 and CD35 were not detected in control tissue sections. Conversely, in meningitis, the ependyma, subependyma and choroid plexus epithelia were strongly stained for CD46 and CD35. Conclusion This study delineates for the first time the capacity of brain ependymal and epithelial cells to respond to and possibly sustain the innate complement-mediated inflammatory insult.

  19. Social support modulates stress-related gene expression in various brain regions of piglets

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    Ellen Kanitz

    2016-11-01

    Full Text Available The presence of an affiliative conspecific may alleviate an individual's stress response in threatening conditions. However, the mechanisms and neural circuitry underlying the process of social buffering have not yet been elucidated. Using the domestic pig as an animal model, we examined the effect of a 4-h maternal and littermate deprivation on stress hormones and on mRNA expression of the glucocorticoid receptor (GR, mineralocorticoid receptor (MR, 11ß-hydroxysteroid dehydrogenase (11ß-HSD types 1 and 2 and the immediate early gene c-fos in various brain regions of 7-, 21- and 35-day old piglets. The deprivation occurred either alone or with a familiar or unfamiliar age-matched piglet. Compared to piglets deprived alone, the presence of a conspecific animal significantly reduced free plasma cortisol concentrations and altered the MR/GR balance and 11ß-HSD2 and c-fos mRNA expression in the prefrontal cortex (PFC, amygdala and hypothalamus, but not in the hippocampus. The alterations in brain mRNA expression were particularly found in 21- or 35-day old piglets, which may reflect the species-specific postnatal ontogeny of the investigated brain regions. The buffering effects of social support were most pronounced in the amygdala, indicating its significance both for the assessment of social conspecifics as biologically relevant stimuli and for the processing of emotional states. In conclusion, the present findings provide further evidence for the importance of the cortico-limbic network underlying the abilities of individuals to cope with social stress and strongly emphasize the benefits of social partners in livestock with respect to positive welfare and health.

  20. ABAEnrichment: an R package to test for gene set expression enrichment in the adult and developing human brain.

    Science.gov (United States)

    Grote, Steffi; Prüfer, Kay; Kelso, Janet; Dannemann, Michael

    2016-10-15

    We present ABAEnrichment, an R package that tests for expression enrichment in specific brain regions at different developmental stages using expression information gathered from multiple regions of the adult and developing human brain, together with ontologically organized structural information about the brain, both provided by the Allen Brain Atlas. We validate ABAEnrichment by successfully recovering the origin of gene sets identified in specific brain cell-types and developmental stages. ABAEnrichment was implemented as an R package and is available under GPL (≥ 2) from the Bioconductor website (http://bioconductor.org/packages/3.3/bioc/html/ABAEnrichment.html). steffi_grote@eva.mpg.de, kelso@eva.mpg.de or michael_dannemann@eva.mpg.deSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

  1. Reduction of photo bleaching and long term archiving of chemically cleared GFP-expressing mouse brains.

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    Klaus Becker

    Full Text Available Tissue clearing allows microscopy of large specimens as whole mouse brains or embryos. However, lipophilic tissue clearing agents as dibenzyl ether limit storage time of GFP-expressing samples to several days and do not prevent them from photobleaching during microscopy. To preserve GFP fluorescence, we developed a transparent solid resin formulation, which maintains the specimens' transparency and provides a constant signal to noise ratio even after hours of continuous laser irradiation. If required, high-power illumination or long exposure times can be applied with virtually no loss in signal quality and samples can be archived for years.

  2. Expression

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    Wang-Xia Wang

    2014-02-01

    Full Text Available The miR-15/107 family comprises a group of 10 paralogous microRNAs (miRNAs, sharing a 5′ AGCAGC sequence. These miRNAs have overlapping targets. In order to characterize the expression of miR-15/107 family miRNAs, we employed customized TaqMan Low-Density micro-fluid PCR-array to investigate the expression of miR-15/107 family members, and other selected miRNAs, in 11 human tissues obtained at autopsy including the cerebral cortex, frontal cortex, primary visual cortex, thalamus, heart, lung, liver, kidney, spleen, stomach and skeletal muscle. miR-103, miR-195 and miR-497 were expressed at similar levels across various tissues, whereas miR-107 is enriched in brain samples. We also examined the expression patterns of evolutionarily conserved miR-15/107 miRNAs in three distinct primary rat brain cell preparations (enriched for cortical neurons, astrocytes and microglia, respectively. In primary cultures of rat brain cells, several members of the miR-15/107 family are enriched in neurons compared to other cell types in the central nervous system (CNS. In addition to mature miRNAs, we also examined the expression of precursors (pri-miRNAs. Our data suggested a generally poor correlation between the expression of mature miRNAs and their precursors. In summary, we provide a detailed study of the tissue and cell type-specific expression profile of this highly expressed and phylogenetically conserved family of miRNA genes.

  3. Differential Fairness Decisions and Brain Responses after Expressed Emotions of Others in Boys with Autism Spectrum Disorders

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    Klapwijk, Eduard T.; Aghajani, Moji; Lelieveld, Gert-Jan; van Lang, Natasja D. J.; Popma, Arne; van der Wee, Nic J. A.; Colins, Olivier F.; Vermeiren, Robert R. J. M.

    2017-01-01

    Little is known about how emotions expressed by others influence social decisions and associated brain responses in autism spectrum disorders (ASD). We investigated the neural mechanisms underlying fairness decisions in response to explicitly expressed emotions of others in boys with ASD and typically developing (TD) boys. Participants with ASD…

  4. Infants of Depressed and Nondepressed Mothers Exhibit Differences in Frontal Brain Electrical Activity during the Expression of Negative Emotions.

    Science.gov (United States)

    Dawson, Geraldine; And Others

    1997-01-01

    Examined electrical brain activity during negative and positive emotion expression in infants of depressed and nondepressed mothers. Found that, compared with infants of nondepressed mothers, infants of depressed mothers exhibited increased EEG activation in the frontal but not parietal region when expressing negative emotions. There were no…

  5. Enhanced fos expression in the zebra finch (Taeniopygia guttata) brain following first courtship.

    Science.gov (United States)

    Sadananda, Monika; Bischof, Hans-Joachim

    2002-06-24

    Young zebra finch males that court a female for the first time develop a stable preference for the females of that species. On the neuronal level, consolidation of the imprinted information takes place. Here we demonstrate that first courtship or being chased around in the cage leads to enhanced fos expression in forebrain areas implicated in learning and imprinting in zebra finch males compared with birds reared in isolation or in the aviary. Two of the forebrain areas highly active during first courtship (as demonstrated by the 14C-2-deoxyglucose technique), the imprinting locus latral neo/hyperstriatum ventrale (LNH) and the secondary visual area hyperstriatum accessorium/dorsale (HAD), demonstrate enhanced fos expression. Two other imprinting-related areas, the medial neo/hyperstriatum ventrale (MNH) and archistriatum/neostriatum caudale (ANC), do show c-fos induction; however, the areas are not congruous with those demarcated by the 2-DG autoradiographic studies. Additional telencephalic areas include the olfactory lobe, the information storage site lobus parolfactorius (LPO), the memory site hippocampus, the auditory caudomedial neostriatum implicated in the strength of song learning, and the caudolateral neostriatum, which is comparable to the mammalian prefrontal cortex. In addition, c-fos is induced by first courtship and chasing in neurosecretory cell groups of the preoptic area and hypothalamus associated with the repertoire of sexual behavior and stress or enhanced arousal. Enhanced fos expression is also observed in brainstem sources of specific (noradrenergic, catecholaminergic) and nonspecific (reticular formation) activating pathways with inputs to higher brain areas implicated in the imprinting process. Birds reared in isolation or alternatively in the aviary with social and sexual contact to conspecifics showed attenuated or no fos expression in most of the above-mentioned areas. First courtship and chasing both lead to enhanced uptake of 2-DG in

  6. Cloning and expression of the programmed cell death regulator Bad in the rat brain.

    Science.gov (United States)

    D'Agata, V; Magro, G; Travali, S; Musco, S; Cavallaro, S

    1998-02-27

    The Bcl-2 family of proteins consists of both antagonists (e.g. Bcl-2) and agonists (e.g. Bax) that regulate apoptosis and compete through dimerization. In the present study we cloned the cDNA encoding the rat brain BAD, a distant member of the Bcl-2 family that was shown to promote cell death. The cloned cDNA encoded a protein of 205 amino acids, containing three putative Bcl-2 homology domains (BH1, BH2 and BH3) and no C-terminal signal-anchor sequence. The predicted amino acid sequence was identical to the Bad-cDNA recently cloned from the rat ovary with the exception of a stretch of six amino acids, thus indicating the existence of two Bad alternative splice variants or a sequence artifact in the rat ovary Bad-cDNA. Immunohistochemical analysis in the rat brain revealed the exclusive expression of Bad in the epithelial cells of the choroid plexus, a result which is consistent with a very specialized function of Bad in the brain.

  7. Molecular characterization and temporal expression profiling of presenilins in the developing porcine brain

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    Fredholm Merete

    2007-09-01

    Full Text Available Abstract Background The transmembrane presenilin (PSEN proteins, PSEN1 and PSEN2, have been proposed to be the catalytic components of the γ-secretase protein complex, which is an intramembranous multimeric protease involved in development, cell regulatory processes, and neurodegeneration in Alzheimer's disease. Here we describe the sequencing, chromosomal mapping, and polymorphism analysis of PSEN1 and PSEN2 in the domestic pig (Sus scrofa domesticus. Results The porcine presenilin proteins showed a high degree of homology over their entire sequences to the PSENs from mouse, bovine, and human. PSEN1 and PSEN2 transcription was examined during prenatal development of the brain stem, hippocampus, cortex, basal ganglia, and cerebellum at embryonic days 60, 80, 100, and 114, which revealed distinct temporal- and tissue-specific expression profiles. Furthermore, immunohistochemical analysis of PSEN1 and PSEN2 showed similar localization of the proteins predominantly in neuronal cells in all examined brain areas. Conclusion The data provide evidence for structural and functional conservation of PSENs in mammalian lineages, and may suggest that the high sequence similarity and colocalization of PSEN1 and PSEN2 in brain tissue reflect a certain degree of functional redundancy. The data show that pigs may provide a new animal model for detailed analysis of the developmental functions of the PSENs.

  8. Glucocorticoid receptor represses brain-derived neurotrophic factor expression in neuron-like cells.

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    Chen, Hui; Lombès, Marc; Le Menuet, Damien

    2017-04-12

    Brain-derived neurotrophic factor (BDNF) is involved in many functions such as neuronal growth, survival, synaptic plasticity and memorization. Altered expression levels are associated with many pathological situations such as depression, epilepsy, Alzheimer's, Huntington's and Parkinson's diseases. Glucocorticoid receptor (GR) is also crucial for neuron functions, via binding of glucocorticoid hormones (GCs). GR actions largely overlap those of BDNF. It has been proposed that GR could be a regulator of BDNF expression, however the molecular mechanisms involved have not been clearly defined yet. Herein, we analyzed the effect of a GC agonist dexamethasone (DEX) on BDNF expression in mouse neuronal primary cultures and in the newly characterized, mouse hippocampal BZ cell line established by targeted oncogenesis. Mouse Bdnf gene exhibits a complex genomic structure with 8 untranslated exons (I to VIII) splicing onto one common and unique coding exon IX. We found that DEX significantly downregulated total BDNF mRNA expression by around 30%. Expression of the highly expressed exon IV and VI containing transcripts was also reduced by DEX. The GR antagonist RU486 abolished this effect, which is consistent with specific GR-mediated action. Transient transfection assays allowed us to define a short 275 bp region within exon IV promoter responsible for GR-mediated Bdnf repression. Chromatin immunoprecipitation experiments demonstrated GR recruitment onto this fragment, through unidentified transcription factor tethering. Altogether, GR downregulates Bdnf expression through direct binding to Bdnf regulatory sequences. These findings bring new insights into the crosstalk between GR and BDNF signaling pathways both playing a major role in physiology and pathology of the central nervous system.

  9. Molecular Imaging of Gene Expression and Efficacy following Adenoviral-Mediated Brain Tumor Gene Therapy

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    Alnawaz Rehemtulla

    2002-01-01

    Full Text Available Cancer gene therapy is an active area of research relying upon the transfer and subsequent expression of a therapeutic transgene into tumor cells in order to provide for therapeutic selectivity. Noninvasive assessment of therapeutic response and correlation of the location, magnitude, and duration of transgene expression in vivo would be particularly useful in the development of cancer gene therapy protocols by facilitating optimization of gene transfer protocols, vector development, and prodrug dosing schedules. In this study, we developed an adenoviral vector containing both the therapeutic transgene yeast cytosine deaminase (yCD along with an optical reporter gene (luciferase. Following intratumoral injection of the vector into orthotopic 9L gliomas, anatomical and diffusion-weighted MR images were obtained over time in order to provide for quantitative assessment of overall therapeutic efficacy and spatial heterogeneity of cell kill, respectively. In addition, bioluminescence images were acquired to assess the duration and magnitude of gene expression. MR images revealed significant reduction in tumor growth rates associated with yCD/5-fluorocytosine (5FC gene therapy. Significant increases in mean tumor diffusion values were also observed during treatment with 5FC. Moreover, spatial heterogeneity in tumor diffusion changes were also observed revealing that diffusion magnetic resonance imaging could detect regional therapeutic effects due to the nonuniform delivery and/or expression of the therapeutic yCD transgene within the tumor mass. In addition, in vivo bioluminescence imaging detected luciferase gene expression, which was found to decrease over time during administration of the prodrug providing a noninvasive surrogate marker for monitoring gene expression. These results demonstrate the efficacy of the yCD/5FC strategy for the treatment of brain tumors and reveal the feasibility of using multimodality molecular and functional imaging

  10. Coordinated Gene Expression of Neuroinflammatory and Cell Signaling Markers in Dorsolateral Prefrontal Cortex during Human Brain Development and Aging

    Science.gov (United States)

    Primiani, Christopher T.; Ryan, Veronica H.; Rao, Jagadeesh S.; Cam, Margaret C.; Ahn, Kwangmi; Modi, Hiren R.; Rapoport, Stanley I.

    2014-01-01

    Background Age changes in expression of inflammatory, synaptic, and neurotrophic genes are not well characterized during human brain development and senescence. Knowing these changes may elucidate structural, metabolic, and functional brain processes over the lifespan, as well vulnerability to neurodevelopmental or neurodegenerative diseases. Hypothesis Expression levels of inflammatory, synaptic, and neurotrophic genes in the human brain are coordinated over the lifespan and underlie changes in phenotypic networks or cascades. Methods We used a large-scale microarray dataset from human prefrontal cortex, BrainCloud, to quantify age changes over the lifespan, divided into Development (0 to 21 years, 87 brains) and Aging (22 to 78 years, 144 brains) intervals, in transcription levels of 39 genes. Results Gene expression levels followed different trajectories over the lifespan. Many changes were intercorrelated within three similar groups or clusters of genes during both Development and Aging, despite different roles of the gene products in the two intervals. During Development, changes were related to reported neuronal loss, dendritic growth and pruning, and microglial events; TLR4, IL1R1, NFKB1, MOBP, PLA2G4A, and PTGS2 expression increased in the first years of life, while expression of synaptic genes GAP43 and DBN1 decreased, before reaching plateaus. During Aging, expression was upregulated for potentially pro-inflammatory genes such as NFKB1, TRAF6, TLR4, IL1R1, TSPO, and GFAP, but downregulated for neurotrophic and synaptic integrity genes such as BDNF, NGF, PDGFA, SYN, and DBN1. Conclusions Coordinated changes in gene transcription cascades underlie changes in synaptic, neurotrophic, and inflammatory phenotypic networks during brain Development and Aging. Early postnatal expression changes relate to neuronal, glial, and myelin growth and synaptic pruning events, while late Aging is associated with pro-inflammatory and synaptic loss changes. Thus, comparable

  11. Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain

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    Mignot Emmanuel

    2007-05-01

    Full Text Available Abstract Background Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the hypocretin system are well established as the origin of the condition; both from studies in humans who lack the hypocretin ligand (HCRT and in dogs with a mutation in hypocretin receptor 2 (HCRTR2. However, little is known about molecular alterations downstream of the hypocretin signals. Results By using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 [HCRTR-2-2] mutation, and their unaffected heterozygous siblings. We identified two neuropeptide precursor molecules, Tachykinin precursor 1 (TAC1 and Proenkephalin (PENK, that together with Suppressor of cytokine signaling 2 (SOCS2, showed reduced expression in narcoleptic brains. The difference was particularly pronounced in the amygdala, where mRNA levels of PENK were 6.2 fold lower in narcoleptic dogs than in heterozygous siblings, and TAC1 and SOCS2 showed 4.4 fold and 2.8 fold decrease in expression, respectively. The results obtained from microarray experiments were confirmed by real-time RT-PCR. Interestingly, it was previously shown that a single dose of amphetamine-like stimulants able to increase wakefulness in the dogs, also produce an increase in the expression of both TAC1 and PENK in mice. Conclusion These results suggest that TAC1, PENK and SOCS2 might be intimately connected with the excessive daytime sleepiness not only in dogs, but also in other species, possibly including humans.

  12. Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain.

    Science.gov (United States)

    Lindberg, Julia; Saetre, Peter; Nishino, Seiji; Mignot, Emmanuel; Jazin, Elena

    2007-05-23

    Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the hypocretin system are well established as the origin of the condition; both from studies in humans who lack the hypocretin ligand (HCRT) and in dogs with a mutation in hypocretin receptor 2 (HCRTR2). However, little is known about molecular alterations downstream of the hypocretin signals. By using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 [HCRTR-2-2] mutation), and their unaffected heterozygous siblings. We identified two neuropeptide precursor molecules, Tachykinin precursor 1 (TAC1) and Proenkephalin (PENK), that together with Suppressor of cytokine signaling 2 (SOCS2), showed reduced expression in narcoleptic brains. The difference was particularly pronounced in the amygdala, where mRNA levels of PENK were 6.2 fold lower in narcoleptic dogs than in heterozygous siblings, and TAC1 and SOCS2 showed 4.4 fold and 2.8 fold decrease in expression, respectively. The results obtained from microarray experiments were confirmed by real-time RT-PCR. Interestingly, it was previously shown that a single dose of amphetamine-like stimulants able to increase wakefulness in the dogs, also produce an increase in the expression of both TAC1 and PENK in mice. These results suggest that TAC1, PENK and SOCS2 might be intimately connected with the excessive daytime sleepiness not only in dogs, but also in other species, possibly including humans.

  13. Region-specific alterations in glucocorticoid receptor expression in the postmortem brain of teenage suicide victims.

    Science.gov (United States)

    Pandey, Ghanshyam N; Rizavi, Hooriyah S; Ren, Xinguo; Dwivedi, Yogesh; Palkovits, Miklós

    2013-11-01

    Abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of depression and suicide. The purpose of this study was to test the hypothesis that the reported dysregulation of the HPA axis in suicide may be related to a disturbed feedback inhibition caused by decreased corticoid receptors in the brain. We therefore determined the protein and gene expression of glucocorticoid (GR) and mineralocorticoid receptors (MR) in the postmortem brain of teenage suicide victims and matched normal controls. Protein and mRNA expression of GR (GR-α and GR-β) and MR and the mRNA expression of glucocorticoid-induced leucine zipper (GILZ), a target gene for GR were determined by immunolabeling using Western blot technique and the real-time RT-polymerase chain reaction (qPCR) technique in the prefrontal cortex (PFC), hippocampus, subiculum, and amygdala obtained from 24 teenage suicide victims and 24 teenage control subjects. We observed that protein and gene expression of GR-α was significantly decreased in the PFC and amygdala, but not in the hippocampus or subiculum, of teenage suicide victims compared with normal control subjects. Also, the mRNA levels of GR inducible target gene GILZ was significantly decreased in PFC and amygdaloid nuclei but not in hippocampus compared with controls. In contrast, no significant differences were observed in protein or gene expression of MR in any of the areas studied between teenage suicide victims and normal control subjects. There was no difference in the expression of GR-β in the PFC between suicide victims and normal controls. These results suggested that the observed dysregulation of the HPA axis in suicide may be related to a decreased expression of GR-α and GR inducible genes in the PFC and amygdala of teenage suicide victims. The reason why GR receptors are not dysregulated in the hippocampus or subiculum, presumably two sites of stress action, are not clear at this time. Copyright

  14. The brain-specific Beta4 subunit downregulates BK channel cell surface expression.

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    Sonal Shruti

    Full Text Available The large-conductance K(+ channel (BK channel can control neural excitability, and enhanced channel currents facilitate high firing rates in cortical neurons. The brain-specific auxiliary subunit β4 alters channel Ca(++- and voltage-sensitivity, and β4 knock-out animals exhibit spontaneous seizures. Here we investigate β4's effect on BK channel trafficking to the plasma membrane. Using a novel genetic tag to track the cellular location of the pore-forming BKα subunit in living cells, we find that β4 expression profoundly reduces surface localization of BK channels via a C-terminal ER retention sequence. In hippocampal CA3 neurons from C57BL/6 mice with endogenously high β4 expression, whole-cell BK channel currents display none of the characteristic properties of BKα+β4 channels observed in heterologous cells. Finally, β4 knock-out animals exhibit a 2.5-fold increase in whole-cell BK channel current, indicating that β4 also regulates current magnitude in vivo. Thus, we propose that a major function of the brain-specific β4 subunit in CA3 neurons is control of surface trafficking.

  15. Duration of exclusive breastfeeding is associated with differences in infants’ brain responses to emotional body expressions

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    Kathleen Marie Krol

    2015-01-01

    Full Text Available Much research has recognized the general importance of maternal behavior in the early development and programming of the mammalian offspring’s brain. Exclusive breastfeeding duration, the amount of time in which breastfed meals are the only source of sustenance, plays a prominent role in promoting healthy brain and cognitive development in human children. However, surprisingly little is known about the influence of breastfeeding on social and emotional development in infancy. In the current study, we examined whether and how the duration of exclusive breastfeeding impacts the neural processing of emotional signals by measuring electro-cortical responses to body expressions in 8-month-old infants. Our analyses revealed that infants with high exclusive breastfeeding experience show a significantly greater neural sensitivity to happy body expressions than those with low exclusive breastfeeding experience. Moreover, regression analyses revealed that the neural bias toward happiness or fearfulness differs as a function of the duration of exclusive breastfeeding. Specifically, longer breastfeeding duration is associated with a happy bias, whereas shorter breastfeeding duration is associated with a fear bias. These findings suggest that breastfeeding experience can shape the way in which infants respond to emotional signals.

  16. Gene expression alterations in brains of mice infected with three strains of scrapie

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    Race Richard E

    2006-05-01

    Full Text Available Abstract Background Transmissible spongiform encephalopathies (TSEs or prion diseases are fatal neurodegenerative disorders which occur in humans and various animal species. Examples include Creutzfeldt-Jakob disease (CJD in humans, bovine spongiform encephalopathy (BSE in cattle, chronic wasting disease (CWD in deer and elk, and scrapie in sheep, and experimental mice. To gain insights into TSE pathogenesis, we made and used cDNA microarrays to identify disease-associated alterations in gene expression. Brain gene expression in scrapie-infected mice was compared to mock-infected mice at pre-symptomatic and symptomatic time points. Three strains of mouse scrapie that show striking differences in neuropathology were studied: ME7, 22L, and Chandler/RML. Results In symptomatic mice, over 400 significant gene expression alterations were identified. In contrast, only 22 genes showed significant alteration in the pre-symptomatic animals. We also identified genes that showed significant differences in alterations in gene expression between strains. Genes identified in this study encode proteins that are involved in many cellular processes including protein folding, endosome/lysosome function, immunity, synapse function, metal ion binding, calcium regulation and cytoskeletal function. Conclusion These studies shed light on the complex molecular events that occur during prion disease, and identify genes whose further study may yield new insights into strain specific neuropathogenesis and ante-mortem tests for TSEs.

  17. Developmentally Regulated Expression of the Nerve Growth Factor Receptor Gene in the Periphery and Brain

    Science.gov (United States)

    Buck, C. R.; Martinez, Humberto J.; Black, Ira B.; Chao, Moses V.

    1987-05-01

    Nerve growth factor (NGF) regulates development and maintenance of function of peripheral sympathetic and sensory neurons. A potential role for the trophic factor in brain has been detected only recently. The ability of a cell to respond to NGF is due, in part, to expression of specific receptors on the cell surface. To study tissue-specific expression of the NGF receptor gene, we have used sensitive cRNA probes for detection of NGF receptor mRNA. Our studies indicate that the receptor gene is selectively and specifically expressed in sympathetic (superior cervical) and sensory (dorsal root) ganglia in the periphery, and by the septum-basal forebrain centrally, in the neonatal rat in vivo. Moreover, examination of tissues from neonatal and adult rats reveals a marked reduction in steady-state NGF receptor mRNA levels in sensory ganglia. In contrast, a 2- to 4-fold increase was observed in the basal forebrain and in the sympathetic ganglia over the same time period. Our observations suggest that NGF receptor mRNA expression is developmentally regulated in specific areas of the nervous system in a differential fashion.

  18. Age-dependent changes of glyoxalase I expression in human brain.

    Science.gov (United States)

    Kuhla, Björn; Boeck, Katharina; Lüth, Hans-Joachim; Schmidt, Angela; Weigle, Bernd; Schmitz, Marc; Ogunlade, Vera; Münch, Gerald; Arendt, Thomas

    2006-06-01

    Increased modification and crosslinking of proteins by advanced glycation end products (AGEs) is a characteristic feature of aging, and contributes to the formation of many of the lesions of neurodegenerative diseases including neurofibrillary tangles and amyloid plaques in Alzheimer's disease. Therefore, defense mechanisms against AGE formation or detoxification of their precursors such as the glyoxalase system are of particular interest in aging research. Thus, we investigated the age-dependent protein expression, the activity as well as the RNA level of glyoxalase I in Brodmann area 22 (auditory association area of superior temporal gyrus) of the human cerebral cortex. Our immunohistochemical results demonstrate the localization of glyoxalase I in neurons, predominantly pyramidal cells, as well as in astroglia, located predominantly in the subpial region. The number of glyoxalase I expressing neurons and astroglia increases with age, with a peak at approximately 55 years, and progressively decreases thereafter. These results were confirmed by biochemical investigations in total brain tissue, where the RNA, the protein level as well as the activity of glyoxalase I enzyme were analyzed in different age groups. In conclusion, the increase in glyoxalase I expression up to the age of 55 may be a compensatory mechanism against high oxoaldyde levels and the accumulation of AGEs. However, the decline of glyoxalase expression and activity in old age, possibly caused by impairment in transcription or/and translation, may subsequently lead to increased levels of reactive carbonyl compounds, followed by protein crosslinking, inflammation, oxidative stress and neuronal degeneration.

  19. The Pattern of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampus of Diabetic Rats

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    Iraj Salehi

    2010-06-01

    Full Text Available Objective(sThe aim of this study was to evaluate the effects of regular exercise in preventing diabetes complication in the hippocampus of streptozotocin (STZ-induced diabetic rat.Materials and MethodsA total of 48 male wistar rats were divided into four groups (control, control exercise, diabetic and diabetic exercise. Diabetes was induced by injection of single dose of STZ. Exercise was performed for one hr every day, over a period of 8 weeks. The antioxidant enzymes (SOD, GPX, CAT and GR and oxidant indexes with brain-derived neurotrophic factor (BDNF protein and its mRNA and apoptosis were measured in hippocampus of rats. ResultsA significant decrease in antioxidant enzymes activities and increased malondialdehyde (MDA level were observed in diabetic rats (P= 0.004. In response to exercise, antioxidant enzymes activities increased (P= 0.004. In contrast, MDA level decreased in diabetic rats (P= 0.004. Induction of diabetes caused an increase of BDNF protein and its mRNA expression. In response to exercise, BDNF protein and its mRNA expression reduced in hippocampus of diabetic rats. ConclusionDiabetes induced oxidative stress and increased BDNF gene expression. Exercise ameliorated oxidative stress and decreased BDNF gene expression.

  20. An optimized ERP brain-computer interface based on facial expression changes

    Science.gov (United States)

    Jin, Jing; Daly, Ian; Zhang, Yu; Wang, Xingyu; Cichocki, Andrzej

    2014-06-01

    Objective. Interferences from spatially adjacent non-target stimuli are known to evoke event-related potentials (ERPs) during non-target flashes and, therefore, lead to false positives. This phenomenon was commonly seen in visual attention-based brain-computer interfaces (BCIs) using conspicuous stimuli and is known to adversely affect the performance of BCI systems. Although users try to focus on the target stimulus, they cannot help but be affected by conspicuous changes of the stimuli (such as flashes or presenting images) which were adjacent to the target stimulus. Furthermore, subjects have reported that conspicuous stimuli made them tired and annoyed. In view of this, the aim of this study was to reduce adjacent interference, annoyance and fatigue using a new stimulus presentation pattern based upon facial expression changes. Our goal was not to design a new pattern which could evoke larger ERPs than the face pattern, but to design a new pattern which could reduce adjacent interference, annoyance and fatigue, and evoke ERPs as good as those observed during the face pattern. Approach. Positive facial expressions could be changed to negative facial expressions by minor changes to the original facial image. Although the changes are minor, the contrast is big enough to evoke strong ERPs. In this paper, a facial expression change pattern between positive and negative facial expressions was used to attempt to minimize interference effects. This was compared against two different conditions, a shuffled pattern containing the same shapes and colours as the facial expression change pattern, but without the semantic content associated with a change in expression, and a face versus no face pattern. Comparisons were made in terms of classification accuracy and information transfer rate as well as user supplied subjective measures. Main results. The results showed that interferences from adjacent stimuli, annoyance and the fatigue experienced by the subjects could be

  1. Postresuscitative Changes of Brain-Derived Neurotrophic Factor (BDNF Protein Expression: Association With Neuronal Death

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    M. Sh. Avrushchenko

    2017-01-01

    Full Text Available Aim of the study: to evaluate expression level of BDNF and its association with the postresuscitative neuronal death in highly hypoxia-sensitive brain regions.Materials and methods. Cardiac arrest in adult albino male rats was evoked by intrathoracic clamping of supracardiac bundle of vessels for 10 min. Pyramidal neurons of the hippocampus and Purkinje cells of the cerebellum were analyzed at various time points after resuscitation (days 1, 4, 7, 14. Shame-operated rats served as controls. The expression of BDNF protein was immunohistochemically determined. The BDNF expression level was determined by evalution on the base of the average optical density. The number of neurons with different BDNF expression levels and the total number of neurons per 1 mm of the layer length were computed. Image analysis systems (Intel personal computer, Olympus BX-41 microscope, ImageScopeM, ImageJ 1,48v and MS Excel 2007 software packages were used in the study. Data statistical processing was performed with the aid of Statistica 7.0 program and Kolmogorov-Smirnov λ-test, Mann-Whitney U-test and Student's t-test.Results. The dynamics of postresuscitative shifts of BDNF immunoreactivity in neuronal populations of hippocampal pyramidal cells and cerebellar Purkinje cells was established. It was shown that the level of BDNF expression within the two neuronal populations decreased, that was accompanied by neuronal death. In the Purkinje cell population the neuronal death occurred by the 4th day after resuscitation, while in the hippocampus, it occurs only by the 7th day. Notably, only BDNF-negative neurons or neurons with low level of BDNF expression died in both neuronal populations.Conclusion. The results of the study indicate the existence of an interrelation between the shifts in BDNF expression and the postresuscitative neuronal death. It was shown that only the cells with none or poor BDNF expression underwent death in highly hypoxia-sensitive neuronal

  2. Beta-Amyloid Downregulates MDR1-P-Glycoprotein (Abcb1 Expression at the Blood-Brain Barrier in Mice

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    Anja Brenn

    2011-01-01

    Full Text Available Neurovascular dysfunction is an important component of Alzheimer's disease, leading to reduced clearance across the blood-brain barrier and accumulation of neurotoxic β-amyloid (Aβ peptides in the brain. It has been shown that the ABC transport protein P-glycoprotein (P-gp, ABCB1 is involved in the export of Aβ from the brain into the blood. To determine whether Aβ influences the expression of key Aβ transporters, we studied the effects of 1-day subcutaneous Aβ1-40 and Aβ1-42 administration via Alzet mini-osmotic pumps on P-gp, BCRP, LRP1, and RAGE expression in the brain of 90-day-old male FVB mice. Our results demonstrate significantly reduced P-gp, LRP1, and RAGE mRNA expression in mice treated with Aβ1-42 compared to controls, while BCRP expression was not affected. The expression of the four proteins was unchanged in mice treated with Aβ1-40 or reverse-sequence peptides. These findings indicate that, in addition to the age-related decrease of P-gp expression, Aβ1-42 itself downregulates the expression of P-gp and other Aβ-transporters, which could exacerbate the intracerebral accumulation of Aβ and thereby accelerate neurodegeneration in Alzheimer's disease and cerebral β-amyloid angiopathy.

  3. Functional Genomics of Sleep and Circadian Rhythm: Invited Review: How sleep deprivation affects gene expression in the brain: a review of recent findings

    National Research Council Canada - National Science Library

    Cirelli, Chiara

    2002-01-01

    .... To determine what molecular changes occur in the brain during the sleep-waking cycle and after sleep deprivation, our laboratory is performing a systematic screening of brain gene expression in rats...

  4. Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain.

    Science.gov (United States)

    Sedmak, Goran; Jovanov-Milošević, Nataša; Puskarjov, Martin; Ulamec, Monika; Krušlin, Božo; Kaila, Kai; Judaš, Miloš

    2016-12-01

    Work on rodents demonstrated that steep upregulation of KCC2, a neuron-specific Cl - extruder of cation-chloride cotransporter (CCC) family, commences in supraspinal structures at around birth, leading to establishment of hyperpolarizing GABAergic responses. We describe spatiotemporal expression profiles of the entire CCC family in human brain. KCC2 mRNA was observed already at 10th postconceptional week (PCW) in amygdala, cerebellum, and thalamus. KCC2-immunoreactive (KCC2-ir) neurons were abundant in subplate at 18 PCW. By 25 PCW, numerous subplate and cortical plate neurons became KCC2-ir. The mRNA expression profiles of α- and β-isoforms of Na-K ATPase, which fuels cation-chloride cotransport, as well of tropomyosin receptor kinase B (TrkB), which promotes developmental upregulation of KCC2, were consistent with data from studies on rodents about their interactions with KCC2. Thus, in human brain, expression of KCC2 and its functionally associated proteins begins in early fetal period. Our work facilitates translation of results on CCC functions from animal studies to human and refutes the view that poor efficacy of anticonvulsants in the term human neonate is attributable to the lack of KCC2. We propose that perinatally low threshold for activation of Ca 2+ -dependent protease calpain renders neonates susceptible to downregulation of KCC2 by traumatic events, such as perinatal hypoxia ischemia. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. Natural selection constrains personality and brain gene expression differences in Atlantic salmon (Salmo salar).

    Science.gov (United States)

    Thörnqvist, Per-Ove; Höglund, Erik; Winberg, Svante

    2015-04-01

    In stream-spawning salmonid fishes there is a considerable variation in the timing of when fry leave the spawning nests and establish a feeding territory. The timing of emergence from spawning nests appears to be related to behavioural and physiological traits, e.g. early emerging fish are bolder and more aggressive. In the present study, emerging Atlantic salmon (Salmo salar L.) alevins were sorted into three fractions: early, intermediate and late emerging. At the parr stage, behaviour, stress responses, hindbrain monoaminergic activity and forebrain gene expression were explored in fish from the early and late emerging fractions (first and last 25%). The results show that when subjected to confinement stress, fish from the late emerging fraction respond with a larger activation of the brain serotonergic system than fish from the early fraction. Similarly, in late emerging fish, stress resulted in elevated expression of mRNA coding for serotonin 1A receptors (5-HT1A), GABA-A receptor-associated protein and ependymin, effects not observed in fish from the early emerging fraction. Moreover, fish from the early emerging fraction displayed bolder behaviour than their late emerging littermates. Taken together, these results suggest that time of emergence, boldness and aggression are linked to each other, forming a behavioural syndrome in juvenile salmon. Differences in brain gene expression between early and late emerging salmon add further support to a relationship between stress coping style and timing of emergence. However, early and late emerging salmon do not appear to differ in hypothalamus-pituitary-interrenal (HPI) axis reactivity, another characteristic of divergent stress coping styles. © 2015. Published by The Company of Biologists Ltd.

  6. Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer

    Directory of Open Access Journals (Sweden)

    Mokbel Kefah

    2011-07-01

    Full Text Available Abstract Introduction Brain-derived neurotrophic factor (BDNF has established physiological roles in the development and function of the vertebrate nervous system. BDNF has also been implicated in several human malignancies, including breast cancer (BC. However, the precise biological role of BDNF and its utility as a novel biomarker have yet to be determined. The objective of this study was to determine the mRNA and protein expression of BDNF in a cohort of women with BC. Expression levels were compared with normal background tissues and evaluated against established pathological parameters and clinical outcome over a 10 year follow-up period. Methods BC tissues (n = 127 and normal tissues (n = 33 underwent RNA extraction and reverse transcription, BDNF transcript levels were determined using real-time quantitative PCR. BDNF protein expression in mammary tissues was assessed with standard immuno-histochemical methodology. Expression levels were analyzed against tumour size, grade, nodal involvement, TNM stage, Nottingham Prognostic Index (NPI and clinical outcome over a 10 year follow-up period. Results Immuno-histochemical staining revealed substantially greater BDNF expression within neoplastic cells, compared to normal mammary epithelial cells. Significantly higher mRNA transcript levels were found in the BC specimens compared to background tissues (p = 0.007. The expression of BDNF mRNA was demonstrated to increase with increasing NPI; NPI-1 vs. NPI-2 (p = 0.009. Increased BDNF transcript levels were found to be significantly associated with nodal positivity (p = 0.047. Compared to patients who remained disease free, higher BDNF expression was significantly associated with local recurrence (LR (p = 0.0014, death from BC (p = 0.018 and poor prognosis overall (p = 0.013. After a median follow up of 10 years, higher BDNF expression levels were significantly associated with reduced overall survival (OS (106 vs. 136 months, p = 0.006. BDNF

  7. Adult human dental pulp stem cells promote blood-brain barrier permeability through vascular endothelial growth factor-a expression.

    Science.gov (United States)

    Winderlich, Joshua N; Kremer, Karlea L; Koblar, Simon A

    2016-06-01

    Stem cell therapy is a promising new treatment option for stroke. Intravascular administration of stem cells is a valid approach as stem cells have been shown to transmigrate the blood-brain barrier. The mechanism that causes this effect has not yet been elucidated. We hypothesized that stem cells would mediate localized discontinuities in the blood-brain barrier, which would allow passage into the brain parenchyma. Here, we demonstrate that adult human dental pulp stem cells express a soluble factor that increases permeability across an in vitro model of the blood-brain barrier. This effect was shown to be the result of vascular endothelial growth factor-a. The effect could be amplified by exposing dental pulp stem cell to stromal-derived factor 1, which stimulates vascular endothelial growth factor-a expression. These findings support the use of dental pulp stem cell in therapy for stroke. © The Author(s) 2015.

  8. Regional differences in the expression of brain-derived neurotrophic factor (BDNF) pro-peptide, proBDNF and preproBDNF in the brain confer stress resilience.

    Science.gov (United States)

    Yang, Bangkun; Yang, Chun; Ren, Qian; Zhang, Ji-Chun; Chen, Qian-Xue; Shirayama, Yukihiko; Hashimoto, Kenji

    2016-12-01

    Using learned helplessness (LH) model of depression, we measured protein expression of brain-derived neurotrophic factor (BDNF) pro-peptide, BDNF precursors (proBDNF and preproBDNF) in the brain regions of LH (susceptible) and non-LH rats (resilience). Expression of preproBDNF, proBDNF and BDNF pro-peptide in the medial prefrontal cortex of LH rats, but not non-LH rats, was significantly higher than control rats, although expression of these proteins in the nucleus accumbens of LH rats was significantly lower than control rats. This study suggests that regional differences in conversion of BDNF precursors into BDNF and BDNF pro-peptide by proteolytic cleavage may contribute to stress resilience.

  9. Effect of dietary fat and the circadian clock on the expression of brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Genzer, Yoni; Dadon, Maayan; Burg, Chen; Chapnik, Nava; Froy, Oren

    2016-07-15

    Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain and its decreased levels are associated with the development of obesity and neurodegeneration. Our aim was to test the effect of dietary fat, its timing and the circadian clock on the expression of BDNF and associated signaling pathways in mouse brain and liver. Bdnf mRNA oscillated robustly in brain and liver, but with a 12-h shift between the tissues. Brain and liver Bdnf mRNA showed a 12-h phase shift when fed ketogenic diet (KD) compared with high-fat diet (HFD) or low-fat diet (LFD). Brain or liver Bdnf mRNA did not show the typical phase advance usually seen under time-restricted feeding (RF). Clock knockdown in HT-4 hippocampal neurons led to 86% up-regulation of Bdnf mRNA, whereas it led to 60% down-regulation in AML-12 hepatocytes. Dietary fat in mice or cultured hepatocytes and hippocampal neurons led to increased Bdnf mRNA expression. At the protein level, HFD increased the ratio of the mature BDNF protein (mBDNF) to its precursor (proBDNF). In the liver, RF under LFD or HFD reduced the mBDNF/proBDNF ratio. In the brain, the two signaling pathways related to BDNF, mTOR and AMPK, showed reduced and increased levels, respectively, under timed HFD. In the liver, the reverse was achieved. In summary, Bdnf expression is mediated by the circadian clock and dietary fat. Although RF does not affect its expression phase, in the brain, when combined with high-fat diet, it leads to a unique metabolic state in which AMPK is activated, mTOR is down-regulated and the levels of mBDNF are high. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Metallothionein (MT -I and MT-II expression are induced and cause zinc sequestration in the liver after brain injury.

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    Michael W Pankhurst

    Full Text Available UNLABELLED: Experiments with transgenic over-expressing, and null mutant mice have determined that metallothionein-I and -II (MT-I/II are protective after brain injury. MT-I/II is primarily a zinc-binding protein and it is not known how it provides neuroprotection to the injured brain or where MT-I/II acts to have its effects. MT-I/II is often expressed in the liver under stressful conditions but to date, measurement of MT-I/II expression after brain injury has focused primarily on the injured brain itself. In the present study we measured MT-I/II expression in the liver of mice after cryolesion brain injury by quantitative reverse-transcriptase PCR (RT-PCR and enzyme-linked immunosorbent assay (ELISA with the UC1MT antibody. Displacement curves constructed using MT-I/II knockout (MT-I/II(-/- mouse tissues were used to validate the ELISA. Hepatic MT-I and MT-II mRNA levels were significantly increased within 24 hours of brain injury but hepatic MT-I/II protein levels were not significantly increased until 3 days post injury (DPI and were maximal at the end of the experimental period, 7 DPI. Hepatic zinc content was measured by atomic absorption spectroscopy and was found to decrease at 1 and 3 DPI but returned to normal by 7DPI. Zinc in the livers of MT-I/II(-/- mice did not show a return to normal at 7 DPI which suggests that after brain injury, MT-I/II is responsible for sequestering elevated levels of zinc to the liver. CONCLUSION: MT-I/II is up-regulated in the liver after brain injury and modulates the amount of zinc that is sequestered to the liver.

  11. Correlation of Nr4a2 expression with the neuron progenitors in adult zebrafish brain.

    Science.gov (United States)

    Chen, Sheng; Luo, Guang Rui; Li, Ting; Liu, Ting Xi; Le, Weidong

    2013-11-01

    Our previous study showed that although Nr4a2b transcripts have little co-localization with tyrosine hydroxylase (TH) in the posterior tuberculum area, knockdown of Nr4a2 caused a decrease in the number of TH-positive (TH(+)) neurons in the posterior tuberculum area. It suggests that Nr4a2 expression in the progenitors may play an important role in regulating differentiation rather than survival of TH(+) progenitors in the posterior tuberculum area during early zebrafish embryogenesis. In this study, we determined the correlation between TH and Nr4a2 in adult zebrafish brain and found that Nr4a2b was co-localized with the spindle-shaped TH(+) cells in the posterior tuberculum area and some small round TH(+) cells in the pretectum area, but not with large pear-shaped TH(+) cells in adult zebrafish diencephalon. In the pretectum area, Nr4a2(+) cells were localized next to the dorsal side of TH(+) cells. Furthermore, we demonstrated that Nr4a2 was co-expressed with nestin in the progenitors of pretectum area and caudal periventricular hypothalamic zones with a lateral symmetry pattern beside the diencephalic ventricle. Co-expression of Nr4a2 and nestin in these areas was remarkably declined with aging. These findings indicate that Nr4a2 is expressed in the neuronal progenitors and plays a crucial role in the differentiation process of dopamine neuron from the stem cell. The change in Nr4a2 expression with aging suggests its possible association with neurodegenerative diseases.

  12. Pacific white shrimp (Litopenaeus vannamei) vitellogenesis-inhibiting hormone (VIH) is predominantly expressed in the brain and negatively regulates hepatopancreatic vitellogenin (VTG) gene expression.

    Science.gov (United States)

    Chen, Ting; Zhang, Lv-Ping; Wong, Nai-Kei; Zhong, Ming; Ren, Chun-Hua; Hu, Chao-Qun

    2014-03-01

    Ovarian maturation in crustaceans is temporally orchestrated by two processes: oogenesis and vitellogenesis. The peptide hormone vitellogenesis-inhibiting hormone (VIH), by far the most potent negative regulator of crustacean reproduction known, critically modulates crustacean ovarian maturation by suppressing vitellogenin (VTG) synthesis. In this study, cDNA encoding VIH was cloned from the eyestalk of Pacific white shrimp, Litopenaeus vannamei, a highly significant commercial culture species. Phylogenetic analysis suggests that L. vannamei VIH (lvVIH) can be classified as a member of the type II crustacean hyperglycemic hormone family. Northern blot and RT-PCR results reveal that both the brain and eyestalk were the major sources for lvVIH mRNA expression. In in vitro experiments on primary culture of shrimp hepatopancreatic cells, it was confirmed that some endogenous inhibitory factors existed in L. vannamei hemolymph, brain, and eyestalk that suppressed hepatopancreatic VTG gene expression. Purified recombinant lvVIH protein was effective in inhibiting VTG mRNA expression in both in vitro primary hepatopancreatic cell culture and in vivo injection experiments. Injection of recombinant VIH could also reverse ovarian growth induced by eyestalk ablation. Furthermore, unilateral eyestalk ablation reduced the mRNA level of lvVIH in the brain but not in the remaining contralateral eyestalk. Our study, as a whole, provides new insights on VIH regulation of shrimp reproduction: 1) the brain and eyestalk are both important sites of VIH expression and therefore possible coregulators of hepatopancreatic VTG mRNA expression and 2) eyestalk ablation could increase hepatopancreatic VTG expression by transcriptionally abolishing eyestalk-derived VIH and diminishing brain-derived VIH.

  13. Intraventricular injection of myxoma virus results in transient expression of viral protein in mouse brain ependymal and subventricular cells.

    Science.gov (United States)

    France, Megan R; Thomas, Diana L; Liu, Jia; McFadden, Grant; MacNeill, Amy L; Roy, Edward J

    2011-01-01

    Oncolytic viruses that selectively infect and lyse cancer cells have potential as therapeutic agents. Myxoma virus, a poxvirus that is known to be pathogenic only in rabbits, has not been reported to infect normal tissues in humans or mice. We observed that when recombinant virus was injected directly into the lateral ventricle of the mouse brain, virally encoded red fluorescent protein was expressed in ependymal and subventricular cells. Cells were positive for nestin, a marker of neural stem cells. Rapamycin increased the number of cells expressing the virally encoded protein. However, protein expression was transient. Cells expressing the virally encoded protein did not undergo apoptosis and the ependymal lining remained intact. Myxoma virus appears to be safe when injected into the brain despite the transient expression of virally derived protein in a small population of periventricular cells.

  14. Regulation of expression of atrial and brain natriuretic peptide, biomarkers for heart development and disease.

    Science.gov (United States)

    Sergeeva, Irina A; Christoffels, Vincent M

    2013-12-01

    The mammalian heart expresses two closely related natriuretic peptide (NP) hormones, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). The excretion of the NPs and the expression of their genes strongly respond to a variety of cardiovascular disorders. NPs act to increase natriuresis and decrease vascular resistance, thereby decreasing blood volume, systemic blood pressure and afterload. Plasma levels of BNP are used as diagnostic and prognostic markers for hypertrophy and heart failure (HF), and both ANF and BNP are widely used in biomedical research to assess the hypertrophic response in cell culture or the development of HF related diseases in animal models. Moreover, ANF and BNP are used as specific markers for the differentiating working myocardium in the developing heart, and the ANF promoter serves as platform to investigate gene regulatory networks during heart development and disease. However, despite decades of research, the mechanisms regulating the NP genes during development and disease are not well understood. Here we review current knowledge on the regulation of expression of the genes for ANF and BNP and their role as biomarkers, and give future directions to identify the in vivo regulatory mechanisms. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions. © 2013.

  15. Yueju Pill Rapidly Induces Antidepressant-Like Effects and Acutely Enhances BDNF Expression in Mouse Brain

    Directory of Open Access Journals (Sweden)

    Wenda Xue

    2013-01-01

    Full Text Available The traditional antidepressants have a major disadvantage in delayed onset of efficacy, and the emerging fast-acting antidepressant ketamine has adverse behavioral and neurotoxic effects. Yueju pill, an herb medicine formulated eight hundred years ago by Doctor Zhu Danxi, has been popularly prescribed in China for alleviation of depression-like symptoms. Although several clinical outcome studies reported the relative short onset of antidepressant effects of Yueju, this has not been scientifically investigated. We, therefore, examined the rapid antidepressant effect of Yueju in mice and tested the underlying molecular mechanisms. We found that acute administration of ethanol extract of Yueju rapidly attenuated depressive-like symptoms in learned helpless paradigm, and the antidepressant-like effects were sustained for at least 24 hours in tail suspension test in ICR mice. Additionally, Yueju, like ketamine, rapidly increased the expression of brain-derived neurotrophic factor (BDNF in the hippocampus, whereas the BDNF mRNA expression remained unaltered. Yueju rapidly reduced the phosphorylation of eukaryotic elongation factor 2 (eEF2, leading to desuppression of BDNF synthesis. Unlike ketamine, both the BDNF expression and eEF2 phosphorylation were revered at 24 hours after Yueju administration. This study is the first to demonstrate the rapid antidepressant effects of an herb medicine, offering an opportunity to improve therapy of depression.

  16. Gene expression in the mouse brain following early pregnancy exposure to ethanol

    Directory of Open Access Journals (Sweden)

    Christine R. Zhang

    2016-12-01

    Full Text Available Exposure to alcohol during early embryonic or fetal development has been linked with a variety of adverse outcomes, the most common of which are structural and functional abnormalities of the central nervous system [1]. Behavioural and cognitive deficits reported in individuals exposed to alcohol in utero include intellectual impairment, learning and memory difficulties, diminished executive functioning, attention problems, poor motor function and hyperactivity [2]. The economic and social costs of these outcomes are substantial and profound [3,4]. Improvement of neurobehavioural outcomes following prenatal alcohol exposure requires greater understanding of the mechanisms of alcohol-induced damage to the brain. Here we use a mouse model of relatively moderate ethanol exposure early in pregnancy and profile gene expression in the hippocampus and caudate putamen of adult male offspring. The effects of offspring sex and age on ethanol-sensitive hippocampal gene expression were also examined. All array data are available at the Gene Expression Omnibus (GEO repository under accession number GSE87736.

  17. Infectomic Analysis of Gene Expression Profiles of Human Brain Microvascular Endothelial Cells Infected with Cryptococcus neoformans

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    Ambrose Jong

    2008-01-01

    Full Text Available In order to dissect the pathogenesis of Cryptococcus neoformans meningoencephalitis, a genomic survey of the changes in gene expression of human brain microvascular endothelial cells infected by C. neoformans was carried out in a time-course study. Principal component analysis (PCA revealed sigificant fluctuations in the expression levels of different groups of genes during the pathogen-host interaction. Self-organizing map (SOM analysis revealed that most genes were up- or downregulated 2 folds or more at least at one time point during the pathogen-host engagement. The microarray data were validated by Western blot analysis of a group of genes, including β-actin, Bcl-x, CD47, Bax, Bad, and Bcl-2. Hierarchical cluster profile showed that 61 out of 66 listed interferon genes were changed at least at one time point. Similarly, the active responses in expression of MHC genes were detected at all stages of the interaction. Taken together, our infectomic approaches suggest that the host cells significantly change the gene profiles and also actively participate in immunoregulations of the central nervous system (CNS during C. neoformans infection.

  18. Reconstructing Generalized Logical Networks of Transcriptional Regulation in Mouse Brain from Temporal Gene Expression Data

    Directory of Open Access Journals (Sweden)

    Lodowski Kerrie H

    2009-01-01

    Full Text Available Gene expression time course data can be used not only to detect differentially expressed genes but also to find temporal associations among genes. The problem of reconstructing generalized logical networks to account for temporal dependencies among genes and environmental stimuli from transcriptomic data is addressed. A network reconstruction algorithm was developed that uses statistical significance as a criterion for network selection to avoid false-positive interactions arising from pure chance. The multinomial hypothesis testing-based network reconstruction allows for explicit specification of the false-positive rate, unique from all extant network inference algorithms. The method is superior to dynamic Bayesian network modeling in a simulation study. Temporal gene expression data from the brains of alcohol-treated mice in an analysis of the molecular response to alcohol are used for modeling. Genes from major neuronal pathways are identified as putative components of the alcohol response mechanism. Nine of these genes have associations with alcohol reported in literature. Several other potentially relevant genes, compatible with independent results from literature mining, may play a role in the response to alcohol. Additional, previously unknown gene interactions were discovered that, subject to biological verification, may offer new clues in the search for the elusive molecular mechanisms of alcoholism.

  19. Roles of apolipoprotein E (ApoE and inducible nitric oxide synthase (iNOS in inflammation and apoptosis in preeclampsia pathogenesis and progression.

    Directory of Open Access Journals (Sweden)

    Luyi Mao

    Full Text Available OBJECTIVES: To investigate potential roles of inducible nitric oxide synthase (iNOS and apolipoprotein (apoE in inflammation and apoptosis promoting pathological changes in preeclampsia in pregnant mice with apoE and/or iNOS knock out. METHODS: B6.129 mice were crossed to produce WT, apoE(-/-, apoE(+/-, iNOS(-/-, iNOS(+/- and apoE(-/-iNOS(-/- groups. Variants were confirmed by PCR. Serum lipid parameters (triglycerides, TG; total cholesterol, TC; high density lipoprotein, HDL; and low density lipoprotein, LDL, NO levels and placental electronic microscopic ultrastructures were evaluated, and blood pressure (BP, 24-hour urine protein and pregnancy outcomes were recorded for pregnant F1 generation mice. Placental expressions of inflammatory (tumor necrosis factor-α, TNF-α; interleukin-6, IL-6; nuclear factor-κB, NF-κb and apoptotic markers (Bcl-2 associated X protein, Bax, B-cell lymphoma/leukemia-2, Bcl-2, and Caspase-3 were evaluated via Western blot. RESULTS: Serum lipids, BP and 24-hour urine protein levels were shown to be significantly higher and parturition and placenta weights were lower in apoE(-/- and apoE(-/-iNOS(-/- groups (p0.05 showed no differences. In addition, placenta vascular endothelial and trophoblast cell morphological changes were demonstrated in both the apoE(-/-iNOS(-/- and apoE(-/- groups. CONCLUSION: Elevated lipid metabolism and inflammatory/apoptosis parameters suggest a potentially significant role of apoE in preeclampsia pathology, as well as a relationship between iNOS and preeclampsia progression.

  20. Protein Delivery of an Artificial Transcription Factor Restores Widespread Ube3a Expression in an Angelman Syndrome Mouse Brain

    Science.gov (United States)

    Bailus, Barbara J; Pyles, Benjamin; McAlister, Michelle M; O'Geen, Henriette; Lockwood, Sarah H; Adams, Alexa N; Nguyen, Jennifer Trang T; Yu, Abigail; Berman, Robert F; Segal, David J

    2016-01-01

    Angelman syndrome (AS) is a neurological genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain. Due to brain-specific genetic imprinting at this locus, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. However, widespread delivery of gene regulators to the brain remains challenging. Here, we report an engineered zinc finger-based artificial transcription factor (ATF) that, when injected i.p. or s.c., crossed the blood–brain barrier and increased Ube3a expression in the brain of an adult mouse model of AS. The factor displayed widespread distribution throughout the brain. Immunohistochemistry of both the hippocampus and cerebellum revealed an increase in Ube3a upon treatment. An ATF containing an alternative DNA-binding domain did not activate Ube3a. We believe this to be the first report of an injectable engineered zinc finger protein that can cause widespread activation of an endogenous gene in the brain. These observations have important implications for the study and treatment of AS and other neurological disorders. PMID:26727042

  1. Dopaminergic activation of estrogen receptors induces fos expression within restricted regions of the neonatal female rat brain.

    Directory of Open Access Journals (Sweden)

    Kristin M Olesen

    2008-05-01

    Full Text Available Steroid receptor activation in the developing brain influences a variety of cellular processes that endure into adulthood, altering both behavior and physiology. Recent data suggests that dopamine can regulate expression of progestin receptors within restricted regions of the developing rat brain by activating estrogen receptors in a ligand-independent manner. It is unclear whether changes in neuronal activity induced by dopaminergic activation of estrogen receptors are also region specific. To investigate this question, we examined where the dopamine D1-like receptor agonist, SKF 38393, altered Fos expression via estrogen receptor activation. We report that dopamine D1-like receptor agonist treatment increased Fos protein expression within many regions of the developing female rat brain. More importantly, prior treatment with an estrogen receptor antagonist partially reduced D1-like receptor agonist-induced Fos expression only within the bed nucleus of the stria terminalis and the central amygdala. These data suggest that dopaminergic activation of estrogen receptors alters neuronal activity within restricted regions of the developing rat brain. This implies that ligand-independent activation of estrogen receptors by dopamine might organize a unique set of behaviors during brain development in contrast to the more wide spread ligand activation of estrogen receptors by estrogen.

  2. Dopaminergic Activation of Estrogen Receptors Induces Fos Expression within Restricted Regions of the Neonatal Female Rat Brain

    Science.gov (United States)

    Olesen, Kristin M.; Auger, Anthony P.

    2008-01-01

    Steroid receptor activation in the developing brain influences a variety of cellular processes that endure into adulthood, altering both behavior and physiology. Recent data suggests that dopamine can regulate expression of progestin receptors within restricted regions of the developing rat brain by activating estrogen receptors in a ligand-independent manner. It is unclear whether changes in neuronal activity induced by dopaminergic activation of estrogen receptors are also region specific. To investigate this question, we examined where the dopamine D1-like receptor agonist, SKF 38393, altered Fos expression via estrogen receptor activation. We report that dopamine D1-like receptor agonist treatment increased Fos protein expression within many regions of the developing female rat brain. More importantly, prior treatment with an estrogen receptor antagonist partially reduced D1-like receptor agonist-induced Fos expression only within the bed nucleus of the stria terminalis and the central amygdala. These data suggest that dopaminergic activation of estrogen receptors alters neuronal activity within restricted regions of the developing rat brain. This implies that ligand-independent activation of estrogen receptors by dopamine might organize a unique set of behaviors during brain development in contrast to the more wide spread ligand activation of estrogen receptors by estrogen. PMID:18478050

  3. Combined neuroimaging and gene expression analysis of the genetic basis of brain plasticity indicates across species homology.

    Science.gov (United States)

    Dinai, Yonatan; Wolf, Lior; Assaf, Yaniv

    2014-12-01

    Brain plasticity and memory formation depend on the expression of a large number of genes. This relationship had been studied using several experimental approaches and researchers have identified genes regulating plasticity through a variety of mechanisms. Despite this effort, a great deal remains unknown regarding the role of different genes in brain plasticity. Previous studies usually focused on specific brain structures and many of the genes influencing plasticity have yet to be identified. In this work, we integrate results of in vivo neuroimaging studies of plasticity with whole-brain gene expression data for the study of neuroplasticity. Brain regions, found in the imaging study to be involved in plasticity, are first spatially mapped to the anatomical framework of the genetic database. Feature ranking methods are then applied to identify genes that are differentially expressed in these regions. We find that many of our highly ranked genes are involved in synaptic transmission and that some of these genes have been previously associated with learning and memory. We show these results to be consistent when applying our method to gene expression data from four human subjects. Finally, by performing similar experiments in mice, we reveal significant cross species correlation in the ranking of genes. In addition to the identification of plasticity related candidate genes, our results also demonstrate the potential of data integration approaches as a tool to link high level phenomena such as learning and memory to underlying molecular mechanisms. © 2014 Wiley Periodicals, Inc.

  4. Analysis of cycle gene expression in Aedes aegypti brains by in situ hybridization.

    Science.gov (United States)

    Chahad-Ehlers, Samira; Gentile, Carla; Lima, José Bento Pereira; Peixoto, Alexandre Afranio; Bruno, Rafaela Vieira

    2013-01-01

    Even though the blood-sucking mosquito Aedes aegypti is one of the most important disease vectors, relatively little is known about the molecular mechanisms underlying processes involved in the temporal pattern of its activity and host seeking behavior. In this study, we analyzed the expression of the cycle (cyc) gene, one of the core components of the circadian clock, in Ae. aegypti brains by in situ hybridization at two different time points in light-dark conditions and compared the results with those obtained using a quantitative PCR assay (qPCR). Within the brain, differential labeling was detected according to distinct areas empirically pre-defined. Six out of seven of these areas showed significantly higher staining at ZT3 (three hours after light-on) compared to ZT11 (one before light-off), which is consistent with the qPCR data. Predominant staining was observed in three of those areas which correspond to positions of the optical and antennal lobes, as well as the region where the neurons controlling activity rhythms are presumably localized.

  5. Expression analysis of GSK-3β in diapause pupal brains in the cotton bollworm, Helicoverpa armigera.

    Science.gov (United States)

    Chen, Wei; Xu, Wei-Hua

    2015-10-01

    Diapause is an adaptive response to adverse environmental conditions, but the molecular mechanisms are unclear. Some signaling molecules have been identified in the regulation of diapause. GSK-3β is an important signaling protein involved in several signaling pathways. In this study, GSK-3β from the cotton bollworm, Helicoverpa armigera, was cloned using reverse transcription polymerase chain reaction and rapid amplification of complementary DNA (cDNA) ends techniques. Sequence analysis showed that the full-length cDNA was 1447 bp containing a 292 bp 5'-untranslated region (UTR), a 162 bp 3'-UTR and a 993 bp open reading frame (ORF). The deduced Har-GSK-3β protein has high identity to other known GSK-3β, as determined by Basic Local Alignment Search Tool analysis. Developmental expression of total GSK-3β and p-GSK-3β (Ser9) in diapause and non-diapause pupal brains was investigated by Western blotting. Results indicated that the activity of GSK-3β is down-regulated in diapause pupal brains, which is further confirmed by Western blotting after diapause break. These finding suggest that the down-regulation of Har-GSK-3β activity may be important for pupal diapause. © 2015 Institute of Zoology, Chinese Academy of Sciences.

  6. The effect of alcohol and nicotine abuse on gene expression in the brain.

    Science.gov (United States)

    Flatscher-Bader, Traute; Wilce, Peter A

    2009-12-01

    Alcohol intake at levels posing an acute heath risk is common amongst teenagers. Alcohol abuse is the second most common mental disorder worldwide. The incidence of smoking is decreasing in the Western world but increasing in developing countries and is the leading cause of preventable death worldwide. Considering the longstanding history of alcohol and tobacco consumption in human societies, it might be surprising that the molecular mechanisms underlying alcohol and smoking dependence are still incompletely understood. Effective treatments against the risk of relapse are lacking. Drugs of abuse exert their effect manipulating the dopaminergic mesocorticolimbic system. In this brain region, alcohol has many potential targets including membranes and several ion channels, while other drugs, for example nicotine, act via specific receptors or binding proteins. Repeated consumption of drugs of abuse mediates adaptive changes within this region, resulting in addiction. The high incidence of alcohol and nicotine co-abuse complicates analysis of the molecular basis of the disease. Gene expression profiling is a useful approach to explore novel drug targets in the brain. Several groups have utilised this technology to reveal drug-sensitive pathways in the mesocorticolimbic system of animal models and in human subjects. These studies are the focus of the present review.

  7. A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain.

    Science.gov (United States)

    Nichols, Charles D; Sanders-Bush, Elaine

    2002-05-01

    Hallucinogenic drugs such as lysergic acid diethylamide (LSD) have profound effects on humans including hallucinations and detachment from reality. These remarkable behavioral effects have many similarities to the debilitating symptoms of neuropsychiatric disorders such as schizophrenia. The effects of hallucinogens are thought to be mediated by serotonin receptor activation; however, how these drugs elicit the unusual behavioral effects remains largely a mystery, despite much research. We have undertaken the first comprehensive analysis of gene expression influenced by acute LSD administration in the mammalian brain. These studies represent a novel approach to elucidate the mechanism of action of this class of drugs. We have identified a number of genes that are predicted to be involved in the processes of synaptic plasticity, glutamatergic signaling and cytoskeletal architecture. Understanding these molecular events will lead to new insights into the etiology of disorders whose behavioral symptoms resemble the temporary effects of hallucinogenic drugs, and also may ultimately result in new therapies.

  8. Excitatory amino acid neurotoxicity and modulation of glutamate receptor expression in organotypic brain slice cultures

    DEFF Research Database (Denmark)

    Zimmer, J; Kristensen, Bjarne Winther; Jakobsen, B

    2000-01-01

    -induced excitotoxicity and KA-glutamate receptor subunit mRNA expression after long-term exposure to low, non-toxic doses of KA and NBQX. We conclude that organotypic brain slice cultures, combined with standardized procedures for quantitation of cell damage and receptor subunit changes is of great potential use......Using organotypic slice cultures of hippocampus and cortex-striatum from newborn to 7 day old rats, we are currently studying the excitotoxic effects of kainic acid (KA), AMPA and NMDA and the neuroprotective effects of glutamate receptor blockers, like NBQX. For detection and quantitation......-associated protein 2, and --e) general and specific neuronal and glial cell stains. The results show good correlation between the different markers, and are in accordance with results obtained in vivo. Examples presented in this review will focus on the use of PI uptake to monitor the excitotoxic effects of --a) KA...

  9. The Creatine Transporter Gene Paralogous at 16p11.2 Is Expressed in Human Brain

    Directory of Open Access Journals (Sweden)

    Nadia Bayou

    2008-01-01

    We report on the clinical, cytogenetic, and molecular findings in a boy with autism carrying a de novo translocation t(7;16(p22.1;p11.2. The chromosome 16 breakpoint disrupts the paralogous SLC6A8 gene also called SLC6A10 or CT2. Predicted translation of exons and RT-PCR analysis reveal specific expression of the creatine transporter paralogous in testis and brain. Several studies reported on the role of X-linked creatine transporter mutations in individuals with mental retardation, with or without autism. The existence of disruption in SLC6A8 paralogous gene associated with idiopathic autism suggests that this gene may be involved in the autistic phenotype in our patient.

  10. Reconstructing Generalized Logical Networks of Transcriptional Regulation in Mouse Brain from Temporal Gene Expression Data

    Energy Technology Data Exchange (ETDEWEB)

    Song, Mingzhou (Joe) [New Mexico State University, Las Cruces; Lewis, Chris K. [New Mexico State University, Las Cruces; Lance, Eric [New Mexico State University, Las Cruces; Chesler, Elissa J [ORNL; Kirova, Roumyana [Bristol-Myers Squibb Pharmaceutical Research & Development, NJ; Langston, Michael A [University of Tennessee, Knoxville (UTK); Bergeson, Susan [Texas Tech University, Lubbock

    2009-01-01

    The problem of reconstructing generalized logical networks to account for temporal dependencies among genes and environmental stimuli from high-throughput transcriptomic data is addressed. A network reconstruction algorithm was developed that uses the statistical significance as a criterion for network selection to avoid false-positive interactions arising from pure chance. Using temporal gene expression data collected from the brains of alcohol-treated mice in an analysis of the molecular response to alcohol, this algorithm identified genes from a major neuronal pathway as putative components of the alcohol response mechanism. Three of these genes have known associations with alcohol in the literature. Several other potentially relevant genes, highlighted and agreeing with independent results from literature mining, may play a role in the response to alcohol. Additional, previously-unknown gene interactions were discovered that, subject to biological verification, may offer new clues in the search for the elusive molecular mechanisms of alcoholism.

  11. mRNA expression of the lipid and mechano-gated 2P domain K+ channels during rat brain development.

    Science.gov (United States)

    Xu, Xianghua; Pan, Yaping; Wang, Xiaoliang

    2002-01-01

    mRNAs encoded by genes for the lipid-sensitive mechano-gated K(+) channels TREK-1, TREK-2, and TRAAK were detected in rat brain at different life-cycle stages: 18-day embryos, postnatal days 1, 7, 28, and 60 (adulthood). mRNA expression of TREK-1 or TREK-2 showed no appreciable changes during the development of cortex and hippocampus. TRAAK mRNA expression increased with development and reached an apparent maximum at postnatal day 28 in hippocampus and day 60 in cortex. These data suggest that TRAAK might be important in the development of rat brain.

  12. Lysergic acid diethylamide-induced Fos expression in rat brain: role of serotonin-2A receptors.

    Science.gov (United States)

    Gresch, P J; Strickland, L V; Sanders-Bush, E

    2002-01-01

    Lysergic acid diethylamide (LSD) produces altered mood and hallucinations in humans and binds with high affinity to serotonin-2A (5-HT(2A)) receptors. Although LSD interacts with other receptors, the activation of 5-HT(2A) receptors is thought to mediate the hallucinogenic properties of LSD. The goal of this study was to identify the brain sites activated by LSD and to determine the influence of 5-HT(2A) receptors in this activation. Rats were pretreated with the 5-HT(2A) receptor antagonist MDL 100907 (0.3 mg/kg, i.p.) or vehicle 30 min prior to LSD (500 microg/kg, i.p.) administration and killed 3 h later. Brain tissue was examined for Fos protein expression by immunohistochemistry. LSD administration produced a five- to eight-fold increase in Fos-like immunoreactivity in medial prefrontal cortex, anterior cingulate cortex, and central nucleus of amygdala. However, in dorsal striatum and nucleus accumbens no increase in Fos-like immunoreactivity was observed. Pretreatment with MDL 100907 completely blocked LSD-induced Fos-like immunoreactivity in medial prefrontal cortex and anterior cingulate cortex, but only partially blocked LSD-induced Fos-like immunoreactivity in amygdala. Double-labeled immunohistochemistry revealed that LSD did not induce Fos-like immunoreactivity in cortical cells expressing 5-HT(2A) receptors, suggesting an indirect activation of cortical neurons. These results indicate that the LSD activation of medial prefrontal cortex and anterior cingulate cortex is mediated by 5-HT(2A) receptors, whereas in amygdala 5-HT(2A) receptor activation is a component of the response. These findings support the hypothesis that the medial prefrontal cortex, anterior cingulate cortex, and perhaps the amygdala, are important regions involved in the production of hallucinations. Copyright 2002 IBRO

  13. Differential expression and methylation of brain developmental genes define location-specific subsets of pilocytic astrocytoma.

    Science.gov (United States)

    Lambert, Sally R; Witt, Hendrik; Hovestadt, Volker; Zucknick, Manuela; Kool, Marcel; Pearson, Danita M; Korshunov, Andrey; Ryzhova, Marina; Ichimura, Koichi; Jabado, Nada; Fontebasso, Adam M; Lichter, Peter; Pfister, Stefan M; Collins, V Peter; Jones, David T W

    2013-08-01

    Pilocytic astrocytomas (PAs) are the most common brain tumors in pediatric patients and can cause significant morbidity, including chronic neurological deficiencies. They are characterized by activating alterations in the mitogen-activated protein kinase pathway, but little else is known about their development. To map the global DNA methylation profiles of these tumors, we analyzed 62 PAs and 7 normal cerebellum samples using Illumina 450K microarrays. These data revealed two subgroups of PA that separate according to tumor location (infratentorial versus supratentorial), and identified key neural developmental genes that are differentially methylated between the two groups, including NR2E1 and EN2. Integration with transcriptome microarray data highlighted significant expression differences, which were unexpectedly associated with a strong positive correlation between methylation and expression. Differentially methylated probes were often identified within the gene body and/or regions up- or downstream of the gene, rather than at the transcription start site. We also identified a large number of differentially methylated genes between cerebellar PAs and normal cerebellum, which were again enriched for developmental genes. In addition, we found a significant association between differentially methylated genes and SUZ12 binding sites, indicating potential disruption of the polycomb repressor complex 2 (PRC2). Taken together, these data suggest that PA from different locations in the brain may arise from region-specific cells of origin, and highlight the potential disruption of key developmental regulators during tumorigenesis. These findings have implications for future basic research and clinical trials, as therapeutic targets and drug sensitivity may differ according to tumor location.

  14. RNAi-induced down-regulation of Mecp2 expression in the rat brain.

    Science.gov (United States)

    Jin, Jing; Bao, Xinhua; Wang, Hansen; Pan, Hong; Zhang, Yuzhi; Wu, Xiru

    2008-08-01

    The MECP2 (methyl-CpG-binding protein 2) gene has been implicated in the pathogenesis of Rett Syndrome. A rat model with a down-regulated Mecp2 was established using a recombinant lentiviral vector expressing small hairpin RNA of the rat Mecp2 gene. Four recombinant vectors were constructed by inserting sequences of small hairpin RNA targeting the rat Mecp2 gene. To determine which vector resulted in optimal down-regulation, rat skin fibroblasts were transfected with four recombinant vectors, respectively. The recombinant vector mecp2-sh-1 decreased expression of Mecp2 mRNA and protein relative to the Control group. 12-24h after birth, neonatal rat pups were divided into three groups, Re-Lenti group (injected with recombinant lentiviral vector, mecp2-sh-1), Lenti group (injected with lentivirus containing no inserted sequences) and a non-injected Control group (Control group). Rats in the injection groups were given intraventricular injections. 7 days and 21 days following injection, no inflammation was observed in the rat brain in the two injected groups, whereas EGFP expression was readily detectable. Sensory-motor reflexes were transiently abnormal in Re-Lenti group, whereas no abnormality was observed in either Control group. Mecp2 mRNA was lower in the hippocampus and cerebral cortex in the Re-Lenti group relative to the Lenti and Control groups. Although no typical RTT like symptoms were observed, the neonatal rats injected with recombinant lentivirus displayed some transient neurobehavioral abnormalities during early development. Bdnf mRNA expression decreased in the hippocampus, supporting the hypothesis that Bdnf may be a target gene of MeCP2 in the CNS.

  15. Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise.

    Science.gov (United States)

    Russo-Neustadt, Amelia A; Alejandre, Hilda; Garcia, Celithelma; Ivy, Autumn S; Chen, Michael J

    2004-12-01

    The antidepressants, reboxetine and citalopram, were used in conjunction with voluntary physical exercise (wheel running) in order to assess the contribution of noradrenergic and serotonergic activation to enhancements in hippocampal brain-derived neurotrophic factor (BDNF) expression resulting from antidepressant treatment and exercise. Reboxetine (40 mg/kg/day), citalopram (10 mg/kg/day), voluntary physical activity, and the combination of antidepressants with exercise were applied to rats for a range of treatment intervals (2 to 14 days). Hippocampal BDNF transcription levels (full-length BDNF, as well as exons I-IV) were then assessed via in situ hybridization. Reboxetine treatment led to a rapid (evident at 2 days) enhancement in BDNF transcription in several hippocampal regions. This increase was also observed when reboxetine treatment was combined with voluntary physical activity for 2 weeks. Treatment with citalopram led to an increase in BDNF mRNA in only one hippocampal region (CA2) after short-term (2 days) treatment, and when combined with exercise, increased BDNF mRNA in the CA4 and dentate gyrus after 2 weeks. As reported in previous studies, voluntary physical activity enhanced BDNF transcription in several hippocampal areas, both on its own and in combination with antidepressant treatments. Examination of the levels of individual BDNF transcript variants influenced by each of these antidepressants revealed distinct patterns of expression in response to the various treatments, and showed that exercise-plus-antidepressant produced significant changes where antidepressant alone failed. Overall, treatment with the norephinephrine-selective antidepressant, reboxetine, in combination with exercise, led to both rapid and sustained increases in hippocampal BDNF mRNA expression. The serotonergic agent, citalopram, appeared to require longer treatment intervals in order to influence BDNF expression positively.

  16. Pharmacoepigenetics of the role of DNA methylation in μ-opioid receptor expression in different human brain regions.

    Science.gov (United States)

    Knothe, Claudia; Oertel, Bruno G; Ultsch, Alfred; Kettner, Mattias; Schmidt, Peter Harald; Wunder, Cora; Toennes, Stefan W; Geisslinger, Gerd; Lötsch, Jörn

    2016-12-01

    Exposure to opioids has been associated with epigenetic effects. Studies in rodents suggested a role of varying degrees of DNA methylation in the differential regulation of μ-opioid receptor expression across the brain. In a translational investigation, using tissue acquired postmortem from 21 brain regions of former opiate addicts, representing a human cohort with chronic opioid exposure, μ-opioid receptor expression was analyzed at the level of DNA methylation, mRNA and protein. While high or low μ-opioid receptor expression significantly correlated with local OPRM1 mRNA levels, there was no corresponding association with OPRM1 methylation status. Additional experiments in human cell lines showed that changes in DNA methylation associated with changes in μ-opioid expression were an order of magnitude greater than differences in brain. Hence, different degrees of DNA methylation associated with chronic opioid exposure are unlikely to exert a major role in the region-specificity of μ-opioid receptor expression in the human brain.

  17. Biological Computation Indexes of Brain Oscillations in Unattended Facial Expression Processing Based on Event-Related Synchronization/Desynchronization

    Directory of Open Access Journals (Sweden)

    Bo Yu

    2016-01-01

    Full Text Available Estimation of human emotions from Electroencephalogram (EEG signals plays a vital role in affective Brain Computer Interface (BCI. The present study investigated the different event-related synchronization (ERS and event-related desynchronization (ERD of typical brain oscillations in processing Facial Expressions under nonattentional condition. The results show that the lower-frequency bands are mainly used to update Facial Expressions and distinguish the deviant stimuli from the standard ones, whereas the higher-frequency bands are relevant to automatically processing different Facial Expressions. Accordingly, we set up the relations between each brain oscillation and processing unattended Facial Expressions by the measures of ERD and ERS. This research first reveals the contributions of each frequency band for comprehension of Facial Expressions in preattentive stage. It also evidences that participants have emotional experience under nonattentional condition. Therefore, the user’s emotional state under nonattentional condition can be recognized in real time by the ERD/ERS computation indexes of different frequency bands of brain oscillations, which can be used in affective BCI to provide the user with more natural and friendly ways.

  18. Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain.

    Directory of Open Access Journals (Sweden)

    Jun Xu

    2008-07-01

    Full Text Available Jarid1c, an X-linked gene coding for a histone demethylase, plays an important role in brain development and function. Notably, JARID1C mutations cause mental retardation and increased aggression in humans. These phenotypes are consistent with the expression patterns we have identified in mouse brain where Jarid1c mRNA was detected in hippocampus, hypothalamus, and cerebellum. Jarid1c expression and associated active histone marks at its 5'end are high in P19 neurons, indicating that JARID1C demethylase plays an important role in differentiated neuronal cells. We found that XX mice expressed Jarid1c more highly than XY mice, independent of their gonadal types (testes versus ovaries. This increased expression in XX mice is consistent with Jarid1c escape from X inactivation and is not compensated by expression from the Y-linked paralogue Jarid1d, which is expressed at a very low level compared to the X paralogue in P19 cells. Our observations suggest that sex-specific expression of Jarid1c may contribute to sex differences in brain function.

  19. Expression and deposition of basement membrane proteins by brain capillary endothelial cells in a primary murine model of the blood-brain barrier

    DEFF Research Database (Denmark)

    Thomsen, Maj Schneider; Birkelund, Svend; Larsen, Annette Burkhart

    2016-01-01

    The blood-brain barrier (BBB) represents the interface between the blood and the brain parenchyma and consists of endothelial cells which are tightly sealed together by tight junction proteins. The endothelial cells are in addition supported by pericytes, which are embedded in the vascular basement...... membrane, and astrocyte endfeet. To study the interaction of the different cells of the BBB, construction of in vitro BBB models is valuable. However, the modulation and contribution of the cells of the BBB to the synthesis of basement membrane proteins in vitro is not fully elaborated. Thus, the aim...... of the present study was to create four different in vitro constructs of the murine BBB to characterise if the expression and secretion of basement membrane proteins by the murine brain capillary endothelial cells (mBCECs) was affected by co-culturing with pericytes, mixed glial cells, or both. Primary m...

  20. Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia

    Directory of Open Access Journals (Sweden)

    Yao Linli

    2013-02-01

    Full Text Available Abstract Background Hypoxia induces microglial activation which causes damage to the developing brain. Microglia derived inflammatory mediators may contribute to this process. Toll-like receptor 4 (TLR4 has been reported to induce microglial activation and cytokines production in brain injuries; however, its role in hypoxic injury remains uncertain. We investigate here TLR4 expression and its roles in neuroinflammation in neonatal rats following hypoxic injury. Methods One day old Wistar rats were subjected to hypoxia for 2 h. Primary cultured microglia and BV-2 cells were subjected to hypoxia for different durations. TLR4 expression in microglia was determined by RT-PCR, western blot and immunofluorescence staining. Small interfering RNA (siRNA transfection and antibody neutralization were employed to downregulate TLR4 in BV-2 and primary culture. mRNA and protein expression of tumor necrosis factor-alpha (TNF-α, interleukin-1 beta (IL-1β and inducible nitric oxide synthase (iNOS was assessed. Reactive oxygen species (ROS, nitric oxide (NO and NF-κB levels were determined by flow cytometry, colorimetric and ELISA assays respectively. Hypoxia-inducible factor-1 alpha (HIF-1α mRNA and protein expression was quantified and where necessary, the protein expression was depleted by antibody neutralization. In vivo inhibition of TLR4 with CLI-095 injection was carried out followed by investigation of inflammatory mediators expression via double immunofluorescence staining. Results TLR4 immunofluorescence and protein expression in the corpus callosum and cerebellum in neonatal m