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Sample records for mice showed elevated

  1. Adolescent C57BL/6J mice show elevated alcohol intake, but reduced taste aversion, as compared to adult mice: a potential behavioral mechanism for binge drinking.

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    Holstein, Sarah E; Spanos, Marina; Hodge, Clyde W

    2011-10-01

    Binge alcohol drinking during adolescence is a serious health problem that may increase future risk of an alcohol use disorder. Although there are several different procedures by which to preclinically model binge-like alcohol intake, limited-access procedures offer the advantage of achieving high voluntary alcohol intake and pharmacologically relevant blood alcohol concentrations (BACs). Therefore, in the current study, developmental differences in binge-like alcohol drinking using a limited-access cycling procedure were examined. In addition, as alcohol drinking has been negatively correlated with sensitivity to the aversive properties of alcohol, we examined developmental differences in sensitivity to an alcohol-induced conditioned taste aversion (CTA). Binge-like alcohol consumption was investigated in adolescent (4 weeks) and adult (10 weeks) male C57BL/6J mice for 2 to 4 h/d for 16 days. Developmental differences in sensitivity to an alcohol-induced CTA were examined in adolescent and adult mice, with saline or alcohol (3 or 4 g/kg) repeatedly paired with the intake of a novel tastant (NaCl). Adolescent mice showed a significant increase in alcohol intake as compared to adults, with adolescents achieving higher BACs and increasing alcohol consumption over successive cycles of the binge procedure. Conversely, adolescent mice exhibited a dose-dependent reduction in sensitivity to the aversive properties of alcohol, as compared to adult mice, with adolescent mice failing to develop a CTA to 3 g/kg alcohol. Finally, extinction of an alcohol CTA was observed following conditioning with a higher dose of alcohol in adolescent, versus adult, mice. These results indicate that adolescent mice consume more alcohol, per kilogram body weight, than adults in a binge-like model of alcohol drinking and demonstrate a blunted sensitivity to the conditioned aversive effects of alcohol. Overall, this supports a behavioral framework by which heightened binge alcohol intake during

  2. Bex1 knock out mice show altered skeletal muscle regeneration

    International Nuclear Information System (INIS)

    Koo, Jae Hyung; Smiley, Mark A.; Lovering, Richard M.; Margolis, Frank L.

    2007-01-01

    Bex1 and Calmodulin (CaM) are upregulated during skeletal muscle regeneration. We confirm this finding and demonstrate the novel finding that they interact in a calcium-dependent manner. To study the role of Bex1 and its interaction with CaM in skeletal muscle regeneration, we generated Bex1 knock out (Bex1-KO) mice. These mice appeared to develop normally and are fertile, but displayed a functional deficit in exercise performance compared to wild type (WT) mice. After intramuscular injection of cardiotoxin, which causes extensive and reproducible myotrauma followed by recovery, regenerating muscles of Bex1-KO mice exhibited elevated and prolonged cell proliferation, as well as delayed cell differentiation, compared to WT mice. Thus, our results provide the first evidence that Bex1-KO mice show altered muscle regeneration, and allow us to propose that the interaction of Bex1 with Ca 2+ /CaM may be involved in skeletal muscle regeneration

  3. Soil nematodes show a mid-elevation diversity maximum and elevational zonation on Mt. Norikura, Japan.

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    Dong, Ke; Moroenyane, Itumeleng; Tripathi, Binu; Kerfahi, Dorsaf; Takahashi, Koichi; Yamamoto, Naomichi; An, Choa; Cho, Hyunjun; Adams, Jonathan

    2017-06-08

    Little is known about how nematode ecology differs across elevational gradients. We investigated the soil nematode community along a ~2,200 m elevational range on Mt. Norikura, Japan, by sequencing the 18S rRNA gene. As with many other groups of organisms, nematode diversity showed a high correlation with elevation, and a maximum in mid-elevations. While elevation itself, in the context of the mid domain effect, could predict the observed unimodal pattern of soil nematode communities along the elevational gradient, mean annual temperature and soil total nitrogen concentration were the best predictors of diversity. We also found nematode community composition showed strong elevational zonation, indicating that a high degree of ecological specialization that may exist in nematodes in relation to elevation-related environmental gradients and certain nematode OTUs had ranges extending across all elevations, and these generalized OTUs made up a greater proportion of the community at high elevations - such that high elevation nematode OTUs had broader elevational ranges on average, providing an example consistent to Rapoport's elevational hypothesis. This study reveals the potential for using sequencing methods to investigate elevational gradients of small soil organisms, providing a method for rapid investigation of patterns without specialized knowledge in taxonomic identification.

  4. Mice lacking neuropeptide Y show increased sensitivity to cocaine

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Woldbye, David Paul Drucker

    2012-01-01

    There is increasing data implicating neuropeptide Y (NPY) in the neurobiology of addiction. This study explored the possible role of NPY in cocaine-induced behavior using NPY knockout mice. The transgenic mice showed a hypersensitive response to cocaine in three animal models of cocaine addiction...

  5. Chromatin decondensed by acetylation shows an elevated radiation response

    International Nuclear Information System (INIS)

    Nackerdien, Z.; Michie, J.; Boehm, L.

    1989-01-01

    V-79 Chinese hamster lung fibroblasts exposed to 5 mM n-sodium butyrate were irradiated with 60Co gamma rays and cell survival was determined by the cell colony assay. In a separate set of experiments the acetylated chromatin obtained from these cells was irradiated and the change of molecular weight of the DNA was evaluated by alkaline sucrose density centrifugation. At a survival level of 10(-2) to 10(-4) cells exposed to butyrate were found to be 1.3-1.4 times more radiosensitive than control cells. Exposure of isolated chromatin to 100 Gy of 60Co gamma irradiation generated 0.9 +/- 0.03 single-strand breaks (ssb) per 10 Gy per 10(8) Da and 2.0 +/- 0.3 ssb/10 Gy/10(8) Da for control and acetylated chromatin, respectively. The elevated radiation sensitivity of chromatin relaxed by acetylation is in good agreement with previous results on chromatin expanded by histone H1 depletion. Packing and accessibility of DNA in chromatin appear to be major factors which influence the radiation sensitivity. The intrinsic radiation sensitivity of chromatin in various packing states is discussed in light of the variation of radiation sensitivity of whole cells in the cell cycle which incorporates repair

  6. Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy.

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    Mader, Jessica R; Resch, Zachary T; McLean, Gary R; Mikkelsen, Jakob H; Oxvig, Claus; Marler, Ronald J; Conover, Cheryl A

    2013-10-01

    We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess the possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old WT and Papp-A knockout (KO) mice. Renal histopathology was evaluated after 4 months of stable hyperglycemia. Kidneys from diabetic WT mice showed multiple abnormalities including thickening of Bowman's capsule (100% of mice), increased glomerular size (80% of mice), tubule dilation (80% of mice), and mononuclear cell infiltration (90% of mice). Kidneys of age-matched non-diabetic WT mice had similar evidence of tubule dilation and mononuclear cell infiltration to those of diabetic WT mice, indicating that these changes were predominantly age-related. However, thickened Bowman's capsule and increased glomerular size appeared specific for the experimental diabetes. Kidneys from diabetic Papp-A KO mice had significantly reduced or no evidence of changes in Bowman's capsule thickening and glomerular size. There was also a shift to larger mesangial area and increased macrophage staining in diabetic WT mice compared with Papp-A KO mice. In summary, elevated PAPP-A expression in glomeruli is associated with diabetic nephropathy in humans and absence of PAPP-A is associated with resistance to the development of indicators of diabetic nephropathy in mice. These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy.

  7. Pumilio2-deficient mice show a predisposition for epilepsy

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    Philipp Follwaczny

    2017-11-01

    Full Text Available Epilepsy is a neurological disease that is caused by abnormal hypersynchronous activities of neuronal ensembles leading to recurrent and spontaneous seizures in human patients. Enhanced neuronal excitability and a high level of synchrony between neurons seem to trigger these spontaneous seizures. The molecular mechanisms, however, regarding the development of neuronal hyperexcitability and maintenance of epilepsy are still poorly understood. Here, we show that pumilio RNA-binding family member 2 (Pumilio2; Pum2 plays a role in the regulation of excitability in hippocampal neurons of weaned and 5-month-old male mice. Almost complete deficiency of Pum2 in adult Pum2 gene-trap mice (Pum2 GT causes misregulation of genes involved in neuronal excitability control. Interestingly, this finding is accompanied by the development of spontaneous epileptic seizures in Pum2 GT mice. Furthermore, we detect an age-dependent increase in Scn1a (Nav1.1 and Scn8a (Nav1.6 mRNA levels together with a decrease in Scn2a (Nav1.2 transcript levels in weaned Pum2 GT that is absent in older mice. Moreover, field recordings of CA1 pyramidal neurons show a tendency towards a reduced paired-pulse inhibition after stimulation of the Schaffer-collateral-commissural pathway in Pum2 GT mice, indicating a predisposition to the development of spontaneous seizures at later stages. With the onset of spontaneous seizures at the age of 5 months, we detect increased protein levels of Nav1.1 and Nav1.2 as well as decreased protein levels of Nav1.6 in those mice. In addition, GABA receptor subunit alpha-2 (Gabra2 mRNA levels are increased in weaned and adult mice. Furthermore, we observe an enhanced GABRA2 protein level in the dendritic field of the CA1 subregion in the Pum2 GT hippocampus. We conclude that altered expression levels of known epileptic risk factors such as Nav1.1, Nav1.2, Nav1.6 and GABRA2 result in enhanced seizure susceptibility and manifestation of epilepsy in the

  8. Memory-Enhancing Activity of Palmatine in Mice Using Elevated Plus Maze and Morris Water Maze

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    Dinesh Dhingra

    2012-01-01

    Full Text Available The present study was designed to evaluate the effect of palmatine on memory of Swiss young male albino mice. Palmatine (0.1, 0.5, 1 mg/kg, i.p. and physostigmine (0.1 mg/kg, i.p. per se were administered for 10 successive days to separate groups of mice. Effect of drugs on learning and memory of mice was evaluated using elevated plus maze and Morris water maze. Brain acetylcholinesterase activity was also estimated. Effect of palmatine on scopolamine- and diazepam-induced amnesia was also investigated. Palmatine (0.5 and 1 mg/kg and physostigmine significantly improved learning and memory of mice, as indicated by decrease in transfer latency using elevated plus maze, and decrease in escape latency during training and increase in time spent in target quadrant during retrieval using Morris water maze. The drugs did not show any significant effect on locomotor activity of the mice. Memory-enhancing activity of palmatine (1 mg/kg was comparable to physostigmine. Palmatine (1 mg/kg significantly reversed scopolamine- and diazepam-induced amnesia in mice. Palmatine and physostigmine also significantly reduced brain acetylcholinesterase activity of mice. Thus, palmatine showed memory-enhancing activity in mice probably by inhibiting brain acetylcholinesterase activity, through involvement of GABA-benzodiazepine pathway, and due to its antioxidant activity.

  9. Heterozygous Che-1 KO mice show deficiencies in object recognition memory persistence.

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    Zalcman, Gisela; Corbi, Nicoletta; Di Certo, Maria Grazia; Mattei, Elisabetta; Federman, Noel; Romano, Arturo

    2016-10-06

    Transcriptional regulation is a key process in the formation of long-term memories. Che-1 is a protein involved in the regulation of gene transcription that has recently been proved to bind the transcription factor NF-κB, which is known to be involved in many memory-related molecular events. This evidence prompted us to investigate the putative role of Che-1 in memory processes. For this study we newly generated a line of Che-1(+/-) heterozygous mice. Che-1 homozygous KO mouse is lethal during development, but Che-1(+/-) heterozygous mouse is normal in its general anatomical and physiological characteristics. We analyzed the behavioral characteristic and memory performance of Che-1(+/-) mice in two NF-κB dependent types of memory. We found that Che-1(+/-) mice show similar locomotor activity and thigmotactic behavior than wild type (WT) mice in an open field. In a similar way, no differences were found in anxiety-like behavior between Che-1(+/-) and WT mice in an elevated plus maze as well as in fear response in a contextual fear conditioning (CFC) and object exploration in a novel object recognition (NOR) task. No differences were found between WT and Che-1(+/-) mice performance in CFC training and when tested at 24h or 7days after training. Similar performance was found between groups in NOR task, both in training and 24h testing performance. However, we found that object recognition memory persistence at 7days was impaired in Che-1(+/-) heterozygous mice. This is the first evidence showing that Che-1 is involved in memory processes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Chronic Toxoplasma gondii in Nurr1-null heterozygous mice exacerbates elevated open field activity.

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    Eells, Jeffrey B; Varela-Stokes, Andrea; Guo-Ross, Shirley X; Kummari, Evangel; Smith, Holly M; Cox, Erin; Lindsay, David S

    2015-01-01

    Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population) and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%), genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/-) mice and wild-type (+/+) mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI) prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice.

  11. Chronic Toxoplasma gondii in Nurr1-null heterozygous mice exacerbates elevated open field activity.

    Directory of Open Access Journals (Sweden)

    Jeffrey B Eells

    Full Text Available Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%, genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/- mice and wild-type (+/+ mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice.

  12. Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

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    Wang, Yuehai [Cardiovascular Department, Liaocheng People’s Hospital of Shandong University, Liaocheng, Shandong 252000 (China); Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lu, Huixia [The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China); Huang, Ziyang, E-mail: huangziyang666@126.com [Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lin, Huili [Cardiovascular Department, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lei, Zhenmin [Department of OB/GYN, University of Louisville School of Medicine, Louisville, KY 40292 (United States); Chen, Xiaoqing [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Tang, Mengxiong; Gao, Fei; Dong, Mei [The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012 (China); Li, Rongda [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China); Lin, Ling, E-mail: qzlinl@163.com [Department of Rheumatism and Immunology, The Second Clinical Medical College of Fujian Medical University, Quanzhou, Fujian 362000 (China)

    2014-07-18

    Highlights: • Titers of ANA and anti-dsDNA antibodies were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • The spleen weights and glomerular areas were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • Expressions of IgG and C3 in glomeruli were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • IgG, C3 and macrophage infiltration in aortic plaques were found in ApoE{sup −/−} mice. - Abstract: Background: Apolipoprotein E-knockout (ApoE{sup −/−}) mice is a classic model of atherosclerosis. We have found that ApoE{sup −/−} mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE{sup −/−} mice show autoimmune injury remains unclear. Methods and results: Six females and six males in each group, ApoE{sup −/−}, Fas{sup −/−} and B6 mice, were used in this study. The titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein were measured by ELISA after 4 months of high-fat diet. The spleen weight and the glomerular area were determined. The expressions of IgG, C3 and macrophage in kidney and atherosclerotic plaque were detected by immunostaining followed by morphometric analysis. Similar to the characteristics of Fas{sup −/−} mice, a model of systemic lupus erythematosus (SLE), ApoE{sup −/−} mice, especially female, displayed significant increases of spleen weight and glomerular area when compared to B6 mice. Also, elevated titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein. Moreover, the expressions of IgG, C3 and macrophage in glomeruli and aortic plaques were found in ApoE{sup −/−} mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE{sup −/−} mice compared with males. Conclusions: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta.

  13. Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

    International Nuclear Information System (INIS)

    Wang, Yuehai; Lu, Huixia; Huang, Ziyang; Lin, Huili; Lei, Zhenmin; Chen, Xiaoqing; Tang, Mengxiong; Gao, Fei; Dong, Mei; Li, Rongda; Lin, Ling

    2014-01-01

    Highlights: • Titers of ANA and anti-dsDNA antibodies were similar in ApoE −/− and Fas −/− mice. • The spleen weights and glomerular areas were similar in ApoE −/− and Fas −/− mice. • Expressions of IgG and C3 in glomeruli were similar in ApoE −/− and Fas −/− mice. • IgG, C3 and macrophage infiltration in aortic plaques were found in ApoE −/− mice. - Abstract: Background: Apolipoprotein E-knockout (ApoE −/− ) mice is a classic model of atherosclerosis. We have found that ApoE −/− mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE −/− mice show autoimmune injury remains unclear. Methods and results: Six females and six males in each group, ApoE −/− , Fas −/− and B6 mice, were used in this study. The titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein were measured by ELISA after 4 months of high-fat diet. The spleen weight and the glomerular area were determined. The expressions of IgG, C3 and macrophage in kidney and atherosclerotic plaque were detected by immunostaining followed by morphometric analysis. Similar to the characteristics of Fas −/− mice, a model of systemic lupus erythematosus (SLE), ApoE −/− mice, especially female, displayed significant increases of spleen weight and glomerular area when compared to B6 mice. Also, elevated titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein. Moreover, the expressions of IgG, C3 and macrophage in glomeruli and aortic plaques were found in ApoE −/− mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE −/− mice compared with males. Conclusions: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

  14. IL-1 receptor-antagonist (IL-1Ra) knockout mice show anxiety-like behavior by aging.

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    Wakabayashi, Chisato; Numakawa, Tadahiro; Odaka, Haruki; Ooshima, Yoshiko; Kiyama, Yuji; Manabe, Toshiya; Kunugi, Hiroshi; Iwakura, Yoichiro

    2015-07-10

    Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. Men with elevated testosterone levels show more affiliative behaviours during interactions with women

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    van der Meij, Leander; Almela, Mercedes; Buunk, Abraham P.; Fawcett, Tim W.; Salvador, Alicia

    2012-01-01

    Testosterone (T) is thought to play a key role in male–male competition and courtship in many vertebrates, but its precise effects are unclear. We explored whether courtship behaviour in humans is modulated and preceded by changes in T. Pairs of healthy male students first competed in a non-physical contest in which their T levels became elevated. Each participant then had a short, informal interaction with either an unfamiliar man or woman. The sex of the stimulus person did not affect the participants' behaviour overall. However, in interactions with women, those men who had experienced a greater T increase during the contest subsequently showed more interest in the woman, engaged in more self-presentation, smiled more and made more eye contact. No such effects were seen in interactions with other men. This is the first study to provide direct evidence that elevating T during male–male competition is followed by increased affiliative behaviour towards women. PMID:21632627

  16. Hepcidin is elevated in mice injected with Mycoplasma arthritidis

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    Kaplan Jerry

    2009-11-01

    Full Text Available Abstract Mycoplasma arthritidis causes arthritis in specific mouse strains. M. arthritidis mitogen (MAM, a superantigen produced by M. arthritidis, activates T cells by forming a complex between the major histocompatability complex II on antigen presenting cells and the T cell receptor on CD4+ T lymphocytes. The MAM superantigen is also known to interact with Toll-like receptors (TLR 2 and 4. Hepcidin, an iron regulator protein, is upregulated by TLR4, IL-6, and IL-1. In this study, we evaluated serum hepcidin, transferrin saturation, ferritin, IL-6, IL-1, and hemoglobin levels in M. arthritidis injected C3H/HeJ (TLR2+/+, TLR4-/- mice and C3H/HeSnJ (TLR2+/+, TLR4+/+ mice over a 21 day period. C3H/HeJ mice have a defective TLR4 and an inability to produce IL-6. We also measured arthritis severity in these mice and the amount of hepcidin transcripts produced by the liver and spleen. C3H/HeJ mice developed a more severe arthritis than that of C3H/HeSnJ mice. Both mice had an increase in serum hepcidin within three days after infection. Hepcidin levels were greater in C3H/HeJ mice despite a nonfunctioning TLR4 and low serum levels of IL-6. Splenic hepcidin production in C3H/HeJ mice was delayed compared to C3H/HeSnJ mice. Unlike C3H/HeSnJ mice, C3H/HeJ mice did not develop a significant rise in serum IL-6 levels but did develop a significant increase in IL-1β during the first ten days after injection. Both mice had an increase in serum ferritin but a decrease in serum transferrin saturation. In conclusion, serum hepcidin regulation in C3H/HeJ mice does not appear to be solely dependent upon TLR4 or IL-6.

  17. Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine

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    Aunis Dominique

    2010-12-01

    Full Text Available Abstract Background- Mice deficient for the stable tubule only peptide (STOP display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission. Results- In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p. produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice. Conclusions- Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.

  18. Connexin30-deficient mice show increased emotionality and decreased rearing activity in the open-field along with neurochemical changes.

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    Dere, E; De Souza-Silva, M A; Frisch, C; Teubner, B; Söhl, G; Willecke, K; Huston, J P

    2003-08-01

    Gap-junction channels in the brain, formed by connexin (Cx) proteins with a distinct regional/cell-type distribution, allow intercellular electrical and metabolic communication. In astrocytes, mainly the connexins 43, 26 and 30 are expressed. In addition, connexin30 is expressed in ependymal and leptomeningeal cells, as well as in skin and cochlea. The functional implications of the astrocytic gap-junctional network are not well understood and evidence regarding their behavioural relevance is lacking. Thus, we have tested groups of Cx30-/-, Cx30+/-, and Cx30+/+ mice in the open-field, an object exploration task, in the graded anxiety test and on the rotarod. The Cx30-/- mice showed reduced exploratory activity in terms of rearings but not locomotion in the open-field and object exploration task. Furthermore, Cx30-/- mice exhibited anxiogenic behaviour as shown by higher open-field centre avoidance and corner preference. Graded anxiety test and rotarod performance was similar across groups. The Cx30-/- mice had elevated choline levels in the ventral striatum, possibly related to their aberrant behavioural phenotypes. The Cx30+/- mice had lower dopamine and metabolite levels in the amygdala and ventral striatum and lower hippocampal 5-hydroxyindole acid (5-HIAA) concentrations relative to Cx30+/+ mice. Furthermore, the Cx30+/- mice had lower acetylcholine concentrations in the ventral striatum and higher choline levels in the neostriatum, relative to Cx30+/+ mice. Our data suggest that the elimination of connexin30 can alter the reactivity to novel environments, pointing to the importance of gap-junctional signalling in behavioural processes.

  19. High Sensitivity of Aged Mice to Deoxynivalenol (Vomitoxin)-Induced Anorexia Corresponds to Elevated Proinflammatory Cytokine and Satiety Hormone Responses.

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    Clark, Erica S; Flannery, Brenna M; Gardner, Elizabeth M; Pestka, James J

    2015-10-19

    Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos) and adult (3 mos) mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg) and dietary (1, 2.5, 10 ppm) DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes.

  20. High Sensitivity of Aged Mice to Deoxynivalenol (Vomitoxin-Induced Anorexia Corresponds to Elevated Proinflammatory Cytokine and Satiety Hormone Responses

    Directory of Open Access Journals (Sweden)

    Erica S. Clark

    2015-10-01

    Full Text Available Deoxynivalenol (DON, a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos and adult (3 mos mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg and dietary (1, 2.5, 10 ppm DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes.

  1. BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine.

    Science.gov (United States)

    Manning, Elizabeth E; Halberstadt, Adam L; van den Buuse, Maarten

    2016-04-01

    One of the most devastating consequences of methamphetamine abuse is increased risk of psychosis. Brain-derived neurotrophic factor has been implicated in both psychosis and neuronal responses to methamphetamine. We therefore examined persistent psychosis-like behavioral effects of methamphetamine in brain-derived neurotrophic factor heterozygous mice. Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-amphetamine challenge was tested in photocell cages after a 2-week withdrawal period. Methamphetamine-treated wild-type mice, but not brain-derived neurotrophic factor heterozygous mice, showed locomotor sensitization to acute 3mg/kg D-amphetamine. Qualitative analysis of exploration revealed tolerance to D-amphetamine effects on entropy in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice, but not wild-type mice. Chronic methamphetamine exposure induces contrasting profiles of behavioral changes in wild-type and brain-derived neurotrophic factor heterozygous mice, with attenuation of behaviors relevant to psychosis in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice. This suggests that brain-derived neurotrophic factor signalling changes may contribute to development of psychosis in methamphetamine users. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  2. Complement activation in leprosy: a retrospective study shows elevated circulating terminal complement complex in reactional leprosy.

    Science.gov (United States)

    Bahia El Idrissi, N; Hakobyan, S; Ramaglia, V; Geluk, A; Morgan, B Paul; Das, P Kumar; Baas, F

    2016-06-01

    Mycobacterium leprae infection gives rise to the immunologically and histopathologically classified spectrum of leprosy. At present, several tools for the stratification of patients are based on acquired immunity markers. However, the role of innate immunity, particularly the complement system, is largely unexplored. The present retrospective study was undertaken to explore whether the systemic levels of complement activation components and regulators can stratify leprosy patients, particularly in reference to the reactional state of the disease. Serum samples from two cohorts were analysed. The cohort from Bangladesh included multi-bacillary (MB) patients with (n = 12) or without (n = 46) reaction (R) at intake and endemic controls (n = 20). The cohort from Ethiopia included pauci-bacillary (PB) (n = 7) and MB (n = 23) patients without reaction and MB (n = 15) patients with reaction. The results showed that the activation products terminal complement complex (TCC) (P ≤ 0·01), C4d (P ≤ 0·05) and iC3b (P ≤ 0·05) were specifically elevated in Bangladeshi patients with reaction at intake compared to endemic controls. In addition, levels of the regulator clusterin (P ≤ 0·001 without R; P < 0·05 with R) were also elevated in MB patients, irrespective of a reaction. Similar analysis of the Ethiopian cohort confirmed that, irrespective of a reaction, serum TCC levels were increased significantly in patients with reactions compared to patients without reactions (P ≤ 0·05). Our findings suggests that serum TCC levels may prove to be a valuable tool in diagnosing patients at risk of developing reactions. © 2016 British Society for Immunology.

  3. Mice with Sort1 deficiency display normal cognition but elevated anxiety-like behavior.

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    Ruan, Chun-Sheng; Yang, Chun-Rui; Li, Jia-Yi; Luo, Hai-Yun; Bobrovskaya, Larisa; Zhou, Xin-Fu

    2016-07-01

    Exposure to stressful life events plays a central role in the development of mood disorders in vulnerable individuals. However, the mechanisms that link mood disorders to stress are poorly understood. Brain-derived neurotrophic factor (BDNF) has long been implicated in positive regulation of depression and anxiety, while its precursor (proBDNF) recently showed an opposing effect on such mental illnesses. P75(NTR) and sortilin are co-receptors of proBDNF, however, the role of these receptors in mood regulation is not established. Here, we aimed to investigate the role of sortilin in regulating mood-related behaviors and its role in the proBDNF-mediated mood abnormality in mice. We found that sortilin was up-regulated in neocortex (by 78.3%) and hippocampus (by 111%) of chronically stressed mice as assessed by western blot analysis. These changes were associated with decreased mobility in the open field test and increased depression-like behavior in the forced swimming test. We also found that sortilin deficiency in mice resulted in hyperlocomotion in the open field test and increased anxiety-like behavior in both the open field and elevated plus maze tests. No depression-like behavior in the forced swimming test and no deficit in spatial cognition in the Morris water maze test were found in the Sort1-deficient mice. Moreover, the intracellular and extracellular levels of mature BDNF and proBDNF were not changed when sortilin was absent in vivo and in vitro. Finally, we found that both WT and Sort1-deficient mice injected with proBDNF in lateral ventricle displayed increased depression-like behavior in the forced swimming test but not anxiety-like behaviors in the open field and elevated plus maze tests. The present study suggests that sortilin functions as a negative regulator of mood performance and can be a therapeutic target for the treatment of mental illness. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

  4. Transgenic Mice Overexpressing Vitamin D Receptor (VDR) Show Anti-Inflammatory Effects in Lung Tissues.

    Science.gov (United States)

    Ishii, Masaki; Yamaguchi, Yasuhiro; Isumi, Kyoko; Ogawa, Sumito; Akishita, Masahiro

    2017-12-01

    Vitamin D insufficiency is increasingly recognized as a prevalent problem worldwide, especially in patients with a chronic lung disease. Chronic obstructive pulmonary disease (COPD) is a type of chronic inflammatory lung disease. Previous clinical studies have shown that COPD leads to low vitamin D levels, which further increase the severity of COPD. Vitamin D homeostasis represents one of the most important factors that potentially determine the severity of COPD. Nonetheless, the mechanisms underlying the anti-inflammatory effects of vitamin D receptor (VDR) in lung tissues are still unclear. To investigate the anti-inflammatory effects of VDR, we generated transgenic mice that show lung-specific VDR overexpression under the control of the surfactant protein C promoter (TG mice). The TG mice were used to study the expression patterns of proinflammatory cytokines using real-time polymerase chain reaction and immunohistochemistry. The TG mice had lower levels of T helper 1 (Th1)-related cytokines than wild-type (WT) mice did. No significant differences in the expression of Th2 cytokines were observed between TG and WT mice. This study is the first to achieve lung-specific overexpression of VDR in TG mice: an interesting animal model useful for studying the relation between airway cell inflammation and vitamin D signaling. VDR expression is an important factor that influences anti-inflammatory responses in lung tissues. Our results show the crucial role of VDR in anti-inflammatory effects in lungs; these data are potentially useful for the treatment or prevention of COPD.

  5. Obese Neuronal PPARγ Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility.

    Science.gov (United States)

    Fernandez, Marina O; Sharma, Shweta; Kim, Sun; Rickert, Emily; Hsueh, Katherine; Hwang, Vicky; Olefsky, Jerrold M; Webster, Nicholas J G

    2017-01-01

    The peroxisome-proliferator activated receptor γ (PPARγ) is expressed in the hypothalamus in areas involved in energy homeostasis and glucose metabolism. In this study, we created a deletion of PPARγ brain-knockout (BKO) in mature neurons in female mice to investigate its involvement in metabolism and reproduction. We observed that there was no difference in age at puberty onset between female BKOs and littermate controls, but the BKOs gave smaller litters when mated and fewer oocytes when ovulated. The female BKO mice had regular cycles but showed an increase in the number of cycles with prolonged estrus. The mice also had increased luteinizing hormone (LH) levels during the LH surge and histological examination showed hemorrhagic corpora lutea. The mice were challenged with a 60% high-fat diet (HFD). Metabolically, the female BKO mice showed normal body weight, glucose and insulin tolerance, and leptin levels but were protected from obesity-induced leptin resistance. The neuronal knockout also prevented the reduction in estrous cycles due to the HFD. Examination of ovarian histology showed a decrease in the number of primary and secondary follicles in both genotypes due to the HFD, but the BKO ovaries showed an increase in the number of hemorrhagic follicles. In summary, our results show that neuronal PPARγ is required for optimal female fertility but is also involved in the adverse effects of diet-induced obesity by creating leptin resistance potentially through induction of the repressor Socs3. Copyright © 2017 by the Endocrine Society.

  6. Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities.

    Science.gov (United States)

    Katayama, K; Yamada, K; Ornthanalai, V G; Inoue, T; Ota, M; Murphy, N P; Aruga, J

    2010-02-01

    Mutations in SLITRK1 are found in patients with Tourette's syndrome and trichotillomania. SLITRK1 encodes a transmembrane protein containing leucine-rich repeats that is produced predominantly in the nervous system. However, the role of this protein is largely unknown, except that it can modulate neurite outgrowth in vitro. To clarify the role of Slitrk1 in vivo, we developed Slitrk1-knockout mice and analyzed their behavioral and neurochemical phenotypes. Slitrk1-deficient mice exhibited elevated anxiety-like behavior in the elevated plus-maze test as well as increased immobility time in forced swimming and tail suspension tests. Neurochemical analysis revealed that Slitrk1-knockout mice had increased levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol. Administration of clonidine, an alpha2-adrenergic agonist that is frequently used to treat patients with Tourette's syndrome, attenuated the anxiety-like behavior of Slitrk1-deficient mice in the elevated plus-maze test. These results lead us to conclude that noradrenergic mechanisms are involved in the behavioral abnormalities of Slitrk1-deficient mice. Elevated anxiety due to Slitrk1 dysfunction may contribute to the pathogenesis of neuropsychiatric diseases such as Tourette's syndrome and trichotillomania.

  7. Isolating the role of elevated Phlda2 in asymmetric late fetal growth restriction in mice

    Directory of Open Access Journals (Sweden)

    Simon J. Tunster

    2014-10-01

    Full Text Available Pleckstrin homology-like domain family A member 2 (PHLDA2 is a maternally expressed imprinted gene whose elevated expression has been linked to fetal growth restriction in a number of human studies. In mice, Phlda2 negatively regulates placental growth and limits the accumulation of placental glycogen. We previously reported that a three-copy transgene spanning the Phlda2 locus drove a fetal growth restriction phenotype late in gestation, suggesting a causative role for PHLDA2 in human growth restriction. However, in this mouse model, Phlda2 was overexpressed by fourfold, alongside overexpression of a second imprinted gene, Slc22a18. Here, we genetically isolate the role of Phlda2 in driving late fetal growth restriction in mice. We furthermore show that this Phlda2-driven growth restriction is asymmetrical, with a relative sparing of the brain, followed by rapid catch-up growth after birth, classic features of placental insufficiency. Strikingly, fetal growth restriction showed strain-specific differences, being apparent on the 129S2/SvHsd (129 genetic background and absent on the C57BL6 (BL6 background. A key difference between these two strains is the placenta. Specifically, BL6 placentae possess a more extensive endocrine compartment and substantially greater stores of placental glycogen. Taken together, these data support a direct role for elevated Phlda2 in limiting fetal growth but also suggest that growth restriction only manifests when there is limited placental reserve. These findings should be taken into account in interpreting the results from human studies.

  8. A Valepotriate Fraction of Valeriana glechomifolia Shows Sedative and Anxiolytic Properties and Impairs Recognition But Not Aversive Memory in Mice

    Directory of Open Access Journals (Sweden)

    Natasha Maurmann

    2011-01-01

    Full Text Available Plants of the genus Valeriana (Valerianaceae are used in traditional medicine as a mild sedative, antispasmodic and tranquilizer in many countries. This study was undertaken to explore the neurobehavioral effects of systemic administration of a valepotriate extract fraction of known quantitative composition of Valeriana glechomifolia (endemic of southern Brazil in mice. Adult animals were treated with a single intraperitoneal injection of valepotriate fraction (VF in the concentrations of 1, 3 or 10 mg kg-1, or with vehicle in the pre-training period before each behavioral test. During the exploration of an open field, mice treated with 10 mg kg-1 of VF showed reduced locomotion and exploratory behavior. Although overall habituation sessions for locomotion and exploratory behavior among vehicle control and doses of VF were not affected, comparison between open-field and habituation sessions within each treatment showed that VF administration at 1 and 10 mg kg-1 impaired habituation. In the elevated plus-maze test, mice treated with VF (10 mg kg-1 showed a significant increase in the percentage of time spent in the open arms without significant effects in the number of total arm entries. VF at 3 mg kg-1 produced an impairment of novel-object recognition memory. In contrast, VF did not affect fear-related memory assessed in an inhibitory avoidance task. The results indicate that VF can have sedative effects and affect behavioral parameters related to recognition memory.

  9. Mice lacking hippocampal left-right asymmetry show non-spatial learning deficits.

    Science.gov (United States)

    Shimbo, Akihiro; Kosaki, Yutaka; Ito, Isao; Watanabe, Shigeru

    2018-01-15

    Left-right asymmetry is known to exist at several anatomical levels in the brain and recent studies have provided further evidence to show that it also exists at a molecular level in the hippocampal CA3-CA1 circuit. The distribution of N-methyl-d-aspartate (NMDA) receptor NR2B subunits in the apical and basal synapses of CA1 pyramidal neurons is asymmetrical if the input arrives from the left or right CA3 pyramidal neurons. In the present study, we examined the role of hippocampal asymmetry in cognitive function using β2-microglobulin knock-out (β2m KO) mice, which lack hippocampal asymmetry. We tested β2m KO mice in a series of spatial and non-spatial learning tasks and compared the performances of β2m KO and C57BL6/J wild-type (WT) mice. The β2m KO mice appeared normal in both spatial reference memory and spatial working memory tasks but they took more time than WT mice in learning the two non-spatial learning tasks (i.e., a differential reinforcement of lower rates of behavior (DRL) task and a straight runway task). The β2m KO mice also showed less precision in their response timing in the DRL task and showed weaker spontaneous recovery during extinction in the straight runway task. These results indicate that hippocampal asymmetry is important for certain characteristics of non-spatial learning. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Socially dominant mice in C57BL6 background show increased social motivation.

    Science.gov (United States)

    Kunkel, Thaddeus; Wang, Hongbing

    2018-01-15

    A series of behavioral tests measuring social dominance, social motivation, and non-social motivation are examined in adult male C57BL6 mice. By using the well-known tube dominance test to determine social dominance and rank, we find that, in the absence of competition for resource and mating, group-housed mouse cage-mates display stable and mostly linear and transitive social hierarchies. Mice with top and bottom social ranks are subjected to a three-chamber social interaction test to measure social motivation. The top ranked mice spend more time interacting with a stranger mouse than the bottom ranked mice, suggesting that social dominance may positively influence social motivation. When subjected to a novel environment, mice with different social ranks show similar locomotion and exploring activity in the open field test, suggesting no detectable difference in certain aspects of non-social motivation. These results demonstrate a behavioral correlation between social dominance and social motivation. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Ghrelin knockout mice show decreased voluntary alcohol consumption and reduced ethanol-induced conditioned place preference.

    Science.gov (United States)

    Bahi, Amine; Tolle, Virginie; Fehrentz, Jean-Alain; Brunel, Luc; Martinez, Jean; Tomasetto, Catherine-Laure; Karam, Sherif M

    2013-05-01

    Recent work suggests that stomach-derived hormone ghrelin receptor (GHS-R1A) antagonism may reduce motivational aspects of ethanol intake. In the current study we hypothesized that the endogenous GHS-R1A agonist ghrelin modulates alcohol reward mechanisms. For this purpose ethanol-induced conditioned place preference (CPP), ethanol-induced locomotor stimulation and voluntary ethanol consumption in a two-bottle choice drinking paradigm were examined under conditions where ghrelin and its receptor were blocked, either using ghrelin knockout (KO) mice or the specific ghrelin receptor (GHS-R1A) antagonist "JMV2959". We showed that ghrelin KO mice displayed lower ethanol-induced CPP than their wild-type (WT) littermates. Consistently, when injected during CPP-acquisition, JMV2959 reduced CPP-expression in C57BL/6 mice. In addition, ethanol-induced locomotor stimulation was lower in ghrelin KO mice. Moreover, GHS-R1A blockade, using JMV2959, reduced alcohol-stimulated locomotion only in WT but not in ghrelin KO mice. When alcohol consumption and preference were assessed using the two-bottle choice test, both genetic deletion of ghrelin and pharmacological antagonism of the GHS-R1A (JMV2959) reduced voluntary alcohol consumption and preference. Finally, JMV2959-induced reduction of alcohol intake was only observed in WT but not in ghrelin KO mice. Taken together, these results suggest that ghrelin neurotransmission is necessary for the stimulatory effect of ethanol to occur, whereas lack of ghrelin leads to changes that reduce the voluntary intake as well as conditioned reward by ethanol. Our findings reveal a major, novel role for ghrelin in mediating ethanol behavior, and add to growing evidence that ghrelin is a key mediator of the effects of multiple abused drugs. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Memory-impairing effects of local anesthetics in an elevated plus-maze test in mice

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    S.L. Blatt

    1998-04-01

    Full Text Available Post-training intracerebroventricular administration of procaine (20 µg/µl and dimethocaine (10 or 20 µg/µl, local anesthetics of the ester class, prolonged the latency (s in the retention test of male and female 3-month-old Swiss albino mice (25-35 g body weight; N = 140 in the elevated plus-maze (mean ± SEM for 10 male mice: control = 41.2 ± 8.1; procaine = 78.5 ± 10.3; 10 µg/µl dimethocaine = 58.7 ± 12.3; 20 µg/µl dimethocaine = 109.6 ± 5.73; for 10 female mice: control = 34.8 ± 5.8; procaine = 55.3 ± 13.4; 10 µg/µl dimethocaine = 59.9 ± 12.3 and 20 µg/µl dimethocaine = 61.3 ± 11.1. However, lidocaine (10 or 20 µg/µl, an amide class type of local anesthetic, failed to influence this parameter. Local anesthetics at the dose range used did not affect the motor coordination of mice exposed to the rota-rod test. These results suggest that procaine and dimethocaine impair some memory process(es in the plus-maze test. These findings are interpreted in terms of non-anesthetic mechanisms of action of these drugs on memory impairment and also confirm the validity of the elevated plus-maze for the evaluation of drugs affecting learning and memory in mice

  13. Brain mitochondria from DJ-1 knockout mice show increased respiration-dependent hydrogen peroxide consumption

    Directory of Open Access Journals (Sweden)

    Pamela Lopert

    2014-01-01

    Full Text Available Mutations in the DJ-1 gene have been shown to cause a rare autosomal-recessive genetic form of Parkinson’s disease (PD. The function of DJ-1 and its role in PD development has been linked to multiple pathways, however its exact role in the development of PD has remained elusive. It is thought that DJ-1 may play a role in regulating reactive oxygen species (ROS formation and overall oxidative stress in cells through directly scavenging ROS itself, or through the regulation of ROS scavenging systems such as glutathione (GSH or thioredoxin (Trx or ROS producing complexes such as complex I of the electron transport chain. Previous work in this laboratory has demonstrated that isolated brain mitochondria consume H2O2 predominantly by the Trx/Thioredoxin Reductase (TrxR/Peroxiredoxin (Prx system in a respiration dependent manner (Drechsel et al., Journal of Biological Chemistry, 2010. Therefore we wanted to determine if mitochondrial H2O2 consumption was altered in brains from DJ-1 deficient mice (DJ-1−/−. Surprisingly, DJ-1−/− mice showed an increase in mitochondrial respiration-dependent H2O2 consumption compared to controls. To determine the basis of the increased H2O2 consumption in DJ1−/− mice, the activities of Trx, Thioredoxin Reductase (TrxR, GSH, glutathione disulfide (GSSG and glutathione reductase (GR were measured. Compared to control mice, brains from DJ-1−/− mice showed an increase in (1 mitochondrial Trx activity, (2 GSH and GSSG levels and (3 mitochondrial glutaredoxin (GRX activity. Brains from DJ-1−/− mice showed a decrease in mitochondrial GR activity compared to controls. The increase in the enzymatic activities of mitochondrial Trx and total GSH levels may account for the increased H2O2 consumption observed in the brain mitochondria in DJ-1−/− mice perhaps as an adaptive response to chronic DJ-1 deficiency.

  14. Nav 1.8-null mice show stimulus-dependent deficits in spinal neuronal activity

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    Wood John N

    2006-02-01

    Full Text Available Abstract Background The voltage gated sodium channel Nav 1.8 has a highly restricted expression pattern to predominantly nociceptive peripheral sensory neurones. Behaviourally Nav 1.8-null mice show an increased acute pain threshold to noxious mechanical pressure and also deficits in inflammatory and visceral, but not neuropathic pain. Here we have made in vivo electrophysiology recordings of dorsal horn neurones in intact anaesthetised Nav 1.8-null mice, in response to a wide range of stimuli to further the understanding of the functional roles of Nav 1.8 in pain transmission from the periphery to the spinal cord. Results Nav 1.8-null mice showed marked deficits in the coding by dorsal horn neurones to mechanical, but not thermal, -evoked responses over the non-noxious and noxious range compared to littermate controls. Additionally, responses evoked to other stimulus modalities were also significantly reduced in Nav 1.8-null mice where the reduction observed to pinch > brush. The occurrence of ongoing spontaneous neuronal activity was significantly less in mice lacking Nav 1.8 compared to control. No difference was observed between groups in the evoked activity to electrical activity of the peripheral receptive field. Conclusion This study demonstrates that deletion of the sodium channel Nav 1.8 results in stimulus-dependent deficits in the dorsal horn neuronal coding to mechanical, but not thermal stimuli applied to the neuronal peripheral receptive field. This implies that Nav 1.8 is either responsible for, or associated with proteins involved in mechanosensation.

  15. The influence of elevated endogenous free radical production on apoptosis and genomic instability in transgenic growth hormone mice

    International Nuclear Information System (INIS)

    Lemon, J.A.; Rollo, D.; Boreham, D.R.

    2003-01-01

    Full text: Previous studies have shown transgenic growth hormone mice (TGM) have significantly elevated levels of endogenous reactive oxygen species (ROS) and lipid peroxidation, shortened lifespan (approximately 50% of normal siblings), greatly enhanced learning in youth, and accelerated aging with a rapid age-related loss of cognitive abilities. A complex oral antioxidant supplement was found to completely abolish the cognitive decline and significantly extend longevity in TGM. We have determined in a recently completed experiment studying radiation-induced apoptosis that the antioxidant supplement significantly reduces the elevated level of apoptosis seen in untreated old TGM compared to age-matched controls. It was also determined that older normal mice treated with the supplement also show a reduction in apoptosis. We are conducting experiments using spectral karyotyping to examine genomic instability in TGM and their normal siblings, that indicate, given their elevated ROS, TGM show an increase in chromosome aberrations compared to normal controls. Based on our previous experiments we speculate that TGM treated with the antioxidant supplement are expected to show a reduction in ROS induced chromosome aberrations

  16. Elevation of endogenous anandamide impairs LTP, learning, and memory through CB1 receptor signaling in mice.

    Science.gov (United States)

    Basavarajappa, Balapal S; Nagre, Nagaraja N; Xie, Shan; Subbanna, Shivakumar

    2014-07-01

    In rodents, many exogenous and endogenous cannabinoids, such as anandamide (AEA) and 2-arachidonyl glycerol (2-AG), have been shown to play an important role in certain hippocampal memory processes. However, the mechanisms by which endogenous AEA regulate this processes are not well understood. Here the effects of AEA on long-term potentiation (LTP), hippocampal-dependent learning and memory tasks, pERK1/2, pCaMKIV, and pCREB signaling events in both cannabinoid receptor type 1 (CB1R) wild-type (WT) and knockout (KO) mice were assessed following administration of URB597, an inhibitor of the fatty acid amide hydrolase (FAAH). Acute administration of URB597 enhanced AEA levels without affecting the levels of 2-AG or CB1R in the hippocampus and neocortex as compared to vehicle. In hippocampal slices, URB597 impaired LTP in CB1R WT but not in KO littermates. URB597 impaired object recognition, spontaneous alternation and spatial memory in the Y-maze test in CB1R WT mice but not in KO mice. Furthermore, URB597 enhanced ERK phosphorylation in WT without affecting total ERK levels in WT or KO mice. URB597 impaired CaMKIV and CREB phosphorylation in WT but not in KO mice. CB1R KO mice have a lower pCaMKIV/CaMKIV ratio and higher pCREB/CREB ratio as compared to WT littermates. Our results indicate that pharmacologically elevated AEA impair LTP, learning and memory and inhibit CaMKIV and CREB phosphorylation, via the activation of CB1Rs. Collectively, these findings also suggest that pharmacological elevation of AEA beyond normal concentrations is also detrimental for the underlying physiological responses. © 2014 Wiley Periodicals, Inc.

  17. Mice lacking pituitary tumor transforming gene show elevated exposure of DGalNAc carbohydrate determinants

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    Lutsyk A. D.

    2012-04-01

    Full Text Available Aim. To investigate the influence of pituitary tumor transforming gene (pttg-1 knockout on glycome of parenchimal organs by means of lectin histochemistry. Methods. DGalNAc, DGlcNAc, NeuNAc carbohydrate determinants were labelled with soybean agglutinin (SBA and wheat germ agglutinin (WGA, conjugated to peroxidase, with subsequent visualization of the lectin-binding sites with diaminobenzidine. The testes and kidneys of murine strain BL6/C57 with the pttg-1 gene knockout (PTTG-KO were compared to the wild type (PTTG-WT animals, both groups 1 month of age. Results. Knockout of the pttg-1 gene was accompanied by enhanced exposure of the DGalNAc sugar residues within the Golgi complex of secondary spermatocytes, in a brush border of renal tubules and on the lumenal surface of collecting ducts. Conclusions. This study suggests that knockout of the pttg-1 gene may lead to the changes in carbohydrate processing in mammalian organism.

  18. Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction

    Science.gov (United States)

    Lygate, Craig A.; Bohl, Steffen; ten Hove, Michiel; Faller, Kiterie M.E.; Ostrowski, Philip J.; Zervou, Sevasti; Medway, Debra J.; Aksentijevic, Dunja; Sebag-Montefiore, Liam; Wallis, Julie; Clarke, Kieran; Watkins, Hugh; Schneider, Jürgen E.; Neubauer, Stefan

    2012-01-01

    Aims Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia and heart failure. However, testing this hypothesis has not been possible since oral creatine supplementation is ineffectual at elevating myocardial creatine levels. We therefore used mice overexpressing creatine transporter in the heart (CrT-OE) to test for the first time whether elevated creatine is beneficial in clinically relevant disease models of heart failure and ischaemia/reperfusion (I/R) injury. Methods and results CrT-OE mice were selected for left ventricular (LV) creatine 20–100% above wild-type values and subjected to acute and chronic coronary artery ligation. Increasing myocardial creatine up to 100% was not detrimental even in ageing CrT-OE. In chronic heart failure, creatine elevation was neither beneficial nor detrimental, with no effect on survival, LV remodelling or dysfunction. However, CrT-OE hearts were protected against I/R injury in vivo in a dose-dependent manner (average 27% less myocardial necrosis) and exhibited greatly improved functional recovery following ex vivo I/R (59% of baseline vs. 29%). Mechanisms contributing to ischaemic protection in CrT-OE hearts include elevated PCr and glycogen levels and improved energy reserve. Furthermore, creatine loading in HL-1 cells did not alter antioxidant defences, but delayed mitochondrial permeability transition pore opening in response to oxidative stress, suggesting an additional mechanism to prevent reperfusion injury. Conclusion Elevation of myocardial creatine by 20–100% reduced myocardial stunning and I/R injury via pleiotropic mechanisms, suggesting CrT activation as a novel, potentially translatable target for cardiac protection from ischaemia. PMID:22915766

  19. Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear.

    Science.gov (United States)

    Xu, Meiyu; Li, Lina; Ohtsu, Hiroshi; Pittenger, Christopher

    2015-05-19

    Tics, such as are seen in Tourette syndrome (TS), are common and can cause profound morbidity, but they are poorly understood. Tics are potentiated by psychostimulants, stress, and sleep deprivation. Mutations in the gene histidine decarboxylase (Hdc) have been implicated as a rare genetic cause of TS, and Hdc knockout mice have been validated as a genetic model that recapitulates phenomenological and pathophysiological aspects of the disorder. Tic-like stereotypies in this model have not been observed at baseline but emerge after acute challenge with the psychostimulant d-amphetamine. We tested the ability of an acute stressor to stimulate stereotypies in this model, using tone fear conditioning. Hdc knockout mice acquired conditioned fear normally, as manifested by freezing during the presentation of a tone 48h after it had been paired with a shock. During the 30min following tone presentation, knockout mice showed increased grooming. Heterozygotes exhibited normal freezing and intermediate grooming. These data validate a new paradigm for the examination of tic-like stereotypies in animals without pharmacological challenge and enhance the face validity of the Hdc knockout mouse as a pathophysiologically grounded model of tic disorders. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Trigeminal ganglion neurons of mice show intracellular chloride accumulation and chloride-dependent amplification of capsaicin-induced responses.

    Directory of Open Access Journals (Sweden)

    Nicole Schöbel

    Full Text Available Intracellular Cl(- concentrations ([Cl(-](i of sensory neurons regulate signal transmission and signal amplification. In dorsal root ganglion (DRG and olfactory sensory neurons (OSNs, Cl(- is accumulated by the Na(+-K(+-2Cl(- cotransporter 1 (NKCC1, resulting in a [Cl(-](i above electrochemical equilibrium and a depolarizing Cl(- efflux upon Cl(- channel opening. Here, we investigate the [Cl(-](i and function of Cl(- in primary sensory neurons of trigeminal ganglia (TG of wild type (WT and NKCC1(-/- mice using pharmacological and imaging approaches, patch-clamping, as well as behavioral testing. The [Cl(-](i of WT TG neurons indicated active NKCC1-dependent Cl(- accumulation. Gamma-aminobutyric acid (GABA(A receptor activation induced a reduction of [Cl(-](i as well as Ca(2+ transients in a corresponding fraction of TG neurons. Ca(2+ transients were sensitive to inhibition of NKCC1 and voltage-gated Ca(2+ channels (VGCCs. Ca(2+ responses induced by capsaicin, a prototypical stimulus of transient receptor potential vanilloid subfamily member-1 (TRPV1 were diminished in NKCC1(-/- TG neurons, but elevated under conditions of a lowered [Cl(-](o suggesting a Cl(--dependent amplification of capsaicin-induced responses. Using next generation sequencing (NGS, we found expression of different Ca(2+-activated Cl(- channels (CaCCs in TGs of mice. Pharmacological inhibition of CaCCs reduced the amplitude of capsaicin-induced responses of TG neurons in Ca(2+ imaging and electrophysiological recordings. In a behavioral paradigm, NKCC1(-/- mice showed less avoidance of the aversive stimulus capsaicin. In summary, our results strongly argue for a Ca(2+-activated Cl(--dependent signal amplification mechanism in TG neurons that requires intracellular Cl(- accumulation by NKCC1 and the activation of CaCCs.

  1. Dryland biological soil crust cyanobacteria show unexpected decreases in abundance under long-term elevated CO2

    Science.gov (United States)

    Steven, Blaire; Gallegos-Graves, La Verne; Yeager, Chris M.; Belnap, Jayne; Evans, R. David; Kuske, Cheryl R.

    2012-01-01

    Biological soil crusts (biocrusts) cover soil surfaces in many drylands globally. The impacts of 10 years of elevated atmospheric CO2 on the cyanobacteria in biocrusts of an arid shrubland were examined at a large manipulated experiment in Nevada, USA. Cyanobacteria-specific quantitative PCR surveys of cyanobacteria small-subunit (SSU) rRNA genes suggested a reduction in biocrust cyanobacterial biomass in the elevated CO2 treatment relative to the ambient controls. Additionally, SSU rRNA gene libraries and shotgun metagenomes showed reduced representation of cyanobacteria in the total microbial community. Taxonomic composition of the cyanobacteria was similar under ambient and elevated CO2 conditions, indicating the decline was manifest across multiple cyanobacterial lineages. Recruitment of cyanobacteria sequences from replicate shotgun metagenomes to cyanobacterial genomes representing major biocrust orders also suggested decreased abundance of cyanobacteria sequences across the majority of genomes tested. Functional assignment of cyanobacteria-related shotgun metagenome sequences indicated that four subsystem categories, three related to oxidative stress, were differentially abundant in relation to the elevated CO2 treatment. Taken together, these results suggest that elevated CO2 affected a generalized decrease in cyanobacteria in the biocrusts and may have favoured cyanobacteria with altered gene inventories for coping with oxidative stress.

  2. Elevated carbon monoxide in the exhaled breath of mice during a systemic bacterial infection.

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    Alan G Barbour

    Full Text Available Blood is the specimen of choice for most laboratory tests for diagnosis and disease monitoring. Sampling exhaled breath is a noninvasive alternative to phlebotomy and has the potential for real-time monitoring at the bedside. Improved instrumentation has advanced breath analysis for several gaseous compounds from humans. However, application to small animal models of diseases and physiology has been limited. To extend breath analysis to mice, we crafted a means for collecting nose-only breath samples from groups and individual animals who were awake. Samples were subjected to gas chromatography and mass spectrometry procedures developed for highly sensitive analysis of trace volatile organic compounds (VOCs in the atmosphere. We evaluated the system with experimental systemic infections of severe combined immunodeficiency Mus musculus with the bacterium Borrelia hermsii. Infected mice developed bacterial densities of ∼10(7 per ml of blood by day 4 or 5 and in comparison to uninfected controls had hepatosplenomegaly and elevations of both inflammatory and anti-inflammatory cytokines. While 12 samples from individual infected mice on days 4 and 5 and 6 samples from uninfected mice did not significantly differ for 72 different VOCs, carbon monoxide (CO was elevated in samples from infected mice, with a mean (95% confidence limits effect size of 4.2 (2.8-5.6, when differences in CO2 in the breath were taken into account. Normalized CO values declined to the uninfected range after one day of treatment with the antibiotic ceftriaxone. Strongly correlated with CO in the breath were levels of heme oxygenase-1 protein in serum and HMOX1 transcripts in whole blood. These results (i provide further evidence of the informativeness of CO concentration in the exhaled breath during systemic infection and inflammation, and (ii encourage evaluation of this noninvasive analytic approach in other various other rodent models of infection and for utility in

  3. Coumarin Compounds of Biebersteinia Multifida Roots Show Potential Anxiolytic Effects In Mice

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    Hamid Reza Monsef-Esfahani

    2013-06-01

    Full Text Available Background:Traditional preparations of the root of Biebersteinia multifida DC (Geraniaceae, a native medicinal plant of Irano-Turanian floristic region, have been used for the treatment of phobias as anxiolytic herbal preparation.Methods:We utilized the phobic behavior of mice in an elevated plus-maze as a model to evaluate the anxiolytic effect of the plant extract and bio-guided fractionation was applied to isolate the active compounds. Total root extract, alkaline and ether fraction were administered to mice at different doses 30 and 90 min prior to the maze test. Saline and diazepam were administered as negative and positive controls, respectively. The time spent in open and closed arms, an index of anxiety behavior and entry time, was measured as an index of animal activity.Results:The total root extract exhibited anxiolytic effect which was comparable to diazepam but with longer duration. This sustained effect of the crude extract was sustained for 90 min and was even more after injection of 45 mg/kg while the effect of diazepam had been reduced by 90 min. The anxiolytic effect factor was only present in the alkaline fraction and displayed its effect at lower doses than diazepam while pure vasicinone as the previously known alkaloid did not shown anxiolytic effect. The effect of the alkaline fraction was in a dose dependent manner starting at 0.2 mg/kg with a maximum at 1.0 mg/kg. Bio-guided fractionation using a variety of chromatographic methods led to isolation and purification of three coumarin derivatives from the bioactive fraction, including umbelliferone, scopoletin, and ferulic acid.Conclusion:For the first time, bio-guided fractionation of the root extract of B. multifida indicates significant sustained anxiolytic effects which led to isolation of three coumarin derivatives with well-known potent MAO inhibitory and anti-anxiety effects. These data contribute to evidence-based traditional use of B. multifida root for anxiety

  4. Two Genetically Similar H9N2 Influenza A Viruses Show Different Pathogenicity in Mice

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    Qingtao Liu

    2016-11-01

    Full Text Available H9N2 Avian influenza virus has repeatedly infected humans and other mammals, which highlights the need to determine the pathogenicity and the corresponding mechanism of this virus for mammals. In this study, we found two H9N2 viruses with similar genetic background but with different pathogenicity in mice. The A/duck/Nanjing/06/2003 (NJ06 virus was highly pathogenic for mice, with a 50% mouse lethal dose of 102.83 50% egg infectious dose, whereas the A/duck/Nanjing/01/1999 (NJ01 virus was low pathogenic for mice, with a 50% mouse lethal dose of >106.81 50% egg infectious dose. Further studies showed that the NJ06 virus grew faster and reached significantly higher titers than NJ01 in vivo and in vitro. Moreover, the NJ06 virus induced more severe lung lesions, and higher levels of inflammatory cellular infiltration and cytokine response in lungs than NJ01 did. However, only twelve different amino acid residues (HA-K157E, NA-A9T, NA-R435K, PB2-T149P, PB2-K627E, PB1-R187K, PA-L548M, PA-M550L, NP-G127E, NP-P277H, NP-D340N, NS1-D171N were found between the two viruses, and all these residues except for NA-R435K were located in the known functional regions involved in interaction of viral proteins or between the virus and host factors. Summary, our results suggest that multiple amino acid differences may be responsible for the higher pathogenicity of the NJ06 virus for mice, resulting in lethal infection, enhanced viral replication, severe lung lesions, and excessive inflammatory cellular infiltration and cytokine response in lungs. These observations will be helpful for better understanding the pathogenic potential and the corresponding molecular basis of H9N2 viruses that might pose threats to human health in the future.

  5. AβPP/PS1 Transgenic Mice Show Sex Differences in the Cerebellum Associated with Aging.

    Science.gov (United States)

    Ordoñez-Gutierrez, Lara; Fernandez-Perez, Ivan; Herrera, Jose Luis; Anton, Marta; Benito-Cuesta, Irene; Wandosell, Francisco

    2016-09-06

    Cerebellar pathology has been related to presenilin 1 mutations in certain pedigrees of familial Alzheimer's disease. However, cerebellum tissue has not been intensively analyzed in transgenic models of mutant presenilins. Furthermore, the effect of the sex of the mice was not systematically analyzed, despite the fact that important gender differences in the evolution of the disease in the human population have been described. We analyzed whether the progression of amyloidosis in a double transgenic mouse, AβPP/PS1, is susceptible to aging and differentially affects males and females. The accumulation of amyloid in the cerebellum differentially affects males and females of the AβPP/PS1 transgenic line, which was found to be ten-fold higher in 15-month-old females. Amyloid-β accumulation was more evident in the molecular layer of the cerebellum, but glia reaction was only observed in the granular layer of the older mice. The sex divergence was also observed in other neuronal, survival, and autophagic markers. The cerebellum plays an important role in the evolution of the pathology in this transgenic mouse model. Sex differences could be crucial for a complete understanding of this disease. We propose that the human population could be studied in this way. Sex-specific treatment strategies in human populations could show a differential response to the therapeutic approach.

  6. SOD1 aggregation in ALS mice shows simplistic test tube behavior.

    Science.gov (United States)

    Lang, Lisa; Zetterström, Per; Brännström, Thomas; Marklund, Stefan L; Danielsson, Jens; Oliveberg, Mikael

    2015-08-11

    A longstanding challenge in studies of neurodegenerative disease has been that the pathologic protein aggregates in live tissue are not amenable to structural and kinetic analysis by conventional methods. The situation is put in focus by the current progress in demarcating protein aggregation in vitro, exposing new mechanistic details that are now calling for quantitative in vivo comparison. In this study, we bridge this gap by presenting a direct comparison of the aggregation kinetics of the ALS-associated protein superoxide dismutase 1 (SOD1) in vitro and in transgenic mice. The results based on tissue sampling by quantitative antibody assays show that the SOD1 fibrillation kinetics in vitro mirror with remarkable accuracy the spinal cord aggregate buildup and disease progression in transgenic mice. This similarity between in vitro and in vivo data suggests that, despite the complexity of live tissue, SOD1 aggregation follows robust and simplistic rules, providing new mechanistic insights into the ALS pathology and organism-level manifestation of protein aggregation phenomena in general.

  7. Elevated prostacyclin biosynthesis in mice impacts memory and anxiety-like behavior.

    Science.gov (United States)

    Vollert, Craig; Ohia, Odochi; Akasaka, Hironari; Berridge, Casey; Ruan, Ke-He; Eriksen, Jason L

    2014-01-01

    Prostacyclin is an endogenous lipid metabolite with properties of vasodilation and anti-platelet aggregation. While the effects of prostacyclin on the vascular protection have been well-documented, the role of this eicosanoid in the central nervous system has not been extensively studied. Recently, a transgenic mouse containing a hybrid enzyme, of cyclooxygenase-1 linked to prostacyclin synthase, was developed that produces elevated levels of prostacyclin in vivo. The goal of this study was to investigate whether increased prostacyclin biosynthesis could affect behavioral phenotypes in mice. Our results uncovered that elevated levels of prostacyclin broadly affect both cognitive and non-cognitive behaviors, including decreased anxiety-like behavior and improved learning in the fear-conditioning memory test. This study demonstrates that prostacyclin plays an important, but previously unrecognized, role in central nervous system function and behavior. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. BACE1 elevation engendered by GGA3 deletion increases β-amyloid pathology in association with APP elevation and decreased CHL1 processing in 5XFAD mice.

    Science.gov (United States)

    Kim, WonHee; Ma, Liang; Lomoio, Selene; Willen, Rachel; Lombardo, Sylvia; Dong, Jinghui; Haydon, Philip G; Tesco, Giuseppina

    2018-02-02

    β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in the production of amyloid beta (Aβ), the toxic peptide that accumulates in the brains of Alzheimer's disease (AD) patients. Our previous studies have shown that the clathrin adaptor Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) plays a key role in the trafficking of BACE1 to lysosomes, where it is normally degraded. GGA3 depletion results in BACE1 stabilization both in vitro and in vivo. Moreover, levels of GGA3 are reduced and inversely related to BACE1 levels in post-mortem brains of AD patients. In order to assess the effect of GGA3 deletion on AD-like phenotypes, we crossed GGA3 -/- mice with 5XFAD mice. BACE1-mediated processing of APP and the cell adhesion molecule L1 like protein (CHL1) was measured as well as levels of Aβ42 and amyloid burden. In 5XFAD mice, we found that hippocampal and cortical levels of GGA3 decreased while BACE1 levels increased with age, similar to what is observed in human AD brains. GGA3 deletion prevented age-dependent elevation of BACE1 in GGA3KO;5XFAD mice. We also found that GGA3 deletion resulted in increased hippocampal levels of Aβ42 and amyloid burden in 5XFAD mice at 12 months of age. While levels of BACE1 did not change with age and gender in GGAKO;5XFAD mice, amyloid precursor protein (APP) levels increased with age and were higher in female mice. Moreover, elevation of APP was associated with a decreased BACE1-mediated processing of CHL1 not only in 12 months old 5XFAD mice but also in human brains from subjects affected by Down syndrome, most likely due to substrate competition. This study demonstrates that GGA3 depletion is a leading candidate mechanism underlying elevation of BACE1 in AD. Furthermore, our findings suggest that BACE1 inhibition could exacerbate mechanism-based side effects in conditions associated with APP elevation (e.g. Down syndrome) owing to impairment of BACE1-mediated processing of CHL1

  9. ELEVATED TRANS-MAMMARY TRANSMISSION OF Toxocara canis LARVAE IN BALB/c MICE

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    Paula de Lima Telmo

    2015-02-01

    Full Text Available Toxocariasis is a widespread zoonosis and is considered an important worldwide public health problem. The aim of this study was to investigate the frequency of trans-mammary Toxocara canis infection in newborn BALB/c mice nursed by females experimentally infected with 1,200 eggs after delivery. After 50 days of age, the presence of larvae in different organs of the offspring was investigated. Trans-mammary infection was confirmed in 73.9% of the mice that had been nursed by infected females. These data show a high trans-mammary transmission of T. canis and confirm the significance of this transmission route in paratenic hosts.

  10. Hes1-deficient mice show precocious differentiation of Paneth cells in the small intestine

    International Nuclear Information System (INIS)

    Suzuki, Katsumasa; Fukui, Hirokazu; Kayahara, Takahisa; Sawada, Mitsutaka; Seno, Hiroshi; Hiai, Hiroshi; Kageyama, Ryoichiro; Okano, Hideyuki; Chiba, Tsutomu

    2005-01-01

    We have previously shown that Hes1 is expressed both in putative epithelial stem cells just above Paneth cells and in the crypt base columnar cells between Paneth cells, while Hes1 is completely absent in Paneth cells. This study was undertaken to clarify the role of Hes1 in Paneth cell differentiation, using Hes1-knockout (KO) newborn (P0) mice. Electron microscopy revealed premature appearance of distinct cells containing cytoplasmic granules in the intervillous region in Hes1-KO P0 mice, whereas those cells were absent in wild-type (WT) P0 mice. In Hes1-KO P0 mice, the gene expressions of cryptdins, exclusively present in Paneth cells, were all enhanced compared with WT P0 mice. Immunohistochemistry demonstrated increased number of both lysozyme-positive and cryptdin-4-positive cells in the small intestinal epithelium of Hes1-KO P0 mice as compared to WT P0 mice. Thus, Hes1 appears to have an inhibitory role in Paneth cell differentiation in the small intestine

  11. Dietary linoleic acid elevates endogenous 2-arachidonoylglycerol and anandamide in Atlantic salmon (Salmo salar L.) and mice, and induces weight gain and inflammation in mice

    DEFF Research Database (Denmark)

    Alvheim, Anita R.; Torstensen, Bente E.; Lin, Yu Hong

    2013-01-01

    , arachidonic acid (AA), decreased EPA and DHA, elevated the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), and increased TAG accumulation in the salmon liver. In mice, the SO salmon diet increased LA and AA and decreased EPA and DHA in the liver and erythrocyte phospholipids, and elevated......Dietary intake of linoleic acid (LA) has increased dramatically during the twentieth century and is associated with a greater prevalence of obesity. Vegetable oils are recognised as suitable alternatives to fish oil (FO) in feed for Atlantic salmon (Salmo salar L.) but introduce high amounts of LA......-inflammatory properties of EPA and DHA in mice....

  12. Live tissue imaging shows reef corals elevate pH under their calcifying tissue relative to seawater.

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    Alexander Venn

    Full Text Available The threat posed to coral reefs by changes in seawater pH and carbonate chemistry (ocean acidification raises the need for a better mechanistic understanding of physiological processes linked to coral calcification. Current models of coral calcification argue that corals elevate extracellular pH under their calcifying tissue relative to seawater to promote skeleton formation, but pH measurements taken from the calcifying tissue of living, intact corals have not been achieved to date. We performed live tissue imaging of the reef coral Stylophora pistillata to determine extracellular pH under the calcifying tissue and intracellular pH in calicoblastic cells. We worked with actively calcifying corals under flowing seawater and show that extracellular pH (pHe under the calicoblastic epithelium is elevated by ∼0.5 and ∼0.2 pH units relative to the surrounding seawater in light and dark conditions respectively. By contrast, the intracellular pH (pHi of the calicoblastic epithelium remains stable in the light and dark. Estimates of aragonite saturation states derived from our data indicate the elevation in subcalicoblastic pHe favour calcification and may thus be a critical step in the calcification process. However, the observed close association of the calicoblastic epithelium with the underlying crystals suggests that the calicoblastic cells influence the growth of the coral skeleton by other processes in addition to pHe modification. The procedure used in the current study provides a novel, tangible approach for future investigations into these processes and the impact of environmental change on the cellular mechanisms underpinning coral calcification.

  13. A 10-Day Developmental Voyage: Converging Evidence from Three Studies Showing that Self-Esteem May Be Elevated and Maintained without Negative Outcomes

    Science.gov (United States)

    Kafka, S.; Hunter, J. A.; Hayhurst, J.; Boyes, M.; Thomson, R. L.; Clarke, H.; Grocott, A. M.; Stringer, M.; O'Brien, K. S.

    2012-01-01

    Empirical evidence shows that educational experiences in the context of the outdoors lead to elevated self-esteem. Although elevated self-esteem is widely assumed to promote beneficial outcomes, recent evidence suggests that elevated self-esteem may also facilitate a variety of negative outcomes (i.e., increased prejudice, aggression, drug and…

  14. Elevated Hypothalamic Glucocorticoid Levels Are Associated With Obesity and Hyperphagia in Male Mice.

    Science.gov (United States)

    Sefton, Charlotte; Harno, Erika; Davies, Alison; Small, Helen; Allen, Tiffany-Jayne; Wray, Jonathan R; Lawrence, Catherine B; Coll, Anthony P; White, Anne

    2016-11-01

    Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects. The Gc receptor (GR) is widely expressed throughout the body, including brain regions such as the hypothalamus. However, the extent to which chronic Gcs affect Gc concentrations in the hypothalamus and impact on GR and target genes is unknown. To investigate this, we used a murine model of corticosterone (Cort)-induced obesity and analyzed Cort levels in the hypothalamus and expression of genes relevant to Gc action. Mice were administered Cort (75 μg/mL) or ethanol (1%, vehicle) in drinking water for 4 weeks. Cort-treated mice had increased body weight, food intake, and adiposity. As expected, Cort increased plasma Cort levels at both zeitgeber time 1 and zeitgeber time 13, ablating the diurnal rhythm. Liquid chromatography dual tandem mass spectrometry revealed a 4-fold increase in hypothalamic Cort, which correlated with circulating levels and concentrations of Cort in other brain regions. This occurred despite decreased 11β-hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme that regenerates active Gcs, whereas efflux transporter Abcb1 mRNA was unaltered. In addition, although Cort decreased hypothalamic GR (Nr3c1) expression 2-fold, the Gc-induced leucine zipper (Tsc22d3) mRNA increased, which indicated elevated GR activation. In keeping with the development of hyperphagia and obesity, Cort increased Agrp, but there were no changes in Pomc, Npy, or Cart mRNA in the hypothalamus. In summary, chronic Cort treatment causes chronic increases in hypothalamic Cort levels and a persistent elevation in Agrp, a mediator in the development of metabolic disturbances.

  15. Socially disadvantaged city districts show a higher incidence of acute ST-elevation myocardial infarctions with elevated cardiovascular risk factors and worse prognosis.

    Science.gov (United States)

    Schmucker, J; Seide, S; Wienbergen, H; Fiehn, E; Stehmeier, J; Günther, K; Ahrens, W; Hambrecht, R; Pohlabeln, H; Fach, A

    2017-09-22

    The importance of socioeconomic status (SES) for coronary heart disease (CHD)-morbidity is subject of ongoing scientific investigations. This study was to explore the association between SES in different city-districts of Bremen/Germany and incidence, severity, treatment modalities and prognosis for patients with ST-elevation myocardial infarctions (STEMI). Since 2006 all STEMI-patients from the metropolitan area of Bremen are documented in the Bremen STEMI-registry. Utilizing postal codes of their home address they were assigned to four groups in accordance to the Bremen social deprivation-index (G1: high, G2: intermediate high, G3: intermediate low, G4: low socioeconomic status). Three thousand four hundred sixty-two consecutive patients with STEMI admitted between 2006 and 2015 entered analysis. City areas with low SES showed higher adjusted STEMI-incidence-rates (IR-ratio 1.56, G4 vs. G1). This elevation could be observed in both sexes (women IRR 1.63, men IRR 1.54) and was most prominent in inhabitants  3000 U/l, OR 1.95, 95% CI 1.4-2.8) and severe impairment of LV-function post-STEMI (OR 2.0, 95% CI 1.2-3.4). Long term follow-up revealed that lower SES was associated with higher major adverse cardiac or cerebrovascular event (MACCE)-rates after 5 years: G1 30.8%, G2 35.7%, G3 36.0%, G4 41.1%, p (for trend) = 0.02. This worse prognosis could especially be shown for young STEMI-patients (<50 yrs. of age) 5-yr. mortality-rates(G4 vs. G1) 18.4 vs. 3.1%, p = 0.03 and 5-year-MACCE-rates (G4 vs. G1) 32 vs. 6.3%, p = 0.02. This registry-data confirms the negative association of low socioeconomic status and STEMI-incidence, with higher rates of smoking and obesity, more extensive infarctions and worse prognosis for the socio-economically deprived.

  16. Functional measures show improvements after a home exercise program following supervised balance training in older adults with elevated fall risk.

    Science.gov (United States)

    Tisher, Kristen; Mann, Kimberly; VanDyke, Sarah; Johansson, Charity; Vallabhajosula, Srikant

    2018-03-05

    Supervised balance training shows immediate benefit for older adults at fall risk. The long-term effectiveness of such training can be enhanced by implementing a safe and simple home exercise program (HEP). We investigated the effects of a12-week unsupervised HEP following supervised clinic-based balance training on functional mobility, balance, fall risk, and gait. Six older adults with an elevated fall risk obtained an HEP and comprised the HEP group (HEPG) and five older adults who were not given an HEP comprised the no HEP group (NoHEPG). The HEP consisted of three static balance exercises: feet-together, single-leg stance, and tandem. Each exercise was to be performed twice for 30-60 s, once per day, 3 days per week for 12 weeks. Participants were educated on proper form, safety, and progression of exercises. Pre- and post-HEP testing included Berg Balance Scale (BBS), Timed Up and Go, Short Physical Performance Battery (SPPB) assessments, Activities-Balance Confidence, Late-Life Functional Disability Instrument and instrumented assessments of balance and gait (Limits of Stability, modified Clinical Test of Sensory Interaction on Balance, Gait). A healthy control group (HCG; n = 11) was also tested. For most of the measures, the HEPG improved to the level of HCG. Though task-specific improvements like BBS and SPPB components were seen, the results did not carry over to more dynamic assessments. Results provide proof of concept that a simple HEP can be independently implemented and effective for sustaining and/or improving balance in older adults at elevated fall-risk after they have undergone a clinic-based balance intervention.

  17. Akita spontaneously type 1 diabetic mice exhibit elevated vascular arginase and impaired vascular endothelial and nitrergic function.

    Science.gov (United States)

    Toque, Haroldo A; Nunes, Kenia P; Yao, Lin; Xu, Zhimin; Kondrikov, Dmitry; Su, Yunchao; Webb, R Clinton; Caldwell, Ruth B; Caldwell, R William

    2013-01-01

    Elevated arginase (Arg) activity is reported to be involved in diabetes-induced vascular endothelial dysfunction. It can reduce L-arginine availability to nitric oxide (NO) synthase (NOS) and NO production. Akita mice, a genetic non-obese type 1 diabetes model, recapitulate human diabetes. We determined the role of Arg in a time-course of diabetes-associated endothelial dysfunction in aorta and corpora cavernosa (CC) from Akita mice. Endothelium-dependent relaxation, Arg and NOS activity, and protein expression levels of Arg and constitutive NOS were assessed in aortas and CC from Akita and non-diabetic wild type (WT) mice at 4, 12 and 24 wks of age. Systolic blood pressure (SBP) was assessed by tail cuff. In aorta and CC, Akita mice exhibited a progressive impairment of vascular endothelial and nitrergic function increased Arg activity and expression (Arg1 in aorta and both Arg1 and Arg2 in CC) compared with that of age-matched WT mice. Treatment of aorta and CC from Akita mice with an Arg inhibitor (BEC or ABH) reduced diabetes-induced elevation of Arg activity and restored endothelial and nitrergic function. Reduced levels of phospho-eNOS at Ser(1177) (in aorta and CC) and nNOS expression (in CC) were observed in Akita mice at 12 and 24 wks. Akita mice also had decreased NOS activity in aorta and CC at 12 and 24 wks that was restored by BEC treatment. Further, Akita mice exhibited moderately increased SBP at 24 wks and increased sensitivity to PE-induced contractions in aorta and sympathetic nerve stimulation in CC at 12 and 24 wks. Over 24 wks of diabetes in Akita mice, both aortic and cavernosal tissues exhibited increased Arg activity/expression, contributing to impaired endothelial and nitrergic function and reduced NO production. Our findings demonstrate involvement of Arg activity in diabetes-induced impairment of vascular function in Akita mouse.

  18. Akita spontaneously type 1 diabetic mice exhibit elevated vascular arginase and impaired vascular endothelial and nitrergic function.

    Directory of Open Access Journals (Sweden)

    Haroldo A Toque

    Full Text Available Elevated arginase (Arg activity is reported to be involved in diabetes-induced vascular endothelial dysfunction. It can reduce L-arginine availability to nitric oxide (NO synthase (NOS and NO production. Akita mice, a genetic non-obese type 1 diabetes model, recapitulate human diabetes. We determined the role of Arg in a time-course of diabetes-associated endothelial dysfunction in aorta and corpora cavernosa (CC from Akita mice.Endothelium-dependent relaxation, Arg and NOS activity, and protein expression levels of Arg and constitutive NOS were assessed in aortas and CC from Akita and non-diabetic wild type (WT mice at 4, 12 and 24 wks of age. Systolic blood pressure (SBP was assessed by tail cuff. In aorta and CC, Akita mice exhibited a progressive impairment of vascular endothelial and nitrergic function increased Arg activity and expression (Arg1 in aorta and both Arg1 and Arg2 in CC compared with that of age-matched WT mice. Treatment of aorta and CC from Akita mice with an Arg inhibitor (BEC or ABH reduced diabetes-induced elevation of Arg activity and restored endothelial and nitrergic function. Reduced levels of phospho-eNOS at Ser(1177 (in aorta and CC and nNOS expression (in CC were observed in Akita mice at 12 and 24 wks. Akita mice also had decreased NOS activity in aorta and CC at 12 and 24 wks that was restored by BEC treatment. Further, Akita mice exhibited moderately increased SBP at 24 wks and increased sensitivity to PE-induced contractions in aorta and sympathetic nerve stimulation in CC at 12 and 24 wks.Over 24 wks of diabetes in Akita mice, both aortic and cavernosal tissues exhibited increased Arg activity/expression, contributing to impaired endothelial and nitrergic function and reduced NO production. Our findings demonstrate involvement of Arg activity in diabetes-induced impairment of vascular function in Akita mouse.

  19. Interleukin-18 gene-deficient mice show enhanced defense and reduced inflammation during pneumococcal meningitis

    NARCIS (Netherlands)

    Zwijnenburg, Petra J. G.; van der Poll, Tom; Florquin, Sandrine; Akira, Shizuo; Takeda, Kiyoshi; Roord, John J.; van Furth, A. Marceline

    2003-01-01

    To determine the role of endogenous interleukin-18 (IL-18) in pneumococcal meningitis, meningitis was induced in IL-18 gene-deficient (IL-18(-/-)) and wild-type (WT) mice by intranasal inoculation of Streptococcus pneumoniae with hyaluronidase. Induction of meningitis resulted in an upregulation of

  20. Mu-opioid receptor knockout mice show diminished food-anticipatory activity

    NARCIS (Netherlands)

    Kas, Martien J H; van den Bos, Ruud; Baars, Annemarie M; Lubbers, Marianne; Lesscher, Heidi M B; Hillebrand, Jacquelien J G; Schuller, Alwin G; Pintar, John E; Spruijt, Berry M

    We have previously suggested that during or prior to activation of anticipatory behaviour to a coming reward, mu-opioid receptors are activated. To test this hypothesis schedule induced food-anticipatory activity in mu-opioid receptor knockout mice was measured using running wheels. We hypothesized

  1. Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation

    DEFF Research Database (Denmark)

    Chidgey, M; Brakebusch, C; Gustafsson, E

    2001-01-01

    epidermis because environmental insults are more stringent and wound healing is less rapid than in neonatal mice. This dermatitis is accompanied by localized hair loss associated with formation of utriculi and dermal cysts, denoting hair follicle degeneration. Possible resemblance of the lesions to human...

  2. Interleukin-18 gene-deficient mice show enhanced defense and reduced inflammation during pneumococcal meningitis.

    NARCIS (Netherlands)

    Zwijnenburg, P.J.G.; Poll, van der T.; Florquin, S; Akira, S; Takeda, K; Roord, J.J.; Furth, van A.M.

    2003-01-01

    To determine the role of endogenous interleukin-18 (IL-18) in pneumococcal meningitis, meningitis was induced in IL-18 gene-deficient (IL-18(-/-)) and wild-type (WT) mice by intranasal inoculation of Streptococcus pneumoniae with hyaluronidase. Induction of meningitis resulted in an upregulation of

  3. Characterization of Peripheral Activity States and Cortical Local Field Potentials of Mice in an Elevated Plus Maze Test.

    Science.gov (United States)

    Okonogi, Toya; Nakayama, Ryota; Sasaki, Takuya; Ikegaya, Yuji

    2018-01-01

    Elevated plus maze (EPM) tests have been used to assess animal anxiety levels. Little information is known regarding how physiological activity patterns of the brain-body system are altered during EPM tests. Herein, we monitored cortical local field potentials (LFPs), electrocardiograms (ECGs), electromyograms (EMGs), and respiratory signals in individual mice that were repeatedly exposed to EPM tests. On average, mouse heart rates were higher in open arms. In closed arms, the mice occasionally showed decreased heart and respiratory rates lasting for several seconds or minutes, characterized as low-peripheral activity states of peripheral signals. The low-activity states were observed only when the animals were in closed arms, and the frequencies of the states increased as the testing days proceeded. During the low-activity states, the delta and theta powers of cortical LFPs were significantly increased and decreased, respectively. These results demonstrate that cortical oscillations crucially depend on whether an animal exhibits low-activity states in peripheral organs rather than the EPM arm in which the animal is located. These results suggest that combining behavioral tests with physiological makers enables a more accurate evaluation of rodent mental states.

  4. Characterization of Peripheral Activity States and Cortical Local Field Potentials of Mice in an Elevated Plus Maze Test

    Directory of Open Access Journals (Sweden)

    Toya Okonogi

    2018-04-01

    Full Text Available Elevated plus maze (EPM tests have been used to assess animal anxiety levels. Little information is known regarding how physiological activity patterns of the brain-body system are altered during EPM tests. Herein, we monitored cortical local field potentials (LFPs, electrocardiograms (ECGs, electromyograms (EMGs, and respiratory signals in individual mice that were repeatedly exposed to EPM tests. On average, mouse heart rates were higher in open arms. In closed arms, the mice occasionally showed decreased heart and respiratory rates lasting for several seconds or minutes, characterized as low-peripheral activity states of peripheral signals. The low-activity states were observed only when the animals were in closed arms, and the frequencies of the states increased as the testing days proceeded. During the low-activity states, the delta and theta powers of cortical LFPs were significantly increased and decreased, respectively. These results demonstrate that cortical oscillations crucially depend on whether an animal exhibits low-activity states in peripheral organs rather than the EPM arm in which the animal is located. These results suggest that combining behavioral tests with physiological makers enables a more accurate evaluation of rodent mental states.

  5. Female Nur77-deficient mice show increased susceptibility to diet-induced obesity.

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    Sonia Perez-Sieira

    Full Text Available Adipose tissue is essential in the regulation of body weight. The key process in fat catabolism and the provision of energy substrate during times of nutrient deprivation or enhanced energy demand is the hydrolysis of triglycerides and the release of fatty acids and glycerol. Nur77 is a member of the NR4A subfamily of nuclear receptors that plays an important metabolic role, modulating hepatic glucose metabolism and lipolysis in muscle. However, its endogenous role on white adipose tissue, as well as the gender dependency of these mechanisms, remains largely unknown. Male and female wild type and Nur77 deficient mice were fed with a high fat diet (45% calories from fat for 4 months. Mice were analyzed in vivo with the indirect calorimetry system, and tissues were analyzed by real-time PCR and Western blot analysis. Female, but not male Nur77 deficient mice, gained more weight and fat mass when compared to wild type mice fed with high fat diet, which can be explained by decreased energy expenditure. The lack of Nur77 also led to a decreased pHSL/HSL ratio in white adipose tissue and increased expression of CIDEA in brown adipose tissue of female Nur77 deficient mice. Overall, these findings suggest that Nur77 is an important physiological modulator of lipid metabolism in adipose tissue and that there are gender differences in the sensitivity to deletion of the Nur77 signaling. The decreased energy expenditure and the actions of Nur77 on liver, muscle, brown and white adipose tissue contribute to the increased susceptibility to diet-induced obesity in females lacking Nur77.

  6. Adolescent mice show anxiety- and aggressive-like behavior and the reduction of long-term potentiation in mossy fiber-CA3 synapses after neonatal maternal separation.

    Science.gov (United States)

    Shin, S Y; Han, S H; Woo, R-S; Jang, S H; Min, S S

    2016-03-01

    Exposure to maternal separation (MS) during early life is an identified risk factor for emotional disorders such as anxiety and depression later in life. This study investigated the effects of neonatal MS on the behavior and long-term potentiation (LTP) as well as basic synaptic transmission at hippocampal CA3-CA1 and mossy fiber (MF)-CA3 synapses in adolescent mice for 19days. When mice were adolescents, we measured depression, learning, memory, anxious and aggressive behavior using the forced swimming test (FST), Y-maze, Morris water maze (MWM), elevated plus maze (EPM), three consecutive days of the open field test, the social interaction test, the tube-dominance test and the resident-intruder test. The results showed that there was no difference in FST, Y-maze, and MWM performance. However, MS mice showed more anxiety-like behavior in the EPM test and aggressive-like behavior in the tube-dominance and resident-intruder tests. In addition, the magnitude of LTP and release probability in the MF-CA3 synapses was reduced in the MS group but not in the CA3-CA1 synapse. Our results indicate that early life stress due to MS may induce anxiety- and aggressive-like behavior during adolescence, and these effects are associated with synaptic plasticity at the hippocampal MF-CA3 synapses. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. ASIC1a Deficient Mice Show Unaltered Neurodegeneration in the Subacute MPTP Model of Parkinson Disease.

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    Daniel Komnig

    Full Text Available Inflammation contributes to the death of dopaminergic neurons in Parkinson disease and can be accompanied by acidification of extracellular pH, which may activate acid-sensing ion channels (ASIC. Accordingly, amiloride, a non-selective inhibitor of ASIC, was protective in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of Parkinson disease. To complement these findings we determined MPTP toxicity in mice deficient for ASIC1a, the most common ASIC isoform in neurons. MPTP was applied i.p. in doses of 30 mg per kg on five consecutive days. We determined the number of dopaminergic neurons in the substantia nigra, assayed by stereological counting 14 days after the last MPTP injection, the number of Nissl positive neurons in the substantia nigra, and the concentration of catecholamines in the striatum. There was no difference between ASIC1a-deficient mice and wildtype controls. We are therefore not able to confirm that ASIC1a are involved in MPTP toxicity. The difference might relate to the subacute MPTP model we used, which more closely resembles the pathogenesis of Parkinson disease, or to further targets of amiloride.

  8. Mice with cancer-induced bone pain show a marked decline in day/night activity.

    Science.gov (United States)

    Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T; Kuskowski, Michael A; Mantyh, Patrick W

    2017-09-01

    Cancer-induced bone pain (CIBP) is the most common type of pain with cancer. In humans, this pain can be difficult to control and highly disabling. A major problem with CIBP in humans is that it increases on weight-bearing and/or movement of a tumor-bearing bone limiting the activity and functional status of the patient. Currently, there is less data concerning whether similar negative changes in activity occur in rodent models of CIBP. To determine whether there are marked changes in activity in a rodent model of CIBP and compare this to changes in skin hypersensitivity. Osteosarcoma cells were injected and confined to 1 femur of the adult male mouse. Every 7 days, spontaneous horizontal and vertical activities were assessed over a 20-hour day and night period using automated activity boxes. Mechanical hypersensitivity of the hind paw skin was assessed using von Frey testing. As the tumor cells grew within the femur, there was a significant decline in horizontal and vertical activity during the times of the day/night when the mice are normally most active. Mice also developed significant hypersensitivity in the skin of the hind paw in the tumor-bearing limb. Even when the tumor is confined to a single load-bearing bone, CIBP drives a significant loss of activity, which increases with disease progression. Understanding the mechanisms that drive this reduction in activity may allow the development of therapies that allow CIBP patients to better maintain their activity and functional status.

  9. Atp1a3-deficient heterozygous mice show lower rank in the hierarchy and altered social behavior.

    Science.gov (United States)

    Sugimoto, H; Ikeda, K; Kawakami, K

    2017-10-23

    Atp1a3 is the Na-pump alpha3 subunit gene expressed mainly in neurons of the brain. Atp1a3-deficient heterozygous mice (Atp1a3 +/- ) show altered neurotransmission and deficits of motor function after stress loading. To understand the function of Atp1a3 in a social hierarchy, we evaluated social behaviors (social interaction, aggression, social approach and social dominance) of Atp1a3 +/- and compared the rank and hierarchy structure between Atp1a3 +/- and wild-type mice within a housing cage using the round-robin tube test and barbering observations. Formation of a hierarchy decreases social conflict and promote social stability within the group. The hierarchical rank is a reflection of social dominance within a cage, which is heritable and can be regulated by specific genes in mice. Here we report: (1) The degree of social interaction but not aggression was lower in Atp1a3 +/- than wild-type mice, and Atp1a3 +/- approached Atp1a3 +/- mice more frequently than wild type. (2) The frequency of barbering was lower in the Atp1a3 +/- group than in the wild-type group, while no difference was observed in the mixed-genotype housing condition. (3) Hierarchy formation was not different between Atp1a3 +/- and wild type. (4) Atp1a3 +/- showed a lower rank in the mixed-genotype housing condition than that in the wild type, indicating that Atp1a3 regulates social dominance. In sum, Atp1a3 +/- showed unique social behavior characteristics of lower social interaction and preference to approach the same genotype mice and a lower ranking in the hierarchy. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  10. Elevate Anterior/Apical: 12-Month Data Showing Safety and Efficacy in Surgical Treatment of Pelvic Organ Prolapse

    NARCIS (Netherlands)

    Stanford, Edward J.; Moore, Robert D.; Roovers, Jan-Paul W. R.; Courtieu, Christophe; Lukban, James C.; Bataller, Eduardo; Liedl, Bernhard; Sutherland, Suzette E.

    2013-01-01

    Objective: This study aimed to assess the safety and efficacy of the Elevate Anterior/Apical transvaginal mesh procedure in pelvic organ prolapse (POP) repair at 12-months follow-up. Methods: This prospective, multicenter, multinational study enrolled 142 patients experiencing anterior vaginal

  11. Intestinal microbiota shifts towards elevated commensal Escherichia coli loads abrogate colonization resistance against Campylobacter jejuni in mice.

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    Lea-Maxie Haag

    Full Text Available BACKGROUND: The zoonotic pathogen Campylobacter jejuni is a leading cause of bacterial foodborne enterocolitis in humans worldwide. The understanding of immunopathology underlying human campylobacteriosis is hampered by the fact that mice display strong colonization resistance against the pathogen due to their host specific gut microbiota composition. METHODOLOGY/PRINCIPAL FINDINGS: Since the microbiota composition changes significantly during intestinal inflammation we dissected factors contributing to colonization resistance against C. jejuni in murine ileitis, colitis and in infant mice. In contrast to healthy animals C. jejuni could stably colonize mice suffering from intestinal inflammation. Strikingly, in mice with Toxoplasma gondii-induced acute ileitis, C. jejuni disseminated to mesenteric lymphnodes, spleen, liver, kidney, and blood. In infant mice C. jejuni infection induced enterocolitis. Mice suffering from intestinal inflammation and C. jejuni susceptible infant mice displayed characteristical microbiota shifts dominated by increased numbers of commensal Escherichia coli. To further dissect the pivotal role of those distinct microbiota shifts in abrogating colonization resistance, we investigated C. jejuni infection in healthy adult mice in which the microbiota was artificially modified by feeding live commensal E. coli. Strikingly, in animals harboring supra-physiological intestinal E. coli loads, colonization resistance was significantly diminished and C. jejuni infection induced enterocolitis mimicking key features of human campylobacteriosis. CONCLUSION/SIGNIFICANCE: Murine colonization resistance against C. jejuni is abrogated by changes in the microbiota composition towards elevated E. coli loads during intestinal inflammation as well as in infant mice. Intestinal inflammation and microbiota shifts thus represent potential risk factors for C. jejuni infection. Corresponding interplays between C. jejuni and microbiota might

  12. Mice doubly-deficient in lysosomal hexosaminidase A and neuraminidase 4 show epileptic crises and rapid neuronal loss.

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    Volkan Seyrantepe

    2010-09-01

    Full Text Available Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts G(M2 to G(M3 ganglioside. Hexa(-/- mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise G(M2 ganglioside via a lysosomal sialidase into glycolipid G(A2, which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4(-/-;Hexa(-/- show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa(-/- or Neu4(-/- siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating G(M2 ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa(-/- mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa(-/- mice.

  13. Hearts of dystonia musculorum mice display normal morphological and histological features but show signs of cardiac stress.

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    Justin G Boyer

    2010-03-01

    Full Text Available Dystonin is a giant cytoskeletal protein belonging to the plakin protein family and is believed to crosslink the major filament systems in contractile cells. Previous work has demonstrated skeletal muscle defects in dystonin-deficient dystonia musculorum (dt mice. In this study, we show that the dystonin muscle isoform is localized at the Z-disc, the H zone, the sarcolemma and intercalated discs in cardiac tissue. Based on this localization pattern, we tested whether dystonin-deficiency leads to structural defects in cardiac muscle. Desmin intermediate filament, microfilament, and microtubule subcellular organization appeared normal in dt hearts. Nevertheless, increased transcript levels of atrial natriuretic factor (ANF, 66% beta-myosin heavy chain (beta-MHC, 95% and decreased levels of sarcoplasmic reticulum calcium pump isoform 2A (SERCA2a, 26%, all signs of cardiac muscle stress, were noted in dt hearts. Hearts from two-week old dt mice were assessed for the presence of morphological and histological alterations. Heart to body weight ratios as well as left ventricular wall thickness and left chamber volume measurements were similar between dt and wild-type control mice. Hearts from dt mice also displayed no signs of fibrosis or calcification. Taken together, our data provide new insights into the intricate structure of the sarcomere by situating dystonin in cardiac muscle fibers and suggest that dystonin does not significantly influence the structural organization of cardiac muscle fibers during early postnatal development.

  14. Anti-depressant and anxiolytic like behaviors in PKCI/HINT1 knockout mice associated with elevated plasma corticosterone level

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    Wang Jia

    2009-11-01

    Full Text Available Abstract Background Protein kinase C interacting protein (PKCI/HINT1 is a small protein belonging to the histidine triad (HIT family proteins. Its brain immunoreactivity is located in neurons and neuronal processes. PKCI/HINT1 gene knockout (KO mice display hyper-locomotion in response to D-amphetamine which is considered a positive symptom of schizophrenia in animal models. Postmortem studies identified PKCI/HINT1 as a candidate molecule for schizophrenia and bipolar disorder. We investigated the hypothesis that the PKCI/HINT1 gene may play an important role in regulating mood function in the CNS. We submitted PKCI/HINT1 KO mice and their wild type (WT littermates to behavioral tests used to study anti-depressant, anxiety like behaviors, and goal-oriented behavior. Additionally, as many mood disorders coincide with modifications of hypothalamic-pituitary-adrenal (HPA axis function, we assessed the HPA activity through measurement of plasma corticosterone levels. Results Compared to the WT controls, KO mice exhibited less immobility in the forced swim (FST and the tail suspension (TST tests. Activity in the TST tended to be attenuated by acute treatment with valproate at 300 mg/kg in KO mice. The PKCI/HINT1 KO mice presented less thigmotaxis in the Morris water maze and spent progressively more time in the lit compartment in the light/dark test. In a place navigation task, KO mice exhibited enhanced acquisition and retention. Furthermore, the afternoon basal plasma corticosterone level in PKCI/HINT1 KO mice was significantly higher than in the WT. Conclusion PKCI/HINT1 KO mice displayed a phenotype of behavioral and endocrine features which indicate changes of mood function, including anxiolytic-like and anti-depressant like behaviors, in conjunction with an elevated corticosterone level in plasma. These results suggest that the PKCI/HINT 1 gene could be important for the mood regulation function in the CNS.

  15. Female mice deficient in alpha-fetoprotein show female-typical neural responses to conspecific-derived pheromones.

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    Olivier Brock

    Full Text Available The neural mechanisms controlling sexual behavior are sexually differentiated by the perinatal actions of sex steroid hormones. We recently observed using female mice deficient in alpha-fetoprotein (AFP-KO and which lack the protective actions of AFP against maternal estradiol, that exposure to prenatal estradiol completely defeminized the potential to show lordosis behavior in adulthood. Furthermore, AFP-KO females failed to show any male-directed mate preferences following treatment with estradiol and progesterone, indicating a reduced sexual motivation to seek out the male. In the present study, we asked whether neural responses to male- and female-derived odors are also affected in AFP-KO female mice. Therefore, we compared patterns of Fos, the protein product of the immediate early gene, c-fos, commonly used as a marker of neuronal activation, between wild-type (WT and AFP-KO female mice following exposure to male or estrous female urine. We also tested WT males to confirm the previously observed sex differences in neural responses to male urinary odors. Interestingly, AFP-KO females showed normal, female-like Fos responses, i.e. exposure to urinary odors from male but not estrous female mice induced equivalent levels of Fos protein in the accessory olfactory pathways (e.g. the medial part of the preoptic nucleus, the bed nucleus of the stria terminalis, the amygdala, and the lateral part of the ventromedial hypothalamic nucleus as well as in the main olfactory pathways (e.g. the piriform cortex and the anterior cortical amygdaloid nucleus, as WT females. By contrast, WT males did not show any significant induction of Fos protein in these brain areas upon exposure to either male or estrous female urinary odors. These results thus suggest that prenatal estradiol is not involved in the sexual differentiation of neural Fos responses to male-derived odors.

  16. Elevation of blood levels of zinc protoporphyrin in mice following whole-body irradiation

    International Nuclear Information System (INIS)

    Walden, T.L. Jr.

    1983-01-01

    Elevation of zinc protoporphyrin (ZPP) levels in the blood has served as an indicator of lead poisoning and iron deficiency anemia for many years. The author has discovered that sublethal doses of whole body irradiation with X-rays also elevates ZPP two- to three-fold over normal levels. The ZPP level does not begin to increase until days 12 to 14 post-irradiation and peaks between days 18 to 20 before returning to normal levels between days 28 to 35. Increasing the radiation dose delays the onset of the rise in ZPP but does not affect the magnitude of the elevation. At lethal doses, ZPP elevation is not observed. Neither of the two previously described mechanisms which cause elevations of ZPP, namely iron deficiency and inhibition of ferrochelatase, are responsible for the radiation induced elevation of ZPP. The elevation of ZPP appears to be correlated with the recovery of the hematopoietic system from radiation injury

  17. The elevation of blood levels of zinc protoporphyrin in mice following whole body irradiation

    International Nuclear Information System (INIS)

    Walden, T.L.; Draganac, P.S.; Farkas, W.R.

    1984-01-01

    Elevation of zinc protoporphyrin (ZPP) levels in the blood has served as an indicator of lead poisoning and iron deficiency anemia for many years. We have discovered that sublethal doses of whole body irradiation with x-rays also elevates ZPP 2-3-fold over normal levels. The ZPP level does not begin to increase until days 12-14 postirradiation and peaks between days 18 and 20 before returning to normal levels between days 28 and 35. Increasing the radiation dose delays the onset of the rise in ZPP, but does not affect the magnitude of the elevation. At lethal doses, ZPP elevation is not observed. Neither of the two previously described mechanisms that cause elevations of ZPP, namely iron deficiency and inhibition of ferrochelatase, are responsible for the radiation-induced elevation of ZPP. The elevation of ZPP appears to be correlated with the recovery of the hematopoietic system from radiation injury

  18. HIV-1 Nef mutations abrogating downregulation of CD4 affect other Nef functions and show reduced pathogenicity in transgenic mice

    International Nuclear Information System (INIS)

    Hanna, Zaher; Priceputu, Elena; Hu, Chunyan; Vincent, Patrick; Jolicoeur, Paul

    2006-01-01

    HIV-1 Nef has the ability to downmodulate CD4 cell surface expression. Several studies have shown that CD4 downregulation is required for efficient virus replication and high infectivity. However, the pathophysiological relevance of this phenomenon in vivo, independently of its role in sustaining high virus loads, remains unclear. We studied the impact of the CD4 downregulation function of Nef on its pathogenesis in vivo, in the absence of viral replication, in the CD4C/HIV transgenic (Tg) mouse model. Two independent Nef mutants (RD35/36AA and D174K), known to abrogate CD4 downregulation, were tested in Tg mice. Flow cytometry analysis showed that downregulation of murine CD4 was severely decreased or abrogated on Tg T cells expressing respectively Nef RD35/36AA and Nef D174K . Similarly, the severe depletion of double-positive CD4 + CD8 + and of single-positive CD4 + CD8 - thymocytes, usually observed with Nef Wt , was not detected in Nef RD35/36AA and Nef D174K Tg mice. However, both mutant Tg mice showed a partial depletion of peripheral CD4 + T cells. This was accompanied, as previously reported for Net Wt Tg mice, by the presence of an activated/memory-like phenotype (CD69 + , CD25 + , CD44 + , CD45RB Low , CD62 Low ) of CD4 + T cells expressing Nef RD35/36AA and to a lesser extent Nef D174K . In addition, both mutants retained the ability to block CD4 + T cell proliferation in vitro after anti-CD3 stimulation, but not to enhance apoptosis/death of CD4 + T cells. Therefore, it appears that Nef-mediated CD4 downregulation is associated with thymic defects, but segregates independently of the activated/memory-like phenotype, of the partial depletion and of the impaired in vitro proliferation of peripheral CD4 + T cells. Histopathological assessment revealed the total absence of or decrease severity and frequency of organ AIDS-like diseases (lung, heart and kidney pathologies) in respectively Nef RD35/36AA and Nef D174K Tg mice, relative to those developing in

  19. Ilexgenin A, a novel pentacyclic triterpenoid extracted from Aquifoliaceae shows reduction of LPS-induced peritonitis in mice.

    Science.gov (United States)

    Sun, Weidong; Liu, Chang; Zhang, Yaqi; Qiu, Xia; Zhang, Li; Zhao, Hongxia; Rong, Yi; Sun, Yun

    2017-02-15

    Ilexgenin A (IA) is a novel pentacyclic triterpenoid, which extracted from leaves of Ilex hainanensis Merr. In the present study, we aim to explore anti-inflammatory activity of IA on LPS-induced peritonitis and its underlying molecular mechanism. The results determined that IA was capable of suppressing peritonitis in mice induced by intraperitoneal (i.p.) injection of lipopolysaccaride (LPS). Furthermore, the results showed that IA dramatically inhibited levels of inflammatory cells infiltration in peritoneal cavity and serum in LPS-induced mice peritonitis model. Besides, IA could dramatically inhibit levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) in peritoneal cavity in LPS-induced mice peritonitis model. In vitro study, the results showed that IA inhibited production of IL-1β, IL-6 and TNF-α at transcriptional and translational levels in RAW 264.7 cells induced by LPS. Furthermore, IA could suppress the LPS-induced activation of Akt and downstream degradation and phosphorylation of kappa B-α (IκB-α). Moreover, IA could significantly inhibit ERK 1/2 phosphorylation in RAW 264.7 cells induced by LPS. These results were concurrent with molecular docking which revealed ERK1/2 inhibition. These results demonstrated that IA might as an anti-inflammatory agent candidate for inflammatory disease therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Zonulin transgenic mice show altered gut permeability and increased morbidity/mortality in the DSS colitis model.

    Science.gov (United States)

    Sturgeon, Craig; Lan, Jinggang; Fasano, Alessio

    2017-06-01

    Increased small intestinal permeability (IP) has been proposed to be an integral element, along with genetic makeup and environmental triggers, in the pathogenies of chronic inflammatory diseases (CIDs). We identified zonulin as a master regular of intercellular tight junctions linked to the development of several CIDs. We aim to study the role of zonulin-mediated IP in the pathogenesis of CIDs. Zonulin transgenic Hp2 mice (Ztm) were subjected to dextran sodium sulfate (DSS) treatment for 7 days, followed by 4-7 days' recovery and compared to C57Bl/6 (wild-type (WT)) mice. IP was measured in vivo and ex vivo, and weight, histology, and survival were monitored. To mechanistically link zonulin-dependent impairment of small intestinal barrier function with clinical outcome, Ztm were treated with the zonulin inhibitor AT1001 added to drinking water in addition to DSS. We observed increased morbidity (more pronounced weight loss and colitis) and mortality (40-70% compared with 0% in WT) at 11 days post-DSS treatment in Ztm compared with WT mice. Both in vivo and ex vivo measurements showed an increased IP at baseline in Ztm compared to WT mice, which was exacerbated by DSS treatment and was associated with upregulation of zonulin gene expression (fourfold in the duodenum, sixfold in the jejunum). Treatment with AT1001 prevented the DSS-induced increased IP both in vivo and ex vivo without changing zonulin gene expression and completely reverted morbidity and mortality in Ztm. Our data show that zonulin-dependent small intestinal barrier impairment is an early step leading to the break of tolerance with subsequent development of CIDs. © 2017 New York Academy of Sciences.

  1. High basal metabolic rate does not elevate oxidative stress during reproduction in laboratory mice.

    Science.gov (United States)

    Brzęk, Paweł; Książek, Aneta; Ołdakowski, Łukasz; Konarzewski, Marek

    2014-05-01

    Increased oxidative stress (OS) has been suggested as a physiological cost of reproduction. However, previous studies reported ambiguous results, with some even showing a reduction of oxidative damage during reproduction. We tested whether the link between reproduction and OS is mediated by basal metabolic rate (BMR), which has been hypothesized to affect both the rate of radical oxygen species production and antioxidative capacity. We studied the effect of reproduction on OS in females of laboratory mice divergently selected for high (H-BMR) and low (L-BMR) BMR, previously shown to differ with respect to parental investment. Non-reproducing L-BMR females showed higher oxidative damage to lipids (quantified as the level of malondialdehyde in internal organ tissues) and DNA (quantified as the level of 8-oxodG in blood serum) than H-BMR females. Reproduction did not affect oxidative damage to lipids in either line; however, it reduced damage to DNA in L-BMR females. Reproduction increased catalase activity in liver (significantly stronger in L-BMR females) and decreased it in kidneys. We conclude that the effect of reproduction on OS depends on the initial variation in BMR and varies between studied internal organs and markers of OS.

  2. Pomegranate (Punica granatum Juice Shows Antioxidant Activity against Cutaneous Leishmaniasis-Induced Oxidative Stress in Female BALB/c Mice

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    Badriah Alkathiri

    2017-12-01

    Full Text Available Leishmania species are parasites that multiply within phagocytes and cause several clinical diseases characterized by single or multiple ulcerations. One of the complications that can induce tissue damage and the resulting scars is caused by secondary bacterial infections. Studies to find new, effective, and safe oral drugs for treating leishmaniasis are being conducted since several decades, owing to the problems associated with the use of antimonials available. Previously, the antiparasitic and antioxidant properties of Punica granatum (pomegranate, P. granatum have been reported. Therefore, in the present study, we aimed to investigate the antileishmanial activity of pomegranate aqueous juice in vitro and in female BALB/c mice. A 3-(4.5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay in Leishmania major promastigotes and alterations in the antioxidant status, liver function, and skin histological changes in L. major-infected mice orally treated with pomegranate juice alone and in combination with the antibiotic ciprofloxacin, were used to investigate the in vitro and in vivo antileishmanial activity of pomegranate juice, respectively. Oral P. granatum juice treatment significantly reduced the average size of cutaneous leishmaniasis lesions compared with that of the untreated mice. This antileishmanial activity of P. granatum was associated with enhanced antioxidant enzyme activities. Histopathological evaluation proved the antileishmanial activity of P. granatum, but did not reveal changes in the treated animals, compared to the positive control. In conclusion, P. granatum shows high and fast antileishmanial activity probably by boosting the endogenous antioxidant activity.

  3. Pomegranate (Punica granatum) Juice Shows Antioxidant Activity against Cutaneous Leishmaniasis-Induced Oxidative Stress in Female BALB/c Mice.

    Science.gov (United States)

    Alkathiri, Badriah; El-Khadragy, Manal F; Metwally, Dina M; Al-Olayan, Ebtesam M; Bakhrebah, Muhammed A; Abdel Moneim, Ahmed E

    2017-12-18

    Leishmania species are parasites that multiply within phagocytes and cause several clinical diseases characterized by single or multiple ulcerations. One of the complications that can induce tissue damage and the resulting scars is caused by secondary bacterial infections. Studies to find new, effective, and safe oral drugs for treating leishmaniasis are being conducted since several decades, owing to the problems associated with the use of antimonials available. Previously, the antiparasitic and antioxidant properties of Punica granatum (pomegranate, P. granatum ) have been reported. Therefore, in the present study, we aimed to investigate the antileishmanial activity of pomegranate aqueous juice in vitro and in female BALB/c mice. A 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in Leishmania major promastigotes and alterations in the antioxidant status, liver function, and skin histological changes in L. major -infected mice orally treated with pomegranate juice alone and in combination with the antibiotic ciprofloxacin, were used to investigate the in vitro and in vivo antileishmanial activity of pomegranate juice, respectively. Oral P. granatum juice treatment significantly reduced the average size of cutaneous leishmaniasis lesions compared with that of the untreated mice. This antileishmanial activity of P. granatum was associated with enhanced antioxidant enzyme activities. Histopathological evaluation proved the antileishmanial activity of P. granatum , but did not reveal changes in the treated animals, compared to the positive control. In conclusion, P. granatum shows high and fast antileishmanial activity probably by boosting the endogenous antioxidant activity.

  4. Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice.

    Science.gov (United States)

    Zhang, Honghao; Kamiya, Nobuhiro; Tsuji, Takehito; Takeda, Haruko; Scott, Greg; Rajderkar, Sudha; Ray, Manas K; Mochida, Yoshiyuki; Allen, Benjamin; Lefebvre, Veronique; Hung, Irene H; Ornitz, David M; Kunieda, Tetsuo; Mishina, Yuji

    2016-12-01

    Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome.

  5. Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice.

    Directory of Open Access Journals (Sweden)

    Honghao Zhang

    2016-12-01

    Full Text Available Ellis-van Creveld (EvC syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN. While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome.

  6. Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice

    Science.gov (United States)

    Zhang, Honghao; Kamiya, Nobuhiro; Tsuji, Takehito; Takeda, Haruko; Scott, Greg; Ray, Manas K.; Mochida, Yoshiyuki; Lefebvre, Veronique; Hung, Irene H.; Kunieda, Tetsuo; Mishina, Yuji

    2016-01-01

    Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome. PMID:28027321

  7. Quercetin prevents pyrrolizidine alkaloid clivorine-induced liver injury in mice by elevating body defense capacity.

    Directory of Open Access Journals (Sweden)

    Lili Ji

    Full Text Available Quercetin is a plant-derived flavonoid that is widely distributed in nature. The present study is designed to analyze the underlying mechanism in the protection of quercetin against pyrrolizidine alkaloid clivorine-induced acute liver injury in vivo. Serum transaminases, total bilirubin analysis, and liver histological evaluation demonstrated the protection of quercetin against clivorine-induced liver injury. Terminal dUTP nick end-labeling assay demonstrated that quercetin reduced the increased amount of liver apoptotic cells induced by clivorine. Western-blot analysis of caspase-3 showed that quercetin inhibited the cleaved activation of caspase-3 induced by clivorine. Results also showed that quercetin reduced the increase in liver glutathione and lipid peroxidative product malondialdehyde induced by clivorine. Quercetin reduced the enhanced liver immunohistochemical staining for 4-hydroxynonenal induced by clivorine. Results of the Mouse Stress and Toxicity PathwayFinder RT2 Profiler PCR Array demonstrated that the expression of genes related with oxidative or metabolic stress and heat shock was obviously altered after quercetin treatment. Some of the alterations were confirmed by real-time PCR. Our results demonstrated that quercetin prevents clivorine-induced acute liver injury in vivo by inhibiting apoptotic cell death and ameliorating oxidative stress injury. This protection may be caused by the elevation of the body defense capacity induced by quercetin.

  8. Quercetin Prevents Pyrrolizidine Alkaloid Clivorine-Induced Liver Injury in Mice by Elevating Body Defense Capacity

    Science.gov (United States)

    Ji, Lili; Ma, Yibo; Wang, Zaiyong; Cai, Zhunxiu; Pang, Chun; Wang, Zhengtao

    2014-01-01

    Quercetin is a plant-derived flavonoid that is widely distributed in nature. The present study is designed to analyze the underlying mechanism in the protection of quercetin against pyrrolizidine alkaloid clivorine-induced acute liver injury in vivo. Serum transaminases, total bilirubin analysis, and liver histological evaluation demonstrated the protection of quercetin against clivorine-induced liver injury. Terminal dUTP nick end-labeling assay demonstrated that quercetin reduced the increased amount of liver apoptotic cells induced by clivorine. Western-blot analysis of caspase-3 showed that quercetin inhibited the cleaved activation of caspase-3 induced by clivorine. Results also showed that quercetin reduced the increase in liver glutathione and lipid peroxidative product malondialdehyde induced by clivorine. Quercetin reduced the enhanced liver immunohistochemical staining for 4-hydroxynonenal induced by clivorine. Results of the Mouse Stress and Toxicity PathwayFinder RT2 Profiler PCR Array demonstrated that the expression of genes related with oxidative or metabolic stress and heat shock was obviously altered after quercetin treatment. Some of the alterations were confirmed by real-time PCR. Our results demonstrated that quercetin prevents clivorine-induced acute liver injury in vivo by inhibiting apoptotic cell death and ameliorating oxidative stress injury. This protection may be caused by the elevation of the body defense capacity induced by quercetin. PMID:24905073

  9. Liver protein synthesis stays elevated after chemotherapy in tumour-bearing mice.

    Science.gov (United States)

    Samuels, Sue E; McLaren, Teresa A; Knowles, Andrew L; Stewart, Sarah A; Madelmont, Jean-Claude; Attaix, Didier

    2006-07-28

    We studied the effect of chemotherapy on liver protein synthesis in mice bearing colon 26 adenocarcinoma (C26). Liver protein mass decreased (-32%; Psynthesis increased (20-35%; Psynthesis. Increased protein synthesis in tumour-bearing mice was primarily mediated by increasing ( approximately 15%; Psynthesis (Cs; mg RNA/g protein). Cystemustine, a nitrosourea chemotherapy that cures C26 with 100% efficacy, rapidly restored liver protein mass; protein synthesis however stayed higher than in healthy mice ( approximately 15%) throughout the initial and later stages of recovery. Chemotherapy had no significant effect on liver protein mass and synthesis in healthy mice. Reduced food intake was not a factor in this model. These data suggest a high priority for liver protein synthesis during cancer cachexia and recovery.

  10. Chronic Toxoplasma gondii in Nurr1-Null Heterozygous Mice Exacerbates Elevated Open Field Activity

    OpenAIRE

    Eells, Jeffrey B.; Varela-Stokes, Andrea; Guo-Ross, Shirley X.; Kummari, Evangel; Smith, Holly M.; Cox, Erin; Lindsay, David S.

    2015-01-01

    Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population) and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%), genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/-) mice and wild-type (+/+) mice were evaluate using an emergence test, activity in an open fie...

  11. Collagen VII deficient mice show morphologic and histologic corneal changes that phenotypically mimic human dystrophic epidermolysis bullosa of the eye.

    Science.gov (United States)

    Chen, Vicki M; Shelke, Rajani; Nyström, Alexander; Laver, Nora; Sampson, James F; Zhiyi, Cao; Bhat, Najma; Panjwani, Noorjahan

    2018-06-16

    Absence of collagen VII causes blistering of the skin, eyes and many other tissues. This disease is termed dystrophic epidermolysis bullosa (DEB). Corneal fibrosis occurs in up to 41% and vision loss in up to 64% of patients. Standard treatments are supportive and there is no cure. The immune-histologic and morphologic changes in the corneas of the mouse model for this disease have not been described in the literature. Our purpose is to characterize the eyes of these mice to determine if this is an appropriate model for study of human therapeutics. Western blot analysis (WB) and immunohistochemistry (IHC) were performed to assess the relative collagen VII protein levels and its location within the cornea. Additional IHC for inflammatory and fibrotic biomarkers alpha-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), proteinase 3, tenascin C and collagen III were performed. Clinical photographs documenting opacification of the corneas of animals of differing ages were assessed and scored independently by 2 examiners. Histology was then used to investigate morphologic changes. IHC and WB confirmed that these mice are deficient in collagen VII production at the level of the basement membrane when compared with wild-types. IHC showed anomalous deposition of collagen III throughout the stroma. Of the 5 biomarkers tested, TGF-β showed the strongest and most consistently staining. Photographs documented corneal opacities only in mice older than 10 weeks, opacities were not seen in younger animals. Histology showed multiple abnormalities, including epithelial hyperplasia, ulceration, fibrosis, edema, dysplasia, neovascularization and bullae formation. The collagen VII hypomorphic mouse shows reduced collagen VII production at the level of the corneal basement membrane. Corneal changes are similar to pathology seen in humans with this disease. The presence of anomalous stromal collagen III and TGF-β appear to be

  12. Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine synergize to enhance haematopoietic reconstitution in irradiated mice

    Energy Technology Data Exchange (ETDEWEB)

    Pospisil, M.; Hofer, M.; Netikova, J.; Hola, J.; Vacek, A. [Academy of Sciences of the Czech Republic, Inst. of Biophysics, Brno (Czech Republic); Znojil, V.; Vacha, J. [Masaryk Univ., Medical Faculty, Brno (Czech Republic)

    1998-03-01

    The activation of adenosine receptors has recently been demonstrated to stimulate haematopoiesis. In the present study, we investigated the ability of drugs elevating extracellular adenosine to influence curative effects of granulocyte colony-stimulating factor (G-CSF) in mice exposed to a sublethal dose of 4 Gy of {sup 60}Co radiation. Elevation of extracellular adenosine in mice was induced by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug. The effects of dipyridamole plus AMP, and G-CSF, administered either alone or in combination, were evaluated. The drugs were injected to mice in a 4-d treatment regimen starting on d 3 after irradiation and the haematopoietic response was evaluated on d 7, 10, 14, 18 and 24 after irradiation. While the effects of G-CSF on the late maturation stages of blood cells, appearing shortly after the completion of the treatment, were not influenced by dipyridamole plus AMP, positive effects of the combination therapy occurred in the post-irradiation recovery phase which is dependent on the repopulation of haematopoietic stem cells. This was indicated by the significant elevation of counts of granulocyte-macrophage progenitor cells (GM-CFC) and granulocytic cells in the bone marrow (d 14), of GM-CFC (d 14), granulocytic and erythroid cells (d 14 and 18) in the spleen, and of neutrophils (d 18), monocytes (d 14 and 18) and platelets (d 18) in the peripheral blood. These effects suggest that the repopulation potential of the combination therapy lies in a common multi-lineage cell population. The results of this study implicate the promising possibility to enhance the curative effects of G-CSF under conditions of myelosuppressive state induced by radiation exposure. (au) 43 refs.

  13. Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine synergize to enhance haematopoietic reconstitution in irradiated mice

    International Nuclear Information System (INIS)

    Pospisil, M.; Hofer, M.; Netikova, J.; Hola, J.; Vacek, A.; Znojil, V.; Vacha, J.

    1998-01-01

    The activation of adenosine receptors has recently been demonstrated to stimulate haematopoiesis. In the present study, we investigated the ability of drugs elevating extracellular adenosine to influence curative effects of granulocyte colony-stimulating factor (G-CSF) in mice exposed to a sublethal dose of 4 Gy of 60 Co radiation. Elevation of extracellular adenosine in mice was induced by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug. The effects of dipyridamole plus AMP, and G-CSF, administered either alone or in combination, were evaluated. The drugs were injected to mice in a 4-d treatment regimen starting on d 3 after irradiation and the haematopoietic response was evaluated on d 7, 10, 14, 18 and 24 after irradiation. While the effects of G-CSF on the late maturation stages of blood cells, appearing shortly after the completion of the treatment, were not influenced by dipyridamole plus AMP, positive effects of the combination therapy occurred in the post-irradiation recovery phase which is dependent on the repopulation of haematopoietic stem cells. This was indicated by the significant elevation of counts of granulocyte-macrophage progenitor cells (GM-CFC) and granulocytic cells in the bone marrow (d 14), of GM-CFC (d 14), granulocytic and erythroid cells (d 14 and 18) in the spleen, and of neutrophils (d 18), monocytes (d 14 and 18) and platelets (d 18) in the peripheral blood. These effects suggest that the repopulation potential of the combination therapy lies in a common multi-lineage cell population. The results of this study implicate the promising possibility to enhance the curative effects of G-CSF under conditions of myelosuppressive state induced by radiation exposure. (au)

  14. Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.

    Science.gov (United States)

    Akman, Hasan O; Dorado, Beatriz; López, Luis C; García-Cazorla, Angeles; Vilà, Maya R; Tanabe, Lauren M; Dauer, William T; Bonilla, Eduardo; Tanji, Kurenai; Hirano, Michio

    2008-08-15

    Mitochondrial DNA (mtDNA) depletion syndrome (MDS), an autosomal recessive condition, is characterized by variable organ involvement with decreased mtDNA copy number and activities of respiratory chain enzymes in affected tissues. MtDNA depletion has been associated with mutations in nine autosomal genes, including thymidine kinase (TK2), which encodes a ubiquitous mitochondrial protein. To study the pathogenesis of TK2-deficiency, we generated mice harboring an H126N Tk2 mutation. Homozygous Tk2 mutant (Tk2(-/-)) mice developed rapidly progressive weakness after age 10 days and died between ages 2 and 3 weeks. Tk2(-/-) animals showed Tk2 deficiency, unbalanced dNTP pools, mtDNA depletion and defects of respiratory chain enzymes containing mtDNA-encoded subunits that were most prominent in the central nervous system. Histopathology revealed an encephalomyelopathy with prominent vacuolar changes in the anterior horn of the spinal cord. The H126N TK2 mouse is the first knock-in animal model of human MDS and demonstrates that the severity of TK2 deficiency in tissues may determine the organ-specific phenotype.

  15. Comprehensive behavioral analysis of Ox1r-/- mice showed implication of orexin receptor-1 in mood, anxiety and social behavior

    Directory of Open Access Journals (Sweden)

    Md Golam Abbas

    2015-12-01

    Full Text Available Neuropeptides orexin A and orexin B, which are exclusively produced by neurons in the lateral hypothalamic area, play an important role in the regulation of a wide range of behaviors and homeostatic processes, including regulation of sleep/wakefulness states and energy homeostasis. The orexin system has close anatomical and functional relationships with systems that regulate the autonomic nervous system, emotion, mood, the reward system and sleep/wakefulness states. Recent pharmacological studies using selective antagonists have suggested that orexin receptor-1 (OX1R is involved in physiological processes that regulate emotion, the reward system and autonomic nervous system. Here, we examined Ox1r-/- mice with a comprehensive behavioral test battery to screen additional OX1R functions. Ox1r-/- mice showed increased anxiety-like behavior, altered depression-like behavior, slightly decreased spontaneous locomotor activity, reduced social interaction, increased startle response and decreased prepulse inhibition. These results suggest that OX1R plays roles in social behaviour and sensory motor gating in addition to roles in mood and anxiety.

  16. Grain elevator workers show work-related pulmonary function changes and dose-effect relationships with dust exposure.

    Science.gov (United States)

    Corey, P; Hutcheon, M; Broder, I; Mintz, S

    1982-01-01

    The purpose of this study was to determine whether grain handlers underwent work-related changes in their pulmonary function and, if so, to examine the dose-effect relationships with dust exposure. The pulmonary function of grain handlers was measured at the beginning and end of work shifts over a period of one week, during which their exposure to dust was measured daily. The results showed changes indicative of a within-day obstructive change, in addition to a small restrictive defect occurring over the course of a week. Civic outside labourers who were examined as a control group showed a similar within-week obstructive change without any associated restriction of lung volume. The data on the grain handlers were also used to examine the dose-effect relationships of dust exposure, both on baseline pulmonary function and on within-day changes in these measurements. The baseline flow rates of workers who did not wear a mask were found to vary inversely with their average exposure to respirable dust. In addition, the flow rates underwent a within-day decrease that varied directly with their corresponding exposure to respirable dust and was unrelated to mask wearing. The median of the slopes for this relationship indicated that 50% of the subjects had a decrease of at least 923 ml/s in the value of their Vmax50%VC for each 1 mg/m3 increase in the concentration of respirable dust. Non-respirable dust did not have a measurable effect either on the baseline or the within-day changes in pulmonary function. The acute changes were unaffected by age, duration of employment, or extent of smoking. PMID:7138793

  17. Colitic scid mice fed Lactobacillus spp. show an ameliorated gut histopathology and an altered cytokine profile by local T cells

    DEFF Research Database (Denmark)

    Møller, Peter Lange; Paerregaard, Anders; Gad, Monika

    2005-01-01

    BACKGROUND: Scid mice transplanted with CD4 T blast cells develop colitis. We investigated if the disease was influenced in colitic mice treated with antibiotic and fed Lactobacillus spp. METHODS: Colitic scid mice were treated for 1 week with antibiotics (vancomycin/meropenem) followed or not fo......-gamma production than mice not fed probiotics. CONCLUSIONS: Our data suggest that probiotics added to the drinking water may ameliorate local histopathological changes and influence local cytokine levels in colitic mice but not alter the colitis-associated weight loss....

  18. Abstinent adult daily smokers show reduced anticipatory but elevated saccade-related brain responses during a rewarded antisaccade task.

    Science.gov (United States)

    Geier, Charles F; Sweitzer, Maggie M; Denlinger, Rachel; Sparacino, Gina; Donny, Eric C

    2014-08-30

    Chronic smoking may result in reduced sensitivity to non-drug rewards (e.g., money), a phenomenon particularly salient during abstinence. During a quit attempt, this effect may contribute to biased decision-making (smoking>alternative reinforcers) and relapse. Although relevant for quitting, characterization of reduced reward function in abstinent smokers remains limited. Moreover, how attenuated reward function affects other brain systems supporting decision-making has not been established. Here, we use a rewarded antisaccade (rAS) task to characterize non-drug reward processing and its influence on inhibitory control, key elements underlying decision-making, in abstinent smokers vs. non-smokers. Abstinent (12-hours) adult daily smokers (N=23) and non-smokers (N=11) underwent fMRI while performing the rAS. Behavioral performances improved on reward vs. neutral trials. Smokers showed attenuated activation in ventral striatum during the reward cue and in superior precentral sulcus and posterior parietal cortex during response preparation, but greater responses during the saccade response in posterior cingulate and parietal cortices. Smokers' attenuated anticipatory responses suggest reduced motivation from monetary reward, while heightened activation during the saccade response suggests that additional circuitry may be engaged later to enhance inhibitory task performance. Overall, this preliminary study highlights group differences in decision-making components and the utility of the rAS to characterize these effects. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Obesity and Hepatic Steatosis Are Associated with Elevated Serum Amyloid Beta in Metabolically Stressed APPswe/PS1dE9 Mice.

    Directory of Open Access Journals (Sweden)

    Feng-Shiun Shie

    Full Text Available Diabesity-associated metabolic stresses modulate the development of Alzheimer's disease (AD. For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum β-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD.

  20. MK-801 induced amnesia for the elevated plus-maze in mice

    Czech Academy of Sciences Publication Activity Database

    Hliňák, Zdeněk; Krejčí, I.

    2002-01-01

    Roč. 131, 1-2 (2002), s. 221-225 ISSN 0166-4328 R&D Projects: GA ČR GA309/00/1644 Institutional research plan: CEZ:AV0Z5011922 Keywords : amnesia * elevated plus-maze * MK-801 Subject RIV: FH - Neurology Impact factor: 2.791, year: 2002

  1. Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of Pde10a.

    Science.gov (United States)

    Hufgard, Jillian R; Williams, Michael T; Skelton, Matthew R; Grubisha, Olivera; Ferreira, Filipa M; Sanger, Helen; Wright, Mary E; Reed-Kessler, Tracy M; Rasmussen, Kurt; Duman, Ronald S; Vorhees, Charles V

    2017-06-01

    Major depressive disorder is a leading cause of suicide and disability. Despite this, current antidepressants provide insufficient efficacy in more than 60% of patients. Most current antidepressants are presynaptic reuptake inhibitors; postsynaptic signal regulation has not received as much attention as potential treatment targets. We examined the effects of disruption of the postsynaptic cyclic nucleotide hydrolyzing enzyme, phosphodiesterase (PDE) 1b, on depressive-like behavior and the effects on PDE1B protein in wild-type (WT) mice following stress. Littermate knockout (KO) and WT mice were tested in locomotor activity, tail suspension (TST), and forced swim tests (FST). FST was also used to compare the effects of two antidepressants, fluoxetine and bupropion, in KO versus WT mice. Messenger RNA (mRNA) expression changes were also determined. WT mice underwent acute or chronic stress and markers of stress and PDE1B expression were examined. Pde1b KO mice exhibited decreased TST and FST immobility. When treated with antidepressants, both WT and KO mice showed decreased FST immobility and the effect was additive in KO mice. Mice lacking Pde1b had increased striatal Pde10a mRNA expression. In WT mice, acute and chronic stress upregulated PDE1B expression while PDE10A expression was downregulated after chronic but not acute stress. PDE1B is a potential therapeutic target for depression treatment because of the antidepressant-like phenotype seen in Pde1b KO mice.

  2. Elevated interleukin-8 enhances prefrontal synaptic transmission in mice with persistent inflammatory pain

    Directory of Open Access Journals (Sweden)

    Cui Guang-bin

    2012-02-01

    Full Text Available Abstract Background Interleukin-8 (IL-8 is known for its roles in inflammation and plays critical roles in the development of pain. Its expression increases in the brain after peripheral inflammation. Prefrontal cortex, including the anterior cingulate cortex (ACC, is a forebrain structure known for its roles in pain transmission and modulation. Painful stimuli potentiate the prefrontal synaptic transmission, however, little is known about the expression of IL-8 and its role in the enhanced ACC synaptic transmission in animals with persistent inflammatory pain. Findings In the present study, we examined IL-8 expression in the ACC, somatosensory cortex (SSC, and the dorsal horn of lumbar spinal cord following hind-paw administration of complete Freund's adjuvant (CFA in mice and its effects on the ACC synaptic transmission. Quantification of IL-8 at protein level (by ELISA revealed enhanced expression in the ACC and spinal cord during the chronic phases of CFA-induced peripheral inflammation. In vitro whole-cell patch-clamp recordings revealed that IL-8 significantly enhanced synaptic transmission through increased probability of neurotransmitter release in the ACC slice. ACC local infusion of repertaxin, a non-competitive allosteric blocker of IL-8 receptors, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in mice. Conclusions Our findings suggest that up-regulation of IL-8 in the ACC partly attributable to the enhanced prefrontal synaptic transmission in the mice with persistent inflammatory pain.

  3. PIXE analysis showed that the preirradiation enhanced recovery of bone marrow elements after challenging irradiation in C57BL/6N Mice

    International Nuclear Information System (INIS)

    Matsuda, Y.; Yonezawa, M.; Nishiyama, F.

    2000-01-01

    Priming X-irradiation with 0.3-0.5 Gy induces radio-resistance in C57BL/6 strain of mice 2 weeks afterward. Elements in the bone marrow, sampled 11 days after challenging exposure to 5.0 Gy, were determined by PIXE. The challenging irradiation decreased Mg, P, S, K, Ca and Zn as well as dried bone marrow weight. The pre-irradiation enhanced recovery of these levels, indicating stimulated recovery of the metabolism int he tissue. Fe in both control (without pre-irradiation) and experimental groups increased to about twice the original value, showing elevated hemoglobin synthesis after challenging exposure. In previous studies we have reported that recovery of peripheral blood cell counts after sub-lethal irradiation was enhanced by the pre-irradiation. Further, study on accumulation of p53 and Bax proteins, which lead to apoptotic cell death, revealed that the pre-irradiation significantly suppressed accumulation of these proteins in the spleen after challenging irradiation with 3 Gy. These results and our present study suggest that the pre-irradiation decreased the spleen cell death, and favored re-growth of the spleen cells, resulting in stimulated recovery of metabolism for hematopoiesis in the bone marrow as well as in the spleen after challenging high dose irradiation. Stimulated recovery of Mg, P, S, K, Ca and Zn levels might indicate the importance of these elements in hematopoiesis. (author)

  4. High-salt diet combined with elevated angiotensin II accelerates atherosclerosis in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Johansson, Maria E; Bernberg, Evelina; Andersson, Irene J

    2009-01-01

    OBJECTIVES: High-salt diet likely elevates blood pressure (BP), thus increasing the risk of cardiovascular events. We hypothesized that a high-salt diet plays a critical role in subjects whose renin-angiotensin systems cannot adjust to variable salt intake, rendering them more susceptible...... to atherosclerosis. METHODS: Apolipoprotein E-deficient (ApoE-/-) mice received standard or high-salt diet (8%) alone or in combination with fixed angiotensin II (Ang II) infusion (0.5 microg/kg per min). BP was measured using telemetry, and plaque burden was assessed in the thoracic aorta and innominate artery. We...... used urinary isoprostane as a marker for oxidative stress. RESULTS: Although high-salt diet per se did not affect plaque extension, high salt combined with Ang II increased plaque area significantly in both the aorta and the innominate artery as compared with Ang II or salt alone (P

  5. Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft.

    Science.gov (United States)

    Ukon, Naoyuki; Zhao, Songji; Yu, Wenwen; Shimizu, Yoichi; Nishijima, Ken-Ichi; Kubo, Naoki; Kitagawa, Yoshimasa; Tamaki, Nagara; Higashikawa, Kei; Yasui, Hironobu; Kuge, Yuji

    2016-12-01

    Sorafenib, an oral multikinase inhibitor, has anti-proliferative and anti-angiogenic activities and is therapeutically effective against renal cell carcinoma (RCC). Recently, we have evaluated the tumor responses to sorafenib treatment in a RCC xenograft using [Methyl- 3 H(N)]-3'-fluoro-3'-deoxythythymidine ([ 3 H]FLT). Contrary to our expectation, the FLT level in the tumor significantly increased after the treatment. In this study, to clarify the reason for the elevated FLT level, dynamic 3'-[ 18 F]fluoro-3'-deoxythymidine ([ 18 F]FLT) positron emission tomography (PET) and kinetic studies were performed in mice bearing a RCC xenograft (A498). The A498 xenograft was established in nude mice, and the mice were assigned to the control (n = 5) and treatment (n = 5) groups. The mice in the treatment group were orally given sorafenib (20 mg/kg/day p.o.) once daily for 3 days. Twenty-four hours after the treatment, dynamic [ 18 F]FLT PET was performed by small-animal PET. Three-dimensional regions of interest (ROIs) were manually defined for the tumors. A three-compartment model fitting was carried out to estimate four rate constants using the time activity curve (TAC) in the tumor and the blood clearance rate of [ 18 F]FLT. The dynamic pattern of [ 18 F]FLT levels in the tumor significantly changed after the treatment. The rate constant of [ 18 F]FLT phosphorylation (k 3 ) was significantly higher in the treatment group (0.111 ± 0.027 [1/min]) than in the control group (0.082 ± 0.009 [1/min]). No significant changes were observed in the distribution volume, the ratio of [ 18 F]FLT forward transport (K 1 ) to reverse transport (k 2 ), between the two groups (0.556 ± 0.073 and 0.641 ± 0.052 [mL/g] in the control group). Our dynamic PET studies indicated that the increase in FLT level may be caused by the phosphorylation of FLT in the tumor after the sorafenib treatment in the mice bearing a RCC xenograft. Dynamic PET studies with kinetic

  6. Relations between open-field, elevated plus-maze, and emergence tests as displayed by C57/BL6J and BALB/c mice.

    Science.gov (United States)

    Lalonde, R; Strazielle, C

    2008-06-15

    The relations between open-field, elevated plus-maze, and emergence tests were examined in two strains of mice. In the open-field, C57BL/6J mice had more ambulatory movements and rears but not stereotyped movements relative to BALB/c. In addition, C57BL/6J mice entered more often than BALB/c into enclosed and open arms of the elevated plus-maze. When placed inside a large enclosure, C57BL/6J mice emerged more quickly than BALB/c from a small toy object. In the entire series of mice, ambulation and rears in the open-field were linearly correlated with open and enclosed arm visits in the elevated plus-maze. Ambulatory movements and rears were also correlated with emergence latencies. In contrast, stereotyped movements were correlated with emergence latencies, but not with any elevated plus-maze value. These results specify the extent and limits of association between the three tests.

  7. Menthol attenuates respiratory irritation and elevates blood cotinine in cigarette smoke exposed mice.

    Directory of Open Access Journals (Sweden)

    Michael A Ha

    Full Text Available Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol's effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8, the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may

  8. Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests.

    Science.gov (United States)

    Ribeiro, A; Ferraz-de-Paula, V; Pinheiro, M L; Palermo-Neto, J

    2009-06-01

    The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped dose-response effects of drugs that modulate the endocannabinoid levels. However, there are no studies showing the effects of different doses of exogenous anandamide, an endocannabinoid, in animal models of anxiety. Thus, in the present study, we determined the dose-response effects of exogenous anandamide at doses of 0.01, 0.1, and 1.0 mg/kg in C57BL/6 mice (N = 10/group) sequentially submitted to the open field and elevated plus-maze. Anandamide was diluted in 0.9% saline, ethyl alcohol, Emulphor (18:1:1) and administered ip (0.1 mL/10 g body weight); control animals received the same volume of anandamide vehicle. Anandamide at the dose of 0.1 mg/kg (but not of 0.01 or 1 mg/kg) increased (P open field, as well as the exploration of the open arms of the elevated plus-maze. Thus, exogenous anandamide, like pharmacological compounds that increase endocannabinoid levels, promoted a characteristic inverted U-shaped dose-response effect in animal models of anxiety. Furthermore, anandamide (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze (P open field test.

  9. Elevation of extracellular adenosine enhances haemopoiesis-stimulating effects of G-CSF in normal and gamma-irradiated mice

    Energy Technology Data Exchange (ETDEWEB)

    Hofer, M.; Pospisil, M.; Netikiva, J.; Hola, J. [Institute of Biophysics, Academy of Sciences of the Czech Republic (Czech Republic)

    1997-03-01

    Effects of combined treatment with drugs elevating extracellular adenosine (dipyridamole /DP/, inhibiting the extracellular uptake of adenosine, and adenosine monophosphate /AMP/, an adenosine pro-drug), and G-CSF (granulocyte colony-stimulating factor) on haemopoiesis of normal and gamma-irradiated mice were ascertained. The agents were administered alone or in combination in a 4-day regimen. In normal, unirradiated animals, the haematological endpoints were determined 24 hours after the completion of the treatment. It was shown that the effects of G-CSF, i.e., increases in peripheral blood neutrophils, granulocyte-macrophage progenitor cells (GM-CFC) and morphologically recognizable granulocyte cells in femoral marrow and a decrease in the marrow erythroid cells, can be enhanced by the combination of DP plus AMP administrated 30 minutes before G-CSF. Furthermore, it was found that the stimulatory action of DP plus AMP was expressed particularly at lower doses of G-CSF (1.5, 3, and 4.5 {mu}g/d). In experiments with irradiated mice, when the 4-day therapeutic regimen was applied on days 3 to 6 following irradiation with the dose of 4 Gy, analogical stimulation of granulopoiesis was observed in the recovery phase on days 14 and 18 after irradiation. As example, see Fig. 1 for counts of granulocyte cells in femoral bone marrow. (authors)

  10. Elevation of extracellular adenosine enhances haemopoiesis-stimulating effects of G-CSF in normal and gamma-irradiated mice

    International Nuclear Information System (INIS)

    Hofer, M.; Pospisil, M.; Netikiva, J.; Hola, J.

    1997-01-01

    Effects of combined treatment with drugs elevating extracellular adenosine (dipyridamole /DP/, inhibiting the extracellular uptake of adenosine, and adenosine monophosphate /AMP/, an adenosine pro-drug), and G-CSF (granulocyte colony-stimulating factor) on haemopoiesis of normal and gamma-irradiated mice were ascertained. The agents were administered alone or in combination in a 4-day regimen. In normal, unirradiated animals, the haematological endpoints were determined 24 hours after the completion of the treatment. It was shown that the effects of G-CSF, i.e., increases in peripheral blood neutrophils, granulocyte-macrophage progenitor cells (GM-CFC) and morphologically recognizable granulocyte cells in femoral marrow and a decrease in the marrow erythroid cells, can be enhanced by the combination of DP plus AMP administrated 30 minutes before G-CSF. Furthermore, it was found that the stimulatory action of DP plus AMP was expressed particularly at lower doses of G-CSF (1.5, 3, and 4.5 μg/d). In experiments with irradiated mice, when the 4-day therapeutic regimen was applied on days 3 to 6 following irradiation with the dose of 4 Gy, analogical stimulation of granulopoiesis was observed in the recovery phase on days 14 and 18 after irradiation. As example, see Fig. 1 for counts of granulocyte cells in femoral bone marrow. (authors)

  11. Sunitinib DDI with paracetamol, diclofenac, mefenamic acid and ibuprofen shows sex-divergent effects on the tissue uptake and distribution pattern of sunitinib in mice.

    Science.gov (United States)

    Tan, Siok Yean; Wong, Mei Mei; Tiew, Angela Lu Wun; Choo, Yai Wen; Lim, Suat Hun; Ooi, Ing Hong; Modamio, Pilar; Fernández, Cecilia; Mariño, Eduardo L; Segarra, Ignacio

    2016-10-01

    Pharmacokinetic interaction of sunitinib with diclofenac, paracetamol, mefenamic acid and ibuprofen was evaluated due to their P450 mediated metabolism and OATP1B1, OATP1B3, ABCB1, ABCG2 transporters overlapping features. Male and female mice were administered 6 sunitinib doses (60 mg/kg) PO every 12 h and 30 min before the last dose were administered vehicle (control groups), 250 mg/kg paracetamol, 30 mg/kg diclofenac, 50 mg/kg mefenamic acid or 30 mg/kg ibuprofen (study groups), euthanized 6 h post last administration and sunitinib plasma, liver, kidney, brain concentrations analyzed. Ibuprofen halved sunitinib plasma concentration in female mice (p Diclofenac and paracetamol female mice showed 45 and 25 % higher plasma concentrations than male mice which were 27 % lower in mefenamic acid female mice. Paracetamol increased 2.2 (p diclofenac, paracetamol, mefenamic acid and ibuprofen (p diclofenac group in male mice (liver, brain) and female mice (liver, kidney). These results portray gender-based sunitinib pharmacokinetic differences and NSAIDs selective effects on male or female mice, with potential clinical translatability.

  12. Heart tissue of harlequin (hq)/Big Blue mice has elevated reactive oxygen species without significant impact on the frequency and nature of point mutations in nuclear DNA

    Energy Technology Data Exchange (ETDEWEB)

    Crabbe, Rory A. [Department of Biology, University of Western Ontario, London, Ontario, N6A 5B7 (Canada); Hill, Kathleen A., E-mail: khill22@uwo.ca [Department of Biology, University of Western Ontario, London, Ontario, N6A 5B7 (Canada)

    2010-09-10

    Age is a major risk factor for heart disease, and cardiac aging is characterized by elevated mitochondrial reactive oxygen species (ROS) with compromised mitochondrial and nuclear DNA integrity. To assess links between increased ROS levels and mutations, we examined in situ levels of ROS and cII mutation frequency, pattern and spectrum in the heart of harlequin (hq)/Big Blue mice. The hq mouse is a model of premature aging with mitochondrial dysfunction and increased risk of oxidative stress-induced heart disease with the means for in vivo mutation detection. The hq mutation produces a significant downregulation in the X-linked apoptosis-inducing factor gene (Aif) impairing both the antioxidant and oxidative phosphorylation functions of AIF. Brain and skin of hq disease mice have elevated frequencies of point mutations in nuclear DNA and histopathology characterized by cell loss. Reports of associated elevations in ROS in brain and skin have mixed results. Herein, heart in situ ROS levels were elevated in hq disease compared to AIF-proficient mice (p < 0.0001) yet, mutation frequency and pattern were similar in hq disease, hq carrier and AIF-proficient mice. Heart cII mutations were also assessed 15 days following an acute exposure to an exogenous ROS inducer (10 mg paraquat/kg). Acute paraquat exposure with a short mutant manifestation period was insufficient to elevate mutation frequency or alter mutation pattern in the post-mitotic heart tissue of AIF-proficient mice. Paraquat induction of ROS requires mitochondrial complex I and thus is likely compromised in hq mice. Results of this preliminary survey and the context of recent literature suggest that determining causal links between AIF deficiency and the premature aging phenotypes of specific tissues is better addressed with assay of mitochondrial ROS and large-scale changes in mitochondrial DNA in specific cell types.

  13. Heart tissue of harlequin (hq)/Big Blue mice has elevated reactive oxygen species without significant impact on the frequency and nature of point mutations in nuclear DNA

    International Nuclear Information System (INIS)

    Crabbe, Rory A.; Hill, Kathleen A.

    2010-01-01

    Age is a major risk factor for heart disease, and cardiac aging is characterized by elevated mitochondrial reactive oxygen species (ROS) with compromised mitochondrial and nuclear DNA integrity. To assess links between increased ROS levels and mutations, we examined in situ levels of ROS and cII mutation frequency, pattern and spectrum in the heart of harlequin (hq)/Big Blue mice. The hq mouse is a model of premature aging with mitochondrial dysfunction and increased risk of oxidative stress-induced heart disease with the means for in vivo mutation detection. The hq mutation produces a significant downregulation in the X-linked apoptosis-inducing factor gene (Aif) impairing both the antioxidant and oxidative phosphorylation functions of AIF. Brain and skin of hq disease mice have elevated frequencies of point mutations in nuclear DNA and histopathology characterized by cell loss. Reports of associated elevations in ROS in brain and skin have mixed results. Herein, heart in situ ROS levels were elevated in hq disease compared to AIF-proficient mice (p < 0.0001) yet, mutation frequency and pattern were similar in hq disease, hq carrier and AIF-proficient mice. Heart cII mutations were also assessed 15 days following an acute exposure to an exogenous ROS inducer (10 mg paraquat/kg). Acute paraquat exposure with a short mutant manifestation period was insufficient to elevate mutation frequency or alter mutation pattern in the post-mitotic heart tissue of AIF-proficient mice. Paraquat induction of ROS requires mitochondrial complex I and thus is likely compromised in hq mice. Results of this preliminary survey and the context of recent literature suggest that determining causal links between AIF deficiency and the premature aging phenotypes of specific tissues is better addressed with assay of mitochondrial ROS and large-scale changes in mitochondrial DNA in specific cell types.

  14. Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

    Science.gov (United States)

    Imai, Rika; Asai, Kanae; Hanai, Jun-ichi; Takenaka, Masaru

    2015-07-01

    Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

  15. A rabies virus vampire bat variant shows increased neuroinvasiveness in mice when compared to a carnivore variant.

    Science.gov (United States)

    Mesquita, Leonardo Pereira; Gamon, Thais Helena Martins; Cuevas, Silvia Elena Campusano; Asano, Karen Miyuki; Fahl, Willian de Oliveira; Iamamoto, Keila; Scheffer, Karin Correa; Achkar, Samira Maria; Zanatto, Dennis Albert; Mori, Cláudia Madalena Cabrera; Maiorka, Paulo César; Mori, Enio

    2017-12-01

    Rabies is one of the most important zoonotic diseases and is caused by several rabies virus (RABV) variants. These variants can exhibit differences in neurovirulence, and few studies have attempted to evaluate the neuroinvasiveness of variants derived from vampire bats and wild carnivores. The aim of this study was to evaluate the neuropathogenesis of infection with two Brazilian RABV street variants (variant 3 and crab-eating fox) in mice. BALB/c mice were inoculated with RABV through the footpad, with the 50% mouse lethal dose (LD 50 ) determined by intracranial inoculation. The morbidity of rabies in mice infected with variant 3 and the crab-eating fox strain was 100% and 50%, respectively, with an incubation period of 7 and 6 days post-inoculation (dpi), respectively. The clinical disease in mice was similar with both strains, and it was characterized initially by weight loss, ruffled fur, hunched posture, and hind limb paralysis progressing to quadriplegia and recumbency at 9 to 12 dpi. Histological lesions within the central nervous system (CNS) characterized by nonsuppurative encephalomyelitis with neuronal degeneration and necrosis were observed in mice infected with variant 3 and those infected with the crab-eating fox variant. However, lesions and the presence of RABV antigen, were more widespread within the CNS of variant-3-infected mice, whereas in crab-eating fox-variant-infected mice, RABV antigens were more restricted to caudal areas of the CNS, such as the spinal cord and brainstem. In conclusion, the results shown here demonstrate that the RABV vampire bat strain (variant 3) has a higher potential for neuroinvasiveness than the carnivore variant.

  16. Elevated dietary magnesium during pregnancy and postnatal life prevents ectopic mineralization in Enpp1asj mice, a model for generalized arterial calcification of infancy.

    Science.gov (United States)

    Kingman, Joshua; Uitto, Jouni; Li, Qiaoli

    2017-06-13

    Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder caused by mutations in the ENPP1 gene. It is characterized by mineralization of the arterial blood vessels, often diagnosed prenatally, and associated with death in early childhood. There is no effective treatment for this devastating disorder. We previously characterized the Enpp1asjmutant mouse as a model of GACI, and we have now explored the effect of elevated dietary magnesium (five-fold) in pregnant mothers and continuing for the first 14 weeks of postnatal life. The mothers were kept on either control diet or experimental diet supplemented with magnesium. Upon weaning at 4 weeks of age the pups were placed either on control diet or high magnesium diet. The degree of mineralization was assessed at 14 weeks of age by histopathology and a chemical calcium assay in muzzle skin, kidney and aorta. Mice placed on high magnesium diet showed little, if any, evidence of mineralization when their corresponding mothers were also placed on diet enriched with magnesium during pregnancy and nursing. The reduced ectopic mineralization in these mice was accompanied by increased calcium and magnesium content in the urine, suggesting that magnesium competes calcium-phosphate binding thereby preventing the mineral deposition. These results have implications for dietary management of pregnancies in which the fetus is suspected of having GACI. Moreover, augmenting a diet with high magnesium may be beneficial for other ectopic mineralization diseases, including nephrocalcinosis.

  17. Relations between open-field, elevated plus-maze, and emergence tests in C57BL/6J and BALB/c mice injected with GABA- and 5HT-anxiolytic agents.

    Science.gov (United States)

    Lalonde, Robert; Strazielle, Catherine

    2010-06-01

    Two 5HT(1A) receptor agonists and chlordiazepoxide were examined in open-field, elevated plus maze, and emergence tests. At doses with no effect in the open-field, chlordiazepoxide increased open and open/total arm visits as well as open arm duration in the elevated plus maze, whereas 5HT(1A) receptor agonists showed an anxiolytic response on a single measure. The anxiolytic action of chlordiazepoxide was limited to the less active BALB/c strain. Unlike the 5HT(1A) receptor agonists, chlordiazepoxide was also anxiolytic in the emergence test, once again only in BALB/c and not C57BL/6J mice. Significant correlations were found between emergence latencies and specific indicators of anxiety in the elevated plus-maze in chlordiazepoxide-treated but not in mice treated with buspirone and 8-OH-DPAT. These results indicate that elevated plus-maze and emergence tests depend on benzodiazepine receptors. In contrast, 5HT(1A) receptor agonists were ineffective in the emergence test and no correlation was found between emergence latencies and specific indicators of anxiety in the elevated plus-maze. Though superficially similar, the emergence test seems to tap into a partially separate facet of anxiety.

  18. Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory

    DEFF Research Database (Denmark)

    Brakebusch, Cord; Seidenbecher, Constanze I; Asztely, Fredrik

    2002-01-01

    to be less prominent in mutant than in wild-type mice. Brevican-deficient mice showed significant deficits in the maintenance of hippocampal long-term potentiation (LTP). However, no obvious impairment of excitatory and inhibitory synaptic transmission was found, suggesting a complex cause for the LTP defect....... Detailed behavioral analysis revealed no statistically significant deficits in learning and memory. These data indicate that brevican is not crucial for brain development but has restricted structural and functional roles....

  19. Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes

    International Nuclear Information System (INIS)

    Wu, Hsu-Pin; Hsu, Shu-Yuan; Wu, Wen-Ai; Hu, Ji-Wei; Ouyang, Pin

    2014-01-01

    Highlights: •Pnn CCD domain functions as a dominant negative mutant regulating Pnn expression and function. •Pnn CCD mutant Tg mice have a muscle wasting phenotype during development and show dystrophic histological features. •Pnn mutant muscles are susceptible to slow fiber type gene transition and NEB reduction. •The Tg mouse generated by overexpression of the Pnn CCD domain displays many characteristics resembling NEB +/− mice. -- Abstract: Pinin (Pnn) is a nuclear speckle-associated SR-like protein. The N-terminal region of the Pnn protein sequence is highly conserved from mammals to insects, but the C-terminal RS domain-containing region is absent in lower species. The N-terminal coiled-coil domain (CCD) is, therefore, of interest not only from a functional point of view, but also from an evolutionarily standpoint. To explore the biological role of the Pnn CCD in a physiological context, we generated transgenic mice overexpressing Pnn mutant in skeletal muscle. We found that overexpression of the CCD reduces endogenous Pnn expression in cultured cell lines as well as in transgenic skeletal muscle fibers. Pnn mutant mice exhibited reduced body mass and impaired muscle function during development. Mutant skeletal muscles show dystrophic histological features with muscle fibers heavily loaded with centrally located myonuclei. Expression profiling and pathway analysis identified over-representation of genes in gene categories associated with muscle contraction, specifically those related to slow type fiber. In addition nebulin (NEB) expression level is repressed in Pnn mutant skeletal muscle. We conclude that Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity

  20. Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Hsu-Pin; Hsu, Shu-Yuan [Department of Anatomy, Chang Gung University Medical College, Taiwan (China); Wu, Wen-Ai; Hu, Ji-Wei [Transgenic Mouse Core Laboratory, Chang Gung University, Taiwan (China); Ouyang, Pin, E-mail: ouyang@mail.cgu.edu.tw [Department of Anatomy, Chang Gung University Medical College, Taiwan (China); Transgenic Mouse Core Laboratory, Chang Gung University, Taiwan (China); Molecular Medicine Research Center, Chang Gung University, Taiwan (China)

    2014-01-03

    Highlights: •Pnn CCD domain functions as a dominant negative mutant regulating Pnn expression and function. •Pnn CCD mutant Tg mice have a muscle wasting phenotype during development and show dystrophic histological features. •Pnn mutant muscles are susceptible to slow fiber type gene transition and NEB reduction. •The Tg mouse generated by overexpression of the Pnn CCD domain displays many characteristics resembling NEB{sup +/−} mice. -- Abstract: Pinin (Pnn) is a nuclear speckle-associated SR-like protein. The N-terminal region of the Pnn protein sequence is highly conserved from mammals to insects, but the C-terminal RS domain-containing region is absent in lower species. The N-terminal coiled-coil domain (CCD) is, therefore, of interest not only from a functional point of view, but also from an evolutionarily standpoint. To explore the biological role of the Pnn CCD in a physiological context, we generated transgenic mice overexpressing Pnn mutant in skeletal muscle. We found that overexpression of the CCD reduces endogenous Pnn expression in cultured cell lines as well as in transgenic skeletal muscle fibers. Pnn mutant mice exhibited reduced body mass and impaired muscle function during development. Mutant skeletal muscles show dystrophic histological features with muscle fibers heavily loaded with centrally located myonuclei. Expression profiling and pathway analysis identified over-representation of genes in gene categories associated with muscle contraction, specifically those related to slow type fiber. In addition nebulin (NEB) expression level is repressed in Pnn mutant skeletal muscle. We conclude that Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity.

  1. Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels.

    Science.gov (United States)

    Pedraza-Arévalo, S; Córdoba-Chacón, J; Pozo-Salas, A I; L-López, F; de Lecea, L; Gahete, M D; Castaño, J P; Luque, R M

    2015-06-01

    Somatostatin (SST) and cortistatin (CORT) are two highly related neuropeptides involved in the regulation of various endocrine secretions. In particular, SST and CORT are two primary negative regulators of GH secretion. Consequently, single SST or CORT knockout mice exhibit elevated GH levels; however, this does not lead to increased IGF-1 levels or somatic growth. This apparent lack of correspondence has been suggested to result from compensatory mechanisms between both peptides. To test this hypothesis, in this study we explored, for the first time, the consequences of simultaneously deleting endogenous SST and CORT by generating a double SST/CORT knockout mouse model and exploring its endocrine and metabolic phenotype. Our results demonstrate that simultaneous deletion of SST and CORT induced a drastic elevation of endogenous GH levels, which, surprisingly, did not lead to changes in growth rate or IGF-1 levels, suggesting the existence of additional factors/systems that, in the absence of endogenous SST and CORT, could counteract GH actions. Notably, elevation in circulating GH levels were not accompanied by changes in pituitary GH expression or by alterations in the expression of its main regulators (GHRH and ghrelin) or their receptors (GHRH receptor, GHS receptor, or SST/CORT receptors) at the hypothalamic or pituitary level. However, although double-SST/CORT knockout male mice exhibited normal glucose and insulin levels, they had improved insulin sensitivity compared with the control mice. Therefore, these results suggest the existence of an intricate interplay among the known (SST/CORT), and likely unknown, inhibitory components of the GH/IGF-1 axis to regulate somatic growth and glucose/insulin homeostasis.

  2. Female Mice Deficient in Alpha-Fetoprotein Show Female-Typical Neural Responses to Conspecific-Derived Pheromones

    NARCIS (Netherlands)

    Brock, O.; Keller, M.; Douhard, Q.; Bakker, J.

    2012-01-01

    The neural mechanisms controlling sexual behavior are sexually differentiated by the perinatal actions of sex steroid hormones. We recently observed using female mice deficient in alpha-fetoprotein (AFP-KO) and which lack the protective actions of AFP against maternal estradiol, that exposure to

  3. Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency.

    Science.gov (United States)

    Zhou, Xiaolai; Sun, Lirong; Brady, Owen Adam; Murphy, Kira A; Hu, Fenghua

    2017-01-26

    Mutations resulting in haploinsufficiency of progranulin (PGRN) cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. Accumulating evidence suggest a crucial role of progranulin in maintaining proper lysosomal function during aging. TMEM106B has been identified as a risk factor for frontotemporal lobar degeneration with progranulin mutations and elevated mRNA and protein levels of TMEM106B are associated with increased risk for frontotemporal lobar degeneration. Increased levels of TMEM106B alter lysosomal morphology and interfere with lysosomal degradation. However, how progranulin and TMEM106B interact to regulate lysosomal function and frontotemporal lobar degeneration (FTLD) disease progression is still unclear. Here we report that progranulin deficiency leads to increased TMEM106B protein levels in the mouse cortex with aging. To mimic elevated levels of TMEM106B in frontotemporal lobar degeneration (FTLD) cases, we generated transgenic mice expressing TMEM106B under the neuronal specific promoter, CamKII. Surprisingly, we found that the total protein levels of TMEM106B are not altered despite the expression of the TMEM106B transgene at mRNA and protein levels, suggesting a tight regulation of TMEM106B protein levels in the mouse brain. However, progranulin deficiency results in accumulation of TMEM106B protein from the transgene expression during aging, which is accompanied by exaggerated lysosomal abnormalities and increased lipofuscin accumulation. In summary, our mouse model nicely recapitulates the interaction between progranulin and TMEM106B in human patients and supports a critical role of lysosomal dysfunction in the frontotemporal lobar degeneration (FTLD) disease progression.

  4. Poliomyelitis in MuLV-infected ICR-SCID mice after injection of basement membrane matrix contaminated with lactate dehydrogenase-elevating virus.

    Science.gov (United States)

    Carlson Scholz, Jodi A; Garg, Rohit; Compton, Susan R; Allore, Heather G; Zeiss, Caroline J; Uchio, Edward M

    2011-10-01

    The arterivirus lactate dehydrogenase-elevating virus (LDV) causes life-long viremia in mice. Although LDV infection generally does not cause disease, infected mice that are homozygous for the Fv1(n) allele are prone to develop poliomyelitis when immunosuppressed, a condition known as age-dependent poliomyelitis. The development of age-dependent poliomyelitis requires coinfection with endogenous murine leukemia virus. Even though LDV is a common contaminant of transplantable tumors, clinical signs of poliomyelitis after inadvertent exposure to LDV have not been described in recent literature. In addition, LDV-induced poliomyelitis has not been reported in SCID or ICR mice. Here we describe the occurrence of poliomyelitis in ICR-SCID mice resulting from injection of LDV-contaminated basement membrane matrix. After exposure to LDV, a subset of mice presented with clinical signs including paresis, which was associated with atrophy of the hindlimb musculature, and tachypnea; in addition, some mice died suddenly with or without premonitory signs. Mice presenting within the first 6 mo after infection had regions of spongiosis, neuronal necrosis and astrocytosis of the ventral spinal cord, and less commonly, brainstem. Axonal degeneration of ventral roots prevailed in more chronically infected mice. LDV was identified by RT-PCR in 12 of 15 mice with typical neuropathology; positive antiLDV immunolabeling was identified in all PCR-positive animals (n = 7) tested. Three of 8 mice with neuropathology but no clinical signs were LDV negative by RT-PCR. RT-PCR yielded murine leukemia virus in spinal cords of all mice tested, regardless of clinical presentation or neuropathology.

  5. MRI of Mouse Models for Gliomas Shows Similarities to Humans and Can Be Used to Identify Mice for Preclinical Trials

    Directory of Open Access Journals (Sweden)

    Jason A. Koutcher

    2002-01-01

    Full Text Available Magnetic resonance imaging (MRI has been utilized for screening and detecting brain tumors in mice based upon their imaging characteristics appearance and their pattern of enhancement. Imaging of these tumors reveals many similarities to those observed in humans with identical pathology. Specifically, high-grade murine gliomas have histologic characteristics of glioblastoma multiforme (GBM with contrast enhancement after intravenous administration of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA, implying disruption of the blood-brain barrier in these tumors. In contrast, low-grade murine oligodendrogliomas do not reveal contrast enhancement, similar to human tumors. MRI can be used to identify mice with brain neoplasms as inclusion criteria in preclinical trials.

  6. Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance

    OpenAIRE

    Akman, Hasan O.; Dorado, Beatriz; López, Luis C.; García-Cazorla, Ángeles; Vilà, Maya R.; Tanabe, Lauren M.; Dauer, William T.; Bonilla, Eduardo; Tanji, Kurenai; Hirano, Michio

    2008-01-01

    Mitochondrial DNA (mtDNA) depletion syndrome (MDS), an autosomal recessive condition, is characterized by variable organ involvement with decreased mtDNA copy number and activities of respiratory chain enzymes in affected tissues. MtDNA depletion has been associated with mutations in nine autosomal genes, including thymidine kinase (TK2), which encodes a ubiquitous mitochondrial protein. To study the pathogenesis of TK2-deficiency, we generated mice harboring an H126N Tk2 mutation. Homozygous...

  7. Chyawanprash, a formulation of traditional Ayurvedic medicine, shows a protective effect on skin photoaging in hairless mice.

    Science.gov (United States)

    Takauji, Yuki; Morino, Kyoko; Miki, Kensuke; Hossain, Mohammad; Ayusawa, Dai; Fujii, Michihiko

    2016-11-01

    Chronic exposure to ultraviolet (UV) radiation induces skin photoaging (premature skin aging). UV irradiation generates reactive oxygen species (ROS), which are shown to play a pivotal role in skin photoaging. Ayurveda is a holistic traditional medical system, and Chyawanprash is one of the most popular formulations in Ayurveda. Since maintenance of the function and appearance of skin is important, we examined whether Chyawanprash has a protective effect on skin photoaging. To examine the effect of Chyawanprash on skin photoaging, hairless mice were administered with Chyawanprash in drinking water for 3 weeks, and then repeatedly exposed to ultraviolet light B (UVB) irradiation (225 or 450 mJ/cm 2 ) to induce skin photoaging. To further examine the function of Chyawanprash, its effects were examined in cells cultured in vitro. Chyawanprash was added in culture medium, and examined for the effect on the growth of human keratinocytes, and for the ability to eliminate ROS which generated by paraquat (50 μmol/L) in HeLa cells. UVB irradiation caused symptoms such as rough skin, erythema, and edema on the skin in hairless mice, but administration of Chyawanprash relieved these symptoms. Further, Chyawanprash significantly suppressed epidermal thickening, a typical marker of skin photoaging, in mice. We then analyzed the effect of Chyawanprash in human cells in culture, and found that Chyawanprash enhanced the growth of human keratinocytes, and efficiently eliminated ROS, which are causally involved in skin photoaging, in HeLa cells. These findings suggested that Chyawanprash may have beneficial effects on slowing skin photoaging.

  8. Enzyme-treated Asparagus officinalis extract shows neuroprotective effects and attenuates cognitive impairment in senescence-accelerated mice.

    Science.gov (United States)

    Sakurai, Takuya; Ito, Tomohiro; Wakame, Koji; Kitadate, Kentaro; Arai, Takashi; Ogasawara, Junetsu; Kizaki, Takako; Sato, Shogo; Ishibashi, Yoshinaga; Fujiwara, Tomonori; Akagawa, Kimio; Ishida, Hitoshi; Ohno, Hideki

    2014-01-01

    Increases in the number of patients with dementia involving Alzheimer's disease (AD) are seen as a grave public health problem. In neurodegenerative disorders involving AD, biological stresses, such as oxidative and inflammatory stress, induce neural cell damage. Asparagus (Asparagus officinalis) is a popular vegetable, and an extract prepared from this reportedly possesses various beneficial biological activities. In the present study, we investigated the effects of enzyme-treated asparagus extract (ETAS) on neuronal cells and early cognitive impairment of senescence-accelerated mouse prone 8 (SAMP8) mice. The expression of mRNAs for factors that exert cytoprotective and anti-apoptotic functions, such as heat-shock protein 70 and heme oxygenase-1, was upregulated in NG108-15 neuronal cells by treatment with ETAS. Moreover, when release of lactate dehydrogenase from damaged NG108-15 cells was increased for cells cultured in medium containing either the nitric oxide donor sodium nitroprusside or the hypoxia mimic reagent cobalt chloride, ETAS significantly attenuated this cell damage. Also, when contextual fear memory, which is considered to be a hippocampus-dependent memory, was significantly impaired in SAMP8 mice, ETAS attenuated the cognitive impairment. These results suggest that ETAS produces cytoprotective effects in neuronal cells and attenuates the effects on the cognitive impairment of SAMP8 mice.

  9. Experimental Chagas disease in Balb/c mice previously vaccinated with T. rangeli. II. The innate immune response shows immunological memory: reality or fiction?

    Science.gov (United States)

    Basso, B; Marini, V

    2015-03-01

    Trypanosoma cruzi is a real challenge to the host's immune system, because it requires strong humoral and cellular immune response to remove circulating trypomastigote forms, and to prevent the replication of amastigote forms in tissues, involving many regulator and effector components. This protozoan is responsible for Chagas disease, a major public health problem in Latinamerica. We have developed a model of vaccination with Trypanosoma rangeli, a parasite closely related to T. cruzi, but nonpathogenic to humans, which reduces the infectiousness in three different species of animals, mice, dogs and guinea pigs, against challenge with T. cruzi. In a previous work, we demonstrated that mice vaccinated with T. rangeli showed important soluble mediators that stimulate phagocytic activity versus only infected groups. The aim of this work was to study the innate immune response in mice vaccinated or not with T. rangeli. Different population cells and some soluble mediators (cytokines) in peritoneal fluid and plasma in mice vaccinated-infected and only infected with T. cruzi were studied. In the first hours of challenge vaccinated mice showed an increase of macrophages, NK, granulocytes, and regulation of IL6, IFNγ, TNFα and IL10, with an increase of IL12, with respect to only infected mice. Furthermore an increase was observed of Li T, Li B responsible for adaptative response. Finally the findings showed that the innate immune response plays an important role in vaccinated mice for the early elimination of the parasites, complementary with the adaptative immune response, suggesting that vaccination with T. rangeli modulates the innate response, which develops some kind of immunological memory, recognizing shared antigens with T. cruzi. These results could contribute to the knowledge of new mechanisms which would have an important role in the immune response to Chagas disease. Copyright © 2014 Elsevier GmbH. All rights reserved.

  10. Proteomic data show an increase in autoantibodies and alpha-fetoprotein and a decrease in apolipoprotein A-II with time in sera from senescence-accelerated mice

    Energy Technology Data Exchange (ETDEWEB)

    Guo, S.J. [Beijing Institute of Pharmacology and Toxicology, Beijing (China); Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Qi, C.H.; Zhou, W.X.; Zhang, Y.X. [Beijing Institute of Pharmacology and Toxicology, Beijing (China); Zhang, X.M.; Wang, J.; Wang, H.X. [National Center of Biomedical Analysis, Beijing (China)

    2013-04-12

    We evaluated changes in levels by comparing serum proteins in senescence-accelerated mouse-prone 8 (SAMP8) mice at 2, 6, 12, and 15 months of age (SAMP8-2 m, -6 m, -12 m, -15 m) to age-matched SAM-resistant 1 (SAMR1) mice. Mice were sacrificed, and blood was analyzed by 2-dimensional electrophoresis combined with mass spectrometry. Five protein spots were present in all SAMP8 serum samples, but only appeared in SAMR1 samples at 15 months of age except for spot 3, which also showed a slight expression in SAMR1-12 m sera. Two proteins decreased in the sera from SAMP8-2 m, -6 m, and -12 m mice, and divided into 2 spots each in SAMP8-15 m sera. Thus, the total number of altered spots in SAMP8 sera was 7; of these, 4 were identified as Ig kappa chain V region (M-T413), chain A of an activity suppressing Fab fragment to cytochrome P450 aromatase (32C2-A), alpha-fetoprotein, and apolipoprotein A-II. M-T413 is a monoclonal CD4 antibody, which inhibits T cell proliferation. We found that M-T413 RNA level was significantly enhanced in splenocytes from SAMP8-2 m mice. This agreed with serum M-T413 protein alterations and a strikingly lower blood CD4{sup +} T cell count in SAMP8 mice when compared to the age-matched SAMR1 mice, with the latter negatively correlating with serum M-T413 protein volume. Age-related changes in serum proteins favored an increase in autoantibodies and alpha-fetoprotein and a decrease of apolipoprotein A-II, which occurred in SAMP8 mice at 2 months of age and onwards. These proteins may serve as candidate biomarkers for early aging.

  11. Proteomic data show an increase in autoantibodies and alpha-fetoprotein and a decrease in apolipoprotein A-II with time in sera from senescence-accelerated mice

    International Nuclear Information System (INIS)

    Guo, S.J.; Qi, C.H.; Zhou, W.X.; Zhang, Y.X.; Zhang, X.M.; Wang, J.; Wang, H.X.

    2013-01-01

    We evaluated changes in levels by comparing serum proteins in senescence-accelerated mouse-prone 8 (SAMP8) mice at 2, 6, 12, and 15 months of age (SAMP8-2 m, -6 m, -12 m, -15 m) to age-matched SAM-resistant 1 (SAMR1) mice. Mice were sacrificed, and blood was analyzed by 2-dimensional electrophoresis combined with mass spectrometry. Five protein spots were present in all SAMP8 serum samples, but only appeared in SAMR1 samples at 15 months of age except for spot 3, which also showed a slight expression in SAMR1-12 m sera. Two proteins decreased in the sera from SAMP8-2 m, -6 m, and -12 m mice, and divided into 2 spots each in SAMP8-15 m sera. Thus, the total number of altered spots in SAMP8 sera was 7; of these, 4 were identified as Ig kappa chain V region (M-T413), chain A of an activity suppressing Fab fragment to cytochrome P450 aromatase (32C2-A), alpha-fetoprotein, and apolipoprotein A-II. M-T413 is a monoclonal CD4 antibody, which inhibits T cell proliferation. We found that M-T413 RNA level was significantly enhanced in splenocytes from SAMP8-2 m mice. This agreed with serum M-T413 protein alterations and a strikingly lower blood CD4 + T cell count in SAMP8 mice when compared to the age-matched SAMR1 mice, with the latter negatively correlating with serum M-T413 protein volume. Age-related changes in serum proteins favored an increase in autoantibodies and alpha-fetoprotein and a decrease of apolipoprotein A-II, which occurred in SAMP8 mice at 2 months of age and onwards. These proteins may serve as candidate biomarkers for early aging

  12. Lithium ameliorates open-field and elevated plus maze behaviors, and brain phospho-glycogen synthase kinase 3-beta expression in fragile X syndrome model mice.

    Science.gov (United States)

    Chen, Xi; Sun, Weiwen; Pan, Ying; Yang, Quan; Cao, Kaiyi; Zhang, Jin; Zhang, Yizhi; Chen, Mincong; Chen, Feidi; Huang, Yueling; Dai, Lijun; Chen, Shengqiang

    2013-10-01

    To investigate whether lithium modifies open-field and elevated plus maze behavior, and brain phospho-glycogen synthase kinase 3 (P-GSK3beta) expression in Fmr1 knockout mice. One hundred and eighty FVB mice, including knockout and wild type, with an age of 30 days were used. An open-field and elevated plus maze was utilized to test behavior, while western blot was used to measure the P-GSK3beta expression. Six groups were formed: control (saline), lithium chloride 30, 60, 90, 120, and 200 mg/kg. The experiments were carried out in the Institute of Neuroscience, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China between January and June 2012. Lithium significantly decreased total distance, crossing, central area time, and center entry in the open-field test (popen-arm tracking, open-arm entry, and open-arm time in the elevated plus maze (popen-field and elevated plus maze behaviors of Fmr1 knockout mice. This effect may be related to its enhancement of P-GSK3beta expression. Our findings suggest that lithium might have a therapeutic effect in fragile X syndrome.

  13. Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline.

    Science.gov (United States)

    Openshaw, R L; Thomson, D M; Penninger, J M; Pratt, J A; Morris, B J

    2017-01-01

    Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear. In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment. Attentional function in mice haploinsufficient for Map2k7 (Map2k7 +/- mice) was investigated using the five-choice serial reaction time task (5-CSRTT). Once stable performance had been achieved, Map2k7 +/- mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline-a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia-signs of improvement in attentional performance were detected. Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline.

  14. Behavioral assessments of BTBR T+Itpr3tf/J mice by tests of object attention and elevated open platform: Implications for an animal model of psychiatric comorbidity in autism.

    Science.gov (United States)

    Chao, Owen Y; Yunger, Richelle; Yang, Yi-Mei

    2018-07-16

    Autism spectrum disorders (ASD) are diagnosed based on the behavioral criteria of impaired social interaction, defective communication and repetitive behaviors. Psychiatric comorbidities, such as anxiety and intellectual disability, are commonly present in ASD. The BTBR T+ Itpr3tf/J (BTBR) mice display a range of autistic phenotypes, yet whether this mouse model is appropriate to study psychiatric comorbidity in ASD remains unclear. We addressed this issue by subjecting the BTBR animals to three-chambered apparatus, open field, object attention test and elevated open platform. Compared to C57BL/6J control mice, the BTBR mice displayed hyperactivity in most of the tests. In the three-chamber assessment, they exhibited deficits in sociability. In the open field, more grooming and thigmotaxis and less rearing behaviors were observed. They also showed impaired object-based attention. On the elevated open platform, the BTBR animals stayed more to the edges than in the center of the platform. To further examine the properties of this test, naïve C57BL/6J mice were randomly administrated with saline or an anxiogenic substance, caffeine. The caffeine group demonstrated a similar behavioral pattern as the BTBR mice. When the saline group was re-exposed to the same platform, the time they stayed in the center substantially increased, likely due to reduced anxiety by habituation. These results indicate that the BTBR were more anxious than control mice on the open platform. Taken together, the BTBR strain exhibit emotional and cognitive impairments in addition to autistic behaviors, suggesting that they can be a valid model for ASD with psychiatric comorbidity. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Lactobacillus casei Zhang and vitamin K2 prevent intestinal tumorigenesis in mice via adiponectin-elevated different signaling pathways.

    Science.gov (United States)

    Zhang, Yong; Ma, Chen; Zhao, Jie; Xu, Haiyan; Hou, Qiangchuan; Zhang, Heping

    2017-04-11

    The incidence of colon cancer has increased considerably and the intestinal microbiota participate in the development of colon cancer. We showed that the L. casei Zhang or vitamin K2 (Menaquinone-7) intervention significantly alleviated intestinal tumor burden in mice. This was associated with increased serum adiponectin levels in both treatments. But osteocalcin level was only increased by L. casei Zhang. Furthermore, the anti-carcinogenic actions of L. casei Zhang were mediated by hepatic Chloride channel-3(CLCN3)/Nuclear Factor Kappa B(NF-κB) and intestinal Claudin15/Chloride intracellular channel 4(CLIC4)/Transforming Growth Factor Beta(TGF-β) signaling, while the vitamin K2 effect involved a hepatic Vitamin D Receptor(VDR)-phosphorylated AMPK signaling pathway. Fecal DNA sequencing by the Pacbio RSII method revealed there was significantly lower Helicobacter apodemus, Helicobacter mesocricetorum, Allobaculum stercoricanis and Adlercreutzia equolifaciens following both interventions compared to the model group. Moreover, different caecum acetic acid and butyric acid levels and enrichment of other specific microbes also determined the activity of the different regulatory pathways. Together these data show that L. casei Zhang and Vitamin K2 can suppress gut risk microbes and promote beneficial microbial metabolites to reduce colonic tumor development in mice.

  16. Factors secreted from dental pulp stem cells show multifaceted benefits for treating acute lung injury in mice.

    Science.gov (United States)

    Wakayama, Hirotaka; Hashimoto, Naozumi; Matsushita, Yoshihiro; Matsubara, Kohki; Yamamoto, Noriyuki; Hasegawa, Yoshinori; Ueda, Minoru; Yamamoto, Akihito

    2015-08-01

    Acute respiratory distress syndrome (ARDS) is a severe inflammatory disorder characterized by acute respiratory failure, resulting from severe, destructive lung inflammation and irreversible lung fibrosis. We evaluated the use of stem cells derived from human exfoliated deciduous teeth (SHEDs) or SHED-derived serum-free conditioned medium (SHED-CM) as treatments for bleomycin (BLM)-induced mice acute lung injury (ALI), exhibiting several pathogenic features associated with the human disease ARDS. Mice with BLM-induced ALI with or without SHED or SHED-CM treatment were examined for weight loss and survival. The lung tissue was characterized by histological and real-time quantitative polymerase chain reaction analysis. The effects of SHED-CM on macrophage differentiation in vitro were also assessed. A single intravenous administration of either SHEDs or SHED-CM attenuated the lung injury and weight loss in BLM-treated mice and improved their survival rate. Similar recovery levels were seen in the SHEDs and SHED-CM treatment groups, suggesting that SHED improves ALI by paracrine mechanisms. SHED-CM contained multiple therapeutic factors involved in lung-regenerative mechanisms. Importantly, SHED-CM attenuated the BLM-induced pro-inflammatory response and generated an anti-inflammatory/tissue-regenerating environment, accompanied by the induction of anti-inflammatory M2-like lung macrophages. Furthermore, SHED-CM promoted the in vitro differentiation of bone marrow-derived macrophages into M2-like cells, which expressed high levels of Arginase1, CD206 and Ym-1. Our results suggest that SHED-secreted factors provide multifaceted therapeutic effects, including a strong M2-inducing activity, for treating BLM-induced ALI. This work may open new avenues for research on stem cell-based ARDS therapies. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  17. Remote measurement of canopy reflectance shows the effects of elevated carbon dioxide and ozone on the structure and functioning of soybeans in a field setting.

    Science.gov (United States)

    Gray, S.; Dermody, O.; Delucia, E.

    2006-12-01

    By altering physiological processes and modifying canopy structure, elevated atmospheric CO2 and O3 directly and indirectly change the productivity of agroecosystems. Remote sensing of canopy reflectance can be used to monitor physiological and structural changes in an ecosystem over a growing season. To examine effects of changing tropospheric chemistry on water content, chlorophyll content, and changes in leaf area index (LAI), Free-Air Concentration Enrichment (FACE) technology was used to expose large plots of soybean (Glycine max) to elevated atmospheric CO2, elevated O3 (1.5 x ambient), and combined elevated CO2 and O3. The following indices were calculated from weekly measurements of reflectance: water index (WI), photochemical reflectance index (PRI), chlorophyll index, near-infrared/ red (NIR/red), and normalized difference vegetation index (NDVI). NIR/red and LAI were strongly correlated throughout the growth season; however NDVI and LAI were highly correlated only up to LAI of 3. Exposure to elevated CO2 accelerated early-season canopy development and delayed late-season senescence. Growth in elevated O3 had the opposite effect. Additionally, elevated CO2 compensated for negative effects of O3 when the canopy was exposed to both gases simultaneously. Reflectance indices revealed several physiological and structural responses of this agroecosystem to tropospheric change, and ultimately that elevated CO2 and O3 significantly affected this system's productivity and period for carbon gain.

  18. Pax6 interacts with Iba1 and shows age-associated alterations in brain of aging mice.

    Science.gov (United States)

    Maurya, Shashank Kumar; Mishra, Rajnikant

    2017-07-01

    The Pax6, a transcriptional regulator and multifunctional protein, has been found critical for neurogenesis, neuro-degeneration, mental retardation, neuroendocrine tumors, glioblastoma and astrocytomas. The age-associated alteration in the expression of Pax6 in neuron and glia has also been observed in the immunologically privileged brain. Therefore, it is presumed that Pax6 may modulate brain immunity by activation of microglia either directly interacting with genes or proteins of microglia or indirectly though inflammation associated with neurodegeneration. This report describes evaluation of expression, co-localization and interactions of Pax6 with Ionized binding protein1 (Iba1) in brain of aging mice by Immunohistochemistry, Chromatin Immuno-precipitation (ChIP) and Co-immunoprecipitation (Co-IP), respectively. The co-localization of Pax6 with Iba1 was observed in the cerebellum, cerebral cortex, hippocampus, midbrain and olfactory lobe. The Pax6 and Iba1 also interact physically. The age-dependent alteration in their expression and co-localization were also observed in mice. Results indicate Pax6-dependent activities of Iba1 in the remodelling of microglia during immunological surveillance of the brain. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice.

    Directory of Open Access Journals (Sweden)

    Hideki Hayashi

    Full Text Available Inflammation is a common denominator in chronic diseases of aging. Yet, how inflammation fuels these diseases remains unknown. Neutrophils are the primary leukocytes involved in the early phase of innate immunity and inflammation. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs by releasing decondensed chromatin lined with cytotoxic proteins. NETs have been shown to induce tissue injury and thrombosis. Here, we demonstrated that Sirt3, a nicotinamide adenine dinucleotide (NAD+-dependent protein deacetylase, an enzyme linked to human longevity, was expressed in mouse neutrophils and platelets. Using Sirt3-/- mice as a model of accelerated aging, we investigated the effects of Sirt3 deficiency on NETosis and platelet function, aiming to detect enhancement of thrombosis. More mitochondrial reactive oxygen species (ROS were generated in neutrophils and platelets of Sirt3-/- mice compared to WT, when stimulated with a low concentration of phorbol 12-myristate 13-acetate (PMA and a high concentration of thrombin, respectively. There were no differences in in vitro NETosis, with or without stimulation. Platelet aggregation was mildly augmented in Sirt3-/- mice compared to WT mice, when stimulated with a low concentration of collagen. The effect of Sirt3 deficiency on platelet and neutrophil activation in vivo was examined by the venous thrombosis model of inferior vena cava stenosis. Elevation of plasma DNA concentration was observed after stenosis in both genotypes, but no difference was shown between the two genotypes. The systemic response to thrombosis was enhanced in Sirt3-/- mice with significantly elevated neutrophil count and reduced platelet count. However, no differences were observed in incidence of thrombus formation, thrombus weight and thrombin-antithrombin complex generation between WT and Sirt3-/- mice. We conclude that Sirt3 does not considerably impact NET formation, platelet function, or venous

  20. 7-NI and ODQ Disturbs Memory in the Elevated Plus Maze, Morris Water Maze, and Radial Arm Maze Tests in Mice.

    Science.gov (United States)

    Mutlu, Oguz; Akar, Furuzan; Celikyurt, Ipek Komsuoglu; Tanyeri, Pelin; Ulak, Guner; Erden, Faruk

    2015-01-01

    Nitric oxide (NO) is an atypical neurotransmitter that causes changes in cognition. Nitric oxide synthase (NOS) and guanylate cyclase (GC) inhibitors have been shown to exert some effects on cognition in previous studies; however, the findings have been controversial. This study was aimed at understanding the effects of an NOS inhibitor, 7-nitroindazole (7-NI), and a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), on spatial memory in modified elevated plus maze (mEPM), Morris water maze (MWM), and radial arm maze (RAM) tests. Male Balb-c mice were treated via intraperitoneal injections with 7-NI (15 mg/kg), ODQ (3, 10 mg/kg), L-arginine (100 mg/kg) + 7-NI (15 mg/kg), or physiological saline. ODQ (3 mg/kg) and 7-NI (15 mg/kg) significantly increased the second-day latency in the mEPM test. 7-NI (15 mg/kg) and ODQ (10 mg/kg) significantly increased the escape latency in second, third, and fourth sessions, decreased the time spent in the escape platform's quadrant, and increased the mean distance to the platform in the probe trial of the MWM test. ODQ (3, 10 mg/kg) and 7-NI (15 mg/kg) significantly increased the number of errors, whereas only 7-NI increased the latency in the RAM test. The administration of L-arginine (100 mg/kg) prior to 7-NI inverted the effects of 7-NI, which supports the role of NO on cognition. Our study shows that the NO/cGMP/GS pathway can regulate spatial memory in mice.

  1. 7-NI and ODQ Disturbs Memory in the Elevated plus Maze, Morris Water Maze, and Radial Arm Maze Tests in Mice

    Directory of Open Access Journals (Sweden)

    Oguz Mutlu

    2015-01-01

    Full Text Available Nitric oxide (NO is an atypical neurotransmitter that causes changes in cognition. Nitric oxide synthase (NOS and guanylate cyclase (GC inhibitors have been shown to exert some effects on cognition in previous studies; however, the findings have been controversial. This study was aimed at understanding the effects of an NOS inhibitor, 7-nitroindazole (7-NI, and a guanylate cyclase inhibitor, 1 H -[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, on spatial memory in modified elevated plus maze (mEPM, Morris water maze (MWM, and radial arm maze (RAM tests. Male Balb-c mice were treated via intraperitoneal injections with 7-NI (15 mg/kg, ODQ (3, 10 mg/kg, L-arginine (100 mg/kg + 7-NI (15 mg/kg, or physiological saline. ODQ (3 mg/kg and 7-NI (15 mg/kg significantly increased the second-day latency in the mEPM test. 7-NI (15 mg/kg and ODQ (10 mg/kg significantly increased the escape latency in second, third, and fourth sessions, decreased the time spent in the escape platform's quadrant, and increased the mean distance to the platform in the probe trial of the MWM test. ODQ (3, 10 mg/kg and 7-NI (15 mg/kg significantly increased the number of errors, whereas only 7-NI increased the latency in the RAM test. The administration of L-arginine (100 mg/kg prior to 7-NI inverted the effects of 7-NI, which supports the role of NO on cognition. Our study shows that the NO/cGMP/GS pathway can regulate spatial memory in mice.

  2. Mice expressing a “hyper-sensitive” form of the CB1 cannabinoid receptor (CB1) show modestly enhanced alcohol preference and consumption

    Science.gov (United States)

    Gonek, Maciej; Zee, Michael L.; Farnsworth, Jill C.; Amin, Randa A.; Andrews, Mary-Jeanette; Davis, Brian J.; Mackie, Ken; Morgan, Daniel J.

    2017-01-01

    We recently characterized S426A/S430A mutant mice expressing a desensitization-resistant form of the CB1 receptor. These mice display an enhanced response to endocannabinoids and ∆9-THC. In this study, S426A/S430A mutants were used as a novel model to test whether ethanol consumption, morphine dependence, and reward for these drugs are potentiated in mice with a “hyper-sensitive” form of CB1. Using an unlimited-access, two-bottle choice, voluntary drinking paradigm, S426A/S430A mutants exhibit modestly increased intake and preference for low (6%) but not higher concentrations of ethanol. S426A/S430A mutants and wild-type mice show similar taste preference for sucrose and quinine, exhibit normal sensitivity to the hypothermic and ataxic effects of ethanol, and have normal blood ethanol concentrations following administration of ethanol. S426A/S430A mutants develop robust conditioned place preference for ethanol (2 g/kg), morphine (10 mg/kg), and cocaine (10 mg/kg), demonstrating that drug reward is not changed in S426A/S430A mutants. Precipitated morphine withdrawal is also unchanged in opioid-dependent S426A/S430A mutant mice. Although ethanol consumption is modestly changed by enhanced CB1 signaling, reward, tolerance, and acute sensitivity to ethanol and morphine are normal in this model. PMID:28426670

  3. Mice expressing a "hyper-sensitive" form of the CB1 cannabinoid receptor (CB1 show modestly enhanced alcohol preference and consumption.

    Directory of Open Access Journals (Sweden)

    David J Marcus

    Full Text Available We recently characterized S426A/S430A mutant mice expressing a desensitization-resistant form of the CB1 receptor. These mice display an enhanced response to endocannabinoids and ∆9-THC. In this study, S426A/S430A mutants were used as a novel model to test whether ethanol consumption, morphine dependence, and reward for these drugs are potentiated in mice with a "hyper-sensitive" form of CB1. Using an unlimited-access, two-bottle choice, voluntary drinking paradigm, S426A/S430A mutants exhibit modestly increased intake and preference for low (6% but not higher concentrations of ethanol. S426A/S430A mutants and wild-type mice show similar taste preference for sucrose and quinine, exhibit normal sensitivity to the hypothermic and ataxic effects of ethanol, and have normal blood ethanol concentrations following administration of ethanol. S426A/S430A mutants develop robust conditioned place preference for ethanol (2 g/kg, morphine (10 mg/kg, and cocaine (10 mg/kg, demonstrating that drug reward is not changed in S426A/S430A mutants. Precipitated morphine withdrawal is also unchanged in opioid-dependent S426A/S430A mutant mice. Although ethanol consumption is modestly changed by enhanced CB1 signaling, reward, tolerance, and acute sensitivity to ethanol and morphine are normal in this model.

  4. Variant BDNF-Val66Met Polymorphism is Associated with Layer-Specific Alterations in GABAergic Innervation of Pyramidal Neurons, Elevated Anxiety and Reduced Vulnerability of Adolescent Male Mice to Activity-Based Anorexia.

    Science.gov (United States)

    Chen, Yi-Wen; Surgent, Olivia; Rana, Barkha S; Lee, Francis; Aoki, Chiye

    2017-08-01

    Previously, we determined that rodents' vulnerability to food restriction (FR)-evoked wheel running during adolescence (activity-based anorexia, ABA) is associated with failures to increase GABAergic innervation of hippocampal and medial prefrontal pyramidal neurons. Since brain-derived neurotrophic factor (BDNF) promotes GABAergic synaptogenesis, we hypothesized that individual differences in this vulnerability may arise from differences in the link between BDNF bioavailability and FR-evoked wheel running. We tested this hypothesis in male BDNF-Val66Met knock-in mice (BDNFMet/Met), known for reduction in the activity-dependent BDNF secretion and elevated anxiety-like behaviors. We found that 1) in the absence of FR or a wheel (i.e., control), BDNFMet/Met mice are more anxious than wild-type (WT) littermates, 2) electron microscopically verified GABAergic innervations of pyramidal neurons of BDNFMet/Met mice are reduced at distal dendrites in hippocampal CA1 and medial prefrontal cortex, 3) following ABA, WT mice exhibit anxiety equal to those of the BDNFMet/Met mice and have lost GABAergic innervation along distal dendrites, 4) BDNFMet/Met mice show blunted ABA vulnerability, and 5) unexpectedly, GABAergic innervation is higher at somata of BDNFMet/Met mice than of WT. We conclude that lamina-specific GABAergic inhibition is important for regulating anxiety, whether arising from environmental stress, such as food deprivation, or genetically, such as BDNFMet/Met single nucleotide polymorphism. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. L-histidine provokes a state-dependent memory retrieval deficit in mice re-exposed to the elevated plus-maze

    Directory of Open Access Journals (Sweden)

    K.R. Serafim

    2010-01-01

    Full Text Available The effects of L-histidine (LH on anxiety and memory retrieval were investigated in adult male Swiss Albino mice (weight 30-35 g using the elevated plus-maze. The test was performed on two consecutive days: trial 1 (T1 and trial 2 (T2. In T1, mice received an intraperitoneal injection of saline (SAL or LH before the test and were then injected again and retested 24 h later. LH had no effect on anxiety at the dose of 200 mg/kg since there was no difference between the SAL-SAL and LH-LH groups at T1 regarding open-arm entries (OAE and open-arm time (OAT (mean ± SEM; OAE: 4.0 ± 0.71, 4.80 ± 1.05; OAT: 40.55 ± 9.90, 51.55 ± 12.10, respectively; P > 0.05, Kruskal-Wallis test, or at the dose of 500 mg/kg (OAE: 5.27 ± 0.73, 4.87 ± 0.66; OAT: 63.93 ± 11.72, 63.58 ± 10.22; P > 0.05, Fisher LSD test. At T2, LH-LH animals did not reduce open-arm activity (OAE and OAT at the dose of 200 mg/kg (T1: 4.87 ± 0.66, T2: 5.47 ± 1.05; T1: 63.58 ± 10.22; T2: 49.01 ± 8.43 for OAE and OAT, respectively; P > 0.05, Wilcoxon test or at the dose of 500 mg/kg (T1: 4.80 ± 1.60, T2: 4.70 ± 1.04; T1: 51.55 ± 12.10, T2: 43.88 ± 10.64 for OAE and OAT, respectively; P > 0.05, Fisher LSD test, showing an inability to evoke memory 24 h later. These data suggest that LH does not act on anxiety but does induce a state-dependent memory retrieval deficit in mice.

  6. GPR30 activation decreases anxiety in the open field test but not in the elevated plus maze test in female mice.

    Science.gov (United States)

    Anchan, Divya; Clark, Sara; Pollard, Kevin; Vasudevan, Nandini

    2014-01-01

    The GPR30 is a novel estrogen receptor (ER) that is a candidate membrane ER based on its binding to 17β estradiol and its rapid signaling properties such as activation of the extracellular-regulated kinase (ERK) pathway. Its distribution in the mouse limbic system predicts a role for this receptor in the estrogenic modulation of anxiety behaviors in the mouse. A previous study showed that chronic administration of a selective agonist to the GPR30 receptor, G-1, in the female rat can improve spatial memory, suggesting that GPR30 plays a role in hippocampal-dependent cognition. In this study, we investigated the effect of a similar chronic administration of G-1 on behaviors that denote anxiety in adult ovariectomized female mice, using the elevated plus maze (EPM) and the open field test as well as the activation of the ERK pathway in the hippocampus. Although estradiol benzoate had no effect on behaviors in the EPM or the open field, G-1 had an anxiolytic effect solely in the open field that was independent of ERK signaling in either the ventral or dorsal hippocampus. Such an anxiolytic effect may underlie the ability of G-1 to increase spatial memory, by acting on the hippocampus.

  7. Bone marrow from Balb/c mice radiocontaminated with 241Am in utero shows a deficient in vitro haemopoiesis

    International Nuclear Information System (INIS)

    Heuvel, R.L. van den

    1990-01-01

    Radiation damage from 241 Am to bone marrow cells was manifest in long-term bone marrow cultures (LTC) from offspring of mice radiocontaminated at 14th day of gestation (119, 479, 803, 1754 kBq 241 Am kg). Offspring were reared by their own contaminated mother for 3 weeks postnatal. LTC from these offspring were less able to support in vitro CFC proliferation than control LTC. This radiation damage persisted 71 weeks after radiocontamination in utero. Damage was observed at lower doses if 241 Am contamination occurred at foetal rather than adult ages. Radiation damage was observed only using LTC. After culturing LTC in 25% FCS and recharging the stromal adherent layer with bone marrow cell suspensions originating either from control offspring or from offspring contaminated with 241 Am in utero evidence was found that the proliferation capacity of haemopoietic cells was diminished. However, the nature of effects on the stromal elements is currently somewhat equivocal. Following in utero contamination stromal adherent cells appeared to support better production of in vitro CFC. (author)

  8. Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke-Korsakoff syndrome.

    Science.gov (United States)

    Inaba, Hiroyoshi; Kishimoto, Takuya; Oishi, Satoru; Nagata, Kan; Hasegawa, Shunsuke; Watanabe, Tamae; Kida, Satoshi

    2016-12-01

    Patients with severe Wernicke-Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation.

  9. Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke–Korsakoff syndrome

    Science.gov (United States)

    Inaba, Hiroyoshi; Kishimoto, Takuya; Oishi, Satoru; Nagata, Kan; Hasegawa, Shunsuke; Watanabe, Tamae; Kida, Satoshi

    2016-01-01

    Patients with severe Wernicke–Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation. PMID:27576603

  10. Transient elevation of element contents as a result of neuronal death in mutant-mice cerebellum studied by neutron activation analysis

    International Nuclear Information System (INIS)

    Kranda, K.; Kucera, J.; Baeurle, J.

    2006-01-01

    Accumulation of some metals, in particular iron or manganese, has long been considered to trigger or accentuate neurodegenerative processes in humans. The two most frequently cited examples are Parkinson's and Alzheimer diseases, where excitotoxic processes lead to neuronal death. However, these neuropathies are somewhat unsuitable for investigating the time course of the metal accumulation because the applied analytical methods such as neutron activation analysis (NAA) are invasive. Hence, only one measurement can be made after the patient's death. Animal models of Parkinson's type neurodegeneration, such as mice mutants, are more suitable as a larger number of animals can be investigated at various postnatal ages. In this study we used one type of mice mutants weaver, where primary neurodegeneration is principally confined to the cerebellum and centred in time around the postnatal age of six days. Elemental composition of brain segments with dry mass as low as 0.5 mg, which were isolated from weaver and wild type (normal) mice were investigated using a combination of INAA and RNAA. Elevated concentration of the following elements Fe, Zn, Cu, K, Na, Rb, and Br that were observed in the weaver's cerebella closely followed the time course of neurodegeneration documented for this type of mutant. The transient elevation of these elements never preceded the onset of neurodegeneration but closely mirrored its time course reaching its peak on the sixth day. The concentration of these elements in the weaver's cerebella declined afterwards to converge on the elemental time course observed in the wild type mice. In conclusion, metal and other elemental elevation observed in the cerebella of these mutants are an expression of neurodegenerative processes rather than its precondition. (author)

  11. Diet-induced obesity elevates colonic TNF-α in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer.

    Science.gov (United States)

    Liu, Zhenhua; Brooks, Ryan S; Ciappio, Eric D; Kim, Susan J; Crott, Jimmy W; Bennett, Grace; Greenberg, Andrew S; Mason, Joel B

    2012-10-01

    Inflammation associated with obesity may play a role in colorectal carcinogenesis, but the underlying mechanism remains unclear. This study investigated whether the Wnt pathway, an intracellular signaling cascade that plays a critical role in colorectal carcinogenesis, is activated by obesity-induced elevation of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α). Animal studies were conducted on C57BL/6 mice, and obesity was induced by utilizing a high-fat diet (60% kcal). An inflammation-specific microarray was performed, and results were confirmed with real-time polymerase chain reaction. The array revealed that diet-induced obesity increased the expression of TNF-α in the colon by 72% (P=.004) and that of interleukin-18 by 41% (P=.023). The concentration of colonic TNF-α protein, determined by ex vivo culture assay, was nearly doubled in the obese animals (P=.002). The phosphorylation of glycogen synthase kinase 3 beta (GSK3β), an important intermediary inhibitor of Wnt signaling and a potential target of TNF-α, was quantitated by immunohistochemistry. The inactivated (phosphorylated) form of GSK3β was elevated in the colonic mucosa of obese mice (P<.02). Moreover, β-catenin, the key effector of canonical Wnt signaling, was elevated in the colons of obese mice (P<.05), as was the expression of a downstream target gene, c-myc (P<.05). These data demonstrate that diet-induced obesity produces an elevation in colonic TNF-α and instigates a number of alterations of key components within the Wnt signaling pathway that are protransformational in nature. Thus, these observations offer evidence for a biologically plausible avenue, the Wnt pathway, by which obesity increases the risk of colorectal cancer. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Cerebellar nuclei neurons show only small excitatory responses to optogenetic olivary stimulation in transgenic mice: in vivo and in vitro studies

    Directory of Open Access Journals (Sweden)

    Huo eLu

    2016-03-01

    Full Text Available To study the olivary input to the cerebellar nuclei (CN we used optogenetic stimulation in transgenic mice expressing channelrhodopsin-2 (ChR2 in olivary neurons. We obtained in vivo extracellular Purkinje cell (PC and CN recordings in anesthetized mice while stimulating the contralateral inferior olive (IO with a blue laser (single pulse, 10 - 50 ms duration. Peri-stimulus histograms were constructed to show the spike rate changes after optical stimulation. Among 29 CN neurons recorded, 15 showed a decrease in spike rate of variable strength and duration, and only 1 showed a transient spiking response. These results suggest that direct olivary input to CN neurons is usually overridden by stronger Purkinje cell inhibition triggered by climbing fiber responses. To further investigate the direct input from the climbing fiber collaterals we also conducted whole cell recordings in brain slices, where we used local stimulation with blue light. Due to the expression of ChR2 in Purkinje cell axons as well as the IO in our transgenic line, strong inhibitory responses could be readily triggered with optical stimulation (13 of 15 neurons. After blocking this inhibition with GABAzine, only in 5 of 13 CN neurons weak excitatory responses were revealed. Therefore our in vitro results support the in vivo findings that the excitatory input to CN neurons from climbing fiber collaterals in adult mice is masked by the inhibition under normal conditions.

  13. Somatostatin receptor 2 knockout/lacZ knockin mice show impaired motor coordination and reveal sites of somatostatin action within the striatum.

    Science.gov (United States)

    Allen, Jeremy P; Hathway, Gareth J; Clarke, Neil J; Jowett, Mike I; Topps, Stephanie; Kendrick, Keith M; Humphrey, Patrick P A; Wilkinson, Lawrence S; Emson, Piers C

    2003-05-01

    The peptide somatostatin can modulate the functional output of the basal ganglia. The exact sites and mechanisms of this action, however, are poorly understood, and the physiological context in which somatostatin acts is unknown. Somatostatin acts as a neuromodulator via a family of five 7-transmembrane G protein-coupled receptors, SSTR1-5, one of which, SSTR2, is known to be functional in the striatum. We have investigated the role of SSTR2 in basal ganglia function using mice in which Sstr2 has been inactivated and replaced by the lacZ reporter gene. Analysis of Sstr2lacZ expression in the brain by beta-galactosidase histochemistry demonstrated a widespread pattern of expression. By comparison to previously published in situ hybridization and immunohistochemical data, Sstr2lacZ expression was shown to accurately recapitulate that of Sstr2 and thus provided a highly sensitive model to investigate cell-type-specific expression of Sstr2. In the striatum, Sstr2 expression was identified in medium spiny projection neurons restricted to the matrix compartment and in cholinergic interneurons. Sstr2 expression was not detected in any other nuclei of the basal ganglia except for a sparse number of nondopaminergic neurons in the substantia nigra. Microdialysis in the striatum showed Sstr2-null mice were selectively refractory to somatostatin-induced dopamine and glutamate release. In behavioural tests, Sstr2-null mice showed normal levels of locomotor activity and normal coordination in undemanding tasks. However, in beam-walking, a test of fine motor control, Sstr2-null mice were severely impaired. Together these data implicate an important neuromodulatory role for SSTR2 in the striatum.

  14. Elevation of susceptibility to ozone-induced acute tracheobronchial injury in transgenic mice deficient in Clara cell secretory protein

    International Nuclear Information System (INIS)

    Plopper, C.G.; Mango, G.W.; Hatch, G.E.; Wong, V.J.; Toskala, E.; Reynolds, S.D.; Tarkington, B.K.; Stripp, B.R.

    2006-01-01

    Increases in Clara cell abundance or cellular expression of Clara cell secretory protein (CCSP) may cause increased tolerance of the lung to acute oxidant injury by repeated exposure to ozone (O 3 ). This study defines how disruption of the gene for CCSP synthesis affects the susceptibility of tracheobronchial epithelium to acute oxidant injury. Mice homozygous for a null allele of the CCSP gene (CCSP-/-) and wild type (CCSP+/+) littermates were exposed to ozone (0.2 ppm, 8 h; 1 ppm, 8 h) or filtered air. Injury was evaluated by light and scanning electron microscopy, and the abundance of necrotic, ciliated, and nonciliated cells was estimated by morphometry. Proximal and midlevel intrapulmonary airways and terminal bronchioles were evaluated. There was no difference in airway epithelial composition between CCSP+/+ and CCSP-/- mice exposed to filtered air, and exposure to 0.2 ppm ozone caused little injury to the epithelium of both CCSP+/+ and CCSP-/- mice. After exposure to 1.0 ppm ozone, CCSP-/- mice suffered from a greater degree of epithelial injury throughout the airways compared to CCSP+/+ mice. CCSP-/- mice had both ciliated and nonciliated cell injury. Furthermore, lack of CCSP was associated with a shift in airway injury to include proximal airway generations. Therefore, we conclude that CCSP modulates the susceptibility of the epithelium to oxidant-induced injury. Whether this is due to the presence of CCSP on the acellular lining layer surface and/or its intracellular distribution in the secretory cell population needs to be defined

  15. Cavin-3 knockout mice show that cavin-3 is not essential for caveolae formation, for maintenance of body composition, or for glucose tolerance.

    Directory of Open Access Journals (Sweden)

    Libin Liu

    Full Text Available The cavins are a family of proteins associated with caveolae, cavin-1, -2 and -3 being widely expressed while cavin-4 is restricted to striated muscle. Deletion of cavin-1 results in phenotypes including metabolic changes consistent with adipocyte dysfunction, and caveolae are completely absent. Deletion of cavin-2 causes tissue-specific loss of caveolae. The consequences of cavin-3 deletion are less clear, as there are divergent data on the abundance of caveolae in cavin-3 null mice. Here we examine the consequences of cavin-3 deficiency in vivo by making cavin-3 knockout mice. We find that loss of cavin-3 has minimal or no effects on the levels of other caveolar proteins, does not appear to play a major role in formation of protein complexes important for caveolar morphogenesis, and has no significant effect on caveolae abundance. Cavin-3 null mice have the same body weight and fat mass as wild type animals at ages 8 through 30 weeks on both normal chow and high fat diets. Likewise, the two mouse strains exhibit identical glucose tolerance tests on both diets. Microarray analysis from adipose tissue shows that the changes in mRNA expression between cavin-3 null and wild type mouse are minimal. We conclude that cavin-3 is not absolutely required for making caveolae, and suggest that the mechanistic link between cavin-3 and metabolic regulation remains uncertain.

  16. A Newly Emergent Turkey Arthritis Reovirus Shows Dominant Enteric Tropism and Induces Significantly Elevated Innate Antiviral and T Helper-1 Cytokine Responses.

    Directory of Open Access Journals (Sweden)

    Tamer A Sharafeldin

    Full Text Available Newly emergent turkey arthritis reoviruses (TARV were isolated from tendons of lame 15-week-old tom turkeys that occasionally had ruptured leg tendons. Experimentally, these TARVs induced remarkable tenosynovitis in gastrocnemius tendons of turkey poults. The current study aimed to characterize the location and the extent of virus replication as well as the cytokine response induced by TARV during the first two weeks of infection. One-week-old male turkeys were inoculated orally with TARV (O'Neil strain. Copy numbers of viral genes were estimated in intestines, internal organs and tendons at ½, 1, 2, 3, 4, 7, 14 days Post inoculation (dpi. Cytokine profile was measured in intestines, spleen and leg tendons at 0, 4, 7 and 14 dpi. Viral copy number peaked in jejunum, cecum and bursa of Fabricius at 4 dpi. Copy numbers increased dramatically in leg tendons at 7 and 14 dpi while minimal copies were detected in internal organs and blood during the same period. Virus was detected in cloacal swabs at 1-2 dpi, and peaked at 14 dpi indicating enterotropism of the virus and its early shedding in feces. Elevation of IFN-α and IFN-β was observed in intestines at 7 dpi as well as a prominent T helper-1 response (IFN-γ at 7 and 14 dpi. IFN-γ and IL-6 were elevated in gastrocnemius tendons at 14 dpi. Elevation of antiviral cytokines in intestines occurred at 7dpi when a significant decline of viral replication in intestines was observed. T helper-1 response in intestines and leg tendons was the dominant T-helper response. These results suggest the possible correlation between viral replication and cytokine response in early infection of TARV in turkeys. Our findings provide novel insights which help elucidate viral pathogenesis in turkey tendons infected with TARV.

  17. Relative Biological Effectiveness of Energetic Heavy Ions for Intestinal Tumorigenesis Shows Male Preponderance and Radiation Type and Energy Dependence in APC{sup 1638N/+} Mice

    Energy Technology Data Exchange (ETDEWEB)

    Suman, Shubhankar; Kumar, Santosh; Moon, Bo-Hyun; Strawn, Steve J.; Thakor, Hemang; Fan, Ziling [Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia (United States); Shay, Jerry W. [Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas (United States); Fornace, Albert J. [Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia (United States); Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah (Saudi Arabia); Datta, Kamal, E-mail: kd257@georgetown.edu [Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia (United States)

    2016-05-01

    Purpose: There are uncertainties associated with the prediction of colorectal cancer (CRC) risk from highly energetic heavy ion (HZE) radiation. We undertook a comprehensive assessment of intestinal and colonic tumorigenesis induced after exposure to high linear energy transfer (high-LET) HZE radiation spanning a range of doses and LET in a CRC mouse model and compared the results with the effects of low-LET γ radiation. Methods and Materials: Male and female APC{sup 1638N/+} mice (n=20 mice per group) were whole-body exposed to sham-radiation, γ rays, {sup 12}C, {sup 28}Si, or {sup 56}Fe radiation. For the >1 Gy HZE dose, we used γ-ray equitoxic doses calculated using relative biological effectiveness (RBE) determined previously. The mice were euthanized 150 days after irradiation, and intestinal and colon tumor frequency was scored. Results: The highest number of tumors was observed after {sup 28}Si, followed by {sup 56}Fe and {sup 12}C radiation, and tumorigenesis showed a male preponderance, especially after {sup 28}Si. Analysis showed greater tumorigenesis per unit of radiation (per cGy) at lower doses, suggesting either radiation-induced elimination of target cells or tumorigenesis reaching a saturation point at higher doses. Calculation of RBE for intestinal and colon tumorigenesis showed the highest value with {sup 28}Si, and lower doses showed greater RBE relative to higher doses. Conclusions: We have demonstrated that the RBE of heavy ion radiation-induced intestinal and colon tumorigenesis is related to ion energy, LET, gender, and peak RBE is observed at an LET of 69 keV/μm. Our study has implications for understanding risk to astronauts undertaking long duration space missions.

  18. Chronic social isolation and chronic variable stress during early development induce later elevated ethanol intake in adult C57BL/6J mice.

    Science.gov (United States)

    Lopez, Marcelo F; Doremus-Fitzwater, Tamara L; Becker, Howard C

    2011-06-01

    ). For mice that did not experience CVS, early social isolation resulted in greater ethanol intake compared with group-housed mice (Experiment 3). CVS subsequently resulted in a significant increase in ethanol intake in group-housed mice, but CVS failed to further increase ethanol intake in mice that experienced chronic social isolation early in life (Experiment 3). Overall, female mice consumed more ethanol than males, whether isolated (early or late) or group housed. These results indicate that early but not late social isolation can subsequently influence ethanol consumption in C57BL/6J mice. Thus, the developmental timing of chronic social isolation appears to be an important factor in defining later effects on ethanol self-administration behavior. In addition, experience with CVS early in life results in elevated ethanol intake later in adulthood. Taken together, these results emphasize the important role of early stress experiences that modulate later voluntary ethanol intake during adulthood. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Separating the roles of nitrogen and oxygen in high pressure-induced blood-borne microparticle elevations, neutrophil activation, and vascular injury in mice.

    Science.gov (United States)

    Yang, Ming; Bhopale, Veena M; Thom, Stephen R

    2015-08-01

    An elevation in levels of circulating microparticles (MPs) due to high air pressure exposure and the associated inflammatory changes and vascular injury that occur with it may be due to oxidative stress. We hypothesized that these responses arise due to elevated partial pressures of N2 and not because of high-pressure O2. A comparison was made among high-pressure air, normoxic high-pressure N2, and high-pressure O2 in causing an elevation in circulating annexin V-positive MPs, neutrophil activation, and vascular injury by assessing the leakage of high-molecular-weight dextran in a murine model. After mice were exposed for 2 h to 790 kPa air, there were over 3-fold elevations in total circulating MPs as well as subgroups bearing Ly6G, CD41, Ter119, CD31, and CD142 surface proteins-evidence of neutrophil activation; platelet-neutrophil interaction; and vascular injury to brain, omentum, psoas, and skeletal muscles. Similar changes were found in mice exposed to high-pressure N2 using a gas mixture so that O2 partial pressure was the same as that of ambient air, whereas none of these changes occurred after exposures to 166 kPa O2, the same partial pressure that occurs during high-pressure air exposures. We conclude that N2 plays a central role in intra- and perivascular changes associated with exposure to high air pressure and that these responses appear to be a novel form of oxidative stress. Copyright © 2015 the American Physiological Society.

  20. Histopathological studies show protective efficacy of Hippophae leaf extract against damage to jejunum in whole body 60Co-a-irradiated mice

    International Nuclear Information System (INIS)

    Gupta, Manish; Prasad, Jagdish; Madhu Bala

    2012-01-01

    Background: Ionizing radiation affect living tissue by causing majority of in vivo damage by free radical production. Earlier we reported that our preparation from Hippophae leaf offered survival benefit to >90% mice population which was whole body irradiated ( 60 Co-a-rays, 10 Gy). Objective: This study was planned to examine the protective effects of our drug (from Hippophae leaf) on ( 60 Co-a-ray induced oxidative damage and histopathological changes in jejunum. Methods: Around 2 months old adult male Strain 'A' mice were irradiated (10 Gy). Drug was administered intraperitoneally (-30 mm.). Histological parameters were studied after staining the sections with hematoxylin and eosin. Malondialdehyde formation (index of lipid peroxidation), alkaline phosphatase activity, and total thiol content were determined by biochemical techniques. The data was obtained at different time interval upto 30 days. Results: Biochemical studies showed that in comparison to the untreated controls, in the irradiated (10 Gy) mice, there was significant increase in the alkaline phosphatase activity and level of malondialdehyde whereas decrease in total thiol content within 2 days. Histological studies showed that whole body irradiation (10 Gy), damaged the jejunam crypt cells and decreased the villi height within 2 days. Intra-peritoneal administration of drug, 30 mm prior to irradiation, protected the crypt cells and villi height, countered the radiation induced increase in alkaline phosphatase activity and lipid peroxidation and values were comparable to the level of control in 30 days. Conclusions: These biochemical and histopathological studies suggested that our drug can offer effective radioprotection against the oxidative damage to jejunum in vivo. (author)

  1. High-salt diet combined with elevated angiotensin II accelerates atherosclerosis in apolipoprotein E-deficient mice

    DEFF Research Database (Denmark)

    Johansson, Maria E; Bernberg, Evelina; Andersson, Irene J

    2009-01-01

    to atherosclerosis. METHODS: Apolipoprotein E-deficient (ApoE-/-) mice received standard or high-salt diet (8%) alone or in combination with fixed angiotensin II (Ang II) infusion (0.5 microg/kg per min). BP was measured using telemetry, and plaque burden was assessed in the thoracic aorta and innominate artery. We...

  2. Eicosanoyl-5-hydroxytryptamide (EHT prevents Alzheimer's disease-related cognitive and electrophysiological impairments in mice exposed to elevated concentrations of oligomeric beta-amyloid.

    Directory of Open Access Journals (Sweden)

    Kesava Asam

    Full Text Available Soluble forms of oligomeric beta-amyloid (Aβ are thought to play a central role in Alzheimer's disease (AD. Transgenic manipulation of methylation of the serine/threonine protein phosphatase, PP2A, was recently shown to alter the sensitivity of mice to AD-related impairments resulting from acute exposure to elevated levels of Aβ. In addition, eicosanoyl-5-hydroxytryptamide (EHT, a naturally occurring component from coffee beans that modulates PP2A methylation, was shown to confer therapeutic benefits in rodent models of AD and Parkinson's disease. Here, we tested the hypothesis that EHT protects animals from the pathological effects of exposure to elevated levels of soluble oligomeric Aβ. We treated mice with EHT-containing food at two different doses and assessed the sensitivity of these animals to Aβ-induced behavioral and electrophysiological impairments. We found that EHT administration protected animals from Aβ-induced cognitive impairments in both a radial-arm water maze and contextual fear conditioning task. We also found that both chronic and acute EHT administration prevented Aβ-induced impairments in long-term potentiation. These data add to the accumulating evidence suggesting that interventions with pharmacological agents, such as EHT, that target PP2A activity may be therapeutically beneficial for AD and other neurological conditions.

  3. Antigens of worms and eggs showed a differentiated detection of specific IgG according to the time of Schistosoma mansoni infection in mice

    Directory of Open Access Journals (Sweden)

    Rafaella Fortini Queiroz Grenfell

    2012-08-01

    Full Text Available INTRODUCTION: The correlation between the immunological assay and the antibody titer can offer a tool for the experimental analysis of different phases of the disease. METHODS: Two simple immunological assays for Schistosoma mansoni in mice sera samples based on specific IgG detection for worms soluble antigens and eggs soluble antigens were standardized and evaluated in our laboratory. Fifty mice were used in negative and positive groups and the results obtained by enzyme-linked immunosorbent assays (ELISA assays were compared with the number of worms counted and the IgG titers at different times of infection. RESULTS: Data showed that ELISA using adult worm antigens (ELISA-SWAP presented a satisfactory correlation between the absorbance value of IgG titers and the individual number of worms counted after perfusion technique (R²=0.62. In addition, ELISA-SWAP differentially detected positive samples with 30 and 60 days post infection (p=0.011 and 0.003, respectively, whereas ELISA using egg antigens (ELISA-SEA detected samples after 140 days (p=0.03. CONCLUSIONS: These data show that the use of different antigens in immunological methods can be used as potential tools for the analysis of the chronological evolution of S. mansoni infection in murine schistosomiasis. Correlations with human schistosomiasis are discussed.

  4. Human neuroblastoma SH-SY5Y cells show increased resistance to hyperthermic stress after differentiation, associated with elevated levels of Hsp72.

    Science.gov (United States)

    Cheng, Lesley; Smith, Danielle J; Anderson, Robin L; Nagley, Phillip

    2011-01-01

    Terminally differentiated neurones in the central nervous system need to be protected from stress. We ask here whether differentiation of progenitor cells to neurones is accompanied by up-regulation of Hsp72, with acquisition of enhanced thermotolerance. Human neuroblastoma SH-SY5Y cells were propagated in an undifferentiated form and subsequently differentiated into neurone-like cells. Thermotolerance tests were carried out by exposure of cells to various temperatures, monitoring nuclear morphology as index of cell death. Abundance of Hsp72 was measured in cell lysates by western immunoblotting. The differentiation of SH-SY5Y cells was accompanied by increased expression of Hsp72. Further, in both cell states, exposure to mild hyperthermic stress (43°C for 30 min) increased Hsp72 expression. After differentiation, SH-SY5Y cells were more resistant to hyperthermic stress compared to their undifferentiated state, correlating with levels of Hsp72. Stable exogenous expression of Hsp72 in SH-SY5Y cells (transfected line 5YHSP72.1, containing mildly elevated levels of Hsp72), led to enhanced resistance to hyperthermic stress. Hsp72 was found to be inducible in undifferentiated 5YHSP72.1 cells; such heat-treated cells displayed enhanced thermotolerance. Treatment of cells with KNK437, a suppressor of Hsp72 induction, resulted in acute thermosensitisation of all cell types tested here. Hsp72 has a major role in the enhanced hyperthermic resistance acquired during neuronal differentiation of SH-SY5Y cells. These findings model the requirement in intact organisms for highly differentiated neurones to be specially protected against thermal stress.

  5. Ghrelin is produced in taste cells and ghrelin receptor null mice show reduced taste responsivity to salty (NaCl and sour (citric acid tastants.

    Directory of Open Access Journals (Sweden)

    Yu-Kyong Shin

    2010-09-01

    Full Text Available The gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved.Using immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present within the taste buds of the tongue. Prepro-ghrelin, prohormone convertase 1/3 (PC 1/3, ghrelin, its cognate receptor (GHSR, and ghrelin-O-acyltransferase (GOAT , the enzyme that activates ghrelin are expressed in Type I, II, III and IV taste cells of mouse taste buds. In addition, ghrelin and GHSR co-localize in the same taste cells, suggesting that ghrelin works in an autocrine manner in taste cells. To determine a role for ghrelin in modifying taste perception, we performed taste behavioral tests using GHSR null mice. GHSR null mice exhibited significantly reduced taste responsivity to sour (citric acid and salty (sodium chloride tastants.These findings suggest that ghrelin plays a local modulatory role in determining taste bud signaling and function and could be a novel mechanism for the modulation of salty and sour taste responsivity.

  6. Comprehensive Behavioral Analysis of Male Ox1r−/− Mice Showed Implication of Orexin Receptor-1 in Mood, Anxiety, and Social Behavior

    Science.gov (United States)

    Abbas, Md. G.; Shoji, Hirotaka; Soya, Shingo; Hondo, Mari; Miyakawa, Tsuyoshi; Sakurai, Takeshi

    2015-01-01

    Neuropeptides orexin A and orexin B, which are exclusively produced by neurons in the lateral hypothalamic area, play an important role in the regulation of a wide range of behaviors and homeostatic processes, including regulation of sleep/wakefulness states and energy homeostasis. The orexin system has close anatomical and functional relationships with systems that regulate the autonomic nervous system, emotion, mood, the reward system, and sleep/wakefulness states. Recent pharmacological studies using selective antagonists have suggested that orexin receptor-1 (OX1R) is involved in physiological processes that regulate emotion, the reward system, and autonomic nervous system. Here, we examined Ox1r−/− mice with a comprehensive behavioral test battery to screen additional OX1R functions. Ox1r−/− mice showed increased anxiety-like behavior, altered depression-like behavior, slightly decreased spontaneous locomotor activity, reduced social interaction, increased startle response, and decreased prepulse inhibition. These results suggest that OX1R plays roles in social behavior and sensory motor gating in addition to roles in mood and anxiety. PMID:26696848

  7. The environmental chemical tributyltin chloride (TBT) shows both estrogenic and adipogenic activities in mice which might depend on the exposure dose

    International Nuclear Information System (INIS)

    Penza, M.; Jeremic, M.; Marrazzo, E.; Maggi, A.; Ciana, P.; Rando, G.; Grigolato, P.G.; Di Lorenzo, D.

    2011-01-01

    Exposure during early development to chemicals with hormonal action may be associated with weight gain during adulthood because of altered body homeostasis. It is known that organotins affect adipose mass when exposure occurs during fetal development, although no knowledge of effects are available for exposures after birth. Here we show that the environmental organotin tributyltin chloride (TBT) exerts adipogenic action when peripubertal and sexually mature mice are exposed to the chemical. The duration and extent of these effects depend on the sex and on the dose of the compound, and the effects are relevant at doses close to the estimated human intake (0.5 μg/kg). At higher doses (50-500 μg/kg), TBT also activated estrogen receptors (ERs) in adipose cells in vitro and in vivo, based on results from acute and longitudinal studies in ERE/luciferase reporter mice. In 3T3-L1 cells (which have no ERs), transiently transfected with the ERE-dependent reporter plus or minus ERα or ERβ, TBT (in a dose range of 1-100 nM) directly targets each ER subtype in a receptor-specific manner through a direct mechanism mediated by ERα in undifferentiated preadipocytic cells and by ERβ in differentiating adipocytes. The ER antagonist ICI-182,780 inhibits this effect. In summary, the results of this work suggest that TBT is adipogenic at all ages and in both sexes and that it might be an ER activator in fat cells. These findings might help to resolve the apparent paradox of an adipogenic chemical being also an estrogen receptor activator by showing that the two apparently opposite actions are separated by the different doses to which the organism is exposed. - Research highlights: → The environmental organotin tributyltin chloride shows dose-dependent estrogenic and adipogenic activities in mice. → The duration and extent of these effects depend on the sex and the dose of the compound. → The estrogenic and adipogenic effects of TBT occur at doses closed to the estimated

  8. Chronic self-administration of alcohol results in elevated ΔFosB: comparison of hybrid mice with distinct drinking patterns

    Directory of Open Access Journals (Sweden)

    Ozburn Angela R

    2012-10-01

    Full Text Available Abstract Background The inability to reduce or regulate alcohol intake is a hallmark symptom for alcohol use disorders. Research on novel behavioral and genetic models of experience-induced changes in drinking will further our knowledge on alcohol use disorders. Distinct alcohol self-administration behaviors were previously observed when comparing two F1 hybrid strains of mice: C57BL/6J x NZB/B1NJ (BxN show reduced alcohol preference after experience with high concentrations of alcohol and periods of abstinence while C57BL/6J x FVB/NJ (BxF show sustained alcohol preference. These phenotypes are interesting because these hybrids demonstrate the occurrence of genetic additivity (BxN and overdominance (BxF in ethanol intake in an experience dependent manner. Specifically, BxF exhibit sustained alcohol preference and BxN exhibit reduced alcohol preference after experience with high ethanol concentrations; however, experience with low ethanol concentrations produce sustained alcohol preference for both hybrids. In the present study, we tested the hypothesis that these phenotypes are represented by differential production of the inducible transcription factor, ΔFosB, in reward, aversion, and stress related brain regions. Results Changes in neuronal plasticity (as measured by ΔFosB levels were experience dependent, as well as brain region and genotype specific, further supporting that neuronal circuitry underlies motivational aspects of ethanol consumption. BxN mice exhibiting reduced alcohol preference had lower ΔFosB levels in the Edinger-Westphal nucleus than mice exhibiting sustained alcohol preference, and increased ΔFosB levels in central medial amygdala as compared with control mice. BxN mice showing sustained alcohol preference exhibited higher ΔFosB levels in the ventral tegmental area, Edinger-Westphal nucleus, and amygdala (central and lateral divisions. Moreover, in BxN mice ΔFosB levels in the Edinger-Westphal nucleus and ventral

  9. Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.

    Directory of Open Access Journals (Sweden)

    Syed Nuruddin

    Full Text Available Research on Alzheimer's disease (AD has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh and its receptor (Gnrhr were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate. The study was performed on mice carrying the Arctic and Swedish amyloid-β precursor protein (AβPP mutations (tgArcSwe. At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental

  10. The environmental chemical tributyltin chloride (TBT) shows both estrogenic and adipogenic activities in mice which might depend on the exposure dose.

    Science.gov (United States)

    Penza, M; Jeremic, M; Marrazzo, E; Maggi, A; Ciana, P; Rando, G; Grigolato, P G; Di Lorenzo, D

    2011-08-15

    Exposure during early development to chemicals with hormonal action may be associated with weight gain during adulthood because of altered body homeostasis. It is known that organotins affect adipose mass when exposure occurs during fetal development, although no knowledge of effects are available for exposures after birth. Here we show that the environmental organotin tributyltin chloride (TBT) exerts adipogenic action when peripubertal and sexually mature mice are exposed to the chemical. The duration and extent of these effects depend on the sex and on the dose of the compound, and the effects are relevant at doses close to the estimated human intake (0.5μg/kg). At higher doses (50-500μg/kg), TBT also activated estrogen receptors (ERs) in adipose cells in vitro and in vivo, based on results from acute and longitudinal studies in ERE/luciferase reporter mice. In 3T3-L1 cells (which have no ERs), transiently transfected with the ERE-dependent reporter plus or minus ERα or ERβ, TBT (in a dose range of 1-100nM) directly targets each ER subtype in a receptor-specific manner through a direct mechanism mediated by ERα in undifferentiated preadipocytic cells and by ERβ in differentiating adipocytes. The ER antagonist ICI-182,780 inhibits this effect. In summary, the results of this work suggest that TBT is adipogenic at all ages and in both sexes and that it might be an ER activator in fat cells. These findings might help to resolve the apparent paradox of an adipogenic chemical being also an estrogen receptor activator by showing that the two apparently opposite actions are separated by the different doses to which the organism is exposed. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action

    Science.gov (United States)

    Currie, Richard A.; Peffer, Richard C.; Goetz, Amber K.; Omiecinski, Curtis J.; Goodman, Jay I.

    2014-01-01

    Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA. PMID:24675475

  12. Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action

    International Nuclear Information System (INIS)

    Currie, Richard A.; Peffer, Richard C.; Goetz, Amber K.; Omiecinski, Curtis J.; Goodman, Jay I.

    2014-01-01

    Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA

  13. Elevated mRNA-levels of distinct mitochondrial and plasma membrane Ca2+ transporters in individual hypoglossal motor neurons of endstage SOD1 transgenic mice.

    Directory of Open Access Journals (Sweden)

    Tobias eMühling

    2014-11-01

    Full Text Available Disturbances in Ca2+ homeostasis and mitochondrial dysfunction have emerged as major pathogenic features in familial and sporadic forms of Amyotrophic Lateral Sclerosis (ALS, a fatal degenerative motor neuron disease. However, the distinct molecular ALS-pathology remains unclear. Recently, an activity-dependent Ca2+ homeostasis deficit, selectively in highly vulnerable cholinergic motor neurons in the hypoglossal nucleus (hMNs from a common ALS mouse model, endstage superoxide dismutase SOD1G93A transgenic mice, was described. This functional deficit was defined by a reduced hMN mitochondrial Ca2+ uptake capacity and elevated Ca2+ extrusion across the plasma membrane. To address the underlying molecular mechanisms, here we quantified mRNA-levels of respective potential mitochondrial and plasma membrane Ca2+ transporters in individual, choline-acetyltransferase (ChAT positive hMNs from wildtype (WT and endstage SOD1G93A mice, by combining UV laser microdissection with RT-qPCR techniques, and specific data normalization. As ChAT cDNA levels as well as cDNA and genomic DNA levels of the mitochondrially encoded NADH dehydrogenase ND1 were not different between hMNs from WT and endstage SOD1G93A mice, these genes were used to normalize hMN-specific mRNA-levels of plasma membrane and mitochondrial Ca2+ transporters, respectively. We detected about 2-fold higher levels of the mitochondrial Ca2+ transporters MCU/MICU1, Letm1 and UCP2 in remaining hMNs from endstage SOD1G93A mice. These higher expression-levels of mitochondrial Ca2+ transporters in individual hMNs were not associated with a respective increase in number of mitochondrial genomes, as evident from hMN specific ND1 DNA quantification. Normalized mRNA-levels for the plasma membrane Na2+/Ca2+exchanger NCX1 was also about 2-fold higher in hMNs from SOD1G93A mice. Thus, pharmacological stimulation of Ca2+ transporters in highly vulnerable hMNs might offer a novel neuroprotective strategy for ALS.

  14. Influence of spatial and temporal manipulations on the anxiolytic efficacy of chlordiazepoxide in mice previously exposed to the elevated plus-maze.

    Science.gov (United States)

    Holmes, A; Rodgers, R J

    1999-11-01

    It has been widely reported that the anxiolytic efficacy of benzodiazepines in the elevated plus-maze test is abolished in subjects (rats or mice) that have been given a single prior undrugged experience of the test apparatus. The present series of experiments was designed to further characterise the key experiential determinants of this intriguing phenomenon in Swiss Webster mice. Using a standard 5 min test duration for both trials, Experiment 1 confirmed the anxiolytic efficacy of chlordiazepoxide (CDP; 5-20 mg/kg) in mice naive to the plus-maze, but a virtual elimination of drug effects in animals that had been pre-exposed to the maze 24 h earlier. Experiments 2 and 3 demonstrated that, while extending the duration of initial exposure to 10 min did not prevent the loss of CDP (10 mg/kg) efficacy in a standard-duration second trial, increasing the duration of both trials reinstated an anxiolytic profile for the compound. Finally, although trial 1 confinement to an open arm did not compromise CDP efficacy when animals were subsequently allowed to freely explore the maze (Experiment 4), closed arm confinement during initial exposure abolished the drug's anxiolytic action upon retest (Experiment 5). In contrast to previous findings in rats, these data suggest that the experientially induced loss of benzodiazepine efficacy in the mouse plus-maze depends rather critically upon prior discovery and exploration of relatively safe areas of the maze (i.e. closed arms). Results are discussed in relation to the hypothesis that the absence of an anxiolytic response to benzodiazepines in plus-maze-experienced subjects reflects the acquisition of an open arm phobia during trial 1.

  15. A water-soluble extract of chicken reduced plasma triacylglycerols, but showed no anti-atherosclerotic activity in apoE−/− mice

    Directory of Open Access Journals (Sweden)

    Rita Vik

    2015-08-01

    Conclusion: Chicken protein displayed a slight potential to increase mitochondrial fatty acid oxidation and reduce plasma TAG. However, CP did not affect plasma cholesterol levels, inflammation status or atherosclerotic development in apoE−/− mice. Based on these results, dietary intervention with CP does not have sufficient capacity to influence atherosclerotic development in apoE−/− mice.

  16. Time-dependent toxicity of cadmium telluride quantum dots on liver and kidneys in mice: histopathological changes with elevated free cadmium ions and hydroxyl radicals.

    Science.gov (United States)

    Wang, Mengmeng; Wang, Jilong; Sun, Hubo; Han, Sihai; Feng, Shuai; Shi, Lu; Meng, Peijun; Li, Jiayi; Huang, Peili; Sun, Zhiwei

    2016-01-01

    A complete understanding of the toxicological behavior of quantum dots (QDs) in vivo is of great importance and a prerequisite for their application in humans. In contrast with the numerous cytotoxicity studies investigating QDs, only a few in vivo studies of QDs have been reported, and the issue remains controversial. Our study aimed to understand QD-mediated toxicity across different time points and to explore the roles of free cadmium ions (Cd(2+)) and hydroxyl radicals (·OH) in tissue damage. Male ICR mice were administered a single intravenous dose (1.5 µmol/kg) of CdTe QDs, and liver and kidney function and morphology were subsequently examined at 1, 7, 14, and 28 days. Furthermore, ·OH production in the tissue was quantified by trapping · OH with salicylic acid (SA) as 2,3-dihydroxybenzoic acid (DHBA) and detecting it using a high-performance liquid chromatography fluorescence method. We used the induction of tissue metallothionein levels and 2,3-DHBA:SA ratios as markers for elevated Cd(2+) from the degradation of QDs and ·OH generation in the tissue, respectively. Our experimental results revealed that the QD-induced histopathological changes were time-dependent with elevated Cd(2+) and ·OH, and could recover after a period of time. The Cd(2+) and ·OH exhibited delayed effects in terms of histopathological abnormalities. Histological assessments performed at multiple time points might facilitate the evaluation of the biological safety of QDs.

  17. Elevating your elevator talk

    Science.gov (United States)

    An important and often overlooked item that every early career researcher needs to do is compose an elevator talk. The elevator talk, named because the talk should not last longer than an average elevator ride (30 to 60 seconds), is an effective method to present your research and yourself in a clea...

  18. Liver-specific Aquaporin 11 knockout mice show rapid vacuolization of the rough endoplasmic reticulum in periportal hepatocytes after amino acid feeding

    DEFF Research Database (Denmark)

    Rojek, Aleksandra; Füchtbauer, Ernst-Martin; Füchtbauer, Annette C.

    2013-01-01

    -specific Aqp11 KO mice, allowing us to study the role of AQP11 protein in liver of mice with normal kidney function. The unchallenged liver-specific Aqp11 KO mice have normal longevity, their livers appeared normal, and the plasma biochemistries revealed only a minor defect in lipid handling. Fasting......Aquaporin 11 (AQP11) is a protein channel expressed intracellularly in multiple organs, yet its physiological function is unclear. Aqp11 knockout (KO) mice die early due to malfunction of the kidney, a result of hydropic degeneration of proximal tubule cells. Here we report the generation of liver...... protein or larger doses of various amino acids. The fasting/refeeding challenge is associated with increased expression of markers of ER stress Grp78 and GADD153 and decreased glutathione levels, suggesting that ER stress may play role in the development of vacuoles in the AQP11-deficient hepatocytes. NMR...

  19. Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks.

    Science.gov (United States)

    Bour, Alexandra; Grootendorst, Jeannette; Vogel, Elise; Kelche, Christian; Dodart, Jean-Cosme; Bales, Kelly; Moreau, Pierre-Henri; Sullivan, Patrick M; Mathis, Chantal

    2008-11-21

    Apolipoprotein (apo) E4, one of three human apoE (h-apoE) isoforms, has been identified as a major genetic risk factor for Alzheimer's disease and for cognitive deficits associated with aging. However, the biological mechanisms involving apoE in learning and memory processes are unclear. A potential isoform-dependent role of apoE in cognitive processes was studied in human apoE targeted-replacement (TR) mice. These mice express either the human apoE3 or apoE4 gene under the control of endogenous murine apoE regulatory sequences, resulting in physiological expression of h-apoE in both a temporal and spatial pattern similar to humans. Male and female apoE3-TR, apoE4-TR, apoE-knockout and C57BL/6J mice (15-18 months) were tested with spatial memory and avoidance conditioning tasks. Compared to apoE3-TR mice, spatial memory in female apoE4-TR mice was impaired based on their poor performances in; (i) the probe test of the water-maze reference memory task, (ii) the water-maze working memory task and (iii) an active avoidance Y-maze task. Retention performance on a passive avoidance task was also impaired in apoE4-TR mice, but not in other genotypes. These deficits in both spatial and avoidance memory tasks may be related to the anatomical and functional abnormalities previously reported in the hippocampus and the amygdala of apoE4-TR mice. We conclude that the apoE4-TR mice provide an excellent model for understanding the mechanisms underlying apoE4-dependent susceptibility to cognitive decline.

  20. Transdermal and oral dl-methylphenidate-ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations.

    Science.gov (United States)

    Bell, Guinevere H; Novak, Andrew J; Griffin, William C; Patrick, Kennerly S

    2011-07-01

    We tested the hypothesis that C57BL/6J mice will model human metabolic interactions between dl-methylphenidate (MPH) and ethanol, placing an emphasis on the MPH transdermal system (MTS). Specifically, we asked: (1) will ethanol increase d-MPH biological concentrations, (2) will MTS facilitate the systemic bioavailability of l-MPH, and (3) will l-MPH enantioselectively interact with ethanol to yield l-ethylphenidate (l-EPH)? Mice were dosed with MTS (¼ of a 12.5 cm(2) patch on shaved skin) or a comparable oral dl-MPH dose (7.5 mg/kg), with or without ethanol (3.0 g/kg), and then placed in metabolic cages for 3 h. MPH and EPH isomer concentrations in blood, brain, and urine were analyzed by gas chromatographic-mass spectrometry monitoring of N-(S)-prolylpiperidyl fragments. As in humans, MTS greatly facilitated the absorption of l-MPH in this mouse strain. Similarly, ethanol led to the enantioselective formation of l-EPH and to an elevation in d-MPH concentrations with both MTS and oral MPH. Although only guarded comparisons between MTS and oral MPH can be made due to route-dependent drug absorption rate differences, MTS was associated with significant MPH-ethanol interactions. Ethanol-mediated increases in circulating concentrations of d-MPH carry toxicological and abuse liability implications should this animal model hold for ethanol-consuming attention-deficit hyperactivity disorder patients or coabusers. Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

  1. Elevated Thyroid Peroxidase Antibody Increases Risk of Post-partum Depression by Decreasing Prefrontal Cortex BDNF and 5-HT Levels in Mice.

    Science.gov (United States)

    Zhou, Yingying; Wang, Xinyi; Zhao, Yuhang; Liu, Aihua; Zhao, Tong; Zhang, Yuanyuan; Shan, Zhongyan; Teng, Weiping

    2016-01-01

    Post-partum depression (PPD) is a common mental disease in the perinatal period that profoundly affects mothers and their offspring. Some clinical studies have found that PPD is related to thyroid peroxidase antibodies (TPOAbs); however, the mechanism underlying this relationship is unclear. Female C57BL/6 mice immunized with adenovirus encoding the cDNA of the full-length mTPO (mTPO-Ad) were used to establish the isolated TPOAb-positive mouse model in the present study. Maternal depressive-like behaviors were assessed using the forced swimming test (FST), sucrose preference test (SPT), and tail suspension test (TST) post-partum. The serum TPOAb titer was measured by enzyme-linked immunosorbent assay (ELISA) before pregnancy and post-partum. Furthermore, in the prefrontal cortex, the mRNA and protein expression levels of brain-derived neurotrophic factor (BDNF) were measured, serotonin (5-HT) levels were measured by ultra-high-performance liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS), and total thyroxine (TT4) levels were determined by ELISA. Compared with the controls, the mice immunized with mTPO-Ad displayed depressive behaviors, with a significantly lower sucrose preference (SP) at the 12-h time point and a longer immobility time in the FST and TST, which were accompanied by a lower expression of BDNF and 5-HT but no change in the TT4 concentration in the prefrontal cortex. Together, these findings suggest that elevated TPOAb may increase the risk of subsequent PPD and decrease the concentration of BDNF and 5-HT in the prefrontal cortex.

  2. A pseudotype baculovirus expressing the capsid protein of foot-and-mouth disease virus and a T-Cell immunogen shows enhanced immunogenicity in mice

    Directory of Open Access Journals (Sweden)

    Liu Xiangtao

    2011-02-01

    Full Text Available Abstract Background Foot-and-mouth disease (FMD is a highly contagious disease of livestock which causes severe economic loss in cloven-hoofed animals. Vaccination is still a major strategy in developing countries to control FMD. Currently, inactivated vaccine of FMDV has been used in many countries with limited success and safety concerns. Development of a novel effective vaccine is must. Methods In the present study, two recombinant pseudotype baculoviruses, one expressing the capsid of foot-and-mouth disease virus (FMDV under the control of a cytomegalovirus immediate early enhancer/promoter (CMV-IE, and the other the caspid plus a T-cell immunogen coding region under a CAG promoter were constructed, and their expression was characterized in mammalian cells. In addition, their immunogenicity in a mouse model was investigated. The humoral and cell-mediated immune responses induced by pseudotype baculovirus were compared with those of inactivated vaccine. Results Indirect immunofluorescence assay (IFA and indirect sandwich-ELISA (IS-ELISA showed both recombinant baculoviruses (with or without T-cell epitopes were transduced efficiently and expressed target proteins in BHK-21 cells. In mice, intramuscular inoculation of recombinants with 1 × 109 or 1 × 1010 PFU/mouse induced the production of FMDV-specific neutralizing antibodies and gamma interferon (IFN-γ. Furthermore, recombinant baculovirus with T-cell epitopes had better immunogenicity than the recombinant without T-cell epitopes as demonstrated by significantly enhanced IFN-γ production (P P Conclusions These results indicate that pseudotype baculovirus-mediated gene delivery could be a alternative strategy to develop a new generation of vaccines against FMDV infection.

  3. Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: Investigation of nicotinic acid receptor agonists

    International Nuclear Information System (INIS)

    Zgoda-Pols, Joanna R.; Chowdhury, Swapan; Wirth, Mark; Milburn, Michael V.; Alexander, Danny C.; Alton, Kevin B.

    2011-01-01

    An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC-MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development. - Research highlights: → Nicotinic acid receptor agonist, SCH 900424, caused acute kidney injury in mice. → MS-based metabolomics was conducted to identify potential small molecule markers of renal toxicity. → 3-indoxyl-sulfate was found to be as a more sensitive marker of renal toxicity than

  4. APOA-1Milano muteins, orally delivered via genetically modified rice, show anti-atherogenic and anti-inflammatory properties in vitro and in Apoe-/- atherosclerotic mice.

    Science.gov (United States)

    Romano, Gabriele; Reggi, Serena; Kutryb-Zajac, Barbara; Facoetti, Amanda; Chisci, Elisa; Pettinato, Mariateresa; Giuffrè, Maria Rita; Vecchio, Federica; Leoni, Silvia; De Giorgi, Marco; Avezza, Federica; Cadamuro, Massimiliano; Crippa, Luca; Leone, Biagio Eugenio; Lavitrano, Marialuisa; Rivolta, Ilaria; Barisani, Donatella; Smolenski, Ryszard Tomasz; Giovannoni, Roberto

    2018-06-11

    Atherosclerosis is a slowly progressing, chronic multifactorial disease characterized by the accumulation of lipids, inflammatory cells, and fibrous tissue that drives to the formation of asymmetric focal thickenings in the tunica intima of large and mid-sized arteries. Despite the high therapeutic potential of ApoA-1 proteins, the purification and delivery into the disordered organisms of these drugs is still limited by low efficiency in these processes. We report here a novel production and delivery system of anti-atherogenic APOA-1Milano muteins (APOA-1M) by means of genetically modified rice plants. APOA-1M, delivered as protein extracts from transgenic rice seeds, significantly reduced macrophage activation and foam cell formation in vitro in oxLDL-loaded THP-1 model. The APOA-1M delivery method and therapeutic efficacy was tested in healthy mice and in Apoe -/- mice fed with high cholesterol diet (Western Diet, WD). APOA-1M rice milk significantly reduced atherosclerotic plaque size and lipids composition in aortic sinus and aortic arch of WD-fed Apoe -/- mice as compared to wild type rice milk-treated, WD-fed Apoe -/- mice. APOA-1M rice milk also significantly reduced macrophage number in liver of WD-fed Apoe -/- mice as compared to WT rice milk treated mice. The delivery of therapeutic APOA-1M full length proteins via oral administration of rice seeds protein extracts (the 'rice milk') to the disordered organism, without any need of purification, might overcome the main APOA1-based therapies' limitations and improve the use of this molecules as therapeutic agents for cardiovascular patients. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  5. PrP0\\0 mice show behavioral abnormalities that suggest PrPC has a role in maintaining the cytoskeleton.

    Science.gov (United States)

    Background/Introduction. PrPC is highly conserved among mammals, but its natural function is unclear. Prnp ablated mice (PrP0/0) appear to develop normally and are able to reproduce. These observations seem to indicate that the gene is not essential for viability, in spite of it being highly conse...

  6. MicroRNA and Transcriptomic Profiling Showed miRNA-Dependent Impairment of Systemic Regulation and Synthesis of Biomolecules in Rag2 KO Mice

    Directory of Open Access Journals (Sweden)

    Abu Musa Md Talimur Reza

    2018-02-01

    Full Text Available The Rag2 knockout (KO mouse is a well-established immune-compromised animal model for biomedical research. A comparative study identified the deregulated expression of microRNAs (miRNAs and messenger RNAs (mRNAs in Rag2 KO mice. However, the interaction between deregulated genes and miRNAs in the alteration of systemic (cardiac, renal, hepatic, nervous, and hematopoietic regulations and the synthesis of biomolecules (such as l-tryptophan, serotonin, melatonin, dopamine, alcohol, noradrenaline, putrescine, and acetate are unclear. In this study, we analyzed both miRNA and mRNA expression microarray data from Rag2 KO and wild type mice to investigate the possible role of miRNAs in systemic regulation and biomolecule synthesis. A notable finding obtained from this analysis is that the upregulation of several genes which are target molecules of the downregulated miRNAs in Rag2 KO mice, can potentially trigger the degradation of l-tryptophan, thereby leading to the systemic impairment and alteration of biomolecules synthesis as well as changes in behavioral patterns (such as stress and fear responses, and social recognition memory in Rag2 gene-depleted mice. These findings were either not observed or not explicitly described in other published Rag2 KO transcriptome analyses. In conclusion, we have provided an indication of miRNA-dependent regulations of clinical and pathological conditions in cardiac, renal, hepatic, nervous, and hematopoietic systems in Rag2 KO mice. These results may significantly contribute to the prediction of clinical disease caused by Rag2 deficiency.

  7. MicroRNA and Transcriptomic Profiling Showed miRNA-Dependent Impairment of Systemic Regulation and Synthesis of Biomolecules in Rag2 KO Mice.

    Science.gov (United States)

    Reza, Abu Musa Md Talimur; Choi, Yun-Jung; Kim, Jin-Hoi

    2018-02-27

    The Rag2 knockout (KO) mouse is a well-established immune-compromised animal model for biomedical research. A comparative study identified the deregulated expression of microRNAs (miRNAs) and messenger RNAs (mRNAs) in Rag2 KO mice. However, the interaction between deregulated genes and miRNAs in the alteration of systemic (cardiac, renal, hepatic, nervous, and hematopoietic) regulations and the synthesis of biomolecules (such as l-tryptophan, serotonin, melatonin, dopamine, alcohol, noradrenaline, putrescine, and acetate) are unclear. In this study, we analyzed both miRNA and mRNA expression microarray data from Rag2 KO and wild type mice to investigate the possible role of miRNAs in systemic regulation and biomolecule synthesis. A notable finding obtained from this analysis is that the upregulation of several genes which are target molecules of the downregulated miRNAs in Rag2 KO mice, can potentially trigger the degradation of l-tryptophan, thereby leading to the systemic impairment and alteration of biomolecules synthesis as well as changes in behavioral patterns (such as stress and fear responses, and social recognition memory) in Rag2 gene-depleted mice. These findings were either not observed or not explicitly described in other published Rag2 KO transcriptome analyses. In conclusion, we have provided an indication of miRNA-dependent regulations of clinical and pathological conditions in cardiac, renal, hepatic, nervous, and hematopoietic systems in Rag2 KO mice. These results may significantly contribute to the prediction of clinical disease caused by Rag2 deficiency.

  8. Time-dependent toxicity of cadmium telluride quantum dots on liver and kidneys in mice: histopathological changes with elevated free cadmium ions and hydroxyl radicals

    Directory of Open Access Journals (Sweden)

    Wang M

    2016-05-01

    Full Text Available Mengmeng Wang,1,2,* Jilong Wang,1,2,* Hubo Sun,1,2 Sihai Han,3 Shuai Feng,1 Lu Shi,1 Peijun Meng,1,2 Jiayi Li,1,2 Peili Huang,1,2 Zhiwei Sun1,2 1Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, 2Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 3College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, People’s Republic of China *These authors contributed equally to this work Abstract: A complete understanding of the toxicological behavior of quantum dots (QDs in vivo is of great importance and a prerequisite for their application in humans. In contrast with the numerous cytotoxicity studies investigating QDs, only a few in vivo studies of QDs have been reported, and the issue remains controversial. Our study aimed to understand QD-mediated toxicity across different time points and to explore the roles of free cadmium ions (Cd2+ and hydroxyl radicals (·OH in tissue damage. Male ICR mice were administered a single intravenous dose (1.5 µmol/kg of CdTe QDs, and liver and kidney function and morphology were subsequently examined at 1, 7, 14, and 28 days. Furthermore, ·OH production in the tissue was quantified by trapping ·OH with salicylic acid (SA as 2,3-dihydroxybenzoic acid (DHBA and detecting it using a high-performance liquid chromatography fluorescence method. We used the induction of tissue metallothionein levels and 2,3-DHBA:SA ratios as markers for elevated Cd2+ from the degradation of QDs and ·OH generation in the tissue, respectively. Our experimental results revealed that the QD-induced histopathological changes were time-dependent with elevated Cd2+ and ·OH, and could recover after a period of time. The Cd2+ and ·OH exhibited delayed effects in terms of histopathological abnormalities. Histological assessments performed at multiple time points might facilitate the evaluation of the biological safety of

  9. Carcinogenicity study of 3-monochloropropane-1, 2-diol (3-MCPD) administered by drinking water to B6C3F1 mice showed no carcinogenic potential.

    Science.gov (United States)

    Jeong, Jayoung; Han, Beom Seok; Cho, Wan-Seob; Choi, Mina; Ha, Chang-Su; Lee, Byoung-Seok; Kim, Yong-Bum; Son, Woo-Chan; Kim, Choong-Yong

    2010-09-01

    3-Monochloropropane-1, 2-diol (or 3-chloro-1,2-propanediol, 3-MCPD) is a well-known food processing contaminant found in a wide range of foods and ingredients. It has been classified as non-genotoxic carcinogen but its carcinogenic potential in the rodents has been controversial. The carcinogenicity to B6C3F1 mice by drinking water administration was assessed over a period of 104 weeks. Three groups, each comprising 50 male and 50 female mice received 3-MCPD at dosages of 30, 100 or 300 ppm up to Day 100 and 200 ppm onward (4.2, 14.3 and 33.0 mg/kg for males; 3.7, 12.2, and 31.0 mg/kg for females), were allocated. Survival was good, with at least 80% of males and 72% of females in each group surviving 104 weeks. Body weights and body weight gain were decreased in males and females receiving 200 ppm. Water and food consumptions of both sexes at 300/200 ppm were lowered. Emaciated or crouching position was observed for animals of both sexes exposed to 200 ppm. There were some differences in hematology and serum biochemistry compared with controls, although there was no histopathological evidence to support those changes. Histopathological examination did not reveal any neoplastic or non-neoplastic findings attributable to treatment with 3-MCPD. It is concluded that drinking water administration of 3-MCPD for 104 weeks revealed no evidence of carcinogenic potential.

  10. Mutation in the α2 isoform of Na,K-ATPase associated Familial Hemiplegic Migraine type 2 (FHM2) leads to elevated contractility and vasodilatation of cerebral arteries in mice

    DEFF Research Database (Denmark)

    Hangaard, Lise; Lykke-Hartmann, Karin; Xie, Zijian

    is associated with few point mutations in the α2 isoform Na,K-ATPase. Mice bearing a mutation corresponding to the inherited mutation in FHM2 patients (G301R) were used in functional studies of middle cerebral arteries. Middle cerebral arteries from heterozygote G301R mice were not different in total α2 Na......,K-ATPase mRNA in comparison with WT, but 51±11% of their mRNA contained G301R mutation. G301R mice had elevated blood pressure and unchanged heart rate. Inner diameter of cerebral arteries from G301R mice was significantly larger than in WT. G301R arteries were more sensitive and had higher maximal...... contraction to U46619, endothelin and K+-depolarization. This was associated with increased depolarization and sensitization to [Ca2+]i (in spite of reduced Ca2+ influx) in G301R arteries. pNaKtide, a peptide inhibiting the Na,K-ATPase-dependent Src activation, abolished differences between G301R and WT mice...

  11. Effects of interleukin-1beta and lipopolysaccharide on behavior of mice in the elevated plus-maze and open field tests.

    Science.gov (United States)

    Swiergiel, Artur H; Dunn, Adrian J

    2007-04-01

    It has been postulated that infections, inflammatory processes and resulting cytokines may be causative factors in emotional disorders, including depression and anxiety. Support for this possibility has been sought in studies of animal behavior following administration of interleukin-1 (IL-1) and lipopolysaccharide (LPS). However, such treatments induce a variety of behavioral responses, collectively known as sickness behavior, some of which could affect the performance in tests used to assess anxiety and depression. Thus the effects of peripheral administration of IL-1beta and LPS on the behavior of mice were studied in the elevated plus-maze (EPM) and the open field (OF). Mouse IL-1beta (30, 100, 300, and 1000 ng) was injected intraperitoneally 30 or 60 min, and LPS (0.5, 1 and 5 microg) 120 min before the tests. IL-1beta and LPS induced dose-dependent decreases in open arm entries and the time spent on the open arms in the EPM, effects considered to reflect anxiety-like behavior. However, entries to all arms were also reduced in a dose-dependent manner, indicating a decrease in general activity. In the OF, IL-1beta and LPS decreased the number of line crossings in the center of the field, that can also be considered to reflect anxiety-like behavior. However, this effect was accompanied by a similar decrease in line crossings in the periphery, as well as in rears and climbs. Thus the doses of IL-1beta and LPS necessary to induce these effects also decreased locomotor activity in the EPM and OF. Therefore, the behavioral responses induced by IL-1beta and LPS in the EPM and the OF considered to reflect anxiety must be interpreted in the light of this reduction in overall activity. Thus the results do not provide unequivocal support for the suggestion that LPS or IL-1 mediate anxiety. Nevertheless, because infections, endotoxins, and the ensuing cytokines cause alterations in CNS norepinephrine and serotonin, they may contribute to emotionality, and perhaps to

  12. Mice lacking Ras-GRF1 show contextual fear conditioning but not spatial memory impairments: convergent evidence from two independently generated mouse mutant lines

    Directory of Open Access Journals (Sweden)

    Raffaele ed'Isa

    2011-12-01

    Full Text Available Ras-GRF1 is a neuronal specific guanine exchange factor that, once activated by both ionotropic and metabotropic neurotransmitter receptors, can stimulate Ras proteins, leading to long-term phosphorylation of downstream signaling. The two available reports on the behavior of two independently generated Ras-GRF1 deficient mouse lines provide contrasting evidence on the role of Ras-GRF1 in spatial memory and contextual fear conditioning. These discrepancies may be due to the distinct alterations introduced in the mouse genome by gene targeting in the two lines that could differentially affect expression of nearby genes located in the imprinted region containing the Ras-grf1 locus. In order to determine the real contribution of Ras-GRF1 to spatial memory we compared in Morris Water Maze learning the Brambilla’s mice with a third mouse line (GENA53 in which a nonsense mutation was introduced in the Ras-GRF1 coding region without additional changes in the genome and we found that memory in this task is normal. Also, we measured both contextual and cued fear conditioning, which were previously reported to be affected in the Brambilla’s mice, and we confirmed that contextual learning but not cued conditioning is impaired in both mouse lines. In addition, we also tested both lines for the first time in conditioned place aversion in the Intellicage, an ecological and remotely controlled behavioral test, and we observed normal learning. Finally, based on previous reports of other mutant lines suggesting that Ras-GRF1 may control body weight, we also measured this non-cognitive phenotype and we confirmed that both Ras-GRF1 deficient mutants are smaller than their control littermates. In conclusion, we demonstrate that Ras-GRF1 has no unique role in spatial memory while its function in contextual fear conditioning is likely to be due not only to its involvement in amygdalar functions but possibly to some distinct hippocampal connections specific to

  13. Phenotypic Dichotomy Following Developmental Exposure to Perfluorooctanic Acid (PFOA) Exposure in CD-1 Mice: Low Doses Induce Elevated Serum, Leptin, Insulin, and Overweight in Mid-Life.

    Science.gov (United States)

    The synthetic surfactant, perfluorooctanoic acid (PFOA) is a proven developmental toxicant in mice, causing prenatal pregnancy loss, increased neonatal mortality, delayed eye opening, and abnormal mammary gland growth in animals exposed during fetal life. PFOA is found in the ser...

  14. The nitroxide radical TEMPOL prevents obesity, hyperlipidaemia, elevation of inflammatory cytokines, and modulates atherosclerotic plaque composition in apoE(-/-) mice

    DEFF Research Database (Denmark)

    Kim, Christine H. J.; Mitchell, James B.; Bursill, Christina A.

    2015-01-01

    and a decrease in adiponectin. TEMPOL supplementation reversed these effects. When compared to HFD-fed mice, TEMPOL supplementation increased plaque collagen content, decreased lipid content and increased macrophage numbers. CONCLUSIONS: These data indicate that in a well-established model of obesity-associated......OBJECTIVE: The nitroxide compound TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl radical) has been shown to prevent obesity-induced changes in adipokines in cell and animal systems. In this study we investigated whether supplementation with TEMPOL inhibits inflammation and atherosclerosis...... in apoE(-/-) mice fed a high fat diet (HFD). METHODS: ApoE(-/-) mice were fed for 12 weeks on standard chow diet or a high-fat diet. Half the mice were supplemented with 10 mg/g TEMPOL in their food. Plasma samples were analysed for triglycerides, cholesterol, low- and high-density lipoprotein...

  15. Deletion of the Androgen Receptor in Adipose Tissue in Male Mice Elevates Retinol Binding Protein 4 and Reveals Independent Effects on Visceral Fat Mass and on Glucose Homeostasis

    Science.gov (United States)

    McInnes, Kerry J.; Smith, Lee B.; Hunger, Nicole I.; Saunders, Philippa T.K.; Andrew, Ruth; Walker, Brian R.

    2012-01-01

    Testosterone deficiency is epidemic in obese ageing males with type 2 diabetes, but the direction of causality remains unclear. Testosterone-deficient males and global androgen receptor (AR) knockout mice are insulin resistant with increased fat, but it is unclear whether AR signaling in adipose tissue mediates body fat redistribution and alters glucose homoeostasis. To investigate this, mice with selective knockdown of AR in adipocytes (fARKO) were generated. Male fARKO mice on normal diet had reduced perigonadal fat but were hyperinsulinemic and by age 12 months, were insulin deficient in the absence of obesity. On high-fat diet, fARKO mice had impaired compensatory insulin secretion and hyperglycemia, with increased susceptibility to visceral obesity. Adipokine screening in fARKO mice revealed a selective increase in plasma and intra-adipose retinol binding protein 4 (RBP4) that preceded obesity. AR activation in murine 3T3 adipocytes downregulated RBP4 mRNA. We conclude that AR signaling in adipocytes not only protects against high-fat diet–induced visceral obesity but also regulates insulin action and glucose homeostasis, independently of adiposity. Androgen deficiency in adipocytes in mice resembles human type 2 diabetes, with early insulin resistance and evolving insulin deficiency. PMID:22415878

  16. Antistress, Adoptogenic Activity of Sida cordifolia Roots in Mice.

    Science.gov (United States)

    Sumanth, Meera; Mustafa, S S

    2009-05-01

    Ethanol extract of roots of Sida cordifolia was evaluated for antistress, adaptogenic activity using cold restraint stress and swim endurance in mice. Mice pretreated with extract of Sida cordifolia showed significant improvement in the swim duration and reduced the elevated WBC, blood glucose and plasma cortisone.

  17. Mutagenicity of nicotine in Schistosoma mansoni - infected mice ...

    African Journals Online (AJOL)

    Analysis of meiotic chromosomes showed significant elevation in the Schistosoma-infected mice. Administration of nicotine to infected mice substantially increased the percentages of micronucleated cells and total CAs. The percentage of chromosomal abnormalities in spermatocyte metaphase-I cells increased significantly ...

  18. Inhibition of intestinal bile acid transporter Slc10a2 improves triglyceride metabolism and normalizes elevated plasma glucose levels in mice.

    Directory of Open Access Journals (Sweden)

    Thomas Lundåsen

    Full Text Available Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2 and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c. Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF 15 mRNA and normalized bile acid synthesis in Slc10a2-/- mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2-Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes.

  19. Pancreatic beta cells from db/db mice show cell-specific [Ca2+]i and NADH responses to glucose but not to alpha-ketoisocaproic acid

    DEFF Research Database (Denmark)

    Gustavsson, Natalia; Larsson-Nyrén, Gerd; Lindström, Per

    2005-01-01

    OBJECTIVE: We recently showed that timing and magnitude of the glucose-induced cytoplasmic calcium [Ca2+]i response are reproducible and specific for the individual beta cell. We now wanted to identify which step(s) of stimulus-secretion coupling determine the cell specificity of the [Ca2+]i resp...

  20. Fossil mice and rats show isotopic evidence of niche partitioning and change in dental ecomorphology related to dietary shift in Late Miocene of Pakistan.

    Science.gov (United States)

    Kimura, Yuri; Jacobs, Louis L; Cerling, Thure E; Uno, Kevin T; Ferguson, Kurt M; Flynn, Lawrence J; Patnaik, Rajeev

    2013-01-01

    Stable carbon isotope analysis in tooth enamel is a well-established approach to infer C3 and C4 dietary composition in fossil mammals. The bulk of past work has been conducted on large herbivorous mammals. One important finding is that their dietary habits of fossil large mammals track the late Miocene ecological shift from C3 forest and woodland to C4 savannah. However, few studies on carbon isotopes of fossil small mammals exist due to limitations imposed by the size of rodent teeth, and the isotopic ecological and dietary behaviors of small mammals to climate change remain unknown. Here we evaluate the impact of ecological change on small mammals by fine-scale comparisons of carbon isotope ratios (δ(13)C) with dental morphology of murine rodents, spanning 13.8 to ∼2.0 Ma, across the C3 to C4 vegetation shift in the Miocene Siwalik sequence of Pakistan. We applied in-situ laser ablation GC-IRMS to lower first molars and measured two grazing indices on upper first molars. Murine rodents yield a distinct, but related, record of past ecological conditions from large herbivorous mammals, reflecting available foods in their much smaller home ranges. In general, larger murine species show more positive δ(13)C values and have higher grazing indices than smaller species inhabiting the same area at any given age. Two clades of murine rodents experienced different rates of morphological change. In the faster-evolving clade, the timing and trend of morphological innovations are closely tied to consumption of C4 diet during the vegetation shift. This study provides quantitative evidence of linkages among diet, niche partitioning, and dental morphology at a more detailed level than previously possible.

  1. Fossil Mice and Rats Show Isotopic Evidence of Niche Partitioning and Change in Dental Ecomorphology Related to Dietary Shift in Late Miocene of Pakistan

    Science.gov (United States)

    Kimura, Yuri; Jacobs, Louis L.; Cerling, Thure E.; Uno, Kevin T.; Ferguson, Kurt M.; Flynn, Lawrence J.; Patnaik, Rajeev

    2013-01-01

    Stable carbon isotope analysis in tooth enamel is a well-established approach to infer C3 and C4 dietary composition in fossil mammals. The bulk of past work has been conducted on large herbivorous mammals. One important finding is that their dietary habits of fossil large mammals track the late Miocene ecological shift from C3 forest and woodland to C4 savannah. However, few studies on carbon isotopes of fossil small mammals exist due to limitations imposed by the size of rodent teeth, and the isotopic ecological and dietary behaviors of small mammals to climate change remain unknown. Here we evaluate the impact of ecological change on small mammals by fine-scale comparisons of carbon isotope ratios (δ13C) with dental morphology of murine rodents, spanning 13.8 to ∼2.0 Ma, across the C3 to C4 vegetation shift in the Miocene Siwalik sequence of Pakistan. We applied in-situ laser ablation GC-IRMS to lower first molars and measured two grazing indices on upper first molars. Murine rodents yield a distinct, but related, record of past ecological conditions from large herbivorous mammals, reflecting available foods in their much smaller home ranges. In general, larger murine species show more positive δ13C values and have higher grazing indices than smaller species inhabiting the same area at any given age. Two clades of murine rodents experienced different rates of morphological change. In the faster-evolving clade, the timing and trend of morphological innovations are closely tied to consumption of C4 diet during the vegetation shift. This study provides quantitative evidence of linkages among diet, niche partitioning, and dental morphology at a more detailed level than previously possible. PMID:23936324

  2. Fossil mice and rats show isotopic evidence of niche partitioning and change in dental ecomorphology related to dietary shift in Late Miocene of Pakistan.

    Directory of Open Access Journals (Sweden)

    Yuri Kimura

    Full Text Available Stable carbon isotope analysis in tooth enamel is a well-established approach to infer C3 and C4 dietary composition in fossil mammals. The bulk of past work has been conducted on large herbivorous mammals. One important finding is that their dietary habits of fossil large mammals track the late Miocene ecological shift from C3 forest and woodland to C4 savannah. However, few studies on carbon isotopes of fossil small mammals exist due to limitations imposed by the size of rodent teeth, and the isotopic ecological and dietary behaviors of small mammals to climate change remain unknown. Here we evaluate the impact of ecological change on small mammals by fine-scale comparisons of carbon isotope ratios (δ(13C with dental morphology of murine rodents, spanning 13.8 to ∼2.0 Ma, across the C3 to C4 vegetation shift in the Miocene Siwalik sequence of Pakistan. We applied in-situ laser ablation GC-IRMS to lower first molars and measured two grazing indices on upper first molars. Murine rodents yield a distinct, but related, record of past ecological conditions from large herbivorous mammals, reflecting available foods in their much smaller home ranges. In general, larger murine species show more positive δ(13C values and have higher grazing indices than smaller species inhabiting the same area at any given age. Two clades of murine rodents experienced different rates of morphological change. In the faster-evolving clade, the timing and trend of morphological innovations are closely tied to consumption of C4 diet during the vegetation shift. This study provides quantitative evidence of linkages among diet, niche partitioning, and dental morphology at a more detailed level than previously possible.

  3. Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids

    Energy Technology Data Exchange (ETDEWEB)

    Agbor, Larry N.; Walsh, Mary T.; Boberg, Jason R.; Walker, Mary K., E-mail: mwalker@salud.unm.edu

    2012-11-01

    In vitro cytochrome P4501A1 (CYP1A1) metabolizes omega − 3 polyunsaturated fatty acids (n − 3 PUFAs); eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), primarily to 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP), respectively. These metabolites have been shown to mediate vasodilation via increases in nitric oxide (NO) and activation of potassium channels. We hypothesized that genetic deletion of CYP1A1 would reduce vasodilatory responses to n − 3 PUFAs, but not the metabolites, and increase blood pressure (BP) due to decreases in NO. We assessed BP by radiotelemetry in CYP1A1 wildtype (WT) and knockout (KO) mice ± NO synthase (NOS) inhibitor. We also assessed vasodilation to acetylcholine (ACh), EPA, DHA, 17,18-EEQ and 19,20-EDP in aorta and mesenteric arterioles. Further, we assessed vasodilation to an NO donor and to DHA ± inhibitors of potassium channels. CYP1A1 KO mice were hypertensive, compared to WT, (mean BP in mm Hg, WT 103 ± 1, KO 116 ± 1, n = 5/genotype, p < 0.05), and exhibited a reduced heart rate (beats per minute, WT 575 ± 5; KO 530 ± 7; p < 0.05). However, BP responses to NOS inhibition and vasorelaxation responses to ACh and an NO donor were normal in CYP1A1 KO mice, suggesting that NO bioavailability was not reduced. In contrast, CYP1A1 KO mice exhibited significantly attenuated vasorelaxation responses to EPA and DHA in both the aorta and mesenteric arterioles, but normal vasorelaxation responses to the CYP1A1 metabolites, 17,18-EEQ and 19,20-EDP, and normal responses to potassium channel inhibition. Taken together these data suggest that CYP1A1 metabolizes n − 3 PUFAs to vasodilators in vivo and the loss of these vasodilators may lead to increases in BP. -- Highlights: ► CYP1A1 KO mice are hypertensive. ► CYP1A1 KO mice exhibit reduced vasodilation responses to n-3 PUFAs. ► Constitutive CYP1A1 expression regulates blood pressure and vascular function.

  4. Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega − 3 polyunsaturated fatty acids

    International Nuclear Information System (INIS)

    Agbor, Larry N.; Walsh, Mary T.; Boberg, Jason R.; Walker, Mary K.

    2012-01-01

    In vitro cytochrome P4501A1 (CYP1A1) metabolizes omega − 3 polyunsaturated fatty acids (n − 3 PUFAs); eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), primarily to 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP), respectively. These metabolites have been shown to mediate vasodilation via increases in nitric oxide (NO) and activation of potassium channels. We hypothesized that genetic deletion of CYP1A1 would reduce vasodilatory responses to n − 3 PUFAs, but not the metabolites, and increase blood pressure (BP) due to decreases in NO. We assessed BP by radiotelemetry in CYP1A1 wildtype (WT) and knockout (KO) mice ± NO synthase (NOS) inhibitor. We also assessed vasodilation to acetylcholine (ACh), EPA, DHA, 17,18-EEQ and 19,20-EDP in aorta and mesenteric arterioles. Further, we assessed vasodilation to an NO donor and to DHA ± inhibitors of potassium channels. CYP1A1 KO mice were hypertensive, compared to WT, (mean BP in mm Hg, WT 103 ± 1, KO 116 ± 1, n = 5/genotype, p < 0.05), and exhibited a reduced heart rate (beats per minute, WT 575 ± 5; KO 530 ± 7; p < 0.05). However, BP responses to NOS inhibition and vasorelaxation responses to ACh and an NO donor were normal in CYP1A1 KO mice, suggesting that NO bioavailability was not reduced. In contrast, CYP1A1 KO mice exhibited significantly attenuated vasorelaxation responses to EPA and DHA in both the aorta and mesenteric arterioles, but normal vasorelaxation responses to the CYP1A1 metabolites, 17,18-EEQ and 19,20-EDP, and normal responses to potassium channel inhibition. Taken together these data suggest that CYP1A1 metabolizes n − 3 PUFAs to vasodilators in vivo and the loss of these vasodilators may lead to increases in BP. -- Highlights: ► CYP1A1 KO mice are hypertensive. ► CYP1A1 KO mice exhibit reduced vasodilation responses to n-3 PUFAs. ► Constitutive CYP1A1 expression regulates blood pressure and vascular function.

  5. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2.

    Science.gov (United States)

    Le Bacquer, Olivier; Petroulakis, Emmanuel; Paglialunga, Sabina; Poulin, Francis; Richard, Denis; Cianflone, Katherine; Sonenberg, Nahum

    2007-02-01

    The most common pathology associated with obesity is insulin resistance, which results in the onset of type 2 diabetes mellitus. Several studies have implicated the mammalian target of rapamycin (mTOR) signaling pathway in obesity. Eukaryotic translation initiation factor 4E-binding (eIF4E-binding) proteins (4E-BPs), which repress translation by binding to eIF4E, are downstream effectors of mTOR. We report that the combined disruption of 4E-BP1 and 4E-BP2 in mice increased their sensitivity to diet-induced obesity. Increased adiposity was explained at least in part by accelerated adipogenesis driven by increased expression of CCAAT/enhancer-binding protein delta (C/EBPdelta), C/EBPalpha, and PPARgamma coupled with reduced energy expenditure, reduced lipolysis, and greater fatty acid reesterification in the adipose tissue of 4E-BP1 and 4E-BP2 double KO mice. Increased insulin resistance in 4E-BP1 and 4E-BP2 double KO mice was associated with increased ribosomal protein S6 kinase (S6K) activity and impairment of Akt signaling in muscle, liver, and adipose tissue. These data clearly demonstrate the role of 4E-BPs as a metabolic brake in the development of obesity and reinforce the idea that deregulated mTOR signaling is associated with the development of the metabolic syndrome.

  6. Low-dose thioperamide injected into the cerebellar vermis of mice immediately after exposure to the elevated plus-maze impairs their avoidance behavior on re-exposure to the apparatus

    Directory of Open Access Journals (Sweden)

    J. Costa Neto

    2013-11-01

    Full Text Available The present study investigated the effect of thioperamide (THIO, an H3 histaminergic receptor antagonist, microinjected into the cerebellar vermis on emotional memory consolidation in male Swiss albino mice re-exposed to the elevated plus-maze (EPM. We implanted a guide cannula into the cerebellar vermis using stereotactic surgery. On the third day after surgery, we performed behavioral tests for two consecutive days. On the first day (exposure, the mice (n=10/group were exposed to the EPM and received THIO (0.06, 0.3, or 1.5 ng/0.1 µL immediately after the end of the session. Twenty-four hours later, the mice were re-exposed to the EPM under the same experimental conditions, but without drug injection. A reduction in the exploration of the open arms upon re-exposure to the EPM (percentage of number of entries and time spent in open arms compared with the initial exposure was used as an indicator of learning and memory. One-way analysis of variance (ANOVA followed by the Duncan post hoc test was used to analyze the data. Upon re-exposure, exploratory activity in the open arms was reduced in the control group, and with the two highest THIO doses: 0.3 and 1.5 ng/0.1 µL. No reduction was seen with the lowest THIO dose (0.06 ng/0.1 µL, indicating inhibition of the consolidation of emotional memory. None of the doses interfered with the animals' locomotor activity. We conclude that THIO at the lowest dose (0.06 ng/0.1 µL microinjected into the cerebellum impaired emotional memory consolidation in mice.

  7. Lithium ameliorates sleep deprivation-induced mania-like behavior, hypothalamic-pituitary-adrenal (HPA) axis alterations, oxidative stress and elevations of cytokine concentrations in the brain and serum of mice.

    Science.gov (United States)

    Valvassori, Samira S; Resende, Wilson R; Dal-Pont, Gustavo; Sangaletti-Pereira, Heron; Gava, Fernanda F; Peterle, Bruna R; Carvalho, André F; Varela, Roger B; Dal-Pizzol, Felipe; Quevedo, João

    2017-06-01

    The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice subjected to an animal model of mania induced by paradoxical sleep deprivation (PSD). Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels. The results showed that PSD induced hyperactivity in mice, which is considered a mania-like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania-like behavior, oxidative damage and cytokine alterations induced by PSD. Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system - alterations presented in the animal models of mania - is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests

    OpenAIRE

    Ribeiro,A.; Ferraz-de-Paula,V.; Pinheiro,M.L.; Palermo-Neto,J.

    2009-01-01

    The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped...

  9. Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice

    International Nuclear Information System (INIS)

    Liu, Zhi-Qin; Liu, Ting; Chen, Chuan; Li, Ming-Yan; Wang, Zi-Yu; Chen, Ruo-song; Wei, Gui-xiang; Wang, Xiao-yi; Luo, Du-Qiang

    2015-01-01

    Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathways, and its increased activity and expression are implicated in the pathogenesis of insulin resistance. Therefore, the inhibition of PTP1B is anticipated to become a potential therapeutic strategy to treat T2DM. Fumosorinone (FU), a new natural product isolated from insect fungi Isaria fumosorosea, was found to inhibit PTP1B activity in our previous study. Herein, the effects of FU on insulin resistance and mechanism in vitro and in vivo were investigated. FU increased the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, and also reduced blood glucose and lipid levels of type 2 diabetic KKAy mice. FU decreased the expression of PTP1B both in insulin-resistant HepG2 cells and in liver tissues of diabetic KKAy mice. Furthermore, FU increased the phosphorylation of IRβ, IRS-2, Akt, GSK3β and Erk1/2 in insulin-resistant HepG2 cells, as well as the phosphorylation of IRβ, IRS-2, Akt in liver tissues of diabetic KKAy mice. These results showed that FU increased glucose uptake and improved insulin resistance by down-regulating the expression of PTP1B and activating the insulin signaling pathway, suggesting that it may possess antidiabetic properties. - Highlights: • Fumosorinone is a new PTP1B inhibitor isolated from insect pathogenic fungi. • Fumosorinone attenuated the insulin resistance both in vitro and in vivo. • Fumosorinone decreased the expression of PTP1B both in vitro and in vivo. • Fumosorinone activated the insulin signaling pathway both in vitro and in vivo

  10. Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Zhi-Qin [College of Life Sciences, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002 (China); College of Pharmaceutical Sciences, key laboratory of pharmaceutical quality control of Hebei province, Hebei University, Baoding 071002 (China); Liu, Ting; Chen, Chuan [College of Life Sciences, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002 (China); Li, Ming-Yan; Wang, Zi-Yu; Chen, Ruo-song; Wei, Gui-xiang; Wang, Xiao-yi [College of Pharmaceutical Sciences, key laboratory of pharmaceutical quality control of Hebei province, Hebei University, Baoding 071002 (China); Luo, Du-Qiang, E-mail: duqiangluo999@126.com [College of Life Sciences, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002 (China)

    2015-05-15

    Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathways, and its increased activity and expression are implicated in the pathogenesis of insulin resistance. Therefore, the inhibition of PTP1B is anticipated to become a potential therapeutic strategy to treat T2DM. Fumosorinone (FU), a new natural product isolated from insect fungi Isaria fumosorosea, was found to inhibit PTP1B activity in our previous study. Herein, the effects of FU on insulin resistance and mechanism in vitro and in vivo were investigated. FU increased the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, and also reduced blood glucose and lipid levels of type 2 diabetic KKAy mice. FU decreased the expression of PTP1B both in insulin-resistant HepG2 cells and in liver tissues of diabetic KKAy mice. Furthermore, FU increased the phosphorylation of IRβ, IRS-2, Akt, GSK3β and Erk1/2 in insulin-resistant HepG2 cells, as well as the phosphorylation of IRβ, IRS-2, Akt in liver tissues of diabetic KKAy mice. These results showed that FU increased glucose uptake and improved insulin resistance by down-regulating the expression of PTP1B and activating the insulin signaling pathway, suggesting that it may possess antidiabetic properties. - Highlights: • Fumosorinone is a new PTP1B inhibitor isolated from insect pathogenic fungi. • Fumosorinone attenuated the insulin resistance both in vitro and in vivo. • Fumosorinone decreased the expression of PTP1B both in vitro and in vivo. • Fumosorinone activated the insulin signaling pathway both in vitro and in vivo.

  11. p21WAF1/Cip1/Sdi1 knockout mice respond to doxorubicin with reduced cardiotoxicity

    International Nuclear Information System (INIS)

    Terrand, Jerome; Xu, Beibei; Morrissy, Steve; Dinh, Thai Nho; Williams, Stuart; Chen, Qin M.

    2011-01-01

    Doxorubicin (Dox) is an antineoplastic agent that can cause cardiomyopathy in humans and experimental animals. As an inducer of reactive oxygen species and a DNA damaging agent, Dox causes elevated expression of p21 WAF1/Cip1/Sdi1 (p21) gene. Elevated levels of p21 mRNA and p21 protein have been detected in the myocardium of mice following Dox treatment. With chronic treatment of Dox, wild type (WT) animals develop cardiomyopathy evidenced by elongated nuclei, mitochondrial swelling, myofilamental disarray, reduced cardiac output, reduced ejection fraction, reduced left ventricular contractility, and elevated expression of ANF gene. In contrast, p21 knockout (p21KO) mice did not show significant changes in the same parameters in response to Dox treatment. In an effort to understand the mechanism of the resistance against Dox induced cardiomyopathy, we measured levels of antioxidant enzymes and found that p21KO mice did not contain elevated basal or inducible levels of glutathione peroxidase and catalase. Measurements of 6 circulating cytokines indicated elevation of IL-6, IL-12, IFNγ and TNFα in Dox treated WT mice but not p21KO mice. Dox induced elevation of IL-6 mRNA was detected in the myocardium of WT mice but not p21KO mice. While the mechanism of the resistance against Dox induced cardiomyopathy remains unclear, lack of inflammatory response may contribute to the observed cardiac protection in p21KO mice. -- Highlights: ► Doxorubicin induces p21 elevation in the myocardium. ► Doxorubicin causes dilated cardiomyopathy in wild type mice. ► p21 Knockout mice are resistant against doxorubicin induced cardiomyopathy. ► Lack of inflammatory response correlates with the resistance in p21 knockout mice.

  12. Data Elevator

    Energy Technology Data Exchange (ETDEWEB)

    2017-04-29

    Data Elevator: Efficient Asynchronous Data Movement in Hierarchical Storage Systems Multi-layer storage subsystems, including SSD-based burst buffers and disk-based parallel file systems (PFS), are becoming part of HPC systems. However, software for this storage hierarchy is still in its infancy. Applications may have to explicitly move data among the storage layers. We propose Data Elevator for transparently and efficiently moving data between a burst buffer and a PFS. Users specify the final destination for their data, typically on PFS, Data Elevator intercepts the I/O calls, stages data on burst buffer, and then asynchronously transfers the data to their final destination in the background. This system allows extensive optimizations, such as overlapping read and write operations, choosing I/O modes, and aligning buffer boundaries. In tests with large-scale scientific applications, Data Elevator is as much as 4.2X faster than Cray DataWarp, the start-of-art software for burst buffer, and 4X faster than directly writing to PFS. The Data Elevator library uses HDF5's Virtual Object Layer (VOL) for intercepting parallel I/O calls that write data to PFS. The intercepted calls are redirected to the Data Elevator, which provides a handle to write the file in a faster and intermediate burst buffer system. Once the application finishes writing the data to the burst buffer, the Data Elevator job uses HDF5 to move the data to final destination in an asynchronous manner. Hence, using the Data Elevator library is currently useful for applications that call HDF5 for writing data files. Also, the Data Elevator depends on the HDF5 VOL functionality.

  13. Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation.

    Science.gov (United States)

    Kim, Chai-Wan; Addy, Carol; Kusunoki, Jun; Anderson, Norma N; Deja, Stanislaw; Fu, Xiaorong; Burgess, Shawn C; Li, Cai; Ruddy, Marcie; Chakravarthy, Manu; Previs, Steve; Milstein, Stuart; Fitzgerald, Kevin; Kelley, David E; Horton, Jay D

    2017-08-01

    Inhibiting lipogenesis prevents hepatic steatosis in rodents with insulin resistance. To determine if reducing lipogenesis functions similarly in humans, we developed MK-4074, a liver-specific inhibitor of acetyl-CoA carboxylase (ACC1) and (ACC2), enzymes that produce malonyl-CoA for fatty acid synthesis. MK-4074 administered to subjects with hepatic steatosis for 1 month lowered lipogenesis, increased ketones, and reduced liver triglycerides by 36%. Unexpectedly, MK-4074 increased plasma triglycerides by 200%. To further investigate, mice that lack ACC1 and ACC2 in hepatocytes (ACC dLKO) were generated. Deletion of ACCs decreased polyunsaturated fatty acid (PUFA) concentrations in liver due to reduced malonyl-CoA, which is required for elongation of essential fatty acids. PUFA deficiency induced SREBP-1c, which increased GPAT1 expression and VLDL secretion. PUFA supplementation or siRNA-mediated knockdown of GPAT1 normalized plasma triglycerides. Thus, inhibiting lipogenesis in humans reduced hepatic steatosis, but inhibiting ACC resulted in hypertriglyceridemia due to activation of SREBP-1c and increased VLDL secretion. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Adenosine monophosphate is elevated in the bronchoalveolar lavage fluid of mice with acute respiratory toxicity induced by nanoparticles with high surface hydrophobicity.

    Science.gov (United States)

    Dailey, Lea Ann; Hernández-Prieto, Raquel; Casas-Ferreira, Ana Maria; Jones, Marie-Christine; Riffo-Vasquez, Yanira; Rodríguez-Gonzalo, Encarnación; Spina, Domenico; Jones, Stuart A; Smith, Norman W; Forbes, Ben; Page, Clive; Legido-Quigley, Cristina

    2015-02-01

    Inhaled nanomaterials present a challenge to traditional methods and understanding of respiratory toxicology. In this study, a non-targeted metabolomics approach was used to investigate relationships between nanoparticle hydrophobicity, inflammatory outcomes and the metabolic fingerprint in bronchoalveolar fluid. Measures of acute lung toxicity were assessed following single-dose intratracheal administration of nanoparticles with varying surface hydrophobicity (i.e. pegylated lipid nanocapsules, polyvinyl acetate nanoparticles and polystyrene beads; listed in order of increasing hydrophobicity). Broncho-alveolar lavage (BAL) fluid was collected from mice exposed to nanoparticles at a surface area dose of 220 cm(2) and metabolite fingerprints were acquired via ultra pressure liquid chromatography-mass spectrometry-based metabolomics. Particles with high surface hydrophobicity were pro-inflammatory. Multivariate analysis of the resultant small molecule fingerprints revealed clear discrimination between the vehicle control and polystyrene beads (p < 0.05), as well as between nanoparticles of different surface hydrophobicity (p < 0.0001). Further investigation of the metabolic fingerprints revealed that adenosine monophosphate (AMP) concentration in BAL correlated with neutrophilia (p < 0.01), CXCL1 levels (p < 0.05) and nanoparticle surface hydrophobicity (p < 0.001). Our results suggest that extracellular AMP is an intermediary metabolite involved in adenine nucleotide-regulated neutrophilic inflammation as well as tissue damage, and could potentially be used to monitor nanoparticle-induced responses in the lung following pulmonary administration.

  15. An elevator

    Energy Technology Data Exchange (ETDEWEB)

    Loginovskiy, V.I.; Medinger, N.V.; Rasskazov, V.A.; Solonitsyn, V.A.

    1983-01-01

    An elevator is proposed which includes a body, spring loaded cams and a shut-off ring. To increase the reliability of the elevator by eliminating the possibility of spontaneous shifting of the shut-off ring, the latter is equipped with handles hinged to it and is made with evolvent grooves. The cams are equipped with rollers installed in the evolvent grooves of the shut off ring, where the body is made with grooves for the handles.

  16. Monocular Elevation Deficiency - Double Elevator Palsy

    Science.gov (United States)

    ... Español Condiciones Chinese Conditions Monocular Elevation Deficiency/ Double Elevator Palsy En Español Read in Chinese What is monocular elevation deficiency (Double Elevator Palsy)? Monocular Elevation Deficiency, also known by the ...

  17. Inner ear dysfunction in caspase-3 deficient mice

    Directory of Open Access Journals (Sweden)

    Woo Minna

    2011-10-01

    Full Text Available Abstract Background Caspase-3 is one of the most downstream enzymes activated in the apoptotic pathway. In caspase-3 deficient mice, loss of cochlear hair cells and spiral ganglion cells coincide closely with hearing loss. In contrast with the auditory system, details of the vestibular phenotype have not been characterized. Here we report the vestibular phenotype and inner ear anatomy in the caspase-3 deficient (Casp3-/- mouse strain. Results Average ABR thresholds of Casp3-/- mice were significantly elevated (P Casp3+/- mice and Casp3+/+ mice at 3 months of age. In DPOAE testing, distortion product 2F1-F2 was significantly decreased (P Casp3-/- mice, whereas Casp3+/- and Casp3+/+ mice showed normal and comparable values to each other. Casp3-/- mice were hyperactive and exhibited circling behavior when excited. In lateral canal VOR testing, Casp3-/- mice had minimal response to any of the stimuli tested, whereas Casp3+/- mice had an intermediate response compared to Casp3+/+ mice. Inner ear anatomical and histological analysis revealed gross hypomorphism of the vestibular organs, in which the main site was the anterior semicircular canal. Hair cell numbers in the anterior- and lateral crista, and utricle were significantly smaller in Casp3-/- mice whereas the Casp3+/- and Casp3+/+ mice had normal hair cell numbers. Conclusions These results indicate that caspase-3 is essential for correct functioning of the cochlea as well as normal development and function of the vestibule.

  18. Postpartum estrogen withdrawal impairs hippocampal neurogenesis and causes depression- and anxiety-like behaviors in mice.

    Science.gov (United States)

    Zhang, Zhuan; Hong, Juan; Zhang, Suyun; Zhang, Tingting; Sha, Sha; Yang, Rong; Qian, Yanning; Chen, Ling

    2016-04-01

    Postpartum estrogen withdrawal is known to be a particularly vulnerable time for depressive symptoms. Ovariectomized adult mice (OVX-mice) treated with hormone-simulated pregnancy (HSP mice) followed by a subsequent estradiol benzoate (EB) withdrawal (EW mice) exhibited depression- and anxiety-like behaviors, as assessed by forced swim, tail suspension and elevated plus-maze, while HSP mice, OVX mice or EB-treated OVX mice (OVX/EB mice) did not. The survival and neurite growth of newborn neurons in hippocampal dentate gyrus were examined on day 5 after EW. Compared with controls, the numbers of 28-day-old BrdU(+) and BrdU(+)/NeuN(+) cells were increased in HSP mice but significantly decreased in EW mice; the numbers of 10-day-old BrdU(+) cells were increased in HSP mice and OVX/EB mice; and the density of DCX(+) fibers was reduced in EW mice and OVX mice. The phosphorylation of hippocampal NMDA receptor (NMDAr) NR2B subunit or Src was increased in HSP mice but decreased in EW mice. NMDAr agonist NMDA prevented the loss of 28-day-old BrdU(+) cells and the depression- and anxiety-like behaviors in EW mice. NR2B inhibitor Ro25-6981 or Src inhibitor dasatinib caused depression- and anxiety-like behaviors in HSP mice with the reduction of 28-day-old BrdU(+) cells. The hippocampal BDNF levels were reduced in EW mice and OVX mice. TrkB receptor inhibitor K252a reduced the density of DCX(+) fibers in HSP mice without the reduction of 28-day-old BrdU(+) cells, or the production of affective disorder. Collectively, these results indicate that postpartum estrogen withdrawal impairs hippocampal neurogenesis in mice that show depression- and anxiety-like behaviors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Elevation data for floodplain mapping

    National Research Council Canada - National Science Library

    Committee on Floodplain Mapping Technologies; National Research Council; Division on Earth and Life Studies; National Research Council

    2007-01-01

    .... Elevation Data for Floodplain Mapping shows that there is sufficient two-dimensional base map imagery to meet FEMA's flood map modernization goals, but that the three-dimensional base elevation data...

  20. GPR30 activation decreases anxiety in the open field test but not in the elevated plus maze test in female mice

    OpenAIRE

    Anchan, Divya; Clark, Sara; Pollard, Kevin; Vasudevan, Nandini

    2014-01-01

    The GPR30 is a novel estrogen receptor (ER) that is a candidate membrane ER based on its binding to 17beta estradiol and its rapid signaling properties such as activation of the extracellular-regulated kinase (ERK) pathway. Its distribution in the mouse limbic system predicts a role for this receptor in the estrogenic modulation of anxiety behaviors in the mouse. A previous study showed that chronic administration of a selective agonist to the GPR30 receptor, G-1, in the female rat can improv...

  1. p21{sup WAF1/Cip1/Sdi1} knockout mice respond to doxorubicin with reduced cardiotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Terrand, Jerome; Xu, Beibei; Morrissy, Steve; Dinh, Thai Nho [Department of Pharmacology,College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724 (United States); Williams, Stuart [Biomedical Engineering Program, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724 (United States); Chen, Qin M., E-mail: qchen@email.arizona.edu [Department of Pharmacology,College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724 (United States)

    2011-11-15

    Doxorubicin (Dox) is an antineoplastic agent that can cause cardiomyopathy in humans and experimental animals. As an inducer of reactive oxygen species and a DNA damaging agent, Dox causes elevated expression of p21{sup WAF1/Cip1/Sdi1} (p21) gene. Elevated levels of p21 mRNA and p21 protein have been detected in the myocardium of mice following Dox treatment. With chronic treatment of Dox, wild type (WT) animals develop cardiomyopathy evidenced by elongated nuclei, mitochondrial swelling, myofilamental disarray, reduced cardiac output, reduced ejection fraction, reduced left ventricular contractility, and elevated expression of ANF gene. In contrast, p21 knockout (p21KO) mice did not show significant changes in the same parameters in response to Dox treatment. In an effort to understand the mechanism of the resistance against Dox induced cardiomyopathy, we measured levels of antioxidant enzymes and found that p21KO mice did not contain elevated basal or inducible levels of glutathione peroxidase and catalase. Measurements of 6 circulating cytokines indicated elevation of IL-6, IL-12, IFN{gamma} and TNF{alpha} in Dox treated WT mice but not p21KO mice. Dox induced elevation of IL-6 mRNA was detected in the myocardium of WT mice but not p21KO mice. While the mechanism of the resistance against Dox induced cardiomyopathy remains unclear, lack of inflammatory response may contribute to the observed cardiac protection in p21KO mice. -- Highlights: Black-Right-Pointing-Pointer Doxorubicin induces p21 elevation in the myocardium. Black-Right-Pointing-Pointer Doxorubicin causes dilated cardiomyopathy in wild type mice. Black-Right-Pointing-Pointer p21 Knockout mice are resistant against doxorubicin induced cardiomyopathy. Black-Right-Pointing-Pointer Lack of inflammatory response correlates with the resistance in p21 knockout mice.

  2. Elevator wheel

    Energy Technology Data Exchange (ETDEWEB)

    Zhornik, V.I.; Cherkov, Ye.M.; Simonov, A.A.

    1982-01-01

    An elevator wheel is suggested for unloading a sunken product from a bath of a heavy-average separator including discs of a bucket with inner walls, and covering sheets hinged to the buckets. In order to improve the degree of dehydration of the removed product, the inner wall of each bucket is made of sheets installed in steps with gaps of one in relation to the other.

  3. An elevator

    Energy Technology Data Exchange (ETDEWEB)

    Gusev, A.S.; Peshkov, L.P.; Rozin, M.M.; Shestov, A.G.

    1983-01-01

    An elevator is proposed which includes a body, a flap, a lock with a catch and a spring-loaded shut-off clamp in the form of upper and lower horizontal levers which are connected by a handle and an axle and one end of which is made in the form of an eccentric cam. The size of the eccentricity of the cam of the levers is increased toward the handle of the clamp in order to increase the operational reliability and to extend the service life.

  4. An elevator

    Energy Technology Data Exchange (ETDEWEB)

    Rastorguyev, M.A.; Maloyarovslavtesv, D.A.; Prokopov, O.I.; Tukayev, Sh.V.; Zanilov, I.F.

    1983-01-01

    An elevator is proposed which includes a body with a turning collar locking device and a rod with longitudinal grooves, which are flexibly linked with jaws positioned in grooves in the body. To increase safety through ensuring automatic locking of the jaws in the closed position, the locking device is made in the form of head on wedges, spring loaded relative to the collar and made with cams and positioned with the capability of interacting with the grooves of the rod and through the cams with the collar.

  5. Elevated environmental temperature and methamphetamine neurotoxicity

    International Nuclear Information System (INIS)

    Miller, Diane B.; O'Callaghan, James P.

    2003-01-01

    Amphetamines have been of considerable research interest for the last several decades. More recent work has renewed interest in the role of ambient temperature in both the toxicity and neurotoxicity of these drugs. We have determined that the striatal dopaminergic neurotoxicity observed in the mouse is linked in some fashion to both body and environmental temperature. Most studies of d-methamphetamine (d-METH) neurotoxicity are conducted at standard laboratory ambient temperatures (e.g., ∼21-22 deg. C) and utilizing a repeated dosage regimen (e.g., three to four injections spaced 2 h apart). A lowering of the ambient temperature provides neuro protection, while an elevation increases neurotoxicity. d-METH causes long-term depletions of triatal dopamine (DA) that are accompanied by other changes that are indicative of nerve terminal degeneration. These include argyrophilia, as detected by silver degeneration stains, and an elevation in glial fibrillary acidic protein (GFAP), a marker of reactive gliosis in response to injury, as well as a long-term decrease in tyrosine hydroxylase (TH) protein levels. here we show that increasing the ambient temperature during and for some time following dosing increases the neurotoxicity of d-METH. Mice (female 57BL6/J) given a single dosage of d-METH (20 mg/kg s.c.) and maintained at the usual laboratory ambient temperature show minimal striatal damage (an ∼15% depletion of DA and an ∼ 86% increase in GFAP). substantial striatal damage (e.g., an ∼70% depletion of DA and an ∼200% elevation in GFAP) was induced by this regimen if mice were maintained at 27 deg. C for 24 or 72 h following dosing. An increase in neurotoxicity was also apparent in mice kept at an elevated temperature for only 5 or 9 h, but keeping animals at 27 deg. C for 24 or 72 h was the most effective in increasing the neurotoxicity of d-METH. Our data show how a relatively minor change in ambient temperature can have a major impact on the degree of

  6. Bucket elevator

    OpenAIRE

    Chromek, Jiří

    2013-01-01

    Cílem této bakalářské práce je návrh svislého korečkového elevátoru, který má sloužit k dopravě obilovin s dopravní výškou 19 m a dopravovaným množstvím 100 t/hod. Práce se skládá z popisu korečkového elevátoru a jeho hlavních částí, zmiňující se v úvodní rešerši. Tato práce je zaměřena na funkční a kapacitní výpočet, určení pohonu a napínacího zařízení. Další výpočet je kontrolní, skládající se z pevnostní kontroly hnacího hřídele, výpočtu pera, životnosti ložisek a výpočtu napínacího zaříze...

  7. Social factors modulate restraint stress induced hyperthermia in mice.

    Science.gov (United States)

    Watanabe, Shigeru

    2015-10-22

    Stress-induced hyperthermia (SIH) was examined in three different social conditions in mice by thermographic measurement of the body surface temperature. Placing animals in cylindrical holders induced restraint stress. I examined the effect of the social factors in SIH using the thermograph (body surface temperature). Mice restrained in the holders alone showed SIH. Mice restrained in the holders at the same time as other similarly restrained cage mates (social equality condition) showed less hyperthermia. Interestingly, restrained mice with free moving cage mates (social inequality condition) showed the highest hyperthermia. These results are consistent with a previous experiment measuring the memory-enhancing effects of stress and the stress-induced elevation of corticosterone, and suggest that social inequality enhances stress. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Behavioral characterization of CD36 knockout mice with SHIRPA primary screen.

    Science.gov (United States)

    Zhang, Shuxiao; Wang, Wei; Li, Juan; Cheng, Ke; Zhou, Jingjing; Zhu, Dan; Yang, Deyu; Liang, Zihong; Fang, Liang; Liao, Li; Xie, Peng

    2016-02-15

    CD36 is a member of the class B scavenger receptor family of cell surface proteins, which plays a major role in fatty acid, glucose and lipid metabolism. Besides, CD36 functions as a microglial surface receptor for amyloid beta peptide. Regarding this, we suggest CD36 might also contribute to neuropsychiatric disease. The aim of this study was to achieve a behavioral phenotype of CD36 knockout (CD36(-/-)) mice. We characterized the behavior of CD36(-/-) mice and C57BL/6J mice by subjecting them to a series of tests, which include SHIRPA primary behavioral screen test, 1% sucrose preference test, elevated plus-maze test, open-field test and forced swimming test. The results showed that CD36(-/-) mice traversed more squares, emitted more defecation, exhibited higher tail elevation and had more aggressive behaviors than C57BL/6J mice. The CD36(-/-) mice spent more time and traveled longer distance in periphery zone in the open-field test. Meanwhile, the numbers that CD36(-/-) mice entered in the open arms of elevated plus-maze were reduced. These findings suggest that CD36(-/-) mice present an anxious phenotype and might be involved in neuropsychiatric disorders. Copyright © 2015. Published by Elsevier B.V.

  9. Aqueous extract from pecan nut [Carya illinoinensis (Wangenh) C. Koch] shell show activity against breast cancer cell line MCF-7 and Ehrlich ascites tumor in Balb-C mice.

    Science.gov (United States)

    Hilbig, Josiane; Policarpi, Priscila de Britto; Grinevicius, Valdelúcia Maria Alves de Souza; Mota, Nádia Sandrine Ramos Santos; Toaldo, Isabela Maia; Luiz, Marilde Terezinha Bordignon; Pedrosa, Rozangela Curi; Block, Jane Mara

    2018-01-30

    In Brazil many health disorders are treated with the consumption of different varieties of tea. Shell extracts of pecan nut (Carya illinoinensis), which have significant amounts of phenolic compounds in their composition, are popularly taken as tea to prevent diverse pathologies. Phenolic compounds from pecan nut shell extract have been associated with diverse biological effects but the effect on tumor cells has not been reported yet. The aim of the current work was to evaluate the relationship between DNA fragmentation, cell cycle arrest and apoptosis induced by pecan nut shell extract and its antitumor activity. Cytotoxicity, proliferation, cell death and cell cycle were evaluated in MCF-7 cells by MTT, colony assay, differential coloring and flow cytometry assays, respectively. DNA damage effects were evaluated through intercalation into CT-DNA and plasmid DNA cleavage. Tumor growth inhibition, survival time increase, apoptosis and cell cycle arrest were assessed in Ehrlich ascites tumor in Balb/C mice. The cytotoxic effect of pecan nut shell extracts, the induction of cell death by apoptosis and also the cell cycle arrest in MCF-7 cells have been demonstrated. The survival time in mice with Ehrlich ascites tumor increased by 67%. DNA damage was observed in the CT-DNA, plasmid DNA and comet assays. The mechanism involved in the antitumor effect of pecan nut shell extracts may be related to the activation of key proteins involved in apoptosis cell death (Bcl-XL, Bax and p53) and on the cell cycle regulation (cyclin A, cyclin B and CDK2). These results were attributed to the phenolic profile of the extract, which presented compounds such as gallic, 4-hydroxybenzoic, chlorogenic, vanillic, caffeic and ellagic acid, and catechin, epicatechin, epigallocatechin and epicatechin gallate. The results indicated that pecan nut shell extracts are effective against tumor cells growth and may be considered as an alternative to the treatment of cancer. Copyright © 2017

  10. Effects of Chronic Exposure to Ultrasound of Alternating Frequencies on the Levels of Aggression and Anxiety in CBA and BALB/c mice.

    Science.gov (United States)

    Pavlov, D A; Gorlova, A V; Ushakova, V M; Zubkov, E A; Morozova, A Yu; Inozemtsev, A N; Chekhonin, V P

    2017-08-01

    Stress-induced changes in the behavior of CBA and BALB/c mice were studied after 3-week ultrasound exposure (22-45 kHz). The mice of both lines demonstrated increased aggression in the resident-intruder and social interest paradigms and reduced number of social interactions in the social interest test. Elevated plus maze test showed a decrease in anxiety level in CBA mice and an increase in this parameter in BALB/c mice. Chronic exposure to ultrasound induced an increase in aggression level in mice of both lines that was not directly related to changes in anxiety level.

  11. Mice lacking Brinp2 or Brinp3, or both, exhibit behaviours consistent with neurodevelopmental disorders

    Directory of Open Access Journals (Sweden)

    Susie Ruth Berkowicz

    2016-10-01

    Full Text Available Background: Brinps 1 – 3, and Astrotactins (Astn 1 and 2, are members of the Membrane Attack Complex / Perforin (MACPF superfamily that are predominantly expressed in the mammalian brain during development. Genetic variation at the human BRINP2/ASTN1 and BRINP1/ASTN2 loci has been implicated in neurodevelopmental disorders. We, and others, have previously shown that Brinp1-/- mice exhibit behaviour reminiscent of autism spectrum disorder (ASD and attention deficit hyperactivity disorder (ADHD.Method: We created Brinp2-/- mice and Brinp3-/- mice via the Cre-mediated LoxP system to investigate the effect of gene deletion on anatomy and behaviour. Additionally, Brinp2-/-Brinp3-/- double knock-out mice were generated by interbreeding Brinp2-/- and Brinp3-/- mice. Genomic validation was carried out for each knock-out line, followed by histological, weight and behavioural examination. Brinp1-/-Brinp2-/-Brinp3-/- triple knock-out mice were also generated by crossing Brinp2/3 double knock-out mice with previously generated Brinp1-/- mice, and examined by weight and histological analysis.Results: Brinp2-/- and Brinp3-/- mice differ in their behaviour: Brinp2-/- mice are hyperactive, whereas Brinp3-/- mice exhibit marked changes in anxiety-response on the elevated plus maze. Brinp3-/- mice also show evidence of altered sociability. Both Brinp2-/- and Brinp3-/- mice have normal short-term memory, olfactory responses, pre-pulse inhibition and motor learning. The double knock-out mice show behaviours of Brinp2-/- and Brinp3-/- mice, without evidence of new or exacerbated phenotypes. Conclusion: Brinp3 is important in moderation of anxiety, with potential relevance to anxiety disorders. Brinp2 dysfunction resulting in hyperactivity may be relevant to the association of ADHD with chromosome locus 1q25.2. Brinp2-/- and Brinp3-/- genes do not compensate in the mammalian brain and likely have distinct molecular or cell-type specific functions.

  12. Interpretation of elevated plasma visfatin concentrations in patients with ST-elevation myocardial infarction.

    Science.gov (United States)

    Lu, Li-Fen; Wang, Chao-Ping; Yu, Teng-Hung; Hung, Wei-Chin; Chiu, Cheng-An; Chung, Fu-Mei; Tsai, I-Ting; Yang, Chih-Ying; Cheng, Ya-Ai; Lee, Yau-Jiunn; Yeh, Lee-Ren

    2012-01-01

    Visfatin is a cytokine that is expressed in many tissues, including the heart, and has been proposed to play a role in plaque destabilization leading to acute myocardial injury. The present study evaluates plasma levels of visfatin in acute ST-elevation myocardial infarction (STEMI) patients and examines the temporal changes in visfatin levels from the acute period to the subacute period to determine a correlation with the degree of myocardial ischemia. We evaluated 54 patients with STEMI. Circulating levels of visfatin and brain natriuretic peptide (BNP) were measured by ELISA. In addition, local expression of visfatin and BNP were detected by quantitative real-time polymerase chain reaction and immunohistochemical (IHC) analysis of left ventricular myocytes in a mouse model of myocardial infarction (MI). Plasma levels of visfatin were significantly increased in patients with STEMI on admission, relative to controls (effort angina patients and individuals without coronary artery disease). The visfatin levels reached a peak 24h after percutaneous coronary intervention (PCI) and then decreased toward the control range during the first week after PCI. The basal plasma visfatin levels were found to correlate with peak troponin-I, peak creatine kinase-MB, total white blood cell count, and BNP levels. Trend analyses confirmed that visfatin levels correlated with the number of diseased coronary arteries. Further, in MI mice, mRNA levels of visfatin and BNP were found to be higher than in sham-treated mice. IHC analysis showed that visfatin and BNP immunoreactivity was diffusely observable in left ventricular myocytes of the MI mice. This study indicates that plasma visfatin levels are significantly higher in STEMI patients and that these higher visfatin levels correlate with elevated levels of cardiac enzymes, suggesting that increased plasma visfatin may be closely related to the degree of myocardial damage. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Specific-locus experiments show that female mice exposed near the time of birth to low-LET ionizing radiation exhibit both a low mutational response and a dose-rate effect

    International Nuclear Information System (INIS)

    Selby, P.B.; Lee, S.S.; Kelly, E.M.; Bangham, J.W.; Raymer, G.D.; Hunsicker, P.R.

    1991-01-01

    Female mice were exposed to 300 R of 73-93 R/min X-radiation either as fetuses at 18.5d post conception (p.c.) or within 9h after birth. Combining the similar results from these 2 groups yielded a specific-locus mutation frequency of 9.4x10 -8 mutation/locus/R, which is statistically significantly higher than the historical-control mutation frequency, but much lower than the rate obtained by irradiating mature and maturing oocytes in adults. Other females, exposed at 18.5 days p.c. to 300 R of 0.79 R/min γ-radiation, yielded a mutation frequency that was statistically significantly lower than the frequency at high dose rates. The low-dose-rate group also had markedly higher fertility. It appears that the doe-rate effect for mutations induced near the time of birth may be more pronounced than that reported for mature and maturing oocytes of adults. A hypothesis sometimes advanced to explain low mutation frequencies recovered from cell populations that experience considerable radiation-induced cell killing is that there is selection against mutant cells. The reason for the relatively low mutational response following acute irradiation in the experiments is unknown; however, the finding of a dose-rate effect in these oocytes in the presence of only minor radiation-induced cell killing (as judged from fertility) makes it seem unlikely that selection was responsible for the low mutational response following acute exposure. Had selection been an important factor, the mutation frequency should have increased when oocyte killing was markedly reduced. (author). 32 refs.; 5 figs.; 5 tabs

  14. Effects of exercise and enrichment on behaviour in CD-1 mice.

    Science.gov (United States)

    Aujnarain, Amiirah B; Luo, Owen D; Taylor, Natalie; Lai, Jonathan K Y; Foster, Jane A

    2018-04-16

    A host of scholarly work has characterized the positive effects of exercise and environmental enrichment on behaviour and cognition in animal studies. The purpose of this study was to investigate the uptake and longitudinal impact of exercise and enrichment on the behavioural phenotype of male and female CD-1 mice. CD-1 mice housed in standard (STD) or exercise and enrichment (EE) conditions post-weaning were tested in the 3-chamber sociability test, open field, and elevated plus maze and exercise activity was monitored throughout the enrichment protocol. Male and female EE mice both showed reduced anxiety and activity in the open field and elevated plus maze relative to sex-matched STD mice. EE altered social behaviours in a sex-specific fashion, with only female EE mice showing increased social preference relative to female STD mice and a preference for social novelty only present in male EE mice. This sexual dimorphism was not observed to be a product of exercise uptake, as CD-1 mice of both sexes demonstrated a consistent trend of wheel rotation frequencies. These findings suggest the importance of considering variables such as sex and strain on experimental design variables in future work on environmental enrichment. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Plasma sphingosine-1-phosphate is elevated in obesity.

    Directory of Open Access Journals (Sweden)

    Greg M Kowalski

    Full Text Available BACKGROUND: Dysfunctional lipid metabolism is a hallmark of obesity and insulin resistance and a risk factor for various cardiovascular and metabolic complications. In addition to the well known increase in plasma triglycerides and free fatty acids, recent work in humans and rodents has shown that obesity is associated with elevations in the bioactive class of sphingolipids known as ceramides. However, in obesity little is known about the plasma concentrations of sphinogsine-1-phosphate (S1P, the breakdown product of ceramide, which is an important signaling molecule in mammalian biology. Therefore, the purpose of this study was to examine the impact of obesity on circulating S1P concentration and its relationship with markers of glucose metabolism and insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: Plasma S1P levels were determined in high-fat diet (HFD-induced and genetically obese (ob/ob mice along with obese humans. Circulating S1P was elevated in both obese mouse models and in obese humans compared with lean healthy controls. Furthermore, in humans, plasma S1P positively correlated with total body fat percentage, body mass index (BMI, waist circumference, fasting insulin, HOMA-IR, HbA1c (%, total and LDL cholesterol. In addition, fasting increased plasma S1P levels in lean healthy mice. CONCLUSION: We show that elevations in plasma S1P are a feature of both human and rodent obesity and correlate with metabolic abnormalities such as adiposity and insulin resistance.

  16. National Elevation Dataset (NED)

    Data.gov (United States)

    Kansas Data Access and Support Center — The U.S. Geological Survey has developed a National Elevation Database (NED). The NED is a seamless mosaic of best-available elevation data. The 7.5-minute elevation...

  17. Elevated Liver Enzymes

    Science.gov (United States)

    Symptoms Elevated liver enzymes By Mayo Clinic Staff Elevated liver enzymes may indicate inflammation or damage to cells in the liver. Inflamed or ... than normal amounts of certain chemicals, including liver enzymes, into the bloodstream, which can result in elevated ...

  18. Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6

    Directory of Open Access Journals (Sweden)

    Isaac Mohar

    2014-01-01

    Full Text Available The mechanism by which acetaminophen (APAP causes liver damage evokes many aspects drug metabolism, oxidative chemistry, and genetic-predisposition. In this study, we leverage the relative resistance of female C57BL/6 mice to APAP-induced liver damage (AILD compared to male C57BL/6 mice in order to identify the cause(s of sensitivity. Furthermore, we use mice that are either heterozygous (HZ or null (KO for glutamate cysteine ligase modifier subunit (Gclm, in order to titrate the toxicity relative to wild-type (WT mice. Gclm is important for efficient de novo synthesis of glutathione (GSH. APAP (300 mg/kg, ip or saline was administered and mice were collected at 0, 0.5, 1, 2, 6, 12, and 24 h. Male mice showed marked elevation in serum alanine aminotransferase by 6 h. In contrast, female WT and HZ mice showed minimal toxicity at all time points. Female KO mice, however, showed AILD comparable to male mice. Genotype-matched male and female mice showed comparable APAP–protein adducts, with Gclm KO mice sustaining significantly greater adducts. ATP was depleted in mice showing toxicity, suggesting impaired mitochondria function. Indeed, peroxiredoxin-6, a GSH-dependent peroxiredoxin, was preferentially adducted by APAP in mitochondria of male mice but rarely adducted in female mice. These results support parallel mechanisms of toxicity where APAP adduction of peroxiredoxin-6 and sustained GSH depletion results in the collapse of mitochondria function and hepatocyte death. We conclude that adduction of peroxiredoxin-6 sensitizes male C57BL/6 mice to toxicity by acetaminophen.

  19. Characteristics of gait ataxia in δ2 glutamate receptor mutant mice, ho15J.

    Directory of Open Access Journals (Sweden)

    Eri Takeuchi

    Full Text Available The cerebellum plays a fundamental, but as yet poorly understood, role in the control of locomotion. Recently, mice with gene mutations or knockouts have been used to investigate various aspects of cerebellar function with regard to locomotion. Although many of the mutant mice exhibit severe gait ataxia, kinematic analyses of limb movements have been performed in only a few cases. Here, we investigated locomotion in ho15J mice that have a mutation of the δ2 glutamate receptor. The cerebellum of ho15J mice shows a severe reduction in the number of parallel fiber-Purkinje synapses compared with wild-type mice. Analysis of hindlimb kinematics during treadmill locomotion showed abnormal hindlimb movements characterized by excessive toe elevation during the swing phase, and by severe hyperflexion of the ankles in ho15J mice. The great trochanter heights in ho15J mice were lower than in wild-type mice throughout the step cycle. However, there were no significant differences in various temporal parameters between ho15J and wild-type mice. We suggest that dysfunction of the cerebellar neuronal circuits underlies the observed characteristic kinematic abnormality of hindlimb movements during locomotion of ho15J mice.

  20. Effect of the histaminergic antagonist over the pulmonary oedema growth in P. berghei - infected mice

    International Nuclear Information System (INIS)

    Martins, M.A.

    1985-01-01

    The involvement of histaminergic mechanisms in the pathogenesis of pulmonary oedema observed in p. berghei - infected mice was investigated. Histamine concentrations in plasma and whole blood of infected and normal mice were determined by radioenzymatic assay during the seven days of the infection. Elevated plasma and whole blood histamine levels were found at the last stages of infection (sixth day and seventh day) after intraperitoneal injection of parasitized erythrocytes, showing a close temporal correlation between the development of the oedema and the elevation of the circulating histamine concentrations. The participation of H 1 and H 2 receptors in the increase in vascular permeability (IVP) induced by histamine was also verified. (author)

  1. Oral vaccine of Lactococcus lactis harbouring pandemic H1N1 2009 haemagglutinin1 and nisP anchor fusion protein elevates anti-HA1 sIgA levels in mice.

    Science.gov (United States)

    Joan, Stella Siaw Xiu; Pui-Fong, Jee; Song, Adelene Ai-Lian; Chang, Li-Yen; Yusoff, Khatijah; AbuBakar, Sazaly; Rahim, Raha Abdul

    2016-05-01

    An oral lactococcal-based vaccine which haboured the haemagglutinin1 (HA1) antigen fused to nisP anchor protein for the purpose of surface displaying the HA1 antigen was developed against H1N1 virus. Recombinant L. lactis strains expressed HA1-nisP fusion proteins when induced with nisin, as confirmed through western blotting. However, immunofluorescense did not detect any surface-displayed proteins, suggesting that the protein was either unsuccessfully translocated or improperly displayed. Despite this, oral administration of recombinant L. lactis strains to BALB/c mice revealed that significant levels of anti-HA1 sIgA antibodies were detected in mice fecal suspension samples of mice group NZ9000 (pNZ:HN) when compared to the negative control NZ9000 (pNZ8048) group. Specific anti-HA1 sIgA antibodies were locally produced and live recombinant lactococcal vaccine was able to elicit humoral response of BALB/c mice despite unsuccessful surface display of the HA1 epitope.

  2. Ultraviolet Radiation–Induced Cataract in Mice: The Effect of Age and the Potential Biochemical Mechanism

    Science.gov (United States)

    Zhang, Jie; Yan, Hong; Löfgren, Stefan; Tian, Xiaoli; Lou, Marjorie F.

    2012-01-01

    Purpose. To study the effect of age on the morphologic and biochemical alterations induced by in vivo exposure of ultraviolet radiation (UV). Methods. Young and old C57BL/6 mice were exposed to broadband UVB+UVA and euthanized after 2 days. Another batch of UV-exposed young mice was monitored for changes after 1, 2, 4, and 8 days. Age-matched nonexposed mice served as controls. Lens changes were documented in vivo by slit-lamp biomicroscopy and dark field microscopy photographs ex vivo. Lens homogenates were analyzed for glutathione (GSH) level, and the activities of thioredoxin (Trx), thioltransferase (TTase), and glyceraldehyde-3-phosphate dehydrogenase (G3PD). Glutathionylated lens proteins (PSSGs) were detected by immunoblotting using GSH antibody. Western blot analysis was also done for the expression levels of TTase and Trx. Results. Both age groups developed epithelial and superficial anterior subcapsular cataract at 2 days postexposure. The lens GSH level and G3PD activity were decreased, and PSSGs were elevated in both age groups, but more prominent in the older mice. TTase and Trx activity and protein expression were elevated only in the young mice. Interestingly, lens TTase and Trx in the young mice showed a transient increase, peaking at 2 days after UV exposure and returning to baseline at day 8, corroborated by lens transparency. Conclusions. The lenses of old mice were more susceptible to UV radiation–induced cataract. The upregulated TTase and Trx likely provided oxidation damage repair in the young mice. PMID:23010639

  3. Increased anxiety-related behaviour in Hint1 knockout mice.

    Science.gov (United States)

    Varadarajulu, Jeeva; Lebar, Maria; Krishnamoorthy, Gurumoorthy; Habelt, Sonja; Lu, Jia; Bernard Weinstein, I; Li, Haiyang; Holsboer, Florian; Turck, Christoph W; Touma, Chadi

    2011-07-07

    Several reports have implicated a role for the histidine triad nucleotide-binding protein-1 (Hint1) in psychiatric disorders. We have studied the emotional behaviour of male Hint1 knockout (Hint1 KO) mice in a battery of tests and performed biochemical analyses on brain tissue. The behavioural analysis revealed that Hint1 KO mice exhibit an increased emotionality phenotype compared to wildtype (WT) mice, while no significant differences in locomotion or general exploratory activity were noted. In the elevated plus-maze (EPM) test, the Hint1 KO animals entered the open arms of the apparatus less often than WT littermates. Similarly, in the dark-light box test, Hint1 KO mice spent less time in the lit compartment and the number of entries were reduced, which further confirmed an increased anxiety-related behaviour. Moreover, the Hint1 KO animals showed significantly more struggling and less floating behaviour in the forced swim test (FST), indicating an increased emotional arousal in aversive situations. Hint1 is known as a protein kinase C (PKC) interacting protein. Western blot analysis showed that PKCγ expression was elevated in Hint1 KO compared to WT mice. Interestingly, PKCγ mRNA levels of the two groups did not show a significant difference, implying a post-transcriptional PKCγ regulation. In addition, PKC enzymatic activity was increased in Hint1 KO compared to WT mice. In summary, our results indicate a role for Hint1 and PKCγ in modulating anxiety-related and stress-coping behaviour in mice. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Context-Aware Elevator Scheduling

    OpenAIRE

    Strang, Thomas; Bauer, Christian

    2007-01-01

    Research on context-aware systems is usually user-centric and thus focussed on the context of a specific user to serve his or her needs in an optimized way. In this paper, we want to apply core concepts developed in research on context-awareness in a system-centric way, namely to elevator systems. We show with three different examples that the performance of an elevator system can be significantly improved if the elevator control has access to contextual knowledge. The first example demons...

  5. APPswe/PS1dE9 mice with cortical amyloid pathology show a reduced NAA/Cr ratio without apparent brain atrophy: A MRS and MRI study.

    Science.gov (United States)

    Kuhla, Angela; Rühlmann, Claire; Lindner, Tobias; Polei, Stefan; Hadlich, Stefan; Krause, Bernd J; Vollmar, Brigitte; Teipel, Stefan J

    2017-01-01

    Transgenic animal models of Aβ pathology provide mechanistic insight into some aspects of Alzheimer disease (AD) pathology related to Aβ accumulation. Quantitative neuroimaging is a possible aid to improve translation of mechanistic findings in transgenic models to human end phenotypes of brain morphology or function. Therefore, we combined MRI-based morphometry, MRS-based NAA-assessment and quantitative histology of neurons and amyloid plaque load in the APPswe/PS1dE9 mouse model to determine the interrelationship between morphological changes, changes in neuron numbers and amyloid plaque load with reductions of NAA levels as marker of neuronal functional viability. The APPswe/PS1dE9 mouse showed an increase of Aβ plaques, loss of neurons and an impairment of NAA/Cr ratio, which however was not accompanied with brain atrophy. As brain atrophy is one main characteristic in human AD, conclusions from murine to human AD pathology should be drawn with caution.

  6. Data in support of fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice

    Directory of Open Access Journals (Sweden)

    Du-Qiang Luo

    2015-09-01

    Full Text Available This data article contains data related to the research article entitled “Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice” in the Toxicology and Applied Pharmacology [1]. Fumosorinone (FU is a new inhibitor of protein phosphatase 1B inhibitor, which was isolated from insect pathogenic fungi Isaria fumosorosea. FU was found to inhibit PTP1B activity in our previous study [2]. PTP1B is the physiological antagonist of the insulin signalling pathway. Inhibition of PTP 1B may increase insulin sensitivity [3]. PTP1B has been considered promising as an insulin-sensitive drug target for the prevention and the treatment of insulin-based diseases [4]. We determined the effect of FU on the glucose consumption of IR HepG2 cells. FU caused significant enhancement in glucose consumption by insulin-resistant HepG2 cells compared with control cells.

  7. Mice with targeted disruption of the acyl-CoA binding protein display attenuated urine concentrating ability and diminished renal aquaporin-3 abundance

    DEFF Research Database (Denmark)

    Langaa, Stine; Bloksgaard, Maria; Bek, Signe

    2012-01-01

    epithelial cells. Here we show that ACBP is widely expressed in human and mouse kidney epithelium with the highest expression in the proximal convoluted tubules. To elucidate the role of ACBP in the renal epithelium, mice with targeted disruption of the ACBP gene (ACBP(-/-)) were used to study water and Na......Cl balance as well as urine concentrating ability in metabolic cages. Food intake and urinary excretion of Na(+) and K(+) did not differ between ACBP(-/-) and (+/+) mice. Water intake and diuresis were significantly higher at baseline in ACBP(-/-) mice compared to that of (+/+) mice. Subsequent to 20h water...... deprivation, ACBP(-/-) mice exhibited increased diuresis, reduced urine osmolality, elevated hematocrit and higher relative weight loss compared to (+/+) mice. There were no significant differences in plasma concentrations of renin, corticosterone and aldosterone between mice of the two genotypes. At baseline...

  8. Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

    DEFF Research Database (Denmark)

    Alkharusi, Amira; Mirecki-Garrido, Mercedes; Ma, Zuheng

    2016-01-01

    Background: Diabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can...... prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity. Methodology: The elevated sensitivity of SOCS2-/- mice to GH and possibly to PRL was the rationale to analyze the effects of multiple low dose streptozotocin (MLDSTZ)-induced diabetes...... in SOCS2-/- mice. Results: We show that 6-month-old SOCS2-/- mice, but not 2-month-old mice, were less sensitive to MLDSTZ-induced diabetes, compared to controls. MLDSTZ treatment induced glucose intolerance in both SOCS2+/+ and SOCS2-/- mice, as shown by glucose tolerance tests, with SOCS2+/+ mice...

  9. Targeted Deletion of Kynurenine 3-Monooxygenase in Mice

    Science.gov (United States)

    Giorgini, Flaviano; Huang, Shao-Yi; Sathyasaikumar, Korrapati V.; Notarangelo, Francesca M.; Thomas, Marian A. R.; Tararina, Margarita; Wu, Hui-Qiu; Schwarcz, Robert; Muchowski, Paul J.

    2013-01-01

    Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation, has been suggested to play a major role in physiological and pathological events involving bioactive KP metabolites. To explore this role in greater detail, we generated mice with a targeted genetic disruption of Kmo and present here the first biochemical and neurochemical characterization of these mutant animals. Kmo−/− mice lacked KMO activity but showed no obvious abnormalities in the activity of four additional KP enzymes tested. As expected, Kmo−/− mice showed substantial reductions in the levels of its enzymatic product, 3-hydroxykynurenine, in liver, brain, and plasma. Compared with wild-type animals, the levels of the downstream metabolite quinolinic acid were also greatly decreased in liver and plasma of the mutant mice but surprisingly were only slightly reduced (by ∼20%) in the brain. The levels of three other KP metabolites: kynurenine, kynurenic acid, and anthranilic acid, were substantially, but differentially, elevated in the liver, brain, and plasma of Kmo−/− mice, whereas the liver and brain content of the major end product of the enzymatic cascade, NAD+, did not differ between Kmo−/− and wild-type animals. When assessed by in vivo microdialysis, extracellular kynurenic acid levels were found to be significantly elevated in the brains of Kmo−/− mice. Taken together, these results provide further evidence that KMO plays a key regulatory role in the KP and indicate that Kmo−/− mice will be useful for studying tissue-specific functions of individual KP metabolites in health and disease. PMID:24189070

  10. Show-Bix &

    DEFF Research Database (Denmark)

    2014-01-01

    The anti-reenactment 'Show-Bix &' consists of 5 dias projectors, a dial phone, quintophonic sound, and interactive elements. A responsive interface will enable the Dias projectors to show copies of original dias slides from the Show-Bix piece ”March på Stedet”, 265 images in total. The copies are...

  11. Space Elevators Preliminary Architectural View

    Science.gov (United States)

    Pullum, L.; Swan, P. A.

    Space Systems Architecture has been expanded into a process by the US Department of Defense for their large scale systems of systems development programs. This paper uses the steps in the process to establishes a framework for Space Elevator systems to be developed and provides a methodology to manage complexity. This new approach to developing a family of systems is based upon three architectural views: Operational View OV), Systems View (SV), and Technical Standards View (TV). The top level view of the process establishes the stages for the development of the first Space Elevator and is called Architectural View - 1, Overview and Summary. This paper will show the guidelines and steps of the process while focusing upon components of the Space Elevator Preliminary Architecture View. This Preliminary Architecture View is presented as a draft starting point for the Space Elevator Project.

  12. Are Sema5a mutant mice a good model of autism? A behavioral analysis of sensory systems, emotionality and cognition

    Science.gov (United States)

    Gunn, Rhian K.; Huentelman, Matthew J.; Brown, Richard E.

    2011-01-01

    Semaphorin 5A (Sema5A) expression is reduced in the brain of individuals with autism, thus mice with reduced Sema5A levels may serve as a model of this neurodevelopmental disorder. We tested male and female Sema5a knockout mice (B6.129P2SEMA5A/J) and C57BL/6J controls for emotionality, visual ability, prepulse inhibition, motor learning and cognition. Overall, there were only two genotype differences in emotionality: Sema5a mutant mice had more stretch-attend postures in the elevated plus-maze and more defecations in the open field. All mice could see, but Sema5a mice had better visual ability than C57BL/6J mice. There were no genotype differences in sensory-motor gating. Sema5a mice showed higher levels of activity in the elevated plus-maze and light/dark transition box, and there were sex by genotype differences in the Rotarod, suggesting a sex difference in balance and coordination differentially affected by Sema5a. There were no genotype effects on cognition: Sema5a mice did not differ from C57BL/6J in the Morris water maze, set-shifting or cued and contextual fear conditioning. In the social recognition test, all mice preferred social stimuli, but there was no preference for social novelty, thus the Sema5A mice do not have a deficit in social behavior. Overall, there were a number of sex differences, with females showing greater activity and males performing better in tests of spatial learning and memory, but no deficits in the behavior of Sema5A mice. We conclude that the Sema5a mice do not meet the behavioral criteria for a mouse model of autism. PMID:21777623

  13. Th2 Regulation of Viral Myocarditis in Mice: Different Roles for TLR3 versus TRIF in Progression to Chronic Disease

    Directory of Open Access Journals (Sweden)

    Eric D. Abston

    2012-01-01

    Full Text Available Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3 myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL-4-dominant T helper (Th2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.

  14. Iowa Bedrock Surface Elevation

    Data.gov (United States)

    Iowa State University GIS Support and Research Facility — This Digital Elevation Model (DEM) of the bedrock surface elevation in Iowa was compiled using all available data, principally information from GEOSAM, supplemented...

  15. Impaired intestinal proglucagon processing in mice lacking prohormone convertase 1

    DEFF Research Database (Denmark)

    Ugleholdt, Randi; Zhu, Xiaorong; Deacon, Carolyn F

    2003-01-01

    proglucagon processing showed marked defects. Tissue proglucagon levels in null mice were elevated, and proglucagon processing to glicentin, oxyntomodulin, and glucagon-like peptide-1 and -2 (GLP-1 and GLP-2) was markedly decreased, indicating that PC1 is essential for the processing of all the intestinal...... proglucagon cleavage sites. This includes the monobasic site R(77) and, thereby, production of mature, biologically active GLP-1. We also found elevated glucagon levels, suggesting that factors other than PC1 that are capable of processing to mature glucagon are present in the secretory granules of the L cell......The neuroendocrine prohormone convertases 1 and 2 (PC1 and PC2) are expressed in endocrine intestinal L cells and pancreatic A cells, respectively, and colocalize with proglucagon in secretory granules. Mice lacking PC2 have multiple endocrinopathies and cannot process proglucagon to mature...

  16. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance

    Science.gov (United States)

    Loh, Kim; Fukushima, Atsushi; Zhang, Xinmei; Galic, Sandra; Briggs, Dana; Enriori, Pablo J.; Simonds, Stephanie; Wiede, Florian; Reichenbach, Alexander; Hauser, Christine; Sims, Natalie A.; Bence, Kendra K.; Zhang, Sheng; Zhang, Zhong-Yin; Kahn, Barbara B.; Neel, Benjamin G.; Andrews, Zane B.; Cowley, Michael A.; Tiganis, Tony

    2011-01-01

    SUMMARY In obesity, anorectic responses to leptin are diminished, giving rise to the concept of ‘leptin resistance’. Increased expression of protein tyrosine phosphatase 1B (PTP1B) has been associated with the attenuation of leptin signaling and development of cellular leptin resistance. Here we report that hypothalamic levels of the tyrosine phosphatase TCPTP are also elevated in obesity to attenuate the leptin response. We show that mice that lack TCPTP in neuronal cells have enhanced leptin sensitivity and are resistant to high fat diet-induced weight gain and the development of leptin resistance. Also, intracerebroventricular administration of a TCPTP inhibitor enhances leptin signaling and responses in mice. Moreover, the combined deletion of TCPTP and PTP1B in neuronal cells has additive effects in the prevention of diet-induced obesity. Our results identify TCPTP as a critical negative regulator of hypothalamic leptin signaling and causally link elevated TCPTP to the development of cellular leptin resistance in obesity. PMID:22000926

  17. Graded Elevation of c-Jun in Schwann Cells In Vivo: Gene Dosage Determines Effects on Development, Remyelination, Tumorigenesis, and Hypomyelination.

    Science.gov (United States)

    Fazal, Shaline V; Gomez-Sanchez, Jose A; Wagstaff, Laura J; Musner, Nicolo; Otto, Georg; Janz, Martin; Mirsky, Rhona; Jessen, Kristján R

    2017-12-13

    , and suppression of myelination. To analyze the functions of c-Jun, we have used transgenic mice with graded elevation of Schwann cell c-Jun. We show that high c-Jun elevation is a potential pathogenic mechanism because it inhibits myelination. Conversely, we did not find a link between c-Jun elevation and tumorigenesis. Modest c-Jun elevation, which is beneficial for regeneration, is well tolerated during Schwann cell development and in the adult and is compatible with restoration of myelination and nerve function after injury. Copyright © 2017 Fazal, Gomez-Sanchez et al.

  18. Effects of Social Defeat Stress on Sleep in Mice.

    Science.gov (United States)

    Henderson, Fiona; Vialou, Vincent; El Mestikawy, Salah; Fabre, Véronique

    2017-01-01

    Stress plays a key role in the development of psychiatric disorders and has a negative impact on sleep integrity. In mice, chronic social defeat stress (CSDS) is an ethologically valid model of stress-related disorders but little is known about its effects on sleep regulation. Here, we investigated the immediate and long-term effects of 10 consecutive days of social defeat (SD) on vigilance states in C57Bl/6J male mice. Social behavior was assessed to identify susceptible mice, i.e., mice that develop long-lasting social avoidance, and unsusceptible mice. Sleep-wake stages in mice of both groups were analyzed by means of polysomnographic recordings at baseline, after the first, third, and tenth stress sessions and on the 5th recovery day (R5) following the 10-day CSDS. In susceptible mice, each SD session produced biphasic changes in sleep-wake states that were preserved all along 10-day CSDS. These sessions elicited a short-term enhancement of wake time while rapid eye-movement (REM) sleep was strongly inhibited. Concomitantly, delta power was increased during non REM (NREM) sleep. During the following dark period, an increase in total sleep time, as well as wake fragmentation, were observed after each analyzed SD session. Similar changes were observed in unsusceptible mice. At R5, elevated high-frequency EEG activity, as observed in insomniacs, emerged during NREM sleep in both susceptible and unsusceptible groups suggesting that CSDS impaired sleep quality. Furthermore, susceptible but not unsusceptible mice displayed stress-anticipatory arousal during recovery, a common feature of anxiety disorders. Altogether, our findings show that CSDS has profound impacts on vigilance states and further support that sleep is tightly regulated by exposure to stressful events. They also revealed that susceptibility to chronic psychological stress is associated with heightened arousal, a physiological feature of stress vulnerability.

  19. Effects of Social Defeat Stress on Sleep in Mice

    Directory of Open Access Journals (Sweden)

    Fiona Henderson

    2017-11-01

    Full Text Available Stress plays a key role in the development of psychiatric disorders and has a negative impact on sleep integrity. In mice, chronic social defeat stress (CSDS is an ethologically valid model of stress-related disorders but little is known about its effects on sleep regulation. Here, we investigated the immediate and long-term effects of 10 consecutive days of social defeat (SD on vigilance states in C57Bl/6J male mice. Social behavior was assessed to identify susceptible mice, i.e., mice that develop long-lasting social avoidance, and unsusceptible mice. Sleep-wake stages in mice of both groups were analyzed by means of polysomnographic recordings at baseline, after the first, third, and tenth stress sessions and on the 5th recovery day (R5 following the 10-day CSDS. In susceptible mice, each SD session produced biphasic changes in sleep-wake states that were preserved all along 10-day CSDS. These sessions elicited a short-term enhancement of wake time while rapid eye-movement (REM sleep was strongly inhibited. Concomitantly, delta power was increased during non REM (NREM sleep. During the following dark period, an increase in total sleep time, as well as wake fragmentation, were observed after each analyzed SD session. Similar changes were observed in unsusceptible mice. At R5, elevated high-frequency EEG activity, as observed in insomniacs, emerged during NREM sleep in both susceptible and unsusceptible groups suggesting that CSDS impaired sleep quality. Furthermore, susceptible but not unsusceptible mice displayed stress-anticipatory arousal during recovery, a common feature of anxiety disorders. Altogether, our findings show that CSDS has profound impacts on vigilance states and further support that sleep is tightly regulated by exposure to stressful events. They also revealed that susceptibility to chronic psychological stress is associated with heightened arousal, a physiological feature of stress vulnerability.

  20. Talking with TV shows

    DEFF Research Database (Denmark)

    Sandvik, Kjetil; Laursen, Ditte

    2014-01-01

    User interaction with radio and television programmes is not a new thing. However, with new cross-media production concepts such as X Factor and Voice, this is changing dramatically. The second-screen logic of these productions encourages viewers, along with TV’s traditional one-way communication...... mode, to communicate on interactive (dialogue-enabling) devices such as laptops, smartphones and tablets. Using the TV show Voice as our example, this article shows how the technological and situational set-up of the production invites viewers to engage in new ways of interaction and communication...

  1. Immunobiology of congenitally athymic-asplenic mice

    International Nuclear Information System (INIS)

    Gershwin, M.E.; Ahmed, A.; Ikeda, R.M.; Shifrine, M.; Wilson, F.

    1978-01-01

    A study has been made of congenitally athymic-asplenic mice obtained by the mating of nude by hereditarily asplenic (Dh/+) mice. The mice survived for up to 9 months, under specific pathogen-free conditions, with no evidence for increased risk of spontaneous neoplasia. Although lymphocyte surface markers and sera immunoglobulin levels of athymic-asplenic mice were similar to those of their nude and asplenic littermates, there were a number of major immunologic differences. The athymic-asplenic mice appeared more immunologically compromised than nude mice. There was an elevated rate of growth and a lower inoculated cell threshold needed for successful transplantation of a human malignant melanoma. There was no evidence for auto-antibody production in mice up to 9 months of age. Congenitally athymic-asplenic mice can be used for a variety of studies in which other immunologically deprived mouse mutants are desired. (author)

  2. Talk Show Science.

    Science.gov (United States)

    Moore, Mitzi Ruth

    1992-01-01

    Proposes having students perform skits in which they play the roles of the science concepts they are trying to understand. Provides the dialog for a skit in which hot and cold gas molecules are interviewed on a talk show to study how these properties affect wind, rain, and other weather phenomena. (MDH)

  3. Obesity in show cats.

    Science.gov (United States)

    Corbee, R J

    2014-12-01

    Obesity is an important disease with a high prevalence in cats. Because obesity is related to several other diseases, it is important to identify the population at risk. Several risk factors for obesity have been described in the literature. A higher incidence of obesity in certain cat breeds has been suggested. The aim of this study was to determine whether obesity occurs more often in certain breeds. The second aim was to relate the increased prevalence of obesity in certain breeds to the official standards of that breed. To this end, 268 cats of 22 different breeds investigated by determining their body condition score (BCS) on a nine-point scale by inspection and palpation, at two different cat shows. Overall, 45.5% of the show cats had a BCS > 5, and 4.5% of the show cats had a BCS > 7. There were significant differences between breeds, which could be related to the breed standards. Most overweight and obese cats were in the neutered group. It warrants firm discussions with breeders and cat show judges to come to different interpretations of the standards in order to prevent overweight conditions in certain breeds from being the standard of beauty. Neutering predisposes for obesity and requires early nutritional intervention to prevent obese conditions. Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH.

  4. Honored Teacher Shows Commitment.

    Science.gov (United States)

    Ratte, Kathy

    1987-01-01

    Part of the acceptance speech of the 1985 National Council for the Social Studies Teacher of the Year, this article describes the censorship experience of this honored social studies teacher. The incident involved the showing of a videotape version of the feature film entitled "The Seduction of Joe Tynan." (JDH)

  5. A comparison of various methods of blood sampling in mice and rats: Effects on animal welfare

    DEFF Research Database (Denmark)

    Harikrishnan, Vs; Hansen, Axel K; Abelson, Klas Sp

    2018-01-01

    -puncture activity and anxiety levels of rats and mice were measured using an elevated plus maze test and an open field test. Stress levels 24 h post-puncture were assessed by analysing faecal corticosteroid metabolites. Sucrose intake and faecal corticosteroid levels were not affected by the blood sampling...... procedures. Rats showed reduced activity in the open field test and an increased level of anxiety in the elevated plus maze test following retrobulbar plexus puncture and isoflurane anaesthesia. In mice, nest building activity was affected in all the groups compared with the control group, except for animals...... subjected to facial vein puncture. Retrobulbar sinus puncture, tail vein puncture and sublingual puncture in mice resulted in reduced activity and increased anxiety. We conclude that, of the tested methods, puncture of the tail vein and the sublingual vein have the least adverse effects in rats, whereas...

  6. The energy show

    International Nuclear Information System (INIS)

    1988-01-01

    The Energy Show is a new look at the problems of world energy, where our supplies come from, now and in the future. The programme looks at how we need energy to maintain our standards of living. Energy supply is shown as the complicated set of problems it is - that Fossil Fuels are both raw materials and energy sources, that some 'alternatives' so readily suggested as practical options are in reality a long way from being effective. (author)

  7. INTERACTION BETWEEN DELTA OPIOID RECEPTORS AND BENZODIAZEPINES IN CO2- INDUCED RESPIRATORY RESPONSES IN MICE

    Science.gov (United States)

    Borkowski, Anne H.; Barnes, Dylan C.; Blanchette, Derek R.; Castellanos, F. Xavier; Klein, Donald F.; Wilson, Donald A.

    2011-01-01

    The false-suffocation hypothesis of panic disorder (Klein, 1993) suggested δ-opioid receptors as a possible source of the respiratory dysfunction manifested in panic attacks occurring in panic disorder (Preter and Klein, 2008). This study sought to determine if a lack of δ-opioid receptors in a mouse model affects respiratory response to elevated CO2, and whether the response is modulated by benzodiazepines, which are widely used to treat panic disorder. In a whole-body plethysmograph, respiratory responses to 5% CO2 were compared between δ-opioid receptor knockout mice and wild-type mice after saline, diazepam (1 mg/kg), and alprazolam (0.3 mg/kg) injection. The results show that lack of δ-opioid receptors does not affect normal response to elevated CO2, but does prevent benzodiazepines from modulating that response. Thus, in the presence of benzodiazepine agonists, respiratory responses to elevated CO2 were enhanced in δ-opioid receptor knockout mice compared to wild-type mice. This suggests an interplay between benzodiazepine receptors and δ-opioid receptors in regulating the respiratory effects of elevated CO2, which might be related to CO2 induced panic. PMID:21561601

  8. BAX and tumor suppressor TRP53 are important in regulating mutagenesis in spermatogenic cells in mice.

    Science.gov (United States)

    Xu, Guogang; Vogel, Kristine S; McMahan, C Alex; Herbert, Damon C; Walter, Christi A

    2010-12-01

    During the first wave of spermatogenesis, and in response to ionizing radiation, elevated mutant frequencies are reduced to a low level by unidentified mechanisms. Apoptosis is occurring in the same time frame that the mutant frequency declines. We examined the role of apoptosis in regulating mutant frequency during spermatogenesis. Apoptosis and mutant frequencies were determined in spermatogenic cells obtained from Bax-null or Trp53-null mice. The results showed that spermatogenic lineage apoptosis was markedly decreased in Bax-null mice and was accompanied by a significantly increased spontaneous mutant frequency in seminiferous tubule cells compared to that of wild-type mice. Apoptosis profiles in the seminiferous tubules for Trp53-null were similar to control mice. Spontaneous mutant frequencies in pachytene spermatocytes and in round spermatids from Trp53-null mice were not significantly different from those of wild-type mice. However, epididymal spermatozoa from Trp53-null mice displayed a greater spontaneous mutant frequency compared to that from wild-type mice. A greater proportion of spontaneous transversions and a greater proportion of insertions/deletions 15 days after ionizing radiation were observed in Trp53-null mice compared to wild-type mice. Base excision repair activity in mixed germ cell nuclear extracts prepared from Trp53-null mice was significantly lower than that for wild-type controls. These data indicate that BAX-mediated apoptosis plays a significant role in regulating spontaneous mutagenesis in seminiferous tubule cells obtained from neonatal mice, whereas tumor suppressor TRP53 plays a significant role in regulating spontaneous mutagenesis between postmeiotic round spermatid and epididymal spermatozoon stages of spermiogenesis.

  9. Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain.

    Science.gov (United States)

    Giorgini, Flaviano; Huang, Shao-Yi; Sathyasaikumar, Korrapati V; Notarangelo, Francesca M; Thomas, Marian A R; Tararina, Margarita; Wu, Hui-Qiu; Schwarcz, Robert; Muchowski, Paul J

    2013-12-20

    Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation, has been suggested to play a major role in physiological and pathological events involving bioactive KP metabolites. To explore this role in greater detail, we generated mice with a targeted genetic disruption of Kmo and present here the first biochemical and neurochemical characterization of these mutant animals. Kmo(-/-) mice lacked KMO activity but showed no obvious abnormalities in the activity of four additional KP enzymes tested. As expected, Kmo(-/-) mice showed substantial reductions in the levels of its enzymatic product, 3-hydroxykynurenine, in liver, brain, and plasma. Compared with wild-type animals, the levels of the downstream metabolite quinolinic acid were also greatly decreased in liver and plasma of the mutant mice but surprisingly were only slightly reduced (by ∼20%) in the brain. The levels of three other KP metabolites: kynurenine, kynurenic acid, and anthranilic acid, were substantially, but differentially, elevated in the liver, brain, and plasma of Kmo(-/-) mice, whereas the liver and brain content of the major end product of the enzymatic cascade, NAD(+), did not differ between Kmo(-/-) and wild-type animals. When assessed by in vivo microdialysis, extracellular kynurenic acid levels were found to be significantly elevated in the brains of Kmo(-/-) mice. Taken together, these results provide further evidence that KMO plays a key regulatory role in the KP and indicate that Kmo(-/-) mice will be useful for studying tissue-specific functions of individual KP metabolites in health and disease.

  10. De stille elever

    DEFF Research Database (Denmark)

    Winther-Lindqvist, Ditte Alexandra

    2012-01-01

    Det er blevet en afgørende samværskompetence i uddannelsessystemet at stå aktivt frem og deltage verbalt i skoleklassens liv både fagligt og socialt. Men ikke alle elever deltager lige villigt verbalt i plenum. Artiklen handler om de stille elever og konsekvenserne af stillehed i skolen. Det...... foreslås at skolesystemet sanktionerer ældre elever hårdere for stillehed end yngre elever og det forklares med at skolelivet også er en kultivering henimod elevhed som social identitet og denne er der forventning om at eleverne mestrer i udskolingen....

  11. Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Manuela Sailer

    Full Text Available In humans, plasma amino acid concentrations of branched-chain amino acids (BCAA and aromatic amino acids (AAA increase in states of obesity, insulin resistance and diabetes. We here assessed whether these putative biomarkers can also be identified in two different obesity and diabetic mouse models. C57BL/6 mice with diet-induced obesity (DIO mimic the metabolic impairments of obesity in humans characterized by hyperglycemia, hyperinsulinemia and hepatic triglyceride accumulation. Mice treated with streptozotocin (STZ to induce insulin deficiency were used as a type 1 diabetes model. Plasma amino acid profiling of two high fat (HF feeding trials revealed that citrulline and ornithine concentrations are elevated in obese mice, while systemic arginine bioavailability (ratio of plasma arginine to ornithine + citrulline is reduced. In skeletal muscle, HF feeding induced a reduction of arginine levels while citrulline levels were elevated. However, arginine or citrulline remained unchanged in their key metabolic organs, intestine and kidney. Moreover, the intestinal conversion of labeled arginine to ornithine and citrulline in vitro remained unaffected by HF feeding excluding the intestine as prime site of these alterations. In liver, citrulline is mainly derived from ornithine in the urea cycle and DIO mice displayed reduced hepatic ornithine levels. Since both amino acids share an antiport mechanism for mitochondrial import and export, elevated plasma citrulline may indicate impaired hepatic amino acid handling in DIO mice. In the insulin deficient mice, plasma citrulline and ornithine levels also increased and additionally these animals displayed elevated BCAA and AAA levels like insulin resistant and diabetic patients. Therefore, type 1 diabetic mice but not DIO mice show the "diabetic fingerprint" of plasma amino acid changes observed in humans. Additionally, citrulline may serve as an early indicator of the obesity-dependent metabolic

  12. Showing Value (Editorial

    Directory of Open Access Journals (Sweden)

    Denise Koufogiannakis

    2009-06-01

    Full Text Available When Su Cleyle and I first decided to start Evidence Based Library and Information Practice, one of the things we agreed upon immediately was that the journal be open access. We knew that a major obstacle to librarians using the research literature was that they did not have access to the research literature. Although Su and I are both academic librarians who can access a wide variety of library and information literature from our institutions, we belong to a profession where not everyone has equal access to the research in our field. Without such access to our own body of literature, how can we ever hope for practitioners to use research evidence in their decision making? It would have been contradictory to the principles of evidence based library and information practice to do otherwise.One of the specific groups we thought could use such an open access venue for discovering research literature was school librarians. School librarians are often isolated and lacking access to the research literature that may help them prove to stakeholders the importance of their libraries and their role within schools. Certainly, school libraries have been in decline and the use of evidence to show value is needed. As Ken Haycock noted in his 2003 report, The Crisis in Canada’s School Libraries: The Case for Reform and Reinvestment, “Across the country, teacher-librarians are losing their jobs or being reassigned. Collections are becoming depleted owing to budget cuts. Some principals believe that in the age of the Internet and the classroom workstation, the school library is an artifact” (9. Within this context, school librarians are looking to our research literature for evidence of the impact that school library programs have on learning outcomes and student success. They are integrating that evidence into their practice, and reflecting upon what can be improved locally. They are focusing on students and showing the impact of school libraries and

  13. Effects of low-dose rate irradiation on two types of type II diabetes model mice

    International Nuclear Information System (INIS)

    Nomura, Takaji; Sakai, Kazuo

    2004-01-01

    The effects of low-dose rate gamma-irradiation were investigated in two mouse strains - C57BL/KsJ-db/db (db mouse) and AKITA (AKITA mouse)-for type II diabetes mellitus. Both strains develop the developed type II diabetes by about 8 weeks of age due to dysfunction of the insulin/insulin receptor. The db Mouse' shows obese and exhibits hyperinsulinism, and the onset of Type II diabetes like resembles that for Westerners. On the other hand, the AKITA mouse has exhibits disordered insulin secretion, and the diabetes such as resembles that of Asians. Ten-week old female mice, in groups of 8 or 12, were irradiated at 0.65 mGy/hr in the low-dose rate irradiation facility in the Low Dose Radiation Research Center. The level of urine glucose was measured with test slips. The urine glucose levels of all of the mice were highly elevated the beginning of the irradiation. In the irradiated group of db mice, three mice showed decrease in glucose level compare to the level of non-irradiated diabetes mice after 35, 52 or 80 weeks of irradiation. All had maintained a normal level thereafter. No such improvement in diabetes was ever observed in the 12 mice of in the non-irradiated control group. The AKITA mice, however, did not decrease the glucose level regardless of the irradiation. Both the db mice and AKITA mice had their lives prolonged their life by the irradiation. The survival rate of db mice at the age of 90 weeks was 75% in the irradiated group, but 50% in the non-irradiated group. The average life span was 104 weeks in the irradiated group and 87 weeks in the control group. Furthermore, a marked difference was furthermore observed in the appearance of the coat hair, skin, and tail; appearances were well preserved in the irradiated group. The average life span in the irradiated AKITA mice was also longer than that for the non-irradiated mice, 51 weeks and 41 weeks in the irradiated and non-irradiated group respectively. These results suggest that the low-dose irradiation

  14. Host resistance of CD18 knockout mice against systemic infection with Listeria monocytogenes

    Science.gov (United States)

    Wu, Huaizhu; Prince, Joseph E.; Brayton, Cory F.; Shah, Chirayu; Zeve, Daniel; Gregory, Stephen H.; Smith, C. Wayne; Ballantyne, Christie M.

    2003-01-01

    Mice with targeted mutations of CD18, the common beta2 subunit of CD11/CD18 integrins, have leukocytosis, impaired transendothelial neutrophil emigration, and reduced host defense to Streptococcus pneumoniae, a gram-positive extracellular bacterium. Previous studies using blocking monoclonal antibodies suggested roles for CD18 and CD11b in hepatic neutrophil recruitment and host innate response to Listeria monocytogenes, a gram-positive intracellular bacterium. We induced systemic listeriosis in CD18 knockout (CD18-ko) and wild-type (WT) mice by tail vein injection with Listeria. By 14 days postinjection (dpi), 8 of 10 WT mice died, compared with 2 of 10 CD18-ko mice (P Listeria organisms in livers and spleens were similar in both groups at 20 min postinfection. By 3, 5, and 7 dpi, however, numbers of Listeria organisms were significantly lower in livers and spleens of CD18-ko mice than in WT mice. Histopathology showed that following Listeria infection, CD18-ko mice had milder inflammatory and necrotizing lesions in both spleens and livers than did WT mice. Cytokine assays indicated that baseline interleukin-1beta and granulocyte colony-stimulating factor (G-CSF) levels were higher in CD18-ko mice than in WT mice and that CD18-ko splenocytes produced higher levels of interleukin-1beta and G-CSF than WT splenocytes under the same amount of Listeria stimulation. These findings show that CD18 is not an absolute requirement for antilisterial innate immunity or hepatic neutrophil recruitment. We propose that the absence of CD18 in the mice results in the priming of innate immunity, as evidenced by elevated cytokine expression, and neutrophilic leukocytosis, which augments antilisterial defense.

  15. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1

    NARCIS (Netherlands)

    Jong, M. C.; Gijbels, M. J.; Dahlmans, V. E.; Gorp, P. J.; Koopman, S. J.; Ponec, M.; Hofker, M. H.; Havekes, L. M.

    1998-01-01

    Transgenic mice were generated with different levels of human apolipoprotein C1 (APOC1) expression in liver and skin. At 2 mo of age, serum levels of cholesterol, triglycerides (TG), and FFA were strongly elevated in APOC1 transgenic mice compared with wild-type mice. These elevated levels of serum

  16. Effect of fenbendazole on three behavioral tests in male C57BL/6N mice.

    Science.gov (United States)

    Gadad, Bharathi S; Daher, João P L; Hutchinson, Eric K; Brayton, Cory F; Dawson, Ted M; Pletnikov, Mikhail V; Watson, Julie

    2010-11-01

    Pinworms are highly contagious parasites of laboratory rodents that often are treated with fenbendazole. To our knowledge, the effect of fenbendazole at therapeutic dosages on behavioral tests in mice has not been evaluated. Here we studied 6-wk-old male C57BL/6N mice. We compared the behavior of control mice (fed regular diet) with 3 groups of mice treated with dietary fenbendazole. Treatment groups were 4 wk of fenbendazole, 2 wk of fenbendazole followed by 2 wk of regular diet, and 2 wk of regular diet followed by 2 wk of fenbendazole. At the end of dietary treatment all groups were tested by open field for central, peripheral and vertical activity; elevated plus maze for anxiety; and rotarod for motor ability and then evaluated by clinical pathology and selected histopathology. Treated and control groups showed no differences in open field or elevated plus maze testing, histopathology, or clinical pathology. However mice treated for 4 wk with fenbendazole or 2 wk of fenbendazole followed by 2 wk regular diet stayed on the rotarod for shorter periods than did controls, and mice treated with 2 wk of regular diet followed by 2 wk fenbendazole showed a trend toward shorter rotarod times. In light of this study, we suggest that open field and elevated plus maze testing is unlikely to be affected by 4 wk fenbendazole treatment in male C57BL/6 mice; however, behavioral tests of motor ability such as rotarod tests may be affected during and for at least 2 wk after fenbendazole treatment.

  17. Relations between open-field, elevated plus-maze, and emergence tests in C57BL/6JIco and BALB/cAnN@Ico mice injected with ethanol.

    Science.gov (United States)

    Lalonde, R; Strazielle, C

    2012-04-01

    The effects of ethanol were examined on three tests of exploratory activity in two mouse strains. Although ethanol reduced open-field rearing in both strains, it increased ambulation only in the less active BALB/cAnN@Ico strain, not in the C57BL/6JIco strain. Likewise, ethanol increased open and enclosed arm entries in the elevated plus-maze only in the more anxious BALB/cAnN@Ico strain. However, both strains injected with ethanol emerged faster than placebo from a small chamber at doses not affecting behaviors in the other two tests. Significant correlations were found between emergence latencies on one hand and either slow stereotyped movements or open and enclosed arm entries on the other. The strain-specific effects may be attributable to differences in GABA(A) -related receptor binding or catalase activity. © 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.

  18. Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice.

    Science.gov (United States)

    Schlegel, Victoria; Thieme, Markus; Holzmann, Carsten; Witt, Martin; Grittner, Ulrike; Rolfs, Arndt; Wree, Andreas

    2016-11-09

    Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1 nih Npc1 -/- mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1 -/- animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.

  19. Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice

    Directory of Open Access Journals (Sweden)

    Victoria Schlegel

    2016-11-01

    Full Text Available Niemann-Pick Type C1 (NPC1 is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1nihNpc1−/− mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1−/− animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.

  20. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice

    Science.gov (United States)

    Suidan, Georgette L.; Demers, Melanie; Herr, Nadine; Carbo, Carla; Brill, Alexander; Cifuni, Stephen M.; Mauler, Maximilian; Cicko, Sanja; Bader, Michael; Idzko, Marco; Bode, Christoph

    2013-01-01

    The majority of peripheral serotonin is stored in platelets, which secrete it on activation. Serotonin releases Weibel-Palade bodies (WPBs) and we asked whether absence of platelet serotonin affects neutrophil recruitment in inflammatory responses. Tryptophan hydroxylase (Tph)1–deficient mice, lacking non-neuronal serotonin, showed mild leukocytosis compared with wild-type (WT), primarily driven by an elevated neutrophil count. Despite this, 50% fewer leukocytes rolled on unstimulated mesenteric venous endothelium of Tph1−/− mice. The velocity of rolling leukocytes was higher in Tph1−/− mice, indicating fewer selectin-mediated interactions with endothelium. Stimulation of endothelium with histamine, a secretagogue of WPBs, or injection of serotonin normalized the rolling in Tph1−/− mice. Diminished rolling in Tph1−/− mice resulted in reduced firm adhesion of leukocytes after lipopolysaccharide treatment. Blocking platelet serotonin uptake with fluoxetine in WT mice reduced serum serotonin by > 80% and similarly reduced leukocyte rolling and adhesion. Four hours after inflammatory stimulation, neutrophil extravasation into lung, peritoneum, and skin wounds was reduced in Tph1−/− mice, whereas in vitro neutrophil chemotaxis was independent of serotonin. Survival of lipopolysaccharide-induced endotoxic shock was improved in Tph1−/− mice. In conclusion, platelet serotonin promotes the recruitment of neutrophils in acute inflammation, supporting an important role for platelet serotonin in innate immunity. PMID:23243271

  1. Undervisning af tosprogede elever

    DEFF Research Database (Denmark)

    Horst, Christian

    2003-01-01

    Artiklen fremdrager hovedresultaterne fra Virginia P. Collier's og Wayne P. Thomas's længdeundersøgelser af tosprogede elever i USA, som formentlig er de mest omfattende undersøgelser af undervisningen af tosprogede elever overhovedet. Resultaterne diskuteres i relation til udviklingen af en...

  2. Effects of elevated CO

    NARCIS (Netherlands)

    Xue, Sha; Yang, Xiaomei; Liu, Guobin; Gai, Lingtong; Zhang, Changsheng; Ritsema, Coen J.; Geissen, Violette

    2017-01-01

    Elevated CO2 and drought are key consequences of climate change and affect soil processes and plant growth. This study investigated the effects of elevated CO2 and drought on the microbial biomass and enzymatic activities in the rhizospheres of Bothriochloa ischaemum and

  3. Ghrelin treatment prevents development of activity based anorexia in mice.

    Science.gov (United States)

    Legrand, Romain; Lucas, Nicolas; Breton, Jonathan; Azhar, Saïda; do Rego, Jean-Claude; Déchelotte, Pierre; Coëffier, Moïse; Fetissov, Sergueï O

    2016-06-01

    Stimulation of feeding is necessary for treatment of pathological conditions of chronic malnutrition due to anorexia. Ghrelin, a hunger hormone, is one of the candidate for pharmacological treatments of anorexia, but because of its instability in plasma has limited efficacy. We previously showed that plasmatic IgG protect ghrelin from degradation and that IgG from obese subjects and mice may increase ghrelin׳s orexigenic effect. In this study we tested if ghrelin alone or combined with IgG may improve feeding in chronically food-restricted mice with or without physical activity-based anorexia (ABA) induced by free access to a running wheel. Mice received a single daily intraperitoneal injection of ghrelin (1nM) together or not with total IgG (1nM) from obese ob/ob or lean mice before access to food during 8 days of 3h/day feeding time. We found that both ghrelin and ghrelin combined with IgG from obese, but not lean mice, prevented ABA, however, they were not able to diminish body weight loss. Physical activity was lower during the feeding period and was increased shortly after feeding in mice receiving ghrelin together with IgG from obese mice. In food-restricted mice without ABA, ghrelin treatments did not have significant effects on food intake. Thus, this study supports pharmacological use of ghrelin or ghrelin combined with IgG from obese animals for treatment of anorexia accompanied by elevated physical activity. The utility of combining ghrelin with protective IgG should be further determined in animal models of anorexia with unrestricted access to food. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  4. GPR40/FFAR1 deficient mice increase noradrenaline levels in the brain and exhibit abnormal behavior

    Directory of Open Access Journals (Sweden)

    Fuka Aizawa

    2016-12-01

    Full Text Available The free fatty acid receptor 1 (GPR40/FFAR1 is a G protein-coupled receptor, which is activated by long chain fatty acids. We have previously demonstrated that activation of brain GPR40/FFAR1 exerts an antinociceptive effect that is mediated by the modulation of the descending pain control system. However, it is unclear whether brain GPR40/FFAR1 contributes to emotional function. In this study, we investigated the involvement of GPR40/FFAR1 in emotional behavior using GPR40/FFAR1 deficient (knockout, KO mice. The emotional behavior in wild and KO male mice was evaluated at 9–10 weeks of age by the elevated plus-maze test, open field test, social interaction test, and sucrose preference test. Brain monoamines levels were measured using LC–MS/MS. The elevated plus-maze test and open field tests revealed that the KO mice reduced anxiety-like behavior. There were no differences in locomotor activity or social behavior between the wild and KO mice. In the sucrose preference test, the KO mice showed reduction in sucrose preference and intake. The level of noradrenaline was higher in the hippocampus, medulla oblongata, hypothalamus and midbrain of KO mice. Therefore, these results suggest that brain GPR40/FFAR1 is associated with anxiety- and depression-related behavior regulated by the increment of noradrenaline in the brain.

  5. GPR40/FFAR1 deficient mice increase noradrenaline levels in the brain and exhibit abnormal behavior.

    Science.gov (United States)

    Aizawa, Fuka; Nishinaka, Takashi; Yamashita, Takuya; Nakamoto, Kazuo; Kurihara, Takashi; Hirasawa, Akira; Kasuya, Fumiyo; Miyata, Atsuro; Tokuyama, Shogo

    2016-12-01

    The free fatty acid receptor 1 (GPR40/FFAR1) is a G protein-coupled receptor, which is activated by long chain fatty acids. We have previously demonstrated that activation of brain GPR40/FFAR1 exerts an antinociceptive effect that is mediated by the modulation of the descending pain control system. However, it is unclear whether brain GPR40/FFAR1 contributes to emotional function. In this study, we investigated the involvement of GPR40/FFAR1 in emotional behavior using GPR40/FFAR1 deficient (knockout, KO) mice. The emotional behavior in wild and KO male mice was evaluated at 9-10 weeks of age by the elevated plus-maze test, open field test, social interaction test, and sucrose preference test. Brain monoamines levels were measured using LC-MS/MS. The elevated plus-maze test and open field tests revealed that the KO mice reduced anxiety-like behavior. There were no differences in locomotor activity or social behavior between the wild and KO mice. In the sucrose preference test, the KO mice showed reduction in sucrose preference and intake. The level of noradrenaline was higher in the hippocampus, medulla oblongata, hypothalamus and midbrain of KO mice. Therefore, these results suggest that brain GPR40/FFAR1 is associated with anxiety- and depression-related behavior regulated by the increment of noradrenaline in the brain. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  6. Mice exposed to dim light at night exaggerate inflammatory responses to lipopolysaccharide.

    Science.gov (United States)

    Fonken, Laura K; Weil, Zachary M; Nelson, Randy J

    2013-11-01

    The mammalian circadian system regulates many physiological functions including inflammatory responses. Appropriately timed light information is essential for maintaining circadian organization. Over the past ∼120 years, urbanization and the widespread adoption of electric lights have dramatically altered lighting environments. Exposure to light at night (LAN) is pervasive in modern society and disrupts core circadian clock mechanisms. Because microglia are the resident macrophages in the brain and macrophages contain intrinsic circadian clocks, we hypothesized that chronic exposure to LAN would alter microglia cytokine expression and sickness behavior following LPS administration. Exposure to 4 weeks of dim LAN elevated inflammatory responses in mice. Mice exposed to dimly lit, as compared to dark, nights exaggerated changes in body temperature and elevated microglia pro-inflammatory cytokine expression following LPS administration. Furthermore, dLAN mice had a prolonged sickness response following the LPS challenge. Mice exposed to dark or dimly lit nights had comparable sickness behavior directly following the LPS injection; however, dLAN mice showed greater reductions in locomotor activity, increased anorectic behavior, and increased weight loss than mice maintained in dark nights 24h post-LPS injection. Overall, these data suggest that chronic exposure to even very low levels of light pollution may alter inflammatory responses. These results may have important implications for humans and other urban dwelling species that commonly experience nighttime light exposure. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Elevator and hydraulics; Elevator to yuatsu

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, I. [Hitachi, Ltd., Tokyo (Japan)

    1994-07-15

    A hydraulic type elevator is installed in relatively lower buildings as compared with a rope type elevator, but the ratio in the number of installation of the former elevator is increasing. This paper explains from its construction and features to especially various control systems for the riding comfort and safety. A direct push-up system with hydraulic jacks arranged beneath a car, and an indirect push-up system that has hydraulic jacks arranged on flank of a car and transmits the movement of a plunger via a rope are available. The latter system eliminates the need of large holes to embed hydraulic jacks. While the speed is controlled by controlling flow rates of high-pressure oil, the speed, position, acceleration and even time differential calculus of the acceleration must be controlled severely. The system uses two-step control for the through-speed and the landing speed. Different systems that have been realized may include compensation for temperatures in flow rate control valves, load pressures, and oil viscosity, from learning control to fuzzy control for psychological effects, or control of inverters in motors. 13 refs., 12 figs., 1 tab.

  8. Co-segregation of hyperactivity, active coping styles and cognitive dysfunction in mice selectively bred for low levels of anxiety

    Directory of Open Access Journals (Sweden)

    Yi-Chun eYen

    2013-08-01

    Full Text Available We established mouse models of extremes in trait anxiety, which are based on selective breeding for low vs. normal vs. high open-arm exploration on the elevated plus-maze. Genetically selected low anxiety-related behavior (LAB coincided with hyperactivity in the home cage. Given the fact that several psychiatric disorders such as schizophrenia, mania and attention deficit hyperactivity disorder (ADHD share hyperactivity symptom, we systematically examined LAB mice with respect to unique and overlapping endophenotypes of the three diseases. To this end Venn diagrams were used as an instrument for discrimination of possible models. We arranged the endophenotypes in Venn diagrams and translated them into different behavioral tests. LAB mice showed elevated levels of locomotion in the open field test with deficits in habituation, compared to mice bred for normal (NAB and high anxiety-related behavior (HAB. Cross-breeding of hypoactive HAB and hyperactive LAB mice resulted in offspring showing a low level of locomotion comparable to HAB mice, indicating that the HAB alleles are dominant over LAB alleles in determining the level of locomotion. In a holeboard test, LAB mice spent less time in hole exploration, as shown in patients with schizophrenia and ADHD; however, LAB mice displayed no impairments in social interaction and prepulse inhibition, implying a unlikelihood of LAB as an animal model of schizophrenia. Although LAB mice displayed hyperarousal, active coping styles and cognitive deficits, symptoms shared by mania and ADHD, they failed to reveal the classic manic endophenotypes, such as increased hedonia and object interaction. The neuroleptic haloperidol reduced locomotor activity in all mouse lines. The mood stabilizer lithium and the psychostimulant amphetamine, in contrast, selectively reduced hyperactivity in LAB mice. Based on the behavioral and pharmacological profiles, LAB mice are suggested as a novel rodent model of ADHD

  9. Co-segregation of hyperactivity, active coping styles, and cognitive dysfunction in mice selectively bred for low levels of anxiety.

    Science.gov (United States)

    Yen, Yi-Chun; Anderzhanova, Elmira; Bunck, Mirjam; Schuller, Julia; Landgraf, Rainer; Wotjak, Carsten T

    2013-01-01

    We established mouse models of extremes in trait anxiety, which are based on selective breeding for low vs. normal vs. high open-arm exploration on the elevated plus-maze. Genetically selected low anxiety-related behavior (LAB) coincided with hyperactivity in the home cage. Given the fact that several psychiatric disorders such as schizophrenia, mania, and attention deficit hyperactivity disorder (ADHD) share hyperactivity symptom, we systematically examined LAB mice with respect to unique and overlapping endophenotypes of the three diseases. To this end Venn diagrams were used as an instrument for discrimination of possible models. We arranged the endophenotypes in Venn diagrams and translated them into different behavioral tests. LAB mice showed elevated levels of locomotion in the open field (OF) test with deficits in habituation, compared to mice bred for normal (NAB) and high anxiety-related behavior (HAB). Cross-breeding of hypoactive HAB and hyperactive LAB mice resulted in offspring showing a low level of locomotion comparable to HAB mice, indicating that the HAB alleles are dominant over LAB alleles in determining the level of locomotion. In a holeboard test, LAB mice spent less time in hole exploration, as shown in patients with schizophrenia and ADHD; however, LAB mice displayed no impairments in social interaction and prepulse inhibition (PPI), implying a unlikelihood of LAB as an animal model of schizophrenia. Although LAB mice displayed hyperarousal, active coping styles, and cognitive deficits, symptoms shared by mania and ADHD, they failed to reveal the classic manic endophenotypes, such as increased hedonia and object interaction. The neuroleptic haloperidol reduced locomotor activity in all mouse lines. The mood stabilizer lithium and the psychostimulant amphetamine, in contrast, selectively reduced hyperactivity in LAB mice. Based on the behavioral and pharmacological profiles, LAB mice are suggested as a novel rodent model of ADHD-like symptoms.

  10. Co-segregation of hyperactivity, active coping styles, and cognitive dysfunction in mice selectively bred for low levels of anxiety

    Science.gov (United States)

    Yen, Yi-Chun; Anderzhanova, Elmira; Bunck, Mirjam; Schuller, Julia; Landgraf, Rainer; Wotjak, Carsten T.

    2013-01-01

    We established mouse models of extremes in trait anxiety, which are based on selective breeding for low vs. normal vs. high open-arm exploration on the elevated plus-maze. Genetically selected low anxiety-related behavior (LAB) coincided with hyperactivity in the home cage. Given the fact that several psychiatric disorders such as schizophrenia, mania, and attention deficit hyperactivity disorder (ADHD) share hyperactivity symptom, we systematically examined LAB mice with respect to unique and overlapping endophenotypes of the three diseases. To this end Venn diagrams were used as an instrument for discrimination of possible models. We arranged the endophenotypes in Venn diagrams and translated them into different behavioral tests. LAB mice showed elevated levels of locomotion in the open field (OF) test with deficits in habituation, compared to mice bred for normal (NAB) and high anxiety-related behavior (HAB). Cross-breeding of hypoactive HAB and hyperactive LAB mice resulted in offspring showing a low level of locomotion comparable to HAB mice, indicating that the HAB alleles are dominant over LAB alleles in determining the level of locomotion. In a holeboard test, LAB mice spent less time in hole exploration, as shown in patients with schizophrenia and ADHD; however, LAB mice displayed no impairments in social interaction and prepulse inhibition (PPI), implying a unlikelihood of LAB as an animal model of schizophrenia. Although LAB mice displayed hyperarousal, active coping styles, and cognitive deficits, symptoms shared by mania and ADHD, they failed to reveal the classic manic endophenotypes, such as increased hedonia and object interaction. The neuroleptic haloperidol reduced locomotor activity in all mouse lines. The mood stabilizer lithium and the psychostimulant amphetamine, in contrast, selectively reduced hyperactivity in LAB mice. Based on the behavioral and pharmacological profiles, LAB mice are suggested as a novel rodent model of ADHD-like symptoms

  11. Elevators or stairs?

    Science.gov (United States)

    Shah, Sachin; O’Byrne, Michael; Wilson, Merne; Wilson, Thomas

    2011-01-01

    Background: Staff in hospitals frequently travel between floors and choose between taking the stairs or elevator. We compared the time savings with these two options. Methods: Four people aged 26–67 years completed 14 trips ranging from one to six floors, both ascending and descending. We compared the amount of time per floor travelled by stairs and by two banks of elevators. Participants reported their fatigue levels using a modified Borg scale. We performed two-way analysis of variance to compare the log-transformed data, with participant and time of day as independent variables. Results: The mean time taken to travel between each floor was 13.1 (standard deviation [SD] 1.7) seconds by stairs and 37.5 (SD 19.0) and 35.6 (SD 23.1) seconds by the two elevators (F = 8.61, p elevator equaled about 15 minutes a day. Self-reported fatigue was less than 13 (out of 20) on the Borg scale for all participants, and they all stated that they were able to continue their duties without resting. The extra time associated with elevator use was because of waiting for its arrival. There was a difference in the amount of time taken to travel by elevator depending on the time of day and day of the week. Interpretation: Taking the stairs rather than the elevator saved about 15 minutes each workday. This 3% savings per workday could translate into improved productivity as well as increased fitness. PMID:22159365

  12. Dynamic multibody modeling for tethered space elevators

    Science.gov (United States)

    Williams, Paul

    2009-08-01

    This paper presents a fundamental modeling strategy for dealing with powered and propelled bodies moving along space tethers. The tether is divided into a large number of discrete masses, which are connected by viscoelastic springs. The tether is subject to the full range of forces expected in Earth orbit in a relatively simple manner. Two different models of the elevator dynamics are presented. In order to capture the effect of the elevator moving along the tether, the elevator dynamics are included as a separate body in both models. One model treats the elevator's motion dynamically, where propulsive and friction forces are applied to the elevator body. The second model treats the elevator's motion kinematically, where the distance along the tether is determined by adjusting the lengths of tether on either side of the elevator. The tether model is used to determine optimal configurations for the space elevator. A modal analysis of two different configurations is presented which show that the fundamental mode of oscillation is a pendular one around the anchor point with a period on the order of 160 h for the in-plane motion, and 24 h for the out-of-plane motion. Numerical simulation results of the effects of the elevator moving along the cable are presented for different travel velocities and different elevator masses.

  13. PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice

    Science.gov (United States)

    Banno, Ryoichi; Zimmer, Derek; De Jonghe, Bart C.; Atienza, Marybless; Rak, Kimberly; Yang, Wentian; Bence, Kendra K.

    2010-01-01

    Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain–containing protein tyrosine phosphatase–2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuron–specific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron–specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b–/– mice) had reduced adiposity, improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron–specific deletion of the gene encoding SHP2 (referred to herein as POMC-Shp2–/– mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b–/– mice showed substantially improved glucose homeostasis on a high-fat diet, and hyperinsulinemic-euglycemic clamp studies revealed that insulin sensitivity in these mice was improved on a standard chow diet in the absence of any weight difference. In contrast, POMC-Shp2–/– mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and α–melanocyte-stimulating hormone (αMSH) peptide levels were markedly reduced in POMC-Shp2–/– mice. These studies implicate PTP1B and SHP2 as important components of POMC neuron regulation of energy balance and point to what we believe to be a novel role for SHP2 in the normal function of the melanocortin system. PMID:20160350

  14. Predictors of backrest elevation in critical care.

    Science.gov (United States)

    Grap, Mary Jo; Munro, Cindy L; Bryant, Sandra; Ashtiani, Brooke

    2003-04-01

    Low backrest and supine positions are associated with increased mortality and ventilator associated pneumonia (VAP). Data are not available across ICU settings about the level of backrest position used and its relationship to enteral feeding and hemodynamic status. The purpose of this descriptive study was to document the level of backrest elevation and position and identify factors associated with and predict positioning in a medical, surgical and neuroscience intensive care unit. Data were collected randomly in each unit over a 6-week period, resulting in 506 observations for170 patients. Backrest elevation was determined by electronic bed read-out or bed frame elevation gauge. BP, HR and enteral feeding status were retrieved from the medical record. Results showed that mean backrest elevation was 19.2 degrees and 70% of subjects were supine. No difference in backrest elevation among units was found. Significant correlations between backrest elevation and systolic BP (r=0.15, P=0.006); and backrest and diastolic BP (r=0.13, P=0.02) were found. There was no difference in backrest elevation between patients being fed and not being fed. Differences in backrest elevation for intubated versus nonintubated patients approached significance (P=0.07) with intubated patients at lower backrest elevations. In summary, use of higher backrest elevations (>30 degrees ) is minimal, is not related to feeding and minimally related to hemodynamic status. Strategies to meet published recommendations for backrest elevation (30-45 degrees ) must include repeated feedback about nurse's use of backrest elevation and estimates of elevation.

  15. Elevated temperature fracture mechanics

    International Nuclear Information System (INIS)

    Tomkins, B.

    1979-01-01

    The application of fracture mechanics concepts to cracks at elevated temperatures is examined. Particular consideration is given to the characterisation of crack tip stress-strain fields and parameters controlling crack extension under static and cyclic loads. (author)

  16. Indsatser for tosprogede elever

    DEFF Research Database (Denmark)

    Andersen, Dines; Jakobsen, Vibeke; Jensen, Vibeke Myrup

    Fagligt set klarer tosprogede elever sig dårligere i skolen og det videre uddannelsessystem end ’danske’ elever. Kommuner og folkeskoler har derfor sat en række tiltag i værk, som sigter mod at forbedre de tosprogede elevers skole- og uddannelsessituation. Rapporten kortlægger og analyserer...... af klasseundervisningen. Analysen viser, at de elever, der bliver taget ud af klassen for at få ekstra undervisning i dansk som andetsprog, klarer sig dårligere end elever, der modtager ekstraundervisningen i klassen eller uden for skoletid. Undersøgelsen er baseret på spørgeskemaundersøgelser blandt...... kommunale forvaltningschefer, skoleledere, lærere og forældre til børn i 2. klasse samt lærere til og elever i 9. klasse, SFI’s forløbsundersøgelse af årgang 1995 og registerdata. Undersøgelsen er via Ministeriet for Børn og Undervisning betalt med midler fra satspuljeaftalen 2009 om integration....

  17. Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice.

    Science.gov (United States)

    Yuan, Xidi; Klein, Dennis; Kerscher, Susanne; West, Brian L; Weis, Joachim; Katona, Istvan; Martini, Rudolf

    2018-05-09

    Aging is known as a major risk factor for the structure and function of the nervous system. There is urgent need to overcome such deleterious effects of age-related neurodegeneration. Here we show that peripheral nerves of 24-month-old aging C57BL/6 mice of either sex show similar pathological alterations as nerves from aging human individuals, whereas 12-month-old adult mice lack such alterations. Specifically, nerve fibers showed demyelination, remyelination and axonal lesion. Moreover, in the aging mice, neuromuscular junctions showed features typical for dying-back neuropathies, as revealed by a decline of presynaptic markers, associated with α-bungarotoxin-positive postsynapses. In line with these observations were reduced muscle strengths. These alterations were accompanied by elevated numbers of endoneurial macrophages, partially comprising the features of phagocytosing macrophages. Comparable profiles of macrophages could be identified in peripheral nerve biopsies of aging persons. To determine the pathological impact of macrophages in aging mice, we selectively targeted the cells by applying an orally administered CSF-1R specific kinase (c-FMS) inhibitor. The 6-month-lasting treatment started before development of degenerative changes at 18 months and reduced macrophage numbers in mice by ∼70%, without side effects. Strikingly, nerve structure was ameliorated and muscle strength preserved. We show, for the first time, that age-related degenerative changes in peripheral nerves are driven by macrophages. These findings may pave the way for treating degeneration in the aging peripheral nervous system by targeting macrophages, leading to reduced weakness, improved mobility, and eventually increased quality of life in the elderly. SIGNIFICANCE STATEMENT Aging is a major risk factor for the structure and function of the nervous system. Here we show that peripheral nerves of 24-month-old aging mice show similar degenerative alterations as nerves from aging

  18. DBI/ACBP loss-of-function does not affect anxiety-like behaviour but reduces anxiolytic responses to diazepam in mice

    DEFF Research Database (Denmark)

    Budry, Lionel; Bouyakdan, Khalil; Tobin, Stephanie

    2016-01-01

    . Male and female ACBP(GFAP) KO and ACBP KO mice do not show significant changes in anxiety-like behaviour compared to control littermates during elevated plus maze (EPM) and open field (OF) tests. Surprisingly, ACBP(GFAP) KO and ACBP KO mice were unresponsive to the anxiolytic effect of a low dose...... of diazepam during EPM tests. In conclusion, our experiments using genetic ACBP loss-of-function models suggest that endozepines deficiency does not affect anxiety-like behaviour in mice and impairs the anxiolytic action of diazepam....

  19. Transient anhedonia phenotype and altered circadian timing of behaviour during night-time dim light exposure in Per3−/− mice, but not wildtype mice

    Science.gov (United States)

    Martynhak, Bruno Jacson; Hogben, Alexandra L.; Zanos, Panos; Georgiou, Polymnia; Andreatini, Roberto; Kitchen, Ian; Archer, Simon N.; von Schantz, Malcolm; Bailey, Alexis; van der Veen, Daan R.

    2017-01-01

    Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are ‘direct’ effects of light on affect, an ‘indirect’ pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3−/− mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3−/−) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2–3 of dim light at night, whereas WT mice did not. Per3−/− mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3−/− nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3−/− phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light. PMID:28071711

  20. Transient anhedonia phenotype and altered circadian timing of behaviour during night-time dim light exposure in Per3-/- mice, but not wildtype mice.

    Science.gov (United States)

    Martynhak, Bruno Jacson; Hogben, Alexandra L; Zanos, Panos; Georgiou, Polymnia; Andreatini, Roberto; Kitchen, Ian; Archer, Simon N; von Schantz, Malcolm; Bailey, Alexis; van der Veen, Daan R

    2017-01-10

    Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are 'direct' effects of light on affect, an 'indirect' pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3 -/- mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3 -/- ) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2-3 of dim light at night, whereas WT mice did not. Per3 -/- mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3 -/- nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3 -/- phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light.

  1. Oxidative Stress Induced Age Dependent Meibomian Gland Dysfunction in Cu, Zn-Superoxide Dismutase-1 (Sod1) Knockout Mice

    Science.gov (United States)

    Ibrahim, Osama M. A.; Dogru, Murat; Matsumoto, Yukihiro; Igarashi, Ayako; Kojima, Takashi; Wakamatsu, Tais Hitomi; Inaba, Takaaki; Shimizu, Takahiko; Shimazaki, Jun; Tsubota, Kazuo

    2014-01-01

    Purpose The purpose of our study was to investigate alterations in the meibomian gland (MG) in Cu, Zn-Superoxide Dismutase-1 knockout (Sod1 −/−) mouse. Methods Tear function tests [Break up time (BUT) and cotton thread] and ocular vital staining test were performed on Sod1 −/− male mice (n = 24) aged 10 and 50 weeks, and age and sex matched wild–type (+/+) mice (n = 25). Tear and serum samples were collected at sacrifice for inflammatory cytokine assays. MG specimens underwent Hematoxylin and Eosin staining, Mallory staining for fibrosis, Oil Red O lipid staining, TUNEL staining, immunohistochemistry stainings for 4HNE, 8-OHdG and CD45. Transmission electron microscopic examination (TEM) was also performed. Results Corneal vital staining scores in the Sod1 −/− mice were significantly higher compared with the wild type mice throughout the follow-up. Tear and serum IL-6 and TNF-α levels also showed significant elevations in the 10 to 50 week Sod1 −/− mice. Oil Red O staining showed an accumulation of large lipid droplets in the Sod1 −/− mice at 50 weeks. Immunohistochemistry revealed both increased TUNEL and oxidative stress marker stainings of the MG acinar epithelium in the Sod1 −/− mice compared to the wild type mice. Immunohistochemistry staining for CD45 showed increasing inflammatory cell infiltrates from 10 to 50 weeks in the Sod1 −/− mice compared to the wild type mice. TEM revealed prominent mitochondrial changes in 50 week Sod1 −/− mice. Conclusions Our results suggest that reactive oxygen species might play a vital role in the pathogensis of meibomian gland dysfunction. The Sod1 −/− mouse appears to be a promising model for the study of reactive oxygen species associated MG alterations. PMID:25036096

  2. Orally administered nicotine induces urothelial hyperplasia in rats and mice

    International Nuclear Information System (INIS)

    Dodmane, Puttappa R.; Arnold, Lora L.; Pennington, Karen L.; Cohen, Samuel M.

    2014-01-01

    Highlights: • Rats and mice orally administered with nicotine tartrate for total of 4 weeks. • No treatment-related death or whole body toxicity observed in any of the groups. • Urothelium showed simple hyperplasia in treated rats and mice. • No significant change in BrdU labeling index or SEM classification of urothelium. - Abstract: Tobacco smoking is a major risk factor for multiple human cancers including urinary bladder carcinoma. Tobacco smoke is a complex mixture containing chemicals that are known carcinogens in humans and/or animals. Aromatic amines a major class of DNA-reactive carcinogens in cigarette smoke, are not present at sufficiently high levels to fully explain the incidence of bladder cancer in cigarette smokers. Other agents in tobacco smoke could be excreted in urine and enhance the carcinogenic process by increasing urothelial cell proliferation. Nicotine is one such major component, as it has been shown to induce cell proliferation in multiple cell types in vitro. However, in vivo evidence specifically for the urothelium is lacking. We previously showed that cigarette smoke induces increased urothelial cell proliferation in mice. In the present study, urothelial proliferative and cytotoxic effects were examined after nicotine treatment in mice and rats. Nicotine hydrogen tartrate was administered in drinking water to rats (52 ppm nicotine) and mice (514 ppm nicotine) for 4 weeks and urothelial changes were evaluated. Histopathologically, 7/10 rats and 4/10 mice showed simple hyperplasia following nicotine treatment compared to none in the controls. Rats had an increased mean BrdU labeling index compared to controls, although it was not statistically significantly elevated in either species. Scanning electron microscopic visualization of the urothelium did not reveal significant cytotoxicity. These findings suggest that oral nicotine administration induced urothelial hyperplasia (increased cell proliferation), possibly due to a

  3. Motivational Disturbances and Effects of L-dopa Administration in Neurofibromatosis-1 Model Mice

    Science.gov (United States)

    Wozniak, David F.; Diggs-Andrews, Kelly A.; Conyers, Sara; Yuede, Carla M.; Dearborn, Joshua T.; Brown, Jacquelyn A.; Tokuda, Kazuhiro; Izumi, Yukitoshi; Zorumski, Charles F.; Gutmann, David H.

    2013-01-01

    Children with neurofibromatosis type 1 (NF1) frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice). In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below) suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening) under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg) administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at ameliorating NF1

  4. Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice.

    Directory of Open Access Journals (Sweden)

    David F Wozniak

    Full Text Available Children with neurofibromatosis type 1 (NF1 frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice. In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at

  5. Lack of the Lysosomal Membrane Protein, GLMP, in Mice Results in Metabolic Dysregulation in Liver.

    Directory of Open Access Journals (Sweden)

    Xiang Yi Kong

    Full Text Available Ablation of glycosylated lysosomal membrane protein (GLMP, formerly known as NCU-G1 has been shown to cause chronic liver injury which progresses into liver fibrosis in mice. Both lysosomal dysfunction and chronic liver injury can cause metabolic dysregulation. Glmp gt/gt mice (formerly known as Ncu-g1gt/gt mice were studied between 3 weeks and 9 months of age. Body weight gain and feed efficiency of Glmp gt/gt mice were comparable to wild type siblings, only at the age of 9 months the Glmp gt/gt siblings had significantly reduced body weight. Reduced size of epididymal fat pads was accompanied by hepatosplenomegaly in Glmp gt/gt mice. Blood analysis revealed reduced levels of blood glucose, circulating triacylglycerol and non-esterified fatty acids in Glmp gt/gt mice. Increased flux of glucose, increased de novo lipogenesis and lipid accumulation were detected in Glmp gt/gt primary hepatocytes, as well as elevated triacylglycerol levels in Glmp gt/gt liver homogenates, compared to hepatocytes and liver from wild type mice. Gene expression analysis showed an increased expression of genes involved in fatty acid uptake and lipogenesis in Glmp gt/gt liver compared to wild type. Our findings are in agreement with the metabolic alterations observed in other mouse models lacking lysosomal proteins, and with alterations characteristic for advanced chronic liver injury.

  6. Juvenile spermatogonial depletion (jsd): a genetic defect of germ cell proliferation of male mice.

    Science.gov (United States)

    Beamer, W G; Cunliffe-Beamer, T L; Shultz, K L; Langley, S H; Roderick, T H

    1988-05-01

    Adult C57BL/6J male mice homozygous for the mutant gene, juvenile spermatogonial depletion (jsd/jsd), show azoosper4ia and testes reduced to one-third normal size, but are otherwise phenotypically normal. In contrast, adult jsd/jsd females are fully fertile. This feature facilitated mapping the jsd gene to the centromeric end of chromosome 1; the gene order is jsd-Isocitrate dehydrogenase-1 (Idh-1)-Peptidase-3 (Pep-3). Analysis of testicular histology from jsd/jsd mice aged 3-10 wk revealed that these mutant mice experience one wave of spermatogenesis, but fail to continue mitotic proliferation of type A spermatogonial cells at the basement membrane. As a consequence, histological sections of testes from mutant mice aged 8-52 wk showed tubules populated by modest numbers of Sertoli cells, with only an occasional spermatogonial cell. Some sperm with normal morphology and motility were observed in epididymides of 6.5- but not in 8-wk or older mutants. Treatment with retinol failed to alter the loss of spermatogenesis in jsd/jsd mice. Analyses of serum hormones of jsd/jsd males showed that testosterone levels were normal at all ages--a finding corroborated by normal seminal vesicle and vas deferens weights, whereas serum follicle-stimulating hormone levels were significantly elevated in mutant mice from 4 to 20 wk of age. We hypothesize the jsd/jsd male may be deficient in proliferative signals from Sertoli cells that are needed for spermatogenesis.

  7. Food restriction by intermittent fasting induces diabetes and obesity and aggravates spontaneous atherosclerosis development in hypercholesterolaemic mice.

    Science.gov (United States)

    Dorighello, Gabriel G; Rovani, Juliana C; Luhman, Christopher J F; Paim, Bruno A; Raposo, Helena F; Vercesi, Anibal E; Oliveira, Helena C F

    2014-03-28

    Different regimens of food restriction have been associated with protection against obesity, diabetes and CVD. In the present study, we hypothesised that food restriction would bring benefits to atherosclerosis- and diabetes-prone hypercholesterolaemic LDL-receptor knockout mice. For this purpose, 2-month-old mice were submitted to an intermittent fasting (IF) regimen (fasting every other day) over a 3-month period, which resulted in an overall 20 % reduction in food intake. Contrary to our expectation, epididymal and carcass fat depots and adipocyte size were significantly enlarged by 15, 72 and 68 %, respectively, in the IF mice compared with the ad libitum-fed mice. Accordingly, plasma levels of leptin were 50 % higher in the IF mice than in the ad libitum-fed mice. In addition, the IF mice showed increased plasma levels of total cholesterol (37 %), VLDL-cholesterol (195 %) and LDL-cholesterol (50 %). As expected, in wild-type mice, the IF regimen decreased plasma cholesterol levels and epididymal fat mass. Glucose homeostasis was also disturbed by the IF regimen in LDL-receptor knockout mice. Elevated levels of glycaemia (40 %), insulinaemia (50 %), glucose intolerance and insulin resistance were observed in the IF mice. Systemic inflammatory markers, TNF-α and C-reactive protein, were significantly increased and spontaneous atherosclerosis development were markedly increased (3-fold) in the IF mice. In conclusion, the IF regimen induced obesity and diabetes and worsened the development of spontaneous atherosclerosis in LDL-receptor knockout mice. Although being efficient in a wild-type background, this type of food restriction is not beneficial in the context of genetic hypercholesterolaemia.

  8. National Elevation Dataset

    Science.gov (United States)

    ,

    2002-01-01

    The National Elevation Dataset (NED) is a new raster product assembled by the U.S. Geological Survey. NED is designed to provide National elevation data in a seamless form with a consistent datum, elevation unit, and projection. Data corrections were made in the NED assembly process to minimize artifacts, perform edge matching, and fill sliver areas of missing data. NED has a resolution of one arc-second (approximately 30 meters) for the conterminous United States, Hawaii, Puerto Rico and the island territories and a resolution of two arc-seconds for Alaska. NED data sources have a variety of elevation units, horizontal datums, and map projections. In the NED assembly process the elevation values are converted to decimal meters as a consistent unit of measure, NAD83 is consistently used as horizontal datum, and all the data are recast in a geographic projection. Older DEM's produced by methods that are now obsolete have been filtered during the NED assembly process to minimize artifacts that are commonly found in data produced by these methods. Artifact removal greatly improves the quality of the slope, shaded-relief, and synthetic drainage information that can be derived from the elevation data. Figure 2 illustrates the results of this artifact removal filtering. NED processing also includes steps to adjust values where adjacent DEM's do not match well, and to fill sliver areas of missing data between DEM's. These processing steps ensure that NED has no void areas and artificial discontinuities have been minimized. The artifact removal filtering process does not eliminate all of the artifacts. In areas where the only available DEM is produced by older methods, then "striping" may still occur.

  9. A H2S Donor GYY4137 Exacerbates Cisplatin-Induced Nephrotoxicity in Mice

    Directory of Open Access Journals (Sweden)

    Mi Liu

    2016-01-01

    Full Text Available Accumulating evidence demonstrated that hydrogen sulfide (H2S is highly involved in inflammation, oxidative stress, and apoptosis and contributes to the pathogenesis of kidney diseases. However, the role of H2S in cisplatin nephrotoxicity is still debatable. Here we investigated the effect of GYY4137, a novel slow-releasing H2S donor, on cisplatin nephrotoxicity in mice. Male C57BL/6 mice were pretreated with GYY4137 for 72 h prior to cisplatin injection. After cisplatin treatment for 72 h, mice developed obvious renal dysfunction and kidney injury as evidenced by elevated blood urea nitrogen (BUN and histological damage. Consistently, these mice also showed increased proinflammatory cytokines such as TNF-α, IL-6, and IL-1β in circulation and/or kidney tissues. Meanwhile, circulating thiobarbituric aid-reactive substances (TBARS and renal apoptotic indices including caspase-3, Bak, and Bax were all elevated. However, application of GYY4137 further aggravated renal dysfunction and kidney structural injury in line with promoted inflammation, oxidative stress, and apoptotic response following cisplatin treatment. Taken together, our results suggested that GYY4137 exacerbated cisplatin-induced nephrotoxicity in mice possibly through promoting inflammation, oxidative stress, and apoptotic response.

  10. Serum cholinesterases are differentially regulated in normal and dystrophin-deficient mutant mice

    Directory of Open Access Journals (Sweden)

    Andrea R. Durrant

    2012-06-01

    Full Text Available The cholinesterases, acetylcholinesterase and butyrylcholinesterase (pseudocholinesterase, are abundant in the nervous system and in other tissues. The role of acetylcholinesterase in terminating transmitter action in the peripheral and central nervous system is well understood. However, both knowledge of the function(s of the cholinesterases in serum, and of their metabolic and endocrine regulation under normal and pathological conditions, is limited. This study investigates acetylcholinesterase and butyrylcholinesterase in sera of dystrophin-deficient mdx mutant mice, an animal model for the human Duchenne muscular dystrophy and in control healthy mice. The data show systematic and differential variations in the concentrations of both enzymes in the sera, and specific changes dictated by alteration of hormonal balance in both healthy and dystrophic mice. While acetylcholinesterase in mdx-sera is elevated, butyrylcholinesterase is markedly diminished, resulting in an overall cholinesterase decrease compared to sera of healthy controls. The androgen testosterone (T is a negative modulator of butyrylcholinesterase, but not of acetylcholinesterase, in male mouse sera. T-removal elevated both butyrylcholinesterase activity and the butyrylcholinesterase/acetylcholinesterase ratio in mdx male sera to values resembling those in healthy control male mice. Mechanisms of regulation of the circulating cholinesterases and their impairment in the dystrophic mice are suggested, and clinical implications for diagnosis and treatment are considered.

  11. Is moral elevation an approach-oriented emotion?

    OpenAIRE

    Van de Vyver, Julie; Abrams, Dominic

    2016-01-01

    Abstract Two studies were designed to test whether moral elevation should be conceptualized as an approach-oriented emotion. The studies examined the relationship between moral elevation and the behavioral activation and inhibition systems. Study 1 (N?=?80) showed that individual differences in moral elevation were associated with individual differences in behavioral activation but not inhibition. Study 2 (N?=?78) showed that an elevation-inducing video promoted equally high levels of approac...

  12. Overactivation of Hedgehog Signaling Alters Development of the Ovarian Vasculature in Mice1

    Science.gov (United States)

    Ren, Yi; Cowan, Robert G.; Migone, Fernando F.; Quirk, Susan M.

    2012-01-01

    ABSTRACT The hedgehog (HH) signaling pathway is critical for ovarian function in Drosophila, but its role in the mammalian ovary has not been defined. Previously, expression of a dominant active allele of the HH signal transducer protein smoothened (SMO) in Amhr2cre/+SmoM2 mice caused anovulation in association with a lack of smooth muscle in the theca of developing follicles. The current study examined events during the first 2 wk of life in Amhr2cre/+SmoM2 mice to gain insight into the cause of anovulation. Expression of transcriptional targets of HH signaling, Gli1, Ptch1, and Hhip, which are used as measures of pathway activity, were elevated during the first several days of life in Amhr2cre/+SmoM2 mice compared to controls but were similar to controls in older mice. Microarray analysis showed that genes with increased expression in 2-day-old mutants compared to controls were enriched for the processes of vascular and tube development and steroidogenesis. The density of platelet endothelial cell adhesion molecule (PECAM)-labeled endothelial tubes was increased in the cortex of newborn ovaries of mutant mice. Costaining of preovulatory follicles for PECAM and smooth muscle actin showed that muscle-type vascular support cells are deficient in theca of mutant mice. Expression of genes for steroidogenic enzymes that are normally expressed in the fetal adrenal gland were elevated in newborn ovaries of mutant mice. In summary, overactivation of HH signaling during early life alters gene expression and vascular development and this is associated with the lifelong development of anovulatory follicles in which the thecal vasculature fails to mature appropriately. PMID:22402963

  13. Interaktive tavler - interaktive elever

    DEFF Research Database (Denmark)

    Reusch, Charlotte F.; Otzen, Elsebeth

    Abstract, Poster-præsentation 13.-14. juni 2012, Pilotprojekt: Interaktive tavler – interaktive elever Lektor, cand. pæd., Elsebeth Otzen og Lektor, cand. mag., Charlotte Reusch, Institut for Skole og Læring, Læreruddannelsen, Professionshøjskolen Metropol, København Hvordan motiverer en interaktiv...... tavle lærere og elever? Hvad sker der mellem elev, stof og lærer, når læreren bliver i stand til at billedliggøre og dynamisere sine oplæg på tavlen? Bliver læreroplæg prioriteret? Bliver eleverne aktive, eller ender den interaktive tavle med blot at understøtte lærerens envejskommunikation til klassen......? Og hvad sker der mellem eleverne? Disse spørgsmål var igangsættende for arbejdet med pilotprojektet Interaktive tavler – interaktive elever, som blev afviklet i skoleåret 2010-2011. Projektet blev udført af en tværfaglig gruppe, bestående af lektorer i matematik, biologi og dansk i læreruddannelsen...

  14. Udeskole og elevers handlekompetence

    DEFF Research Database (Denmark)

    Breiting, Søren

    2011-01-01

    Elever elsker at komme væk fra undervisningen i skolen. Er det positivt eller negativt? Og hvad har betydning for, at eleverne får mest muligt ud af oplevelserne uden for skolen? Forskellige former for udeskole giver nogle oplagte muligheder, så eleverne udvikler sig som engagerede borgere i et...

  15. Interaktive tavler - interaktive elever

    DEFF Research Database (Denmark)

    Reusch, Charlotte; Otzen, Elsebeth

    Abstract, Poster-præsentation 13.-14. juni 2012, Pilotprojekt: Interaktive tavler ? interaktive elever Lektor, cand. pæd., Elsebeth Otzen og Lektor, cand. mag., Charlotte Reusch, Institut for Skole og Læring, Læreruddannelsen, Professionshøjskolen Metropol, København Hvordan motiverer en interaktiv...... tavle lærere og elever? Hvad sker der mellem elev, stof og lærer, når læreren bliver i stand til at billedliggøre og dynamisere sine oplæg på tavlen? Bliver læreroplæg prioriteret? Bliver eleverne aktive, eller ender den interaktive tavle med blot at understøtte lærerens envejskommunikation til klassen......? Og hvad sker der mellem eleverne? Disse spørgsmål var igangsættende for arbejdet med pilotprojektet Interaktive tavler ? interaktive elever, som blev afviklet i skoleåret 2010-2011. Projektet blev udført af en tværfaglig gruppe, bestående af lektorer i matematik, biologi og dansk i læreruddannelsen...

  16. Resistance to early-life stress in mice: effects of genetic background and stress duration

    Directory of Open Access Journals (Sweden)

    Helene M. Savignac

    2011-04-01

    Full Text Available Early-life stress can induce marked behavioural and physiological impairments in adulthood including cognitive deficits, depression, anxiety and gastrointestinal dysfunction. Although robust rat models of early-life stress exist there are few established effective paradigms in the mouse. Genetic background and protocol parameters used are two critical variables in such model development.Thus we investigated the impact of two different early-life stress protocols in two commonly used inbred mouse strains. C57BL/6 and innately anxious BALB/c male mice were maternally deprived 3 hrs daily, either from postnatal day 1 to 14 (Protocol 1 or 6 to 10 (Protocol 2. Animals were assessed in adulthood for cognitive performance (spontaneous alternation behaviour test, anxiety (open field, light/dark box and elevated plus maze tests and depression-related behaviours (forced swim test in addition to stress-sensitive physiological changes. Overall, the results showed that early-life stressed mice from both strains displayed good cognitive ability and no elevations in anxiety. However, paradoxical changes occurred in C57BL/6 mice as the longer protocol (protocol 1 decreased anxiety in the light-dark box and increased exploration in the elevated plus maze. In BALB/c mice there were also limited effects of maternal separation with both separation protocols inducing reductions in stress-induced defecation and protocol 1 reducing the colon length. These data suggest that, independent of stress duration, mice from both strains were on the whole resilient to the maladaptive effects of early-life stress. Thus maternal-separation models of brain-gut axis dysfunction should rely on either different stressor protocols or other strains of mice.

  17. Germline mutation rates at tandem repeat loci in DNA-repair deficient mice

    International Nuclear Information System (INIS)

    Barber, Ruth C.; Miccoli, Laurent; Buul, Paul P.W. van; Burr, Karen L.-A.; Duyn-Goedhart, Annemarie van; Angulo, Jaime F.; Dubrova, Yuri E.

    2004-01-01

    Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germline of non-exposed and irradiated severe combined immunodeficient (scid) and poly(ADP-ribose) polymerase (PARP-1 -/- ) deficient male mice. Non-exposed scid and PARP -/- male mice showed considerably elevated ESTR mutation rates, far higher than those in wild-type isogenic mice and other inbred strains. The irradiated scid and PARP-1 -/- male mice did not show any detectable increases in their mutation rate, whereas significant ESTR mutation induction was observed in the irradiated wild-type isogenic males. ESTR mutation spectra in the scid and PARP-1 -/- strains did not differ from those in the isogenic wild-type strains. Considering these data and the results of previous studies, we propose that a delay in repair of DNA damage in scid and PARP-1 -/- mice could result in replication fork pausing which, in turn, may affect ESTR mutation rate in the non-irradiated males. The lack of mutation induction in irradiated scid and PARP-1 -/- can be explained by the high cell killing effects of irradiation on the germline of deficient mice

  18. Biological Effect of Ganoderma lucidum in Mice Suffering from Ehrlich Carcinoma and Gamma Radiation

    International Nuclear Information System (INIS)

    Fahim, Th.M.; Sherif, N.H.; Abd El-Azime, A.Sh.

    2013-01-01

    The popular edible mushroom Ganoderma lucidum (G. lucidum) has been widely used for the general promotion of health and longevity in oriental countries. The present study was performed to investigate the antitumor effect of G. lucidum on Ehrlich carcinoma (EC) cells and/or gamma radiation-induced oxidative stress, kidney dysfunction and histopathological changes in the albino mouse. G. lucidum was orally administered via gavages to mice for a period of 3 weeks at a dose of 100 mg/kg body weight begins on the 10th day of tumor inoculation. Animals were exposed to 4 Gy whole body γ radiation after 2 weeks of tumor inoculation. The antitumor effect of G. lucidum was evident in terms of a reduction in tumor viable cells count, inhibited both weight loss and tumor growth rate of EC-tumor bearing mice alone and in combination with gamma-radiation. Inoculation of mice with EC cells resulted in biochemical and histopathological changes leading to kidney damage. Oral administration of G. lucidum improved kidney functions through a recovery of the elevated levels of serum urea, creatinine, uric acid and increased albumin level and decreased the levels of tumor markers. Also, treatment of mice with G. lucidum induced a reduction of lipid peroxidation (MDA) level, improvement in glutathione content (GSH) and superoxide dismutase (SOD) activity in the kidney compared with those EC and /or irradiated damaged mice. On the other hand, treatment EC bearing mice with gamma radiation or G. lucidum combined showed increase in MDA level and decrease in GSH content and SOD activity, as compared to EC bearing mice. Histopathological studies showed that suffering from EC caused fatty degeneration, presence of necrosis and enlargement of kidney cells nuclei. Furthermore, an elevation of tail DNA % was recorded in the tumor tissue of mice treated with G. lucidum and/or γ radiation compared to EC control group. Treatment of EC bearing mice with G. lucidum and/or γ radiation exhibited

  19. Adiponectin gene therapy ameliorates high-fat, high-sucrose diet-induced metabolic perturbations in mice.

    Science.gov (United States)

    Kandasamy, A D; Sung, M M; Boisvenue, J J; Barr, A J; Dyck, J R B

    2012-09-10

    Adiponectin is an adipokine secreted primarily from adipose tissue that can influence circulating plasma glucose and lipid levels through multiple mechanisms involving a variety of organs. In humans, reduced plasma adiponectin levels induced by obesity are associated with insulin resistance and type 2 diabetes, suggesting that low adiponectin levels may contribute the pathogenesis of obesity-related insulin resistance. The objective of the present study was to investigate whether gene therapy designed to elevate circulating adiponectin levels is a viable strategy for ameliorating insulin resistance in mice fed a high-fat, high-sucrose (HFHS) diet. Electroporation-mediated gene transfer of mouse adiponectin plasmid DNA into gastrocnemius muscle resulted in elevated serum levels of globular and high-molecular weight adiponectin compared with control mice treated with empty plasmid. In comparison to HFHS-fed mice receiving empty plasmid, mice receiving adiponectin gene therapy displayed significantly decreased weight gain following 13 weeks of HFHS diet associated with reduced fat accumulation, and exhibited increased oxygen consumption and locomotor activity as measured by indirect calorimetry, suggesting increased energy expenditure in these mice. Consistent with improved whole-body metabolism, mice receiving adiponectin gene therapy also had lower blood glucose and insulin levels, improved glucose tolerance and reduced hepatic gluconeogenesis compared with control mice. Furthermore, immunoblot analysis of livers from mice receiving adiponectin gene therapy showed an increase in insulin-stimulated phosphorylation of insulin signaling proteins. Based on these data, we conclude that adiponectin gene therapy ameliorates the metabolic abnormalities caused by feeding mice a HFHS diet and may be a potential therapeutic strategy to improve obesity-mediated impairments in insulin sensitivity.

  20. Depletion of GGA1 and GGA3 mediates post-injury elevation of BACE1

    Science.gov (United States)

    Walker, Kendall R.; Kang, Eugene L.; Whalen, Michael J.; Shen, Yong; Tesco, Giuseppina

    2012-01-01

    Traumatic brain injury (TBI) is one of the most robust environmental risk factors for Alzheimer’s disease (AD). Compelling evidence is accumulating that a single event of TBI is associated with increased levels of Aβ. However, the underlying molecular mechanisms remain unknown. We report here that the BACE1 interacting protein, GGA3, is depleted while BACE1 levels increase in the acute phase post-injury (48hrs) in a mouse model of TBI. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. We next found that head trauma potentiates BACE1 elevation in GGA3 null mice in the acute phase post-TBI and discovered that GGA1, a GGA3 homologue, is a novel caspase-3 substrate depleted at 48 hrs post-TBI. Moreover, GGA1 silencing potentiates BACE1 elevation induced by GGA3 deletion in neurons in vitro indicating that GGA1 and GGA3 synergistically regulate BACE1. Accordingly, we found that levels of both GGA1 and GGA3 are depleted while BACE1 levels are increased in a series of post-mortem AD brains. Finally, we show that GGA3 haploinsufficiency results in sustained elevation of BACE1 and Aβ levels while GGA1 levels are restored in the subacute phase (7 days) post-injury. In conclusion, our data indicate that depletion of GGA1 and GGA3 engender a rapid and robust elevation of BACE1 in the acute phase post-injury. However, the efficient disposal of the acutely accumulated BACE1 solely depends on GGA3 levels in the sub-acute phase of injury. PMID:22836275

  1. Depletion of GGA1 and GGA3 mediates postinjury elevation of BACE1.

    Science.gov (United States)

    Walker, Kendall R; Kang, Eugene L; Whalen, Michael J; Shen, Yong; Tesco, Giuseppina

    2012-07-25

    Traumatic brain injury (TBI) is one of the most robust environmental risk factors for Alzheimer's disease (AD). Compelling evidence is accumulating that a single event of TBI is associated with increased levels of Aβ. However, the underlying molecular mechanisms remain unknown. We report here that the BACE1 interacting protein, GGA3, is depleted while BACE1 levels increase in the acute phase after injury (48 h) in a mouse model of TBI. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3-null mice. We next found that head trauma potentiates BACE1 elevation in GGA3-null mice in the acute phase after TBI, and discovered that GGA1, a GGA3 homolog, is a novel caspase-3 substrate depleted at 48 h after TBI. Moreover, GGA1 silencing potentiates BACE1 elevation induced by GGA3 deletion in neurons in vitro, indicating that GGA1 and GGA3 synergistically regulate BACE1. Accordingly, we found that levels of both GGA1 and GGA3 are depleted while BACE1 levels are increased in a series of postmortem AD brains. Finally, we show that GGA3 haploinsufficiency results in sustained elevation of BACE1 and Aβ levels while GGA1 levels are restored in the subacute phase (7 d) after injury. In conclusion, our data indicate that depletion of GGA1 and GGA3 engender a rapid and robust elevation of BACE1 in the acute phase after injury. However, the efficient disposal of the acutely accumulated BACE1 solely depends on GGA3 levels in the subacute phase of injury.

  2. Remarkable changes in behavior and physiology of laboratory mice after the massive 2011 Tohoku earthquake in Japan.

    Science.gov (United States)

    Yanai, Shuichi; Semba, Yuki; Endo, Shogo

    2012-01-01

    A devastating earthquake and tsunami hit Japan on March 11, 2011, followed by several long and intense aftershocks. Laboratory mice housed in the Tokyo, located approximately 330 km south of this earthquake's epicenter, displayed remarkable changes in a variety of behaviors and physiological measures. Although unusual pre-earthquake behaviors have been previously reported in laboratory animals, little is known about behavioral and physiological changes that occur after a great earthquake. In the present study, the effects of Tohoku earthquake on mice behavior were investigated. "Earthquake-experienced" mice displayed a marked increase in food consumption without gaining body weight in response to the earthquake. They also displayed enhanced anxiety, and in a formal fear memory task, showed significantly greater tone- and context-dependent conditioned freezing. Water maze performance of earthquake-experienced mice showed the quicker acquisition of the task, faster swim speed and longer swim distance than the naive mice. Serum corticosterone levels were elevated compared to the naive mice, indicating that the earthquake and aftershocks were stressful for the mice. These results demonstrate that great earthquakes strongly affect mouse behaviors and physiology. Although the effects of a variety of experimental manipulations on mouse behaviors in disease models or in models of higher cognitive functions have been extensively examined, researchers need to be aware how natural phenomena, such as earthquakes and perhaps other natural environmental factors, influence laboratory animal behaviors and physiology.

  3. Remarkable changes in behavior and physiology of laboratory mice after the massive 2011 Tohoku earthquake in Japan.

    Directory of Open Access Journals (Sweden)

    Shuichi Yanai

    Full Text Available A devastating earthquake and tsunami hit Japan on March 11, 2011, followed by several long and intense aftershocks. Laboratory mice housed in the Tokyo, located approximately 330 km south of this earthquake's epicenter, displayed remarkable changes in a variety of behaviors and physiological measures. Although unusual pre-earthquake behaviors have been previously reported in laboratory animals, little is known about behavioral and physiological changes that occur after a great earthquake. In the present study, the effects of Tohoku earthquake on mice behavior were investigated. "Earthquake-experienced" mice displayed a marked increase in food consumption without gaining body weight in response to the earthquake. They also displayed enhanced anxiety, and in a formal fear memory task, showed significantly greater tone- and context-dependent conditioned freezing. Water maze performance of earthquake-experienced mice showed the quicker acquisition of the task, faster swim speed and longer swim distance than the naive mice. Serum corticosterone levels were elevated compared to the naive mice, indicating that the earthquake and aftershocks were stressful for the mice. These results demonstrate that great earthquakes strongly affect mouse behaviors and physiology. Although the effects of a variety of experimental manipulations on mouse behaviors in disease models or in models of higher cognitive functions have been extensively examined, researchers need to be aware how natural phenomena, such as earthquakes and perhaps other natural environmental factors, influence laboratory animal behaviors and physiology.

  4. Remarkable Changes in Behavior and Physiology of Laboratory Mice after the Massive 2011 Tohoku Earthquake in Japan

    Science.gov (United States)

    Yanai, Shuichi; Semba, Yuki; Endo, Shogo

    2012-01-01

    A devastating earthquake and tsunami hit Japan on March 11, 2011, followed by several long and intense aftershocks. Laboratory mice housed in the Tokyo, located approximately 330 km south of this earthquake’s epicenter, displayed remarkable changes in a variety of behaviors and physiological measures. Although unusual pre-earthquake behaviors have been previously reported in laboratory animals, little is known about behavioral and physiological changes that occur after a great earthquake. In the present study, the effects of Tohoku earthquake on mice behavior were investigated. “Earthquake-experienced” mice displayed a marked increase in food consumption without gaining body weight in response to the earthquake. They also displayed enhanced anxiety, and in a formal fear memory task, showed significantly greater tone- and context-dependent conditioned freezing. Water maze performance of earthquake-experienced mice showed the quicker acquisition of the task, faster swim speed and longer swim distance than the naive mice. Serum corticosterone levels were elevated compared to the naive mice, indicating that the earthquake and aftershocks were stressful for the mice. These results demonstrate that great earthquakes strongly affect mouse behaviors and physiology. Although the effects of a variety of experimental manipulations on mouse behaviors in disease models or in models of higher cognitive functions have been extensively examined, researchers need to be aware how natural phenomena, such as earthquakes and perhaps other natural environmental factors, influence laboratory animal behaviors and physiology. PMID:22957073

  5. Skuldertesten "Kombineret Elevation"

    DEFF Research Database (Denmark)

    Clausen, Mikkel Bek; Overkær, Brian

    2010-01-01

    Formål: At udarbejde en testprotokol for testen Kombineret Elevation (KE) og undersøge test-retest variationen ved test af elite svømmere, samt diskutere testens relevans og validitet. Materiale og Metode: 9 elite og 10 sub-elite svømmere, heraf var 11 mænd og 8 kvinder, gennemførte testen KE 2...

  6. PLC VVVF Elevator Control System

    OpenAIRE

    Tang, Yujian; Gui, Tianyu

    2016-01-01

    The aim of the thesis is to introduce the PLC VVVF elevator and its control system. The thesis can be divided into three parts. The first part is about the overview of the lift: the kinds of the lift and the structure of the lift, it shows the knowledge about the components and the operating systems of the lift. The second part is about the PLC control system, it’s about the operations of the lift from the introduction about the hardware and software of the PLC control system. And the thi...

  7. Elevation of blood levels of zinc protoporphyrin by radiomimetic drugs and friend leukemia virus

    International Nuclear Information System (INIS)

    Walden, T.L.; Al-Ansari, H.M.; Farkas, W.R.; Tennessee Univ., Knoxville; Tennessee Univ., Knoxville

    1987-01-01

    Sublethal doses of whole-body irradiation induced the elevation of zinc protoporphyrin (ZPP). Experiments were conducted to determine if recovery from radiomimetic drugs also resulted in elevation of ZPP. Daily injections with hydroxyurea and other cytotoxic drugs for 10 days caused ZPP elevation and a dose of radiation too low to cause ZPP elevation by itself caused ZPP elevation when hydroxyurea was administered prior to irradiation. Friend leukemia virus also brought about an elevation of ZPP. However, not all factors that increased erythropoiesis brought about ZPP elevation. The elevated erythropoiesis in response to hypoxia and the enhanced erythropoiesis that followed administration of folic acid to folic acid-deficient mice was not accompanied by ZPP elevation. (orig.)

  8. Elevation of blood levels of zinc protoporphyrin by radiomimetic drugs and friend leukemia virus

    Energy Technology Data Exchange (ETDEWEB)

    Walden, T.L.; Al-Ansari, H.M.; Farkas, W.R.

    1987-01-01

    Sublethal doses of whole-body irradiation induced the elevation of zinc protoporphyrin (ZPP). Experiments were conducted to determine if recovery from radiomimetic drugs also resulted in elevation of ZPP. Daily injections with hydroxyurea and other cytotoxic drugs for 10 days caused ZPP elevation and a dose of radiation too low to cause ZPP elevation by itself caused ZPP elevation when hydroxyurea was administered prior to irradiation. Friend leukemia virus also brought about an elevation of ZPP. However, not all factors that increased erythropoiesis brought about ZPP elevation. The elevated erythropoiesis in response to hypoxia and the enhanced erythropoiesis that followed administration of folic acid to folic acid-deficient mice was not accompanied by ZPP elevation.

  9. Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders.

    Science.gov (United States)

    Erhardt, Sophie; Pocivavsek, Ana; Repici, Mariaelena; Liu, Xi-Cong; Imbeault, Sophie; Maddison, Daniel C; Thomas, Marian A R; Smalley, Joshua L; Larsson, Markus K; Muchowski, Paul J; Giorgini, Flaviano; Schwarcz, Robert

    2017-11-15

    Kynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway-which is implicated as dysfunctional in various psychiatric disorders-toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia. In the present study, we investigated adaptive-and possibly regulatory-changes in mice with a targeted deletion of Kmo (Kmo -/- ) and characterized the kynurenine 3-monooxygenase-deficient mice using six behavioral assays relevant for the study of schizophrenia. Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo -/- mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo -/- mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo -/- mice showed potentiated horizontal activity in the open field paradigm. Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders. Copyright © 2016. Published by Elsevier Inc.

  10. Motor impulsivity in APP-SWE mice: a model of Alzheimer's disease.

    Science.gov (United States)

    Adriani, Walter; Ognibene, Elisa; Heuland, Emilie; Ghirardi, Orlando; Caprioli, Antonio; Laviola, Giovanni

    2006-09-01

    Among transgenic mouse models of Alzheimer's disease, APP-SWE mice have been shown to develop beta-amyloid plaques and to exhibit progressive impairment of cognitive function. Human Alzheimer's disease, however, also includes secondary clinical manifestations, spanning from hyperactivity to agitation. The aim of this study was a better characterization of motor impulsivity in APP-SWE mice, observed at 12 months of age, when levels of soluble beta-amyloid are elevated and beta-amyloid neuritic plaques start to appear. Mice were tested for spatial learning abilities in the Morris water maze (seven daily sessions, four trials per day). The distance traveled to reach the hidden platform showed a learning curve in both groups. This profile, however, was somewhat delayed in APP-SWE mice, thus confirming slightly impaired spatial capacities. To evaluate motor impulsivity, animals were trained to nose-poke for a food reward, which was delivered after a waiting interval that increased over days (15-60 s). Further nose-poking during this signaled waiting interval resulted in food-reward loss and electric-shock punishment. APP-SWE mice received an increased quantity of punishment and were able to earn fewer food rewards, suggesting inability to wait already at the lowest delay. After the animals were killed, prefrontal cortex samples were assessed for neurochemical parameters. Serotonin turnover was elevated in the prefrontal cortex of APP-SWE mice compared with controls. The results clearly confirm cognitive deficits, and are consistent with the hypothesis of reduced behavioral-inhibition abilities. Together with recent findings, APP-SWE mice emerge as a suitable animal model, characterized by a number of specific behavioral alterations, resembling primary and secondary symptoms of human Alzheimer's disease.

  11. Metabolic, Reproductive, and Neurologic Abnormalities in Agpat1-Null Mice.

    Science.gov (United States)

    Agarwal, Anil K; Tunison, Katie; Dalal, Jasbir S; Nagamma, Sneha S; Hamra, F Kent; Sankella, Shireesha; Shao, Xinli; Auchus, Richard J; Garg, Abhimanyu

    2017-11-01

    Defects in the biosynthesis of phospholipids and neutral lipids are associated with cell membrane dysfunction, disrupted energy metabolism, and diseases including lipodystrophy. In these pathways, the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) enzymes transfer a fatty acid to the sn-2 carbon of sn-1-acylglycerol-3-phosphate (lysophosphatidic acid) to form sn-1, 2-acylglycerol-3-phosphate [phosphatidic acid (PA)]. PA is a precursor for key phospholipids and diacylglycerol. AGPAT1 and AGPAT2 are highly homologous isoenzymes that are both expressed in adipocytes. Genetic defects in AGPAT2 cause congenital generalized lipodystrophy, indicating that AGPAT1 cannot compensate for loss of AGPAT2 in adipocytes. To further explore the physiology of AGPAT1, we characterized a loss-of-function mouse model (Agpat1-/-). The majority of Agpat1-/- mice died before weaning and had low body weight and low plasma glucose levels, independent of plasma insulin and glucagon levels, with reduced percentage of body fat but not generalized lipodystrophy. These mice also had decreased hepatic messenger RNA expression of Igf-1 and Foxo1, suggesting a decrease in gluconeogenesis. In male mice, sperm development was impaired, with a late meiotic arrest near the onset of round spermatid production, and gonadotropins were elevated. Female mice showed oligoanovulation yet retained responsiveness to gonadotropins. Agpat1-/- mice also demonstrated abnormal hippocampal neuron development and developed audiogenic seizures. In summary, Agpat1-/- mice developed widespread disturbances of metabolism, sperm development, and neurologic function resulting from disrupted phospholipid homeostasis. AGPAT1 appears to serve important functions in the physiology of multiple organ systems. The Agpat1-deficient mouse provides an important model in which to study the contribution of phospholipid and triacylglycerol synthesis to physiology and diseases. Copyright © 2017 Endocrine Society.

  12. Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure.

    Science.gov (United States)

    Rama Rao, Kakulavarapu V; Verkman, A S; Curtis, Kevin M; Norenberg, Michael D

    2014-03-01

    Brain edema and associated astrocyte swelling leading to increased intracranial pressure are hallmarks of acute liver failure (ALF). Elevated blood and brain levels of ammonia have been implicated in the development of brain edema in ALF. Cultured astrocytes treated with ammonia have been shown to undergo cell swelling and such swelling was associated with an increase in the plasma membrane expression of aquaporin-4 (AQP4) protein. Further, silencing the AQP4 gene in cultured astrocytes was shown to prevent the ammonia-induced cell swelling. Here, we examined the evolution of brain edema in AQP4-null mice and their wild type counterparts (WT-mice) in different models of ALF induced by thioacetamide (TAA) or acetaminophen (APAP). Induction of ALF with TAA or APAP significantly increased brain water content in WT mice (by 1.6% ± 0.3 and 2.3 ± 0.4%, respectively). AQP4 protein was significantly increased in brain plasma membranes of WT mice with ALF induced by either TAA or APAP. In contrast to WT-mice, brain water content did not increase in AQP4-null mice. Additionally, AQP4-null mice treated with either TAA or APAP showed a remarkably lesser degree of neurological deficits as compared to WT mice; the latter displayed an inability to maintain proper gait, and demonstrated a markedly reduced exploratory behavior, with the mice remaining in one corner of the cage with its head tilted downwards. These results support a central role of AQP4 in the brain edema associated with ALF. Published by Elsevier Inc.

  13. Autophagy resolves early retinal inflammation in Igf1-deficient mice

    Directory of Open Access Journals (Sweden)

    Ana I. Arroba

    2016-09-01

    Full Text Available Insulin-like growth factor-1 (IGF-1 is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery, and anti-inflammatory properties in the nervous system. Mice that have mutations in the Igf1 gene, rendering the gene product inactive (Igf1−/−, present with age-related visual loss accompanied by structural alterations in the first synapses of the retinal pathway. Recent advances have revealed a crucial role of autophagy in immunity and inflammation. Keeping in mind this close relationship, we aimed to decipher these processes in the context of the defects that occur during ageing in the retina of Igf1−/− mice. Tnfa and Il1b mRNAs, and phosphorylation of JNK and p38 MAPK were elevated in the retinas of 6- and 12-month old Igf1−/− mice compared to those in age-matched Igf1+/+ controls. In 6-month-old Igf1−/− retinas, increased mRNA levels of the autophagy mediators Becn1, Atg9, Atg5 and Atg4, decreased p62 (also known as SQSTM1 protein expression together with an increased LC3-II:LC3-I ratio reflected active autophagic flux. However, in retinas from 12-month-old Igf1−/− mice, Nlrp3 mRNA, processing of the IL1β pro-form and immunostaining of active caspase-1 were elevated compared to those in age-matched Igf1+/+ controls, suggesting activation of the inflammasome. This effect concurred with accumulation of autophagosomes and decreased autophagic flux in the retina. Microglia localization and status of activation in the retinas of 12-month-old Igf1+/+ and Igf1−/− mice, analyzed by immunostaining of Cd11b and Iba-1, showed a specific distribution pattern in the outer plexiform layer (OPL, inner plexiform layer (IPL and inner nuclear layer (INL, and revealed an increased number of activated microglia cells in the retina of 12-month-old blind Igf1−/− mice. Moreover, reactive gliosis was exclusively detected in the retinas from 12-month-old blind Igf1−/− mice. In conclusion, this study

  14. Genetic Deficiency in Neprilysin or Its Pharmacological Inhibition Initiate Excessive Stress-Induced Alcohol Consumption in Mice

    Science.gov (United States)

    Gembardt, Florian; Becker, Axel; Schultheiss, Heinz-Peter; Siems, Wolf-Eberhard; Walther, Thomas

    2012-01-01

    Both acquired and inherited genetic factors contribute to excessive alcohol consumption and the corresponding development of addiction. Here we show that the genetic deficiency in neprilysin [NEP] did not change the kinetics of alcohol degradation but led to an increase in alcohol intake in mice in a 2-bottle-free-choice paradigm after one single stress stimulus (intruder). A repetition of such stress led to an irreversible elevated alcohol consumption. This phenomenon could be also observed in wild-type mice receiving an orally active NEP inhibitor. We therefore elucidated the stress behavior in NEP-deficient mice. In an Elevated Plus Maze, NEP knockouts crossed more often the area between the arms, implicating a significant stronger stress response. Furthermore, such animals showed a decreased locomotor activity under intense light in a locomotor activity test, identifying such mice to be more responsive in aversive situations than their wild-type controls. Since the reduction in NEP activity itself does not lead to significant signs of an altered alcohol preference in mice but requires an environmental stimulus, our findings build a bridge between stress components and genetic factors in the development of alcoholism. Therefore, targeting NEP activity might be a very attractive approach for the treatment of alcohol abuse in a society with increasing social and financial stress. PMID:23185571

  15. Genetic deficiency in neprilysin or its pharmacological inhibition initiate excessive stress-induced alcohol consumption in mice.

    Directory of Open Access Journals (Sweden)

    Björn Maul

    Full Text Available Both acquired and inherited genetic factors contribute to excessive alcohol consumption and the corresponding development of addiction. Here we show that the genetic deficiency in neprilysin [NEP] did not change the kinetics of alcohol degradation but led to an increase in alcohol intake in mice in a 2-bottle-free-choice paradigm after one single stress stimulus (intruder. A repetition of such stress led to an irreversible elevated alcohol consumption. This phenomenon could be also observed in wild-type mice receiving an orally active NEP inhibitor. We therefore elucidated the stress behavior in NEP-deficient mice. In an Elevated Plus Maze, NEP knockouts crossed more often the area between the arms, implicating a significant stronger stress response. Furthermore, such animals showed a decreased locomotor activity under intense light in a locomotor activity test, identifying such mice to be more responsive in aversive situations than their wild-type controls. Since the reduction in NEP activity itself does not lead to significant signs of an altered alcohol preference in mice but requires an environmental stimulus, our findings build a bridge between stress components and genetic factors in the development of alcoholism. Therefore, targeting NEP activity might be a very attractive approach for the treatment of alcohol abuse in a society with increasing social and financial stress.

  16. Radioprotective effect of Tamarindus indica pod extract in Swiss albino mice exposed to whole body electron beam radiation

    International Nuclear Information System (INIS)

    Nandini, S.; Suchetha Kumari, N.; Ganesh Sanjeev; D'sa, Prima

    2013-01-01

    The objective of the study was to investigate the radioprotective effect of Tamarindus indica pod extract against radiation induced damage.The effect of 100 mg of hydroalcoholic extract of Tamarindus indica pod was studied in Swiss albino mice exposed to 6 Gy whole body electron beam radiation. Treatment of mice with extract for 15 days before irradiation reduced the symptoms of radiation sickness when compared with the untreated irradiated group. The irradiated animals showed an elevation in lipid peroxidation and reduction in glutathione, total antioxidants and antioxidant enzymes such as glutathione peroxidase and catalase activities. Radiation induced mice has shown micronucleus in the bone marrow cells. Treatment of mice with Tamarindus indica pod extract before irradiation caused a significant reduction in lipid peroxidation followed by significant elevation in reduced glutathione, total antioxidants, glutathione peroxidase and catalase activity. It also showed a reduction in the micronucleus formation in bone marrow cells. Results indicate that the radioprotective activity of Tamarindus indica pod extract may be due to free radical scavenging attributed as a result of increased antioxidant level in mice. (author)

  17. Spontaneous nonalcoholic fatty liver disease and ER stress in Sidt2 deficiency mice

    International Nuclear Information System (INIS)

    Gao, Jialin; Zhang, Yao; Yu, Cui; Tan, Fengbiao; Wang, Lizhuo

    2016-01-01

    Sidt2 is a newly discovered lysosomal membrane protein that is closely related to glucose metabolism. In the present study, we found that Sidt2 is also closely related to lipid metabolism. Gradual increases in serum triglyceride (TG) and free fatty acid, as well as elevated aspartate transaminase and alanine transaminase levels were observed in Sidt2"−"/"− mice fed a normal diet from the age of 3 months, suggesting the presence of lipid metabolism disorders and impaired liver function in these mice. In the liver slices of 6-month-old Sidt2"−"/"− mice, there were obvious fat degeneration and inflammatory changes. Almost all of the liver cells demonstrated different levels of lipid droplet accumulation and cell swelling, and some of the cells demonstrated balloon-like changes. Infiltration of inflammatory cells was observed in the portal area and hepatic lobule. Electron microscopy showed that macrophages tended to be attached to the endothelial cells, and a large number of lipid droplets were present in the liver cells. Oil red O staining showed that there were significantly increased number of deep straining particles in the liver cells of Sidt2"−"/"− mice, and the TG content in liver tissue was also significantly increased. Detection of key genes and proteins related to fat synthesis showed that mRNA and protein levels of the SREBP1c in the liver of Sidt2"−"/"− mice were significantly elevated, and the downstream genes acetyl-CoA carboxylase, fatty acid synthase, and mitochondrial glycerol 3-phosphate acyltransferase were significantly upregulated. In addition, there was severe endoplasmic reticulum stress (ERS) in the liver of Sidt2"−"/"− mice, which had significantly increased levels of markers specific for unfolded protein response activation, Grp78 and CHOP, as well as significant elevation of downstream p-PERK, p-eIF2a, p-IRE1a, along with ER damage. These results suggest that Sidt2"−"/"− mice had spontaneous nonalcoholic fatty liver

  18. Spontaneous nonalcoholic fatty liver disease and ER stress in Sidt2 deficiency mice

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Jialin [Department of Endocrinology and Genetic Metabolism, Yijishan Hospital of Wannan Medical College, Wuhu, 241002 (China); Anhui Province Key Laboratory of Biological Macro-molecules Research, Wannan Medical College, Wuhu, 241001 (China); Zhang, Yao [Anhui Province Key Laboratory of Biological Macro-molecules Research, Wannan Medical College, Wuhu, 241001 (China); Department of Biochemistry and Molecular Biology, Wannan Medical Collage, Wuhu, 241002 (China); Yu, Cui [Department of Endocrinology and Genetic Metabolism, Yijishan Hospital of Wannan Medical College, Wuhu, 241002 (China); Anhui Province Key Laboratory of Biological Macro-molecules Research, Wannan Medical College, Wuhu, 241001 (China); Tan, Fengbiao [Anhui Province Key Laboratory of Biological Macro-molecules Research, Wannan Medical College, Wuhu, 241001 (China); Department of Biochemistry and Molecular Biology, Wannan Medical Collage, Wuhu, 241002 (China); Wang, Lizhuo, E-mail: 19277924@qq.com [Anhui Province Key Laboratory of Biological Macro-molecules Research, Wannan Medical College, Wuhu, 241001 (China); Department of Biochemistry and Molecular Biology, Wannan Medical Collage, Wuhu, 241002 (China)

    2016-08-05

    Sidt2 is a newly discovered lysosomal membrane protein that is closely related to glucose metabolism. In the present study, we found that Sidt2 is also closely related to lipid metabolism. Gradual increases in serum triglyceride (TG) and free fatty acid, as well as elevated aspartate transaminase and alanine transaminase levels were observed in Sidt2{sup −/−} mice fed a normal diet from the age of 3 months, suggesting the presence of lipid metabolism disorders and impaired liver function in these mice. In the liver slices of 6-month-old Sidt2{sup −/−} mice, there were obvious fat degeneration and inflammatory changes. Almost all of the liver cells demonstrated different levels of lipid droplet accumulation and cell swelling, and some of the cells demonstrated balloon-like changes. Infiltration of inflammatory cells was observed in the portal area and hepatic lobule. Electron microscopy showed that macrophages tended to be attached to the endothelial cells, and a large number of lipid droplets were present in the liver cells. Oil red O staining showed that there were significantly increased number of deep straining particles in the liver cells of Sidt2{sup −/−} mice, and the TG content in liver tissue was also significantly increased. Detection of key genes and proteins related to fat synthesis showed that mRNA and protein levels of the SREBP1c in the liver of Sidt2{sup −/−} mice were significantly elevated, and the downstream genes acetyl-CoA carboxylase, fatty acid synthase, and mitochondrial glycerol 3-phosphate acyltransferase were significantly upregulated. In addition, there was severe endoplasmic reticulum stress (ERS) in the liver of Sidt2{sup −/−} mice, which had significantly increased levels of markers specific for unfolded protein response activation, Grp78 and CHOP, as well as significant elevation of downstream p-PERK, p-eIF2a, p-IRE1a, along with ER damage. These results suggest that Sidt2{sup −/−} mice had spontaneous

  19. Heterozygous disruption of activin receptor-like kinase 1 is associated with increased arterial pressure in mice

    Directory of Open Access Journals (Sweden)

    María González-Núñez

    2015-11-01

    Full Text Available The activin receptor-like kinase 1 (ALK-1 is a type I cell-surface receptor for the transforming growth factor-β (TGF-β family of proteins. Hypertension is related to TGF-β1, because increased TGF-β1 expression is correlated with an elevation in arterial pressure (AP and TGF-β expression is upregulated by the renin-angiotensin-aldosterone system. The purpose of this study was to assess the role of ALK-1 in regulation of AP using Alk1 haploinsufficient mice (Alk1+/−. We observed that systolic and diastolic AP were significantly higher in Alk1+/− than in Alk1+/+ mice, and all functional and structural cardiac parameters (echocardiography and electrocardiography were similar in both groups. Alk1+/− mice showed alterations in the circadian rhythm of AP, with higher AP than Alk1+/+ mice during most of the light period. Higher AP in Alk1+/− mice is not a result of a reduction in the NO-dependent vasodilator response or of overactivation of the peripheral renin-angiotensin system. However, intracerebroventricular administration of losartan had a hypotensive effect in Alk1+/− and not in Alk1+/+ mice. Alk1+/− mice showed a greater hypotensive response to the β-adrenergic antagonist atenolol and higher concentrations of epinephrine and norepinephrine in plasma than Alk1+/+ mice. The number of brain cholinergic neurons in the anterior basal forebrain was reduced in Alk1+/− mice. Thus, we concluded that the ALK-1 receptor is involved in the control of AP, and the high AP of Alk1+/− mice is explained mainly by the sympathetic overactivation shown by these animals, which is probably related to the decreased number of cholinergic neurons.

  20. Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment.

    Science.gov (United States)

    Sun, Yu-Yo; Lee, Jolly; Huang, Henry; Wagner, Mary B; Joiner, Clinton H; Archer, David R; Kuan, Chia-Yi

    2017-12-01

    The effects of lytic stroke therapy in patients with sickle cell anemia are unknown, although a recent study suggested that coexistent sickle cell anemia does not increase the risk of cerebral hemorrhage. This finding calls for systemic analysis of the effects of thrombolytic stroke therapy, first in humanized sickle mice, and then in patients. There is also a need for additional predictive markers of sickle cell anemia-associated vasculopathy. We used Doppler ultrasound to examine the carotid artery of Townes sickle mice tested their responses to repetitive mild hypoxia-ischemia- and transient hypoxia-ischemia-induced stroke at 3 or 6 months of age, respectively. We also examined the effects of tPA (tissue-type plasminogen activator) treatment in transient hypoxia-ischemia-injured sickle mice. Three-month-old sickle cell (SS) mice showed elevated resistive index in the carotid artery and higher sensitivity to repetitive mild hypoxia-ischemia-induced cerebral infarct. Six-month-old SS mice showed greater resistive index and increased flow velocity without obstructive vasculopathy in the carotid artery. Instead, the cerebral vascular wall in SS mice showed ectopic expression of PAI-1 (plasminogen activator inhibitor-1) and P-selectin, suggesting a proadhesive and prothrombotic propensity. Indeed, SS mice showed enhanced leukocyte and platelet adherence to the cerebral vascular wall, broader fibrin deposition, and higher mortality after transient hypoxia-ischemia. Yet, post-transient hypoxia-ischemia treatment with tPA reduced thrombosis and mortality in SS mice. Sickle mice are sensitive to hypoxia/ischemia-induced cerebral infarct but benefit from thrombolytic treatment. An increased resistive index in carotid arteries may be an early marker of sickle cell vasculopathy. © 2017 American Heart Association, Inc.

  1. Prenatal androgenization of female mice programs an increase in firing activity of gonadotropin-releasing hormone (GnRH) neurons that is reversed by metformin treatment in adulthood.

    Science.gov (United States)

    Roland, Alison V; Moenter, Suzanne M

    2011-02-01

    Prenatal androgenization (PNA) of female mice with dihydrotestosterone programs reproductive dysfunction in adulthood, characterized by elevated luteinizing hormone levels, irregular estrous cycles, and central abnormalities. Here, we evaluated activity of GnRH neurons from PNA mice and the effects of in vivo treatment with metformin, an activator of AMP-activated protein kinase (AMPK) that is commonly used to treat the fertility disorder polycystic ovary syndrome. Estrous cycles were monitored in PNA and control mice before and after metformin administration. Before metformin, cycles were longer in PNA mice and percent time in estrus lower; metformin normalized cycles in PNA mice. Extracellular recordings were used to monitor GnRH neuron firing activity in brain slices from diestrous mice. Firing rate was higher and quiescence lower in GnRH neurons from PNA mice, demonstrating increased GnRH neuron activity. Metformin treatment of PNA mice restored firing activity and LH to control levels. To assess whether AMPK activation contributed to the metformin-induced reduction in GnRH neuron activity, the AMPK antagonist compound C was acutely applied to cells. Compound C stimulated cells from metformin-treated, but not untreated, mice, suggesting that AMPK was activated in GnRH neurons, or afferent neurons, in the former group. GnRH neurons from metformin-treated mice also showed a reduced inhibitory response to low glucose. These studies indicate that PNA causes enhanced firing activity of GnRH neurons and elevated LH that are reversible by metformin, raising the possibility that central AMPK activation by metformin may play a role in its restoration of reproductive cycles in polycystic ovary syndrome.

  2. Hydrolyzed whey protein prevents the development of food allergy to β-lactoglobulin in sensitized mice.

    Science.gov (United States)

    Gomes-Santos, Ana Cristina; Fonseca, Roberta Cristelli; Lemos, Luisa; Reis, Daniela Silva; Moreira, Thaís Garcias; Souza, Adna Luciana; Silva, Mauro Ramalho; Silvestre, Marialice Pinto Coelho; Cara, Denise Carmona; Faria, Ana Maria Caetano

    2015-01-01

    Food allergy is an adverse immune response to dietary proteins. Hydrolysates are frequently used for children with milk allergy. However, hydrolysates effects afterwards are poorly studied. The aim of this study was to investigate the immunological consequences of hydrolyzed whey protein in allergic mice. For that, we developed a novel model of food allergy in BALB/c mice sensitized with alum-adsorbed β-lactoglobulin. These mice were orally challenged with either whey protein or whey hydrolysate. Whey-challenged mice had elevated levels of specific IgE and lost weight. They also presented gut inflammation, enhanced levels of SIgA and IL-5 as well as decreased production of IL-4 and IL-10 in the intestinal mucosa. Conversely, mice challenged with hydrolyzate maintained normal levels of IgE, IL-4 and IL-5 and showed no sign of gut inflammation probably due to increased IL-12 production in the gut. Thus, consumption of hydrolysate prevented the development of clinical signs of food allergy in mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Protective effect of metformin on D-galactose-induced aging model in mice.

    Science.gov (United States)

    Fatemi, Iman; Khaluoi, Amin; Kaeidi, Ayat; Shamsizadeh, Ali; Heydari, Sara; Allahtavakoli, Mohammad Aa

    2018-01-01

    Metformin (Met), an antidiabetic biguanide, reduces hyperglycemia via improving glucose utilization and reducing the gluconeogenesis. Met has been shown to exert neuroprotective, antioxidant and anti-inflammatory properties. The present study investigated the possible effect of Met on the D-galactose (D-gal)-induced aging in mice. Met (1 and 10 mg/kg/p.o.), was administrated daily in D-gal-received (500 mg/kg/p.o.) mice model of aging for six weeks. Anxiety-like behavior, cognitive function, and physical power were evaluated by the elevated plus-maze, novel object recognition task (NORT), and forced swimming capacity test, respectively. The brains were analyzed for the level of superoxide dismutase (SOD) and brain-derived neurotrophic factor (BDNF). Met decreased the anxiety-like behavior in D-gal-treated mice. Also, Met treated mice showed significantly improved learning and memory ability in NORT compared to the D-gal-treated mice. Furthermore, Met increased the physical power as well as the activity of SOD and BDNF level in D-gal-treated mice. Our results suggest that the use of Met can be an effective strategy for prevention and treatment of D-gal-induced aging in animal models. This effect seems to be mediated by attenuation of oxidative stress and enhancement of the neurotrophic factors.

  4. Mice lacking prostaglandin E receptor subtype 4 manifest disrupted lipid metabolism attributable to impaired triglyceride clearance.

    Science.gov (United States)

    Cai, Yin; Ying, Fan; Song, Erfei; Wang, Yu; Xu, Aimin; Vanhoutte, Paul M; Tang, Eva Hoi-Ching

    2015-12-01

    Upon high-fat feeding, prostaglandin E receptor subtype 4 (EP4)-knockout mice gain less body weight than their EP4(+/+) littermates. We investigated the cause of the lean phenotype. The mice showed a 68.8% reduction in weight gain with diminished fat mass that was not attributable to reduced food intake, fat malabsorption, or increased energy expenditure. Plasma triglycerides in the mice were elevated by 244.9%. The increase in plasma triglycerides was independent of changes in hepatic very low density lipoprotein (VLDL)-triglyceride production or intestinal chylomicron-triglyceride synthesis. However, VLDL-triglyceride clearance was drastically impaired in the EP4-knockout mice. The absence of EP4 in mice compromised the activation of lipoprotein lipase (LPL), the key enzyme responsible for trafficking of plasma triglycerides into peripheral tissues. Deficiency in EP4 reduced hepatic mRNA expression of the transcriptional factor cAMP response element binding protein H (by 36.8%) and LPL activators, including apolipoprotein (Apo)a5 (by 40.2%) and Apoc2 (by 61.3%). In summary, the lean phenotype of EP4-deficient mice resulted from reduction in adipose tissue and accretion of other peripheral organs caused by impaired triglyceride clearance. The findings identify a new metabolic dimension in the physiologic role played by endogenous EP4. © FASEB.

  5. Peripherally Administered Y2-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice.

    Science.gov (United States)

    Ailanen, Liisa; Vähätalo, Laura H; Salomäki-Myftari, Henriikka; Mäkelä, Satu; Orpana, Wendy; Ruohonen, Suvi T; Savontaus, Eriika

    2018-01-01

    Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y 2 -receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y 2 -receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y 2 -receptor antagonist were studied in healthy and energy-rich conditions with or without excess NPY. Genetically obese mice overexpressing NPY in brain noradrenergic nerves and SNS (OE-NPY DβH ) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y 2 -receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPY DβH and WT mice feeding on chow or Western diet. Treatment with Y 2 -receptor antagonist increased body weight gain in both genotypes on chow diet and caused metabolic disturbances (e.g., hyperinsulinemia and hypercholesterolemia), especially in WT mice. During energy surplus (i.e., on Western diet), blocking of Y 2 -receptors induced obesity in WT mice, whereas OE-NPY DβH mice showed reduced fat mass gain, hepatic glycogen and serum cholesterol levels relative to body adiposity. Thus, it can be concluded that with normal NPY levels, peripheral Y 2 -receptor antagonist has no potential for treating obesity, but oppositely may even induce metabolic disorders. However, when energy-rich diet is combined with elevated NPY levels, e.g., stress combined with an unhealthy diet, Y 2 -receptor antagonism has beneficial effects on metabolic status.

  6. Surfactant protein D is proatherogenic in mice

    DEFF Research Database (Denmark)

    Sorensen, Grith L; Madsen, Jens; Kejling, Karin

    2006-01-01

    Surfactant protein D (SP-D) is an important innate immune defense molecule that mediates clearance of pathogens and modulates the inflammatory response. Moreover, SP-D is involved in lipid homeostasis, and pulmonary accumulation of phospholipids has previously been observed in SP-D-deficient (Spd......-/-) mice. Atherogenesis involves both inflammation and lipid deposition, and we investigated the role of SP-D in the development of atherosclerosis. SP-D synthesis was localized to vascular endothelial cells. Atherosclerotic lesion areas were 5.6-fold smaller in the aortic roots in Spd-/- mice compared...... with wild-type C57BL/6N mice on an atherogenic diet. HDL cholesterol (HDL-C) was significantly elevated in Spd-/- mice. Treatment of Spd-/- mice with a recombinant fragment of human SP-D resulted in decreases of HDL-C (21%) as well as total cholesterol (26%), and LDL cholesterol (28%). Plasma TNF...

  7. Prostaglandin D2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia

    Science.gov (United States)

    Garza, Luis A.; Liu, Yaping; Yang, Zaixin; Alagesan, Brinda; Lawson, John A.; Norberg, Scott M.; Loy, Dorothy E.; Zhao, Tailun; Blatt, Hanz B.; Stanton, David C.; Carrasco, Lee; Ahluwalia, Gurpreet; Fischer, Susan M.; FitzGerald, Garret A.; Cotsarelis, George

    2012-01-01

    Testosterone is necessary for the development of male pattern baldness, known as androgenetic alopecia (AGA); yet, the mechanisms for decreased hair growth in this disorder are unclear. We show that prostaglandin D2 synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA. The product of PTGDS enzyme activity, prostaglandin D2 (PGD2), is similarly elevated in bald scalp. During normal follicle cycling in mice, Ptgds and PGD2 levels increase immediately preceding the regression phase, suggesting an inhibitory effect on hair growth. We show that PGD2 inhibits hair growth in explanted human hair follicles and when applied topically to mice. Hair growth inhibition requires the PGD2 receptor G protein (heterotrimeric guanine nucleotide)–coupled receptor 44 (GPR44), but not the PGD2 receptor 1 (PTGDR). Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD2 in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD2 as an inhibitor of hair growth in AGA and suggest the PGD2-GPR44 pathway as a potential target for treatment. PMID:22440736

  8. A spider elevator

    Energy Technology Data Exchange (ETDEWEB)

    Butylkin, A.V.; Butylkin, V.A.; Izosimov, A.M.

    1983-01-01

    A spider elevator is proposed which contains a body, a wedge clamp with wedges hinged to each other, a subassembly for holding the wedge clamp in the open and closed positions and a mechanism for changing the wedge clamp, which is made in the form of levers with ears for cleats and installed in the body with the capability of turning. To increase reliability in the operational mode through using the external force for clamping the pipe, the free ends of the levers are hinged with the body by a power cylinder.

  9. Elevator Control Strategies

    OpenAIRE

    Ceder, Frederick; Nordin, Alexandra

    2013-01-01

    The purpose of this essay is to investigate if it is eective to switch strategies for elevators during one day in an oce building. This essay describes some of the strategies in use today, followed by a comparison and analysis of two of the strategies described. We have also implemented optimizations to one of these strategies. From our test results we can conclude that our optimized strategy worked and produced better results on average waiting time and total traveling time than the two stra...

  10. Prohibitin-induced obesity leads to anovulation and polycystic ovary in mice

    Directory of Open Access Journals (Sweden)

    Sudharsana Rao Ande

    2017-06-01

    Full Text Available Polycystic ovary syndrome (PCOS is a prevalent endocrine disorder and the most common cause of female infertility. However, its etiology and underlying mechanisms remain unclear. Here we report that a transgenic obese mouse (Mito-Ob developed by overexpressing prohibitin in adipocytes develops polycystic ovaries. Initially, the female Mito-Ob mice were equally fertile to their wild-type littermates. The Mito-Ob mice began to gain weight after puberty, became significantly obese between 3-6 months of age, and ∼25% of them had become infertile by 9 months of age. Despite obesity, female Mito-Ob mice maintained glucose homeostasis and insulin sensitivity similar to their wild-type littermates. Mito-Ob mice showed morphologically distinct polycystic ovaries and elevated estradiol, but normal testosterone and insulin levels. Histological analysis of the ovaries showed signs of impaired follicular dynamics, such as preantral follicular arrest and reduced number, or absence, of corpus luteum. The ovaries of the infertile Mito-Ob mice were closely surrounded by periovarian adipose tissue, suggesting a potential role in anovulation. Collectively, these data suggest that elevated estradiol and obesity per se might lead to anovulation and polycystic ovaries independent of hyperinsulinemia and hyperandrogenism. As obesity often coexists with other abnormalities known to be involved in the development of PCOS such as insulin resistance, compensatory hyperinsulinemia and hyperandrogenism, the precise role of these factors in PCOS remains unclear. Mito-Ob mice provide an opportunity to study the effects of obesity on anovulation and ovarian cyst formation independent of the major drivers of obesity-linked PCOS.

  11. Expression of oxidative phosphorylation components in mitochondria of long-living Ames dwarf mice.

    Science.gov (United States)

    Brown-Borg, Holly M; Johnson, W Thomas; Rakoczy, Sharlene G

    2012-02-01

    Reduced signaling of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) pathway is associated with extended life span in several species. Ames dwarf mice are GH-deficient and live >50% longer than wild-type littermates. Previously, we have shown that tissues from Ames mice exhibit elevated levels of antioxidative enzymes, less H(2)O(2) production, and lower oxidative damage suggesting that mitochondrial function may differ between genotypes. To explore the relationship between hormone deficiency and mitochondria in mice with extended longevity, we evaluated activity, protein, and gene expression of oxidative phosphorylation components in dwarf and wild-type mice at varying ages. Liver complex I + III activity was higher in dwarf mice compared to wild-type mice. The activity of I + III decreased between 3 and 20 months of age in both genotypes with greater declines in wild-type mice in liver and skeletal muscle. Complex IV activities in the kidney were elevated in 3- and 20-month-old dwarf mice relative to wild-type mice. In Ames mice, protein levels of the 39 kDa complex I subunit were elevated at 20 months of age when compared to wild-type mouse mitochondria for every tissue examined. Kidney and liver mitochondria from 20-month-old dwarf mice had elevated levels of both mitochondrially-encoded and nuclear-encoded complex IV proteins compared to wild-type mice (p dwarf mice. Overall, we found that several components of the oxidative phosphorylation (OXPHOS) system were elevated in Ames mice. Mitochondrial to nuclear DNA ratios were not different between genotypes despite the marked increase in PGC-1α levels in dwarf mice. The increased OXPHOS activities, along with lower ROS production in dwarf mice, predict enhanced mitochondrial function and efficiency, two factors likely contributing to long-life in Ames mice.

  12. Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice.

    Science.gov (United States)

    Iñiguez, Sergio D; Riggs, Lace M; Nieto, Steven J; Dayrit, Genesis; Zamora, Norma N; Shawhan, Kristi L; Cruz, Bryan; Warren, Brandon L

    2014-05-01

    Abstract Exposure to stress is highly correlated with the emergence of mood-related illnesses. Because major depressive disorder often emerges in adolescence, we assessed the effects of social defeat stress on responses to depressive-like behaviors in juvenile mice. To do this, postnatal day (PD) 35 male c57BL/6 mice were exposed to 10 days of social defeat stress (PD35-44), while control mice were handled daily. Twenty-four hours after the last episode of defeat (PD45), separate groups of mice were tested in the social interaction, forced swimming, sucrose preference, and elevated plus-maze behavioral assays (n = 7-12 per group). Also, we examined body weight gain across days of social defeat and levels of blood serum corticosterone 40 min after the last episode of defeat stress. Our data indicates that defeated mice exhibited a depressive-like phenotype as inferred from increased social avoidance, increased immobility in the forced swim test, and reduced sucrose preference (a measure of anhedonia), when compared to non-defeated controls. Defeated mice also displayed an anxiogenic-like phenotype when tested on the elevated plus-maze. Lastly, stressed mice displayed lower body weight gain, along with increased blood serum corticosterone levels, when compared to non-stressed controls. Overall, we show that in adolescent male c57BL/6 mice, social defeat stress induces a depression- and anxiety-like phenotype 24 h after the last episode of stress. These data suggest that the social defeat paradigm may be used to examine the etiology of stress-induced mood-related disorders during adolescence.

  13. Automatic pipe elevator

    Energy Technology Data Exchange (ETDEWEB)

    Haney, K.M.; Willis, C.A.

    1987-03-17

    This patent describes an elevator adapted for use with a power swivel for supporting a drilling or production tubular, the elevator comprising: at least two jaws, each jaw having a clamping surface; a connector member for supporting the jaws, the connector member comprising an upper end, a lower end, means for coupling the upper end to the power swivel, means for coupling the lower end to a tubular. The member also comprises means for defining a passageway extending from the upper end to the lower end through the connector member to allow drilling mud to be passed from the power swivel through the bore, into the tubular; and linkage means mounted between the connector member and the jaws for coupling the jaws to the connector member and for maintaining the clamping surfaces of the jaws in clamping engagement with the tubular when the connector member and the tubular are urged apart relative to one another. The linkage means is configured such that the force by which the clamping surfaces clamp the tubular increases as the force urging the connector member and the tubular apart increases.

  14. Effect of Bidens pilosa extract on renal functions and some tumor markers of Ehrlich Ascites Carcinoma bearing mice exposed to γ-radiation

    International Nuclear Information System (INIS)

    El-Kabany, H.; Ibrahim, S.I.

    2013-01-01

    The Ethanolic extract of Bidens pilosa (EtBP) was tested in Swiss albino mice transplanted with Ehrlich ascites carcinoma (EAC) and exposed to γ-radiation. EAC mice received intraperitoneal (i.p) 250 mg/kg body weight EtBP for nine days , 24hr after tumor inoculation. Mice exposed to 4 Gy γ-radiation 30 min after the first dose of EtBP. Seventy female mice were classified into 6 groups (15 mice in each group) as follows, control, mice treated with EtBP for 9 consecutive days, mice bearing EAC cells, EAC bearing mice treated with EtBP, 24 hour after tumor inoculation, EAC bearing mice and irradiated, and EAC bearing mice treated with EtBP and exposed to γ-radiation. Five animals from each group were sacrificed 18 hr after administration of the last EtBP dose. Blood and ascetic fluid were collected and kidneys were removed for biochemical and histopathological studies. The remaining animals were observed daily for recording survival percentage and body weight. Results showed that treatment of EAC bearing mice with EtBP and/or exposure to γ- radiation increased the survival percentage of the animals and decreased their body weight compared to EAC group. Inoculation of mice with EAC cells resulted in biochemical and histopathological changes leading to kidney damage. Animals of EAC bearing mice with EtBP and /or exposure to γ- radiation significantly restored the elevated levels of serum urea and creatinine, tumor necrosis factor-alpha (TNF-α), metalo matrix protein (mmp-2 and mmp9), also the elevated level of lipid peroxidation (MDA) in kidneys tissue, compared to EAC group. On the other hand, a significantly decline was observed in glutathione (GSH) and super oxide dismutase (SOD) contents in kidney tissue of EAC group. Treatment of EAC bearing mice with EtBP and/or exposure to γ-radiation resulted in increase GSH and SOD in kidney tissue and increased caspase-3 in ascetic fluid, comparing to EAC group. It could be concluded that EtBP through its antioxidant

  15. Endogenous IL-1 in cognitive function and anxiety: a study in IL-1RI-/- mice.

    Directory of Open Access Journals (Sweden)

    Carol L Murray

    Full Text Available Interleukin-1 (IL-1 is a key pro-inflammatory cytokine, produced predominantly by peripheral immune cells but also by glia and some neuronal populations within the brain. Its signalling is mediated via the binding of IL-1α or IL-1β to the interleukin-1 type one receptor (IL-1RI. IL-1 plays a key role in inflammation-induced sickness behaviour, resulting in depressed locomotor activity, decreased exploration, reduced food and water intake and acute cognitive deficits. Conversely, IL-1 has also been suggested to facilitate hippocampal-dependent learning and memory: IL-1RI(-/- mice have been reported to show deficits on tasks of visuospatial learning and memory. We sought to investigate whether there is a generalised hippocampal deficit in IL-1RI(-/- animals. Therefore, in the current study we compared wildtype (WT mice to IL-1RI(-/- mice using a variety of hippocampal-dependent learning and memory tasks, as well as tests of anxiety and locomotor activity. We found no difference in performance of the IL-1RI(-/- mice compared to WT mice in a T-maze working memory task. In addition, the IL-1RI(-/- mice showed normal learning in various spatial reference memory tasks including the Y-maze and Morris mater maze, although there was a subtle deficit in choice behaviour in a spatial discrimination, beacon watermaze task. IL-1RI(-/- mice also showed normal memory for visuospatial context in the contextual fear conditioning paradigm. In the open field, IL-1RI(-/- mice showed a significant increase in distance travelled and rearing behaviour compared to the WT mice and in the elevated plus-maze spent more time in the open arms than did the WT animals. The data suggest that, contrary to prior studies, IL-1RI(-/- mice are not robustly impaired on hippocampal-dependent memory and learning but do display open field hyperactivity and decreased anxiety compared to WT mice. The results argue for a careful evaluation of the roles of endogenous IL-1 in hippocampal

  16. Myocarditis with ST elevation and elevated cardiac enzymes misdiagnosed as an ST-elevation myocardial infarction.

    Science.gov (United States)

    Sheldon, Seth H; Crandall, Mark A; Jaffe, Allan S

    2012-12-01

    Acute myocarditis can mimic ST-elevation myocardial infarction (STEMI). Quickly determining the correct diagnosis is critical given the "time is muscle" implication with a STEMI and the potential adverse effects associated with use of fibrinolytic therapy. A 46-year-old man presented to a rural emergency department with chest pain, and an electrocardiogram (ECG) read as showing 0.1 mV of ST-segment elevation in leads III and aVF. His initial cardiac troponin T was 0.44 ng/mL. He received fibrinolytic therapy for presumed STEMI. Cardiac magnetic resonance imaging was later performed and showed epicardial delayed enhancement consistent with myocarditis. Upon further questioning, he acknowledged 3 days of stuttering chest discomfort and a recent upper respiratory infection, as well as similar chest pain in his wife. A systematic evaluation is essential for acute chest pain, including a focused history, identification of cardiac risk factors, and ECG interpretation. A history of recent viral illness, absence of cardiac risk factors, or ECG findings inconsistent with a single anatomic lesion would suggest a potential alternate diagnosis to STEMI. This case emphasizes the importance of a focused history in the initial evaluation of chest pain. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. An unusual ST-segment elevation: apical hypertrophic cardiomyopathy shows the ace up its sleeve.

    Science.gov (United States)

    de Santis, Francesco; Pergolini, Amedeo; Zampi, Giordano; Pero, Gaetano; Pino, Paolo Giuseppe; Minardi, Giovanni

    2013-01-01

    Apical hypertrophic cardiomyopathy is part of the broad clinical and morphologic spectrum of hypertrophic cardiomyopathy. We report a patient with electrocardiographic abnormalities in whom acute coronary syndrome was excluded and apical hypertrophic cardiomyopathy was demonstrated by careful differential diagnosis. Copyright © 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  18. Operation experience with elevated ammonia

    International Nuclear Information System (INIS)

    Vankova, Katerina; Kysela, Jan; Malac, Miroslav; Petrecky, Igor; Svarc, Vladimir

    2011-01-01

    The 10 VVER units in the Czech and Slovak Republics are all in very good water chemistry and radiation condition, yet questions have arisen regarding the optimization of cycle chemistry and improved operation in these units. To address these issues, a comprehensive experimental program for different water chemistries of the primary circuit was carried out at the Rez Nuclear Research Institute, Czech Republic, with the goal of judging the influence of various water chemistries on radiation build-up. Four types of water chemistries were compared: standard VVER water chemistry (in common use), direct hydrogen dosing without ammonia, standard VVER water chemistry with elevated ammonia levels, and zinc dosing to standard VVER water chemistry. The test results showed that the types of water chemistry other than the common one have benefits for the operation of the nuclear power plant (NPP) primary circuit. Operation experience with elevated ammonia at NPP Dukovany Units 3 and 4 is presented which validates the experimental results, demonstrating improved corrosion product volume activity. (orig.)

  19. Effect of cold water-induced stress on immune response, pathology and fertility in mice during Chlamydia muridarum genital infection.

    Science.gov (United States)

    Belay, Tesfaye; Woart, Anthony; Graffeo, Vincent

    2017-07-31

    Genital infection by Chlamydia trachomatis is the most common bacterial sexually transmitted disease worldwide. It causes serious reproductive health complications, including pelvic inflammatory disease and infertility. Stress is implicated as a risk factor for various infections; however, its effect on chlamydia genital infection is unknown. We previously showed that repeated exposure of mice to cold water results in increased severity of chlamydia genital infection. In this study, cold water-induced stress resulted in (i) elevated levels of norepinephrine (NE) and epinephrine in the spleen and genital tract of stressed mice; (ii) elevated IL-1β, TNF-α, IL-6 and nitric oxide production in macrophage-rich peritoneal cells of mice; (iii) supplement of NE in vitro exerts an immunosuppressive effect on splenic T-cell production of cytokines; (iv) decreased C. muridarum shedding in the genital tract of β1Adr/β2Adr receptor KO mice; and (v) a higher rate of infertility in infected mice. These results suggest that cold water stress induces the production of catecholamines, which may play a critical role in the modulation of the immune system leading to increased intensity of C. muridarum genital infection. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Hyperactivity and learning deficits in transgenic mice bearing a human mutant thyroid hormone beta1 receptor gene.

    Science.gov (United States)

    McDonald, M P; Wong, R; Goldstein, G; Weintraub, B; Cheng, S Y; Crawley, J N

    1998-01-01

    Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor beta (TRbeta) gene on chromosome 3, representing a mutation of the ligand-binding domain of the TRbeta gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity, transgenic mice expressing a mutant TRbeta gene were generated. The present experiment tested RTH transgenic mice from the PV kindred on behavioral tasks relevant to the primary features of ADHD: hyperactivity, sustained attention (vigilance), learning, and impulsivity. Male transgenic mice showed elevated locomotor activity in an open field compared to male wild-type littermate controls. Both male and female transgenic mice exhibited impaired learning of an autoshaping task, compared to wild-type controls. On a vigilance task in an operant chamber, there were no differences between transgenics and controls on the proportion of hits, response latency, or duration of stimulus tolerated. On an operant go/no-go task measuring sustained attention and impulsivity, there were no differences between controls and transgenics. These results indicate that transgenic mice bearing a mutant human TRbeta gene demonstrate several behavioral characteristics of ADHD and may serve a valuable heuristic role in elucidating possible candidate genes in converging pathways for other causes of ADHD.

  1. Hyperactivity and Learning Deficits in Transgenic Mice Bearing a Human Mutant Thyroid Hormone β1 Receptor Gene

    Science.gov (United States)

    McDonald, Michael P.; Wong, Rosemary; Goldstein, Gregory; Weintraub, Bruce; Cheng, Sheue-yann; Crawley, Jacqueline N.

    1998-01-01

    Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor β (TRβ) gene on chromosome 3, representing a mutation of the ligandbinding domain of the TRβ gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity, transgenic mice expressing a mutant TRβ gene were generated. The present experiment tested RTH transgenic mice from the PV kindred on behavioral tasks relevant to the primary features of ADHD: hyperactivity, sustained attention (vigilance), learning, and impulsivity. Male transgenic mice showed elevated locomotor activity in an open field compared to male wild-type littermate controls. Both male and female transgenic mice exhibited impaired learning of an autoshaping task, compared to wild-type controls. On a vigilance task in an operant chamber, there were no differences between transgenics and controls on the proportion of hits, response latency, or duration of stimulus tolerated. On an operant go/no-go task measuring sustained attention and impulsivity, there were no differences between controls and transgenics. These results indicate that transgenic mice bearing a mutant human TRβ gene demonstrate several behavioral characteristics of ADHD and may serve a valuable heuristic role in elucidating possible candidate genes in converging pathways for other causes of ADHD. PMID:10454355

  2. Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice

    Directory of Open Access Journals (Sweden)

    Andras Franko

    2017-03-01

    Full Text Available Objective: Recently, we have shown that Bezafibrate (BEZ, the pan-PPAR (peroxisome proliferator-activated receptor activator, ameliorated diabetes in insulin deficient streptozotocin treated diabetic mice. In order to study whether BEZ can also improve glucose metabolism in a mouse model for fatty liver and type 2 diabetes, the drug was applied to TallyHo mice. Methods: TallyHo mice were divided into an early (ED and late (LD diabetes progression group and both groups were treated with 0.5% BEZ (BEZ group or standard diet (SD group for 8 weeks. We analyzed plasma parameters, pancreatic beta-cell morphology, and mass as well as glucose metabolism of the BEZ-treated and control mice. Furthermore, liver fat content and composition as well as hepatic gluconeogenesis and mitochondrial mass were determined. Results: Plasma lipid and glucose levels were markedly reduced upon BEZ treatment, which was accompanied by elevated insulin sensitivity index as well as glucose tolerance, respectively. BEZ increased islet area in the pancreas. Furthermore, BEZ treatment improved energy expenditure and metabolic flexibility. In the liver, BEZ ameliorated steatosis, modified lipid composition and increased mitochondrial mass, which was accompanied by reduced hepatic gluconeogenesis. Conclusions: Our data showed that BEZ ameliorates diabetes probably via reduced steatosis, enhanced hepatic mitochondrial mass, improved metabolic flexibility and elevated hepatic insulin sensitivity in TallyHo mice, suggesting that BEZ treatment could be beneficial for patients with NAFLD and impaired glucose metabolism. Keywords: Bezafibrate, Glucose metabolism, Insulin resistance, Lipid metabolism, NAFLD

  3. Sortilin 1 Loss-of-Function Protects Against Cholestatic Liver Injury by Attenuating Hepatic Bile Acid Accumulation in Bile Duct Ligated Mice.

    Science.gov (United States)

    Li, Jibiao; Woolbright, Benjamin L; Zhao, Wen; Wang, Yifeng; Matye, David; Hagenbuch, Bruno; Jaeschke, Hartmut; Li, Tiangang

    2018-01-01

    Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid (BA) metabolism. This study further investigated the role of Sort1 in modulating BA detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 knockout (KO) mice had attenuated liver injury 24 h after bile duct ligation (BDL), which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger BA pool size than sham-operated wildtype (WT) mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic BA accumulation and smaller BA pool size. After 14 days BDL, Sort1 KO mice showed significantly lower hepatic BA concentration and reduced expression of inflammatory and fibrotic marker genes, but similar degree of liver fibrosis compared with WT mice. Unbiased quantitative proteomics revealed that Sort1 KO mice had increased hepatic BA sulfotransferase 2A1, but unaltered phase-I BA metabolizing cytochrome P450s or phase-III BA efflux transporters. Consistently, Sort1 KO mice showed elevated plasma sulfated taurocholate after BDL. Finally, we found that liver Sort1 was repressed after BDL, which may be due to BA activation of farnesoid x receptor. In conclusion, we report a role of Sort1 in the regulation of hepatic BA detoxification and cholestatic liver injury in mice. The mechanisms underlying increased hepatic BA elimination in Sort1 KO mice after BDL require further investigation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. Emotion and cognition in high and low stress sensitive mouse strains: a combined neuroendocrine and behavioral study in BALB/c and C57BL/6J mice

    Directory of Open Access Journals (Sweden)

    Vera Brinks

    2007-12-01

    Full Text Available Emotionally arousing experiences and stress influence cognitive processes and vice versa. Understanding the relations and interactions between these three systems forms the core of this study. We tested two inbred mouse strains (BALB/c, C57BL/6J; male; 3-month-old for glucocorticoid stress system markers (expression of MR and GR mRNA and protein in hippocampus, amygdala, and prefrontal cortex; blood plasma corticosterone, used behavioral tasks for emotions and cognitive performance (elevated plus maze, holeboard to assess the interdependence of these factors. We hypothesize that BALB/c mice have a stress-vulnerable neuroendocrine phenotype and that emotional expressions in BALB/c and C57BL/6J mice will differentially contribute to learning and memory. We applied factor analyses on emotional and cognitive parameters to determine the behavioral structure of BALB/c and C57BL/6J mice. Glucocorticoid stress system markers indeed show that BALB/c mice are more stress-vulnerable than C57BL/6J mice. Moreover, emotional and explorative factors differed between naïve BALB/c and C57BL/6J mice. BALB/c mice display high movement in anxiogenic zones and high risk assessment, while C57BL/6J mice show little movement in anxiogenic zones and display high vertical exploration. Furthermore, BALB/c mice are superior learners, showing learning related behavior which is highly structured and emotionally biased when exposed to a novel or changing situation. In contrast, C57BL/6J mice display a rather ‘‘chaotic’’ behavioral structure during learning in absence of an emotional factor. These results show that stress vulnerability coincides with more emotionality, which drives well orchestrated goal directed behavior to the benefit of cognition. Both phenotypes have their advantage depending on environmental demands.

  5. An elevator wheel

    Energy Technology Data Exchange (ETDEWEB)

    Zhornik, V.I.; Cherkov, Ye.M.; Simonov, A.A.

    1982-01-01

    This invention deals with mineral enrichment and is primarily for unloading submerged products of enrichment during separation in heavy mediums. An elevator wheel is proposed for unloading the submerged product from the bath of a heavy to medium separator which includes ladle disks with internal walls and overlapping sheets hinged to the ends. In order to increase the degree of dehydration of the unloaded product, the internal wall of each ladle is made of sheets installed in stages with clearances relative to each other. The advantages of the proposed device include an improvement in the degree of dehydration of the submerged product in the ladles and a reduction in the carry away of the heavy medium with the enrichment products.

  6. Anxiety- and depression-like phenotype of hph-1 mice deficient in tetrahydrobiopterin

    DEFF Research Database (Denmark)

    Nasser, Arafat; Birk Møller, Lisbeth; Olesen, Jess Have

    2014-01-01

    as determine hippocampal monoamine and plasma nitric oxide levels. In the elevated zero maze test, hph mice displayed increased anxiety-like responses compared to wild-type mice, while the marble burying test revealed decreased anxiety-like behaviour. This was particularly observed in male mice. In the tail...

  7. Morphogenetic roles of perlecan in the tooth enamel organ: an analysis of overexpression using transgenic mice.

    Science.gov (United States)

    Ida-Yonemochi, Hiroko; Satokata, Ichiro; Ohshima, Hayato; Sato, Toshiya; Yokoyama, Minesuke; Yamada, Yoshihiko; Saku, Takashi

    2011-09-01

    Perlecan, a heparan sulfate proteoglycan, is enriched in the intercellular space of the enamel organ. To understand the role of perlecan in tooth morphogenesis, we used a keratin 5 promoter to generate transgenic (Tg) mice that over-express perlecan in epithelial cells, and examined their tooth germs at tissue and cellular levels. Immunohistochemistry showed that perlecan was more strongly expressed in the enamel organ cells of Tg mice than in wild-type mice. Histopathology showed wider intercellular spaces in the stellate reticulum of the Tg molars and loss of cellular polarity in the enamel organ, especially in its cervical region. Hertwig's epithelial root sheath (HERS) cells in Tg mice were irregularly aligned due to excessive deposits of perlecan along the inner, as well as on the outer sides of the HERS. Tg molars had dull-ended crowns and outward-curved tooth roots and their enamel was poorly crystallized, resulting in pronounced attrition of molar cusp areas. In Tg mice, expression of integrin β1 mRNA was remarkably higher at E18, while expression of bFGF, TGF-β1, DSPP and Shh was more elevated at P1. The overexpression of perlecan in the enamel organ resulted in irregular morphology of teeth, suggesting that the expression of perlecan regulates growth factor signaling in a stage-dependent manner during each step of the interaction between ameloblast-lineage cells and mesenchymal cells. Copyright © 2011 International Society of Matrix Biology. All rights reserved.

  8. Global elevational diversity and diversification of birds.

    Science.gov (United States)

    Quintero, Ignacio; Jetz, Walter

    2018-03-08

    Mountain ranges harbour exceptionally high biodiversity, which is now under threat from rapid environmental change. However, despite decades of effort, the limited availability of data and analytical tools has prevented a robust and truly global characterization of elevational biodiversity gradients and their evolutionary origins. This has hampered a general understanding of the processes involved in the assembly and maintenance of montane communities. Here we show that a worldwide mid-elevation peak in bird richness is driven by wide-ranging species and disappears when we use a subsampling procedure that ensures even species representation in space and facilitates evolutionary interpretation. Instead, richness corrected for range size declines linearly with increasing elevation. We find that the more depauperate assemblages at higher elevations are characterized by higher rates of diversification across all mountain regions, rejecting the idea that lower recent diversification rates are the general cause of less diverse biota. Across all elevations, assemblages on mountains with high rates of past temperature change exhibit more rapid diversification, highlighting the importance of climatic fluctuations in driving the evolutionary dynamics of mountain biodiversity. While different geomorphological and climatic attributes of mountain regions have been pivotal in determining the remarkable richness gradients observed today, our results underscore the role of ongoing and often very recent diversification processes in maintaining the unique and highly adapted biodiversity of higher elevations.

  9. Some factors influencing liver metallothionein levels in rats and mice

    International Nuclear Information System (INIS)

    Jang, T.; Lee, M.

    1981-01-01

    Liver metallothionein (MT) was measured by the 203-mercury binding method of Piotrowski in the livers of rats and mice subjected to bilateral adrenalectomy or to sham adrenalectomy. Sham operation was followed by an increase in the level of MT at 24 hours; this immediately began to decrease, reaching control levels by 7 days. Adrenalectomy was also followed by an increase in MT, but the levels remained elevated for several days before beginning to decline. Mice which were adrenalectomized and allowed to recover for 28 days showed an increase in MT when subjected to sham operation. Ether anaesthesia without an incision did not increase the level of MT. Hypophysectomized mice had higher levels of MT than did controls, and these levels were further increased by sham adrenalectomy. Sprague-Dawley rats showed a similar response to adrenalectomy and to sham operation. It is concluded that the sham operation-induced increase in MT is probably not a result of a stress-induced release of adrenal hormones, but that adrenal hormones may play some role in the degradation or turnover of MT. The pituitary may also have some role in MT turnover

  10. Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis.

    Science.gov (United States)

    Lagishetty, Venu; Misharin, Alexander V; Liu, Nancy Q; Lisse, Thomas S; Chun, Rene F; Ouyang, Yi; McLachlan, Sandra M; Adams, John S; Hewison, Martin

    2010-06-01

    Vitamin D insufficiency is a global health issue. Although classically associated with rickets, low vitamin D levels have also been linked to aberrant immune function and associated health problems such as inflammatory bowel disease (IBD). To test the hypothesis that impaired vitamin D status predisposes to IBD, 8-wk-old C57BL/6 mice were raised from weaning on vitamin D-deficient or vitamin D-sufficient diets and then treated with dextran sodium sulphate (DSS) to induce colitis. Vitamin D-deficient mice showed decreased serum levels of precursor 25-hydroxyvitamin D(3) (2.5 +/- 0.1 vs. 24.4 +/- 1.8 ng/ml) and active 1,25-dihydroxyvitamin D(3) (28.8 +/- 3.1 vs. 45.6 +/- 4.2 pg/ml), greater DSS-induced weight loss (9 vs. 5%), increased colitis (4.71 +/- 0.85 vs. 1.57 +/- 0.18), and splenomegaly relative to mice on vitamin D-sufficient chow. DNA array analysis of colon tissue (n = 4 mice) identified 27 genes consistently (P < 0.05) up-regulated or down-regulated more than 2-fold in vitamin D-deficient vs. vitamin D-sufficient mice, in the absence of DSS-induced colitis. This included angiogenin-4, an antimicrobial protein involved in host containment of enteric bacteria. Immunohistochemistry confirmed that colonic angiogenin-4 protein was significantly decreased in vitamin D-deficient mice even in the absence of colitis. Moreover, the same animals showed elevated levels (50-fold) of bacteria in colonic tissue. These data show for the first time that simple vitamin D deficiency predisposes mice to colitis via dysregulated colonic antimicrobial activity and impaired homeostasis of enteric bacteria. This may be a pivotal mechanism linking vitamin D status with IBD in humans.

  11. M100907 attenuates elevated grooming behavior in the BTBR mouse.

    Science.gov (United States)

    Amodeo, Dionisio A; Rivera, Elaine; Dunn, Jeffrey T; Ragozzino, Michael E

    2016-10-15

    Individuals with autism spectrum disorder (ASD) exhibit social-communication deficits along with restricted interests and repetitive behaviors (RRBs). To date, there is a lack of effective treatments to alleviate RRBs. A recent study found that treatment with the 5HT2A receptor antagonist M100907 attenuates a reversal learning deficit in the BTBR mouse model of autism. The BTBR mouse also exhibits elevated grooming behavior which may model stereotyped motor behaviors also observed in ASD. The present study examined whether 5HT2A receptor blockade with M100907 at either 0.01 or 0.1mg/kg can reduce repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR and C57BL6/J (B6) mice. M100907 at 0.1mg/kg, but not 0.01mg/kg, significantly attenuated repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR mice. M100907 at either dose did not affect grooming behavior in B6 mice. To determine whether 0.1mg/kg M100907 had a more general effect on activity in BTBR mice, a second experiment determined whether M100907 at 0.1mg/kg affected locomotor activity in BTBR mice. M100907 treatment in BTBR and B6 mice did not alter locomotor activity compared to that of vehicle-treated BTBR and B6 mice. The present findings taken together with past results suggest that treatment with a 5HT2A receptor antagonist may be effective in ameliorating RRBs in ASD. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Tissue distribution and effects of fasting and obesity on the ghrelin axis in mice.

    Science.gov (United States)

    Morash, Michael G; Gagnon, Jeffrey; Nelson, Stephanie; Anini, Younes

    2010-08-09

    Ghrelin is a 28 amino acid peptide hormone derived from the 117 amino acid proghrelin, following cleavage by proprotein convertase 1 (PC1). In this study, we comprehensively assessed the tissue distribution and the effect of fasting and obesity on preproghrelin, Exon-4D, PC1 and GOAT expression and proghrelin-derived peptide (PGDP) secretion. The stomach was the major source of preproghrelin expression and PDGPs, followed by the small intestine. The remaining peripheral tissues (including the brain and pancreas) contained negligible expression levels. We detected obestatin in all stomach proghrelin cells, however, 22% of proghrelin cells in the small intestine did not express obestatin. There were strain differences in ghrelin secretion in response to fasting between CD1 and C57BL/6 mice. After a 24 hour-fast, CD1 mice had increased plasma levels of total ghrelin and obestatin with no change in preproghrelin mRNA or PGDP tissues levels. C57BL/6 mice showed a different response to a 24 hour-fast having increased proghrelin mRNA expression, stomach acylated ghrelin peptide and no change in plasma obestatin in C57BL/6 mice. In obese mice (ob/ob and diet-induced obesity (DIO)) there was a significant increase in preproghrelin mRNA levels while tissue and plasma PGDP levels were significantly reduced. Fasting did not affect PGDP in obese mice. Obese models displayed differences in GOAT expression, which was elevated in DIO mice, but reduced in ob/ob mice. We did not find co-localization of the leptin receptor in ghrelin expressing stomach cells, ruling out a direct effect of leptin on stomach ghrelin synthesis and secretion. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  13. Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE-/- mice

    International Nuclear Information System (INIS)

    Srivastava, Sanjay; Vladykovskaya, Elena N.; Haberzettl, Petra; Sithu, Srinivas D.; D'Souza, Stanley E.; States, J. Christopher

    2009-01-01

    Exposure to arsenic-contaminated water has been shown to be associated with cardiovascular disease, especially atherosclerosis. We examined the effect of arsenic exposure on atherosclerotic lesion formation, lesion composition and nature in ApoE-/- mice. Early post-natal exposure (3-week-old mice exposed to 49 ppm arsenic as NaAsO 2 in drinking water for 7 weeks) increased the atherosclerotic lesion formation by 3- to 5-fold in the aortic valve and the aortic arch, without affecting plasma cholesterol. Exposure to arsenic for 13 weeks (3-week-old mice exposed to 1, 4.9 and 49 ppm arsenic as NaAsO 2 in drinking water) increased the lesion formation and macrophage accumulation in a dose-dependent manner. Temporal studies showed that continuous arsenic exposure significantly exacerbated the lesion formation throughout the aortic tree at 16 and 36 weeks of age. Withdrawal of arsenic for 12 weeks after an initial exposure for 21 weeks (to 3-week-old mice) significantly decreased lesion formation as compared with mice continuously exposed to arsenic. Similarly, adult exposure to 49 ppm arsenic for 24 weeks, starting at 12 weeks of age increased lesion formation by 2- to 3.6-fold in the aortic valve, the aortic arch and the abdominal aorta. Lesions of arsenic-exposed mice displayed a 1.8-fold increase in macrophage accumulation whereas smooth muscle cell and T-lymphocyte contents were not changed. Expression of pro-inflammatory chemokine MCP-1 and cytokine IL-6 and markers of oxidative stress, protein-HNE and protein-MDA adducts were markedly increased in lesions of arsenic-exposed mice. Plasma concentrations of MCP-1, IL-6 and MDA were also significantly elevated in arsenic-exposed mice. These data suggest that arsenic exposure increases oxidative stress, inflammation and atherosclerotic lesion formation.

  14. Cytochrome P450-2E1 is involved in aging-related kidney damage in mice through increased nitroxidative stress.

    Science.gov (United States)

    Abdelmegeed, Mohamed A; Choi, Youngshim; Ha, Seung-Kwoon; Song, Byoung-Joon

    2017-11-01

    The aim of this study was to investigate the role of cytochrome P450-2E1 (CYP2E1) in aging-dependent kidney damage since it is poorly understood. Young (7 weeks) and aged female (16-17 months old) wild-type (WT) and Cyp2e1-null mice were used. Kidney histology showed that aged WT mice exhibited typical signs of kidney aging such as cell vacuolation, inflammatory cell infiltration, cellular apoptosis, glomerulonephropathy, and fibrosis, along with significantly elevated levels of renal TNF-α and serum creatinine than all other groups. Furthermore, the highest levels of renal hydrogen peroxide, protein carbonylation and nitration were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of iNOS and mitochondrial nitroxidative stress through altered amounts and activities of the mitochondrial complex proteins and significantly reduced levels of the antioxidant glutathione (GSH). In contrast, the aged Cyp2e1-null mice exhibited significantly higher antioxidant capacity with elevated heme oxygenase-1 and catalase activities compared to all other groups, while maintaining normal GSH levels with significantly less mitochondrial nitroxidative stress compared to the aged WT mice. Thus, CYP2E1 is important in causing aging-related kidney damage most likely through increasing nitroxidative stress and that CYP2E1 could be a potential target in preventing aging-related kidney diseases. Published by Elsevier Ltd.

  15. Splenic CD11clowCD45RBhigh dendritic cells derived from endotoxin-tolerant mice attenuate experimental acute liver failure

    Science.gov (United States)

    Zhang, Sai-Nan; Yang, Nai-Bin; Ni, Shun-Lan; Dong, Jin-Zhong; Shi, Chun-Wei; Li, Shan-Shan; Zhang, Sheng-Guo; Tang, Xin-Yue; Lu, Ming-Qin

    2016-01-01

    Endotoxin tolerance (ET) is suggested to attenuate the severity of acute liver failure (ALF) in mice, possibly through both innate and adaptive immunity. However, the involvement of regulatory dendritic cells (DCregs) in ET has not been fully elucidated. In this study, their effect on ALF in mice was investigated. Splenic DCregs from ET-exposed mice (ET-DCregs) showed lower expression levels of CD40, CD80, and MHC-II markers and stronger inhibition of allogenic T cells and regulation of IL-10 and IL-12 secretion than splenic DCregs from normal mice (nDCregs). Moreover, the mRNA and protein levels of TNF-α and P65 in splenic ET-DCregs were significantly lower than those in the splenic nDCregs. The survival rate was significantly increased and liver injury was mitigated in mice with ALF treated with splenic ET-DCregs. In addition, A20 expression was decreased in the liver of ALF mice, but elevated after infusion of splenic nDCregs and ET-DCregs, and a much higher elevation was observed after infusing the latter cells. The functionality of splenic DCregs was altered after ET exposure, contributing to protection of the livers against D-GalN/LPS-induced ALF. PMID:27625297

  16. Hyperoxia Inhibits T Cell Activation in Mice

    Science.gov (United States)

    Hughes-Fulford, M.; Meissler, J.; Aguayo, E. T.; Globus, R.; Aguado, J.; Candelario, T.

    2013-02-01

    Background: The immune response is blunted in mice and humans in spaceflight. The effects of hyperoxia in mice alter expression of some of the same immune response genes. If these two conditions are additive, there could be an increased risk of infection in long duration missions. Immunosuppression is seen in healthy astronauts who have flown in space; however little is known about the mechanisms that cause the reduced immunity in spaceflight. Here we examine the role of oxidative stress on mice exposed to periods of high O2 levels mimicking pre-breathing protocols and extravehicular activity (EVA). To prevent decompression sickness, astronauts are exposed to elevated oxygen (hyperoxia) before and during EVA activities. Spaceflight missions may entail up to 24 hours of EVA per crewmember per week to perform construction and maintenance tasks. The effectiveness and success of these missions depends on designing EVA systems and protocols that maximize human performance and efficiency while minimizing health and safety risks for crewmembers. To our knowledge, no studies have been conducted on the immune system under 100% oxygen exposures to determine the potential for immune compromise due to prolonged and repeated EVAs. Methods: Animals were exposed to hyperoxic or control conditions for 8 hours per day over a period of 3 days, initiated 4 hours into the dark cycle (12h dark/12h light), using animal environmental control cabinets and oxygen controller (Biospherix, Lacona, NY). Experimental mice were exposed to 98-100% oxygen as a model for pre-breathing and EVA conditions, while control mice were maintained in chambers supplied with compressed air. These are ground control studies where we use real-time RTPCR (qRTPCR) to measure gene expression of the early immune gene expression during bead activation of splenocytes of normoxic and hyperoxic mice. All procedures were reviewed and approved by the IACUC at Ames Research Center. After the last 8h of hyperoxic exposure

  17. Environmental Enrichment Blunts Ethanol Consumption after Restraint Stress in C57BL/6 Mice.

    Directory of Open Access Journals (Sweden)

    Priscila Marianno

    Full Text Available Elevated alcohol intake after abstinence is a key feature of the addiction process. Some studies have shown that environmental enrichment (EE affects ethanol intake and other reinforcing effects. However, different EE protocols may vary in their ability to influence alcohol consumption and stress-induced intake. The present study evaluated whether short (3 h or continuous (24 h EE protocols affect ethanol consumption after periods of withdrawal. Mice were challenged with stressful stimuli (24 h isolation and restraint stress to evaluate the effects of stress on drinking. Male C57BL/6 mice were subjected to a two-bottle choice drinking-in-the-dark paradigm for 15 days (20% ethanol and water, 2 h/day, acquisition phase. Control mice were housed under standard conditions (SC. In the first experiment, one group of mice was housed under EE conditions 24 h/day (EE24h. In the second experiment, the exposure to EE was reduced to 3 h/day (EE3h. After the acquisition phase, the animals were deprived of ethanol for 6 days, followed by 2 h ethanol access once a week. Animals were tested in the elevated plus maze (EPM during ethanol withdrawal. During the last 2 weeks, the mice were exposed to 24 h ethanol access. A 1-h restraint stress test was performed immediately before the last ethanol exposure. EE24h but not EE3h increased anxiety-like behavior during withdrawal compared to controls. Neither EE24h nor EE3h affected ethanol consumption during the 2 h weekly exposure periods. However, EE24h and EE3h mice that were exposed to acute restraint stress consumed less ethanol than controls during a 24 h ethanol access. These results showed that EE reduces alcohol intake after an acute restraint stress.

  18. Postnatal hematopoiesis and gut microbiota in NOD mice deviate from C57BL/6 mice

    DEFF Research Database (Denmark)

    Damlund, Dina Silke Malling; Metzdorff, Stine Broeng; Hasselby, Jane Preuss

    2016-01-01

    , a distinct splenic cell profile high in a granulocytic phenotype was evident in the neonatal NOD mice whereas neonatal C57BL/6 mice showed a profile rich in monocytes. Neonatal expression of Reg3g and Muc2 in the gut was deviating in NOD mice and coincided with fewer bacteria attaching to the Mucosal surface...

  19. Cassava is not a goitrogen in mice

    International Nuclear Information System (INIS)

    Hershman, J.M.; Pekary, A.E.; Sugawara, M.; Adler, M.; Turner, L.; Demetriou, J.A.; Hershman, J.D.

    1985-01-01

    To examine the effect of cassava on the thyroid function of mice, the authors fed fresh cassava root to mice and compared this diet with low iodine diet and Purina. Cassava provided a low iodine intake and increased urine thiocyanate excretion and serum thiocyanate levels. Mice on cassava lost weight. The thyroid glands of mice on cassava were not enlarged, even when normalized for body weight. The 4- and 24-hr thyroid uptakes of mice on cassava were similar to those of mice on low iodine diets. Protein-bound [ 125 I]iodine at 24 hr was high in mice on either the cassava or low iodine diets. The thyroid iodide trap (T/M) was similar in mice on cassava and low iodine diets. When thiocyanate was added in vitro to the incubation medium, T/M was reduced in all groups of mice; under these conditions, thiocyanate caused a dose-related inhibition of T/M. The serum thyroxine (T4) and triiodothyronine (T3) concentrations of mice on cassava were reduced compared with mice on Purina diet. Thyroid T4 and T3 contents of mice on cassava were relatively low compared with mice on Purina diet. Hepatic T3 content and T4 5'-monodeiodination in liver homogenates were reduced in mice on cassava compared with other groups. The data show that cassava does not cause goiter in mice. The thiocyanate formed from ingestation of cassava is insufficient to inhibit thyroid iodide transport or organification of iodide. The cassava diet leads to rapid turnover of hormonal iodine because it is a low iodine diet. It also impairs 5'-monodeiodination of T4 which may be related to nutritional deficiency. These data in mice do not support the concept that cassava per se has goitrogenic action in man

  20. Global patterns of protection of elevational gradients in mountain ranges.

    Science.gov (United States)

    Elsen, Paul R; Monahan, William B; Merenlender, Adina M

    2018-05-21

    Protected areas (PAs) that span elevational gradients enhance protection for taxonomic and phylogenetic diversity and facilitate species range shifts under climate change. We quantified the global protection of elevational gradients by analyzing the elevational distributions of 44,155 PAs in 1,010 mountain ranges using the highest resolution digital elevation models available. We show that, on average, mountain ranges in Africa and Asia have the lowest elevational protection, ranges in Europe and South America have intermediate elevational protection, and ranges in North America and Oceania have the highest elevational protection. We use the Convention on Biological Diversity's Aichi Target 11 to assess the proportion of elevational gradients meeting the 17% suggested minimum target and examine how different protection categories contribute to elevational protection. When considering only strict PAs [International Union for Conservation of Nature (IUCN) categories I-IV, n = 24,706], nearly 40% of ranges do not contain any PAs, roughly half fail to meet the 17% target at any elevation, and ∼75% fail to meet the target throughout ≥50% of the elevational gradient. Observed elevational protection is well below optimal, and frequently below a null model of elevational protection. Including less stringent PAs (IUCN categories V-VI and nondesignated PAs, n = 19,449) significantly enhances elevational protection for most continents, but several highly biodiverse ranges require new or expanded PAs to increase elevational protection. Ensuring conservation outcomes for PAs with lower IUCN designations as well as strategically placing PAs to better represent and connect elevational gradients will enhance ecological representation and facilitate species range shifts under climate change. Copyright © 2018 the Author(s). Published by PNAS.

  1. Global view of the mechanisms of improved learning and memory capability in mice with music-exposure by microarray.

    Science.gov (United States)

    Meng, Bo; Zhu, Shujia; Li, Shijia; Zeng, Qingwen; Mei, Bing

    2009-08-28

    Music has been proved beneficial to improve learning and memory in many species including human in previous research work. Although some genes have been identified to contribute to the mechanisms, it is believed that the effect of music is manifold, behind which must concern a complex regulation network. To further understand the mechanisms, we exposed the mice to classical music for one month. The subsequent behavioral experiments showed improvement of spatial learning capability and elevation of fear-motivated memory in the mice with music-exposure as compared to the naïve mice. Meanwhile, we applied the microarray to compare the gene expression profiles of the hippocampus and cortex between the mice with music-exposure and the naïve mice. The results showed approximately 454 genes in cortex (200 genes up-regulated and 254 genes down-regulated) and 437 genes in hippocampus (256 genes up-regulated and 181 genes down-regulated) were significantly affected in music-exposing mice, which mainly involved in ion channel activity and/or synaptic transmission, cytoskeleton, development, transcription, hormone activity. Our work may provide some hints for better understanding the effects of music on learning and memory.

  2. NF-κB in The Mechanism of Brain Edema in Acute Liver Failure: Studies in Transgenic Mice

    Science.gov (United States)

    Jayakumar, A.R.; Bethea, J.R.; Tong, X.Y.; Gomez, J.; Norenberg, M.D.

    2014-01-01

    Astrocyte swelling and brain edema are major complications of the acute form of hepatic encephalopathy (acute liver failure, ALF). While elevated brain ammonia level is a well-known etiological factor in ALF, the mechanism by which ammonia brings about astrocyte swelling is not well understood. We recently found that astrocyte cultures exposed to ammonia activated nuclear factor-kappaB (NF-κB), and that pharmacological inhibition of such activation led to a reduction in astrocyte swelling. Although these findings suggest the involvement of NF-κB in astrocyte swelling in vitro, it is not known whether NF-κB contributes to the development of brain edema in ALF in vivo. Furthermore, pharmacological agents used to inhibit NF-κB may have non-specific effects. Accordingly, we used transgenic (Tg) mice that have a functional inactivation of astrocytic NF-κB and examined whether these mice are resistant to ALF-associated brain edema. ALF was induced in mice by treatment with the hepatotoxin thioacetamide (TAA). Wild type (WT) mice treated with TAA showed a significant increase in brain water content (1.65%) along with prominent astrocyte swelling and spongiosis of the neuropil, consistent with the presence of cytotoxic edema. These changes were not observed in Tg mice treated with TAA. Additionally, WT mice with ALF showed an increase in inducible nitric oxide synthase (iNOS) immunoreactivity in astrocytes from WT mice treated with TAA (iNOS is known to be activated by NF-κB and to contribute to cell swelling). By contrast, Tg mice treated with TAA did not exhibit brain edema, histological changes nor an increase in iNOS immunoreactivity. We also examined astrocytes cultures derived from Tg mice to determine whether these cells exhibit a lesser degree of swelling and cytopathological changes following exposure to ammonia. Astrocyte cultures derived from Tg mice showed no cell swelling nor morphological abnormalities when exposed to ammonia for 24 h. By contrast

  3. Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration.

    Science.gov (United States)

    McBrayer, Zofeyah L; Dimova, Jiva; Pisansky, Marc T; Sun, Mu; Beppu, Hideyuki; Gewirtz, Jonathan C; O'Connor, Michael B

    2015-01-01

    To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII) in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors.

  4. Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration.

    Directory of Open Access Journals (Sweden)

    Zofeyah L McBrayer

    Full Text Available To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors.

  5. Cloning Mice.

    Science.gov (United States)

    Ogura, Atsuo

    2017-08-01

    Viable and fertile mice can be generated by somatic nuclear transfer into enucleated oocytes, presumably because the transplanted somatic cell genome becomes reprogrammed by factors in the oocyte. The first somatic cloned offspring of mice were obtained by directly injecting donor nuclei into recipient enucleated oocytes. When this method is used (the so-called Honolulu method of somatic cell nuclear transfer [SCNT]), the donor nuclei readily and completely condense within the enucleated metaphase II-arrested oocytes, which contain high levels of M-phase-promoting factor (MPF). It is believed that the condensation of the donor chromosomes promotes complete reprogramming of the donor genome within the mouse oocytes. Another key to the success of mouse cloning is the use of blunt micropipettes attached to a piezo impact-driving micromanipulation device. This system saves a significant amount of time during the micromanipulation of oocytes and thus minimizes the loss of oocyte viability in vitro. For example, a group of 20 oocytes can be enucleated within 10 min by an experienced operator. This protocol is composed of seven parts: (1) preparing micropipettes, (2) setting up the enucleation and injection micropipettes, (3) collecting and enucleating oocytes, (4) preparing nucleus donor cells, (5) injecting donor nuclei, (6) activating embryos and culturing, and (7) transferring cloned embryos. © 2017 Cold Spring Harbor Laboratory Press.

  6. Group control of elevators

    Energy Technology Data Exchange (ETDEWEB)

    Umeda, Yasukazu; Hikita, Shiro; Tuji, Sintaro (Mitsubishi Electric Corp., Tokyo (Japan))

    1988-09-05

    Items to be evaluated in the group control of elevators, and a typical control system are described. A new system in which the fuzzy rule base is employed is introduced together with the configuration. The items to be evaluated are waiting time, riding time, accuracy of forecasting, energy saving, and ease of usage. The everage waiting time of less than 20 seconds with less than 3% waiting rate of more than 60 seconds is accepted as a satisfactory service condition. There are many conflicting matters in group-controlling, and the study for the controlling must deal with the optimization of multi-purpose problems. The standards for group-control evaluation differ according to building structures and the tastes of users, and an important problem is where to give emphasis of the evaluation. The TRAFFIC PATTERN LEARNING METHOD has been applied in the system for careful control to accommodate the traffic. No specific function is provided for the evaluation, but the call allocation is made by fuzzy rule-base. The configuration of a new group-control system is introduced. 7 references, 7 figures, 1 table.

  7. Expanded simple tandem repeat (ESTR) mutation induction in the male germline: Lessons learned from lab mice

    Energy Technology Data Exchange (ETDEWEB)

    Somers, Christopher M. [University of Regina, Department of Biology, 3737 Wascana Parkway, Regina, SK, S4S 0A2 (Canada)]. E-mail: chris.somers@uregina.ca

    2006-06-25

    Expanded simple tandem repeat (ESTR) DNA loci that are unstable in the germline have provided the most sensitive tool ever developed for investigating low-dose heritable mutation induction in laboratory mice. Ionizing radiation exposures have shown that ESTR mutations occur mainly in pre-meiotic spermatogonia and stem cells. The average spermatogonial doubling dose is 0.62-0.69 Gy for low LET, and 0.18-0.34 Gy for high LET radiation. Chemical alkylating agents also cause significant ESTR mutation induction in pre-meiotic spermatogonia and stem cells, but are much less effective per unit dose than radiation. ESTR mutation induction efficiency is maximal at low doses of radiation or chemical mutagens, and may decrease at higher dose ranges. DNA repair deficient mice (SCID and PARP-1) with elevated levels of single and double-strand DNA breaks have spontaneously elevated ESTR mutation frequencies, and surprisingly do not show additional ESTR mutation induction following irradiation. In contrast, ESTR mutation induction in p53 knock-outs is indistinguishable from that of wild-type mice. Studies of sentinel mice exposed in situ to ambient air pollution showed elevated ESTR mutation frequencies in males exposed to high levels of particulate matter. These studies highlight the application of the ESTR assay for assessing environmental hazards under real-world conditions. All ESTR studies to date have shown untargeted mutations that occur at much higher frequencies than predicted. The mechanism of this untargeted mutation induction is unknown, and must be elucidated before we can fully understand the biological significance of ESTR mutations, or use these markers for formal risk assessment. Future studies should focus on the mechanism of ESTR mutation induction, refining dose responses, and developing ESTR markers for other animal species.

  8. Expanded simple tandem repeat (ESTR) mutation induction in the male germline: Lessons learned from lab mice

    International Nuclear Information System (INIS)

    Somers, Christopher M.

    2006-01-01

    Expanded simple tandem repeat (ESTR) DNA loci that are unstable in the germline have provided the most sensitive tool ever developed for investigating low-dose heritable mutation induction in laboratory mice. Ionizing radiation exposures have shown that ESTR mutations occur mainly in pre-meiotic spermatogonia and stem cells. The average spermatogonial doubling dose is 0.62-0.69 Gy for low LET, and 0.18-0.34 Gy for high LET radiation. Chemical alkylating agents also cause significant ESTR mutation induction in pre-meiotic spermatogonia and stem cells, but are much less effective per unit dose than radiation. ESTR mutation induction efficiency is maximal at low doses of radiation or chemical mutagens, and may decrease at higher dose ranges. DNA repair deficient mice (SCID and PARP-1) with elevated levels of single and double-strand DNA breaks have spontaneously elevated ESTR mutation frequencies, and surprisingly do not show additional ESTR mutation induction following irradiation. In contrast, ESTR mutation induction in p53 knock-outs is indistinguishable from that of wild-type mice. Studies of sentinel mice exposed in situ to ambient air pollution showed elevated ESTR mutation frequencies in males exposed to high levels of particulate matter. These studies highlight the application of the ESTR assay for assessing environmental hazards under real-world conditions. All ESTR studies to date have shown untargeted mutations that occur at much higher frequencies than predicted. The mechanism of this untargeted mutation induction is unknown, and must be elucidated before we can fully understand the biological significance of ESTR mutations, or use these markers for formal risk assessment. Future studies should focus on the mechanism of ESTR mutation induction, refining dose responses, and developing ESTR markers for other animal species

  9. Role of Omega 3 Fatty Acids Against Ehrlich Ascites Carcinoma-Induced Hepatic and Brain Dysfunctions in Gamma Irradiated Mice

    International Nuclear Information System (INIS)

    El-Gharib, M.M.M.

    2014-01-01

    Cancer is a deadly disease that has touched the lives of many people in the world today. Omega 3 essential fatty acids (ω-3 FAs); found in high concentrations in fish oil, claim a plethora of health benefits. The present study aimed to evaluate the role of ω-3 FAs supplementation either alone or combined with fractionated γ-radiation exposure against Ehrlich solid tumor-induced inflammation, oxidative stress, biochemical alterations and histopathological changes in the liver, brain and tumor tissues of Albino mice. ω-3 FAs were orally administered via gavages to mice for a period of 30 consecutive days at a dose of 300 mg/kg body weight. On the 7th day of experiment, mice were subcutaneously transplanted in the neck region with 0.2 ml of Ehrlich ascites carcinoma cells for solid tumor induction and on the 17th and 25th days, mice were exposed to a fractionated whole body γ-radiation (0.5 Gy/week for two weeks). The results of the present work showed that Ehrlich carcinoma (EC) and/or γ-irradiation led to systemic inflammation (elevated TNF-α, TLC and CRP levels), hepatic oxidative stress (elevated TBARs level, decreased GSH, GSH-Px, CAT and SOD levels) and biochemical alterations in liver (elevated AST, ALT, ALP and LDH activities) and brain (dopamine, EP,NE and serotonin levels) tissues. On the other hand, ω-3 FAs supplementation to the experimentally irradiated EC-bearing mice, significantly reduced tumor size, depressed the concentrations of inflammatory markers, reduced oxidative stress and also ameliorated the biochemical alterations in liver and brain tissues. Histopathological examinations showed that treatment with ω-3 FAs recorded great destruction of tumor tissue, great disappearance of metastatic EC cells from the liver tissue and normal appearance in cerebrum and cerebellum of brain tissue layers in EC-bearing mice. Combined treatment of EC-bearing mice with ω-3 FAs and γ-irradiation showed necrotic cells and remnant tumor cells in tumor

  10. Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice.

    Directory of Open Access Journals (Sweden)

    Gerhard Sengle

    2015-06-01

    Full Text Available Fibrillins are large extracellular macromolecules that polymerize to form the backbone structure of connective tissue microfibrils. Mutations in the gene for fibrillin-1 cause the Marfan syndrome, while mutations in the gene for fibrillin-2 cause Congenital Contractural Arachnodactyly. Both are autosomal dominant disorders, and both disorders affect musculoskeletal tissues. Here we show that Fbn2 null mice (on a 129/Sv background are born with reduced muscle mass, abnormal muscle histology, and signs of activated BMP signaling in skeletal muscle. A delay in Myosin Heavy Chain 8, a perinatal myosin, was found in Fbn2 null forelimb muscle tissue, consistent with the notion that muscle defects underlie forelimb contractures in these mice. In addition, white fat accumulated in the forelimbs during the early postnatal period. Adult Fbn2 null mice are already known to demonstrate persistent muscle weakness. Here we measured elevated creatine kinase levels in adult Fbn2 null mice, indicating ongoing cycles of muscle injury. On a C57Bl/6 background, Fbn2 null mice showed severe defects in musculature, leading to neonatal death from respiratory failure. These new findings demonstrate that loss of fibrillin-2 results in phenotypes similar to those found in congenital muscular dystrophies and that FBN2 should be considered as a candidate gene for recessive congenital muscular dystrophy. Both in vivo and in vitro evidence associated muscle abnormalities and accumulation of white fat in Fbn2 null mice with abnormally activated BMP signaling. Genetic rescue of reduced muscle mass and accumulation of white fat in Fbn2 null mice was accomplished by deleting a single allele of Bmp7. In contrast to other reports that activated BMP signaling leads to muscle hypertrophy, our findings demonstrate the exquisite sensitivity of BMP signaling to the fibrillin-2 extracellular environment during early postnatal muscle development. New evidence presented here suggests that

  11. Anxiolytic-like effects of ursolic acid in mice.

    Science.gov (United States)

    Colla, André R S; Rosa, Julia M; Cunha, Mauricio P; Rodrigues, Ana Lúcia S

    2015-07-05

    Ursolic acid is a pentacyclic triterpenoid that possesses several biological and neuropharmacological effects including antidepressant-like activity. Anxiety disorders represent common and disability psychiatric conditions that are often associated with depressive symptoms. This work investigated the anxiolytic-like effects of ursolic acid administration in different behavioral paradigms that evaluate anxiety in mice: open field test, elevated plus maze test, light/dark box test and marble burying test. To this end, mice were administered with ursolic acid (0.1, 1 and 10mg/kg, p.o.) or diazepam (2mg/kg, p.o.), positive control, and submitted to the behavioral tests. The results show that ursolic acid (10mg/kg) elicited an anxiolytic-like effect observed by the increased total time in the center and decreased number of rearings responses in the open field test and an increased percentage of entries and total time spent in the open arms of elevated plus maze, similarly to diazepam. No significant effects of ursolic acid were shown in the light/dark box and marble burying test. These data indicate that ursolic acid exhibits anxiolytic-like effects in the open field and elevated plus maze test, but not in the light/dark box and marble burying test, showing the relevance of testing several behavioral paradigms in the evaluation of anxiolytic-like actions. Of note, the results extend the understanding on the effects of ursolic acid in the central nervous system and suggest that it may be a novel approach for the management of anxiety-related disorders. Copyright © 2015. Published by Elsevier B.V.

  12. Purwarupa Sistem Kontrol Elevator Berbasis Programable Logic Control

    Directory of Open Access Journals (Sweden)

    Fathahillah Fathahillah

    2017-12-01

    Full Text Available Various methods / types of controls developed in accordance with industry needs one of them in the field of building automation system. One of the controls in the field of building automation system is the elevator control system (elevator. Early elevator control systems that transport humans or goods as vertical transportation vehicles are still conventional using human power, then evolved using steam engines, until now the elevators use AC motors equipped with control systems. The purpose of this research is to design the prototype of elevator control system using programmable logic control (PLC. The type of PLC controller used in the study using Omron PLC. The results show the design of prototype of elevator control system using PLC successfully and can control eleveator in accordance with its function, besides its programming form can be more simple.

  13. Polyinosine-polycytidylic acid promotes excessive iodine intake induced thyroiditis in non-obese diabetic mice via Toll-like receptor 3 mediated inflammation.

    Science.gov (United States)

    Shi, Ya-nan; Liu, Feng-hua; Yu, Xiu-jie; Liu, Ze-bing; Li, Qing-xin; Yuan, Ji-hong; Zang, Xiao-yi; Li, Lan-ying

    2013-02-01

    Excessive iodine intake and viral infection are recognized as both critical factors associated with autoimmune thyroid diseases. Toll-like receptors (TLRs) have been reported to play an important role in autoimmune and inflammatory disorders. In this study, we aimed to clarify the possible mechanism of TLR3 involved in polyinosine-polycytidylic acid (poly(I:C)) promoting excessive iodine intake induced thyroiditis in non-obese diabetic (NOD) mice. Both NOD and BALB/c mice were randomly assigned to four groups: control group (n = 5), high iodine intake (HI) group (n = 7), poly(I:C) group (n = 7) and combination of excessive iodine and poly(I:C) injection (HIP) group (n = 7). After 8 weeks, mice were weighed and blood samples were collected. All the mice were sacrificed before dissection of spleen and thyroid gland. Then, thyroid histology, thyroid secreted hormone, expression of CD3(+) cells and TLR3 as well as inflammatory mRNA level were evaluated. Both NOD and BALB/c mice from HI and HIP group represented goiter and increasing thyroid relative weight. Thyroid histology evidence indicated that only HIP group of NOD mice showed severe thyroiditis with lymphocytes infiltration in majority of thyroid tissue, severe damage of follicles and general fibrosis. Immunofluorescence staining results displayed a large number of CD3(+) cells in HIP NOD mice. Real-time polymerase chain reaction (PCR) results suggested interferon (IFN)-α increased over 30 folds and IFN-γ expression was doubled compared with control group, but interleukin (IL)-4 remained unchanged in HIP group of NOD mice thyroid. Meanwhile, over one third decrease of blood total thyroxine (TT4) and increased thyroid-stimulating hormone (TSH) was observed in HIP group of NOD mice. Only HIP group of NOD mice represented significantly elevation of TLR3 expression. Poly(I:C) enhanced excessive dietary iodine induced thyroiditis in NOD mice through increasing TLR3 mediated inflammation.

  14. Bacteriophages show promise as antimicrobial agents.

    Science.gov (United States)

    Alisky, J; Iczkowski, K; Rapoport, A; Troitsky, N

    1998-01-01

    The emergence of antibiotic-resistant bacteria has prompted interest in alternatives to conventional drugs. One possible option is to use bacteriophages (phage) as antimicrobial agents. We have conducted a literature review of all Medline citations from 1966-1996 that dealt with the therapeutic use of phage. There were 27 papers from Poland, the Soviet Union, Britain and the U.S.A. The Polish and Soviets administered phage orally, topically or systemically to treat a wide variety of antibiotic-resistant pathogens in both adults and children. Infections included suppurative wound infections, gastroenteritis, sepsis, osteomyelitis, dermatitis, empyemas and pneumonia; pathogens included Staphylococcus, Streptococcus, Klebsiella, Escherichia, Proteus, Pseudomonas, Shigella and Salmonella spp. Overall, the Polish and Soviets reported success rates of 80-95% for phage therapy, with rare, reversible gastrointestinal or allergic side effects. However, efficacy of phage was determined almost exclusively by qualitative clinical assessment of patients, and details of dosages and clinical criteria were very sketchy. There were also six British reports describing controlled trials of phage in animal models (mice, guinea pigs and livestock), measuring survival rates and other objective criteria. All of the British studies raised phage against specific pathogens then used to create experimental infections. Demonstrable efficacy against Escherichia, Acinetobacter, Pseudomonas and Staphylococcus spp. was noted in these model systems. Two U.S. papers dealt with improving the bioavailability of phage. Phage is sequestered in the spleen and removed from circulation. This can be overcome by serial passage of phage through mice to isolate mutants that resist sequestration. In conclusion, bacteriophages may show promise for treating antibiotic resistant pathogens. To facilitate further progress, directions for future research are discussed and a directory of authors from the reviewed

  15. Elevated Steroid Hormone Production in the db/db Mouse Model of Obesity and Type 2 Diabetes.

    Science.gov (United States)

    Hofmann, Anja; Peitzsch, Mirko; Brunssen, Coy; Mittag, Jennifer; Jannasch, Annett; Frenzel, Annika; Brown, Nicholas; Weldon, Steven M; Eisenhofer, Graeme; Bornstein, Stefan R; Morawietz, Henning

    2017-01-01

    Obesity and type 2 diabetes have become a major public health problem worldwide. Steroid hormone dysfunction appears to be linked to development of obesity and type 2 diabetes and correction of steroid abnormalities may offer new approaches to therapy. We therefore analyzed plasma steroids in 15-16 week old obese and diabetic db/db mice using liquid chromatography-tandem mass spectrometry. Lean db/+ served as controls. Db/db mice developed obesity, hyperglycemia, hyperleptinemia, and hyperlipidemia. Hepatic triglyceride storage was increased and adiponectin and pancreatic insulin were lowered. Aldosterone, corticosterone, 11-deoxycorticosterone, and progesterone were respectively increased by 3.6-, 2.9-, 3.4, and 1.7-fold in db/db mice compared to controls. Ratios of aldosterone-to-progesterone and corticosterone-to-progesterone were respectively 2.0- and 1.5-fold higher in db/db mice. Genes associated with steroidogenesis were quantified in the adrenal glands and gonadal adipose tissues. In adrenals, Cyp11b2 , Cyp11b1 , Cyp21a1 , Hsd3b1 , Cyp11a1 , and StAR were all significantly increased in db/db mice compared with db/+ controls. In adipose tissue, no Cyp11b2 or Cyp11b1 transcripts were detected and no differences in Cyp21a1 , Hsd3b1 , Cyp11a1 , or StAR expression were found between db/+ and db/db mice. In conclusion, the present study showed an elevated steroid hormone production and adrenal steroidogenesis in the db/db model of obesity and type 2 diabetes. © Georg Thieme Verlag KG Stuttgart · New York.

  16. Risk Aversion in Game Shows

    DEFF Research Database (Denmark)

    Andersen, Steffen; Harrison, Glenn W.; Lau, Morten I.

    2008-01-01

    We review the use of behavior from television game shows to infer risk attitudes. These shows provide evidence when contestants are making decisions over very large stakes, and in a replicated, structured way. Inferences are generally confounded by the subjective assessment of skill in some games......, and the dynamic nature of the task in most games. We consider the game shows Card Sharks, Jeopardy!, Lingo, and finally Deal Or No Deal. We provide a detailed case study of the analyses of Deal Or No Deal, since it is suitable for inference about risk attitudes and has attracted considerable attention....

  17. Measuring performance at trade shows

    DEFF Research Database (Denmark)

    Hansen, Kåre

    2004-01-01

    Trade shows is an increasingly important marketing activity to many companies, but current measures of trade show performance do not adequately capture dimensions important to exhibitors. Based on the marketing literature's outcome and behavior-based control system taxonomy, a model is built...... that captures a outcome-based sales dimension and four behavior-based dimensions (i.e. information-gathering, relationship building, image building, and motivation activities). A 16-item instrument is developed for assessing exhibitors perceptions of their trade show performance. The paper presents evidence...

  18. Treatment with anti-IL-6 receptor antibody prevented increase in serum hepcidin levels and improved anemia in mice inoculated with IL-6–producing lung carcinoma cells

    International Nuclear Information System (INIS)

    Noguchi-Sasaki, Mariko; Sasaki, Yusuke; Shimonaka, Yasushi; Mori, Kazushige; Fujimoto-Ouchi, Kaori

    2016-01-01

    Hepcidin, a key regulator of iron metabolism, is produced mainly by interleukin-6 (IL-6) during inflammation. A mechanism linking cancer-related anemia and IL-6 through hepcidin production is suggested. To clarify the hypothesis that overproduction of IL-6 elevates hepcidin levels and contributes to the development of cancer-related anemia, we evaluated anti-IL-6 receptor antibody treatment of cancer-related anemia in an IL-6–producing human lung cancer xenograft model. Nude mice were subcutaneously inoculated with cells of the IL-6–producing human lung cancer cell line LC-06-JCK and assessed as a model of cancer-related anemia. Mice bearing LC-06-JCK were administered rat anti-mouse IL-6 receptor antibody MR16-1 and their serum hepcidin levels and hematological parameters were determined. LC-06-JCK–bearing mice developed anemia according to the production of human IL-6 from xenografts, with decreased values of hemoglobin, hematocrit, and mean corpuscular volume (MCV) compared to non–tumor-bearing (NTB) mice. LC-06-JCK–bearing mice showed decreased body weight and serum albumin with increased serum amyloid A. MR16-1 treatment showed significant inhibition of decreased body weight and serum albumin levels, and suppressed serum amyloid A level. There was no difference in tumor volume between MR16-1-treated mice and immunoglobulin G (IgG)-treated control mice. Decreased hemoglobin, hematocrit, and MCV in LC-06-JCK–bearing mice was significantly relieved by MR16-1 treatment. LC-06-JCK–bearing mice showed high red blood cell counts and erythropoietin levels as compared to NTB mice, whereas MR16-1 treatment did not affect their levels. Serum hepcidin and ferritin levels were statistically elevated in mice bearing LC-06-JCK. LC-06-JCK–bearing mice showed lower values of MCV, mean corpuscular hemoglobin (MCH), and serum iron as compared to NTB mice. Administration of MR16-1 to mice bearing LC-06-JCK significantly suppressed levels of both serum hepcidin and

  19. Reducing elevator energy use: A comparison of posted feedback and reduced elevator convenience

    Science.gov (United States)

    Houten, Ron Van; Nau, Paul A.; Merrigan, Michael

    1981-01-01

    The effects of two different procedures for reducing elevator energy use were assessed using a multiple-baseline design. In the first procedure, feedback about the amount of energy consumed by the elevators each week was posted on each elevator door. Later, signs advocating the use of stairs to save energy and improve health were posted next to the feedback signs. In the second procedure, the time required to travel between floors was increased by adding a delay to the elevator door closing mechanisms. Results indicated that neither feedback alone nor feedback plus educational signs reduced the amount of energy consumed by the elevators. However, use of the door delay reduced consumption by one-third in all elevators. A second experiment replicated the effect of the door delay on energy consumption and, in addition, demonstrated that the door delay also produced a reduction in the number of persons using the elevator. The second experiment also showed that, following an initial period during which a full delay was in effect, a gradual reduction of the delay interval resulted in continued energy conservation. Reduced convenience as a general strategy for energy conservation is discussed. PMID:16795648

  20. Elevational distribution and extinction risk in birds.

    Directory of Open Access Journals (Sweden)

    Rachel L White

    Full Text Available Mountainous regions are hotspots of terrestrial biodiversity. Unlike islands, which have been the focus of extensive research on extinction dynamics, fewer studies have examined mountain ranges even though they face increasing threats from human pressures - notably habitat conversion and climate change. Limits to the taxonomic and geographical extent and resolution of previously available information have precluded an explicit assessment of the relative role of elevational distribution in determining extinction risk. We use a new global species-level avian database to quantify the influence of elevational distribution (range, maximum and midpoint on extinction risk in birds at the global scale. We also tested this relationship within biogeographic realms, higher taxonomic levels, and across phylogenetic contrasts. Potential confounding variables (i.e. phylogenetic, distributional, morphological, life history and niche breadth were also tested and controlled for. We show that the three measures of elevational distribution are strong negative predictors of avian extinction risk, with elevational range comparable and complementary to that of geographical range size. Extinction risk was also found to be positively associated with body weight, development and adult survival, but negatively associated with reproduction and niche breadth. The robust and consistent findings from this study demonstrate the importance of elevational distribution as a key driver of variation in extinction dynamics in birds. Our results also highlight elevational distribution as a missing criterion in current schemes for quantifying extinction risk and setting species conservation priorities in birds. Further research is recommended to test for generality across non-avian taxa, which will require an advance in our knowledge of species' current elevational ranges and increased efforts to digitise and centralise such data.

  1. Lærer-elev-relationer

    DEFF Research Database (Denmark)

    Laursen, Per Fibæk; Nielsen, Anne Maj

    2015-01-01

    I kapitlet belyser vi relationskompetence i forholdet mellem lærer og elever og hvordan læreren kan arbejde med forhold til elever og med sin opmærksomhed på relationsarbejdet. Afslutningsvis ser vi på hvordan lærere fortsat kan udvikle deres relationskompetence.......I kapitlet belyser vi relationskompetence i forholdet mellem lærer og elever og hvordan læreren kan arbejde med forhold til elever og med sin opmærksomhed på relationsarbejdet. Afslutningsvis ser vi på hvordan lærere fortsat kan udvikle deres relationskompetence....

  2. Tanzania Elevation and Surface Characteristics

    Data.gov (United States)

    US Agency for International Development — The dataset displays Elevation, Slope, Aspect, Topographic Position Index, Terrain Ruggedness, and Roughness based on Shuttle Radar Topography Mission (SRTM) (3...

  3. Altered Cerebellar Organization and Function in Monoamine Oxidase A Hypomorphic Mice

    Science.gov (United States)

    Alzghoul, Loai; Bortolato, Marco; Delis, Foteini; Thanos, Panayotis K.; Darling, Ryan D.; Godar, Sean C; Zhang, Junlin; Grant, Samuel; Wang, Gene-Jack; Simpson, Kimberly L.; Chen, Kevin; Volkow, Nora D.; Lin, Rick C.S.; Shih, Jean C.

    2012-01-01

    Monoamine oxidase A (MAO-A) is the key enzyme for the degradation of brain serotonin (5-hydroxytryptamine, 5-HT), norepinephrine (NE) and dopamine (DA). We recently generated and characterized a novel line of MAO-A hypormorphic mice (MAO-ANeo), featuring elevated monoamine levels, social deficits and perseverative behaviors as well as morphological changes in the basolateral amygdala and orbitofrontal cortex. Here we showed that MAO-ANeo mice displayed deficits in motor control, manifested as subtle disturbances in gait, motor coordination, and balance. Furthermore, magnetic resonance imaging of the cerebellum revealed morphological changes and a moderate reduction in the cerebellar size of MAO- ANeo mice compared to wild type (WT) mice. Histological and immunohistochemical analyses using calbindin-D-28k (CB) expression of Purkinje cells revealed abnormal cerebellar foliation with vermal hypoplasia and decreased in Purkinje cell count and their dendritic density in MAO- ANeo mice compared to WT. Our current findings suggest that congenitally low MAO-A activity leads to abnormal development of the cerebellum. PMID:22971542

  4. Mechanism of lipid lowering in mice expressing human apolipoprotein A5

    Energy Technology Data Exchange (ETDEWEB)

    Fruchart-Najib, Jamila; Bauge, Eric; Niculescu, Loredan-Stefan; Pham, Tatiana; Thomas, Benoit; Rommens, Corinne; Majd, Zouher; Brewer, Bryan; Rubin, Edward M.; Pennacchio, Len A.; Fruchart, Jean-Charles

    2004-01-15

    Recently, we reported that apoAV plays key role in triglycerides lowering. Here, we attempted to determine the mechanism underlying this hypotriglyceridemic effect. We showed that triglyceride turnover is faster in hAPOA5 transgenic compared to wild type mice. Moreover, both apoB and apoCIII are decreased and LPL activity is increased in postheparin plasma of hAPOA5 transgenic mice. These data suggest a decrease in size and number of VLDL. To further investigate the mechanism of hAPOA5 in hyperlipidemic background, we intercrossed hAPOA5 and hAPOC3 transgenic mice. The effect resulted in a marked decreased of VLDL triglyceride, cholesterol, apolipoproteins B and CIII. In postprandial state, the triglyceride response is abolished in hAPOA5 transgenic mice. We demonstrated that in response to the fat load in hAPOA5XhAPOC3 mice, apoAV shifted from HDL to VLDL, probably to limit the elevation of triglycerides. In vitro, apoAV activates lipoprotein lipase. However, apoAV does not interact with LPL but interacts physically with apoCIII. This interaction does not seem to displace apoCIII from VLDL but may induce conformational change in apoCIII and consequently change in its function leading the activation of lipoprotein lipase.

  5. Novel approach to the behavioural characterization of inbred mice: automated home cage observations.

    Science.gov (United States)

    de Visser, L; van den Bos, R; Kuurman, W W; Kas, M J H; Spruijt, B M

    2006-08-01

    Here we present a newly developed tool for continuous recordings and analysis of novelty-induced and baseline behaviour of mice in a home cage-like environment. Aim of this study was to demonstrate the strength of this method by characterizing four inbred strains of mice, C57BL/6, DBA/2, C3H and 129S2/Sv, on locomotor activity. Strains differed in circadian rhythmicity, novelty-induced activity and the time-course of specific behavioural elements. For instance, C57BL/6 and DBA/2 mice showed a much faster decrease in activity over time than C3H and 129S2/Sv mice. Principal component analysis revealed two major factors within locomotor activity, which were defined as 'level of activity' and 'velocity/stops'. These factors were able to distinguish strains. Interestingly, mice that displayed high levels of activity in the initial phase of the home cage test were also highly active during an open-field test. Velocity and the number of stops during movement correlated positively with anxiety-related behaviour in the elevated plus maze. The use of an automated home cage observation system yields temporal changes in elements of locomotor activity with an advanced level of spatial resolution. Moreover, it avoids the confounding influence of human intervention and saves time-consuming human observations.

  6. Behavioral changes induced by cocaine in mice are modified by a hyperlipidic diet or recombinant leptin

    Directory of Open Access Journals (Sweden)

    E. Erhardt

    2006-12-01

    Full Text Available The objective of the present study was to determine if the acute behavioral effects of cocaine acutely administered intraperitoneally (ip at doses of 5, 10 and 20 mg/kg on white male CF1 mice, 90 days of age, would be influenced by leptin acutely administered ip (at doses of 5, 10 and 20 µg/kg or by endogenous leptin production enhanced by a high-fat diet. The acute behavioral effects of cocaine were evaluated in open-field, elevated plus-maze and forced swimming tests. Results were compared between a group of 80 mice consuming a balanced diet and a high-fat diet, and a group of 80 mice fed a commercially available rodent chow formula (Ralston Purina but receiving recombinant leptin (rLeptin or saline ip. Both the high-fat-fed and rLeptin-treated mice showed decreased locomotion in the open-field test, spent more time in the open arms of the elevated plus-maze and showed less immobility time in the forced swimming test (F(1,68 = 7.834, P = 0.007. There was an interaction between diets and cocaine/saline treatments in locomotion (F(3,34 = 3.751, P = 0.020 and exploration (F(3,34 = 3.581, P = 0.024. These results suggest that anxiolytic effects and increased general activity were induced by leptin in cocaine-treated mice and that low leptin levels are associated with behavioral depression. Chronic changes in diet composition producing high leptin levels or rLeptin treatment may result in an altered response to cocaine in ethologic tests that measure degrees of anxiety and depression, which could be attributed to an antagonistic effect of leptin.

  7. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

    International Nuclear Information System (INIS)

    Wu, Weibin; Liu, Xijun; Peng, Xiaomin; Xue, Ruyi; Ji, Lingling; Shen, Xizhong; Chen, She; Gu, Jianxin; Zhang, Si

    2014-01-01

    Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR −/− ) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR −/− mice fed MCD diet (FXR −/− /MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR −/− /MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR −/− /MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR −/− /MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection

  8. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Weibin; Liu, Xijun; Peng, Xiaomin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Xue, Ruyi [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Ji, Lingling [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Shen, Xizhong [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Chen, She, E-mail: shechen@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhang, Si, E-mail: zhangsi@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China)

    2014-05-23

    Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR{sup −/−}) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR{sup −/−} mice fed MCD diet (FXR{sup −/−}/MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR{sup −/−}/MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR{sup −/−}/MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR{sup −/−}/MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection.

  9. Overexpression of catalase in mice reduces age-related oxidative stress and maintains sperm production.

    Science.gov (United States)

    Selvaratnam, Johanna; Robaire, Bernard

    2016-11-01

    Advanced paternal age is associated with increased complications in pregnancy and genetic diseases in offspring. Oxidative stress is a major contributor to the damage accumulated in sperm during aging. Complex networks of antioxidants regulate reactive oxygen species (ROS) in the testis. While mounting evident shows that redox dysfunction compromises the quality of developing male germ cells, the mechanisms by which aging causes this remain unclear. Furthermore, therapies to successfully alleviate aging-associated loss in germ cell quality are limited. The antioxidant catalase (CAT) has been used in aging-associated pathologies to alleviate oxidative stress. We used mice overexpressing CAT (MCAT) to determine whether CAT overexpression alleviates the redox dysfunction observed with aging. We found that MCAT mice did not exhibit the age-dependent loss of spermatozoa, nor did they show aging associated loss in testicular germ and Sertoli cells seen in wild type (WT). Low overall ROS and reduced peroxynitrite levels were detected in spermatocytes from aged MCAT mice, following exposure to the pro-oxidant tert-butyl hydroperoxide. Germ cells from young MCATs showed elevated levels of DNA-damage repair markers, γ-H2AX and 53BP1, but this response was lost with aging. Finally, we found oxidative stress induced 8-oxodG lesions to increase in sperm with aging; these lesions were significantly reduced in aged MCAT and these mice showed no decrease in the age-dependent number of pups per litter. Thus we conclude that aged MCAT mice generate sperm at the same rate as young mice; these sperm are protected from oxidative stress associated damage. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. N-3 PUFAs protect against aortic inflammation and oxidative stress in angiotensin II-infused apolipoprotein E-/- mice.

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    Kathryn M Wales

    Full Text Available Abdominal aortic aneurysm is associated with infiltration of inflammatory cells into the aortic wall. The inflammatory response is also evident in animal models, such as apolipoprotein E-deficient (ApoE-/- mice that have been infused with angiotensin II, prior to development of aortic aneurysm. Since omega-3 polyunsaturated fatty acids (n-3 PUFAs and their metabolites have anti-inflammatory and pro-resolving activity, we hypothesised that dietary supplementation with n-3 PUFAs would protect against inflammatory processes in this mouse model. Twenty C57 and 20 ApoE-/- 3-4 week old male mice were supplemented with a low (0.14%, n = 10/group or high (0.70%, n = 10/group n-3 PUFA diet for 8 weeks before 2-day infusion with 0.9% saline or angiotensin II (1000 ng/kg/min. Four ApoE-/- mice on the low n-3 PUFA diet and none of the ApoE-/- mice on the high n-3 PUFA diet showed morphological evidence of abdominal aortic dissection. The plasma concentration of the n-3 PUFA metabolite, resolvin D1 was higher in angiotensin II-infused ApoE-/- mice fed the high, compared to the low n-3 PUFA diet. The number of neutrophils and macrophages infiltrating the abdominal aorta was elevated in ApoE-/- mice on the low n-3 PUFA diet, and this was significantly attenuated in mice that were fed the high n-3 PUFA diet. Most neutrophils and macrophages were associated with dissected aortas. Immunoreactivity of the catalytic subunit of nicotinamide-adenine dinucleotide phosphate (NADPH oxidase, Nox2, and superoxide were elevated in ApoE-/- mice that were fed the low n-3 PUFA diet, and this was also significantly attenuated in mice that were fed the high n-3 PUFA diet. Together, the findings indicate that supplementation of ApoE-/- mice with a diet high in n-3 PUFA content protected the mice against pro-inflammatory and oxidative stress responses following short-term infusion with angiotensin II.

  11. Development of Ethanol Withdrawal-Related Sensitization and Relapse Drinking in Mice Selected for High or Low Ethanol Preference

    Science.gov (United States)

    Lopez, Marcelo F.; Grahame, Nicholas J.; Becker, Howard C.

    2010-01-01

    Background Previous studies have shown that high alcohol consumption is associated with low withdrawal susceptiblility, while at the same time, other studies have shown that exposure to ethanol vapor increases alcohol drinking in rats and mice. In the present studies, we sought to shed light on this seeming contradiction by using mice selectively bred for High- (HAP) and Low- (LAP) Alcohol Preference, first, assessing these lines for differences in signs of ethanol withdrawal and second, for differences in the efficacy of intermittent alcohol vapor exposure on elevating subsequent ethanol intake. Methods Experiment 1 examined whether these lines of mice differed in ethanol withdrawal-induced CNS hyperexcitability and the development of sensitization to this effect following intermittent ethanol vapor exposure. Adult HAP and LAP lines (replicates 1 and 2), and the C3H/HeNcr inbred strain (included as a control genotype for comparison purposes) received intermittent exposure to ethanol vapor and were evaluated for ethanol withdrawal-induced seizures assessed by scoring handling-induced convulsions (HIC). Experiment 2 examined the influence of chronic intermittent ethanol exposure on voluntary ethanol drinking. Adult male and female HAP-2 and LAP-2 mice, along with male C57BL/6J (included as comparative controls) were trained to drink 10% ethanol using a limited access (2 hr/day) 2-bottle choice paradigm. After stable baseline daily intake was established, mice received chronic intermittent ethanol vapor exposure in inhalation chambers. Ethanol intake sessions resumed 72 hr after final ethanol (or air) exposure for 5 consecutive days. Results Following chronic ethanol treatment, LAP mice exhibited overall greater withdrawal seizure activity compared to HAP mice. In Experiment 2, chronic ethanol exposure/withdrawal resulted in a significant increase in ethanol intake in male C57BL/6J, and modestly elevated intake in HAP-2 male mice. Ethanol intake for male control mice

  12. Impaired Insulin Signaling is Associated with Hepatic Mitochondrial Dysfunction in IR+/−-IRS-1+/− Double Heterozygous (IR-IRS1dh Mice

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    Andras Franko

    2017-05-01

    Full Text Available Mitochondria play a pivotal role in energy metabolism, but whether insulin signaling per se could regulate mitochondrial function has not been identified yet. To investigate whether mitochondrial function is regulated by insulin signaling, we analyzed muscle and liver of insulin receptor (IR+/−-insulin receptor substrate-1 (IRS-1+/− double heterozygous (IR-IRS1dh mice, a well described model for insulin resistance. IR-IRS1dh mice were studied at the age of 6 and 12 months and glucose metabolism was determined by glucose and insulin tolerance tests. Mitochondrial enzyme activities, oxygen consumption, and membrane potential were assessed using spectrophotometric, respirometric, and proton motive force analysis, respectively. IR-IRS1dh mice showed elevated serum insulin levels. Hepatic mitochondrial oxygen consumption was reduced in IR-IRS1dh animals at 12 months of age. Furthermore, 6-month-old IR-IRS1dh mice demonstrated enhanced mitochondrial respiration in skeletal muscle, but a tendency of impaired glucose tolerance. On the other hand, 12-month-old IR-IRS1dh mice showed improved glucose tolerance, but normal muscle mitochondrial function. Our data revealed that deficiency in IR/IRS-1 resulted in normal or even elevated skeletal muscle, but impaired hepatic mitochondrial function, suggesting a direct cross-talk between insulin signaling and mitochondria in the liver.

  13. The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice.

    Science.gov (United States)

    Kesby, James P; Markou, Athina; Semenova, Svetlana

    2016-10-01

    Depression and psychostimulant abuse are common comorbidities among humans with immunodeficiency virus (HIV) disease. The HIV regulatory protein TAT is one of multiple HIV-related proteins associated with HIV-induced neurotoxicity. TAT-induced dysfunction of dopamine and serotonin systems in corticolimbic brain areas may result in impaired reward function, thus, contributing to depressive symptoms and psychostimulant abuse. Transgenic mice with doxycycline-induced TAT protein expression in the brain (TAT+, TAT- control) show neuropathology resembling brain abnormalities in HIV+ humans. We evaluated brain reward function in response to TAT expression, nicotine and methamphetamine administration in TAT+ and TAT- mice using the intracranial self-stimulation procedure. We evaluated the brain dopamine and serotonin systems with high-performance liquid chromatography. The effects of TAT expression on delay-dependent working memory in TAT+ and TAT- mice using the operant delayed nonmatch-to-position task were also assessed. During doxycycline administration, reward thresholds were elevated by 20% in TAT+ mice compared with TAT- mice. After the termination of doxycycline treatment, thresholds of TAT+ mice remained significantly higher than those of TAT- mice and this was associated with changes in mesolimbic serotonin and dopamine levels. TAT+ mice showed a greater methamphetamine-induced threshold lowering compared with TAT- mice. TAT expression did not alter delay-dependent working memory. These results indicate that TAT expression in mice leads to reward deficits, a core symptom of depression, and a greater sensitivity to methamphetamine-induced reward enhancement. Our findings suggest that the TAT protein may contribute to increased depressive-like symptoms and continued methamphetamine use in HIV-positive individuals. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Vertical vibration analysis for elevator compensating sheave

    International Nuclear Information System (INIS)

    Watanabe, Seiji; Nakazawa, Daisuke; Fukui, Daiki; Okawa, Takeya

    2013-01-01

    Most elevators applied to tall buildings include compensating ropes to satisfy the balanced rope tension between the car and the counter weight. The compensating ropes receive tension by the compensating sheave, which is installed at the bottom space of the elevator shaft. The compensating sheave is only suspended by the compensating ropes, therefore, the sheave can move vertically while the car is traveling. This paper shows the elevator dynamic model to evaluate the vertical motion of the compensating sheave. Especially, behavior in emergency cases, such as brake activation and buffer strike, was investigated to evaluate the maximum upward motion of the sheave. The simulation results were validated by experiments and the most influenced factor for the sheave vertical motion was clarified

  15. Vertical vibration analysis for elevator compensating sheave

    Science.gov (United States)

    Watanabe, Seiji; Okawa, Takeya; Nakazawa, Daisuke; Fukui, Daiki

    2013-07-01

    Most elevators applied to tall buildings include compensating ropes to satisfy the balanced rope tension between the car and the counter weight. The compensating ropes receive tension by the compensating sheave, which is installed at the bottom space of the elevator shaft. The compensating sheave is only suspended by the compensating ropes, therefore, the sheave can move vertically while the car is traveling. This paper shows the elevator dynamic model to evaluate the vertical motion of the compensating sheave. Especially, behavior in emergency cases, such as brake activation and buffer strike, was investigated to evaluate the maximum upward motion of the sheave. The simulation results were validated by experiments and the most influenced factor for the sheave vertical motion was clarified.

  16. Space Elevator Concept Considered a Reality

    Science.gov (United States)

    2000-01-01

    The `once upon a time' science fiction concept of a space elevator has been envisioned and studied as a real mass transportation system in the latter part of the 21st century. David Smitherman of NASA's Marshall Space Flight Center's Advanced Projects Office has compiled plans for such an elevator. The space elevator concept is a structure extending from the surface of the Earth to geostationary Earth orbit (GEO) at 35,786 km in altitude. The tower would be approximately 50 km tall with a cable tethered to the top. Its center mass would be at GEO such that the entire structure orbits the Earth in sync with the Earth's rotation maintaining a stationary position over its base attachment at the equator. Electromagnetic vehicles traveling along the cable could serve as a mass transportation system for transporting people, payloads, and power between space and Earth. This illustration by artist Pat Rawling shows the concept of a space elevator as viewed from the geostationary transfer station looking down the length of the elevator towards the Earth.

  17. Tokyo Motor Show 2003; Tokyo Motor Show 2003

    Energy Technology Data Exchange (ETDEWEB)

    Joly, E.

    2004-01-01

    The text which follows present the different techniques exposed during the 37. Tokyo Motor Show. The report points out the great tendencies of developments of the Japanese automobile industry. The hybrid electric-powered vehicles or those equipped with fuel cells have been highlighted by the Japanese manufacturers which allow considerable budgets in the research of less polluting vehicles. The exposed models, although being all different according to the manufacturer, use always a hybrid system: fuel cell/battery. The manufacturers have stressed too on the intelligent systems for navigation and safety as well as on the design and comfort. (O.M.)

  18. Assessment of carprofen and buprenorphine on recovery of mice after surgical removal of the mammary fat pad.

    Science.gov (United States)

    Adamson, Trinka W; Kendall, Lon V; Goss, Sherri; Grayson, Kevin; Touma, Chadi; Palme, Rupert; Chen, Jane Q; Borowsky, Alexander D

    2010-09-01

    The purpose of this study was to determine the level of pain elicited by mammary fat pad removal surgery and the effects of postoperative analgesics on recovery. Female FVB mice were anesthetized, and mammary fat pad removal was performed. After surgery, mice received carprofen, buprenorphine, a combination of carprofen and buprenorphine, or saline treatment. Additional mice received anesthesia but no surgery or treatment. Food and water intake, body weight, wheel running activity, and a visual assessment score were recorded daily for 4 d after surgery and compared with presurgical findings. Corticosterone metabolites in fecal samples were analyzed at 12 and 24 h postsurgically and compared with baseline values. All surgical groups had significantly decreased food intake at 24 h, with a return to baseline by 48 h. The combination treatment resulted in a significantly decreased water intake and body weight at 24 h. All surgical groups had significantly decreased wheel running activity at 24 h only. The visual assessment scores indicated mild pain for all surgical groups, with the buprenorphine treated mice showing the highest pain index scores, as compared with nonsurgical controls. Fecal corticosterone metabolite levels did not differ significantly between any of the groups or across time. The parameters used in this study did not indicate that administration of these analgesic regimens improved recovery as compared with that of saline-treated mice. Care should be taken when using visual assessment scores to evaluate pain in mice, given that analgesics may have side effects that inadvertently elevate the score.

  19. The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice

    Directory of Open Access Journals (Sweden)

    Lakshini Herat

    2017-04-01

    Full Text Available Obesity and diabetes are major causes of morbidity and mortality globally. The current study builds upon our previous association studies highlighting that A Disintegrin And Metalloproteinase 28 (ADAM28 appears to be implicated in the pathogenesis of obesity and type 2 diabetes in humans. Our novel study characterised the expression of ADAM28 in mice with the metabolic syndrome and used molecular inhibition approaches to investigate the functional role of ADAM28 in the pathogenesis of high fat diet-induced obesity. We identified that ADAM28 mRNA and protein expression was markedly increased in the livers of mice with the metabolic syndrome. In addition, noradrenaline, the major neurotransmitter of the sympathetic nervous system, results in elevated Adam28 mRNA expression in human monocytes. Downregulation of ADAM28 with siRNA technology resulted in a lack of weight gain, promotion of insulin sensitivity/glucose tolerance and decreased liver tumour necrosis factor-α (TNF-α levels in our diet-induced obesity mouse model as well as reduced blood urea nitrogen, alkaline phosphatase and aspartate aminotransferase. In addition, we show that ADAM28 knock-out mice also displayed reduced body weight, elevated high density lipoprotein cholesterol levels, and reductions in blood urea nitrogen, alkaline phosphatase, and aspartate aminotransferase. The results of this study provide important insights into the pathogenic role of the metalloproteinase ADAM28 in the metabolic syndrome and suggests that downregulation of ADAM28 may be a potential therapeutic strategy in the metabolic syndrome.

  20. Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia.

    Science.gov (United States)

    Iriyama, Takayuki; Sun, Kaiqi; Parchim, Nicholas F; Li, Jessica; Zhao, Cheng; Song, Anren; Hart, Laura A; Blackwell, Sean C; Sibai, Baha M; Chan, Lee-Nien L; Chan, Teh-Sheng; Hicks, M John; Blackburn, Michael R; Kellems, Rodney E; Xia, Yang

    2015-02-24

    Preeclampsia is a prevalent hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality worldwide. This pathogenic condition is speculated to be caused by placental abnormalities that contribute to the maternal syndrome. However, the specific factors and signaling pathways that lead to impaired placentas and maternal disease development remain elusive. Using 2 independent animal models of preeclampsia (genetically engineered pregnant mice with elevated adenosine exclusively in placentas and a pathogenic autoantibody-induced preeclampsia mouse model), we demonstrated that chronically elevated placental adenosine was sufficient to induce hallmark features of preeclampsia, including hypertension, proteinuria, small fetuses, and impaired placental vasculature. Genetic and pharmacological approaches revealed that elevated placental adenosine coupled with excessive A₂B adenosine receptor (ADORA2B) signaling contributed to the development of these features of preeclampsia. Mechanistically, we provided both human and mouse evidence that elevated placental CD73 is a key enzyme causing increased placental adenosine, thereby contributing to preeclampsia. We determined that elevated placental adenosine signaling is a previously unrecognized pathogenic factor for preeclampsia. Moreover, our findings revealed the molecular basis underlying the elevation of placental adenosine and the detrimental role of excess placental adenosine in the pathophysiology of preeclampsia, and thereby, we highlight novel therapeutic targets. © 2014 American Heart Association, Inc.

  1. Retinal Ganglion Cell Loss in Diabetes Associated with Elevated Homocysteine

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    Kenneth S. Shindler

    2009-11-01

    Full Text Available A number of studies have suggested that homocysteine may be a contributing factor to development of retinopathy in diabetic patients based on observed correlations between elevated homocysteine levels and the presence of retinopathy. The significance of such a correlation remains to be determined, and potential mechanisms by which homocysteine might induce retinopathy have not been well characterized. Ganapathy and colleagues1 used mutant mice that have endogenously elevated homocysteine levels due to heterozygous deletion of the cystathionine-β-synthase gene to examine changes in retinal pathology following induction of diabetes. Their finding that elevated homocysteine levels hastens loss of cells in the retinal ganglion cell layer suggests that toxicity to ganglion cells may warrant further investigation as a potential mechanism of homocysteine enhanced susceptibility to diabetic retinopathy.

  2. Elevation of the diaphragmatic cupola

    International Nuclear Information System (INIS)

    Semenov, V.M.; Talesnik, M.R.

    1988-01-01

    Altogether 45 patients with elevation of the diaphragmatic cupola were examined. A high frequency of erroneous initial interpretation of examination results was noted in inflammatory and tumorous lesions and congenital conditions. Routine and contrast methods (pneumoperitoneum, bronchography, pleurography and fistulography) were used. Disease-related methods of X-ray investigation were proposed. A variety of causes of diaphragm elevation was indicated

  3. Space Station tethered elevator system

    Science.gov (United States)

    Haddock, Michael H.; Anderson, Loren A.; Hosterman, K.; Decresie, E.; Miranda, P.; Hamilton, R.

    1989-01-01

    The optimized conceptual engineering design of a space station tethered elevator is presented. The tethered elevator is an unmanned, mobile structure which operates on a ten-kilometer tether spanning the distance between Space Station Freedom and a platform. Its capabilities include providing access to residual gravity levels, remote servicing, and transportation to any point along a tether. The report discusses the potential uses, parameters, and evolution of the spacecraft design. Emphasis is placed on the elevator's structural configuration and three major subsystem designs. First, the design of elevator robotics used to aid in elevator operations and tethered experimentation is presented. Second, the design of drive mechanisms used to propel the vehicle is discussed. Third, the design of an onboard self-sufficient power generation and transmission system is addressed.

  4. Over-expression of two different forms of the alpha-secretase ADAM10 affects learning and memory in mice.

    Science.gov (United States)

    Schmitt, Ulrich; Hiemke, Christoph; Fahrenholz, Falk; Schroeder, Anja

    2006-12-15

    Members of the ADAM family (adisintegrin and metalloprotease) are the main candidates for physiologically relevant alpha-secretases. The alpha-secretase cleaves in the non-amyloidogenic pathway the amyloid precursor protein within the region of the Abeta peptides preventing their aggregation in the brain. The increase of alpha-secretase activity in the brain provides a plausible strategy to prevent Abeta formation. Concerning this possibility two transgenic mouse lines (FVB/N) have been created: mice over-expressing the bovine form of the alpha-secretase (ADAM10) and mice over-expressing an inactive form of the alpha-secretase (ADAM10-E348A-HA; ADAM10-dn). For behavioral examination a F1 generation of transgenic mice (C57Bl/6 x FVB/N (tg)) was generated and compared to wild type F1 generation (C57Bl/6 x FVB/N). Behavior was characterized in the following tasks: standard open field, enriched open field, elevated plus-maze, and the Morris water maze hidden platform task. Concerning basal activity, exploration, and anxiety, transgenic mice behaved similar to controls. With respect to learning and memory both transgenic lines showed a significant deficit compared to controls. ADAM10 mice however, showed thigmotaxis with passive floating behavior in the Morris water maze indicating differences in motivation, whereas, ADAM10-dn mice displayed an inconspicuous but limited goal-directed search pattern. Thus variation of the enzymatic activity of alpha-secretase ADAM10 alters learning and memory differentially. Nevertheless, it could be concluded that both, ADAM10 and ADAM10-dn mice are suitable control mice for the assessment of alpha-secretase-related effects in animal models of Alzheimer's disease.

  5. Impact of Triclosan on Female Reproduction through Reducing Thyroid Hormones to Suppress Hypothalamic Kisspeptin Neurons in Mice

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    Xin-Yuan Cao

    2018-01-01

    Full Text Available Triclosan (TCS, a broad-spectrum antimicrobial agent, is widely used in clinical settings and various personal care products. The aim of this study was to evaluate the influence of TCS on reproductive endocrine and function. Here, we show that the exposure of adult female mice to 10 or 100 mg/kg/day TCS caused prolongation of diestrus, and decreases in antral follicles and corpora lutea within 2 weeks. TCS mice showed decreases in the levels of serum luteinizing hormone (LH, follicle-stimulating hormone (FSH and progesterone, and gonadotrophin-releasing hormone (GnRH mRNA with the lack of LH surge and elevation of prolactin (PRL. TCS mice had lower kisspeptin immunoreactivity and kiss1 mRNA in anteroventral periventricular nucleus (AVPV and arcuate nucleus (ARC. Moreover, the estrogen (E2-enhanced AVPV-kisspeptin expression was reduced in TCS mice. In addition, the serum thyroid hormones (triiodothyronine (T3 and thyroxine (T4 in TCS mice were reduced with increases in levels of thyroid stimulating hormone (TSH and thyroid releasing hormone (TRH. In TCS mice, the treatment with Levothyroxine (L-T4 corrected the increases in PRL, TSH and TRH; the administration of L-T4 or type-2 dopamine receptors agonist quinpirole inhibiting PRL release could rescue the decline of kisspeptin expression in AVPV and ARC; the treatment with L-T4, quinpirole or the GPR45 agonist kisspeptin-10 recovered the levels of serum LH and FSH and progesterone, and GnRH mRNA. Furthermore, TCS mice treated with L-T4 or quinpirole resumed regular estrous cycling, follicular development and ovulation. Together, these results indicate that exposing adult female mice to TCS (≥10 mg/kg reduces thyroid hormones causing hyperprolactinemia that then suppresses hypothalamic kisspeptin expression, leading to deficits in reproductive endocrine and function.

  6. Chronic psychosocial stress causes delayed extinction and exacerbates reinstatement of ethanol-induced conditioned place preference in mice.

    Science.gov (United States)

    Bahi, Amine; Dreyer, Jean-Luc

    2014-01-01

    We have shown previously, using an animal model of voluntary ethanol intake and ethanol-conditioned place preference (EtOH-CPP), that exposure to chronic psychosocial stress induces increased ethanol intake and EtOH-CPP acquisition in mice. Here, we examined the impact of chronic subordinate colony (CSC) exposure on EtOH-CPP extinction, as well as ethanol-induced reinstatement of CPP. Mice were conditioned with saline or 1.5 g/kg ethanol and were tested in the EtOH-CPP model. In the first experiment, the mice were subjected to 19 days of chronic stress, and EtOH-CPP extinction was assessed during seven daily trials without ethanol injection. In the second experiment and after the EtOH-CPP test, the mice were subjected to 7 days of extinction trials before the 19 days of chronic stress. Drug-induced EtOH-CPP reinstatement was induced by a priming injection of 0.5 g/kg ethanol. Compared to the single-housed colony mice, CSC mice exhibited increased anxiety-like behavior in the elevated plus maze (EPM) and the open field tests. Interestingly, the CSC mice showed delayed EtOH-CPP extinction. More importantly, CSC mice showed increased alcohol-induced reinstatement of the EtOH-CPP behavior. Taken together, this study indicates that chronic psychosocial stress can have long-term effects on EtOH-CPP extinction as well as drug-induced reinstatement behavior and may provide a suitable model to study the latent effects of chronic psychosocial stress on extinction and relapse to drug abuse.

  7. Altered behaviour and cognitive function following combined deletion of Toll-like receptors 2 and 4 in mice.

    Science.gov (United States)

    Too, Lay Khoon; McGregor, Iain S; Baxter, Alan G; Hunt, Nicholas H

    2016-04-15

    Activation of the immune system due to infection or aging is increasingly linked to impaired neuropsychological function. Toll-like receptors 2 and 4 (TLR2, TLR4) are well-characterised for their role in inflammatory events, and their combined activation has been implicated in neurological diseases. We therefore determined whether TLR2 and TLR4 double gene knockout (GKO) mice showed modified behaviour and cognitive function during a 16-day test sequence that employed the automated IntelliCage test system. The IntelliCage features a home cage environment in which groups of mice live and where water reward is gained through performing various tasks centred on drinking stations in each corner of the apparatus. All mice were tested twice, one month apart (the first sequence termed "R1"and the second "R2"). There were fewer corner visits and nosepokes in TLR2/4 GKO compared to wild-type mice during early exploration in R1, suggesting elevated neophobia in GKO mice. Reduced exploration persisted over subsequent test modules during the dark phase. TLR2/4 GKO mice also displayed increased corner visits during drinking sessions compared to non-drinking sessions, but this was not associated with increased drinking. In subsequent, more complex test modules, TLR2/4 GKO mice had unimpaired spatial learning, but showed markedly poorer performance in a visual discrimination reversal task compared to wild-type mice. These results indicated subtle impairments in behaviour and cognitive functions due to double deficiency in TLR2 and TLR4. These finding are highly relevant to understanding the combined actions of TLR2 and TLR4 on neurological status in a range of different disease conditions. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

  8. Reality show: um paradoxo nietzschiano

    Directory of Open Access Journals (Sweden)

    Ilana Feldman

    2011-01-01

    Full Text Available

    O fenômeno dos reality shows - e a subseqüente relação entre imagem e verdade - assenta-se sobre uma série de paradoxos. Tais paradoxos podem ser compreendidos à luz do pensamento do filósofo alemão Friedrich Nietzsche, que, através dos usos de formulações paradoxais, concebia a realidade como um mundo de pura aparência e a verdade como um acréscimo ficcional, como um efeito. A ficção é então tomada, na filosofia de Nietzsche, não em seu aspecto falsificante e desrealizador - como sempre pleiteou nossa tradição metafísica -, mas como condição necessária para que certa espécie de invenção possa operar como verdade. Sendo assim, a própria expressão reality show, através de sua formulação paradoxal, engendra explicitamente um mundo de pura aparência, em que a verdade, a parte reality da proposição, é da ordem do suplemento, daquilo que se acrescenta ficcionalmente - como um adjetivo - a show. O ornamento, nesse caso, passa a ocupar o lugar central, apontando para o efeito produzido: o efeito-de-verdade. Seguindo, então, o pensamento nietzschiano e sua atualização na contemporaneidade, investigaremos de que forma os televisivos “shows de realidade” operam paradoxalmente, em consonância com nossas paradoxais práticas culturais.

  9. Mitochondrial dysfunction contribute to diabetic neurotoxicity induced by streptozocin in mice: protective effect of Urtica dioica and pioglitazone.

    Science.gov (United States)

    Shokrzadeh, Mohammad; Mirshafa, Atefeh; Yekta Moghaddam, Niusha; Birjandian, Behnoosh; Shaki, Fatemeh

    2018-04-18

    Uncontrolled chronic hyperglycemia in diabetic patients could result in various complications, including neurotoxicity. Urtica dioica L. (UD) is known for its hypoglycemic and antioxidant effects. In this study, we evaluated the efficacy of UD and pioglitazone (PIO) in reduction of neurotoxicity and oxidative stress in streptozocin-induced diabetic mice. Male mice were divided into seven groups: control, diabetic, dimethyl sulfoxide-treated control, PIO-treated, UD-treated, UD-PIO-treated, and vitamin E-treated. For induction of diabetes, streptozocin was injected in a single dose (65 mg/kg, i.p.). All treatments were performed for 5 weeks. Neurotoxicity was evaluated through hot plate and formalin test. Then, animals were killed, brain tissue was separated and the mitochondrial fraction was isolated with different centrifuge technique. Also, oxidative stress markers (reactive oxygen species, lipid peroxidation, protein carbonyl, glutathione) were measured in brain. Mitochondrial function was evaluated by MTT test in brain isolated mitochondria. Elevation of oxidative stress markers and mitochondrial damage were observed in diabetic mice compared to control group. Administration of PIO and UD ameliorated the oxidative stress and mitochondrial damage (p < 0.05) in diabetic mice. Also increase in pain score was shown in diabetic mice that treatment with UD and PIO diminished elevation of pain score in diabetic mice. Interestingly, simultaneous administration of PIO and UD showed synergism effect in attenuation of oxidative stress and hyperglycemia. UD showed a therapeutic potential for the attenuation of oxidative stress and diabetes-induced hyperglycemia that can be considered as co-treatment in treatment of diabetic neurotoxicity.

  10. Monosodium glutamate-associated alterations in open field, anxiety-related and conditioned place preference behaviours in mice.

    Science.gov (United States)

    Onaolapo, Olakunle James; Aremu, Olaleye Samuel; Onaolapo, Adejoke Yetunde

    2017-07-01

    The present study investigated changes in behaviour associated with oral monosodium glutamate (a flavouring agent), using the open field, elevated plus maze and conditioned place preference (CPP) paradigms, respectively. Mice were assigned to two groups for CPP [monosodium glutamate (MSG)-naïve (n = 40) and MSG-pretreated (n = 40)] and two groups for open field (OF) and elevated plus maze (EPM) tests [n = 40 each], respectively. Animals in respective groups were then divided into four subgroups (n = 10) (vehicle or MSG (80, 160 and 320 mg/kg)). MSG-naïve mice were observed in the CPP box in three phases (pre-conditioning, conditioning and post-conditioning). Mice were conditioned to MSG or an equivalent volume of saline. The MSG pretreatment group received vehicle or respective doses of MSG daily for 21 days, prior to conditioning. Mice in the OF or EPM groups received vehicle or doses of MSG (orally) for 21 days, at 10 ml/kg. Open field or EPM behaviours were assessed on days 1 and 21. At the end of the experiments, mice in the OF groups were sacrificed and brain homogenates used to assay glutamate and glutamine. Results showed that administration of MSG was associated with a decrease in rearing, dose-related mixed horizontal locomotor, grooming and anxiety-related response and an increase in brain glutamate/glutamine levels. Following exposure to the CPP paradigm, MSG-naïve and MSG-pretreated mice both showed 'drug-paired' chamber preference. The study concluded that MSG (at the administered doses) was associated with changes in open field activities, anxiety-related behaviours and brain glutamate/glutamine levels; its ingestion also probably leads to a stimulation of the brain reward system.

  11. MKR mice have increased dynamic glucose disposal despite metabolic inflexibility, and hepatic and peripheral insulin insensitivity.

    Science.gov (United States)

    Vaitheesvaran, B; LeRoith, D; Kurland, I J

    2010-10-01

    Recent work has shown that there can be significant differences when glucose disposal is assessed for high-fat induced insulin resistance by static clamp methods vs dynamic assessment during a stable isotope i.p. glucose tolerance test. MKR mice, though lean, have severe insulin resistance and decreased muscle fatty acid oxidation. Our goal was to assess dynamic vs static glucose disposal in MKR mice, and to correlate glucose disposal and muscle-adipose-liver flux interactions with metabolic flexibility (indirect calorimetry) and muscle characteristics. Stable isotope flux phenotyping was performed using [6,6-(2)H(2)]glucose, [U-(13)C(6)]glucose and [2-(13)C]glycerol. Muscle triacylglycerol (TAG) and diacylglycerol (DAG) content was assessed by thin layer chromatography, and histological determination of fibre type and cytochrome c activity performed. Metabolic flexibility was assessed by indirect calorimetry. Indirect calorimetry showed that MKR mice used more glucose than FVB/N mice during fasting (respiratory exchange ratio [RER] 0.88 vs 0.77, respectively). Compared with FVB/N mice, MKR mice had faster dynamic glucose disposal, despite increased whole-muscle DAG and TAG, and similar hepatic glucose production with higher fasting insulin and unchanged basal glucose. Fed MKR muscle had more glycogen, and increased levels of GLUT1 and GLUT4 than FVB/N muscle. Histology indicated that MKR soleus had mildly decreased cytochrome c activity overall and more type II (glycolytic) fibres compared with that in FVB/N mice. MKR muscle adapts to using glucose, with more type II fibres present in red muscle. Fasting RER is elevated and glucose disposal during an i.p. glucose tolerance test is accelerated despite increased muscle DAG and TAG. Metabolic inflexibility may result from the compensatory use of fuel that can be best utilised for energy requirements; static vs dynamic glucose disposal assessments may measure complementary aspects of metabolic flexibility and insulin

  12. Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice

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    Zhang, Rong; Asai, Masato; Mahoney, Carrie E; Joachim, Maria; Shen, Yuan; Gunner, Georgia; Majzoub, Joseph A

    2016-01-01

    A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, while extra-hypothalamic CRH plays a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma ACTH, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open field, elevated plus maze, holeboard, light-dark box, and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus, and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation. PMID:27595593

  13. Effects of Breeding Configuration on Maternal and Weanling Behavior in Laboratory Mice.

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    Braden, Gillian C; Rasmussen, Skye; Monette, Sebastien; Tolwani, Ravi J

    2017-07-01

    Although numerous studies have evaluated the effect of housing density on the wellbeing of laboratory mice, little is known about the effect of breeding configuration on mouse behavior. The 8th edition of the Guide for the Care and Use of Laboratory Animals lists the recommended minimal floor area per animal for a female mouse and her litter as 51 in.2 We sought to determine the effects of pair, trio, and harem breeding configurations on the maternal and weanling behavior of C57BL/6J (B6) and 129S6/SvEvTac (129) mice on the basis of nest scores and performance in pup retrieval tests, open-field test (OFT), elevated plus maze, and tail suspension test; we concurrently evaluated cage microenvironment, reproductive indices, and anatomic and clinical pathology. Harem breeding configurations enhanced B6 maternal behaviors as evidenced by significantly shorter pup retrieval times. Trio- and harem-raised B6 weanlings showed increased exploratory behaviors, as evidenced by greater time spent in the center of the OFT, when compared with pair-raised B6 mice. Conversely, breeding configuration did not alter pup retrieval times for 129 mice, and on the day of weaning trio- and harem-raised 129 mice demonstrated increased anxiety-like behavior, as evidenced by greater time spent in the periphery of the OFT, when compared with pair-raised counterparts. Behavioral differences were not noted on subsequent days for either strain. Trio- and harem-raised B6 and 129 weanling mice had significantly higher weaning weights than weanlings raised in a pair breeding configuration. Trio and harem breeding in a standard 67-in.2 shoebox cage did not detrimentally affect the evaluated welfare parameters in either C57BL/6J or 129S6/SvEvTac mice.

  14. Delayed recovery of skeletal muscle mass following hindlimb immobilization in mTOR heterozygous mice.

    Directory of Open Access Journals (Sweden)

    Susan M Lang

    Full Text Available The present study addressed the hypothesis that reducing mTOR, as seen in mTOR heterozygous (+/- mice, would exaggerate the changes in protein synthesis and degradation observed during hindlimb immobilization as well as impair normal muscle regrowth during the recovery period. Atrophy was produced by unilateral hindlimb immobilization and data compared to the contralateral gastrocnemius. In wild-type (WT mice, the gradual loss of muscle mass plateaued by day 7. This response was associated with a reduction in basal protein synthesis and development of leucine resistance. Proteasome activity was consistently elevated, but atrogin-1 and MuRF1 mRNAs were only transiently increased returning to basal values by day 7. When assessed 7 days after immobilization, the decreased muscle mass and protein synthesis and increased proteasome activity did not differ between WT and mTOR(+/- mice. Moreover, the muscle inflammatory cytokine response did not differ between groups. After 10 days of recovery, WT mice showed no decrement in muscle mass, and this accretion resulted from a sustained increase in protein synthesis and a normalization of proteasome activity. In contrast, mTOR(+/- mice failed to fully replete muscle mass at this time, a defect caused by the lack of a compensatory increase in protein synthesis. The delayed muscle regrowth of the previously immobilized muscle in the mTOR(+/- mice was associated with a decreased raptor•4EBP1 and increased raptor•Deptor binding. Slowed regrowth was also associated with a sustained inflammatory response (e.g., increased TNFα and CD45 mRNA during the recovery period and a failure of IGF-I to increase as in WT mice. These data suggest mTOR is relatively more important in regulating the accretion of muscle mass during recovery than the loss of muscle during the atrophy phase, and that protein synthesis is more sensitive than degradation to the reduction in mTOR during muscle regrowth.

  15. Delayed recovery of skeletal muscle mass following hindlimb immobilization in mTOR heterozygous mice.

    Science.gov (United States)

    Lang, Susan M; Kazi, Abid A; Hong-Brown, Ly; Lang, Charles H

    2012-01-01

    The present study addressed the hypothesis that reducing mTOR, as seen in mTOR heterozygous (+/-) mice, would exaggerate the changes in protein synthesis and degradation observed during hindlimb immobilization as well as impair normal muscle regrowth during the recovery period. Atrophy was produced by unilateral hindlimb immobilization and data compared to the contralateral gastrocnemius. In wild-type (WT) mice, the gradual loss of muscle mass plateaued by day 7. This response was associated with a reduction in basal protein synthesis and development of leucine resistance. Proteasome activity was consistently elevated, but atrogin-1 and MuRF1 mRNAs were only transiently increased returning to basal values by day 7. When assessed 7 days after immobilization, the decreased muscle mass and protein synthesis and increased proteasome activity did not differ between WT and mTOR(+/-) mice. Moreover, the muscle inflammatory cytokine response did not differ between groups. After 10 days of recovery, WT mice showed no decrement in muscle mass, and this accretion resulted from a sustained increase in protein synthesis and a normalization of proteasome activity. In contrast, mTOR(+/-) mice failed to fully replete muscle mass at this time, a defect caused by the lack of a compensatory increase in protein synthesis. The delayed muscle regrowth of the previously immobilized muscle in the mTOR(+/-) mice was associated with a decreased raptor•4EBP1 and increased raptor•Deptor binding. Slowed regrowth was also associated with a sustained inflammatory response (e.g., increased TNFα and CD45 mRNA) during the recovery period and a failure of IGF-I to increase as in WT mice. These data suggest mTOR is relatively more important in regulating the accretion of muscle mass during recovery than the loss of muscle during the atrophy phase, and that protein synthesis is more sensitive than degradation to the reduction in mTOR during muscle regrowth.

  16. Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone

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    Michailidou, Zoi; Coll, Anthony P; Kenyon, Christopher J; Morton, Nicholas M; O'Rahilly, Stephen; Seckl, Jonathan R; Chapman, Karen E

    2007-01-01

    Proopiomelanocortin (POMC) deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigate against insulin resistance, hyperphagia and fat accretion in Pomc−/− mice. Upon exogenous glucocorticoid replacement, corticosterone-supplemented (CORT) Pomc−/− mice show exaggerated responses, including excessive fat accumulation, hyperleptinaemia and insulin resistance. To investigate the peripheral mechanisms underlying this glucocorticoid hypersensitivity, we examined the expression levels of key determinants and targets of glucocorticoid action in adipose tissue and liver. Despite lower basal expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11β-HSD1 mRNA levels was more pronounced in adipose tissues of Pomc−/− mice. Similarly, CORT treatment increased lipoprotein lipase mRNA levels in all fat depots in Pomc−/− mice, consistent with exaggerated fat accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal fat of Pomc−/− mice but were corrected by CORT in the latter depot. In liver, CORT increased phosphoenolpyruvate carboxykinase mRNA levels specifically in Pomc−/− mice, consistent with their insulin-resistant phenotype. Furthermore, CORT induced hypertension in Pomc−/− mice, independently of adipose or liver renin–angiotensin system activation. These data suggest that CORT-inducible 11β-HSD1 expression in fat contributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver. PMID:17592030

  17. Blood lipid-lowering and antioxidant effects of a structured lipid containing monoacylglyceride enriched with monounsaturated fatty acids in C57BL/6 mice.

    Science.gov (United States)

    Cho, Kyung-Hyun; Lee, Jeung-Hee; Kim, Jin-Man; Park, Sang Hyun; Choi, Myung-Sook; Lee, Yun-Mi; Choi, Inh