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Sample records for chronic erythropoietin-treated mice

  1. Erythropoietin improves operant conditioning and stability of cognitive performance in mice

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    Ehrenreich Hannelore

    2009-07-01

    Full Text Available Abstract Background Executive functions, learning and attention are imperative facets of cognitive performance, affected in many neuropsychiatric disorders. Recently, we have shown that recombinant human erythropoietin improves cognitive functions in patients with chronic schizophrenia, and that it leads in healthy mice to enhanced hippocampal long-term potentiation, an electrophysiological correlate of learning and memory. To create an experimental basis for further mechanistic insight into erythropoietin-modulated cognitive processes, we employed the Five Choice Serial Reaction Time Task. This procedure allows the study of the effects of erythropoietin on discrete processes of learning and attention in a sequential fashion. Results Male mice were treated for 3 weeks with erythropoietin (5,000 IU/kg versus placebo intraperitoneally every other day, beginning at postnatal day 28. After termination of treatment, mice were started on the Five Choice Serial Reaction Time Task, with daily training and testing extending to about 3 months. Overall, a significantly higher proportion of erythropoietin-treated mice finished the task, that is, reached the criteria of adequately reacting to a 1.0 sec flash light out of five arbitrarily appearing choices. During acquisition of this capability, that is, over almost all sequential training phases, learning readouts (magazine training, operant and discriminant learning, stability of performance were superior in erythropoietin-treated versus control mice. Conclusion Early erythropoietin treatment leads to lasting improvement of cognitive performance in healthy mice. This finding should be exploited in novel treatment strategies for brain diseases.

  2. Adaptations to chronic rapamycin in mice

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    Sherry G. Dodds

    2016-05-01

    Full Text Available Rapamycin inhibits mechanistic (or mammalian target of rapamycin (mTOR that promotes protein production in cells by facilitating ribosome biogenesis (RiBi and eIF4E-mediated 5'cap mRNA translation. Chronic treatment with encapsulated rapamycin (eRapa extended health and life span for wild-type and cancer-prone mice. Yet, the long-term consequences of chronic eRapa treatment are not known at the organ level. Here, we report our observations of chronic eRapa treatment on mTORC1 signaling and RiBi in mouse colon and visceral adipose. As expected, chronic eRapa treatment decreased detection of phosphorylated mTORC1/S6K substrate, ribosomal protein (rpS6 in colon and fat. However, in colon, contrary to expectations, there was an upregulation of 18S rRNA and some ribosomal protein genes (RPGs suggesting increased RiBi. Among RPGs, eRapa increases rpl22l1 mRNA but not its paralog rpl22. Furthermore, there was an increase in the cap-binding protein, eIF4E relative to its repressor 4E-BP1 suggesting increased translation. By comparison, in fat, there was a decrease in the level of 18S rRNA (opposite to colon, while overall mRNAs encoding ribosomal protein genes appeared to increase, including rpl22, but not rpl22l1 (opposite to colon. In fat, there was a decrease in eIF4E relative to actin (opposite to colon but also an increase in the eIF4E/4E-BP1 ratio likely due to reductions in 4E-BP1 at our lower eRapa dose (similar to colon. Thus, in contrast to predictions of decreased protein production seen in cell-based studies, we provide evidence that colon from chronically treated mice exhibited an adaptive ‘pseudo-anabolic’ state, which is only partially present in fat, which might relate to differing tissue levels of rapamycin, cell-type-specific responses, and/or strain differences.

  3. Induction of Chronic Myeloid Leukemia in Mice.

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    Zhang, Haojian; Li, Shaoguang

    2016-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder derived from a hematopoietic stem cell (HSC), harboring Philadelphia chromosome (Ph chromosome). Formation of the Ph chromosome is caused by a reciprocal translocation between the chromosomes 9 and 22 t(9;22)(q34;q11), resulting in a fusion protein known as BCR-ABL which has constitutive tyrosine kinase activity and promotes the proliferation of leukemia cells via multiple mechanisms. Studies on CML have led to the identification of the first cancer-associated chromosomal abnormality and the subsequent development of tyrosine kinase inhibitors (TKIs) that inhibit BCR-ABL kinase activity in CML. It has become clear that leukemia stem cells (LSCs) in CML are insensitive to inhibition by TKIs, and eradication of LSCs appears to be difficult. Therefore, some of the major issues in current CML therapy are to understand the biology of LSCs and to investigate why LSCs are insensitive to TKIs for developing curative therapeutic strategies. In this regard, application of mouse models recapitulating human CML disease will be critical. In this chapter, we describe methods for induction of CML in mice with BCR-ABL. PMID:27581135

  4. Lymphocytes from Chronically Stressed Mice Confer Antidepressant-Like Effects to Naive Mice

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    Brachman, Rebecca A.; Lehmann, Michael L.; Maric, Dragan; Herkenham, Miles

    2015-01-01

    We examined whether cells of the adaptive immune system retain the memory of psychosocial stress and thereby alter mood states and CNS function in the host. Lymphocytes from mice undergoing chronic social defeat stress or from unstressed control mice were isolated and adoptively transferred into naive lymphopenic Rag2−/− mice. Changes in affective behavior, hippocampal cell proliferation, microglial activation states, and blood cytokine levels were examined in reconstituted stress-naive mice....

  5. Unpredictable chronic mild stress not chronic restraint stress induces depressive behaviours in mice.

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    Zhu, Shenghua; Shi, Ruoyang; Wang, Junhui; Wang, Jun-Feng; Li, Xin-Min

    2014-10-01

    The chronic stress model was developed on the basis of the stress-diathesis hypothesis of depression. However, these behavioural responses associated with different stress paradigms are quite complex. This study examined the effects of two chronic stress regimens on anxiety-like and depressive behaviours. C57BL/6 mice were subjected to unpredictable chronic mild stress or to chronic restraint stress for 4 weeks. Subsequently, both anxiety-like behaviours (open field, elevated plus maze and novelty suppressed feeding) and depression-like behaviours (tail suspension, forced swim and sucrose preference) were evaluated. Both chronic stress models generated anxiety-like behaviours, whereas only unpredictable chronic mild stress could induce depressive behaviours such as increased immobility and decreased sucrose consumption. These results of the present study provide additional evidence on how chronic stress affects behavioural responses and point to the importance of the validity of animal models of chronic stress in studying depression. PMID:25089805

  6. Effects of chronic centrifugation on mice

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    Janer, L.; Duke, J.

    1984-01-01

    Previous studies have shown that exposure to excess gravity in vitro alters the developmental sequence in embryonic mouse limbs and palates (Duke, Janer and Campbell, 1984; Duke, 1983). The effects of excess gravity on in vivo mammalian development was investigated using a small animal centrifuge. Four-week old female mice exposed to excess gravities of 1.8-3.5 G for eight weeks weighed significantly less than controls. Mice were mated after five weeks of adaptation to excess G, and sacrificed either at gestational day 12 or 18. There were fewer pregnancies in the centrifuged group (4/36) than in controls (9/31), and crown rump lengths (CRL) of embryos developing in the centrifuge were less than CRLs of 1-G embryos. These results show that although immersed in amniotic fluid, embryos are responsive to Delta-G.

  7. Therapeutic Effects of Troglitazone in Experimental Chronic Pancreatitis in Mice

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    van Westerloo, David J.; Florquin, Sandrine; de Boer, Anita M; Daalhuisen, Joost; Alex F de Vos; Bruno, Marco J.; van der Poll, Tom

    2005-01-01

    Peroxisome proliferator-activated receptor (PPAR)-γ controls growth, differentiation, and inflammation. PPAR-γ agonists exert anti-inflammatory effects in vitro and inhibit the activation of pancreas stellate cells, implicated in the formation and progression of fibrosis. We determined the influence of troglitazone, a ligand for PPAR-γ, on pancreatic damage and fibrosis in experimental chronic pancreatitis. Mice received six hourly intraperitoneal injections with 50 μg/kg of cerulein or salin...

  8. Memory Deficit Recovery after Chronic Vanadium Exposure in Mice

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    Oluwabusayo Folarin

    2016-01-01

    Full Text Available Vanadium is a transitional metal with an ability to generate reactive oxygen species in the biological system. This work was designed to assess memory deficits in mice chronically exposed to vanadium. A total of 132 male BALB/c mice (4 weeks old were used for the experiment and were divided into three major groups of vanadium treated, matched controls, and animals exposed to vanadium for three months and thereafter vanadium was withdrawn. Animals were tested using Morris water maze and forelimb grip test at 3, 6, 9, and 12 months of age. The results showed that animals across the groups showed no difference in learning but had significant loss in memory abilities after 3 months of vanadium exposure and this trend continued in all vanadium-exposed groups relative to the controls. Animals exposed to vanadium for three months recovered significantly only 9 months after vanadium withdrawal. There was no significant difference in latency to fall in the forelimb grip test between vanadium-exposed groups and the controls in all age groups. In conclusion, we have shown that chronic administration of vanadium in mice leads to memory deficit which is reversible but only after a long period of vanadium withdrawal.

  9. PET imaging of acute and chronic inflammation in living mice

    International Nuclear Information System (INIS)

    In this study, we evaluated the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced acute and chronic inflammation in living mice by PET imaging of TNF-α and integrin αvβ3 expression. TPA was topically applied to the right ear of BALB/c mice every other day to create the inflammation model. 64Cu-DOTA-etanercept and 64Cu-DOTA-E{E[c(RGDyK)]2}2 were used for PET imaging of TNF-α and integrin αvβ3 expression in both acute and chronic inflammation. Hematoxylin and eosin staining, ex vivo autoradiography, direct tissue sampling, and immunofluorescence staining were also performed to confirm the non-invasive PET imaging results. The ear thickness increased significantly and the TNF-α level more than tripled after a single TPA challenge. MicroPET imaging using 64Cu-DOTA-etanercept revealed high activity accumulation in the inflamed ear, reaching 11.1 ± 1.3, 13.0 ± 2.0, 10.9 ± 1.4, 10.2 ± 2.2%ID/g at 1, 4, 16, and 24 h post injection, respectively (n = 3). Repeated TPA challenges caused TPA-specific chronic inflammation and reduced 64Cu-DOTA-etanercept uptake due to lowered TNF-α expression. 64Cu-DOTA-E{E[c(RGDyK)]2}2 uptake in the chronically inflamed ears (after four and eight TPA challenges) was significantly higher than in the control ears and those after one TPA challenge. Immunofluorescence staining revealed increased integrin β3 expression, consistent with the non-invasive PET imaging results using 64Cu-DOTA-E{E[c(RGDyK)]2}2 as an integrin αv β3-specific radiotracer. Biodistribution and autoradiography studies further confirmed the quantification capability of microPET imaging. Successful PET imaging of TNF- α expression in acute inflammation and integrin αv β3 expression in chronic inflammation provides the rationale for multiple target evaluation over time to fully understand the inflammation processes. (orig.)

  10. PET imaging of acute and chronic inflammation in living mice

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    Cao, Qizhen; Cai, Weibo; Li, Zi-Bo; Chen, Kai; He, Lina; Chen, Xiaoyuan [Stanford University School of Medicine, The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford, CA (United States); Li, Hui-Cheng; Hui, Mizhou [AmProtein Corporation, Camarillo, CA (United States)

    2007-11-15

    In this study, we evaluated the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced acute and chronic inflammation in living mice by PET imaging of TNF-{alpha} and integrin {alpha}{sub v}{beta}{sub 3} expression. TPA was topically applied to the right ear of BALB/c mice every other day to create the inflammation model. {sup 64}Cu-DOTA-etanercept and {sup 64}Cu-DOTA-E{l_brace}E[c(RGDyK)]{sub 2}{r_brace}{sub 2} were used for PET imaging of TNF-{alpha} and integrin {alpha}{sub v}{beta}{sub 3} expression in both acute and chronic inflammation. Hematoxylin and eosin staining, ex vivo autoradiography, direct tissue sampling, and immunofluorescence staining were also performed to confirm the non-invasive PET imaging results. The ear thickness increased significantly and the TNF-{alpha} level more than tripled after a single TPA challenge. MicroPET imaging using {sup 64}Cu-DOTA-etanercept revealed high activity accumulation in the inflamed ear, reaching 11.1 {+-} 1.3, 13.0 {+-} 2.0, 10.9 {+-} 1.4, 10.2 {+-} 2.2%ID/g at 1, 4, 16, and 24 h post injection, respectively (n = 3). Repeated TPA challenges caused TPA-specific chronic inflammation and reduced {sup 64}Cu-DOTA-etanercept uptake due to lowered TNF-{alpha} expression. {sup 64}Cu-DOTA-E{l_brace}E[c(RGDyK)]{sub 2}{r_brace}{sub 2} uptake in the chronically inflamed ears (after four and eight TPA challenges) was significantly higher than in the control ears and those after one TPA challenge. Immunofluorescence staining revealed increased integrin {beta}{sub 3} expression, consistent with the non-invasive PET imaging results using {sup 64}Cu-DOTA-E{l_brace}E[c(RGDyK)]{sub 2}{r_brace}{sub 2} as an integrin {alpha}{sub v} {beta}{sub 3}-specific radiotracer. Biodistribution and autoradiography studies further confirmed the quantification capability of microPET imaging. Successful PET imaging of TNF- {alpha} expression in acute inflammation and integrin {alpha}{sub v} {beta}{sub 3} expression in chronic inflammation provides

  11. Development of Biomarkers for Chronic Beryllium Disease in Mice

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    Gordon, Terry

    2013-01-25

    Beryllium is a strategic metal, indispensable for national defense programs in aerospace, telecommunications, electronics, and weaponry. Exposure to beryllium is an extensively documented occupational hazard that causes irreversible, debilitating granulomatous lung disease in as much as 3 - 5% of exposed workers. Mechanistic research on beryllium exposure-disease relationships has been severely limited by a general lack of a sufficient CBD animal model. We have now developed and tested an animal model which can be used for dissecting dose-response relationships and pathogenic mechanisms and for testing new diagnostic and treatment paradigms. We have created 3 strains of transgenic mice in which the human antigen-presenting moiety, HLA-DP, was inserted into the mouse genome. Each mouse strain contains HLA-DPB1 alleles that confer different magnitude of risk for chronic beryllium disease (CBD): HLA-DPB1*0401 (odds ratio = 0.2), HLA-DPB1*0201 (odds ratio = 15), HLA-DPB1*1701 (odds ratio = 240). Our preliminary work has demonstrated that the *1701 allele, as predicted by human studies, results in the greatest degree of sensitization in a mouse ear swelling test. We have also completed dose-response experiments examining beryllium-induced lung granulomas and identified susceptible and resistant inbred strains of mice (without the human transgenes) as well as quantitative trait loci that may contain gene(s) that modify the immune response to beryllium. In this grant application, we propose to use the transgenic and normal inbred strains of mice to identify biomarkers for the progression of beryllium sensitization and CBD. To achieve this goal, we propose to compare the sensitivity and accuracy of the lymphocyte proliferation test (blood and bronchoalveolar lavage fluid) with the ELISPOT test in the three HLA-DP transgenic mice strains throughout a 6 month treatment with beryllium particles. Because of the availability of high-throughput proteomics, we will also identify

  12. Effects of Active Mastication on Chronic Stress-Induced Bone Loss in Mice

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    Azuma, Kagaku; Furuzawa, Manabu; Fujiwara, Shu; YAMADA, Kumiko; Kubo, Kin-Ya

    2015-01-01

    Chronic psychologic stress increases corticosterone levels, which decreases bone density. Active mastication or chewing attenuates stress-induced increases in corticosterone. We evaluated whether active mastication attenuates chronic stress-induced bone loss in mice. Male C57BL/6 (B6) mice were randomly divided into control, stress, and stress/chewing groups. Stress was induced by placing mice in a ventilated restraint tube (60 min, 2x/day, 4 weeks). The stress/chewing group was given a woode...

  13. Chronic consumption of distilled sugarcane spirit induces anxiolytic-like effects in mice

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    Maria Clecia P. Sena; Nunes, Fabíola C; Mirian G. S. Stiebbe Salvadori; Carvalho, Cleyton Charles D; Liana Clebia S. L. Morais; Braga, Valdir A.

    2011-01-01

    OBJECTIVE: Chronic ethanol consumption is a major public health problem throughout the world. We investigated the anxiolytic-like effects and the possible ever injury induced by the chronic consumption of ethanol or sugarcane spirit in mice. METHOD: Adult mice were exposed to a two-bottle free-choice paradigm for 6 weeks. The mice in Group A (n  =  16) had access to sugarcane spirit + distilled water, the mice in Group B (n  =  15) had access to ethanol + distilled water, and the mice in Grou...

  14. Effect of Chronic Lead Intoxication on Risky Behavior in Mice

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    L Mohammadyar

    2010-08-01

    Full Text Available Introduction: With industrialization of human societies, pollutants like lead have entered in the life cycle, causing harmful effects on body organs. No sufficient studies have been done on the effects of pollutants on behavior. The aim of this study was to investigate possible effects of lead on some measurable behaviors of an animal model. Methods: Forty eight male adult mice were divided into 4 groups of 12 each. Lead acetate was added at concentrations of 0, 5, 50, or 500 ppm to the drinking water of the animals for 4 weeks (28 days. On day 29, animals were placed on an Elevated Plus maze (EPM for 5 min and the time in sec spent was measured on closed arms, open arms and the end 1/3rd of the open arms. Increased time on open arms, particularly the end 1/3rd was considered to reflect an enhanced risk-accepting behavior. Results: In this study, it was shown that lead exposure caused an increased number of entrance (P=0.006 and time spent (P=0.034 by mice on open arms of the EPM. There was a positive correlation between the concentration of lead acetate and those two effects. Conclusion: The present study demonstrated that lead poisoning may decrease normal anxiety in mice and increase risky behavior in this species. Clinical studies on human subjects with risky behavior are strongly suggested in order to find a possible relation between chronic exposures to lead as well as plasma concentration of lead with the extent of this kind of behavior.

  15. Microglial disruption in young mice with early chronic lead exposure☆

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    Sobin, Christina; Montoya, Mayra Gisel Flores; Parisi, Natali; Schaub, Tanner; Cervantes, Miguel; Armijos, Rodrigo X.

    2013-01-01

    The mechanisms by which early chronic lead (Pb) exposure alter brain development have not been identified. We examined neuroimmune system effects in C57BL/6J mice with Pb exposure, including levels that may be common among children in lower socioeconomic income environments. Pups were exposed via dams’ drinking water from birth to post-natal day 28 to low, high or no Pb conditions. We compared gene expression of neuroinflammatory markers (study 1); and microglial mean cell body volume and mean cell body number in dentate gyrus, and dentate gyrus volume (study 2). Blood Pb levels in exposed animals at sacrifice (post-natal day 28) ranged from 2.66 to 20.31 μg/dL. Only interleukin-6 (IL6) differed between groups and reductions were dose-dependent. Microglia cell body number also differed between groups and reductions were dose-dependent. As compared with controls, microglia cell body volume was greater but highly variable in only low-dose animals; dentate gyri volumes in low- and high-dose animals were reduced. The results did not support a model of increased neuroinflammation. Instead, early chronic exposure to Pb disrupted microglia via damage to, loss of, or lack of proliferation of microglia in the developing brains of Pb-exposed animals. PMID:23598043

  16. Chronic stress does not further exacerbate the abnormal psychoneuroendocrine phenotype of Cbg-deficient male mice.

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    de Medeiros, Gabriela F; Minni, Amandine M; Helbling, Jean-Christophe; Moisan, Marie-Pierre

    2016-08-01

    Chronic stress leads to a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis which can constitute a base for pathophysiological consequences. Using mice totally deficient in Corticosteroid binding globulin (CBG), we have previously demonstrated the important role of CBG in eliciting an adequate response to an acute stressor. Here, we have studied its role in chronic stress situations. We have submitted Cbg ko and wild-type (WT) male mice to two different chronic stress paradigms - the unpredictable chronic mild stress and the social defeat. Then, their impact on neuroendocrine function - through corticosterone and CBG measurement - and behavioral responses - via anxiety and despair-like behavioral tests - was evaluated. Both chronic stress paradigms increased the display of despair-like behavior in WT mice, while that from Cbg ko mice - which was already high - was not aggravated. We have also found that control and defeated (stressed) Cbg ko mice show no difference in the social interaction test, while defeated WT mice reduce their interaction time when compared to unstressed WT mice. Interestingly, the same pattern was observed for corticosterone levels, where both chronic stress paradigms lowered the corticosterone levels of WT mice, while those from Cbg ko mice remained low and unaltered. Plasma CBG binding capacity remained unaltered in WT mice regardless of the stress paradigm. Through the use of the Cbg ko mice, which only differs genetically from WT mice by the absence of CBG, we demonstrated that CBG is crucial in modulating the effects of stress on plasma corticosterone levels and consequently on behavior. In conclusion, individuals with CBG deficiency, whether genetically or environmentally-induced, are vulnerable to acute stress but do not have their abnormal psychoneuroendocrine phenotype further affected by chronic stress. PMID:27153522

  17. Toxoplasma gondii actively inhibits neuronal function in chronically infected mice.

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    Fahad Haroon

    Full Text Available Upon infection with the obligate intracellular parasite Toxoplasma gondii, fast replicating tachyzoites infect a broad spectrum of host cells including neurons. Under the pressure of the immune response, tachyzoites convert into slow-replicating bradyzoites, which persist as cysts in neurons. Currently, it is unclear whether T. gondii alters the functional activity of neurons, which may contribute to altered behaviour of T. gondii-infected mice and men. In the present study we demonstrate that upon oral infection with T. gondii cysts, chronically infected BALB/c mice lost over time their natural fear against cat urine which was paralleled by the persistence of the parasite in brain regions affecting behaviour and odor perception. Detailed immunohistochemistry showed that in infected neurons not only parasitic cysts but also the host cell cytoplasm and some axons stained positive for Toxoplasma antigen suggesting that parasitic proteins might directly interfere with neuronal function. In fact, in vitro live cell calcium (Ca(2+ imaging studies revealed that tachyzoites actively manipulated Ca(2+ signalling upon glutamate stimulation leading either to hyper- or hypo-responsive neurons. Experiments with the endoplasmatic reticulum Ca(2+ uptake inhibitor thapsigargin indicate that tachyzoites deplete Ca(2+ stores in the endoplasmatic reticulum. Furthermore in vivo studies revealed that the activity-dependent uptake of the potassium analogue thallium was reduced in cyst harbouring neurons indicating their functional impairment. The percentage of non-functional neurons increased over time In conclusion, both bradyzoites and tachyzoites functionally silence infected neurons, which may significantly contribute to the altered behaviour of the host.

  18. Influence of Chronic Moderate Sleep Restriction and Exercise on Inflammation and Carcinogenesis in Mice

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    Zielinski, Mark R.; Davis, J. Mark; Fadel, James R.; YOUNGSTEDT, SHAWN D.

    2012-01-01

    The effects of chronic moderate sleep restriction and exercise training on carcinogenesis were examined in adenomatous polyposis coli multiple intestinal neoplasma (APC Min+/-) mice, a genetic strain which is predisposed to developing adenomatous polyposis. The mice were randomized to one of four 11 week treatments in a 2×2 design involving sleep restriction (by 4 h/day) vs. normal sleep and exercise training (1 h/day) vs. sedentary control. Wild-type control mice underwent identical experime...

  19. Minimally Invasive Monitoring of Chronic Central Venous Catheter Patency in Mice Using Digital Subtraction Angiography (DSA)

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    Figueiredo, Giovanna; Fiebig, Teresa; Kirschner, Stefanie; Nikoubashman, Omid; Kabelitz, Lisa; Othman, Ahmed; Nonn, Andrea; Kramer, Martin; Brockmann, Marc A.

    2015-01-01

    Background Repetitive administration of medication or contrast agents is frequently performed in mice. The introduction of vascular access mini-ports (VAMP) for mice allows long-term vascular catheterization, hereby eliminating the need for repeated vessel puncture. With catheter occlusion being the most commonly reported complication of chronic jugular vein catheterization, we tested whether digital subtraction angiography (DSA) can be utilized to evaluate VAMP patency in mice. Methods Twent...

  20. Strain Differences in the Chronic Mild Stress Animal Model of Depression and Anxiety in Mice

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    Jung, Yang-Hee; Hong, Sa-Ik; Ma, Shi-Xun; Hwang, Ji-Young; Kim, Jun-Sup; lee, Ju-hyun; Seo, Jee-Yeon; Lee, Seok-Yong; Jang, Choon-Gon

    2014-01-01

    Chronic mild stress (CMS) has been reported to induce an anhedonic-like state in mice that resembles some of the symptoms of human depression. In the present study, we used a chronic mild stress animal model of depression and anxiety to examine the responses of two strains of mice that have different behavioral responsiveness. An outbred ICR and an inbred C57BL/6 strain of mice were selected because they are widely used strains in behavioral tests. The results showed that the inbred C57BL/6 a...

  1. Simotang enhances gastrointestinal motility, motilin and cholecystokinin expression in chronically stressed mice

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    Guang-Xian Cai; Bai-Yan Liu; Jian Yi; Xue-Mei Chen; Fu-Ling Liu

    2011-01-01

    AIM: To investigate the effect of Simotang (Decoction of Four Powered Drugs) on gastrointestinal motility, motilin and cholecystokinin expression in chronically stressed mice. METHODS: Forty mice were randomly divided into control group, stress group (model group), mosapride group and Simotang group, 10 in each group. A variety of unpredictable stimulations were used to induce chronic stress in mice. Then, the mice were treated with distilled water, mosapride or Simotang for 7 d. Gastric emptying and intestinal propulsion function were detected. Serum level of motilin was measured by enzyme-linked immunosorbent assay. Expression of cholecystokinin (CCK) in intestine, spinal cord and brain of mice was detected by immunohistochemistry and semi-quantitative reverse transcription polymerase chain reaction, respectively. RESULTS: Simotang improved the gastric emptying and intestinal propulsion in chronically stressed mice. Furthermore, the serum motilin level was significantly higher and the expression levels of CCK-positive cells and genes were significantly lower in intestine, spinal cord and brain of Simotang group than in those of model group (P < 0.05). No significant difference was found in serum motilin level and expression levels of CCK-positive cells and genes between the mosapride and Simotang groups. CONCLUSION: Simotang enhances the gastrointestinal motility in chronically stressed mice by regulating the serum motilin level and the expression of cholecystokinin.

  2. Sustained acceleration of colonic transit following chronic homotypic stress in oxytocin knockout mice.

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    Babygirija, Reji; Bülbül, Mehmet; Cerjak, Diana; Ludwig, Kirk; Takahashi, Toku

    2011-05-01

    Acute restraint stress delays gastric emptying and accelerates colonic transit via central corticotropin releasing factor (CRF) in rats. In contrast, central oxytocin has anxiolytic effects and attenuates the hypothalamus-pituitary-adrenal (HPA) axis in response to stress. Our recent study showed that up regulated oxytocin expression attenuates hypothalamic CRF expression and restores impaired gastric motility following chronic homotypic stress in mice. We studied the effects of acute and chronic homotypic stress on colonic transit and hypothalamic CRF mRNA expression in wild type (WT) and oxytocin knockout (OXT-KO) mice. Colonic transit was measured following acute restraint stress or chronic homotypic stress (repeated restraint stress for 5 consecutive days). (51)Cr was injected via a catheter into the proximal colon. Ninety minutes after restraint stress loading, the entire colon was removed. The geometric center (GC) was calculated to evaluate colonic transit. Expression of CRF mRNA in the supraoptic nucleus (SON) was measured by real time RT-PCR. Colonic transit was significantly accelerated following acute stress in WT (GC=8.1±0.8; n=7) and OXT KO mice (GC=9.4±0.3; n=7). The accelerated colonic transit was significantly attenuated in WT mice (GC=6.6±0.5; n=9) following chronic homotypic stress while it was still accelerated in OXT KO mice (GC=9.3±0.5; n=8). The increase in CRF mRNA expression at the SON was much greater in OXT-KO mice, compared to WT mice following chronic homotypic stress. It is suggested that oxytocin plays a pivotal role in mediating the adaptation mechanism following chronic homotypic stress in mice. PMID:21439349

  3. Complement C3 deficiency attenuates chronic hypoxia-induced pulmonary hypertension in mice.

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    Eileen M Bauer

    Full Text Available Evidence suggests a role of both innate and adaptive immunity in the development of pulmonary arterial hypertension. The complement system is a key sentry of the innate immune system and bridges innate and adaptive immunity. To date there are no studies addressing a role for the complement system in pulmonary arterial hypertension.Immunofluorescent staining revealed significant C3d deposition in lung sections from IPAH patients and C57Bl6/J wild-type mice exposed to three weeks of chronic hypoxia to induce pulmonary hypertension. Right ventricular systolic pressure and right ventricular hypertrophy were increased in hypoxic vs. normoxic wild-type mice, which were attenuated in C3-/- hypoxic mice. Likewise, pulmonary vascular remodeling was attenuated in the C3-/- mice compared to wild-type mice as determined by the number of muscularized peripheral arterioles and morphometric analysis of vessel wall thickness. The loss of C3 attenuated the increase in interleukin-6 and intracellular adhesion molecule-1 expression in response to chronic hypoxia, but not endothelin-1 levels. In wild-type mice, but not C3-/- mice, chronic hypoxia led to platelet activation as assessed by bleeding time, and flow cytometry of platelets to determine cell surface P-selectin expression. In addition, tissue factor expression and fibrin deposition were increased in the lungs of WT mice in response to chronic hypoxia. These pro-thrombotic effects of hypoxia were abrogated in C3-/- mice.Herein, we provide compelling genetic evidence that the complement system plays a pathophysiologic role in the development of PAH in mice, promoting pulmonary vascular remodeling and a pro-thrombotic phenotype. In addition we demonstrate C3d deposition in IPAH patients suggesting that complement activation plays a role in the development of PAH in humans.

  4. Effect of chronic pain on fentanyl self-administration in mice.

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    Carrie L Wade

    Full Text Available The development of opioid addiction in subjects with established chronic pain is an area that is poorly understood. It is critically important to clearly understand the neurobiology associated with propensity toward conversion to addiction under conditions of chronic pain. To pose the question whether the presence of chronic pain influences motivation to self-administer opioids for reward, we applied a combination of rodent models of chronic mechanical hyperalgesia and opioid self-administration. We studied fentanyl self-administration in mice under three conditions that induce chronic mechanical hyperalgesia: inflammation, peripheral nerve injury, and repeated chemotherapeutic injections. Responding for fentanyl was compared among these conditions and their respective standard controls (naïve condition, vehicle injection or sham surgery. Acquisition of fentanyl self-administration behavior was reduced or absent in all three conditions of chronic hyperalgesia relative to control mice with normal sensory thresholds. To control for potential impairment in ability to learn the lever-pressing behavior or perform the associated motor tasks, all three groups were evaluated for acquisition of food-maintained responding. In contrast to the opioid, chronic hyperalgesia did not interfere with the reinforcing effect of food. These studies indicate that the establishment of chronic hyperalgesia is associated with reduced or ablated motivation to seek opioid reward in mice.

  5. Chronic Wasting Disease of Deer and Elk in Transgenic Mice: Oral Transmission and Pathobiology

    OpenAIRE

    Trifilo, Matthew J.; Ying, Ge; Teng, Chao; Oldstone, Michael B. A.

    2007-01-01

    To study the pathogenesis of chronic wasting disease (CWD) in deer and elk, transgenic (tg) mice were generated that expressed the prion protein (PrP) of deer containing a glycine at amino acid (aa) 96 and a serine at aa 225 under transcriptional control of the murine PrP promoter. This construct was introduced into murine PrP-deficient mice. As anticipated, neither non-tg mice nor PrP ko mice were susceptible when inoculated intracerebrally (i.c.) or orally with CWD brain material (scrapie p...

  6. Effects of Chronic Mild Stress in Female Bax Inhibitor-1-Gene Knockout Mice

    OpenAIRE

    Sui, Zhi-Yan; Chae, Han-Jung; Huang, Guang-Biao; Zhao, Tong; Shrestha Muna, Sushma; Chung, Young-Chul

    2012-01-01

    Objective The anti-apoptotic protein Bax inhibitor-1 (BI-1) is a regulator of apoptosis linked to endoplasmic reticulum (ER) stress, and BI-1-/- mice exhibit increased sensitivity to tissue damage. The purpose of this study was to investigate the role of BI-1 in the pathogenesis of chronic mild stress (CMS)-induced depression-like behaviors in BI-1-/- mice. Methods We delivered CMS for 2 or 6 weeks in BI-1-knockout and wild-type mice. Control groups of BI-1-knockout and wild-type mice were le...

  7. Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23

    International Nuclear Information System (INIS)

    Research highlights: → The progress of neurodegeration are directly linked to the neuroinflammatory response. → We investigate whether exercise improves the neuroinflammation using Tg-NSE/htau23 mice. → This provides insights that exercise may beneficial effects on the neuroinflammatory disorders. -- Abstract: The objective of the present study was to investigate whether chronic endurance exercise attenuates the neuroinflammation in the brain of mice with NSE/htau23. In this study, the tau-transgenic (Tg) mouse, Tg-NSE/htau23, which over expresses human Tau23 in its brain, was subjected to chronic exercise for 3 months, from 16 months of age. The brains of Tg mice exhibited increased immunoreactivity and active morphological changes in GFAP (astrocyte marker) and MAC-1 (microglia marker) expression in an age-dependent manner. To identify the effects of chronic exercise on gliosis, the exercised Tg mice groups were treadmill run at a speed of 12 m/min (intermediate exercise group) or 19 m/min (high exercise group) for 1 h/day and 5 days/week during the 3 month period. The neuroinflammatory response characterized by activated astroglia and microglia was significantly repressed in the exercised Tg mice in an exercise intensity-dependent manner. In parallel, chronic exercise in Tg mice reduced the increased expression of TNF-α, IL-6, IL-1β, COX-2, and iNOS. Consistently with these changes, the levels of phospho-p38 and phospho-ERK were markedly downregulated in the brain of Tg mice after exercise. In addition, nuclear NF-κB activity was profoundly reduced after chronic exercise in an exercise intensity-dependent manner. These findings suggest that chronic endurance exercise may alleviate neuroinflammation in the Tau pathology of Alzheimer's disease.

  8. Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23

    Energy Technology Data Exchange (ETDEWEB)

    Leem, Yea-Hyun, E-mail: leemyy@empas.com [Exercise Biochemistry Laboratory, Korea National Sport University, Seoul 138-763 (Korea, Republic of); Lee, Young-Ik, E-mail: lee0ik@hanmail.net [Department of Oriental Sports Medicine, Daegu Hanny University, Daegu 712-715 (Korea, Republic of); Son, Hee-Jeong, E-mail: son1106@paran.com [Exercise Physiology Laboratory, Korea National Sport University, Seoul 138-763 (Korea, Republic of); Lee, Sang-Ho, E-mail: run2025@hanmail.net [Department of Sports for All, Kangnam University, Yongin 446-702 (Korea, Republic of)

    2011-03-18

    Research highlights: {yields} The progress of neurodegeration are directly linked to the neuroinflammatory response. {yields} We investigate whether exercise improves the neuroinflammation using T{sub g}-NSE/htau23 mice. {yields} This provides insights that exercise may beneficial effects on the neuroinflammatory disorders. -- Abstract: The objective of the present study was to investigate whether chronic endurance exercise attenuates the neuroinflammation in the brain of mice with NSE/htau23. In this study, the tau-transgenic (Tg) mouse, Tg-NSE/htau23, which over expresses human Tau23 in its brain, was subjected to chronic exercise for 3 months, from 16 months of age. The brains of Tg mice exhibited increased immunoreactivity and active morphological changes in GFAP (astrocyte marker) and MAC-1 (microglia marker) expression in an age-dependent manner. To identify the effects of chronic exercise on gliosis, the exercised Tg mice groups were treadmill run at a speed of 12 m/min (intermediate exercise group) or 19 m/min (high exercise group) for 1 h/day and 5 days/week during the 3 month period. The neuroinflammatory response characterized by activated astroglia and microglia was significantly repressed in the exercised Tg mice in an exercise intensity-dependent manner. In parallel, chronic exercise in Tg mice reduced the increased expression of TNF-{alpha}, IL-6, IL-1{beta}, COX-2, and iNOS. Consistently with these changes, the levels of phospho-p38 and phospho-ERK were markedly downregulated in the brain of Tg mice after exercise. In addition, nuclear NF-{kappa}B activity was profoundly reduced after chronic exercise in an exercise intensity-dependent manner. These findings suggest that chronic endurance exercise may alleviate neuroinflammation in the Tau pathology of Alzheimer's disease.

  9. Effects of Cholinergic Stimulation with Pyridostigmine Bromide on Chronic Chagasic Cardiomyopathic Mice

    Directory of Open Access Journals (Sweden)

    Marília Beatriz de Cuba

    2014-01-01

    Full Text Available The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido, on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con or chronically infected (5 months with Trypanosoma cruzi (chagasic:Chg were treated or not (NT with Pyrido for one month. At the end of this period, electrocardiogram (ECG; cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFNγ with no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response to T. cruzi during experimental chronic Chagas heart disease in mice.

  10. Post-training reward partially restores chronic stress induced effects in mice.

    Directory of Open Access Journals (Sweden)

    Sergiu Dalm

    Full Text Available Reduced responsiveness to positive stimuli is a core symptom of depression, known as anhedonia. In the present study, we assessed the expression of anhedonia in our chronic stress mouse model using a subset of read-out parameters. In line with this, we investigated in how far chronic stress would affect the facilitating effect of post-training self-administration of sugar, as we previously observed in naïve mice. Male C57BL/6J mice were repeatedly and at unpredictable times exposed to rats (no physical contact over the course of two weeks. Following novelty exploration, (non- spatial learning and memory processes with and without post-training sugar acting as reinforcer, emotionality, reward sensitivity and corticosterone levels were determined. We found that (1 the effects of chronic stress persisted beyond the period of the actual rat exposure. (2 Post-training self-administration of sugar as reinforcer improved spatial performance in naïve mice, whereas (3 in stressed mice sugar partially "normalized" the impaired performance to the level of controls without sugar. Chronic stress (4 increased behavioral inhibition in response to novelty; (5 induced dynamic changes in the pattern of circadian corticosterone secretion during the first week after rat stress and (6 increased the intake of sucrose and water. (7 Chronic stress and sugar consumed during spatial training facilitated the memory for the location of the sucrose bottle weeks later. Concluding, our chronic stress paradigm induces the expression of anhedonia in mice, at different levels of behavior. The behavioral inhibition appears to be long lasting in stressed mice. Interestingly, sugar consumed in close context with spatial learning partially rescued the stress-induced emotional and cognitive impairments. This suggests that reward can ameliorate part of the negative consequences of chronic stress on memory.

  11. Chronic escalating cocaine exposure, abstinence/withdrawal, and chronic re-exposure: Effects on striatal dopamine and opioid systems in C57BL/6J mice

    OpenAIRE

    Yong ZHANG; Schlussman, Stefan D; Rabkin, Jacqui; Butelman, Eduardo R.; Ho, Ann; Kreek, Mary Jeanne

    2012-01-01

    Cocaine addiction is a chronic relapsing disease with periods of chronic escalating self-exposure, separated by periods of abstinence/withdrawal of varying duration. Few studies compare such cycles in preclinical models. This study models an “addiction-like cycle” in mice to determine neurochemical/molecular alterations that underlie the chronic, relapsing nature of this disease. Groups of male C57BL/6J mice received acute cocaine exposure (14-day saline/14-day withdrawal /13-day saline + 1-d...

  12. Salmonella Typhimurium undergoes distinct genetic adaption during chronic infections of mice

    DEFF Research Database (Denmark)

    Søndberg, Emilie; Jelsbak, Lotte

    2016-01-01

    type strains of S. Typhimurium 4/74 were used to establish chronic infections of 129X1/SvJ mice. Over the course of infections, S. Typhimurium bacteria were isolated from feces and from livers and spleens upon termination of the experiment. In all samples dominant clones were identified and select...... clones were subjected to whole genome sequencing. Dominant clones isolated from either systemic organs or fecal samples exhibited distinct single nucleotide polymorphisms (SNPs). One mouse appeared to have distinct adapted clones in the spleen and liver, respectively. Three mice were colonized in the...... current study genetic adaptation during experimental chronic S. Typhimurium infections of mice, an established model of chronic typhoid fever, was probed as an approach for studying the molecular mechanisms of host-adaptation during long-term host-association. Results Individually sequence-tagged wild...

  13. Therapeutic effects of stress-programmed lymphocytes transferred to chronically stressed mice.

    Science.gov (United States)

    Scheinert, Rachel B; Haeri, Mitra H; Lehmann, Michael L; Herkenham, Miles

    2016-10-01

    Our group has recently provided novel insights into a poorly understood component of intercommunication between the brain and the immune system by showing that psychological stress can modify lymphocytes in a manner that may boost resilience to psychological stress. To demonstrate the influence of the adaptive immune system on mood states, we previously showed that cells from lymph nodes of socially defeated mice, but not from unstressed mice, conferred anxiolytic and antidepressant-like effects and elevated hippocampal cell proliferation when transferred into naïve lymphopenic Rag2(-/-) mice. In the present study, we asked whether similar transfer could be anxiolytic and antidepressant when done in animals that had been rendered anxious and depressed by chronic psychological stress. First, we demonstrated that lymphopenic Rag2(-/-) mice and their wild-type C57BL/6 mouse counterparts had similar levels of affect normally. Second, we found that following chronic (14days) restraint stress, both groups displayed an anxious and depressive-like phenotype and decreased hippocampal cell proliferation. Third, we showed that behavior in the open field test and light/dark box was normalized in the restraint-stressed Rag2(-/-) mice following adoptive transfer of lymph node cells from green fluorescent protein (GFP) expressing donor mice previously exposed to chronic (14days) of social defeat stress. Cells transferred from unstressed donor mice had no effect on behavior. Immunolabeling of GFP+ cells confirmed that tissue engraftment had occurred at 14days after transfer. We found GFP+ lymphocytes in the spleen, lymph nodes, blood, choroid plexus, and meninges of the recipient Rag2(-/-) mice. The findings suggest that the adaptive immune system may play a key role in promoting recovery from chronic stress. The data support using lymphocytes as a novel therapeutic target for anxiety states. PMID:27109071

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

    OpenAIRE

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

    2015-01-01

    Background: 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. Methods: Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-am...

  15. Chronic exposure to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice

    OpenAIRE

    Cai, Ping; König, Rolf; Boor, Paul J; Kondraganti, Shakuntala; Kaphalia, Bhupendra S.; Khan, M. Firoze; Ansari, G.A.S.

    2007-01-01

    Trichloroethene (TCE) exacerbates the development of autoimmune responses in autoimmune-prone MRL +/+ mice. Although TCE-mediated autoimmune responses are associated with an increase in serum immunoglobulins and autoantibodies, the underlying mechanism of autoimmunity is not known. To determine the progression of TCE-mediated immunotoxicity, female MRL +/+ mice were chronically exposed to TCE through the drinking water (0.5 mg/ml of TCE) for various periods of time. Serum concentrations of an...

  16. Therapy with bone marrow cells reduces liver alterations in mice chronically infected by Schistosoma mansoni

    Institute of Scientific and Technical Information of China (English)

    Sheilla Andrade Oliveira; Bruno Solano Freitas Souza; Cada Adriana Guimar(a)es-Ferreira; Elton Sá Barreto; Siane Campos Souza; Luiz Antonio Rodrigues Freitas; Ricardo Ribeiro-dos-Santos; Milena Botelho Pereira Soares

    2008-01-01

    AIM: To investigate the potential of bone marrow mononuclear cells (BM-MCs) in the regeneration of hepatic lesions induced by Schistosoma mansoni (S.mansoni) chronic infection.METHODS: Female mice chronically infected with S.mansoni were treated with BM-MCs obtained from male green fluorescent protein (GFP) transgenic mice by intravenous or intralobular injections. Control mice received injections of saline in similar conditions. Enzyme-linked immunosorbent assay (ELISA) assay for transforming growth factor-beta (TGF-β), polymerase chain reaction (PCR) for GFP DNA, immunofluorescence and morphometric studies were performed.RESULTS: Transplanted GFP+ cells migrated to granuloma areas and reduced the percentage of liver fibrosis. The presence of donor-derived cells was confirmed by Fluorescence in situ hybridization (FISH) analysis for detection of cells bearing Y chromosome and by PCR analysis for detection of GFP DNA. The levels of TGF-β, a cytokine associated with fibrosis deposition, in liver fragments of mice submitted to therapy were reduced. The number of oval cells in liver sections of S.rnansoni-infected mice increased 3-4 fold after transplantation. A partial recovery in albumin expression, which is decreased upon infection with S.mansoni, was found in livers of infected mice after cellular therapy.CONCLUSION: In conclusion, transplanted BMCs migrate to and reduce the damage of chronic fibrotic liver lesions caused by S.mansoni.

  17. Acute and chronic nephrotoxicity of platinum nanoparticles in mice

    Science.gov (United States)

    Yamagishi, Yoshiaki; Watari, Akihiro; Hayata, Yuya; Li, Xiangru; Kondoh, Masuo; Yoshioka, Yasuo; Tsutsumi, Yasuo; Yagi, Kiyohito

    2013-09-01

    Platinum nanoparticles are being utilized in various industrial applications, including in catalysis, cosmetics, and dietary supplements. Although reducing the size of the nanoparticles improves the physicochemical properties and provides useful performance characteristics, the safety of the material remains a major concern. The aim of the present study was to evaluate the biological effects of platinum particles less than 1 nm in size (snPt1). In mice administered with a single intravenous dose of snPt1, histological analysis revealed necrosis of tubular epithelial cells and urinary casts in the kidney, without obvious toxic effects in the lung, spleen, and heart. These mice exhibited dose-dependent elevation of blood urea nitrogen, an indicator of kidney damage. Direct application of snPt1 to in vitro cultures of renal cells induced significant cytotoxicity. In mice administered for 4 weeks with twice-weekly intraperitoneal snPt1, histological analysis of the kidney revealed urinary casts, tubular atrophy, and inflammatory cell accumulation. Notably, these toxic effects were not observed in mice injected with 8-nm platinum particles, either by single- or multiple-dose administration. Our findings suggest that exposure to platinum particles of less than 1 nm in size may induce nephrotoxicity and disrupt some kidney functions. However, this toxicity may be reduced by increasing the nanoparticle size.

  18. Agmatine increases proliferation of cultured hippocampal progenitor cells and hippocampal neurogenesis in chronically stressed mice

    Institute of Scientific and Technical Information of China (English)

    Yun-feng LI; Hong-xia CHEN; Ying LIU; You-zhi ZHANG; Yan-qin LIU; Jin LI

    2006-01-01

    Aim:To explore the mechanism of agmatine's antidepressant action.Methods: Male mice were subjected to a variety of unpredictable stressors on a daily basis over a 24-d period.The open-field behaviors of the mice were displayed and recorded using a Videomex-V image analytic system automatically.For bromodeoxyuridine (BrdU;thymidine analog as a marker for dividing cells) labeling,the mice were injected with BrdU (100 mg/kg,ip,twice per d for 2 d),and the hippocampal neurogenesis in stressed mice was measured by immunohistochemistry.The proliferation of cultured hippocampal progenitor cells from neonatal rats was determined by colorimetric assay (cell counting kit-8) and 3H-thymidine incorporation assay.Results:After the onset of chronic stress,the locomotor activity of the mice in the open field significantly decreased,while coadministration of agmatine 10 mg/kg (po) blocked it.Furthermore,the number of BrdU-labeled cells in the hippocampal dentate gyrus significantly decreased in chronically stressed mice, which was also blocked by chronic coadministration with agmatine 10 mg/kg (po). Four weeks after the BrdU injection, some of the new born cells matured and became neurons, as determined by double labeling for BrdU and neuron specific enolase (NSE), a marker for mature neurons.In vitro treatment with agmatine 0.1-10 μmo1/L for 3 d significantly increased the proliferation of the cultured hippocampal progenitor cells in a dose-dependent manner.Conclusion:We have found that agmatine increases proliferation of hippocampal progenitor cells in vitro and the hippocampal neurogenesis in vivo in chronically stressed mice.This may be one of the important mechanisms involved in agmatine's antidepressant action.

  19. Chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice.

    Directory of Open Access Journals (Sweden)

    Meriem Gaval-Cruz

    Full Text Available The anti-alcoholism medication, disulfiram (Antabuse, decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH, the enzyme that converts dopamine (DA to norepinephrine (NE in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh -/- mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/- and Dbh -/- mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh -/- mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/- mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/- mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh -/- mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor enhance qualitatively different cocaine-induced behaviors.

  20. Protective Effects of Lentinan against T Lymphocytes Injury in Mice under Chronic Radiation Stress

    Institute of Scientific and Technical Information of China (English)

    WANG; Yong; LI; Ming-chun; FU; Qing-jie

    2013-01-01

    Objective To study the effects of lentinan (LTN) on mice exposed to chronic radiation. Methods Animals were divided into three groups (n = 10), they were animals exposed to radiation (Rad), normal control animals (Ctr), and irradiated animals treated with LTN (Rad + LTN). Animal model of chronic radiation stress injury was induced by irradiating mice with 60 Co γ-ray for 6 weeks from Monday to Friday consecutively. Before radiation, the mice in Rad + LTN group were ip injected with 0.5 mL LTN (0.01 mg/mL), whereas mice in other groups were injected with 0.9% physiological saline. The effects of LTN treatment on irradiated mice were examined by histological analysis on the spleen. The cell numbers and viability of T lymphocytes, which were isolated from the spleen, were determined by Trypan blue staining. Nitric oxide (NO) production and interleukin-2 (IL-2) secretion in T lymphocytes were also measured. Results Chronic radiation significantly reduced the body weights and the spleen and thymus indexes, associated with reduced T lymphocytes viability and functions, and elevated NO production. Treatment with LTN significantly normalized the elevated NO production, and attenuated the negative outcomes resulting from radiation mentioned above. Conclusion The results suggest that radioprotective effect of LTN may be contributed by improved T lymphocytes viability and functions via regulating the NO and IL-2 production in T lymphocytes.

  1. Protective Effects of Lentinan against T Lymphocytes Injury in Mice under Chronic Radiation Stress

    Institute of Scientific and Technical Information of China (English)

    WANG Yong; LI Ming-chun; FU Qing-jie

    2013-01-01

    Objective To study the effects of lentinan (LTN) on mice exposed to chronic radiation.Methods Animals were divided into three groups (n =10),they were animals exposed to radiation (Rad),normal control animals (Ctr),and irradiated animals treated with LTN (Rad + LTN).Animal model of chronic radiation stress injury was induced by irradiating mice with 60Co γ-ray for 6 weeks from Monday to Friday consecutively.Before radiation,the mice in Rad + LTN group were ip injected with 0.5 mL LTN (0.01 mg/mL),whereas mice in other groups were injected with 0.9% physiological saline.The effects of LTN treatment on irradiated mice were examined by histological analysis on the spleen.The cell numbers and viability of T lymphocytes,which were isolated from the spleen,were determined by Trypan blue staining.Nitric oxide (NO) production and interleukin-2 (IL-2) secretion in T lymphocytes were also measured.Results Chronic radiation significantly reduced the body weights and the spleen and thymus indexes,associated with reduced T lymphocytes viability and functions,and elevated NO production.Treatment with LTN significantly normalized the elevated NO production,and attenuated the negative outcomes resulting from radiation mentioned above.Conclusion The results suggest that radioprotective effect of LTN may be contributed by improved T lymphocytes viability and functions via regulating the NO and IL-2 production in T lymphocytes.

  2. Acute and chronic nephrotoxicity of platinum nanoparticles in mice

    OpenAIRE

    Yamagishi, Yoshiaki; Watari, Akihiro; Hayata, Yuya; Li, Xiangru; Kondoh, Masuo; Yoshioka, Yasuo; Tsutsumi, Yasuo; Yagi, Kiyohito

    2013-01-01

    Platinum nanoparticles are being utilized in various industrial applications, including in catalysis, cosmetics, and dietary supplements. Although reducing the size of the nanoparticles improves the physicochemical properties and provides useful performance characteristics, the safety of the material remains a major concern. The aim of the present study was to evaluate the biological effects of platinum particles less than 1 nm in size (snPt1). In mice administered with a single intravenous d...

  3. Chronic Sleep Fragmentation Promotes Obesity in Young Adult Mice

    OpenAIRE

    Wang, Yang; Carreras, Alba; Lee, Seunghoon; Hakim, Fahed; Zhang, Shelley X.; Nair, Deepti; Ye, Honggang; Gozal, David

    2013-01-01

    Objectives Short sleep confers a higher risk of obesity in humans. Restricted sleep increases appetite, promotes higher calorie intake from fat and carbohydrate sources, and induces insulin resistance. However, the effects of fragmented sleep (SF), such as occurs in sleep apnea, on body weight, metabolic rates, and adipose tissue distribution are unknown. Design and Methods C57BL/6 mice were exposed to SF for 8 weeks. Their body weight, food consumption, and metabolic expenditure were monitor...

  4. Opposing actions of chronic stress and chronic nicotine on striatal function in mice

    OpenAIRE

    Salas, Ramiro; De Biasi, Mariella

    2008-01-01

    Stress is a major risk factor in drug addiction development and relapse. Virtually all drugs of abuse act by increasing extracellular dopamine levels in the striatum. To gain an understanding of the interaction between stress and drug exposure, we studied the effects of concomitant chronic nicotine and chronic stress exposure on mouse striatal dopamine levels.

  5. Basic fibroblast growth factor improves learning and memory functions in chronic stress mice

    Institute of Scientific and Technical Information of China (English)

    Xian Qu; Chunying Li; Hongchang Liu; Chang Su

    2011-01-01

    Four weeks of uncertain stress was used to establish an animal model of chronic stress.Basic fibroblast growth factor was injected daily for 15 days following stress induction.Cell morphology in the hippocampal CA3 region of chronic stress mice revealed cell damage.Nitric oxide content and calcium concentration were significantly increased in the hippocampus,and learning and memory functions were significantly decreased.After basic fibroblast growth factor intervention,Ca2+ overload was decreased and neuronal damage was relieved in hippocampal neurons,which improved learning and memory functions in chronic stress mice.Latency was prolonged and the number of errors was decreased in a passive avoidance test.

  6. Neospora caninum: Chronic and congenital infection in consecutive pregnancies of mice.

    Science.gov (United States)

    Mazuz, Monica L; Shkap, Varda; Wollkomirsky, Ricardo; Leibovich, Benjamin; Savitsky, Igor; Fleiderovitz, Ludmila; Noam, Sugar; Elena, Blinder; Molad, Thea; Golenser, Jacob

    2016-03-30

    Neospora caninum, the causative agent of bovine neosporosis is the major cause of abortion in cattle worldwide. The principal route of transmission is via in utero infection of the offspring. Congenitally-infected dams remain persistently infected for life and might undergo abortions in consecutive pregnancies. In the present study, the effect of N. caninum in chronic and congenital infection was examined. CD1 mice were infected intra-peritoneally with live tachyzoites of the NcIs491 isolate, while non-infected mice served as a control. There were no clinical signs of infection observed following inoculation, but high titers of specific anti- N. caninum antibodies were detected. A month after infection, when chronic-infection was established, mice were mated. Fertility, litter size and mortality rate were monitored within two generations of four consecutive pregnancies. During a nine months period of the study all females maintained high level of antibodies, while the non- infected control mice remained seronegative. There was no difference in the fertility rate of the dams, or in the litter size of infected and control mice. Mortality of offspring of the first and second generations of the infected dams was observed within the two first weeks of life. The vertical transmission was analyzed by PCR assay of offspring brains. PCR positive results were found in all 13 litters of the first generation tested during four consecutive pregnancies. The rate of vertical transmission slightly decreased in successive pregnancies being 74.2%, 59.5%, 48.1% and 40% for the first to fourth pregnancies respectively. In the second generation 21 out of 28 litters were found positive and the overall rate of vertical transmission was 28.5%. In chronically and congenitally infected dams N. caninum infection was maintained during all successive pregnancies for about 9 months. The results show that CD-1 outbred mice are a suitable model for studying chronic and congenital neosporosis

  7. Chronic consumption of distilled sugarcane spirit induces anxiolytic-like effects in mice

    Directory of Open Access Journals (Sweden)

    Maria Clecia P. Sena

    2011-01-01

    Full Text Available OBJECTIVE: Chronic ethanol consumption is a major public health problem throughout the world. We investigated the anxiolytic-like effects and the possible ever injury induced by the chronic consumption of ethanol or sugarcane spirit in mice. METHOD: Adult mice were exposed to a two-bottle free-choice paradigm for 6 weeks. The mice in Group A (n = 16 had access to sugarcane spirit + distilled water, the mice in Group B (n = 15 had access to ethanol + distilled water, and the mice in Group C (control, n = 14 had access to distilled water + distilled water. The ethanol content in the beverages offered to Groups A and B was 2% for the first week, 5% for the second week and 10% for the remaining four weeks. At the end of the experimental period, the mice were evaluated using the elevated-plus maze and the hole-board test to assess their anxiety-related behaviors. We also determined the serum aspartate aminotransferase and alanine aminotransferase levels. RESULTS: In the elevated-plus maze, the time spent in the open arms was increased in the mice exposed to chronic ethanol (32 + 8 vs. 7 + 2 s, n = 9 or sugarcane spirit (36 + 9 vs. 7 + 2 s, n = 9 compared to the controls. In the hole-board test, the mice exposed to ethanol or sugarcane spirit displayed increases in their head-dipping frequency (16 + 1 for the control group, 27 + 2 for the ethanol group, and 31 + 3 for the sugarcane-spirit group; n = 9 for each group. In addition, the mice exposed to sugarcane spirit displayed an increase in the aspartate aminotransferase / alanine aminotransferase ratio compared to the ethanol group (1.29 + 0.17 for the control group and 2.67 + 0.17 for the sugarcane spirit group; n = 8 for each group. CONCLUSION: The chronic consumption of sugarcane-spirit produces liver injury and anxiolytic-like effects and the possible liver injury in mice.

  8. Chronic consumption of distilled sugarcane spirit induces anxiolytic-like effects in mice

    Science.gov (United States)

    Sena, Maria Clécia P; Nunes, Fabíola C; Stiebbe Salvadori, Mirian G S; Carvalho, Cleyton Charles D; Morais, Liana Clébia S L; Braga, Valdir A

    2011-01-01

    OBJECTIVE: Chronic ethanol consumption is a major public health problem throughout the world. We investigated the anxiolytic-like effects and the possible ever injury induced by the chronic consumption of ethanol or sugarcane spirit in mice. METHOD: Adult mice were exposed to a two-bottle free-choice paradigm for 6 weeks. The mice in Group A (n  =  16) had access to sugarcane spirit + distilled water, the mice in Group B (n  =  15) had access to ethanol + distilled water, and the mice in Group C (control, n  =  14) had access to distilled water + distilled water. The ethanol content in the beverages offered to Groups A and B was 2% for the first week, 5% for the second week and 10% for the remaining four weeks. At the end of the experimental period, the mice were evaluated using the elevated-plus maze and the hole-board test to assess their anxiety-related behaviors. We also determined the serum aspartate aminotransferase and alanine aminotransferase levels. RESULTS: In the elevated-plus maze, the time spent in the open arms was increased in the mice exposed to chronic ethanol (32 ± 8 vs. 7 ± 2 s, n  =  9) or sugarcane spirit (36 ± 9 vs. 7 ± 2 s, n  =  9) compared to the controls. In the hole-board test, the mice exposed to ethanol or sugarcane spirit displayed increases in their head-dipping frequency (16 ± 1 for the control group, 27 ± 2 for the ethanol group, and 31 ± 3 for the sugarcane-spirit group; n  =  9 for each group). In addition, the mice exposed to sugarcane spirit displayed an increase in the aspartate aminotransferase / alanine aminotransferase ratio compared to the ethanol group (1.29 ± 0.17 for the control group and 2.67 ± 0.17 for the sugarcane spirit group; n  =  8 for each group). CONCLUSION: The chronic consumption of sugarcane-spirit produces liver injury and anxiolytic-like effects and the possible liver injury in mice. PMID:21789394

  9. Thymic epithelium determines a spontaneous chronic neuritis in Icam1(tm1Jcgr)NOD mice.

    Science.gov (United States)

    Meyer zu Horste, Gerd; Mausberg, Anne K; Cordes, Steffen; El-Haddad, Houda; Partke, Hans-Joachim; Leussink, Verena I; Roden, Michael; Martin, Stephan; Steinman, Lawrence; Hartung, Hans-Peter; Kieseier, Bernd C

    2014-09-15

    The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4(+) T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1(tm1Jcgr)NOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17-producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1(tm1Jcgr)NOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1(tm1Jcgr)NOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases. PMID:25108020

  10. Effects of acute and chronic administration of neurosteroid dehydroepiandrosterone sulfate on neuronal excitability in mice

    Science.gov (United States)

    Svob Strac, Dubravka; Vlainic, Josipa; Samardzic, Janko; Erhardt, Julija; Krsnik, Zeljka

    2016-01-01

    Background Neurosteroid dehydroepiandrosterone sulfate (DHEAS) has been associated with important brain functions, including neuronal survival, memory, and behavior, showing therapeutic potential in various neuropsychiatric and cognitive disorders. However, the antagonistic effects of DHEAS on γ-amino-butyric acidA receptors and its facilitatory action on glutamatergic neurotransmission might lead to enhanced brain excitability and seizures and thus limit DHEAS therapeutic applications. The aim of this study was to investigate possible age and sex differences in the neuronal excitability of the mice following acute and chronic DHEAS administration. Methods DHEAS was administered intraperitoneally in male and female adult and old mice either acutely or repeatedly once daily for 4 weeks in a 10 mg/kg dose. To investigate the potential proconvulsant properties of DHEAS, we studied the effects of acute and chronic DHEAS treatment on picrotoxin-, pentylentetrazole-, and N-methyl-D-aspartate-induced seizures in mice. The effects of acute and chronic DHEAS administration on the locomotor activity, motor coordination, and body weight of the mice were also studied. We also investigated the effects of DHEAS treatment on [3H]flunitrazepam binding to the mouse brain membranes. Results DHEAS did not modify the locomotor activity, motor coordination, body weight, and brain [3H]flunitrazepam binding of male and female mice. The results failed to demonstrate significant effects of single- and long-term DHEAS treatment on the convulsive susceptibility in both adult and aged mice of both sexes. However, small but significant changes regarding sex differences in the susceptibility to seizures were observed following DHEAS administration to mice. Conclusion Although our findings suggest that DHEAS treatment might be safe for various potential therapeutic applications in adult as well as in old age, they also support subtle interaction of DHEAS with male and female hormonal status

  11. Effects of chronic methamphetamine exposure on heart function in uninfected and retrovirus-infected mice.

    Science.gov (United States)

    Yu, Qianli; Montes, Sergio; Larson, Douglas F; Watson, Ronald R

    2002-07-12

    Methamphetamine (MA) increases catecholamine levels, which have detrimental effects on heart function through vasoconstriction, myocardial hypertrophy, and fibrosis. Murine retrovirus infection induces dilated cardiomyopathy (DCM). The present study investigated the cardiovascular effects of chronic MA treatment on uninfected and retrovirus-infected mice. C57BL/6 mice were studied after 12 weeks treatment. The four study groups were (group I) uninfected, MA placebo; (group II) infected, MA placebo; (group III) uninfected, MA treatment; and (group IV) infected and MA treatment. MA injections were given i.p. once a day for 5 days/week with a increasing dose from 15 mg/kg to 40 mg/kg. Left ventricular mechanics were measured in situ a using Millar conductance catheter system for pressure-volume loop analysis. Cardiac pathology was determined with histological analysis. In the uninfected mice, the load independent contractile parameters, pre-load recruitable stroke work (PRSW) and dP/dt(max) vs. Ved, significantly decreased by 32% and 35% in MA treated mice when compared to the saline injected mice. In retrovirus-infected mice, although there were no significant difference in Ees, PRSW, and dP/dt(max) vs. Ved due to MA treatment, they were increased 45%, 15% and 42% respectively when compared to saline treated mice. No further lowered heart function during murine AIDS may be due to the counteraction of the retroviral DCM and the MA induced myocardial fibrosis and hypertrophy (thickening of the ventricular walls). This is supported by increases in the End-diastolic volume (Ved, 38%) and End-systolic volume (Ves, 84%) in the retrovirus-infected saline injected mice, the decreases of 33% and 17% in the uninfected MA-treated mice, but no significant changes in the retrovirus-infected MA treated mice when compared to uninfected saline injected mice. These data suggest that MA induced myocardial cellular changes compensate for retrovirus induced DCM. PMID:12084392

  12. Influence of Trypanosoma cruzi strain on the pathogenesis of chronic myocardiopathy in mice

    Directory of Open Access Journals (Sweden)

    Sonia G. Andrade

    1990-03-01

    Full Text Available The murine model of chronic Chaga's myocardiopathy was developed in 201 inbred and outbred mice. The experimental groups consisted of 1st: 73 inbred AKR and A/J mice inoculated with one of the following. Trypanosoma cruzi strains: Peruvian (Type I, 12 SF (Type II or Colombian (Type III; 2nd: 128 outbred Swiss mice, chronically infected either with Type II or Type III strains isolated from human patients from different geographical areas. All T. cruzi strains were previoulsly characterized by their morphobiological behaviour in mice and by isoenzymatic patterns. For the 1st group the inoculum was 5 x 10**4 for the Peruvian strain and 1 x 10**5 for the 12 SF and Colombian strains. In the 2nd group-Swiss mice the inoculum size varied from 2 x 10**4 to 2 x 10**5. The inbred animals were killed at a 3 time-point scale (90, 180 and 240 days post-infection. The Swiss mice were killed from 180 to 660 days after infection. The evaluation of parasitemia and serology (xeodiagnosis and indirect immunofluorescent test was performed. The incidence of macroscopic alterations of the heart and cardiac index were evaluated. Histopathological lesions of the myocardium were graded. The influence of T. cruzi strain on the intensity of cardiac lesions was evaluated by the Chi-square test; the incidence of inflammatory lesions and its relationship to the parasite strain was evaluated by the Fisher test. The influence of the duration of infection was evaluated by using the Gamma Coefficient of Kruskal and Goodman and its measure of significance. Slight to severe microscopic alterations occurred in 85% of the chronically infected nice. There were a clear predominance on the incidence and intensity of inflammatory and fibrotic alterations for the mice infected with Type III strains. Statistical analysis has shown significant differences among the infected groups, in the inflammatory and fibrotic lesions. Macroscopic alterations (right cavities dilatation and apex

  13. Stressful Presentations: Mild Chronic Cold Stress in Mice Influences Baseline Properties of Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Kathleen Marie Kokolus

    2014-02-01

    Full Text Available The ability of dendritic cells to stimulate and regulate T cells is critical to effective anti-tumor immunity. Therefore, it is important to fully recognize any inherent factors which may influence DC function under experimental conditions, especially in laboratory mice since they are used so heavily to study immune responses. Physiological stress is well recognized to impair several arms of immune protection. The goals of this report are to briefly summarize previous work revealing how DCs respond to various forms of physiologically relevant stress and to present new data highlighting the potential for chronic mild cold stress inherent in mice housed at standard ambient temperatures required for laboratory mice to influence baseline DCs properties. Since recent data from our group shows that CD8+ T cell function is altered by mild chronic cold stress and since DC function is crucial for CD8+ T cell activation, we wondered whether mild cold stress may also be influencing DC properties. We found increased numbers of splenic DCs (CD11c+ in cold stressed mice compared to mice housed at a thermoneutral temperature, which significantly reduces cold stress. However, many of the DCs which are expanded in cold stressed mice express an immature phenotype. We also found that antigen presentation and ability of splenocytes to activate T cells were impaired compared to that seen in DCs isolated from mice at thermoneutrality. The new data presented here strongly suggest that the housing temperature of mice can affect fundamental properties of DC function which in turn could be influencing the response of DCs to added experimental stressors or other treatments.

  14. Effects of chronic stress on the onset and progression of Huntington's disease in transgenic mice.

    Science.gov (United States)

    Mo, Christina; Renoir, Thibault; Hannan, Anthony J

    2014-11-01

    Huntington's disease (HD) is a neurodegenerative disease caused by a tandem repeat mutation encoding an expanded polyglutamine tract. Our previous work showed that memory deficits in HD transgenic mice could be accelerated by increased levels of stress hormone, while memory in WT mice remained unaffected. HD patients experience higher levels of stress compared to the general population and symptoms of HD also include motor, cognitive, psychiatric, sexual and olfactory abnormalities, and an associated decline in activities of daily living. Therefore we investigated the impact of a robust stressor (i.e. restraint) on the onset and progression of a range of behavioral phenotypes in R6/1 transgenic HD mice. Restraint was administered for 1h daily from 6weeks of age and continued until R6/1 mice were clearly motor symptomatic at 14weeks of age. Serum corticosterone levels in both R6/1 and WT littermates were elevated immediately after the last restraint session and weight gain was suppressed in restrained animals throughout the treatment period. Motor coordination and locomotor activity were enhanced by chronic restraint in males, regardless of genotype. However, there was no effect of restraint on motor performances in female animals. At 8weeks of age, olfactory sensitivity was impaired by restraint in R6/1 HD female mice, but not in WT mice. In male R6/1 mice, the olfactory deficit was exacerbated by restraint and olfaction was also impaired in male WT mice. The development of deficits in saccharin preference, Y-maze memory, nest-building and sexually-motivated vocalizations was unaffected by chronic restraint in R6/1 and had little impact on such behavioral performances in WT animals. We provide evidence that chronic stress can negatively modulate specific endophenotypes in HD mice, while the same functions were affected to a lesser extent in WT mice. This vulnerability in HD animals seems to be sex-specific depending on the stress paradigm used. It is hoped that our

  15. Late effects of chronic low dose-rate γ-rays irradiation on mice

    International Nuclear Information System (INIS)

    To evaluate late biological effects of chronic low dose-rate radiation, the life-span and pathological changes were evaluated in mice which had been continuously irradiated with gamma-rays for 400 days. Two hundred (100 male and 100 female) specific-pathogen-free (SPF) B6C3F1 mice at six weeks of age were purchased every month. After a 2-week quarantine, they were divided into 4 groups (1 unirradiated control and 3 irradiated). Irradiation was performed using 137Cs gamma-rays at dose-rates of 20 mGy/day, 1 mGy/day and 0.05 mGy/day with accumulated doses equivalent to 8000 mGy, 400 mGy and 20 mGy, respectively. All mice were kept until they died a natural death. Results of the monthly microbiological examinations confirmed that the mice were maintained under SPF-conditions throughout the experimental period. A total of 4000 mice have been admitted into the experiment since it started in February 1996, all of which have received their predetermined doses and have been transferred to the animal room. Data on the 20 mGy/day group of both sexes suggested a shortened life span. The most common lethal neoplasms in pooled data of unirradiated control and irradiated male mice in order of frequency were neoplasms of the lymphohematopoietic system, liver, and lung. In female mice, neoplasms of the lymphohematopoietic system, soft tissue, and endocrine system were common. (author)

  16. Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice

    Science.gov (United States)

    Chiappalupi, Sara; Luca, Giovanni; Mancuso, Francesca; Madaro, Luca; Fallarino, Francesca; Nicoletti, Carmine; Calvitti, Mario; Arato, Iva; Falabella, Giulia; Salvadori, Laura; Di Meo, Antonio; Bufalari, Antonello; Giovagnoli, Stefano; Calafiore, Riccardo; Donato, Rosario; Sorci, Guglielmo

    2015-01-01

    We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (SPF) porcine Sertoli cells (SeC) encapsulated into clinical grade alginate-based microcapsules (SeC-MC) on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD), an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data show that three weeks after i.p. injection of SeC-MC significantly reduced adipose and fibrous tissue deposition, reduced macrophage infiltrate, and reduced numbers of damaged myofibers are found in muscles of 12-month-old mdx mice, which reproduce chronic DMD conditions. Compared with muscles of mock-treated mdx mice muscles of SeC-MC-treated mice show upregulation of the dystrophin paralogue, utrophin which is localized to the periphery of myofibers. Moreover, our data show that i.p. injection of SeC-MC into presymptomatic, 2-week-old mdx mice, although not fully preventing myofiber degeneration, results in protection against myofiber necrosis and muscle inflammation. Extensive discussion of these data can be found in Ref. [1]. PMID:26759818

  17. Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice

    Directory of Open Access Journals (Sweden)

    Sara Chiappalupi

    2015-12-01

    Full Text Available We report data about the effects of intraperitoneal (i.p. injection of specific pathogen-free (SPF porcine Sertoli cells (SeC encapsulated into clinical grade alginate-based microcapsules (SeC-MC on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD, an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data show that three weeks after i.p. injection of SeC-MC significantly reduced adipose and fibrous tissue deposition, reduced macrophage infiltrate, and reduced numbers of damaged myofibers are found in muscles of 12-month-old mdx mice, which reproduce chronic DMD conditions. Compared with muscles of mock-treated mdx mice muscles of SeC-MC-treated mice show upregulation of the dystrophin paralogue, utrophin which is localized to the periphery of myofibers. Moreover, our data show that i.p. injection of SeC-MC into presymptomatic, 2-week-old mdx mice, although not fully preventing myofiber degeneration, results in protection against myofiber necrosis and muscle inflammation. Extensive discussion of these data can be found in Ref. [1].

  18. Chronic exposure to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice

    International Nuclear Information System (INIS)

    Trichloroethene (TCE) exacerbates the development of autoimmune responses in autoimmune-prone MRL +/+ mice. Although TCE-mediated autoimmune responses are associated with an increase in serum immunoglobulins and autoantibodies, the underlying mechanism of autoimmunity is not known. To determine the progression of TCE-mediated immunotoxicity, female MRL +/+ mice were chronically exposed to TCE through the drinking water (0.5 mg/ml of TCE) for various periods of time. Serum concentrations of antinuclear antibodies increased after 36 and 48 weeks of TCE exposure. Histopathological analyses showed lymphocyte infiltration in the livers of MRL +/+ mice exposed to TCE for 36 or 48 weeks. Lymphocyte infiltration was also apparent in the pancreas, lungs, and kidneys of mice exposed to TCE for 48 weeks. Immunoglobulin deposits in kidney glomeruli were found after 48 weeks of exposure to TCE. Our results suggest that chronic exposure to TCE promotes inflammation in the liver, pancreas, lungs, and kidneys, which may lead to SLE-like disease in MRL +/+ mice

  19. Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure.

    Science.gov (United States)

    Manning, Elizabeth E; van den Buuse, Maarten

    2016-05-15

    Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. PMID:26965573

  20. Opioid tolerance in periaqueductal gray neurons isolated from mice chronically treated with morphine

    OpenAIRE

    Bagley, Elena E.; Chieng, Billy C H; Christie, MacDonald J.; Connor, Mark

    2005-01-01

    The midbrain periaqueductal gray (PAG) is a major site of opioid analgesic action, and a significant site of cellular adaptations to chronic morphine treatment (CMT). We examined μ-opioid receptor (MOP) regulation of voltage-gated calcium channel currents (ICa) and G-protein-activated K channel currents (GIRK) in PAG neurons from CMT mice.Mice were injected s.c. with 300 mg kg−1 of morphine base in a slow release emulsion three times over 5 days, or with emulsion alone (vehicles). This protoc...

  1. Rapamycin Prevents Experimental Sclerodermatous Chronic Graft-versus-Host Disease in mice

    OpenAIRE

    Belle, Ludovic; Binsfeld, Marilène; Dubois, Sophie; Hannon, Muriel; Caers, Jo; Briquet, Alexandra; MENTEN, Catherine; Beguin, Yves; Humblet-Baron, S; Baron, Frédéric

    2012-01-01

    Background: The most widely used mice model of chronic graft-versus-host disease (cGvHD) is an MHC-matched bone marrow transplantation model of sclerodermatous cGvHD. A limitation of that model is that mortality is relatively low, making difficult to study the impact of potentially therapeutic compounds. Aims: To develop a more severe model of cGVHD and to assess the impact of Rapamycin administration in that model. Results: Lethally irradiated Balb/C mice were injected with 10x106 bon...

  2. Susceptibility to chronic infection with Toxoplasma gondii does not correlate with susceptibility to acute infection in mice.

    OpenAIRE

    Suzuki, Y.; Orellana, M A; Wong, S Y; Conley, F K; Remington, J S

    1993-01-01

    Resistance against acute and chronic infection with Taxoplasma gondii in BALB/c and CBA/Ca mice was compared. Intraperitoneal inoculation of either 20, 40, or 80 cysts of the ME49 strain resulted in mortality rates in BALB/c mice of 12% (2 of 17), 50% (6 of 12), and 75% (9 of 12), respectively, within 3 weeks after infection (acute stage). There was no mortality in the CBA/Ca mice for any of the doses. In marked contrast, CBA/Ca mice were highly sensitive to chronic infection with developing ...

  3. Chronic wasting disease of deer and elk in transgenic mice: oral transmission and pathobiology.

    Science.gov (United States)

    Trifilo, Matthew J; Ying, Ge; Teng, Chao; Oldstone, Michael B A

    2007-08-15

    To study the pathogenesis of chronic wasting disease (CWD) in deer and elk, transgenic (tg) mice were generated that expressed the prion protein (PrP) of deer containing a glycine at amino acid (aa) 96 and a serine at aa 225 under transcriptional control of the murine PrP promoter. This construct was introduced into murine PrP-deficient mice. As anticipated, neither non-tg mice nor PrP ko mice were susceptible when inoculated intracerebrally (i.c.) or orally with CWD brain material (scrapie pool from six mule deer) and followed for 600+ days (dpi). Deer PrP tg mice were not susceptible to i.c. inoculation with murine scrapie. In contrast, a fatal neurologic disease occurred accompanied by conversion of deer PrPsen to PrPres by western blot and immunohistochemistry after either i.c. inoculation with CWD brain into two lines of tg mice studied (312+32 dpi [mean+2 standard errors] for the heterozygous tg line 33, 275+46 dpi for the heterozygous tg line 39 and 210 dpi for the homozygous tg line 33) or after oral inoculation (381+55 dpi for the homozygous tg line 33 and 370+26 dpi for the homozygous tg line 39). Kinetically, following oral inoculation of CWD brain, PrPres was observed by day 200 when mice were clinically healthy in the posterior surface of the dorsum of the tongue primarily in serous and mucous glands, in the intestines, in large cells at the splenic marginal zone that anatomically resembled follicular dendritic cells and macrophages and in the olfactory bulb and brain stem but did not occur in the cerebellum, cerebral cortex or hippocampus or in hearts, lungs and livers of infected mice. After 350 days when mice become clinically ill the cerebellum, cerebral cortex and hippocampus became positive for PrPres and displayed massive spongiosis, neuronal drop out, gliosis and florid plaques. PMID:17451773

  4. Induction of depression-related behaviors by reactivation of chronic Toxoplasma gondii infection in mice.

    Science.gov (United States)

    Mahmoud, Motamed Elsayed; Ihara, Fumiaki; Fereig, Ragab M; Nishimura, Maki; Nishikawa, Yoshifumi

    2016-02-01

    Although Toxoplasma gondii (T. gondii) infection is relevant to many psychiatric disorders, the fundamental mechanisms of its neurobiological correlation with depression are poorly understood. Here, we show that reactivation of chronic infection by an immunosuppressive regimen caused induction of depressive-like behaviors without obvious sickness symptoms. However, the depression-related behaviors in T. gondii-infected mice, specifically, reduced sucrose preference and increased immobility in the forced-swim test were observed at the reactivation stage, but not in the chronic infection. Interestingly, reactivation of T. gondii was associated with production of interferon-gamma and activation of brain indoleamine 2, 3-dioxygenase, which converts tryptophan to kynurenine and makes it unavailable for serotonin synthesis. Furthermore, serotonin turnover to its major metabolite, 5-hydroxyindoleacetic acid, was also enhanced at the reactivation stage. Thus, enhanced tryptophan catabolic shunt and serotonin turnover may be implicated in development of depressive-like behaviors in mice with reactivated T. gondii. PMID:26554725

  5. Chronic spinal cord injury impairs primary antibody responses, but spares existing humoral immunity in mice

    OpenAIRE

    Oropallo, Michael A.; HELD, KATHERINE S.; Goenka, Radhika; Ahmad, Sifat A.; O’Neill, Patrick J.; Steward, Oswald; Lane, Thomas E.; Cancro, Michael P.

    2012-01-01

    Spinal cord injury (SCI) results in immune depression. To better understand how injury inhibits humoral immunity, the effects of chronic thoracic SCI on B cell development and immune responses to thymus-independent (TI) type-2 and thymus-dependent (TD) antigens were determined. Mice received complete crush injury or control laminectomy at either thoracic level 3 (T3), which disrupts descending autonomic control of the spleen, or at T9, which conserves most splenic sympathetic activity. Althou...

  6. Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice

    OpenAIRE

    Sara Chiappalupi; Giovanni De Luca; Francesca Mancuso; Luca Madaro; Francesca Fallarino; Carmine Nicoletti; Mario Calvitti; Iva Arato; Giulia Falabella; Laura Salvadori; Antonio Di Meo; Antonello Bufalari; Stefano Giovagnoli; Riccardo Calafiore; Rosario Donato

    2015-01-01

    We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (SPF) porcine Sertoli cells (SeC) encapsulated into clinical grade alginate-based microcapsules (SeC-MC) on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD), an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data ...

  7. Toxicogenomic analysis of susceptibility to inhaled urban particulate matter in mice with chronic lung inflammation

    OpenAIRE

    Yauk Carole L; Williams Andrew; Thomson Errol M; Vincent Renaud

    2009-01-01

    Abstract Background Individuals with chronic lung disease are at increased risk of adverse health effects from airborne particulate matter. Characterization of underlying pollutant-phenotype interactions may require comprehensive strategies. Here, a toxicogenomic approach was used to investigate how inflammation modifies the pulmonary response to urban particulate matter. Results Transgenic mice with constitutive pulmonary overexpression of tumour necrosis factor (TNF)-α under the control of ...

  8. Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol

    OpenAIRE

    Meredith, Gloria E.; Totterdell, Susan; Potashkin, Judith A.; Surmeier, D. James

    2008-01-01

    Formidable challenges for Parkinson's disease (PD) research are to understand the processes underlying nigrostriatal degeneration and how to protect the dopamine neurons. Fundamental research relies on good animal models that demonstrate the pathological hallmarks and motor deficits of PD. Using a chronic regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p) in mice, dopamine cell loss exceeds 60%, extracellular glutamate is elevated, cytoplasmic inclusions are forme...

  9. Essential role for telomerase in chronic myeloid leukemia induced by BCR-ABL in mice

    OpenAIRE

    Vicente-Dueñas, Carolina; Barajas-Diego, Marcos; Romero-Camarero, Isabel; González-Herrero, Inés; Flores, Teresa; Sánchez García, Isidro

    2012-01-01

    The telomerase protein is constitutively activated in malignant cells from many patients with cancer, including the chronic myeloid leukemia (CML), but whether telomerase is essential for the pathogenesis of this disease is not known. Here, we used telomerase deficient mice to determine the requirement for telomerase in CML induced by BCR-ABL in mouse models of CML. Loss of one telomerase allele or complete deletion of telomerase prevented the development of leukemia induced by BCR-ABL. Howev...

  10. Intact memory in TGF-β1 transgenic mice featuring chronic cerebrovascular deficit: recovery with pioglitazone

    OpenAIRE

    Nicolakakis, Nektaria; Aboulkassim, Tahar; Aliaga, Antonio; Tong, Xin-Kang; Rosa-Neto, Pedro; Hamel, Edith

    2010-01-01

    The roles of chronic brain hypoperfusion and transforming growth factor-beta 1 (TGF-β1) in Alzheimer's disease (AD) are unresolved. We investigated the interplay between TGF-β1, cerebrovascular function, and cognition using transgenic TGF mice featuring astrocytic TGF-β1 overexpression. We further assessed the impact of short, late therapy in elderly animals with the antioxidant N-acetyl--cysteine (NAC) or the peroxisome proliferator-activated receptor-γ agonist pioglitazone. The latter was a...

  11. Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice.

    Science.gov (United States)

    Viatte, Lydie; Nicolas, Gaël; Lou, Dan-Qing; Bennoun, Myriam; Lesbordes-Brion, Jeanne-Claire; Canonne-Hergaux, François; Schönig, Kai; Bujard, Hermann; Kahn, Axel; Andrews, Nancy C; Vaulont, Sophie

    2006-04-01

    We report the generation of a tetracycline-regulated (Tet ON) transgenic mouse model for acute and chronic expression of the iron regulatory peptide hepcidin in the liver. We demonstrate that short-term and long-term tetracycline-dependent activation of hepcidin in adult mice leads to hypoferremia and iron-limited erythropoiesis, respectively. This clearly establishes the key role of hepcidin in regulating the extracellular iron concentration. We previously demonstrated that, when expressed early in fetal development, constitutive transgenic hepcidin expression prevented iron accumulation in an Hfe-/- mouse model of hemochromatosis. We now explore the effect of chronic hepcidin expression in adult Hfe-/- mice that have already developed liver iron overload. We demonstrate that induction of chronic hepcidin expression in 2-month-old Hfe-/- mice alters their pattern of cellular iron accumulation, leading to increased iron in tissue macrophages and duodenal cells but less iron in hepatocytes. These hepcidin-induced changes in the pattern of cellular iron accumulation are associated with decreased expression of the iron exporter ferroportin in macrophages but no detectable alteration of ferroportin expression in the hepatocytes. We speculate that this change in iron homeostasis could offer a therapeutic advantage by protecting against damage to parenchymal cells. PMID:16339398

  12. Chronic ethanol consumption disrupts diurnal rhythms of hepatic glycogen metabolism in mice

    Science.gov (United States)

    Udoh, Uduak S.; Swain, Telisha M.; Filiano, Ashley N.; Gamble, Karen L.; Young, Martin E.

    2015-01-01

    Chronic ethanol consumption has been shown to significantly decrease hepatic glycogen content; however, the mechanisms responsible for this adverse metabolic effect are unknown. In this study, we examined the impact chronic ethanol consumption has on time-of-day-dependent oscillations (rhythms) in glycogen metabolism processes in the liver. For this, male C57BL/6J mice were fed either a control or ethanol-containing liquid diet for 5 wk, and livers were collected every 4 h for 24 h and analyzed for changes in various genes and proteins involved in hepatic glycogen metabolism. Glycogen displayed a robust diurnal rhythm in the livers of mice fed the control diet, with the peak occurring during the active (dark) period of the day. The diurnal glycogen rhythm was significantly altered in livers of ethanol-fed mice, with the glycogen peak shifted into the inactive (light) period and the overall content of glycogen decreased compared with controls. Chronic ethanol consumption further disrupted diurnal rhythms in gene expression (glycogen synthase 1 and 2, glycogenin, glucokinase, protein targeting to glycogen, and pyruvate kinase), total and phosphorylated glycogen synthase protein, and enzyme activities of glycogen synthase and glycogen phosphorylase, the rate-limiting enzymes of glycogen metabolism. In summary, these results show for the first time that chronic ethanol consumption disrupts diurnal rhythms in hepatic glycogen metabolism at the gene and protein level. Chronic ethanol-induced disruption in these daily rhythms likely contributes to glycogen depletion and disruption of hepatic energy homeostasis, a recognized risk factor in the etiology of alcoholic liver disease. PMID:25857999

  13. Hypericum perforatum treatment: effect on behaviour and neurogenesis in a chronic stress model in mice

    Directory of Open Access Journals (Sweden)

    Cuzzocrea Salvatore

    2011-01-01

    Full Text Available Abstract Background Extracts of Hypericum perforatum (St. John's wort have been traditionally recommended for a wide range of medical conditions, in particular mild-to-moderate depression. The present study was designed to investigate the effect of Hypericum perforatum treatment in a mouse model of anxiety/depressive-like behavior, induced by chronic corticosterone administration. Methods CD1 mice were submitted to 7 weeks corticosterone administration and then behavioral tests as Open Field (OF, Novelty-Suppressed Feeding (NSF, Forced Swim Test (FST were performed. Cell proliferation in hippocampal dentate gyrus (DG was investigated by both 5-bromo-2'-deoxyuridine (BrdU and doublecortin (DCX immunohistochemistry techniques and stereological procedure was used to quantify labeled cells. Golgi-impregnation method was used to evaluate changes in dendritic spines in DG. Hypericum perforatum (30 mg/Kg has been administered for 3 weeks and then neural development in the adult hippocampus and behavioral changes have been examined. Results The anxiety/depressive-like state due to chronic corticosterone treatment was reversed by exogenous administration of Hypericum perforatum; the proliferation of progenitor cells in mice hippocampus was significantly reduced under chronic corticosterone treatment, whereas a long term treatment with Hypericum perforatum prevented the corticosterone-induced decrease in hippocampal cell proliferation. Corticosterone-treated mice exhibited a reduced spine density that was ameliorated by Hypericum perforatum administration. Conclusion These results provide evidence of morphological adaptations occurring in mature hippocampal neurons that might underlie resilient responses to chronic stress and contribute to the therapeutic effects of chronic Hypericum perforatum treatment.

  14. Chronic exposure to ethanol in male mice may be associated with hearing loss in offspring

    Directory of Open Access Journals (Sweden)

    Fei Liang

    2015-01-01

    Full Text Available Although paternal ethanol (EtOH abuse has been shown to affect the growth and behavior of offspring, the exact molecular and mechanistic basis remains largely unclear. Methylation alterations in imprinted genes may be related to well-documented teratogenic effects of ethanol. Here we show that chronic paternal ethanol exposure increases the susceptibility to abnormal behavior in offspring through male game epigenetic alteration. In our study, different doses of ethanol (0, 1.1, 3.3 g kg−1 were administered intra-gastrically to male mice and decreased sperm motility was found in the highest ethanol-exposed group compared with the controls. Data also showed a dose-dependent increase in deaf mice of the paternally ethanol-exposed groups. The methylation of H19, Peg3, Ndn and Snrpn was assessed in paternal spermatozoa and in the cerebral cortices of deaf mice. EtOH affected methylation of Peg3 (CpG 3, 7 and 9 in paternal spermatozoa and in the cerebral cortices of deaf mice, but the level of mRNA expression did not change, suggesting that other gene regulation may be involved in these processes. Overall, chronic paternal ethanol exposure could alter the methylation of imprinted genes in sire spermatozoa that could also be passed on to offspring, giving rise to developmental disorders. Our results provide possible epigenetic evidence for a paternal ethanol exposure contribution to Fetal Alcohol Syndrome (FAS.

  15. Bacillus-produced surfactin attenuates chronic inflammation in atherosclerotic lesions of ApoE(-/-) mice.

    Science.gov (United States)

    Gan, Ping; Jin, Dong; Zhao, Xiuyun; Gao, Zhenqiu; Wang, Shengying; Du, Peng; Qi, Gaofu

    2016-06-01

    Bacillus-produced surfactin can inhibit acute inflammation in vitro and in vivo. However, there is no report whether surfactin could inhibit chronic inflammation in the atherosclerotic lesions. Apoliprotein E deficient (ApoE(-/-)) mice (fed on atherogenic diet) were intragastrically administered with surfactin for 9 doses, then the athero-protective effect of surfactin was determined in vivo. The results showed surfactin could induce anti-inflammatory factors such as IgA, transforming growth factor (TGF)-β and interleukin (IL)-10 in the intestine. Further investigation discovered that surfactin also systemically induced CD4(+)CD25(+)FoxP3(+) Tregs in spleen, which could inhibit T cells to produce pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon (IFN)-γ. The IgG subclass pattern with high titer of IgG1 (Th2-type) but low titer of IgG2a (Th1-type) was also found in the surfactin-treated mice. As a result, the attenuation of chronic inflammation was observed in the surfactin-treated groups accompanying with less TNF-α but more IL-10 in the atherosclerotic lesions. Moreover, surfactin could reduce serum total cholesterol and cholesterol in low-density lipoprotein, and increase serum cholesterol in high-density lipoprotein in mice. Collectively, surfactin could significantly attenuate atherosclerotic lesions on the aorta by restoration of the delicate balance of Th1/Th2 response in mice. PMID:27082998

  16. Sleep loss and the inflammatory response in mice under chronic environmental circadian disruption.

    Directory of Open Access Journals (Sweden)

    Allison J Brager

    Full Text Available Shift work and trans-time zone travel lead to insufficient sleep and numerous pathologies. Here, we examined sleep/wake dynamics during chronic exposure to environmental circadian disruption (ECD, and if chronic partial sleep loss associated with ECD influences the induction of shift-related inflammatory disorder. Sleep and wakefulness were telemetrically recorded across three months of ECD, in which the dark-phase of a light-dark cycle was advanced weekly by 6 h. A three month regimen of ECD caused a temporary reorganization of sleep (NREM and REM and wake processes across each week, resulting in an approximately 10% net loss of sleep each week relative to baseline levels. A separate group of mice were subjected to ECD or a regimen of imposed wakefulness (IW aimed to mimic sleep amounts under ECD for one month. Fos-immunoreactivity (IR was quantified in sleep-wake regulatory areas: the nucleus accumbens (NAc, basal forebrain (BF, and medial preoptic area (MnPO. To assess the inflammatory response, trunk blood was treated with lipopolysaccharide (LPS and subsequent release of IL-6 was measured. Fos-IR was greatest in the NAc, BF, and MnPO of mice subjected to IW. The inflammatory response to LPS was elevated in mice subjected to ECD, but not mice subjected to IW. Thus, the net sleep loss that occurs under ECD is not associated with a pathological immune response.

  17. Attenuation of the cytotoxic T lymphocyte response to lymphocytic choriomeningitis virus in mice subjected to chronic social stress

    OpenAIRE

    Sommershof, Annette; Basler, Michael; Riether, Carsten; Engler, Harald; Gröttrup, Marcus

    2011-01-01

    Chronic stress is suspected to increase the susceptibility to infections but experimental evidence from physiological stress models is scarce. We examined the effects of chronic social stress on virus-specific CTL responses in mice after infection with lymphocytic choriomeningitis virus (LCMV). Mice subjected to social stress on six consecutive days prior to infection showed a significant reduction of IFN-γ producing TCD8+ splenocytes and markedly lowered plasma concentrations of IFN-γ. In co...

  18. Late effects of chronic low dose-rate γ-rays irradiation on mice

    International Nuclear Information System (INIS)

    To evaluate late biological effects of chronic low dose-rate radiation, the life-span and pathological changes were evaluated in mice that were continuously irradiated with gamma-rays for 400 days. Two hundred (100 male and 100 female) specific-pathogen-free (SPF) B6C3F1 mice at six weeks of age were purchased every month. After a 2-week quarantine, they were divided into 4 groups (1 unirradiated control and 3 irradiated). Irradiation was performed using 137Cs gamma-rays at dose-rates of 20 mGy (22 h-day)-1, 1 mGy (22 h-day)-1 and 0.05 mGy (22 h-day)''-1 with accumulated doses equivalent to 8,000 mGy, 400 mGy and 20 mGy, respectively. All mice were kept until they died a natural death. Results of the monthly microbiological examinations confirmed that the mice were maintained under SPF-conditions throughout the experimental period. A total of 4,000 mice have been admitted into the experiment since it started in February 1996, all of which have received their predetermined doses and have been transferred to the animal room. Data on the 20 mGy (22 h-day)-1 group of both sexes suggested a shortened life span. The most common lethal neoplasms in pooled data of unirradiated control male mice and irradiated male mice in order of frequency were neoplasms of the lymphohematopoietic system, liver, lung, and soft tissue. In female mice, neoplasms of the lymphohematopoietic system, soft tissue, endocrine system, and liver were most common. (author)

  19. The pathogenesis of chronic eosinophilic esophagitis in SHARPIN-deficient mice.

    Science.gov (United States)

    Chien, Syu-Jhe; Silva, Kathleen A; Kennedy, Victoria E; HogenEsch, Harm; Sundberg, John P

    2015-12-01

    Increased numbers of eosinophils in the esophagus are common in several esophageal and systemic diseases, and a prominent feature of eosinophilic esophagitis. Mouse models can provide insight into the mechanisms of eosinophil infiltration and their pathogenic role. SHARPIN-deficient cpdm mice develop a chronic proliferative dermatitis and an esophagitis characterized by epithelial hyperplasia and the accumulation of eosinophils in the serosa, submucosa, lamina propria and epithelium of the esophagus. We conducted a detailed investigation of the pathogenesis of the esophagitis by light microscopy, immunohistochemistry, and gene expression as the mice aged from 4 to 10 weeks. The thickness of the esophageal epithelium and the number of eosinophils in the esophagus both increased with age. There were scattered apoptotic epithelial cells in mice at 6-10 weeks of age that reacted with antibodies to activated caspase 3 and caspase 9. The expression of CCL11 (eotaxin-1), IL4, IL13 and TSLP was increased in cpdm mice compared with wild type (WT) mice, and there was no change in the expression of CCL24 (eotaxin-2), IL5 and IL33. The expression of chitinase-like 3 and 4 (YM1 and YM2) proteins, markers of type 2 inflammation, was greatly increased in cpdm mice, and this was replicated in vitro by incubation of WT esophagus in the presence of IL4 and IL13. Immunohistochemistry showed that these proteins were localized in esophageal epithelial cells. The severity of the esophagitis was not affected by crossing SHARPIN-deficient mice with lymphocyte-deficient Rag1 null mice indicating that the inflammation is independent of B and T lymphocytes. PMID:26321245

  20. The Cellular Differences between Acute and Chronic Neutron and Gamma-Ray Irradiation in Mice

    International Nuclear Information System (INIS)

    Data on the shortening of the life span in mice by radiation show that an acute dose of gamma-rays may be as much as four times as effective as an equal dose of the same radiation administered chronically. However, for neutrons, chronic and acute administrations are equally effective. An analysis of these effects shows that for gamma-rays a certain fraction of the radiation injury is reparable, and that the value of this fraction depends on the dose and the dose rate. With neutrons, none of the damage appears reparable. For acute irradiation, the RBE is about 2 for shortening of the life span, but for chronic, may be as high as 8. Chromosome aberrations have been scored in liver cells of mice when treated with both chronic and acute doses of both gamma-rays and thermal neutrons. In all cases the percentage of aberrent cells is proportional to the shortening of the life span produced by the treatment. Further, with neutrons, acute and chronic irradiation is equally effective in producing chromosome abberations. For gamma-rays, acute irradiation may produce as much as four times the chromosomal damage as does chronic irradiation. This shows that some chromosomes can heal themselves following small doses of gamma-rays, but there is no chromosome healing following any dose of neutrons. The RBE using chromosome aberrations as a criterion is the same as for life shortening. These results give a firm cellular basis for the known biological differences between gamma rays and neutrons, and in addition give strong support to the concept that natural and radiation-induced aging are caused by spontaneous and radiation-induced mutations, respectively, in the somatic cells of animals. (author)

  1. Influence of experimental context on the development of anhedonia in male mice imposed to chronic social stress

    OpenAIRE

    Bondar, N. P.; Kovalenko, I. L.; Avgustinovich, D. F.; Kudryavtseva, N. N.

    2007-01-01

    Anhedonia is one of the key symptoms of depression in humans. Consumption of 1% sucrose solution supplemented with 0.2% vanillin was studied in two experimental contexts in male mice living under chronic social stress induced by daily experience of defeats in agonistic interactions and leading to development of depression. In the first experiment, vanillin sucrose solution was made available as an option of water during 10 days to mice living in group home cages. Then the mice were subjected ...

  2. Age influence on mice lung tissue response to [i]Aspergillus fumigatus[/i] chronic exposure

    Directory of Open Access Journals (Sweden)

    Marta Kinga Lemieszek

    2015-02-01

    Full Text Available [b]Introduction and objective[/b]. Exposure to conidia of [i]Aspergillus fumigatus[/i] was described as a causative factor of a number of the respiratory system diseases, including asthma, chronic eosinophilic pneumonia, hypersensitivity pneumonitis and bronchopulmonary aspergillosis. The study investigates the effects of the repeated exposure to [i]A. fumigatus[/i] in mice pulmonary compartment. Our work tackles two, so far insufficiently addressed, important aspects of interaction between affected organism and[i] A. fumigatus[/i]: 1 recurrent character of exposure (characteristic for pathomechanism of the abovementioned disease states and 2 impact of aging, potentially important for the differentiation response to an antigen. [b]Materials and methods[/b]. In order to dissect alterations of the immune system involved with both aging and chronic exposure to [i]A. fumigatus[/i], we used 3- and 18-month-old C57BL/6J mice exposed to repeated[i] A. fumigatus[/i] inhalations for 7 and 28 days. Changes in lung tissue were monitored by histological and biochemical evaluation. Concentration of pro- and anti-inflammatory cytokines in lung homogenates was assessed by ELISA tests. [b]Results and conclusions. [/b]Our study demonstrated that chronic inflammation in pulmonary compartment, characterized by the significant increase of proinflammatory cytokines (IL1, IL6, IL10 levels, was the dominant feature of mice response to repeated [i]A. fumigatus[/i] inhalations. The pattern of cytokines’ profile in the course of exposure was similar in both age groups, however in old mice the growth of the cytokines’ levels was more pronounced (especially in case of IL1.

  3. Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice.

    Science.gov (United States)

    Silvennoinen, Reija; Quesada, Helena; Kareinen, Ilona; Julve, Josep; Kaipiainen, Leena; Gylling, Helena; Blanco-Vaca, Francisco; Escola-Gil, Joan Carles; Kovanen, Petri T; Lee-Rueckert, Miriam

    2015-05-11

    Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids. C57Bl/6J mice exposed to intermittent stress for 5 days exhibited increased transit through the large intestine and enhanced fecal bile acid excretion. Of the transcription factors and transporters that regulate bile acid homeostasis, the mRNA expression levels of the hepatic farnesoid X receptor (FXR), the bile salt export pump (BSEP), and the intestinal fibroblast growth factor 15 (FGF15) were reduced, whereas those of the ileal apical sodium-dependent bile acid transporter (ASBT), responsible for active bile acid absorption, remained unchanged. Neither did the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme regulating bile acid synthesis, change in the stressed mice. Evaluation of the functionality of the m-RCT pathway revealed increased fecal excretion of bile acids that had been synthesized from macrophage-derived cholesterol. Overall, our study reveals that chronic intermittent stress in mice accelerates m-RCT specifically by increasing fecal excretion of bile acids. This novel mechanism of m-RCT induction could have antiatherogenic potential under conditions of chronic stress. PMID:25969465

  4. Antidepressant-like effects of BCEF0083 in the chronic unpredictable stress models in mice

    Institute of Scientific and Technical Information of China (English)

    ZHOU Lan-lan; MING Liang; MA Chuan-geng; CHENG Yan; JIANG Qin

    2005-01-01

    Background Up to now there have been no satisfactory drugs to treat psychiatric disorders, and now bioactive compound from entomagenous fungi (BCEF0083) is a new type of bioactive compound from entomopathogenic fungi. Our previous investigations have shown that BCEF has an inhibition effect on monoamine oxidase. So, BCEF may be a latent antidepressant. This study aimed at observing the antidepressant effects and its mechanism of BCEF in the chronic unpredictable stress models in mice. Methods The antidepressant effects of BCEF were examined on the chronic unpredictable stress models in mice. Sixty mice were randomly divided to six groups. Animals were housed and isolated except saline group. Mice were exposed to different stressors per day randomly from day 1 to day 21. Body weight were weighed on day 1,day 10 and on day 21 during the 21-day stress procedure. Awarding response was detected by using method of calculating the 24-hour consumption of saccharum water. Step through test was used to evaluate the behavioral response. AVP contents in plasma were also detected by using radioimmunoassays. Results Chronic unpredictable stress resulted in a significant decrease of the body weight and could apparently cause escape behavior disturbance and gradual reduction of sensitivity to reward in animal models. Drug treatment (BCEF 25, 50, 100 mg/kg) could significantly ameliorate the decreased body weight and effectively reverse the escape behavior disturbance. The gradual reduction of sensitivity to reward, the anhedonic state, was also effectively reversed by BCEF. BCEF (50, 100 mg/kg) could also effectively restore the AVP content in the plasma.Conclusions This evidence suggests that BCEF can effectively inhibit the depression behavior and show strong antidepressant effect. BCEF can effectively restore the plasma AVP release and this may be an important mechanism of its antidepressant effect.

  5. Chlordecone potentiates hepatic fibrosis in chronic liver injury induced by carbon tetrachloride in mice.

    Science.gov (United States)

    Tabet, Elise; Genet, Valentine; Tiaho, François; Lucas-Clerc, Catherine; Gelu-Simeon, Moana; Piquet-Pellorce, Claire; Samson, Michel

    2016-07-25

    Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver failure and death. Chlordecone is a chlorinated pesticide used in the 1990s. It is not itself hepatotoxic, but its metabolism in the liver triggers hepatomegaly and potentiates hepatotoxic agents. Chlordecone is now banned, but it persists in soil and water, resulting in an ongoing public health problem in the Caribbean area. We assessed the probable impact of chlordecone on the progression of liver fibrosis in the population of contaminated areas, by developing a mouse model of chronic co-exposure to chlordecone and a hepatotoxic agent, carbon tetrachloride (CCl4). After repeated administrations of chlordecone and CCl4 by gavage over a 12-week period, we checked for liver damage in the exposed mice, by determining serum liver transaminase (AST, ALT) levels, histological examinations of the liver and measuring the expression of genes encoding extracellular matrix components. The co-exposure of mice to CCl4 and chlordecone resulted in significant increases in ALT and AST levels. Chlordecone also increased expression of the Col1A2, MMP-2, TIMP-1 and PAI-1 genes in CCl4-treated mice. Finally, we demonstrated, by quantifying areas of collagen deposition and alpha-SMA gene expression, that chlordecone potentiated the hepatic fibrosis induced by CCl4. In conclusion, our data suggest that chlordecone potentiates hepatic fibrosis in mice with CCl4-induced chronic liver injury. PMID:26853152

  6. Sensitivity to Chronic Methamphetamine Administration and Withdrawal in Mice with Relaxin-3/RXFP3 Deficiency.

    Science.gov (United States)

    Haidar, Mouna; Lam, Monica; Chua, Berenice E; Smith, Craig M; Gundlach, Andrew L

    2016-03-01

    Methamphetamine (METH) is a highly addictive psychostimulant, and cessation of use is associated with reduced monoamine signalling, and increased anxiety/depressive states. Neurons expressing the neuropeptide, relaxin-3 (RLN3), and its cognate receptor, RXFP3, constitute a putative 'ascending arousal system', which shares neuroanatomical and functional similarities with serotonin (5-HT)/dorsal raphe and noradrenaline (NA)/locus coeruleus monoamine systems. In light of possible synergistic roles of RLN3 and 5-HT/NA, endogenous RLN3/RXFP3 signalling may compensate for the temporary reduction in monoamine signalling associated with chronic METH withdrawal, which could alter the profile of 'behavioural despair', bodyweight reductions, and increases in anhedonia and anxiety-like behaviours observed following chronic METH administration. In studies to test this theory, Rln3 and Rxfp3 knockout (KO) mice and their wildtype (WT) littermates were injected once daily with saline or escalating doses of METH (2 mg/kg, i.p. on day 1, 4 mg/kg, i.p. on day 2 and 6 mg/kg, i.p. on day 3-10). WT and Rln3 and Rxfp3 KO mice displayed an equivalent sensitivity to behavioural despair (Porsolt swim) during the 2-day METH withdrawal and similar bodyweight reductions on day 3 of METH treatment. Furthermore, during a 3-week period after the cessation of chronic METH exposure, Rln3 KO, Rxfp3 KO and corresponding WT mice displayed similar behavioural responses in paradigms that measured anxiety (light/dark box, elevated plus maze), anhedonia (saccharin preference), and social interaction. These findings indicate that a whole-of-life deficiency in endogenous RLN3/RXFP3 signalling does not markedly alter behavioural sensitivity to chronic METH treatment or withdrawal, but leave open the possibility of a more significant interaction with global or localised manipulations of this peptide system in the adult brain. PMID:26023064

  7. Reversibility of cardiac fibrosis in mice chronically infected with Trypanosoma cruzi, under specific chemotherapy

    Directory of Open Access Journals (Sweden)

    Sonia G. Andrade

    1991-06-01

    Full Text Available This investigation was performed to verify the effect of specific chemotherapy (Benznidazole or MK-346 on the inflammatory and fibrotic cardiac alterations in mice chronically infected with the strains 21 SF (Type II and Colombian (Type III of Trypanosoma cruzi. To obtain chronically infected mice, two groups of 100 Swiss mice each, were infected with either the 21 SF or the Colombian strain (2x 10 [raised to the power of] 4 and 5x 10 [raised to the power of] 4 blood forms respectively. The rate of morality in the acute phase was of 80% for both groups. Twenty surviving mice chronically infected with the 21 SF strain and 20 with the Colombian strain were then divided in treated and untreated groups. Excluding those that died during the course of treatment, 14 mice chronically infected with the 21 SF strain and 15 with the Colombian strain were evaluated in the present study. Chemotherapy was performed with Benznidazole (N-benzil-2-nitro-1-imidazolacetamide in the dose of 100mg/k.b.w/day, for 60 days, or with the MK-436(3(1-methyl-5 nitroimidazol-2-yl in two daily doses of 250 mg/k.b.w, for 20 days. Parasitological cure tests were performed (xenodiagnosis, haemoculture, subinovulation of the blood into newborn mice, and serological indirect immunofluorescence test. The treated and untreated mice as well as intact controls were killed at different periods after treatment and the heart were submitted to histopathological study with hematoxilineosin and picrosirius staining; ultrastructural study; collagen immunotyping, fibronectin and laminin identification by immunofluorescence tests. Results: the untreated controls either infected with 21 SF or Colombian strain, showed inflammatory and fibrotic alterations that were mild to moderate with the 21 SF strain and intense with the Colombian strain. Redpicrosirius staining showed bundles of collagen in the interstitial space and around cardiac fibers. Increased deposits of mitritial components and

  8. Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic hypoxia in mice.

    Science.gov (United States)

    Sunderram, Jagadeeshan; Semmlow, John; Thakker-Varia, Smita; Bhaumik, Mantu; Hoang-Le, Oanh; Neubauer, Judith A

    2009-08-01

    Adaptations to chronic hypoxia (CH) could reflect cellular changes within the cardiorespiratory regions of the rostral ventrolateral medulla (RVLM), the C1 region, and the pre-Bötzinger complex (pre-BötC). Previous studies have shown that the hypoxic chemosensitivity of these regions are heme oxygenase (HO) dependent and that CH induces HO-1. To determine the time course of HO-1 induction within these regions and explore its relevance to the respiratory and sympathetic responses during CH, the expression of HO-1 mRNA and protein in the RVLM and measures of respiration, sigh frequency, and sympathetic activity (spectral analysis of heart rate) were examined during 10 days of CH. Respiratory and sympathetic responses to acute hypoxia were obtained in chronically instrumented awake wild-type (WT) and HO-1 null mice. After 4 days of CH, there was a significant induction of HO-1 within the C1 region and pre-BötC. WT mice acclimated to CH by increasing peak diaphragm EMG after 10 days of CH but had no change in the respiratory response to acute hypoxia. There were no significant differences between WT and HO-1 null mice. In WT mice, hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity initially declined before returning toward baseline after 5 days of CH, correlating with the induction of HO-1. In contrast, HO-1 null mice had a persistent decline in hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity. We conclude that induction of HO-1 in these RVLM cardiorespiratory regions may be important for the hypoxic sensitivity of sighs and sympathetic activity during CH. PMID:19458275

  9. Chronic psychosocial stress causes delayed extinction and exacerbates reinstatement of ethanol-induced conditioned place preference in mice

    OpenAIRE

    Bahi, Amine; Dreyer, Jean-luc

    2014-01-01

    Objective: Here, we examined the impact of chronic subordinate colony (CSC) exposure on EtOH-CPP extinction, as well as ethanol-induced reinstatement of CPP.Methods: 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 s...

  10. Chronic caffeine exposure attenuates blast-induced memory deficit in mice

    Institute of Scientific and Technical Information of China (English)

    Ya-Lei Ning; Nan Yang; Xing Chen; Zi-Ai Zhao; Xiu-Zhu Zhang; Xing-Yun Chen; Ping Li

    2015-01-01

    Objective:To investigate the effects of three different ways of chronic caffeine administration on blastinduced memory dysfunction and to explore the underlying mechanisms.Methods:Adult male C57BL/6 mice were used and randomly divided into five groups:control:without blast exposure,con-water:administrated with water continuously before and after blast-induced traumatic brain injury (bTBI),con-caffeine:administrated with caffeine continuously for 1 month before and after bTBI,pre-caffeine:chronically administrated with caffeine for 1 month before bTBI and withdrawal after bTBI,post-caffeine:chronically administrated with caffeine after bTBI.After being subjected to moderate intensity of blast injury,mice were recorded for learning and memory performance using Morris water maze (MWM) paradigms at 1,4,and 8 weeks post-blast injury.Neurological deficit scoring,glutamate concentration,proinflammatory cytokines production,and neuropathological changes at 24 h,1,4,and 8 weeks post-bTBI were examined to evaluate the brain injury in early and prolonged stages.Adenosine A1 receptor expression was detected using qPCR.Results:All of the three ways of chronic caffeine exposure ameliorated blast-induced memory deficit,which is correlated with the neuroprotective effects against excitotoxicity,inflammation,astrogliosis and neuronal loss at different stages of injury.Continuous caffeine treatment played positive roles in both early and prolonged stages of bTBI;pre-bTBl and post-bTBl treatment of caffeine tended to exert neuroprotective effects at early and prolonged stages of bTBI respectively.Up-regulation of adenosine A1 receptor expression might contribute to the favorable effects of chronic caffeine consumption.Conclusion:Since caffeinated beverages are widely consumed in both civilian and military personnel and are convenient to get,the results may provide a promising prophylactic strategy for blast-induced neurotrauma and the consequent cognitive impairment.

  11. Voluntary exercise and increased food intake after mild chronic stress improve social avoidance behavior in mice.

    Science.gov (United States)

    Otsuka, Airi; Shiuchi, Tetsuya; Chikahisa, Sachiko; Shimizu, Noriyuki; Séi, Hiroyoshi

    2015-11-01

    It is well-established that exercise can influence psychological conditions, cognitive function, and energy metabolism in peripheral tissues including the skeletal muscle. However, it is not clear whether exercise can influence social interaction with others and alleviate defeat stress. This study investigated the effect of voluntary wheel running on impaired social interaction induced by chronic social defeat stress (SDS) using the resident-intruder social defeat model. Mice were divided into three groups: control, stress alone, and stress+exercise. SDS was performed by exposing C57BL/6 mice to retired ICR mice for 2.5 min. The C57BL/6 mice were continuously defeated by these resident (aggressor) mice and, following 5 days of SDS, experienced 2 days of rest with no SDS. Mice in the stress+exercise group were allowed to voluntarily run on a wheel for 2h after every SDS exposure. Two weeks later, compared to the control group, the stress group showed a higher ratio of time spent in the corner zone of a social interaction paradigm even though SDS did not elicit depressive- and anxiety-like behaviors. We also observed that voluntary exercise, which did not affect muscle weight and gene expression, decreased social avoidance behavior of stressed mice without clear changes in brain monoamine levels. Interestingly, food intake in the stress+exercise group was the greatest among the three groups. To test the effect of the exercise-induced increase in food intake on social behavior, we set up a pair-fed group where food intake was restricted. We then compared these mice to mice in the stress alone group. We found that the ratio of time spent in the corner zone of the social interaction test was not different between ad libitum- and pair-fed groups, although pair-fed mice spent more time in the corner zone when an aggressor mouse was present than when it was absent. In addition, pair-feeding did not show exercise-induced reductions of adrenal gland weight and enhanced the

  12. Toxicogenomic analysis of susceptibility to inhaled urban particulate matter in mice with chronic lung inflammation

    Directory of Open Access Journals (Sweden)

    Yauk Carole L

    2009-03-01

    Full Text Available Abstract Background Individuals with chronic lung disease are at increased risk of adverse health effects from airborne particulate matter. Characterization of underlying pollutant-phenotype interactions may require comprehensive strategies. Here, a toxicogenomic approach was used to investigate how inflammation modifies the pulmonary response to urban particulate matter. Results Transgenic mice with constitutive pulmonary overexpression of tumour necrosis factor (TNF-α under the control of the surfactant protein C promoter and wildtype littermates (C57BL/6 background were exposed by inhalation for 4 h to particulate matter (0 or 42 mg/m3 EHC-6802 and euthanized 0 or 24 h post-exposure. The low alveolar dose of particles (16 μg did not provoke an inflammatory response in the lungs of wildtype mice, nor exacerbate the chronic inflammation in TNF animals. Real-time PCR confirmed particle-dependent increases of CYP1A1 (30–100%, endothelin-1 (20–40%, and metallothionein-II (20–40% mRNA in wildtype and TNF mice (p Conclusion Our data support the hypothesis that health effects of acute exposure to urban particles are dominated by activation of specific physiological response cascades rather than widespread changes in gene expression.

  13. Chronic UVB-irradiation actuates perpetuated dermal matrix remodeling in female mice: Protective role of estrogen

    Science.gov (United States)

    Röck, Katharina; Joosse, Simon Andreas; Müller, Julia; Heinisch, Nina; Fuchs, Nicola; Meusch, Michael; Zipper, Petra; Reifenberger, Julia; Pantel, Klaus; Fischer, Jens Walter

    2016-01-01

    Chronic UVB-exposure and declined estradiol production after menopause represent important factors leading to extrinsic and intrinsic aging, respectively. Remodeling of the extracellular matrix (ECM) plays a crucial role in both responses. Whether the dermal ECM is able to recover after cessation of UVB-irradiation in dependence of estradiol is not known, however of relevance when regarding possible treatment options. Therefore, the endogenous sex hormone production was depleted by ovariectomy in female mice. Half of the mice received estradiol substitution. Mice were UVB-irradiated for 20 weeks and afterwards kept for 10 weeks without irradiation. The collagen-, hyaluronan- and proteoglycan- (versican, biglycan, lumican) matrix, collagen cleavage products and functional skin parameters were analyzed. The intrinsic aging process was characterized by increased collagen fragmentation and accumulation of biglycan. Chronic UVB-irradiation additionally augmented the lumican, versican and hyaluronan content of the dermis. In the absence of further UVB-irradiation the degradation of collagen and accumulation of biglycan in the extrinsically aged group was perpetuated in an excessive matter. Whereas estradiol increased the proteoglycan content, it reversed the effects of the perpetuated extrinsic response on collagen degradation. Suspension of the intrinsic pathway might therefore be sufficient to antagonize UVB-evoked long-term damage to the dermal ECM. PMID:27460287

  14. Chronic Pseudomonas aeruginosa lung infection is more severe in Th2 responding BALB/c mice compared to Th1 responding C3H/HeN mice

    DEFF Research Database (Denmark)

    Moser, C; Johansen, H K; Song, Z;

    1997-01-01

    The chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) is characterized by a pronounced antibody response and microcolonies surrounded by numerous polymorphonuclear neutrophils (PMN). Poor prognosis is correlated with a high antibody response to P. aeruginosa antigens. An animal...... was cleared more efficiently in C3H/HeN mice and significantly more C3H/HeN mice showed normal lung histopathology (p

  15. Salmonella Typhimurium undergoes distinct genetic adaption during chronic infections of mice

    DEFF Research Database (Denmark)

    Søndberg, Emilie; Jelsbak, Lotte

    2016-01-01

    . Typhi and serve as the reservoir for the disease. The specific mechanisms and adaptive strategies enabling S. Typhi to survive inside the host for extended periods are incompletely understood. Yet, elucidation of these processes is of major importance for improvement of therapeutic strategies. In the...... type strains of S. Typhimurium 4/74 were used to establish chronic infections of 129X1/SvJ mice. Over the course of infections, S. Typhimurium bacteria were isolated from feces and from livers and spleens upon termination of the experiment. In all samples dominant clones were identified and select...... clones were subjected to whole genome sequencing. Dominant clones isolated from either systemic organs or fecal samples exhibited distinct single nucleotide polymorphisms (SNPs). One mouse appeared to have distinct adapted clones in the spleen and liver, respectively. Three mice were colonized in the...

  16. Ultrastructural Changes of Caudate Nucleus in Mice Chronically Treated with Manganese.

    Science.gov (United States)

    Villalobos, Virginia; Hernández-Fonseca, Juan Pablo; Bonilla, Ernesto; Medina-Leendertz, Shirley; Mora, Marylu; Mosquera, Jesús

    2015-01-01

    Manganese (Mn) is able to cross the blood-brain barrier and induces functional and structural alterations during the intoxication by this metal. Therefore, the effects of chronic administration of Mn in the caudate nucleus of mice were evaluated by electron microscopy. Male albino mice were injected intraperitoneally with MnCl2 (5 mg/kg/d) 5 d per week during 9 weeks. The control group received only 0.9% of NaCl solution. The caudate nuclei were extracted and subsequently processed to be observed on a conventional transmission electron microscope at 2, 4, 6, and 9 weeks after treatment. A high percentage of vacuolated and swollen mitochondria were found throughout all the analyzed periods. Myelin disarrangement and ultrastructural alterations related to edema were observed increased in Mn-treated mice at week 9. Granular degeneration of myelin at week 9 accompanied with deposition of electron dense granules in the neuropil was also observed. Edema in neuropil and glial cells was detected from week 2 to week 9 accompanied by swollen mitochondria. Neuronal bodies, synaptic terminals, and perivascular cells were found swollen. Decreased electron density in postsynaptic areas and decreased and dispersed synaptic vesicles in presynaptic areas were noted in Mn-treated animals. Some neurons from Mn-treated mice showed cisternae dilation of the Golgi apparatus. These results suggest that Mn-treatment produces structural alterations in the caudate nucleus that could be responsible for some of the neurotoxic effects of this metal. PMID:25569534

  17. Effect of Chronic Use of Recreational Drugs on the Sperm Count in Albino Mice

    Directory of Open Access Journals (Sweden)

    Sravonee Purkayastha

    2014-05-01

    Full Text Available Chronic use of various recreational drugs is leading to drug abuse which is increasingly developed in the modern society among the various populations throughout the world. The present study was conducted to investigate the impact of a few recreational drugs viz., anabolic androgenic steroids (AAS, alcohol and nicotine on male fertility status which was assessed by measuring sperm count in male albino mice. Semen samples were collected from normal, AAS-treated, alcohol-treated and nicotine-treated mice and the sperm count (in millions/ml semen was assessed at regular intervals i.e. on 10th, 20th, 30th, 45th,60th,75th and 90th day of treatment during the experimental period of 90 days. The results showed a significant decrease in the sperm count in AAS-treated, nicotine-treated (p<0.01 and alcohol-treated mice (p<0.05 compared to that of the normal mice. The present study clearly indicates suppression of sperm count on AAS, alcohol and nicotine treatment which may be one of the contributing factors in male infertility.

  18. Mice Engrafted With Human Fetal Thymic Tissue And Hematopoietic Stem Cells Develop Pathology Resembling Chronic GVHD

    OpenAIRE

    Lockridge, Jennifer L.; Ying ZHOU; Becker, Yusof A.; Ma, Shidong; Kenney, Shannon C.; Hematti, Peiman; Capitini, Christian M.; Burlingham, William J.; Gendron-Fitzpatrick, Annette; Gumperz, Jenny E.

    2013-01-01

    Chronic Graft versus Host Disease (cGVHD) is a significant roadblock to long-term hematopoeitic stem cell (HSC) transplantation success. Effective treatments for cGVHD have been difficult to develop, in part because of a paucity of animal models that recapitulate the multi-organ pathologies observed in clinical cGVHD. Here we present an analysis of the pathology that occurs in immunodeficient mice engrafted with human fetal HSCs and implanted with fragments of human fetal thymus and liver. St...

  19. Multimodal assessment of painful peripheral neuropathy induced by chronic oxaliplatin-based chemotherapy in mice

    Directory of Open Access Journals (Sweden)

    Dorsey Susan G

    2011-04-01

    Full Text Available Abstract Background A major clinical issue affecting 10-40% of cancer patients treated with oxaliplatin is severe peripheral neuropathy with symptoms including cold sensitivity and neuropathic pain. Rat models have been used to describe the pathological features of oxaliplatin-induced peripheral neuropathy; however, they are inadequate for parallel studies of oxaliplatin's antineoplastic activity and neurotoxicity because most cancer models are developed in mice. Thus, we characterized the effects of chronic, bi-weekly administration of oxaliplatin in BALB/c mice. We first studied oxaliplatin's effects on the peripheral nervous system by measuring caudal and digital nerve conduction velocities (NCV followed by ultrastructural and morphometric analyses of dorsal root ganglia (DRG and sciatic nerves. To further characterize the model, we examined nocifensive behavior and central nervous system excitability by in vivo electrophysiological recording of spinal dorsal horn (SDH wide dynamic range neurons in oxaliplatin-treated mice Results We found significantly decreased NCV and action potential amplitude after oxaliplatin treatment along with neuronal atrophy and multinucleolated DRG neurons that have eccentric nucleoli. Oxaliplatin also induced significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment, and a significant increase in the activity of wide dynamic range neurons in the SDH. Conclusions Our findings demonstrate that chronic treatment with oxaliplatin produces neurotoxic changes in BALB/c mice, confirming that this model is a suitable tool to conduct further mechanistic studies of oxaliplatin-related antineoplastic activity, peripheral neurotoxicity and pain. Further, this model can be used for the preclinical discovery of new neuroprotective and analgesic compounds.

  20. Sex differences in shotgun proteome analyses for chronic oral intake of cadmium in mice.

    Directory of Open Access Journals (Sweden)

    Yoshiharu Yamanobe

    Full Text Available Environmental diseases related to cadmium exposure primarily develop owing to industrial wastewater pollution and/or contaminated food. In regions with high cadmium exposure in Japan, cadmium accumulation occurs primarily in the kidneys of individuals who are exposed to the metal. In contrast, in the itai-itai disease outbreak that occurred in the Jinzu River basin in Toyama Prefecture in Japan, cadmium primarily accumulated in the liver. On the other hand, high concentration of cadmium caused renal tubular disorder and osteomalacia (multiple bone fracture, probably resulting from the renal tubular dysfunction and additional pathology. In this study, we aimed to establish a mouse model of chronic cadmium intake. We administered cadmium-containing drinking water (32 mg/l to female and male mice ad libitum for 11 weeks. Metal analysis using inductively coupled plasma mass spectrometry revealed that cadmium accumulated in the kidneys (927 x 10 + 185 ng/g in females and 661 x 10 + 101 ng/g in males, liver (397 x 10 + 199 ng/g in females and 238 x 10 + 652 ng/g in males, and thyroid gland (293 + 93.7 ng/g in females and 129 + 72.7 ng/g in males of mice. Female mice showed higher cadmium accumulation in the kidney, liver, and thyroid gland than males did (p = 0.00345, p = 0.00213, and p = 0.0331, respectively. Shotgun proteome analyses after chronic oral administration of cadmium revealed that protein levels of glutathione S-transferase Mu2, Mu4, and Mu7 decreased in the liver, and those of A1 and A2 decreased in the kidneys in both female and male mice.

  1. Analysis of hepatic gene expression during fatty liver change due to chronic ethanol administration in mice

    International Nuclear Information System (INIS)

    Chronic consumption of ethanol can cause cumulative liver damage that can ultimately lead to cirrhosis. To explore the mechanisms of alcoholic steatosis, we investigated the global intrahepatic gene expression profiles of livers from mice administered alcohol. Ethanol was administered by feeding the standard Lieber-DeCarli diet, of which 36% (high dose) and 3.6% (low dose) of the total calories were supplied from ethanol for 1, 2, or 4 weeks. Histopathological evaluation of the liver samples revealed fatty changes and punctate necrosis in the high-dose group and ballooning degeneration in the low-dose group. In total, 292 genes were identified as ethanol responsive, and several of these differed significantly in expression compared to those of control mice (two-way ANOVA; p < 0.05). Specifically, the expression levels of genes involved in hepatic lipid transport and metabolism were examined. An overall net increase in gene expression was observed for genes involved in (i) glucose transport and glycolysis, (ii) fatty acid influx and de novo synthesis, (iii) fatty acid esterification to triglycerides, and (iv) cholesterol transport, de novo cholesterol synthesis, and bile acid synthesis. Collectively, these data provide useful information concerning the global gene expression changes that occur due to alcohol intake and provide important insights into the comprehensive mechanisms of chronic alcoholic steatosis

  2. INFECTIOUS VIRUS-ANTIBODY COMPLEX IN THE BLOOD OF CHRONICALLY INFECTED MICE

    Science.gov (United States)

    Notkins, Abner Louis; Mahar, Suellen; Scheele, Christina; Goffman, Joel

    1966-01-01

    If viremic sera from mice chronically infected with lactic dehydrogenase virus (LDV) were first treated with ether or ultraviolet light to inactivate the infectious virus, neutralizing antibody could be demonstrated. Significant amounts of antibody, however, were not detected until the mice had been infected for about 2½ months and its presence did not result in the elimination of the chronic viremia. Virus isolated from sera containing neutralizing antibody was found to be relatively resistant to neutralization by anti-LDV. Further studies revealed that the resistant virus existed in the form of an infectious virus-antibody complex (sensitized virus). The presence of such a complex was demonstrated by the fact that the virus fraction which persisted after in vivo or in vitro exposure to mouse anti-LDV was readily neutralized by goat anti-mouse sera or goat anti-mouse γ-globulin, whereas virus that had not been previously exposed to mouse anti-LDV was completely resistant to neutralization by goat anti-mouse sera. These findings suggest that (a) sensitization may play an important role in the resistance and susceptibility of a virus to neutralization by antiviral antibody, and (b) an anti-γ-globulin may prove useful in neutralizing the resistant fraction and in demonstrating otherwise undetectable antiviral antibody. PMID:5944351

  3. Effects of chronic variable stress on cognition and Bace1 expression among wild-type mice.

    Science.gov (United States)

    Cordner, Z A; Tamashiro, K L K

    2016-01-01

    Stressful life events, activation of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoids are now thought to have a role in the development of several neurodegenerative and psychiatric disorders including Alzheimer's disease (AD) through mechanisms that may include exacerbation of cognitive impairment, neuronal loss, and beta-amyloid (Aβ) and tau neuropathology. In the current study, we use a wild-type mouse model to demonstrate that chronic variable stress impairs cognitive function and that aged mice are particularly susceptible. We also find that stress exposure is associated with a 1.5- to 2-fold increase in the expression of Bace1 in the hippocampus of young adult mice and the hippocampus, prefrontal cortex and amygdala of aged mice. Further, the increased expression of Bace1 was associated with decreased methylation of several CpGs in the Bace1 promoter region. In a second series of experiments, exposure to environmental enrichment (EE) prevented the stress-related changes in cognition, gene expression and DNA methylation. Together, these findings re-affirm the adverse effects of stress on cognition and further suggest that aged individuals are especially susceptible. In addition, demonstrating that chronic stress results in decreased DNA methylation and increased expression of Bace1 in the brain may provide a novel link between stress, Aβ pathology and AD. Finally, understanding the mechanisms by which EE prevented the effects of stress on cognition and Bace1 expression will be an important area of future study that may provide insights into novel approaches to the treatment of AD. PMID:27404286

  4. Darbepoetin alpha reduces oxidative stress and chronic inflammation in atherosclerotic lesions of apo E deficient mice in experimental renal failure.

    Directory of Open Access Journals (Sweden)

    Nicole Arend

    Full Text Available BACKGROUND: Cardiovascular morbidity and mortality is very important in patients with chronic renal failure. This occurs even in mild impairment of renal function and may be related to oxidative stress and chronic inflammation. The nephrectomized apo E knockout mouse is an accepted model for evaluating atherosclerosis in renal dysfunction. Erythropoietin derivates showed anti-oxidative and anti-inflammatory effects. Therefore, this study evaluates the effects of Darbepoetin on markers of oxidative stress and chronic inflammation in atherosclerotic lesions in apo E knockout mice with renal dysfunction. METHODS: Apo E knockout mice underwent unilateral (Unx, n = 20 or subtotal (Snx, n = 26 nephrectomy or sham operation (Sham, n = 16. Mice of each group were either treated with Darbepoetin or saline solution, a part of Snx mice received a tenfold higher dose of Darbepoetin. The aortic plaques were measured and morphologically characterized. Additional immunhistochemical analyses were performed on tissue samples taken from the heart and the aorta. RESULTS: Both Unx and Snx mice showed increased expression of markers of oxidative stress and chronic inflammation. While aortic plaque size was not different, Snx mice showed advanced plaque stages when compared to Unx mice. Darbepoetin treatment elevated hematocrit and lowered Nitrotyrosin as one marker of oxidative stress, inflammation in heart and aorta, plaque stage and in the high dose even plaque cholesterol content. In contrast, there was no influence of Darbepoetin on aortic plaque size; high dose Darbepoetin treatment resulted in elevated renal serum parameters. CONCLUSION: Darbepoetin showed some protective cardiovascular effects irrespective of renal function, i.e. it improved plaque structure and reduced some signs of oxidative stress and chronic inflammation without affecting plaque size. Nevertheless, the dose dependent adverse effects must be considered as high Darbepoetin treatment

  5. Antidepressant-Like Effects of Cordycepin in a Mice Model of Chronic Unpredictable Mild Stress

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    Zhang Tianzhu

    2014-01-01

    Full Text Available Cordycepin (3′-deoxyadenosine, a major bioactive component isolated from Cordyceps militaris, has multiple pharmacological activities. This study is attempted to investigate whether cordycepin (COR possesses beneficial effects on chronic unpredictable mild stress- (CUMS- induced behavioral deficits (depression-like behaviors and explore the possible mechanisms. ICR mice were subjected to chronic unpredictable mild stress for 42 consecutive days. Then, COR and fluoxetine (FLU, positive control drug were administered for 21 consecutive days at the last three weeks of CUMS procedure. The classical behavioral tests, open field test (OFT, sucrose preference test (SPT, tail suspension test (TST, and forced swimming test (FST, were applied to evaluate the antidepressant effects of COR. Then the serotonin (5-HT and noradrenaline (NE concentrations in hippocampal were evaluated by HPLC; tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6 in hippocampal were evaluated, and the proteins of TNF-α, IL-6, NF-κBP65 5-HT receptor (5-HTR, and brain-derived neurotrophic factor (BDNF in hippocampal were evaluated by Western blot. Our results indicated that 6 weeks of CUMS exposure induced significant depression-like behavior, with low 5-HT and NE levels, high TNF-α and IL-6 in brain and high hippocampal TNF-α, IL-6, P-NF-κBP65, and 5-HTR levels, and low BDNF expression levels. Whereas, chronic COR (20, 40 mg/kg treatments reversed the behavioral deficiency induced by CUMS exposure, treatment with COR normalized the change of TNF-α, IL-6, 5-HT, and NE levels, which demonstrated that COR could partially restore CUMS-induced 5-HT receptor impairments and inflammation. Besides, hippocampal BDNF expressions were also upregulated after COR treatments. In conclusion, COR remarkably improved depression-like behavior in CUMS mice and its antidepressant activity is mediated, at least in part, by the upregulating BDNF and downregulating 5-HTR levels and

  6. PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads.

    Directory of Open Access Journals (Sweden)

    Edward Seung

    Full Text Available An estimated 34 million people are living with HIV worldwide (UNAIDS, 2012, with the number of infected persons rising every year. Increases in HIV prevalence have resulted not only from new infections, but also from increases in the survival of HIV-infected persons produced by effective anti-retroviral therapies. Augmentation of anti-viral immune responses may be able to further increase the survival of HIV-infected persons. One strategy to augment these responses is to reinvigorate exhausted anti-HIV immune cells present in chronically infected persons. The PD-1-PD-L1 pathway has been implicated in the exhaustion of virus-specific T cells during chronic HIV infection. Inhibition of PD-1 signaling using blocking anti-PD-1 antibodies has been shown to reduce simian immunodeficiency virus (SIV loads in monkeys. We now show that PD-1 blockade can improve control of HIV replication in vivo in an animal model. BLT (Bone marrow-Liver-Thymus humanized mice chronically infected with HIV-1 were treated with an anti-PD-1 antibody over a 10-day period. The PD-1 blockade resulted in a very significant 45-fold reduction in HIV viral loads in humanized mice with high CD8(+ T cell expression of PD-1, compared to controls at 4 weeks post-treatment. The anti-PD-1 antibody treatment also resulted in a significant increase in CD8(+ T cells. PD-1 blockade did not affect T cell expression of other inhibitory receptors co-expressed with PD-1, including CD244, CD160 and LAG-3, and did not appear to affect virus-specific humoral immune responses. These data demonstrate that inhibiting PD-1 signaling can reduce HIV viral loads in vivo in the humanized BLT mouse model, suggesting that blockade of the PD-1-PD-L1 pathway may have therapeutic potential in the treatment of patients already infected with the AIDS virus.

  7. Chronic escalating cocaine exposure, abstinence/withdrawal, and chronic re-exposure: effects on striatal dopamine and opioid systems in C57BL/6J mice.

    Science.gov (United States)

    Zhang, Yong; Schlussman, Stefan D; Rabkin, Jacqui; Butelman, Eduardo R; Ho, Ann; Kreek, Mary Jeanne

    2013-04-01

    Cocaine addiction is a chronic relapsing disease with periods of chronic escalating self-exposure, separated by periods of abstinence/withdrawal of varying duration. Few studies compare such cycles in preclinical models. This study models an "addiction-like cycle" in mice to determine neurochemical/molecular alterations that underlie the chronic, relapsing nature of this disease. Groups of male C57BL/6J mice received acute cocaine exposure (14-day saline/14-day withdrawal/13-day saline + 1-day cocaine), chronic cocaine exposure (14 day cocaine) or chronic re-exposure (14-day cocaine/14-day withdrawal/14-day cocaine). Escalating-dose binge cocaine (15-30 mg/kg/injection × 3/day, i.p. at hourly intervals) or saline (14-day saline) was administered, modeling initial exposure. In "re-exposure" groups, after a 14-day injection-free period (modeling abstinence/withdrawal), mice that had received cocaine were re-injected with 14-day escalating-dose binge cocaine, whereas controls received saline. Microdialysis was conducted on the 14th day of exposure or re-exposure to determine striatal dopamine content. Messenger RNA levels of preprodynorphin (Pdyn), dopamine D1 (Drd1) and D2 (Drd2) in the caudate putamen were determined by real-time PCR. Basal striatal dopamine levels were lower in mice after 14-day escalating exposure or re-exposure than in those in the acute cocaine group and controls. Pdyn mRNA levels were higher in the cocaine groups than in controls. Long-term adaptation was observed across the stages of this addiction-like cycle, in that the effects of cocaine on dopamine levels were increased after re-exposure compared to exposure. Changes in striatal dopaminergic responses across chronic escalating cocaine exposure and re-exposure are a central feature of the neurobiology of relapsing addictive states. PMID:23164614

  8. Cytogenetic sequelae in sex and somatic cells at mice subjected to chronic irradiation simulating occupational conditions of radiation effect

    International Nuclear Information System (INIS)

    Cytogenetic effect of chronic irradiation in low doses to study chronic radiation effect upon man under professional conditions has been investigated. The experiments have been carried out on white mice, subjected to chronic effect of 60Co gamma irradiation (during 15 - 19 months in doses of 6, 17 and 50 mrad for 6 - 7 hrs a day). It is shown, that under effect of chronic irradiation, modelling the conditions of professional irradiation effect, in sex and somatic cells of the mice chromosomal aberrations appear, which depend on the age of animals and magnitude of every day dose. However direct dependence of these changes on the magnitude of the total dose has not been established

  9. 3xTgAD mice exhibit altered behavior and elevated Aβ after chronic mild social stress

    OpenAIRE

    Rothman, Sarah M.; Herdener, Nathan; Camandola, Simonetta; Texel, Sarah J.; Mughal, Mohamed R.; Cong, Wei-na; Martin, Bronwen; Mattson, Mark P.

    2011-01-01

    Chronic stress may be a risk factor for developing Alzheimer’s disease (AD), but most studies of the effects of stress in models of AD utilize acute adverse stressors of questionable clinical relevance. The goal of this work was to determine how chronic psychosocial stress affects behavioral and pathological outcomes in an animal model of AD, and to elucidate underlying mechanisms. A triple-transgenic mouse model of AD (3xTgAD mice) and nontransgenic control mice were used to test for an affe...

  10. Chronic exposure to low doses of pharmaceuticals disturbs the hepatic expression of circadian genes in lean and obese mice.

    OpenAIRE

    Anthérieu, Sébastien; Le Guillou, Dounia; Coulouarn, Cédric; Begriche, Karima; Trak-Smayra, Viviane; Martinais, Sophie; Porceddu, Mathieu; Robin, Marie-Anne; Fromenty, Bernard

    2014-01-01

    International audience Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can be harmful for the liver, especially during obesity. Hence, the goal of our study was to determine whether chronic exposure to low doses of pharmaceuticals could have deleterious effects on livers of lean and obese mice. To this end, lean and ob/ob male mice were treated for 4 months with a mixture of 11 drugs provided in drinking water at concentrations r...

  11. Development of a Chronic Kidney Disease Model in C57BL/6 Mice with Relevance to Human Pathology

    OpenAIRE

    Huang, Linghong; Scarpellini, Alessandra; Funck, Muriel; Verderio, Elisabetta A. M.; Johnson, Timothy S.

    2013-01-01

    Background Genetically modified mice are used to investigate disease and assess potential interventions. However, research into kidney fibrosis is hampered by a lack of models of chronic kidney disease (CKD) in mice. Recently, aristolochic acid nephropathy (AAN), characterised by severe tubulointerstitial fibrosis, has been identified as a cause of end stage kidney disease and proposed as a model of CKD. Published studies have used various dosing regimens, species and strains, with variable o...

  12. Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice.

    Science.gov (United States)

    Liu, Tong; Han, Qingjian; Chen, Gang; Huang, Ya; Zhao, Lin-Xia; Berta, Temugin; Gao, Yong-Jing; Ji, Ru-Rong

    2016-04-01

    Increasing evidence suggests that Toll-like receptor 4 (TLR4) contributes importantly to spinal cord glial activation and chronic pain sensitization; however, its unique role in acute and chronic itch is unclear. In this study, we investigated the involvement of TLR4 in acute and chronic itch models in male mice using both transgenic and pharmacological approaches. Tlr4 mice exhibited normal acute itch induced by compound 48/80 and chloroquine, but these mice showed substantial reductions in scratching in chronic itch models of dry skin, induced by acetone and diethylether followed by water (AEW), contact dermatitis, and allergic contact dermatitis on the neck. Intrathecal (spinal) inhibition of TLR4 with lipopolysaccharide Rhodobacter sphaeroides did not affect acute itch but suppressed AEW-induced chronic itch. Compound 48/80 and AEW also produced robust alloknesis, a touch-elicited itch in wild-type mice, which was suppressed by intrathecal lipopolysaccharide R sphaeroides and Tlr4 deletion. Acetone and diethylether followed by water induced persistent upregulation of Tlr4 mRNA and increased TLR4 expression in GFAP-expressing astrocytes in spinal cord dorsal horn. Acetone and diethylether followed by water also induced TLR4-dependent astrogliosis (GFAP upregulation) in spinal cord. Intrathecal injection of astroglial inhibitor L-α-aminoadipate reduced AEW-induced chronic itch and alloknesis without affecting acute itch. Spinal TLR4 was also necessary for AEW-induced chronic itch in the cheek model. Interestingly, scratching plays an essential role in spinal astrogliosis because AEW-induced astrogliosis was abrogated by putting Elizabethan collars on the neck to prevent scratching the itchy skin. Our findings suggest that spinal TLR4 signaling is important for spinal astrocyte activation and astrogliosis that may underlie alloknesis and chronic itch. PMID:26645545

  13. Chronic psycho-social stress & colitis: Physiological, neuroendocrine, and immunological studies with male C57BL/6 mice

    OpenAIRE

    Reber, Stefan Oskar

    2007-01-01

    The experiments of the present thesis were designed to investigate the effects of two different models of chronic psycho-social stress (SD/OC; CSC) on the severity of and the regeneration after an experimentally induced colitis and the development of spontaneous colonic inflammation in male mice. In addition, underlying mechanisms were investigated, thereby mainly focusing on the HPA axis as a possible mediator of chronic psycho-social stress effects on colonic inflammation. Further knowledge...

  14. Effect of baclofen on morphine-induced conditioned place preference, extinction, and stress-induced reinstatement in chronically stressed mice

    OpenAIRE

    Meng, Shanshan; Quan, Wuxing; Xu QI; Su, Zhiqiang; Yang, Shanshan

    2013-01-01

    Rationale and Objective A stress-induced increase in excitability can result from a reduction in inhibitory neurotransmission. Modulation of gamma-aminobutyric acid (GABA)ergic transmission is an effective treatment for drug seeking and relapse. This study investigated whether baclofen, a GABAB receptor agonist, had an impact on morphine-induced conditioned place preference (CPP), extinction, and stress-induced relapse in chronically stressed mice. Methods Chronic stress was induced by restra...

  15. Aggravation of Chronic Stress Effects on Hippocampal Neurogenesis and Spatial Memory in LPA1 Receptor Knockout Mice

    OpenAIRE

    Castilla-Ortega, Estela; Hoyo-Becerra, Carolina; Pedraza, Carmen; Chun, Jerold; Rodríguez de Fonseca, Fernando; Estivill-Torrús, Guillermo; Santín, Luis J.

    2011-01-01

    Background The lysophosphatidic acid LPA1 receptor regulates plasticity and neurogenesis in the adult hippocampus. Here, we studied whether absence of the LPA1 receptor modulated the detrimental effects of chronic stress on hippocampal neurogenesis and spatial memory. Methodology/Principal Findings Male LPA1-null (NULL) and wild-type (WT) mice were assigned to control or chronic stress conditions (21 days of restraint, 3 h/day). Immunohistochemistry for bromodeoxyuridine and endogenous marker...

  16. Flupirtine attenuates chronic restraint stress-induced cognitive deficits and hippocampal apoptosis in male mice.

    Science.gov (United States)

    Huang, Pengcheng; Li, Cai; Fu, Tianli; Zhao, Dan; Yi, Zhen; Lu, Qing; Guo, Lianjun; Xu, Xulin

    2015-07-15

    Chronic restraint stress (CRS) causes hippocampal neurodegeneration and hippocampus-dependent cognitive deficits. Flupirtine represents neuroprotective effects and we have previously shown that flupirtine can protect against memory impairment induced by acute stress. The present study aimed to investigate whether flupirtine could alleviate spatial learning and memory impairment and hippocampal apoptosis induced by CRS. CRS mice were restrained in well-ventilated Plexiglass tubes for 6h daily beginning from 10:00 to 16:00 for 21 consecutive days. Mice were injected with flupirtine (10mg/kg and 25mg/kg) or vehicle (10% DMSO) 30min before restraint stress for 21 days. After stressor cessation, the spatial learning and memory, dendritic spine density, injured neurons and the levels of Bcl-2, Bax, p-Akt, p-GSK-3β, p-Erk1/2 and synaptophysin of hippocampal tissues were examined. Our results showed that flupirtine significantly prevented spatial learning and memory impairment induced by CRS in the Morris water maze. In addition, flupirtine (10mg/kg and 25mg/kg) treatment alleviated neuronal apoptosis and the reduction of dendritic spine density and synaptophysin expression in the hippocampal CA1 region of CRS mice. Furthermore, flupirtine (10mg/kg and 25mg/kg) treatment significantly decreased the expression of Bax and increased the p-Akt and p-GSK-3β, and flupirtine (25mg/kg) treatment up-regulated the p-Erk1/2 in the hippocampus of CRS mice. These results suggested that flupirtine exerted protective effects on the CRS-induced cognitive impairment and hippocampal neuronal apoptosis, which is possibly associated with the activation of Akt/GSK-3β and Erk1/2 signaling pathways. PMID:25869780

  17. Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington's disease transgenic mice.

    Science.gov (United States)

    Dowie, M J; Howard, M L; Nicholson, L F B; Faull, R L M; Hannan, A J; Glass, M

    2010-09-29

    Early loss of CB1 receptors is a hallmark of human Huntington's disease. Data from rodent studies suggest that preservation and activation of CB1 receptors may be protective against disease progression. R6/1 transgenic mice are considered to be a model of early pathogenic changes in Huntington's disease. We have shown previously that levels of CB1 in R6/1 mice prior to the onset of motor symptoms (12 weeks of age) remain high enough to justify commencement of cannabinoid drug treatment. Eight weeks of daily treatment with the cannabinoid agonists HU210 (0.01 mg/kg) and Delta(9)-tetrahydrocannabinol (THC, 10.00 mg/kg), or the inhibitor of endocannabinoid metabolism URB597 (0.30 mg/kg), did not alter the progressive deterioration of performance observed in motor behavioural testing. HU210-treated R6/1 mice experienced a significant increase in seizure events suggesting that this therapy may lower the seizure threshold and cautioning against highly efficacious agonists as potential therapy in this disease. Molecular characterisation of brains at the end of the study showed that there were no significant effects of HU210 or THC treatment on the ligand binding of cannabinoid CB1, dopamine D1, D2, serotonin 5HT2A or GABA(A) receptors, nor CB1 or fatty acid amide hydrolase (FAAH) mRNA expression in R6/1 mice. Intriguingly, a significant increase in the number of ubiquitinated aggregates was observed in the striatum with HU210 treatment, indicating an influence of CB1 on the disease process. Chronic URB597 treatment preserved CB1 receptors in the R6/1 striatum, suggesting that the manipulation of endocannabinoid levels warrants further exploration. PMID:20600638

  18. Characterisation of cochlear inflammation in mice following acute and chronic noise exposure.

    Science.gov (United States)

    Tan, Winston J T; Thorne, Peter R; Vlajkovic, Srdjan M

    2016-08-01

    Oxidative stress has been established as the key mechanism of the cochlear damage underlying noise-induced hearing loss, however, emerging evidence suggests that cochlear inflammation may also be a major contributor. This study aimed to improve our understanding of the cochlear inflammatory response associated with acute and chronic noise exposure. C57BL/6 mice were exposed to acute traumatic noise (100 dBSPL, 8-16 kHz for 24 h) and their cochleae collected at various intervals thereafter, up to 7 days. Using quantitative RT-PCR and immunohistochemistry, changes in expression levels of proinflammatory cytokines (TNF-α, IL-1β), chemokines (CCL2) and cell adhesion molecules (ICAM-1) were studied. All gene transcripts displayed similar dynamics of expression, with an early upregulation at 6 h post-exposure, followed by a second peak at 7 days. ICAM-1 immunoexpression increased significantly in the inferior region of the spiral ligament, peaking 24 h post-exposure. The early expression of proinflammatory mediators likely mediates the recruitment and extravasation of inflammatory cells into the noise-exposed cochlea. The occurrence of the latter expression peak is not clear, but it may be associated with reparative processes initiated in response to cochlear damage. Chronic exposure to moderate noise (90 dBSPL, 8-16 kHz, 2 h/day, up to 4 weeks) also elicited an inflammatory response, reaching a maximum after 2 weeks, suggesting that cochlear damage and hearing loss associated with chronic environmental noise exposure may be linked to inflammatory processes in the cochlea. This study thus provides further insight into the dynamics of the cochlear inflammatory response induced by exposure to acute and chronic noise. PMID:27109494

  19. Effects of chronic forced circadian desynchronization on body weight and metabolism in male mice.

    Science.gov (United States)

    Casiraghi, Leandro P; Alzamendi, Ana; Giovambattista, Andrés; Chiesa, Juan J; Golombek, Diego A

    2016-04-01

    Metabolic functions are synchronized by the circadian clock setting daily patterns of food intake, nutrient delivery, and behavioral activity. Here, we study the impact of chronic jet-lag (CJL) on metabolism, and test manipulations aimed to overcome potential alterations. We recorded weight gain in C57Bl/6 mice under chronic 6 h advances or delays of the light-dark cycle every 2 days (ChrA and ChrD, respectively). We have previously reported ChrA, but not ChrD, to induce forced desynchronization of locomotor activity rhythms in mice (Casiraghi et al. 2012). Body weight was rapidly increased under ChrA, with animals tripling the mean weight gain observed in controls by day 10, and doubling it by day 30 (6% vs. 2%, and 15% vs. 7%, respectively). Significant increases in retroperitoneal and epidydimal adipose tissue masses (172% and 61%, respectively), adipocytes size (28%), and circulating triglycerides (39%) were also detected. Daily patterns of food and water intake were abolished under ChrA In contrast, ChrD had no effect on body weight. Wheel-running, housing of animals in groups, and restriction of food availability to hours of darkness prevented abnormal increase in body weight under ChrA Our findings suggest that the observed alterations under ChrA may arise either from a direct effect of circadian disruption on metabolism, from desynchronization between feeding and metabolic rhythms, or both. Direction of shifts, timing of feeding episodes, and other reinforcing signals deeply affect the outcome of metabolic function under CJL Such features should be taken into account in further studies of shift working schedules in humans. PMID:27125665

  20. Injury to the blood-testis barrier after low-dose-rate chronic radiation exposure in mice

    International Nuclear Information System (INIS)

    Exposure to ionising radiation induces male infertility, accompanied by increasing permeability of the blood-testis barrier. However, the effect on male fertility by low-dose-rate chronic radiation has not been investigated. In this study, the effects of low-dose-rate chronic radiation on male mice were investigated by measuring the levels of tight-junction-associated proteins (ZO-1 and occludin-1), Niemann-Pick disease type 2 protein (NPC-2) and anti-sperm antibody (AsAb) in serum. BALB/c mice were exposed to low-dose-rate radiation (3.49 mGy h-1) for total exposures of 0.02 (6 h), 0.17 (2 d) and 1.7 Gy (21 d). Based on histological examination, the diameter and epithelial depth of seminiferous tubules were significantly decreased in 1.7-Gy-irradiated mice. Compared with those of the non-irradiated group, 1.7-Gy-irradiated mice showed significantly decreased ZO-1, occludin-1 and NPC-2 protein levels, accompanied with increased serum AsAb levels. These results suggest potential blood-testis barrier injury and immune infertility in male mice exposed to low-dose-rate chronic radiation. (authors)

  1. Miso (Japanese soybean paste) soup attenuates salt-induced sympathoexcitation and left ventricular dysfunction in mice with chronic pressure overload.

    Science.gov (United States)

    Ito, Koji; Hirooka, Yoshitaka; Sunagawa, Kenji

    2014-02-01

    The hypothalamic mineralocorticoid receptor (MR)-angiotensin II type 1 receptor (AT1R) pathway is activated in mice with chronic pressure overload (CPO). When this activation is combined with high salt intake, it leads to sympathoexcitation, hypertension, and left ventricular (LV) dysfunction. Salt intake is thus an important factor that contributes to heart failure. Miso, a traditional Japanese food made from fermented soybeans, rice, wheat, or oats, can attenuate salt-induced hypertension in rats. However, its effects on CPO mice with salt-induced sympathoexcitation and LV dysfunction are unclear. Here, we investigated whether miso has protective effects in these mice. We also evaluated mechanisms associated with the hypothalamic MR-AT1R pathway. Aortic banding was used to produce CPO, and a sham operation was performed for controls. At 2 weeks after surgery, the mice were given water containing high NaCl levels (0.5%, 1.0%, and 1.5%) for 4 weeks. The high salt loading in CPO mice increased excretion of urinary norepinephrine (uNE), a marker of sympathetic activity, in an NaCl concentration-dependent manner; however, this was not observed in Sham mice. Subsequently, CPO mice were administered 1.0% NaCl water (CPO-H) or miso soup (1.0% NaCl equivalent, CPO-miso). The expression of hypothalamic MR, serum glucocorticoid-induced kinase-1 (SGK-1), and AT1R was higher in the CPO-H mice than in the Sham mice; however, the expression of these proteins was attenuated in the CPO-miso group. Although the CPO-miso mice had higher sodium intake, salt-induced sympathoexcitation was lower in these mice than in the CPO-H group. Our findings indicate that regular intake of miso soup attenuates salt-induced sympathoexcitation in CPO mice via inhibition of the hypothalamic MR-AT1R pathway. PMID:24908908

  2. Antioxidant activity of Inonotus obliquus polysaccharide and its amelioration for chronic pancreatitis in mice.

    Science.gov (United States)

    Hu, Yang; Sheng, Yi; Yu, Min; Li, Koukou; Ren, Guangming; Xu, Xiuhong; Qu, Juanjuan

    2016-06-01

    Inonotus obliquus polysaccharide (IOP) was extracted by water with a yield of 9.83% and purified by an anion-exchange DEAE cellulose column and Sephadex G-200 gel with a polysaccharide content of 98.6%. The scavenging activities for 2,2-diphenyl-1-picryl-hydrazyl (DPPH) and hydroxyl radicals of IOP were 82.3% and 81.3% respectively at a concentration of 5 mg/mL. IOP was composed of Man, Rha, Glu, Gal, Xyl and Ara in a molar ratio of 9.81:3.6:29.1:20.5:21.6:5.4 respectively. The gel permeation chromatography indicated that IOP was a homogeneous polysaccharide with molecular weight of 32.5 kDa. IOP helped to alleviate pancreatic acinar atrophy and weight loss for chronic pancreatitis (CP) mice induced by Diethyldithiocarbamate (DDC). The SOD level was increased most by IOP-H treatment (400 mg/kg body weight). MDA, IL-1β and LDH were significantly decreased by IOP treatment, especially hydroxyproline, IFN-γ and AMS levels were decreased 39.18%, 37.82% and 41.57% by IOP-H treatment respectively compared to MC group. In conclusion, IOP possessed strong antioxidant activity for scavenging free radicals in vitro and vivo which could be propitious to CP therapy in mice. PMID:26955745

  3. Gene expression changes in GABA(A receptors and cognition following chronic ketamine administration in mice.

    Directory of Open Access Journals (Sweden)

    Sijie Tan

    Full Text Available Ketamine is a well-known anesthetic agent and a drug of abuse. Despite its widespread use and abuse, little is known about its long-term effects on the central nervous system. The present study was designed to evaluate the effect of long-term (1- and 3-month ketamine administration on learning and memory and associated gene expression levels in the brain. The Morris water maze was used to assess spatial memory and gene expression changes were assayed using Affymetrix Genechips; a focus on the expression of GABA(A receptors that mediate a tonic inhibition in the brain, was confirmed by quantitative real-time PCR and western blot. Compared with saline controls, there was a decline in learning and memory performance in the ketamine-treated mice. Genechip results showed that 110 genes were up-regulated and 136 genes were down-regulated. An ontology analysis revealed the most significant effects of ketamine were on GABA(A receptors. In particular, there was a significant up-regulation of both mRNA and protein levels of the alpha 5 subunit (Gabra5 of the GABA(A receptors in the prefrontal cortex. In conclusion, chronic exposure to ketamine impairs working memory in mice, which may be explained at least partly by up-regulation of Gabra5 subunits in the prefrontal cortex.

  4. Frontal Lobe Contusion in Mice Chronically Impairs Prefrontal-Dependent Behavior.

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    Austin Chou

    Full Text Available Traumatic brain injury (TBI is a major cause of chronic disability in the world. Moderate to severe TBI often results in damage to the frontal lobe region and leads to cognitive, emotional, and social behavioral sequelae that negatively affect quality of life. More specifically, TBI patients often develop persistent deficits in social behavior, anxiety, and executive functions such as attention, mental flexibility, and task switching. These deficits are intrinsically associated with prefrontal cortex (PFC functionality. Currently, there is a lack of analogous, behaviorally characterized TBI models for investigating frontal lobe injuries despite the prevalence of focal contusions to the frontal lobe in TBI patients. We used the controlled cortical impact (CCI model in mice to generate a frontal lobe contusion and studied behavioral changes associated with PFC function. We found that unilateral frontal lobe contusion in mice produced long-term impairments to social recognition and reversal learning while having only a minor effect on anxiety and completely sparing rule shifting and hippocampal-dependent behavior.

  5. Chronic administration of sulbutiamine improves long term memory formation in mice: possible cholinergic mediation.

    Science.gov (United States)

    Micheau, J; Durkin, T P; Destrade, C; Rolland, Y; Jaffard, R

    1985-08-01

    Thiamine deficiency in both man and animals is known to produce memory dysfunction and cognitive disorders which have been related to an impairment of cholinergic activity. The present experiment was aimed at testing whether, inversely, chronic administration of large doses of sulbutiamine would have a facilitative effect on memory and would induce changes in central cholinergic activity. Accordingly mice received 300 mg/kg of sulbutiamine daily for 10 days. They were then submitted to an appetitive operant level press conditioning test. When compared to control subjects, sulbutiamine treated mice learned the task at the same rate in a single session but showed greatly improved performance when tested 24 hr after partial acquisition of the same task. Parallel neurochemical investigations showed that the treatment induced a slight (+ 10%) but significant increase in hippocampal sodium-dependent high affinity choline uptake. The present findings and previous results suggest that sulbutiamine improves memory formation and that this behavioral effect could be mediated by an increase in hippocampal cholinergic activity. PMID:4059305

  6. Alteration of cytokine profiles in mice exposed to chronic low-dose ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Suk Chul [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of); Lee, Kyung-Mi [Global Research Lab, BAERI Institute, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Kang, Yu Mi [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of); Kim, Kwanghee [Global Research Lab, BAERI Institute, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Kim, Cha Soon; Yang, Kwang Hee; Jin, Young-Woo [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of); Kim, Chong Soon [Department of Nuclear Medicine, Haeundae Paik Hospital, Inje University, Busan 612-030 (Korea, Republic of); Kim, Hee Sun, E-mail: hskimdvm@khnp.co.kr [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of)

    2010-07-09

    While a high-dose of ionizing radiation is generally harmful and causes damage to living organisms, a low-dose of radiation has been shown to be beneficial in a variety of animal models. To understand the basis for the effect of low-dose radiation in vivo, we examined the cellular and immunological changes evoked in mice exposed to low-dose radiation at very low (0.7 mGy/h) and low (3.95 mGy/h) dose rate for the total dose of 0.2 and 2 Gy, respectively. Mice exposed to low-dose radiation, either at very low- or low-dose rate, demonstrated normal range of body weight and complete blood counts. Likewise, the number and percentage of peripheral lymphocyte populations, CD4{sup +} T, CD8{sup +} T, B, or NK cells, stayed unchanged following irradiation. Nonetheless, the sera from these mice exhibited elevated levels of IL-3, IL-4, leptin, MCP-1, MCP-5, MIP-1{alpha}, thrombopoietin, and VEGF along with slight reduction of IL-12p70, IL-13, IL-17, and IFN-{gamma}. This pattern of cytokine release suggests the stimulation of innate immunity facilitating myeloid differentiation and activation while suppressing pro-inflammatory responses and promoting differentiation of naive T cells into T-helper 2, not T-helper 1, types. Collectively, our data highlight the subtle changes of cytokine milieu by chronic low-dose {gamma}-radiation, which may be associated with the functional benefits observed in various experimental models.

  7. Chronic restraint-induced stress has little modifying effect on radiation hematopoietic toxicity in mice

    International Nuclear Information System (INIS)

    Both radiation and stresses cause detrimental effects on humans. Besides possible health effects resulting directly from radiation exposure, the nuclear plant accident is a cause of social psychological stresses. A recent study showed that chronic restraint-induced stresses (CRIS) attenuated Trp53 functions and increased carcinogenesis susceptibility of Trp53-heterozygous mice to total-body X-irradiation (TBXI), having a big impact on the academic world and a sensational effect on the public, especially the residents living in radioactively contaminated areas. It is important to investigate the possible modification effects from CRIS on radiation-induced health consequences in Trp53 wild-type (Trp53wt) animals. Prior to a carcinogenesis study, effects of TBXI on the hematopoietic system under CRIS were investigated in terms of hematological abnormality in the peripheral blood and residual damage in the bone marrow erythrocytes using a mouse restraint model. Five-week-old male Trp53wt C57BL/6J mice were restrained 6 h per day for 28 consecutive days, and TBXI (4 Gy) was given on the 8th day. Results showed that CRIS alone induced a marked decrease in the red blood cell (RBC) and the white blood cell (WBC) count, while TBXI caused significantly lower counts of RBCs, WBCs and blood platelets, and a lower concentration of hemoglobin regardless of CRIS. CRIS alone did not show any significant effect on erythrocyte proliferation and on induction of micronucleated erythrocytes, whereas TBXI markedly inhibited erythrocyte proliferation and induced a significant increase in the incidences of micronucleated erythrocytes, regardless of CRIS. These findings suggest that CRIS does not have a significant impact on radiation-induced detrimental effects on the hematopoietic system in Trp53wt mice. (author)

  8. Human Placenta-Derived Adherent Cells Improve Cardiac Performance in Mice With Chronic Heart Failure

    Science.gov (United States)

    Chen, Hong-Jung; Chen, Chien-Hsi; Chang, Ming-Yao; Tsai, Da-Ching; Baum, Ellen Z.; Hariri, Robert

    2015-01-01

    Human placenta-derived adherent cells (PDACs) are a culture-expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory, anti-inflammatory, angiogenic, and neuroprotective properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. We tested the therapeutic effects of PDA-001 in mice with chronic heart failure (CHF). Three weeks after transaortic constriction surgery to induce CHF, the mice underwent direct intramyocardial (IM) or i.v. injection of PDA-001 at a high (0.5 × 106 cells per mouse), medium (0.5 × 105 cells per mouse), or low (0.5 × 104 cells per mouse) dose. The mice were sacrificed 4 weeks after treatment. Echocardiography and ventricular catheterization showed that IM injection of PDA-001 significantly improved left ventricular systolic and diastolic function compared with injection of vehicle or i.v. injection of PDA-001. IM injection of PDA-001 also decreased cardiac fibrosis, shown by trichrome staining in the vicinity of the injection sites. Low-dose treatment showed the best improvement in cardiac performance compared with the medium- and high-dose groups. In another independent study to determine the mechanism of action with bromodeoxyuridine labeling, the proliferation rates of endothelial cells and cardiomyocytes were significantly increased by low or medium IM dose PDA-001. However, no surviving PDA-001 cells were detected in the heart 1 month after injection. In vivo real-time imaging consistently revealed that the PDA-001 cells were detectable only within 2 days after IM injection of luciferase-expressing PDA-001. Together, these results have demonstrated the cardiac therapeutic potential of PDA-001, likely through a paracrine effect. PMID:25673767

  9. Chronic mild stress (CMS in mice: of anhedonia, 'anomalous anxiolysis' and activity.

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    Martin C Schweizer

    Full Text Available BACKGROUND: In a substantial proportion of depressed patients, stressful life events play a role in triggering the evolution of the illness. Exposure to stress has effects on different levels in laboratory animals as well and for the rat it has been shown that chronic mild stress (CMS can cause antidepressant-reversible depressive-like effects. The adoption of the model to the mouse seems to be problematic, depending on the strain used and behavioural endpoint defined. Our aim was to evaluate the applicability of CMS to mice in order to induce behavioural alterations suggested to reflect depression-like symptoms. METHODOLOGY/PRINCIPAL FINDINGS: A weekly CMS protocol was applied to male mice of different mouse strains (D2Ola, BL/6J and BL/6N and its impact on stress-sensitive behavioural measures (anhedonia-, anxiety- and depression-related parameters and body weight was assessed. Overnight illumination as commonly used stressor in CMS protocols was particularly investigated in terms of its effect on general activity and subsequently derived saccharin intake. CMS application yielded strain-dependent behavioural and physiological responses including 'paradox' anxiolytic-like effects. Overnight illumination was found to be sufficient to mimic anhedonic-like behaviour in BL/6J mice when being applied as sole stressor. CONCLUSIONS/SIGNIFICANCE: The CMS procedure induced some behavioural changes that are compatible with the common expectations, i.e. 'anhedonic' behaviour, but in parallel behavioural alterations were observed which would be described as 'anomalous' (e.g. decreased anxiety. The results suggest that a shift in the pattern of circadian activity has a particular high impact on the anhedonic profile. Changes in activity in response to novelty seem to drive the 'anomalous' behavioural alterations as well.

  10. Alteration of cytokine profiles in mice exposed to chronic low-dose ionizing radiation

    International Nuclear Information System (INIS)

    While a high-dose of ionizing radiation is generally harmful and causes damage to living organisms, a low-dose of radiation has been shown to be beneficial in a variety of animal models. To understand the basis for the effect of low-dose radiation in vivo, we examined the cellular and immunological changes evoked in mice exposed to low-dose radiation at very low (0.7 mGy/h) and low (3.95 mGy/h) dose rate for the total dose of 0.2 and 2 Gy, respectively. Mice exposed to low-dose radiation, either at very low- or low-dose rate, demonstrated normal range of body weight and complete blood counts. Likewise, the number and percentage of peripheral lymphocyte populations, CD4+ T, CD8+ T, B, or NK cells, stayed unchanged following irradiation. Nonetheless, the sera from these mice exhibited elevated levels of IL-3, IL-4, leptin, MCP-1, MCP-5, MIP-1α, thrombopoietin, and VEGF along with slight reduction of IL-12p70, IL-13, IL-17, and IFN-γ. This pattern of cytokine release suggests the stimulation of innate immunity facilitating myeloid differentiation and activation while suppressing pro-inflammatory responses and promoting differentiation of naive T cells into T-helper 2, not T-helper 1, types. Collectively, our data highlight the subtle changes of cytokine milieu by chronic low-dose γ-radiation, which may be associated with the functional benefits observed in various experimental models.

  11. Estrogen receptors alpha mediates postischemic inflammation in chronically estrogen-deprived mice.

    Science.gov (United States)

    Cordeau, Pierre; Lalancette-Hébert, Mélanie; Weng, Yuan Cheng; Kriz, Jasna

    2016-04-01

    Estrogens are known to exert neuroprotective and immuneomodulatory effects after stroke. However, at present, little is known about the role of estrogens and its receptors in postischemic inflammation after menopause. Here, we provide important in vivo evidence of a distinct shift in microglial phenotypes in the model of postmenopause brain. Using a model-system for live imaging of microglial activation in the context of chronic estrogen- and ERα-deficiency associated with aging, we observed a marked deregulation of the TLR2 signals and/or microglial activation in ovariectomized and/or ERα knockout mice. Further analysis revealed a 5.7-fold increase in IL-6, a 4.7-fold increase in phospho-Stat3 levels suggesting an overactivation of JAK/STAT3 pathway and significantly larger infarction in ERα knockouts chronically deprived of estrogen. Taken together, our results suggest that in the experimental model of menopause and/or aging, ERα mediates innate immune responses and/or microglial activation, and ischemia-induced production of IL-6. Based on our results, we propose that the loss of functional ERα may lead to deregulation of postischemic inflammatory responses and increased vulnerability to ischemic injury in aging female brains. PMID:26973103

  12. Chronic restraint stress inhibits hair growth via substance P mediated by reactive oxygen species in mice.

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    Nan Liu

    Full Text Available BACKGROUNDS: Solid evidence has demonstrated that psychoemotional stress induced alteration of hair cycle through neuropeptide substance P (SP mediated immune response, the role of reactive oxygen species (ROS in brain-skin-axis regulation system remains unknown. OBJECTIVES: The present study aims to investigate possible mechanisms of ROS in regulation of SP-mast cell signal pathway in chronic restraint stress (CRS, a model of chronic psychoemotional stress which induced abnormal of hair cycle. METHODS AND RESULTS: Our results have demonstrated that CRS actually altered hair cycle by inhibiting hair follicle growth in vivo, prolonging the telogen stage and delaying subsequent anagen and catagen stage. Up-regulation of SP protein expression in cutaneous peripheral nerve fibers and activation of mast cell were observed accompanied with increase of lipid peroxidation levels and reduction of the activities of superoxide dismutase (SOD and glutathione peroxidase (GSH-Px in CRS mice skin. In addition, SP receptor antagonist (RP67580 reduced mast cell activations and lipid peroxidation levels as well as increased GSH-Px activity and normalized hair cycle. Furthermore, antioxidant Tempol (a free radical scavenger also restored hair cycle, reduced SP protein expression and mast cell activation. CONCLUSIONS: Our study provides the first solid evidence for how ROS play a role in regulation of psychoemotional stress induced SP-Mast cell pathway which may provide a convincing rationale for antioxidant application in clinical treatment with psychological stress induced hair loss.

  13. Moclobemide up-regulates proliferation of hippocampal progenitor cells in chronically stressed mice

    Institute of Scientific and Technical Information of China (English)

    Yun-fengLI; You-zhiZHANG; Yan-qinLIU; Heng-linWANG; LiYUAN; Zhi-puLUO

    2004-01-01

    AIM: To explore the action mechanism of antidepressants. METHODS: The PC 12 cell proliferation was detected by flow cytometry,. The proliferation of hippocampal progenitor cells and level of brain-derived neurotrophic factor (BDNF) were measured by immunohistochemistry. RESULTS: Treatment with N-methylaspartate (NMDA)600 μmol/L for 3 d significantly decreased the percentage of S-phase in PC12 cells, while in the presence of classical antidepressant, moclobemide (MOC) 2 and 10 μnol/L, the percentage in S-phase increased. Furthermore,the proliferation of progenitor cells in hippocampal dentate gyrus (subgranular zone), as well as the level of BDNF in hippocampus significantly decreased in chronically stressed mice, while chronic administration with MOC 40 mg/kg (ip) up-regulated the progenitor cell proliferation and BDNF level in the same time course. CONLUSION:Up-regulation of the proliferation of hippocampal progenitor cells is one of the action mechanisms for MOC, which may be closely related to the elevation of BDNF level at the same time. These results also extend evidence for our hypothesis that up-regulation of the hippocampal neurogenesis is one of the common mechanisms for antidepressants.

  14. Moclobemide up-regulates proliferation of hippocampal progenitor cells in chronically stressed mice

    Institute of Scientific and Technical Information of China (English)

    Yun-feng LI; You-zhi ZHANG; Yan-qin LIU; Heng-lin WANG; Li YUAN; Zhi-pu LUO

    2004-01-01

    AIM: To explore the action mechanism of antidepressants. METHODS: The PC12 cell proliferation was detected by flow cytometry,. The proliferation of hippocampal progenitor cells and level of brain-derived neurotrophic factor (BDNF) were measured by immunohistochemistry. RESULTS: Treatment with N-methylaspartate (NMDA)600 μmol/L for 3 d significantly decreased the percentage of S-phase in PC12 cells, while in the presence of classical antidepressant, moclobemide (MOC) 2 and 10 μmol/L, the percentage in S-phase increased. Furthermore,the proliferation of progenitor cells in hippocampal dentate gyrus (subgranular zone), as well as the level of BDNF in hippocampus significantly decreased in chronically stressed mice, while chronic administration with MOC 40mg/kg (ip) up-regulated the progenitor cell proliferation and BDNF level in the same time course. CONLUSION:Up-regulation of the proliferation of hippocampal progenitor cells is one of the action mechanisms for MOC, which may be closely related to the elevation of BDNF level at the same time. These results also extend evidence for our hypothesis that up-regulation of the hippocampal neurogenesis is one of the common mechanisms for antidepressants.

  15. Activation of pulmonary and lymph node dendritic cells during chronic Pseudomonas aeruginosa lung infection in mice.

    Science.gov (United States)

    Damlund, Dina Silke Malling; Christophersen, Lars; Jensen, Peter Østrup; Alhede, Morten; Høiby, Niels; Moser, Claus

    2016-06-01

    The majority of cystic fibrosis (CF) patients acquire chronic Pseudomonas aeruginosa lung infection, resulting in increased mortality and morbidity. The chronic P. aeruginosa lung infection is characterized by bacteria growing in biofilm surrounded by polymorphonuclear neutrophils (PMNs). However, the infection is not eradicated and the inflammatory response leads to gradual degradation of the lung tissue. In CF patients, a Th2-dominated adaptive immune response with a pronounced antibody response is correlated with poorer outcome. Dendritic cells (DCs) are crucial in bridging the innate immune system with the adaptive immune response. Once activated, the DCs deliver a set of signals to uncommitted T cells that induce development, such as expansion of regulatory T cells and polarization of Th1, Th2 or Th17 subsets. In this study, we characterized DCs in lungs and regional lymph nodes in BALB/c mice infected using intratracheal installation of P. aeruginosa embedded in seaweed alginate in the lungs. A significantly elevated concentration of DCs was detected earlier in the lungs than in the regional lymph nodes. To evaluate whether the chronic P. aeruginosa lung infection leads to activation of DCs, costimulatory molecules CD80 and CD86 were analyzed. During infection, the DCs showed significant elevation of CD80 and CD86 expression in both the lungs and the regional lymph nodes. Interestingly, the percentage of CD86-positive cells was significantly higher than the percentage of CD80-positive cells in the lymph nodes. In addition, cytokine production from Lipopolysaccharides (LPS)-stimulated DCs was analyzed demonstrating elevated production of IL-6, IL-10 and IL-12. However, production of IL-12 was suppressed earlier than IL-6 and IL-10. These results support that DCs are involved in skewing of the Th1/Th2 balance in CF and may be a possible treatment target. PMID:27009697

  16. Chronic cladribine administration increases amyloid beta peptide generation and plaque burden in mice.

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    Crystal D Hayes

    Full Text Available BACKGROUND: The clinical uses of 2-chloro-2'-deoxyadenosine (2-CDA or cladribine which was initially prescribed to patients with hematological and lymphoid cancers is now extended to treat patients with multiple sclerosis (MS. Previous data has shown that 2-CDA has high affinity to the brain and readily passes through the blood brain barrier reaching CSF concentrations 25% of that found in plasma. However, whether long-term administration of 2-CDA can lead to any adverse effects in patients or animal models is not yet clearly known. METHODOLOGY: Here we show that exposure of 2-CDA to CHO cells stably expressing wild-type APP751 increased generation and secretion of amyloid β peptide (Aβ in to the conditioned medium. Interestingly, increased Aβ levels were noticed even at non-toxic concentrations of 2-CDA. Remarkably, chronic treatment of APdE9 mice, a model of Alzheimer's disease with 2-CDA for 60 days increased amyloid plaque burden by more than 1-fold. Increased Aβ generation appears to result from increased turnover of APP as revealed by cycloheximide-chase experiments. Additionally, surface labeling of APP with biotin and immunoprecipitation of surface labeled proteins with anti-biotin antibody also indicated increased APP at the cell surface in 2-CDA treated cells compared to controls. Increased turnover of APP by 2-CDA in turn might be a consequence of decreased protein levels of PIN 1, which is known to regulate cis-trans isomerization and phosphorylation of APP. Most importantly, like many other oncology drugs, 2-CDA administration led to significant delay in acquiring a reward-based learning task in a T maze paradigm. CONCLUSIONS: Taken together, these data provide compelling evidence for the first time that chronic 2-CDA administration can increase amyloidogenic processing of APP leading to robustly increased plaque burden which may be responsible for the observed deficits in learning skills. Thus chronic treatment of mice with 2

  17. An efficient chronic unpredictable stress protocol to induce stress-related responses in C57BL/6 mice

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    Susana eMonteiro

    2015-02-01

    Full Text Available Exposure to chronic stress can have broad effects on health ranging from increased predisposition for neuropsychiatric disorders to deregulation of immune responses. The chronic unpredictable stress (CUS protocol has been widely used to study the impact of stress exposure in several animal models and consists in the random, intermittent and unpredictable exposure to a variety of stressors during several weeks. CUS has consistently been shown to induce behavioral and immunological alterations typical of the chronic stress response. Unfortunately C57BL/6 mice, one of the most widely used mouse strains, due to the great variety of genetically modified lines, seem to be resistant to the commonly used 4-week-long CUS protocol. The definition of an alternative CUS protocol allowing the use of C57BL/6 mice in chronic stress experiments is a need. Here we show that by extending the CUS protocol to 8 weeks is possible to induce a chronic stress response in C57BL/6 mice, as revealed by abrogated body weight gain, increased adrenals weight and an overactive hypothalamic-pituitary-adrenal (HPA axis with increased levels of serum corticosterone. Moreover, we also observed stress-associated behavioral alterations, including the potentiation of anxious-like and depressive-like behaviors and a reduction of exploratory behavior, as well as subtle stress-related changes in the cell population of the thymus and of the spleen.The present protocol for C57BL/6 mice consistently triggers the spectrum of CUS-induced changes observed in rats and, thus, will be highly useful to researchers that need to use this particular mouse strain as an animal model of neuropsychiatric disorders and/or immune deregulation related to chronic unpredictable stress.

  18. Measurement of affective state during chronic nicotine treatment and withdrawal by affective taste reactivity in mice: the role of endocannabinoids.

    Science.gov (United States)

    Wing, Victoria C; Cagniard, Barbara; Murphy, Niall P; Shoaib, Mohammed

    2009-10-01

    Despite tobacco being highly addictive, it is unclear if nicotine has significant affective properties. To address this, we studied taste reactions to gustatory stimuli, palatable sucrose and unpalatable quinine, which are believed to reflect ongoing affective state. Taste reactivity was assessed during chronic nicotine administration and spontaneous withdrawal and the role of the endogenous cannabinoids was also investigated. C57BL6J mice were implanted with intraoral fistula to allow passive administration of solutions. In the first study, taste reactivity was tracked throughout chronic vehicle or nicotine (12 mg/kg/day) infusion via osmotic minipumps and spontaneous withdrawal following removal of minipumps. In the second study, the endocannabinoid CB1-receptor antagonist AM251 (1, 3 and 10mg/kg, intraperitoneal) or vehicle was acutely administered before taste reactivity measurement during chronic nicotine administration. Chronic nicotine treatment and spontaneous withdrawal did not influence taste reactions to sucrose or quinine. AM251 decreased positive reactions to sucrose and increased negative reactions to quinine. The effects of AM251 were respectively attenuated and enhanced in nicotine infused mice. These results suggest chronic nicotine exposure and withdrawal has no apparent affective sequelae, as probed by taste reactivity, and thus may not explain the difficulty tobacco-users have in achieving abstinence. In contrast, endocannabinoids elevate affective state in drug-naïve animals and changes in endogenous endocannabinoid tone may underlie compensations in affective state during chronic nicotine exposure. PMID:19540830

  19. Pseudomonas aeruginosa biofilm aggravates skin inflammatory response in BALB/c mice in a novel chronic wound model

    DEFF Research Database (Denmark)

    Trøstrup, Hannah; Thomsen, Kim; Christophersen, Lars J;

    2013-01-01

    Chronic wounds are presumed to persist in the inflammatory state, preventing healing. Emerging evidence indicates a clinical impact of bacterial biofilms in soft tissues, including Pseudomonas aeruginosa (PA) biofilms. To further investigate this, we developed a chronic PA biofilm wound infection...... model in C3H/HeN and BALB/c mice. The chronic wound was established by an injection of seaweed alginate-embedded P. aeruginosa PAO1 beneath a third-degree thermal lesion providing full thickness skin necrosis, as in human chronic wounds. Cultures revealed growth of PA, and both alginate with or without...... PAO1 generated a polymorphonuclear-dominated inflammation early after infection. However, both at days 4 and 7, there were a more acute polymorphonuclear-dominated and higher degree of inflammation in the PAO1 containing group (p <0.05). Furthermore, PNA-FISH and supplemented DAPI staining showed...

  20. Interferon-gamma deficiency modifies the effects of a chronic stressor in mice: Implications for psychological pathology.

    Science.gov (United States)

    Litteljohn, Darcy; Cummings, Amie; Brennan, Ashley; Gill, Anudip; Chunduri, Siri; Anisman, Hymie; Hayley, Shawn

    2010-03-01

    Pro-inflammatory cytokines promote behavioral and neurochemical variations similar to those evident following stressor exposure, and have been implicated in promoting depressive illness. Indeed, immunotherapeutic application of the cytokine, interferon-alpha, promoted depressive illness in cancer and hepatitis C patients. We assessed the possibility that another interferon cytokine family member, interferon-gamma (IFN-gamma), might contribute to the behavioral and biochemical alterations provoked by a chronic stressor regimen that has been used to model neuropsychiatric pathology in rodents. As predicted, IFN-gamma-deficient mice displayed basal differences in behavior (e.g., reduced open field exploration) and altered neurochemical activity (e.g., increased noradrenergic and serotonergic activity within the central amygdala), relative to their wild-type counterparts. Moreover, stressor-induced elevations of corticosterone and the pro-inflammatory cytokine, tumor necrosis factor-alpha, were attenuated in IFN-gamma-deficient mice. Similarly, the IFN-gamma null mice were refractory to the chronic stressor-induced alterations of dopamine metabolism (within the prefrontal cortex, paraventricular nucleus of the hypothalamus and central amygdala) evident in wild-type mice. Yet, the chronic stressor provoked signs of anxiety (e.g., reduced open field exploration) and depression-like behavior (e.g., increased forced swim immobility, reduced consumption of a palatable solution) among both wild-type and IFN-gamma knockout mice alike, suggesting a dissociation of behavioral functioning from the stressor-induced alterations of immunological, hormonal and dopaminergic activity. Together, these data suggest a complex neurobehavioral phenotype, wherein IFN-gamma deletion engenders a state of heightened basal emotionality coupled with increased monoaminergic activity in the amygdala. At the same time, however, IFN-gamma deficiency appears to blunt some of the neurochemical

  1. 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.

  2. Moderate chronic kidney disease impairs bone quality in C57Bl/6J mice.

    Science.gov (United States)

    Heveran, Chelsea M; Ortega, Alicia M; Cureton, Andrew; Clark, Ryan; Livingston, Eric W; Bateman, Ted A; Levi, Moshe; King, Karen B; Ferguson, Virginia L

    2016-05-01

    Chronic kidney disease (CKD) increases bone fracture risk. While the causes of bone fragility in CKD are not clear, the disrupted mineral homeostasis inherent to CKD may cause material quality changes to bone tissue. In this study, 11-week-old male C57Bl/6J mice underwent either 5/6th nephrectomy (5/6 Nx) or sham surgeries. Mice were fed a normal chow diet and euthanized 11weeks post-surgery. Moderate CKD with high bone turnover was established in the 5/6 Nx group as determined through serum chemistry and bone gene expression assays. We compared nanoindentation modulus and mineral volume fraction (assessed through quantitative backscattered scanning electron microscopy) at matched sites in arrays placed on the cortical bone of the tibia mid-diaphysis. Trabecular and cortical bone microarchitecture and whole bone strength were also evaluated. We found that moderate CKD minimally affected bone microarchitecture and did not influence whole bone strength. Meanwhile, bone material quality decreased with CKD; a pattern of altered tissue maturation was observed with 5/6 Nx whereby the newest 60μm of bone tissue adjacent to the periosteal surface had lower indentation modulus and mineral volume fraction than more interior, older bone. The variance of modulus and mineral volume fraction was also altered following 5/6 Nx, implying that tissue-scale heterogeneity may be negatively affected by CKD. The observed lower bone material quality may play a role in the decreased fracture resistance that is clinically associated with human CKD. PMID:26860048

  3. Immunological changes of chronic oral exposure to depleted uranium in mice.

    Science.gov (United States)

    Hao, Yuhui; Ren, Jiong; Liu, Jing; Yang, Zhangyou; Liu, Cong; Li, Rong; Su, Yongping

    2013-07-01

    Direct ingestion of contaminated soil by depleted uranium (DU) might lead to internal exposure to DU by local populations through hand contamination. The purpose of this study was to assess the immunological changes of long-term exposure to various doses of DU in mice. Three-week-old Kunming mice were divided into the following 4 groups based on the various feeding doses (containing DU): 0 (control group), 3 (DU3 group), 30 (DU30 group), and 300 mg/kg feed (DU300 group). After 4 months of exposure, in the DU300 group, the innate immune function decreased, manifesting as decreased secretion of nitric oxide, interleukin (IL)-1β, IL-18, and tumour necrosis factor (TNF)-α in the peritoneal macrophages, as well as reduced cytotoxicity of the splenic natural killer cells. Moreover, the cellular and humoral immune functions were abnormal, as manifested by decreased proliferation of the splenic T cells, proportion of the cluster of differentiation (CD) 3(+) cells, ratio of CD4(+)/CD8(+) cells and delayed-type hypersensitivity, and increased proliferation of the splenic B cells, total serum immunoglobin (Ig) G and IgE, and proportion of splenic mIgM(+)mIgD(+) cells. Through stimulation, the secretion levels of interferon (IFN)-γ and TNF-α in the splenic cells were reduced, and the levels of IL-4 and IL-10 were increased. By comparison, in the DU30 and DU3 groups, the effects were either minor or indiscernible. In conclusions, chronic intake of higher doses of DU (300 mg/kg) had a significant impact on the immune function, most likely due to an imbalance in T helper (Th) 1 and Th2 cytokines. PMID:23659960

  4. Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice

    International Nuclear Information System (INIS)

    Arsenic is a ubiquitous contaminant in drinking water. Whereas arsenic can be directly hepatotoxic, the concentrations/doses required are generally higher than present in the US water supply. However, physiological/biochemical changes that are alone pathologically inert can enhance the hepatotoxic response to a subsequent stimulus. Such a ‘2-hit’ paradigm is best exemplified in chronic fatty liver diseases. Here, the hypothesis that low arsenic exposure sensitizes liver to hepatotoxicity in a mouse model of non-alcoholic fatty liver disease was tested. Accordingly, male C57Bl/6J mice were exposed to low fat diet (LFD; 13% calories as fat) or high fat diet (HFD; 42% calories as fat) and tap water or arsenic (4.9 ppm as sodium arsenite) for ten weeks. Biochemical and histologic indices of liver damage were determined. High fat diet (± arsenic) significantly increased body weight gain in mice compared with low-fat controls. HFD significantly increased liver to body weight ratios; this variable was unaffected by arsenic exposure. HFD caused steatohepatitis, as indicated by histological assessment and by increases in plasma ALT and AST. Although arsenic exposure had no effect on indices of liver damage in LFD-fed animals, it significantly increased the liver damage caused by HFD. This effect of arsenic correlated with enhanced inflammation and fibrin extracellular matrix (ECM) deposition. These data indicate that subhepatotoxic arsenic exposure enhances the toxicity of HFD. These results also suggest that arsenic exposure might be a risk factor for the development of fatty liver disease in human populations. -- Highlights: ► Characterizes a mouse model of arsenic enhanced NAFLD. ► Arsenic synergistically enhances experimental fatty liver disease at concentrations that cause no overt hepatotoxicity alone. ► This effect is associated with increased inflammation.

  5. Three kinds of Ganoderma lucidum polysaccharides attenuate DDC-induced chronic pancreatitis in mice.

    Science.gov (United States)

    Li, Koukou; Yu, Min; Hu, Yang; Ren, Guangming; Zang, Tingting; Xu, Xiuhong; Qu, Juanjuan

    2016-03-01

    Chronic pancreatitis (CP) is a progressive inflammation of pancreas characterized by irreversible morphologic change and dysfunction. Patients with chronic pancreatitis often present with abdominal pain, diarrhoea, jaundice, weight loss and the development of diabetes. Polysaccharides of Ganoderma lucidum strain S3 (GLPS3) possess antioxidative and immunomodulatory activities. This study was to characterize chemical structures of GLPS3 and determine their effects on diethyldithiocarbamate (DDC)-induced CP in mice. The total sugar content of GLPS3 from fermentation broth (GLPS3-Ⅰ), cultured mycelia (GLPS3-Ⅱ) and fruiting body (GLPS3-Ⅲ) was 90.4%, 92.2% and 91.8% respectively. GLPS3-Ⅰ, GLPS3-Ⅱ and GLPS3-Ⅲ were composed of Glu:Gal:Ara:Xyl, Glu:Gal:Ara:Xyl:Man:Rha, and Glu:Gal:Xyl:Man:Rha:Fuc, with molar ratio of 2.82: 1.33: 1.26: 0.87, 5.84: 2.23: 0.72:1.38: 1.40: 0.51 and 5.34: 2.72: 1.14: 1.10: 0.33: 0.38, respectively. The antioxidative activity of GLPS3-Ⅱfrom cultured mycelia in vitro is higher than other two polysaccharides. The superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in serum were increased while the malondialdehyde (MDA) levels were reversely decreased by GLPS3 treatment. Serum amylase (AMS) and lactic dehydrogenase (LDH) changes indicated the therapeutic effects of GLPS3. Moreover, interleukin-1beta (IL-1β) and interferon-gamma (INF-γ) contents were reduced most by GLPS3-Ⅱ. The results revealed that GLPS3 especially GLPS3-Ⅱfrom cultured mycelia were effective for CP therapy and bioactivity difference might be attributed to monosaccharide composition. PMID:26826268

  6. Expression profiling reveals novel hypoxic biomarkers in peripheral blood of adult mice exposed to chronic hypoxia.

    Directory of Open Access Journals (Sweden)

    Matias Mosqueira

    Full Text Available Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX, exposed for two weeks to normobaric chronic hypoxia (CH or two weeks of CH followed by two weeks of normoxic recovery (REC. Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off, 230 genes were identified and separated into four distinct temporal categories. Class I contained 1 transcript up-regulated in both CH and REC; Class II contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III contained 9 transcripts down-regulated both in CH and REC; Class IV contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1 by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia.

  7. Chronic early postnatal scream sound stress induces learning deficits and NMDA receptor changes in the hippocampus of adult mice.

    Science.gov (United States)

    Hu, Lili; Han, Bo; Zhao, Xiaoge; Mi, Lihua; Song, Qiang; Wang, Jue; Song, Tusheng; Huang, Chen

    2016-04-13

    Chronic scream sounds during adulthood affect spatial learning and memory, both of which are sexually dimorphic. The long-term effects of chronic early postnatal scream sound stress (SSS) during postnatal days 1-21 (P1-P21) on spatial learning and memory in adult mice as well as whether or not these effects are sexually dimorphic are unknown. Therefore, the present study examines the performance of adult male and female mice in the Morris water maze following exposure to chronic early postnatal SSS. Hippocampal NR2A and NR2B levels as well as NR2A/NR2B subunit ratios were tested using immunohistochemistry. In the Morris water maze, stress males showed greater impairment in spatial learning and memory than background males; by contrast, stress and background females performed equally well. NR2B levels in CA1 and CA3 were upregulated, whereas NR2A/NR2B ratios were downregulated in stressed males, but not in females. These data suggest that chronic early postnatal SSS influences spatial learning and memory ability, levels of hippocampal NR2B, and NR2A/NR2B ratios in adult males. Moreover, chronic early stress-induced alterations exert long-lasting effects and appear to affect performance in a sex-specific manner. PMID:27015584

  8. Fluoxetine reverts chronic restraint stress-induced depression-like behaviour and increases neuropeptide Y and galanin expression in mice

    DEFF Research Database (Denmark)

    Christiansen, Søren Hofman Oliveira; Olesen, Mikkel Vestergaard; Wörtwein, Gitta;

    2011-01-01

    -like behaviour, NPY and galanin gene expression was studied in brains of mice subjected to chronic restraint stress (CRS) and concomitant treatment with the antidepressant fluoxetine (FLX). CRS caused a significant increase in depression-like behaviour that was associated with increased NPY mRNA levels in the......Stressful life events and chronic stress are implicated in the development of depressive disorder in humans. Neuropeptide Y (NPY) and galanin have been shown to modulate the stress response, and exert antidepressant-like effects in rodents. To further investigate these neuropeptides in depression...

  9. Zinc and imipramine reverse the depression-like behavior in mice induced by chronic restraint stress.

    Science.gov (United States)

    Ding, Qin; Li, Hongxia; Tian, Xue; Shen, Zhilei; Wang, Xiaoli; Mo, Fengfeng; Huang, Junlong; Shen, Hui

    2016-06-01

    Depression is a common psychopathological disorders. Studies of depression have indicated that zinc play a role in the depression pathophysiology and treatment. In present study, we examined the effects of zinc and imipramine supplement alone or combination of zinc and imipramine in mice induced by chronic restraint stress (CRS). Moreover, the possible roles of zinc receptor (G protein-coupled receptor 39, GPR39)-related pathway was investigated. Decreased weight and increased corticosterone (CORT) were observed after 3 weeks CRS exposure. It was shown that CRS induced lower serum zinc, higher hippocampal zinc, increased immobility time in tail suspension test and decreased movement distance in spontaneous activity test, which could be normalized by zinc (30mg/kg) and imipramine (20mg/kg) supplement alone and combination of zinc (15mg/kg) and imipramine (5mg/kg) for 3 weeks after CRS exposure. Moreover, the changes in mRNA expressions of GPR39, cAMP-response element binding protein (CREB), brain-derived neurotropic factor (BDNF) and n-methytl-d-aspartate receptors (NMDAR) could be reversed by the same treatment mentioned above. These results suggested that zinc dyshomeostasis in serum and hippocampus and depression-like behavior in CRS exposure animals observed in present study could be normalized by zinc and imipramine. The combination of zinc and imipramine in low dose has synergetic effects. The possible mechanism might be correlated to GPR39 receptor-related pathway. PMID:26985741

  10. Effects of chronic carbon monoxide exposure on fetal growth and development in mice

    Directory of Open Access Journals (Sweden)

    Venditti Carolina C

    2011-12-01

    Full Text Available Abstract Background Carbon monoxide (CO is produced endogenously, and can also be acquired from many exogenous sources: ie. cigarette smoking, automobile exhaust. Although toxic at high levels, low level production or exposure lends to normal physiologic functions: smooth muscle cell relaxation, control of vascular tone, platelet aggregation, anti- inflammatory and anti-apoptotic events. In pregnancy, it is unclear at what level maternal CO exposure becomes toxic to the fetus. In this study, we hypothesized that CO would be embryotoxic, and we sought to determine at what level of chronic CO exposure in pregnancy embryo/fetotoxic effects are observed. Methods Pregnant CD1 mice were exposed to continuous levels of CO (0 to 400 ppm from conception to gestation day 17. The effect on fetal/placental growth and development, and fetal/maternal CO concentrations were determined. Results Maternal and fetal CO blood concentrations ranged from 1.12- 15.6 percent carboxyhemoglobin (%COHb and 1.0- 28.6%COHb, respectively. No significant difference was observed in placental histological morphology or in placental mass with any CO exposure. At 400 ppm CO vs. control, decreased litter size and fetal mass (p Conclusions Exposure to levels at or below 300 ppm CO throughout pregnancy has little demonstrable effect on fetal growth and development in the mouse.

  11. Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice.

    OpenAIRE

    Giménez, R.; Raïch, J.; Aguilar, J.

    1991-01-01

    1. Spiroperidol binding (dopamine D2 receptors) and quinuclidinyl benzilate binding (muscarinic receptors) in striata of 19-month old mice was analyzed for animals that had received chronic administration of cytidine 5'-diphosphocholine (CDP-choline) incorporated into the chow consumed (100 or 500 mg kg-1 added per day) for the 7 months before they were killed. 2. Treated animals displayed an increase in the dopamine receptor densities of 11% for those receiving 100 mg kg-1 and 18% for those ...

  12. Withdrawal from Chronic Cocaine Administration Induces Deficits in Brain Reward Function in C57BL/6J Mice

    OpenAIRE

    Stoker, Astrid K.; Markou, Athina

    2011-01-01

    Anhedonia is a major symptom of cocaine withdrawal, whereas euphoria characterizes the effects of acute administration of this drug in humans. These mood states can be measured quantitatively in animals with brain reward thresholds obtained from the intracranial self-stimulation (ICSS) procedure. Studies have previously reported the reward-enhancing effects of acute cocaine administration using the ICSS procedure in mice, but the effects of chronic cocaine administration and withdrawal on bra...

  13. Measurement of affective state during chronic nicotine treatment and withdrawal by affective taste reactivity in mice: the role of endocannabinoids

    OpenAIRE

    Wing, Victoria C.; Cagniard, Barbara; Murphy, Niall P; Shoaib, Mohammed

    2009-01-01

    Abstract Despite tobacco being highly addictive, it is unclear if nicotine has significant affective properties. To address this, we studied taste reactions to gustatory stimuli, palatable sucrose and unpalatable quinine, which are believed to reflect ongoing affective state. Taste reactivity was assessed during chronic nicotine administration and spontaneous withdrawal and the role of the endogenous cannabinoids was also investigated. C57BL6J mice were implanted with intra-oral fi...

  14. Chronic Treatment with Mood-Stabilizers Attenuates Abnormal Hyperlocomotion of GluA1-Subunit Deficient Mice

    OpenAIRE

    Maksimovic, Milica; Vekovischeva, Olga Y.; Aitta-Aho, Teemu; Korpi, Esa R.

    2014-01-01

    Abnormal excitatory glutamate neurotransmission and plasticity have been implicated in schizophrenia and affective disorders. Gria1−/− mice lacking GluA1 subunit (encoded by Gria1 gene) of AMPA-type glutamate receptor show robust novelty-induced hyperactivity, social deficits and heightened approach features, suggesting that they could be used to test for anti-manic activity of drugs. Here, we tested the efficacy of chronic treatment with established anti-manic drugs on behavioural properties...

  15. Exogenous Tryptophan Promotes Cutaneous Wound Healing of Chronically Stressed Mice through Inhibition of TNF-α and IDO Activation

    OpenAIRE

    Bandeira, Luana Graziella; Bortolot, Beatriz Salari; Cecatto, Matheus Jorand; Monte-Alto-Costa, Andréa; Romana-Souza, Bruna

    2015-01-01

    Stress prolongs the inflammatory response compromising the dermal reconstruction and wound closure. Acute stress-induced inflammation increases indoleamine 2, 3-dioxygenase-stimulated tryptophan catabolism. To investigate the role of indoleamine 2, 3-dioxygenase expression and tryptophan administration in adverse effects of stress on cutaneous wound healing, mice were submitted to chronic restraint stress and treated with tryptophan daily until euthanasia. Excisional lesions were created on e...

  16. Bilateral mechanical and thermal hyperalgesia and tactile allodynia after chronic compression of dorsal root ganglion in mice.

    Science.gov (United States)

    Chen, Rong-Gui; Kong, Wei-Wei; Ge, Da-Long; Luo, Ceng; Hu, San-Jue

    2011-08-01

    OBJECTIVE Low back pain is one of the most inextricable problems encountered in clinics. Animal models that imitate symptoms in humans are valuable tools for investigating low back pain mechanisms and the possible therapeutic applications. With the development of genetic technology in pain field, the possibility of mutating specific genes in mice has provided a potent tool for investigating the specific mechanisms of pain. The aim of the present study was to develop a mouse model of chronic compression of dorsal root ganglion (CCD), in which gene mutation can be applied to facilitate the studies of chronic pain. METHODS Chronic compression of L4 and L5 dorsal root ganglia was conducted in mice by inserting fine stainless steel rods into the intervertebral foramina, one at L4 and the other at L5. Mechanical allodynia and thermal hyperalgesia were examined with von Frey filaments and radiating heat stimulator, respectively. RESULTS The CCD mice displayed dramatic mechanical and thermal hyperalgesia as well as tactile allodynia in the hindpaw ipsilateral to CCD. In addition, this mechanical and thermal hyperalgesia as well as tactile allodynia was also found to spread to the contralateral hindpaw. CONCLUSION This model, combined with the possible genetic modification, will strengthen our knowledge of the underlying mechanisms of low back pain. It also favors the development of new treatment strategies for pain and hyperalgesia after spinal injury and other disorders which affect the dorsal root ganglion in humans. PMID:21788994

  17. Chronic social defeat stress increases dopamine D2 receptor dimerization in the prefrontal cortex of adult mice.

    Science.gov (United States)

    Bagalkot, T R; Jin, H-M; Prabhu, V V; Muna, S S; Cui, Y; Yadav, B K; Chae, H-J; Chung, Y-C

    2015-12-17

    The present study aimed to examine the effects of chronic social defeat stress on the dopamine receptors and proteins involved in post-endocytic trafficking pathways. Adult mice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress. Western blot analysis was used to measure the protein expression levels of dopamine D2 receptors (D2Rs), a short (D2S) and a long form (D2L) and, D2R monomers and dimers, dopamine D1 receptors (D1Rs), neuronal calcium sensor-1 (NCS-1) and G protein-coupled receptor-associated sorting protein-1 (GASP-1), and reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA expression levels of D2S, D2L, D2R monomers and dimers, and D1Rs in different brain areas. We observed increased expression of D2S, D2L and D2Rs dimers in the prefrontal cortex (PFC) of susceptible and/or unsusceptible mice compared with controls. The only significant findings with regard to mRNA expression levels were lower expression of D2S mRNA in the amygdala (AMYG) of susceptible and unsusceptible mice compared with controls. The present study demonstrated that chronic social defeat stress induced increased expression of D2S, D2L, and D2R dimers in the PFC of susceptible and/or unsusceptible mice. PMID:26484605

  18. Vulnerability to chronic subordination stress-induced depression-like disorders in adult 129SvEv male mice.

    Science.gov (United States)

    Dadomo, Harold; Sanghez, Valentina; Di Cristo, Luisana; Lori, Andrea; Ceresini, Graziano; Malinge, Isabelle; Parmigiani, Stefano; Palanza, Paola; Sheardown, Malcolm; Bartolomucci, Alessandro

    2011-08-01

    Exposure to stressful life events is intimately linked with vulnerability to neuropsychiatric disorders such as major depression. Pre-clinical animal models offer an effective tool to disentangle the underlying molecular mechanisms. In particular, the 129SvEv strain is often used to develop transgenic mouse models but poorly characterized as far as behavior and neuroendocrine functions are concerned. Here we present a comprehensive characterization of 129SvEv male mice's vulnerability to social stress-induced depression-like disorders and physiological comorbidities. We employed a well characterized mouse model of chronic social stress based on social defeat and subordination. Subordinate 129SvEv mice showed body weight gain, hyperphagia, increased adipose fat pads weight and basal plasma corticosterone. Home cage phenotyping revealed a suppression of spontaneous locomotor activity and transient hyperthermia. Subordinate 129SvEv mice also showed marked fearfulness, anhedonic-like response toward a novel but palatable food, increased anxiety in the elevated plus maze and social avoidance of an unfamiliar male mouse. A direct measured effect of the stressfulness of the living environment, i.e. the amount of daily aggression received, predicted the degree of corticosterone level and locomotor activity but not of the other parameters. This is the first study validating a chronic subordination stress paradigm in 129SvEv male mice. Results demonstrated remarkable stress vulnerability and establish the validity to use this mouse strain as a model for depression-like disorders. PMID:21093519

  19. Chronic subordination stress induces hyperphagia and disrupts eating behavior in mice modeling binge-eating-like disorder

    Directory of Open Access Journals (Sweden)

    Maria eRazzoli

    2015-01-01

    Full Text Available Background: Eating disorders are associated with physical morbidity and appear to have causal factors like stressful life events and negative affect. Binge eating disorder (BED is characterized by eating in a discrete period of time a larger than normal amount of food, a sense of lack of control over eating, and marked distress. There are still unmet needs for the identification of mechanisms regulating excessive eating, which is in part due to the lack of appropriate animal models. We developed a naturalistic murine model of subordination stress induced hyperphagia associated with the development of obesity. Here we tested the hypotheses that the eating responses of subordinate mice recapitulate the BED and that limiting hyperphagia could prevent stress-associated metabolic changes. Methods: Adult male mice were exposed to a model of chronic subordination stress associated with the automated acquisition of food intake and we performed a detailed meal pattern analysis. Additionally, using a pair-feeding protocol was test the hypothesis that the manifestation of obesity and the metabolic syndrome could be prevented by limiting hyperphagia. Results: The architecture of feeding of subordinate mice was disrupted during the stress protocol due to disproportionate amount of food ingested at higher rate and with shorter satiety ratio than control mice. Subordinate mice hyperphagia was further exacerbated in response to either hunger or to the acute application of a social defeat. Notably, the obese phenotype but not the fasting hyperglycemia of subordinate mice was abrogated by preventing hyperphagia in a pair feeding paradigm. Conclusion: Overall these results support the validity of our chronic subordination stress to model binge eating disorder allowing for the determination of the underlying molecular mechanisms and the generation of testable predictions for innovative therapies, based on the understanding of the regulation and the control of food

  20. Chronic social stress during adolescence in mice alters fat distribution in late life: prevention by antidepressant treatment.

    Science.gov (United States)

    Schmidt, M V; Czisch, M; Sterlemann, V; Reinel, C; Sämann, P; Müller, M B

    2009-01-01

    Obesity and visceral fat accumulation are key features of the metabolic syndrome that represents one of the main health problems in western societies due to its neurovascular and cardiovascular complications. Epidemiological studies have identified chronic stress exposure as an important risk factor for the development of obesity and metabolic syndrome, but also psychiatric diseases, especially affective disorders. However, it is still unclear if chronic stress has merely transient or potentially lasting effects on body composition. Here, we investigated the effects of chronic social stress during the adolescent period on body fat composition in mice one year after the cessation of the stressor. We found that stress exposure during the adolescent period decreases subcutaneous fat content, without change in visceral fat, and consequently increases the visceral fat/subcutaneous fat ratio in adulthood. Further, we demonstrated that treatment with a selective serotonin reuptake inhibitor (paroxetine) during stress exposure prevented later effects on body fat distribution. These results from a recently validated chronic stress paradigm in mice provide evidence that stressful experiences during adolescence can alter body fat distribution in adulthood, thereby possibly contributing to an increased risk for metabolic diseases. Antidepressant treatment disrupted this effect underlining the link between the stress hormone system, metabolic homeostasis and affective disorders. PMID:18951248

  1. Dopamine transporter and D2 receptor binding densities in mice prone or resistant to chronic high fat diet-induced obesity.

    Science.gov (United States)

    Huang, Xu-Feng; Zavitsanou, Katerina; Huang, Xin; Yu, Yinghua; Wang, HongQin; Chen, Feng; Lawrence, Andrew J; Deng, Chao

    2006-12-15

    This study examined the density of dopamine transporter (DAT) and D2 receptors in the brains of chronic high-fat diet-induced obese (cDIO), obese-resistant (cDR) and low-fat-fed (LF) control mice. Significantly decreased DAT densities were observed in cDR mice compared to cDIO and LF mice, primarily in the nucleus accumbens, striatal and hypothalamic regions. D2 receptor density was significantly lower in the rostral part of caudate putamen in cDIO mice compared to cDR and LF mice. PMID:17000016

  2. Chronic ethanol exposure downregulates hepatic expression of pregnane X receptor and P450 3A11 in female ICR mice

    International Nuclear Information System (INIS)

    Pregnane X receptor (PXR) is a nuclear receptor that regulates cytochrome P450 3A (CYP3A) gene transcription in a ligand-dependent manner. Ethanol has been reported to be either an inducer or an inhibitor of CYP3A expression. In this study, we investigated the effects of chronic ethanol exposure on PXR and P450 3A11 gene expression in mouse liver. Female ICR mice were administered by gavage with different doses (1000, 2000 and 4000 mg/kg) of ethanol for up to 5 weeks. Hepatic PXR and P450 3A11 mRNA levels were measured using RT-PCR. Erythromycin N-demethylase (ERND) activity was used as an indicator of CYP3A protein expression. Results showed that chronic ethanol exposure markedly decreased hepatic PXR and P450 3A11 mRNA levels. Consistent with downregulation of P450 3A11 mRNA, chronic ethanol exposure significantly decreased ERND activity in a dose-dependent manner. Additional experiment showed that chronic ethanol exposure significantly increased plasma endotoxin level and hepatic CD14 and TLR-4 mRNA expression, all of which were blocked by elimination of Gram-negative bacteria and endotoxin with antibiotics. Correspondingly, pretreatment with antibiotics reversed the downregulation of PXR and P450 3A11 mRNA expression and ERND activity in mouse liver. Furthermore, the downregulation of hepatic PXR and P450 3A11 mRNA expression was significantly attenuated in mice pretreated with GdCl3, a selective Kupffer cell toxicant. GdCl3 pretreatment also significantly attenuated chronically ethanol-induced decrease in ERND activity. These results indicated that activation of Kupffer cells by gut-derived endotoxin contributes to downregulation of hepatic PXR and P450 3A11 expression during chronic alcohol intoxication

  3. Desensitization and Incomplete Recovery of Hepatic Target Genes After Chronic Thyroid Hormone Treatment and Withdrawal in Male Adult Mice.

    Science.gov (United States)

    Ohba, Kenji; Leow, Melvin Khee-Shing; Singh, Brijesh Kumar; Sinha, Rohit Anthony; Lesmana, Ronny; Liao, Xiao-Hui; Ghosh, Sujoy; Refetoff, Samuel; Sng, Judy Chia Ghee; Yen, Paul Michael

    2016-04-01

    Clinical symptoms may vary and not necessarily reflect serum thyroid hormone (TH) levels during acute and chronic hyperthyroidism as well as recovery from hyperthyroidism. We thus examined changes in hepatic gene expression and serum TH/TSH levels in adult male mice treated either with a single T3 (20 μg per 100 g body weight) injection (acute T3) or daily injections for 14 days (chronic T3) followed by 10 days of withdrawal. Gene expression arrays from livers harvested at these time points showed that among positively-regulated target genes, 320 were stimulated acutely and 429 chronically by T3. Surprisingly, only 69 of 680 genes (10.1%) were induced during both periods, suggesting desensitization of the majority of acutely stimulated target genes. About 90% of positively regulated target genes returned to baseline expression levels after 10 days of withdrawal; however, 67 of 680 (9.9%) did not return to baseline despite normalization of serum TH/TSH levels. Similar findings also were observed for negatively regulated target genes. Chromatin immunoprecipitation analysis of representative positively regulated target genes suggested that acetylation of H3K9/K14 was associated with acute stimulation, whereas trimethylation of H3K4 was associated with chronic stimulation. In an in vivo model of chronic intrahepatic hyperthyroidism since birth, adult male monocarboxylate transporter-8 knockout mice also demonstrated desensitization of most acutely stimulated target genes that were examined. In summary, we have identified transcriptional desensitization and incomplete recovery of gene expression during chronic hyperthyroidism and recovery. Our findings may be a potential reason for discordance between clinical symptoms and serum TH levels observed in these conditions. PMID:26866609

  4. Chronic Exposure to Bisphenol A Affects Uterine Function During Early Pregnancy in Mice.

    Science.gov (United States)

    Li, Quanxi; Davila, Juanmahel; Kannan, Athilakshmi; Flaws, Jodi A; Bagchi, Milan K; Bagchi, Indrani C

    2016-05-01

    Environmental and occupational exposure to bisphenol A (BPA), a chemical widely used in polycarbonate plastics and epoxy resins, has received much attention in female reproductive health due to its widespread toxic effects. Although BPA has been linked to infertility and recurrent miscarriage in women, the impact of its exposure on uterine function during early pregnancy remains unclear. In this study, we addressed the effect of prolonged exposure to an environmental relevant dose of BPA on embryo implantation and establishment of pregnancy. Our studies revealed that treatment of mice with BPA led to improper endometrial epithelial and stromal functions thus affecting embryo implantation and establishment of pregnancy. Upon further analyses, we found that the expression of progesterone receptor (PGR) and its downstream target gene, HAND2 (heart and neural crest derivatives expressed 2), was markedly suppressed in BPA-exposed uterine tissues. Previous studies have shown that HAND2 controls embryo implantation by repressing fibroblast growth factor and the MAPK signaling pathways and inhibiting epithelial proliferation. Interestingly, we observed that down-regulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with enhanced activation of fibroblast growth factor and MAPK signaling in the epithelium, thus contributing to aberrant proliferation and lack of uterine receptivity. Further, the differentiation of endometrial stromal cells to decidual cells, an event critical for the establishment and maintenance of pregnancy, was severely compromised in response to BPA. In summary, our studies revealed that chronic exposure to BPA impairs PGR-HAND2 pathway and adversely affects implantation and the establishment of pregnancy. PMID:27022677

  5. Absence of Respiratory Burst in X-linked Chronic Granulomatous Disease Mice Leads to Abnormalities in Both Host Defense and Inflammatory Response to Aspergillus fumigatus

    OpenAIRE

    Morgenstern, David E.; Gifford, Mary A.C.; Li, Ling Lin; Doerschuk, Claire M.; Dinauer, Mary C.

    1997-01-01

    Mice with X-linked chronic granulomatous disease (CGD) generated by targeted disruption of the gp91 phox subunit of the NADPH–oxidase complex (X-CGD mice) were examined for their response to respiratory challenge with Aspergillus fumigatus. This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae. Alveolar macrophages from X-CGD mice were found to kill A. fumigatus co...

  6. The flexDrive: An ultra-light implant for optical control and highly parallel chronic recording of neuronal ensembles in freely moving mice

    OpenAIRE

    Jakob Voigts; Pritchett, Dominique L.; Christopher I Moore

    2013-01-01

    Electrophysiological recordings from ensembles of neurons in behaving mice are a central tool in the study of neural circuits. Despite the widespread use of chronic electrophysiology, the precise positioning of recording electrodes required for high-quality recordings remains a challenge, especially in behaving mice. The complexity of available drive mechanisms, combined with restrictions on implant weight tolerated by mice, limits current methods to recordings from no more than 4-8 electr...

  7. Antihyperglycemic Effect on Chronic Administration of Butanol Fraction of Ethanol Extract of Moringa Stenopetala Leaves in Alloxan Induced Diabetic Mice

    Institute of Scientific and Technical Information of China (English)

    Alemayehu Toma; Eyasu Makonnen; Asfaw Debella; Birhanu Tesfaye

    2012-01-01

    Objective: The present study was conducted to evaluate the antihyperglycemic activity on chronic administration of the butanol fraction of the ethanol extract of Moringa Stenopetala leaves in alloxan induced diabetic mice. Methods: The mice were grouped in four groups; Normal control, Diabetic control, Butanol fraction treated and standard drug treated groups. The Diabetic mice received the butanol fraction of Moringa stenopetala daily for 28 days. Results: The butanol fraction of Moringastenopetala treatment resulted in significant reduction of fasting blood glucose level, serum total cholesterol and triglycerides level. This fraction also showed a tendency to improve body weight gain in diabetic mice. Its oral LD50 was found to be greater than 5000mg/Kg indicating its safety in mice. Conclusions: Though the mechanism of action of Moringa stenopetala seems to be similar to that of sulfonylureas, further studies should be done to confirm its mechanism of antidiabetic action. Furthermore the active principle(s) responsible for the antidabetic effects should also be identified.

  8. Anti-CD4 abrogates rejection and reestablishes long-term tolerance to syngeneic newborn hearts grafted in mice chronically infected with Trypanosoma cruzi

    OpenAIRE

    1992-01-01

    The contribution of autoimmunity in the genesis of chronic Chagas' heart pathology is not clear. In the present study, we show that: (a) BALB/c mice chronically infected with Trypanosoma cruzi reject syngeneic newborn hearts; (b) in vivo treatment with anti-CD4 but not anti-CD8 monoclonal antibodies (mAbs) abrogates rejection; (c) CD4+ T cells from chronically infected mice proliferate in vitro to syngeneic myocardium antigens and induce heart graft destruction when injected in situ; (d) anti...

  9. Acute and Chronic Effects of N-acetylcysteine on Pentylenetetrazole-induced Seizure and Neuromuscular Coordination in Mice

    Directory of Open Access Journals (Sweden)

    Sasan Zaeri

    2015-03-01

    Full Text Available Background: N-acetylcysteine (NAC has been indicated against experimental seizures, but with relatively inconclusive results. This study was undertaken to evaluate whether NAC exerts a dose-dependent anticonvulsant effect and to determine NAC safe therapeutic dose range and its muscle-relaxant activity in both acute and chronic uses. Methods: Following intraperitoneal (i.p. administration of N-acetylcysteine acutely (50-300 mg/kg or chronically for 8 days (25-300 mg/kg, mice were injected with PTZ (90 mg/kg, i.p. and latency times to the onset of myoclonic and clonic seizures and protection against death were recorded. Changes in body weight and mortality rate were considered as parameters for drug safety. The muscle-relaxant activity of NAC was assessed by rotarod test. Results: Acute and chronic treatment with NAC delayed latency times to myoclonic and clonic seizures in a dose-dependent manner, but with no significant prevention against PTZ-induced death. Chronic administration of 300 mg/kg NAC was fully lethal while lower doses (100 and 150 mg/kg resulted in a significant weight loss and decreased stay time on rotarod. Acute treatment with NAC had no significant effect on stay time on rotarod at all studied doses. Conclusion: NAC exerts a dose-dependent anticonvulsant effect in acute and chronic uses, with no muscle relaxant activity. NAC has higher efficacy in preventing seizure in chronic than acute treatment, but its chronic use at higher doses of 75 mg/kg may be associated with side effects and/or toxicity. These findings suggest that low doses of NAC may have a potential use as a prophylactic treatment for absence seizure in human.

  10. Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells

    International Nuclear Information System (INIS)

    Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34+ cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML

  11. Macrophage TCF-4 co-activates p65 to potentiate chronic inflammation and insulin resistance in mice.

    Science.gov (United States)

    Kang, Xia; Hou, Along; Wang, Rui; Liu, Da; Xiang, Wei; Xie, Qingyun; Zhang, Bo; Gan, Lixia; Zheng, Wei; Miao, Hongming

    2016-07-01

    Transcription factor 4 (TCF-4) was recently identified as a candidate gene for the cause of type 2 diabetes, although the mechanisms have not been fully elucidated. In the present study, we demonstrated that the TCF-4 transgene in macrophages aggravated high-fat diet (HFD)-induced insulin resistance and chronic inflammation, characterized by the elevation of proinflammatory cytokines in the blood, liver and white adipose tissue, as well as a proinflammatory profile of immune cells in visceral fats in mice. Mechanistically, TCF-4 functioned as a co-activator of p65 to amplify the saturated free fatty acid (FFA)-stimulated promoter activity, mRNA transcription and secretion of proinflammatory cytokines in primary macrophages. Blockage of p65 with a specific interfering RNA or inhibitor could prevent TCF-4-enhanced expression of proinflammatory cytokines in FFA/lipopolysaccharide-treated primary macrophages. The p65 inhibitor could abolish macrophage TCF-4 transgene-aggravated systemic inflammation, glucose intolerance and insulin resistance in HFD-treated mice. In addition, we demonstrated that the mRNA expression of TCF-4 in the peripheral blood monocytes from humans was positively correlated to the levels of interleukin (IL)-1β, tumour necrosis factor α, IL-6 and fasting plasma glucose. In summary, we identified TCF-4 as a co-activator of p65 in the potentiation of proinflammatory cytokine production in macrophages and aggravation of HFD-induced chronic inflammation and insulin resistance in mice. PMID:27129186

  12. Chronic exposure to low doses of pharmaceuticals disturbs the hepatic expression of circadian genes in lean and obese mice

    Energy Technology Data Exchange (ETDEWEB)

    Anthérieu, Sébastien; Le Guillou, Dounia; Coulouarn, Cédric; Begriche, Karima [INSERM, U991, Université de Rennes 1, 35000 Rennes (France); Trak-Smayra, Viviane [Pathology Department, Saint-Joseph University, Beirut (Lebanon); Martinais, Sophie [INSERM, U991, Université de Rennes 1, 35000 Rennes (France); Porceddu, Mathieu [Mitologics SAS, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris (France); Robin, Marie-Anne [INSERM, U991, Université de Rennes 1, 35000 Rennes (France); Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr [INSERM, U991, Université de Rennes 1, 35000 Rennes (France)

    2014-04-01

    Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can be harmful for the liver, especially during obesity. Hence, the goal of our study was to determine whether chronic exposure to low doses of pharmaceuticals could have deleterious effects on livers of lean and obese mice. To this end, lean and ob/ob male mice were treated for 4 months with a mixture of 11 drugs provided in drinking water at concentrations ranging from 10 to 10{sup 6} ng/l. At the end of the treatment, some liver and plasma abnormalities were observed in ob/ob mice treated with the cocktail containing 10{sup 6} ng/l of each drug. For this dosage, a gene expression analysis by microarray showed altered expression of circadian genes (e.g. Bmal1, Dbp, Cry1) in lean and obese mice. RT-qPCR analyses carried out in all groups of animals confirmed that expression of 8 different circadian genes was modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 10{sup 2}–10{sup 3} ng/l. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were validated in an independent study performed in female mice. Thus, our study showed that chronic exposure to trace pharmaceuticals disturbed hepatic expression of circadian genes, particularly in obese mice. Because some of the 11 drugs can be found in drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, especially for obese individuals exposed to these contaminants. - Highlights: • The contamination of drinking water with drugs may have harmful effects on health. • Some drugs can be more hepatotoxic in the context of obesity and fatty liver. • Effects of chronic exposure of trace drugs were studied in lean and obese mouse liver. Drugs and obesity present additive effects on circadian gene expression and toxicity. • Trace

  13. Chronic exposure to low doses of pharmaceuticals disturbs the hepatic expression of circadian genes in lean and obese mice

    International Nuclear Information System (INIS)

    Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can be harmful for the liver, especially during obesity. Hence, the goal of our study was to determine whether chronic exposure to low doses of pharmaceuticals could have deleterious effects on livers of lean and obese mice. To this end, lean and ob/ob male mice were treated for 4 months with a mixture of 11 drugs provided in drinking water at concentrations ranging from 10 to 106 ng/l. At the end of the treatment, some liver and plasma abnormalities were observed in ob/ob mice treated with the cocktail containing 106 ng/l of each drug. For this dosage, a gene expression analysis by microarray showed altered expression of circadian genes (e.g. Bmal1, Dbp, Cry1) in lean and obese mice. RT-qPCR analyses carried out in all groups of animals confirmed that expression of 8 different circadian genes was modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 102–103 ng/l. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were validated in an independent study performed in female mice. Thus, our study showed that chronic exposure to trace pharmaceuticals disturbed hepatic expression of circadian genes, particularly in obese mice. Because some of the 11 drugs can be found in drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, especially for obese individuals exposed to these contaminants. - Highlights: • The contamination of drinking water with drugs may have harmful effects on health. • Some drugs can be more hepatotoxic in the context of obesity and fatty liver. • Effects of chronic exposure of trace drugs were studied in lean and obese mouse liver. Drugs and obesity present additive effects on circadian gene expression and toxicity. • Trace pharmaceuticals could

  14. Neither Primary nor Memory Immunity to Mycobacterium tuberculosis Infection Is Compromised in Mice with Chronic Enteric Helminth Infection

    Science.gov (United States)

    Rafi, Wasiulla; Bhatt, Kamlesh; Gause, William C.

    2015-01-01

    Previously we had reported that Nippostrongylus brasiliensis, a helminth with a lung migratory phase, affected host resistance against Mycobacterium tuberculosis infection through the induction of alternatively activated (M2) macrophages. Several helminth species do not have an obligatory lung migratory phase but establish chronic infections in the host that include potent immune downregulatory effects, in part mediated through induction of a FoxP3+ T regulatory cell (Treg) response. Treg cells exhibit duality in their functions in host defense against M. tuberculosis infection since their depletion leads to enhanced priming of T cells in the lymph nodes and attendant improved control of M. tuberculosis infection, while their presence in the lung granuloma protects against excessive inflammation. Heligmosomoides polygyrus is a strictly murine enteric nematode that induces a strong FoxP3 Treg response in the host. Therefore, in this study we investigated whether host immunity to M. tuberculosis infection would be modulated in mice with chronic H. polygyrus infection. We report that neither primary nor memory immunity conferred by Mycobacterium bovis BCG vaccination was affected in mice with chronic enteric helminth infection, despite a systemic increase in FoxP3+ T regulatory cells. The findings indicate that anti-M. tuberculosis immunity is not similarly affected by all helminth species and highlight the need to consider this inequality in human coinfection studies. PMID:25605766

  15. Induction of cytogenetic damages by combined action of heavy metal salts, chronic and acute γ-radiation in bone marrow cells of mice and rats

    International Nuclear Information System (INIS)

    The combined action of salts of heavy metals (lead and cadmium), and acute and chronic γ-irradiation on chromosomal aberrations in bone marrow cells of rats and mice is investigated. The dependence of formation of the cytogenetic radiation adaptive response (RAR) induced by chronic γ-irradiation in bone marrow of mice and rats on the adaptive dose is studied. RAR is observed for all doses of chronic irradiation while the adaptive dose of 40 cGy is the most effective for rats and the most effective adaptive dose for mice is 50 cGy. The salts of heavy metals Pb(CH3COO)2 and CdCl2 supplemented to the diet of rats RAR induced by chronic γ-irradiation

  16. Effects of chronic estrogen treatment on modulating age-related bone loss in female mice.

    Science.gov (United States)

    Syed, Farhan A; Mödder, Ulrike Il; Roforth, Matthew; Hensen, Ira; Fraser, Daniel G; Peterson, James M; Oursler, Merry Jo; Khosla, Sundeep

    2010-11-01

    While female mice do not have the equivalent of a menopause, they do undergo reproductive senescence. Thus, to dissociate the effects of aging versus estrogen deficiency on age-related bone loss, we sham-operated, ovariectomized, or ovariectomized and estrogen-replaced female C57/BL6 mice at 6 months of age and followed them to age 18 to 22 months. Lumbar spines and femurs were excised for analysis, and bone marrow hematopoietic lineage negative (lin-) cells (enriched for osteoprogenitor cells) were isolated for gene expression studies. Six-month-old intact control mice were euthanized to define baseline parameters. Compared with young mice, aged/sham-operated mice had a 42% reduction in lumbar spine bone volume/total volume (BV/TV), and maintaining constant estrogen levels over life in ovariectomized/estrogen-treated mice did not prevent age-related trabecular bone loss at this site. By contrast, lifelong estrogen treatment of ovariectomized mice completely prevented the age-related reduction in cortical volumetric bone mineral density (vBMD) and thickness at the tibial diaphysis present in the aged/sham-operated mice. As compared with cells from young mice, lin- cells from aged/sham-operated mice expressed significantly higher mRNA levels for osteoblast differentiation and proliferation marker genes. These data thus demonstrate that, in mice, age-related loss of cortical bone in the appendicular skeleton, but not loss of trabecular bone in the spine, can be prevented by maintaining constant estrogen levels over life. The observed increase in osteoblastic differentiation and proliferation marker gene expression in progenitor bone marrow cells from aged versus young mice may represent a compensatory mechanism in response to ongoing bone loss. PMID:20499336

  17. Chronic alcohol-induced microRNA-155 contributes to neuroinflammation in a TLR4-dependent manner in mice.

    Directory of Open Access Journals (Sweden)

    Dora Lippai

    Full Text Available INTRODUCTION: Alcohol-induced neuroinflammation is mediated by pro-inflammatory cytokines and chemokines including tumor necrosis factor-α (TNFα, monocyte chemotactic protein-1 (MCP1 and interleukin-1-beta (IL-1β. Toll-like receptor-4 (TLR4 pathway induced nuclear factor-κB (NF-κB activation is involved in the pathogenesis of alcohol-induced neuroinflammation. Inflammation is a highly regulated process. Recent studies suggest that microRNAs (miRNAs play crucial role in fine tuning gene expression and miR-155 is a major regulator of inflammation in immune cells after TLR stimulation. AIM: To evaluate the role of miR-155 in the pathogenesis of alcohol-induced neuroinflammation. METHODS: Wild type (WT, miR-155- and TLR4-knockout (KO mice received 5% ethanol-containing or isocaloric control diet for 5 weeks. Microglia markers were measured by q-RTPCR; inflammasome activation was measured by enzyme activity; TNFα, MCP1, IL-1β mRNA and protein were measured by q-RTPCR and ELISA; phospho-p65 protein and NF-κB were measured by Western-blotting and EMSA; miRNAs were measured by q-PCR in the cerebellum. MiR-155 was measured in immortalized and primary mouse microglia after lipopolysaccharide and ethanol stimulation. RESULTS: Chronic ethanol feeding up-regulated miR-155 and miR-132 expression in mouse cerebellum. Deficiency in miR-155 protected mice from alcohol-induced increase in inflammatory cytokines; TNFα, MCP1 protein and TNFα, MCP1, pro-IL-1β and pro-caspase-1 mRNA levels were reduced in miR-155 KO alcohol-fed mice. NF-κB was activated in WT but not in miR-155 KO alcohol-fed mice. However increases in cerebellar caspase-1 activity and IL-1β levels were similar in alcohol-fed miR-155-KO and WT mice. Alcohol-fed TLR4-KO mice were protected from the induction of miR-155. NF-κB activation measured by phosphorylation of p65 and neuroinflammation were reduced in alcohol-fed TLR4-KO compared to control mice. TLR4 stimulation with

  18. The role of fluoxetine on macrophage function in chronic pain (Experimental study in Balb/c mice

    Directory of Open Access Journals (Sweden)

    Dwi Pudjonarko

    2015-11-01

    Full Text Available Chronic pain raises stress conditions such as depression that can lower the cellular immunity. Fluoxetine is an antidepressant  used as an adjuvant in pain management but no one has been linked it with the body immune system. The objectives of this research were to proof the benefits of fluoxetine in  preventing degradation of macrophage function in chronic pain by measuring the macrophage phagocytic index , macrophage NO levels and the liver bacterial count in BALB/c mice infected with Listeria Monocytogenes.A Post Test - Only Control Group Design was conducted using 28 male mice strain BALB /c, age 8-10 weeks. The control group (C, mice got the same standard feed as the other groups. Chronic pain group (P, mice were injected with 20μL intraplantar CFA on day-1. Pain + fluoxetine early group (PFE were treated with P + fluoxetine 5 mg / kg ip day-1, the 4th, the 7th and the 10th, while the Pain + fluoxetine late group (PFL were treated with P + fluoxetine 5 mg / kg ip on day 7th and 10th. All mice were injected with 104 live Listeria monocytogenes iv on day 8th. Termination was performed on day 13th. Differences within groups  were analyzed using  One-way ANOVA and Kruskall Wallis, whereas the correlation of variables were analyzed using  Pearson's product moment. The experimental results showed that The macrophage phagocytic index and NO macrophage level (pg/mL in PFE group(2,24±1,013; 0,24±0,239 was higher than than P group (1,68±0,920; 0,21±0,263 and there was no different in the macrophage phagocytic index of PFE group compared to C group (p=0,583; p=0,805. In PFL group (4,32±1,459; 0,54±0,294 the macrophage phagocytic index as well as NO macrophage level (pg/mL was higher than P group (1,68±0,920; 0,21±0,263 with p=0,002; p=0,017. P group Bacterial count (log cfu/gram (2,30±0,849 was significantly higher than C group(1,15±0,223 (p=0,007, while PFE group bacterial count (1,96±0,653 and PFL group bacterial count (1,84±0

  19. Chronic Protein Restriction in Mice Impacts Placental Function and Maternal Body Weight before Fetal Growth.

    Directory of Open Access Journals (Sweden)

    Paula N Gonzalez

    Full Text Available Mechanisms of resource allocation are essential for maternal and fetal survival, particularly when the availability of nutrients is limited. We investigated the responses of feto-placental development to maternal chronic protein malnutrition to test the hypothesis that maternal low protein diet produces differential growth restriction of placental and fetal tissues, and adaptive changes in the placenta that may mitigate impacts on fetal growth. C57BL/6J female mice were fed either a low-protein diet (6% protein or control isocaloric diet (20% protein. On embryonic days E10.5, 17.5 and 18.5 tissue samples were prepared for morphometric, histological and quantitative RT-PCR analyses, which included markers of trophoblast cell subtypes. Potential endocrine adaptations were assessed by the expression of Prolactin-related hormone genes. In the low protein group, placenta weight was significantly lower at E10.5, followed by reduction of maternal weight at E17.5, while the fetuses became significantly lighter no earlier than at E18.5. Fetal head at E18.5 in the low protein group, though smaller than controls, was larger than expected for body size. The relative size and shape of the cranial vault and the flexion of the cranial base was affected by E17.5 and more severely by E18.5. The junctional zone, a placenta layer rich in endocrine and energy storing glycogen cells, was smaller in low protein placentas as well as the expression of Pcdh12, a marker of glycogen trophoblast cells. Placental hormone gene Prl3a1 was altered in response to low protein diet: expression was elevated at E17.5 when fetuses were still growing normally, but dropped sharply by E18.5 in parallel with the slowing of fetal growth. This model suggests that nutrients are preferentially allocated to sustain fetal and brain growth and suggests the placenta as a nutrient sensor in early gestation with a role in mitigating impacts of poor maternal nutrition on fetal growth.

  20. Chronic Protein Restriction in Mice Impacts Placental Function and Maternal Body Weight before Fetal Growth

    Science.gov (United States)

    Barbeito-Andrés, Jimena; Klenin, Natasha; Cross, James C.; Hallgrímsson, Benedikt

    2016-01-01

    Mechanisms of resource allocation are essential for maternal and fetal survival, particularly when the availability of nutrients is limited. We investigated the responses of feto-placental development to maternal chronic protein malnutrition to test the hypothesis that maternal low protein diet produces differential growth restriction of placental and fetal tissues, and adaptive changes in the placenta that may mitigate impacts on fetal growth. C57BL/6J female mice were fed either a low-protein diet (6% protein) or control isocaloric diet (20% protein). On embryonic days E10.5, 17.5 and 18.5 tissue samples were prepared for morphometric, histological and quantitative RT-PCR analyses, which included markers of trophoblast cell subtypes. Potential endocrine adaptations were assessed by the expression of Prolactin-related hormone genes. In the low protein group, placenta weight was significantly lower at E10.5, followed by reduction of maternal weight at E17.5, while the fetuses became significantly lighter no earlier than at E18.5. Fetal head at E18.5 in the low protein group, though smaller than controls, was larger than expected for body size. The relative size and shape of the cranial vault and the flexion of the cranial base was affected by E17.5 and more severely by E18.5. The junctional zone, a placenta layer rich in endocrine and energy storing glycogen cells, was smaller in low protein placentas as well as the expression of Pcdh12, a marker of glycogen trophoblast cells. Placental hormone gene Prl3a1 was altered in response to low protein diet: expression was elevated at E17.5 when fetuses were still growing normally, but dropped sharply by E18.5 in parallel with the slowing of fetal growth. This model suggests that nutrients are preferentially allocated to sustain fetal and brain growth and suggests the placenta as a nutrient sensor in early gestation with a role in mitigating impacts of poor maternal nutrition on fetal growth. PMID:27018791

  1. Effect of Shenxinning decoction on ventricular remodeling in AT1 receptor-knockout mice with chronic renal insufficiency

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    Xuejun Yang

    2014-01-01

    Full Text Available Objective: To observe the efficacy of Shenxinning Decoction (SXND in ventricular remodeling in AT1 receptor-knockout (AT1-KO mice with chronic renal insufficiency (CRI. Materials and Methods: AT1-KO mice modeled with subtotal (5/6 nephrectomy were intervened with SXND for 12 weeks. Subsequently, blood urea nitrogen (BUN, serum creatinine (SCr, brain natriuretic peptide (BNP, echocardiography (left ventricular end-diastolic diameter, LVDD; left ventricular end-systolic diameter, LVDS; fractional shortening, FS; and ejection fraction, EF, collagen types I and III in the heart and kidney, myocardial mitochondria, and cardiac transforming growth factor-β1 (TGF-β1 of the AT1-KO mice were compared with the same model with nephrectomy only and untreated with SXND. Results: AT1-KO mice did not affect the process of CRI but it could significantly affect cardiac remodeling process. SXND decreased to some extent the AT1-KO mice′s BUN, SCr, BNP, and cardiac LVDD, LVDS, and BNP, improved FS and EF, lowered the expression of collagen type I and III in heart and kidney, increased the quantity of mitochondria and ameliorated their structure, and down-regulated the expression of TGF-β1. Conclusion: SXND may antagonize the renin-angiotensin system (RAS and decrease uremia toxins, thereby ameliorating ventricular remodeling in CRI. Furthermore, SXND has a mechanism correlated with the improvement of myocardial energy metabolism and the down-regulation of TGF-β1.

  2. Decreased expression of extracellular matrix proteins and trophic factors in the amygdala complex of depressed mice after chronic immobilization stress

    Directory of Open Access Journals (Sweden)

    Jung Soonwoong

    2012-06-01

    Full Text Available Abstract Background The amygdala plays an essential role in controlling emotional behaviors and has numerous connections to other brain regions. The functional role of the amygdala has been highlighted by various studies of stress-induced behavioral changes. Here we investigated gene expression changes in the amygdala in the chronic immobilization stress (CIS-induced depression model. Results Eight genes were decreased in the amygdala of CIS mice, including genes for neurotrophic factors and extracellular matrix proteins. Among these, osteoglycin, fibromodulin, insulin-like growth factor 2 (Igf2, and insulin-like growth factor binding protein 2 (Igfbp2 were further analyzed for histological expression changes. The expression of osteoglycin and fibromodulin simultaneously decreased in the medial, basolateral, and central amygdala regions. However, Igf2 and Igfbp2 decreased specifically in the central nucleus of the amygdala. Interestingly, this decrease was found only in the amygdala of mice showing higher immobility, but not in mice displaying lower immobility, although the CIS regimen was the same for both groups. Conclusions These results suggest that the responsiveness of the amygdala may play a role in the sensitivity of CIS-induced behavioral changes in mice.

  3. Frontal cortical mitochondrial dysfunction and mitochondria-related β-amyloid accumulation by chronic sleep restriction in mice.

    Science.gov (United States)

    Zhao, Hongyi; Wu, Huijuan; He, Jialin; Zhuang, Jianhua; Liu, Zhenyu; Yang, Yang; Huang, Liuqing; Zhao, Zhongxin

    2016-08-17

    Mitochondrial dysfunction induced by mitochondria-related β-amyloid (Aβ) accumulation is increasingly being considered a novel risk factor for sporadic Alzheimer's disease pathophysiology. The close relationship between chronic sleep restriction (CSR) and cortical Aβ elevation was confirmed recently. By assessing frontal cortical mitochondrial function (electron microscopy manifestation, cytochrome C oxidase concentration, ATP level, and mitochondrial membrane potential) and the levels of mitochondria-related Aβ in 9-month-old adult male C57BL/6J mice subjected to CSR and as an environmental control (CO) group, we aimed to evaluate the association of CSR with mitochondrial dysfunction and mitochondria-related Aβ accumulation. In this study, frontal cortical mitochondrial dysfunction was significantly more severe in CSR mice compared with CO animals. Furthermore, CSR mice showed higher mitochondria-associated Aβ, total Aβ, and mitochondria-related β-amyloid protein precursor (AβPP) levels compared with CO mice. In the CSR model, mouse frontal cortical mitochondrial dysfunction was correlated with mitochondria-associated Aβ and mitochondria-related AβPP levels. However, frontal cortical mitochondria-associated Aβ levels showed no significant association with cortical total Aβ and mitochondrial AβPP concentrations. These findings indicated that CSR-induced frontal cortical mitochondrial dysfunction and mitochondria-related Aβ accumulation, which was closely related to mitochondrial dysfunction under CSR. PMID:27341212

  4. The mouse as a model for understanding chronic diseases of aging: the histopathologic basis of aging in inbred mice

    Directory of Open Access Journals (Sweden)

    David Harrison

    2011-06-01

    Full Text Available Inbred mice provide a unique tool to study aging populations because of the genetic homogeneity within an inbred strain, their short life span, and the tools for analysis which are available. A large-scale longitudinal and cross-sectional aging study was conducted on 30 inbred strains to determine, using histopathology, the type and diversity of diseases mice develop as they age. These data provide tools that when linked with modern in silico genetic mapping tools, can begin to unravel the complex genetics of many of the common chronic diseases associated with aging in humans and other mammals. In addition, novel disease models were discovered in some strains, such as rhabdomyosarcoma in old A/J mice, to diseases affecting many but not all strains including pseudoxanthoma elasticum, pulmonary adenoma, alopecia areata, and many others. This extensive data set is now available online and provides a useful tool to help better understand strain-specific background diseases that can complicate interpretation of genetically engineered mice and other manipulatable mouse studies that utilize these strains.

  5. 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.

  6. Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice

    OpenAIRE

    Rajashekhar, Gangaraju; Gupta, Akanksha; Marin, Abby; Friedrich, Jessica; Willuweit, Antje; Berg, David T.; Cramer, Martin S.; Sandusky, George E.; Sutton, Timothy A.; Basile, David P.; Grinnell, Brian W.; Clauss, Matthias

    2011-01-01

    Chronic kidney disease pathogenesis involves both tubular and vascular injuries. Despite abundant investigations to identify the risk factors, the involvement of chronic endothelial dysfunction in developing nephropathies is insufficiently explored. Previously, soluble thrombomodulin (sTM), a cofactor in the activation of protein C, has been shown to protect endothelial function in models of acute kidney injury. In this study, the role for sTM in treating chronic kidney disease was explored b...

  7. Persistent virus infection despite chronic cytotoxic T-lymphocyte activation in gamma interferon-deficient mice infected with lymphocytic choriomeningitis virus

    DEFF Research Database (Denmark)

    Bartholdy, C; Christensen, Jan Pravsgaard; Wodarz, D;

    2000-01-01

    The role of gamma interferon (IFN-gamma) in the permanent control of infection with a noncytopathic virus was studied by comparing immune responses in wild-type and IFN-gamma-deficient (IFN-gamma -/-) mice infected with a slowly invasive strain of lymphocytic choriomeningitis virus (LCMV Armstrong......). While wild-type mice rapidly cleared the infection, IFN-gamma -/- mice became chronically infected. Virus persistence in the latter mice did not reflect failure to generate cytotoxic T-lymphocyte (CTL) effectors, as an unimpaired primary CTL response was observed. Furthermore, while ex vivo CTL activity...

  8. Synergistic Effects of Celecoxib and Bupropion in a Model of Chronic Inflammation-Related Depression in Mice

    OpenAIRE

    Maciel, Izaque S; Silva, Rodrigo B. M.; Morrone, Fernanda B; João B Calixto; Campos, Maria M

    2013-01-01

    This study was aimed to characterize the depression-like behaviour in the classical model of chronic inflammation induced by Complete Freund's Adjuvant (CFA). Male Swiss mice received an intraplantar (i.pl.) injection of CFA (50 µl/paw) or vehicle. Behavioural and inflammatory responses were measured at different time-points (1 to 4 weeks), and different pharmacological tools were tested. The brain levels of IL-1β and BDNF, or COX-2 expression were also determined. CFA elicited a time-depende...

  9. Neutralisation of interleukin-13 in mice prevents airway pathology caused by chronic exposure to house dust mite.

    Directory of Open Access Journals (Sweden)

    Kate L Tomlinson

    Full Text Available BACKGROUND: Repeated exposure to inhaled allergen can cause airway inflammation, remodeling and dysfunction that manifests as the symptoms of allergic asthma. We have investigated the role of the cytokine interleukin-13 (IL-13 in the generation and persistence of airway cellular inflammation, bronchial remodeling and deterioration in airway function in a model of allergic asthma caused by chronic exposure to the aeroallergen House Dust Mite (HDM. METHODOLOGY/PRINCIPAL FINDINGS: Mice were exposed to HDM via the intranasal route for 4 consecutive days per week for up to 8 consecutive weeks. Mice were treated either prophylactically or therapeutically with a potent neutralising anti-IL-13 monoclonal antibody (mAb administered subcutaneously (s.c.. Airway cellular inflammation was assessed by flow cytometry, peribronchial collagen deposition by histocytochemistry and airway hyperreactivity (AHR by invasive measurement of lung resistance (R(L and dynamic compliance (C(dyn. Both prophylactic and therapeutic treatment with an anti-IL-13 mAb significantly inhibited (P<0.05 the generation and maintenance of chronic HDM-induced airway cellular inflammation, peribronchial collagen deposition, epithelial goblet cell upregulation. AHR to inhaled methacholine was reversed by prophylactic but not therapeutic treatment with anti-IL-13 mAb. Both prophylactic and therapeutic treatment with anti-IL-13 mAb significantly reversed (P<0.05 the increase in baseline R(L and the decrease in baseline C(dyn caused by chronic exposure to inhaled HDM. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that in a model of allergic lung disease driven by chronic exposure to a clinically relevant aeroallergen, IL-13 plays a significant role in the generation and persistence of airway inflammation, remodeling and dysfunction.

  10. Effect of chronic social defeat stress on behaviors and dopamine receptor in adult mice.

    Science.gov (United States)

    Huang, Guang-Biao; Zhao, Tong; Gao, Xiao-Lei; Zhang, Hong-Xing; Xu, Yu-Ming; Li, Hao; Lv, Lu-Xian

    2016-04-01

    Victims of bullying often undergo depression, low self-esteem, high anxiety and post-traumatic stress disorder symptoms. The social defeat model has become widely accepted for studying experimental animal behavior changes associated with bullying; however, differences in the effects in susceptible and unsusceptible individuals have not been well studied. The present study investigated the effects of social defeat stress on behavior and the expression of dopamine receptors D1 and D2 in the brains of adult mice. Adult mice were divided into susceptible and unsusceptible groups after 10days of social defeat stress. Behavioral tests were conducted, and protein levels in the brains were assessed by Western blotting. The results indicate that all mice undergo decreased locomotion and increased anxiety behavior. However, decreased social interaction and impaired memory performance were only observed in susceptible mice. A significantly decreased expression of D1 was observed in the prefrontal cortex and amygdala of susceptible mice only. No significant differences in D2 expression were shown between control and defeated mice in any area studied. These data indicate that depression-like behavior and cognition impairment caused by social defeat stress in susceptible mice may be related to changes in the dopamine receptor D1. PMID:26655446

  11. Chronic intermittent fasting improves cognitive functions and brain structures in mice.

    Directory of Open Access Journals (Sweden)

    Liaoliao Li

    Full Text Available Obesity is a major health issue. Obesity started from teenagers has become a major health concern in recent years. Intermittent fasting increases the life span. However, it is not known whether obesity and intermittent fasting affect brain functions and structures before brain aging. Here, we subjected 7-week old CD-1 wild type male mice to intermittent (alternate-day fasting or high fat diet (45% caloric supplied by fat for 11 months. Mice on intermittent fasting had better learning and memory assessed by the Barnes maze and fear conditioning, thicker CA1 pyramidal cell layer, higher expression of drebrin, a dendritic protein, and lower oxidative stress than mice that had free access to regular diet (control mice. Mice fed with high fat diet was obese and with hyperlipidemia. They also had poorer exercise tolerance. However, these obese mice did not present significant learning and memory impairment or changes in brain structures or oxidative stress compared with control mice. These results suggest that intermittent fasting improves brain functions and structures and that high fat diet feeding started early in life does not cause significant changes in brain functions and structures in obese middle-aged animals.

  12. Chronic treatment with bark infusion from Croton cajucara lowers plasma triglyceride levels in genetic hyperlipidemic mice.

    Science.gov (United States)

    Bighetti, Eliete J B; Souza-Brito, Alba R M; de Faria, Eliana C; Oliveira, Helena C F

    2004-06-01

    Aqueous infusion and preparations containing dehydrocrotonin (DHC) and essential oil from Croton cajucara bark were tested for plasma lipid-lowering effects in genetically modified hyperlipidemic mice. Two mouse models were tested: 1) primary hypercholesterolemia resulting from the LDL-receptor gene knockout, and 2) combined hyperlipidemia resulting from crosses of LDL-receptor knockout mice with transgenic mice overexpressing apolipo protein (apo) CIII and cholesteryl ester-transfer protein. Mice treated with bark infusion, DHC, essential oil, or placebos for 25 days showed no signals of toxicity as judged by biochemical tests for liver and kidney functions. The bark infusion reduced triglyceride plasma levels by 40%, while essential oil and DHC had no significant effects on plasma lipid levels. The bark infusion treatment promoted a redistribution of cholesterol among the lipoprotein fractions in combined hyperlipidemic mice. There was a marked reduction in the VLDL fraction and an increase in the HDL fraction, in such a way that the (VLDL + LDL)/HDL ratio was reduced by half. The bark infusion treatment did not modify cholesterol distribution in hypercholesterolemic mice. In conclusion, C. cajucara bark infusion reduced plasma triglycerides levels and promoted a redistribution of cholesterol among lipoproteins in genetically combined hyperlipidemic mice. These changes modify risk factors for the development of atherosclerotic diseases. PMID:15381962

  13. Gene Expression Profiling in Lungs of Chronic Asthmatic Mice Treated with Galectin-3: Downregulation of Inflammatory and Regulatory Genes

    Directory of Open Access Journals (Sweden)

    Esther López

    2011-01-01

    Full Text Available Background. Asthma is a disorder characterized by a predominance of Th2 cells and eosinophilic inflammation. Suppressors of cytokine signaling (SOCS proteins act as negative regulators of cytokine signaling. In particular, SOCS1 and SOCS3 play an important role in immune response by controlling the balance between Th1 and Th2 cells. In a previous study, we demonstrated that treatment of chronic asthmatic mice with gene therapy using plasmid encoding galectin-3 (Gal-3 led to an improvement in Th2 allergic inflammation. Methods. Using a microarray approach, this study endeavored to evaluate the changes produced by therapeutic Gal-3 delivered by gene therapy in a well-characterized mouse model of chronic airway inflammation. Results were confirmed by real-time RT-PCR, Western blot and immunohistochemical analysis. Results. We identify a set of genes involved in different pathways whose expression is coordinately decreased/increased in mice treated with Gal-3 gene therapy. We report a correlation between Gal-3 treatment and inhibition of SOCS1 and SOCS3 expression in lungs. Conclusion. These results suggest that negative regulation of SOCS1 and 3 following Gal-3 treatment could be a valuable therapeutic approach in allergic disease.

  14. Removal of high-fat diet after chronic exposure drives binge behavior and dopaminergic dysregulation in female mice.

    Science.gov (United States)

    Carlin, Jesse L; McKee, Sarah E; Hill-Smith, Tiffany; Grissom, Nicola M; George, Robert; Lucki, Irwin; Reyes, Teresa M

    2016-06-21

    A significant contributor to the obesity epidemic is the overconsumption of highly palatable, energy dense foods. Chronic intake of palatable foods is associated with neuroadaptations within the mesocorticolimbic dopamine system adaptations which may lead to behavioral changes, such as overconsumption or bingeing. We examined behavioral and molecular outcomes in mice that were given chronic exposure to a high-fat diet (HFD; 12weeks), with the onset of the diet either in adolescence or adulthood. To examine whether observed effects could be reversed upon removal of the HFD, animals were also studied 4weeks after a return to chow feeding. Most notably, female mice, particularly those exposed to HFD starting in adolescence, demonstrated the emergence of binge-like behavior when given restricted access to a palatable food. Further, changes in dopamine-related gene expression and dopamine content in the prefrontal cortex were observed. Some of these HFD-driven phenotypes reversed upon removal of the diet, whereas others were initiated by removal of the diet. These findings have implications for obesity management and interventions, as both pharmacological and behavioral therapies are often combined with dietary interventions (e.g., reduction in calorie dense foods). PMID:27063418

  15. Bone marrow-derived microglia infiltrate into the paraventricular nucleus of chronic psychological stress-loaded mice.

    Directory of Open Access Journals (Sweden)

    Koji Ataka

    Full Text Available BACKGROUND: Microglia of the central nervous system act as sentinels and rapidly react to infection or inflammation. The pathophysiological role of bone marrow-derived microglia is of particular interest because they affect neurodegenerative disorders and neuropathic pain. The hypothesis of the current study is that chronic psychological stress (chronic PS induces the infiltration of bone marrow-derived microglia into hypothalamus by means of chemokine axes in brain and bone marrow. METHODS AND FINDINGS: Here we show that bone marrow-derived microglia specifically infiltrate the paraventricular nucleus (PVN of mice that received chronic PS. Bone marrow derived-microglia are CX3CR1(lowCCR2(+CXCR4(high, as distinct from CX3CR1(highCCR2(-CXCR4(low resident microglia, and express higher levels of interleukin-1β (IL-1β but lower levels of tumor necrosis factor-α (TNF-α. Chronic PS stimulates the expression of monocyte chemotactic protein-1 (MCP-1 in PVN neurons, reduces stromal cell-derived factor-1 (SDF-1 in the bone marrow and increases the frequency of CXCR4(+ monocytes in peripheral circulation. And then a chemokine (C-C motif receptor 2 (CCR2 or a β3-adrenoceptor blockade prevents infiltration of bone marrow-derived microglia in the PVN. CONCLUSION: Chronic PS induces the infiltration of bone marrow-derived microglia into PVN, and it is conceivable that the MCP-1/CCR2 axis in PVN and the SDF-1/CXCR4 axis in bone marrow are involved in this mechanism.

  16. Chronic Exposure to Rifaximin Causes Hepatic Steatosis in Pregnane X Receptor-Humanized Mice

    OpenAIRE

    Cheng, Jie; Krausz, Kristopher W.; Tanaka, Naoki; Gonzalez, Frank, J.

    2012-01-01

    Rifaximin, a nonsystemic antibiotic that exhibits low gastrointestinal absorption, is a potent agonist of human pregnane X receptor (PXR), which contributes to its therapeutic efficacy in inflammatory bowel disease. To investigate the effects of long-term administration of rifaximin on the liver, PXR-humanized mice were administered rifaximin for 6 months; wild-type and Pxr-null mice were treated in parallel as controls. Histological analysis revealed time-dependent intense hepatocellular fat...

  17. Effects of Chronic Restraint Stress on Body Weight, Food Intake, and Hypothalamic Gene Expressions in Mice

    OpenAIRE

    Jeong, Joo Yeon; Lee, Dong Hoon; Kang, Sang Soo

    2013-01-01

    Background Stress affects body weight and food intake, but the underlying mechanisms are not well understood. Methods We evaluated the changes in body weight and food intake of ICR male mice subjected to daily 2 hours restraint stress for 15 days. Hypothalamic gene expression profiling was analyzed by cDNA microarray. Results Daily body weight and food intake measurements revealed that both parameters decreased rapidly after initiating daily restraint stress. Body weights of stressed mice the...

  18. Immune Responses of Specific-Pathogen-Free Mice to Chronic Helicobacter pylori (Strain SS1) Infection

    OpenAIRE

    Ferrero, Richard L.; Thiberge, Jean-Michel; Huerre, Michel; Labigne, Agnès

    1998-01-01

    A model permitting the establishment of persistent Helicobacter pylori infection in mice was recently described. To evaluate murine immune responses to H. pylori infection, specific-pathogen-free Swiss mice (n = 50) were intragastrically inoculated with 1.2 × 107 CFU of a mouse-adapted H. pylori isolate (strain SS1). Control animals (n = 10) received sterile broth medium alone. Animals were sacrificed at various times, from 3 days to 16 weeks postinoculation (p.i.). Quantitative culture of ga...

  19. Differential spirochetal infectivities to vector ticks of mice chronically infected by the agent of Lyme disease.

    OpenAIRE

    Shih, C M; L. P. LIU; Spielman, A.

    1995-01-01

    We determined whether the infectivity of the Lyme disease spirochete (Borrelia burgdorferi) to vector ticks varies with the duration of infection in laboratory mice. Thus, noninfected nymphal deer ticks were permitted to feed on two strains of early (2 months after infection) and late (8 months after infection) spirochete-infected mice. The attached ticks were removed from their hosts at specified time intervals and were thereafter examined for spirochetes by direct immunofluorescence microsc...

  20. Chronic low-dose UVA irradiation induces local suppression of contact hypersensitivity, Langerhans cell depletion and suppressor cell activation in C3H/HeJ mice

    International Nuclear Information System (INIS)

    It has previously been demonstrated that chronic low-dose solar-simulated UV radiation could induce both local and systemic immunosuppression as well as tolerance to a topically applied hapten. In this study, we have used a chronic low-dose UV-irradiation protocol to investigate the effects of UVA on the skin immune system of C3H/HeJ mice. Irradiation with UVA+B significantly suppressed the local and systemic primary contact hypersensitivity (CHS) response to the hapten 2,4,6-trinitrochlorobenzene. Furthermore, UVA+B reduced Langerhans cell (LC) and dendritic epidermal T cell (DETC) densities in chronically UV-irradiated mice. Ultraviolet A irradiation induced local, but not systemic, immunosuppression and reduced LC (32%) but not DETC from the epidermis compared to the shaved control animals. Treatment of mice with both UVA+B and UVA radiation also induced an impaired secondary CHS response, and this tolerance was transferable with spleen cells. (Author)

  1. Social isolation-induced aggression potentiates anxiety and depressive-like behavior in male mice subjected to unpredictable chronic mild stress.

    Directory of Open Access Journals (Sweden)

    Xian-cang Ma

    Full Text Available BACKGROUND: Accumulating epidemiological evidence shows that life event stressors are major vulnerability factors for psychiatric diseases such as major depression. It is also well known that social isolation in male mice results in aggressive behavior. However, it is not known how social isolation-induced aggression affects anxiety and depressive-like behavior in isolated male mice subjected to unpredictable chronic mild stress (CMS, an animal model of depression. METHODOLOGY/PRINCIPAL FINDINGS: C57/B6 male mice were divided into 3 groups; non-stressed controls, in Group I; isolated mice subjected to the CMS protocol in Group II and aggression by physical contact in socially isolated mice subjected to the CMS protocol in Group III. In the sucrose intake test, ingestion of a 1% sucrose solution by mice in Groups II and III was significantly lower than in Group I. Furthermore, intake of this solution in Group III mice was significantly lower than in Group II mice. In the open field test, mice in Group III, showed reduced locomotor activity and reduced entry and retention time in the central zone, compared to Groups I and II mice. Moreover, the distances moved in 1 hour by Group III mice did not differ between night and morning. In the light/black box test, Groups II and III animals spent significantly less time in the light box compared to Group I animals. In the tail suspension test (TST and forced swimming test (FST, the immobility times of Group II and Group III mice were significantly longer than in Group I mice. In addition, immobility times in the FST were significantly longer in Group III than in Group II mice. CONCLUSIONS/SIGNIFICANCE: These findings show that social isolation-induced aggression could potentiate anxiety and depressive-like behaviors in isolated male mice subjected to CMS.

  2. Development of asthmatic inflammation in mice following early-life exposure to ambient environmental particulates and chronic allergen challenge

    Directory of Open Access Journals (Sweden)

    Cristan Herbert

    2013-03-01

    Childhood exposure to environmental particulates increases the risk of development of asthma. The underlying mechanisms might include oxidant injury to airway epithelial cells (AEC. We investigated the ability of ambient environmental particulates to contribute to sensitization via the airways, and thus to the pathogenesis of childhood asthma. To do so, we devised a novel model in which weanling BALB/c mice were exposed to both ambient particulate pollutants and ovalbumin for sensitization via the respiratory tract, followed by chronic inhalational challenge with a low mass concentration of the antigen. We also examined whether these particulates caused oxidant injury and activation of AEC in vitro. Furthermore, we assessed the potential benefit of minimizing oxidative stress to AEC through the period of sensitization and challenge by dietary intervention. We found that characteristic features of asthmatic inflammation developed only in animals that received particulates at the same time as respiratory sensitization, and were then chronically challenged with allergen. However, these animals did not develop airway hyper-responsiveness. Ambient particulates induced epithelial injury in vitro, with evidence of oxidative stress and production of both pro-inflammatory cytokines and Th2-promoting cytokines such as IL-33. Treatment of AEC with an antioxidant in vitro inhibited the pro-inflammatory cytokine response to these particulates. Ambient particulates also induced pro-inflammatory cytokine expression following administration to weanling mice. However, early-life dietary supplementation with antioxidants did not prevent the development of an asthmatic inflammatory response in animals that were exposed to particulates, sensitized and challenged. We conclude that injury to airway epithelium by ambient environmental particulates in early life is capable of promoting the development of an asthmatic inflammatory response in sensitized and antigen-challenged mice. These

  3. Pyranocoumarin Tissue Distribution, Plasma Metabolome and Prostate Transcriptome Impacts of Sub-Chronic Exposure to Korean Angelica Supplement in Mice.

    Science.gov (United States)

    Zhang, Jinhui; Li, Li; Tang, Suni; Zhang, Yong; Markiewski, Maciej; Xing, Chengguo; Jiang, Cheng; Lü, Junxuan

    2016-04-01

    Herbal products containing Korean Angelica gigas Nakai (AGN) root extract are marketed as dietary supplements for memory enhancement, pain killing, and female menopausal symptom relief. We have shown the anticancer activities of AGN supplements in mouse models. To facilitate human anticancer translational research, we characterized the tissue distribution of AGN marker pyranocoumarin compounds decursin (D) and decursinol angelate (DA) ([Formula: see text]% in AGN) and their metabolite decursinol (DOH), assessed the safety of sub-chronic AGN dietary exposure in mice, and explored its impact on plasma aqueous metabolites and the prostate transcriptome. The data show that after a gavage dose, plasma contained readily detectable DOH, but little D and DA, mirroring patterns in the liver. Extra-hepatic tissues retained greater levels of DA and D than the liver did. For sub-chronic exposures, male mice were provided ad libitum AIN93M-pellet diets with 0.5 and 1% AGN for six weeks. No adverse effects were observed on the plasma biochemistry markers of liver and kidney integrity in spite of their enlargement. Histopathological examinations of the liver, kidney and other visceral organs did not reveal tissue abnormalities. Metabolomic assessment of plasma from mice fed the 1%-AGN diet suggested metabolic shifts of key amino acids especially in the methionine-cysteine cycle, purine cycle, and glycolysis-citrate cycle. Prostate transcriptomic profiling identified gene signature changes in the metabolisms of drugs, lipids and cellular energetics, neuro-muscular features, immunity and inflammation, and tumor suppressor/oncogene balance. The safety profile was corroborated with a daily [Formula: see text] injection of AGN extract (100-300[Formula: see text]mg/kg) for four weeks, which resulted in much greater systemic pyranocoumarin exposure than the dietary route did. PMID:27080944

  4. In vivo evaluation of adeno-associated virus gene transfer in airways of mice with acute or chronic respiratory infection.

    Science.gov (United States)

    Myint, Melissa; Limberis, Maria P; Bell, Peter; Somanathan, Suryanarayan; Haczku, Angela; Wilson, James M; Diamond, Scott L

    2014-11-01

    Patients with cystic fibrosis (CF) often suffer chronic lung infection with concomitant inflammation, a setting that may reduce the efficacy of gene transfer. While gene therapy development for CF often involves viral-based vectors, little is known about gene transfer in the context of an infected airway. In this study, three mouse models were established to evaluate adeno-associated virus (AAV) gene transfer in such an environment. Bordetella bronchiseptica RB50 was used in a chronic, nonlethal respiratory infection in C57BL/6 mice. An inoculum of ∼10(5) CFU allowed B. bronchiseptica RB50 to persist in the upper and lower respiratory tracts for at least 21 days. In this infection model, administration of an AAV vector on day 2 resulted in 2.8-fold reduction of reporter gene expression compared with that observed in uninfected controls. Postponement of AAV administration to day 14 resulted in an even greater (eightfold) reduction of reporter gene expression, when compared with uninfected controls. In another infection model, Pseudomonas aeruginosa PAO1 was used to infect surfactant protein D (SP-D) or surfactant protein A (SP-A) knockout (KO) mice. With an inoculum of ∼10(5) CFU, infection persisted for 2 days in the nasal cavity of either mouse model. Reporter gene expression was approximately ∼2.5-fold lower compared with uninfected mice. In the SP-D KO model, postponement of AAV administration to day 9 postinfection resulted in only a two fold reduction in reporter gene expression, when compared with expression seen in uninfected controls. These results confirm that respiratory infections, both ongoing and recently resolved, decrease the efficacy of AAV-mediated gene transfer. PMID:25144316

  5. T1-mapping for assessment of ischemia-induced acute kidney injury and prediction of chronic kidney disease in mice

    International Nuclear Information System (INIS)

    To investigate whether T1-mapping allows assessment of acute kidney injury (AKI) and prediction of chronic kidney disease (CKD) in mice. AKI was induced in C57Bl/6N mice by clamping of the right renal pedicle for 35 min (moderate AKI, n = 26) or 45 min (severe AKI, n = 23). Sham animals served as controls (n = 9). Renal histology was assessed in the acute (day 1 + day 7; d1 + d7) and chronic phase (d28) after AKI. Furthermore, longitudinal MRI-examinations (prior to until d28 after surgery) were performed using a 7-Tesla magnet. T1-maps were calculated from a fat-saturated echoplanar inversion recovery sequence, and mean and relative T1-relaxation times were determined. Renal histology showed severe tubular injury at d1 + d7 in both AKI groups, whereas, at d28, only animals with prolonged 45-min ischemia showed persistent signs of AKI. Following both AKI severities T1-values significantly increased and peaked at d7. T1-times in the contralateral kidney without AKI remained stable. At d7 relative T1-values in the outer stripe of the outer medulla were significantly higher after severe than after moderate AKI (138 ± 2 % vs. 121 ± 3 %, p = 0.001). T1-elevation persisted until d28 only after severe AKI. Already at d7 T1 in the outer stripe of the outer medulla correlated with kidney volume loss indicating CKD (r = 0.83). T1-mapping non-invasively detects AKI severity in mice and predicts further outcome. (orig.)

  6. T1-mapping for assessment of ischemia-induced acute kidney injury and prediction of chronic kidney disease in mice

    Energy Technology Data Exchange (ETDEWEB)

    Hueper, Katja; Gutberlet, Marcel; Wacker, Frank; Hartung, Dagmar [Hannover Medical School, Department of Radiology, Hannover (Germany); Hannover Medical School, REBIRTH Cluster of Excellence, Hannover (Germany); Peperhove, Matti; Tewes, Susanne; Barrmeyer, Amelie [Hannover Medical School, Department of Radiology, Hannover (Germany); Rong, Song [Hannover Medical School, Department of Nephrology, Hannover (Germany); Zunyi Medical College, Laboratory of Organ Transplantation, Zunyi (China); Gerstenberg, Jessica; Haller, Herman; Gueler, Faikah [Hannover Medical School, Department of Nephrology, Hannover (Germany); Mengel, Michael [University of Alberta, Department of Laboratory Medicine and Pathology, Edmonton (Canada); Meier, Martin [Hannover Medical School, REBIRTH Cluster of Excellence, Hannover (Germany); Hannover Medical School, Institute for Animal Science, Hannover (Germany); Chen, Rongjun [Hannover Medical School, Department of Nephrology, Hannover (Germany); Zhejiang University, The Kidney Disease Center of the First Affiliated Hospital, Hangzhou (China)

    2014-09-15

    To investigate whether T1-mapping allows assessment of acute kidney injury (AKI) and prediction of chronic kidney disease (CKD) in mice. AKI was induced in C57Bl/6N mice by clamping of the right renal pedicle for 35 min (moderate AKI, n = 26) or 45 min (severe AKI, n = 23). Sham animals served as controls (n = 9). Renal histology was assessed in the acute (day 1 + day 7; d1 + d7) and chronic phase (d28) after AKI. Furthermore, longitudinal MRI-examinations (prior to until d28 after surgery) were performed using a 7-Tesla magnet. T1-maps were calculated from a fat-saturated echoplanar inversion recovery sequence, and mean and relative T1-relaxation times were determined. Renal histology showed severe tubular injury at d1 + d7 in both AKI groups, whereas, at d28, only animals with prolonged 45-min ischemia showed persistent signs of AKI. Following both AKI severities T1-values significantly increased and peaked at d7. T1-times in the contralateral kidney without AKI remained stable. At d7 relative T1-values in the outer stripe of the outer medulla were significantly higher after severe than after moderate AKI (138 ± 2 % vs. 121 ± 3 %, p = 0.001). T1-elevation persisted until d28 only after severe AKI. Already at d7 T1 in the outer stripe of the outer medulla correlated with kidney volume loss indicating CKD (r = 0.83). T1-mapping non-invasively detects AKI severity in mice and predicts further outcome. (orig.)

  7. Effects of several degrees of chronic social defeat stress on emotional and spatial memory in CD1 mice.

    Science.gov (United States)

    Monleón, Santiago; Duque, Aranzazu; Vinader-Caerols, Concepción

    2016-03-01

    In the present study, the effects of several degrees of CSDS (Chronic Social Defeat Stress) on emotional and spatial memory in mice were evaluated in separate experiments. Male CD1 mice were randomly assigned to four experimental groups (n=10-12) for each experiment: NS (non-stressed), S5, S10 and S20 (5, 10 and 20 sessions of CSDS, respectively). The S groups underwent the corresponding number of agonistic encounters (10min each) over a 20-day period. 24h after the last session of CSDS, mice performed the inhibitory avoidance (Experiment 1) or the Morris water maze test (Experiment 2). In both experiments, animals were also evaluated in the elevated plus maze for 5min to obtain complementary measures of locomotor activity and emotionality. The results showed that the highest degree of CSDS had impairing effects on inhibitory avoidance, while there were no significant differences between groups in the water maze. The S20 group exhibited higher anxiety levels in the elevated plus maze. No variations in locomotor activity were observed in any experiment. In conclusion, CSDS has a greater impact on emotional memory than on spatial memory. These negative effects of CSDS on memory do not seem to be secondary to the motor or emotional effects of stress. PMID:26679824

  8. Transplanted Bone Marrow Cells Repair Heart Tissue and Reduce Myocarditis in Chronic Chagasic Mice

    OpenAIRE

    MILENA B. P. SOARES; Lima, Ricardo S.; Rocha, Leonardo L.; Takyia, Christina M; Pontes-de-Carvalho, Lain; Campos de Carvalho, Antonio C.; Ribeiro-dos-Santos, Ricardo

    2004-01-01

    A progressive destruction of the myocardium occurs in ∼30% of Trypanosoma cruzi-infected individuals, causing chronic chagasic cardiomyopathy, a disease so far without effective treatment. Syngeneic bone marrow cell transplantation has been shown to cause repair and improvement of heart function in a number of studies in patients and animal models of ischemic cardiopathy. The effects of bone marrow transplant in a mouse model of chronic chagasic cardiomyopathy, in the presence of the disease ...

  9. Plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice

    OpenAIRE

    Shen, Yue; Guo, Yongzhi; Wilczynska, Malgorzata; Li, Jinan; Hellström, Sten; Ny, Tor

    2014-01-01

    Background: Most tympanic membrane (TM) perforations heal spontaneously, but approximately 10-20% remain open as chronic TM perforations. Chronic perforations can lead to an impaired hearing ability and recurrent middle ear infections. Traditionally, these perforations must be surgically closed, which is costly and time consuming. Therefore, there is a need for simpler therapeutic strategies. Previous studies by us have shown that plasminogen (plg) is a potent pro-inflammatory regulator that ...

  10. Central oxytocin is involved in restoring impaired gastric motility following chronic repeated stress in mice

    OpenAIRE

    Babygirija, Reji; Zheng, Jun; Ludwig, Kirk; Takahashi, Toku

    2009-01-01

    Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. The development of gastric symptoms may depend on how humans adapt to the stressful events in their daily lives. Although acute stress delays gastric emptying and alters upper gastrointestinal motility in rodents, the effects of chronic stress on gastric motility and its adaptation mechanism remains unclear. Central oxytocin has been shown to have antistress effects. We studied whether central oxytocin is i...

  11. Upregulation of Cannabinoid Type 1 Receptors in Dopamine D2 Receptor Knockout Mice Is Reversed by Chronic Forced Ethanol Consumption

    Energy Technology Data Exchange (ETDEWEB)

    Thanos, P.K.; Wang, G.; Thanos, P.K.; Gopez, V.; Delis, F.; Michaelides, M.; Grand, D.K.; Wang, G.-J.; Kunos, G.; Volkow, N.D.

    2011-01-01

    The anatomical proximity of the cannabinoid type 1 (CNR1/CB1R) and the dopamine D2 receptors (DRD2), their ability to form CB1R-DRD2 heteromers, their opposing roles in locomotion, and their involvement in ethanol's reinforcing and addictive properties prompted us to study the levels and distribution of CB1R after chronic ethanol intake, in the presence and absence of DRD2. We monitored the drinking patterns and locomotor activity of Drd2+/+ and Drd2-/- mice consuming either water or a 20% (v/v) ethanol solution (forced ethanol intake) for 6 months and used the selective CB1 receptor antagonist [{sup 3}H]SR141716A to quantify CB1R levels in different brain regions with in vitro receptor autoradiography. We found that the lack of DRD2 leads to a marked upregulation (approximately 2-fold increase) of CB1R in the cerebral cortex, the caudate-putamen, and the nucleus accumbens, which was reversed by chronic ethanol intake. The results suggest that DRD2-mediated dopaminergic neurotransmission and chronic ethanol intake exert an inhibitory effect on cannabinoid receptor expression in cortical and striatal regions implicated in the reinforcing and addictive properties of ethanol.

  12. Enalapril in Combination with Benznidazole Reduces Cardiac Inflammation and Creatine Kinases in Mice Chronically Infected with Trypanosoma cruzi.

    Science.gov (United States)

    Penitente, Arlete Rita; Leite, Ana Luísa Junqueira; de Paula Costa, Guilherme; Shrestha, Deena; Horta, Aline Luciano; Natali, Antônio J; Neves, Clóvis A; Talvani, Andre

    2015-11-01

    The protozoan Trypanosoma cruzi triggers an inflammatory process in mammalian heart causing events such as fibrosis, changes in the architecture and functionality in this organ. Enalapril, an angiotensin II-converting enzyme inhibitor, is a drug prescribed to ameliorate this heart dysfunction, and appears to exert a potential role in immune system regulation. Our aim was to evaluate the chronic cardiac inflammatory parameters after therapeutic treatment with enalapril and benznidazole in C57BL/6 mice infected with the VL-10 strain of T. cruzi. After infection, animals were treated with oral doses of enalapril (25 mg/kg), benznidazole (100 mg/kg), or both during 30 days. Morphometric parameters and levels of chemokines (CCL2, CCL5), IL-10, creatine kinases (CKs), and C-reactive protein were evaluated in the heart and serum at the 120th day of infection. Enalapril alone or in combination with benznidazole did not change the number of circulating parasites, but reduced cardiac leukocyte recruitment and total collagen in the cardiac tissue. Interestingly, the combination therapy (enalapril/benznidazole) also reduced the levels of chemokines, CK and CK-MB, and C-reactive proteins in chronic phase. In conclusion, during the chronic experimental T. cruzi infection, the combination therapy using enalapril plus benznidazole potentiated their immunomodulatory effects, resulting in a low production of biomarkers of cardiac lesions. PMID:26350447

  13. Social Isolation-Induced Aggression Potentiates Anxiety and Depressive-Like Behavior in Male Mice Subjected to Unpredictable Chronic Mild Stress

    OpenAIRE

    Xian-cang Ma; Dong Jiang; Wen-hui Jiang; Fen Wang; Min Jia; Jin Wu; Kenji Hashimoto; Yong-hui Dang; Cheng-ge Gao

    2011-01-01

    BACKGROUND: Accumulating epidemiological evidence shows that life event stressors are major vulnerability factors for psychiatric diseases such as major depression. It is also well known that social isolation in male mice results in aggressive behavior. However, it is not known how social isolation-induced aggression affects anxiety and depressive-like behavior in isolated male mice subjected to unpredictable chronic mild stress (CMS), an animal model of depression. METHODOLOGY/PRINCIPAL FIND...

  14. Toxicological Assessment of P-9801091 Plant Mixture Extract after Chronic Administration in CBA/HZg Mice – A Biochemical and Histological Study

    OpenAIRE

    Petlevski, Roberta; Hadžija, Mirko; Slijepčević, Milivoj; Juretić, Dubravka

    2008-01-01

    Acute, subchronic and chronic effects of the P-9801091 plant mixture extract at a dose of 20 mg/kg body mass were assessed in serum of healthy CBA/HZg mice at 24 hours, 7 days, 3 months and 6 months of treatment (experimental group), and compared with the values obtained in the control group of untreated healthy CBA/HZg mice. The P-9801091 plant mixture extract is an antihyperglycemic preparation containing Myrtilli folium (Vaccinium myrtillus L.), Taraxaci radix (Taraxacum offici...

  15. Dysfunction in Ribosomal Gene Expression in the Hypothalamus and Hippocampus following Chronic Social Defeat Stress in Male Mice as Revealed by RNA-Seq

    OpenAIRE

    Smagin, Dmitry A.; Kovalenko, Irina L.; Galyamina, Anna G.; Bragin, Anatoly O.; Orlov, Yuriy L.; Natalia N. Kudryavtseva

    2016-01-01

    Chronic social defeat stress leads to the development of anxiety- and depression-like states in male mice and is accompanied by numerous molecular changes in brain. The influence of 21-day period of social stress on ribosomal gene expression in five brain regions was studied using the RNA-Seq database. Most Rps, Rpl, Mprs, and Mprl genes were upregulated in the hypothalamus and downregulated in the hippocampus, which may indicate ribosomal dysfunction following chronic social defeat stress. T...

  16. Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet

    OpenAIRE

    Lau, Wei Ling; Leaf, Elizabeth M.; Hu, Ming Chang; Takeno, Marc M.; Kuro-o, Makoto; Moe, Orson W.; Giachelli, Cecilia M.

    2012-01-01

    Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times p...

  17. Dissimilar genome response to acute and chronic low-dose radiation in male and female mice

    International Nuclear Information System (INIS)

    The long-term genetic consequences of chronic exposure to low-dose irradiation constitutes a major concern to the general public and research community, especially as chronic radiation has recently been proven to be much more mutagenic and carcinogenic than previously thought. Here we report the results of the first ever comparison of the effects of acute and chronic whole body low-dose radiation exposure on global gene expression. We found a substantial difference between males and females in the expression of genes involved in signaling, growth control, transcription and other pathways upon acute and chronic radiation exposure. Specifically, we found sex differences in the expression of genes coding for G protein-coupled receptors and nuclear receptors. We also found different induction of PKCδ, PKCβ and PKCμ, members of PKC signaling pathway as well as in TGF and WNT signaling in males and females. Very pronounced difference, that was confirmed on the level of protein, was observed in the expression of WNT5A that plays an important role in carcinogenesis and muscle regeneration. WNT5A expression was significantly elevated only in chronically exposed females. We also provide the first evidence of the effect of ionizing radiation on the estrogen receptor in females. Repetitive irradiation of muscle tissue has been linked to development of rhabdomyosarcoma (RMS), which, enigmatically, occurs more frequently in males. Our data may be used to study possible mechanisms of RMS development upon chronic radiation exposure. They may provide some clues about the molecular background of the sex differences of RMS occurrence and may in the future lead to the discovery of new biomarkers for RMS predisposition in the irradiated tissue. Overall, differences in male and female responses to acute and chronic low-dose radiation obtained by this study were more drastic than we could have predicted. If confirmed in other experimental systems, these findings could potentially lead

  18. IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans.

    Science.gov (United States)

    de Luca, Antonella; Smeekens, Sanne P; Casagrande, Andrea; Iannitti, Rossana; Conway, Kara L; Gresnigt, Mark S; Begun, Jakob; Plantinga, Theo S; Joosten, Leo A B; van der Meer, Jos W M; Chamilos, Georgios; Netea, Mihai G; Xavier, Ramnik J; Dinarello, Charles A; Romani, Luigina; van de Veerdonk, Frank L

    2014-03-01

    Patients with chronic granulomatous disease (CGD) have a mutated NADPH complex resulting in defective production of reactive oxygen species; these patients can develop severe colitis and are highly susceptible to invasive fungal infection. In NADPH oxidase-deficient mice, autophagy is defective but inflammasome activation is present despite lack of reactive oxygen species production. However, whether these processes are mutually regulated in CGD and whether defective autophagy is clinically relevant in patients with CGD is unknown. Here, we demonstrate that macrophages from CGD mice and blood monocytes from CGD patients display minimal recruitment of microtubule-associated protein 1 light chain 3 (LC3) to phagosomes. This defect in autophagy results in increased IL-1β release. Blocking IL-1 with the receptor antagonist (anakinra) decreases neutrophil recruitment and T helper 17 responses and protects CGD mice from colitis and also from invasive aspergillosis. In addition to decreased inflammasome activation, anakinra restored autophagy in CGD mice in vivo, with increased Aspergillus-induced LC3 recruitment and increased expression of autophagy genes. Anakinra also increased Aspergillus-induced LC3 recruitment from 23% to 51% (P CGD patients. The clinical relevance of these findings was assessed by treating CGD patients who had severe colitis with IL-1 receptor blockade using anakinra. Anakinra treatment resulted in a rapid and sustained improvement in colitis. Thus, inflammation in CGD is due to IL-1-dependent mechanisms, such as decreased autophagy and increased inflammasome activation, which are linked pathological conditions in CGD that can be restored by IL-1 receptor blockade. PMID:24550444

  19. Effect of quercetin on chronic enhancement of spatial learning and memory of mice

    Institute of Scientific and Technical Information of China (English)

    LIU Jiancai; YU Huqing; NING Xinbao

    2006-01-01

    In this study we evaluated the effect of quercetin on D-galactose-induced aged mice using the Morris water maze (MWM) test. Based on the free radical theory of aging, experiments were performed to study the possible biochemical mechanisms of glutathione (GSH) level and hydroxyl radical (OH-) in the hippocampus and cerebral cortex and the brain tissue enzyme activity of the mice. The results indicated that quercetin can enhance the exploratory behavior, spatial learning and memory of the mice. The effects relate with enhancing the brain functions and inhibiting oxidative stress by quercetin, and relate with increasing the GSH level and decreasing the OH- content. These findings suggest that quercetin can work as a possible natural anti-aging pharmaceutical product.

  20. The hidden cost of housing practices: using noninvasive imaging to quantify the metabolic demands of chronic cold stress of laboratory mice.

    Science.gov (United States)

    David, John M; Chatziioannou, Arion F; Taschereau, Richard; Wang, Hongkai; Stout, David B

    2013-10-01

    Laboratory mice routinely are housed at 20 to 22 °C-well below the murine thermoneutral zone of 29 to 34 °C. Chronic cold stress requires greater energy expenditure to maintain core body temperature and can lead to the failure of mouse models to emulate human physiology. We hypothesized that mice housed at ambient temperatures of 20 to 22 °C are chronically cold-stressed, have greater energy expenditure, and have high glucose utilization in brown adipose tissue. To test our hypotheses, we used indirect calorimetry to measure energy expenditure and substrate utilization in C57BL/6J and Crl:NU-Foxn1(nu) nude mice at routine vivarium (21 °C), intermediate (26 °C), and heated (31 °C) housing temperatures. We also examined the activation of interscapular brown adipose tissue, the primary site of nonshivering thermogenesis, via thermography and glucose uptake in this region by using positron emission tomography. Energy expenditure of mice was significantly higher at routine vivarium temperatures compared with intermediate and heated temperatures and was associated with a shift in metabolism toward glucose utilization. Brown adipose tissue showed significant activation at routine vivarium and intermediate temperatures in both hirsuite and nude mice. Crl:NU-Foxn1(nu) mice experienced greater cold stress than did C57BL/6J mice. Our data indicate mice housed under routine vivarium conditions are chronically cold stress. This novel use of thermography can measure cold stress in laboratory mice housed in vivaria, a key advantage over classic metabolic measurement tools. Therefore, thermography is an ideal tool to evaluate novel husbandry practices designed to alleviate murine cold stress. PMID:24210014

  1. Corticosterone levels and behavioral changes induced by simultaneous exposure to chronic social stress and enriched environments in NMRI male mice.

    Science.gov (United States)

    Mesa-Gresa, Patricia; Ramos-Campos, Marta; Redolat, Rosa

    2016-05-01

    Environmental enrichment (EE) is an experimental model which is believed to counteract some of the effects induced by stressors, although few studies have exposed rodents simultaneously to EE and stress. Our aim was to compare the short- and long-term effects of different housing conditions in mice submitted to chronic stress. 128 NMRI male mice arrived at our laboratory on postnatal day (PND) 21. During Phase I (PND 28), animals were randomly assigned to four experimental conditions: 1) EE+STRESS: mice housed in EE and submitted to social stress (n=32); 2) EE+NO STRESS: mice housed in EE without stress (n=32); 3) SE+STRESS: mice maintained in standard conditions (SE) and submitted to social stress (n=32); and 4) SE+NO STRESS (n=32). At the end of Phase I (PND 77), one cohort of 32 animals was used for behavioral assessment whereas another cohort of 32 was sacrificed for corticosterone analysis. Results indicated that EE animals showed less body weight, higher water and food intake, diminished anxiety response and decreased motor and exploratory behavior than SE mice. Mice exposed to stress gained less body weight, showed higher food and fluid intake and displayed decreased exploratory behavior than non-stressed mice. Furthermore, EE+STRESS group displayed significantly higher corticosterone levels than EE+NO STRESS group whereas EE+NO STRESS group showed lower levels than SE+NO STRESS. On PND 83, Phase II of the study began. Animals (n=96) were assigned to two different housing conditions: EE (n=48) and SE (n=48). On PND 112, corticosterone analysis (n=32) and behavioral study (n=64) were done. The factor "Housing Phase II" reached statistical significance. Results indicated that EE animals showed lower body weight and higher fluid intake than SE group, as well as decreased anxiety. No clear effects on motor and exploratory behavior or learning were observed. When long-term effects were analyzed, results indicated that "Initial Housing" condition was significant

  2. Cytokine and surface receptor diversity of NK cells in resistant C3H/HeN and susceptible BALB/c mice with chronic Pseudomonas aeruginosa lung infection

    DEFF Research Database (Denmark)

    Calum, Henrik; Moser, Claus; Jensen, Peter Østrup;

    2003-01-01

    infection in cystic fibrosis. Lung cell suspensions were depleted of lymphocytes by magnetic cell sorting. The concentrations of IFN-gamma, IL-1beta and GM-CSF were estimated by ELISA at day 1 and 2 after infection. Non-infected mice were used as controls. Flow cytometry was used to estimate the surface...... expression of Fc receptors was significantly lower on NK cells in C3H/HeN mice at day 1 and 2. In conclusion, the present results show phenotypic differences in NK cells in the two mice strains in chronic P. aeruginosa lung infection, indicating different modulating effects in the Th1/Th2 balance....

  3. Alterations in Corticolimbic Dendritic Morphology and Emotional Behavior in Cannabinoid CB1 Receptor–Deficient Mice Parallel the Effects of Chronic Stress

    OpenAIRE

    Hill, Matthew N.; Hillard, Cecilia J.; McEwen, Bruce S.

    2011-01-01

    Many changes produced by chronic stress are similar to those seen in cannabinoid CB1 receptor–deficient mice. In the current study, we examined both anxiety-like behavior and dendritic complexity within the prefrontal cortex and basolateral amygdala (BLA) in wild-type and CB1 receptor–deficient mice, under basal conditions and following exposure to 21 days of protracted restraint stress. CB1 receptor–deficient mice exhibited increased indices of anxiety in the elevated plus maze under basal c...

  4. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.

    Science.gov (United States)

    Le, Caroline P; Nowell, Cameron J; Kim-Fuchs, Corina; Botteri, Edoardo; Hiller, Jonathan G; Ismail, Hilmy; Pimentel, Matthew A; Chai, Ming G; Karnezis, Tara; Rotmensz, Nicole; Renne, Giuseppe; Gandini, Sara; Pouton, Colin W; Ferrari, Davide; Möller, Andreas; Stacker, Steven A; Sloan, Erica K

    2016-01-01

    Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes. PMID:26925549

  5. Deficient production of reactive oxygen species leads to severe chronic DSS-induced colitis in Ncf1/p47phox-mutant mice.

    Directory of Open Access Journals (Sweden)

    Tiago Rodrigues-Sousa

    Full Text Available BACKGROUND: Colitis is a common clinical complication in chronic granulomatous disease (CGD, a primary immunodeficiency caused by impaired oxidative burst. Existing experimental data from NADPH-oxidase knockout mice propose contradictory roles for the involvement of reactive oxygen species in colitis chronicity and severity. Since genetically controlled mice with a point-mutation in the Ncf1 gene are susceptible to chronic inflammation and autoimmunity, we tested whether they presented increased predisposition to develop chronic colitis. METHODS: Colitis was induced in Ncf1-mutant and wild-type mice by a 1st 7-days cycle of dextran sulfate sodium (DSS, intercalated by a 7-days resting period followed by a 2nd 7-days DSS-cycle. Cytokines were quantified locally in the colon inflammatory infiltrates and in the serum. Leukocyte infiltration and morphological alterations of the colon mucosa were assessed by immunohistochemistry. RESULTS: Clinical scores demonstrated a more severe colitis in Ncf1-mutant mice than controls, with no recovery during the resting period and a severe chronic colitis after the 2nd cycle, confirmed by histopathology and presence of infiltrating neutrophils, macrophages, plasmocytes and lymphocytes in the colon. Severe colitis was mediated by increased local expression of cytokines (IL-6, IL-10, TNF-α, IFN-γ and IL-17A and phosphorylation of Leucine-rich repeat kinase 2 (LRRK2. Serological cytokine titers of those inflammatory cytokines were more elevated in Ncf1-mutant than control mice, and were accompanied by systemic changes in functional subsets of monocytes, CD4+ T and B cells. CONCLUSION: This suggests that an ineffective oxidative burst leads to severe chronic colitis through local accumulation of peroxynitrites, pro-inflammatory cytokines and lymphocytes and systemic immune deregulation similar to CGD.

  6. Sub-chronic lung inflammation after airway exposures to Bacillus thuringiensis biopesticides in mice

    DEFF Research Database (Denmark)

    Barfod, Kenneth K; Poulsen, Steen Seier; Hammer, Maria;

    2010-01-01

    The aim of the present study was to assess possible health effects of airway exposures to Bacillus thuringiensis (Bt) based biopesticides in mice. Endpoints were lung inflammation evaluated by presence of inflammatory cells in bronchoalveolar lavage fluid (BALF), clearance of bacteria from the lung...

  7. Blockage of the neurokinin 1 receptor and capsaicin-induced ablation of the enteric afferent nerves protect SCID mice against T-cell-induced chronic colitis

    DEFF Research Database (Denmark)

    Gad, Monika; Pedersen, Anders Elm; Kristensen, Nanna Ny; Fernandez, Carmen de Felipe; Claesson, Mogens H

    2009-01-01

    BACKGROUND: The neurotransmitter substance P (SP) released by, and the transient receptor potential vanilloid (TRPV1), expressed by afferent nerves, have been implicated in mucosal neuro-immune-regulation. To test if enteric afferent nerves are of importance for the development of chronic colitis......, we examined antagonists for the high-affinity neurokinin 1 (NK-1) SP receptor and the TRPV1 receptor agonist capsaicin in a T-cell transfer model for chronic colitis. METHODS: Chronic colitis was induced in SCID mice by injection of CD4(+)CD25(-) T cells. The importance of NK-1 signaling and TRPV1...

  8. Gene expression changes associated with myocarditis and fibrosis in hearts of mice with chronic chagasic cardiomyopathy

    DEFF Research Database (Denmark)

    Soares, Milena Botelho Pereira; de Lima, Ricardo Santana; Rocha, Leonardo Lima;

    2010-01-01

    Chronic chagasic cardiomyopathy is a leading cause of heart failure in Latin American countries. About 30% of Trypanosoma cruzi-infected individuals develop this severe symptomatic form of the disease, characterized by intense inflammatory response accompanied by fibrosis in the heart. We perform...

  9. Chronic Cerebral Hypoperfusion Causes Decrease of O-GlcNAcylation, Hyperphosphorylation of Tau and Behavioral Deficits in Mice

    Directory of Open Access Journals (Sweden)

    Yang eZhao

    2014-02-01

    Full Text Available Chronic cerebral hypoperfusion (CCH is one of the causes of vascular dementia (VaD and is also an etiological factor for Alzheimer's disease (AD. However, how CCH causes cognitive impairment and contributes to Alzheimer’s pathology is poorly understood. Here we produced a mouse model of CCH by unilateral common carotid artery occlusion (UCCAO and studied the behavioral changes and brain abnormalities in mice 2.5 months after UCCAO. We found that CCH caused significant short-term memory deficits and mild long-term spatial memory impairment, as well as decreased level of protein O-GlcNAcylation, increased level of tau phosphorylation, dysregulated synaptic proteins and insulin signaling, and selective neurodegeneration in the brain. These findings provide mechanistic insight into the effects of CCH on memory and cognition and the likely link between AD and VaD.

  10. Studies on the surface antigenicity and susceptibility to antibody-dependent killing of developing schistosomula using sera from chronically infected mice and mice vaccinated with irradiated cercariae

    International Nuclear Information System (INIS)

    Changes in the surface antigenicity and susceptibility to in vitro killing during development of schistosomula of Schistosoma mansoni were studied using serum from chronically infected mice (CIS) and from mice vaccinated with highly irradiated (20 krad) cercariae (VS). Binding of these sera was quantitated by counting the number of P388D1 cells (a transformed, macrophage-like cell of mouse origin, bearing Fc receptors for IgG) binding to the parasite surface. Compared with schistosomula derived in vitro by mechanical transformation (MS), schistosomula recovered 3 hr after skin penetration in vitro (SS) showed a significant loss in surface binding of CIS. Schistosomula recovered 3 hr after skin penetration in vivo (SRS) showed even less binding, and this trend continued such that parasites recovered from the lungs 5 days after infection (LS) showed only minimal binding, and 10-day-old worms from the portal system showed no significant binding. In contrast, VS, which bound significantly less well to MS than CIS, showed enhanced binding to SS, and in the face of their declining antigenicity with respect to CIS, 3- to 24-hr SRS maintained this raised level of antigenicity. Although there appeared to be a decline in binding of VS thereafter, LS remained antigenic, still binding as many cells as MS did despite the fact that they also expressed host antigens detected usng antisera raised against mouse RBC. In spite of this persistence of VS binding up to the lung stage, resistance to eosinophil-mediated killing in vitro had developed by 48 hr post-infection, and LS were totally resistant to both eosinophil- and C-mediated killing

  11. Studies on the surface antigenicity and susceptibility to antibody-dependent killing of developing schistosomula using sera from chronically infected mice and mice vaccinated with irradiated cercariae

    Energy Technology Data Exchange (ETDEWEB)

    Bickle, Q.D.; Ford, M.J.

    1982-05-01

    Changes in the surface antigenicity and susceptibility to in vitro killing during development of schistosomula of Schistosoma mansoni were studied using serum from chronically infected mice (CIS) and from mice vaccinated with highly irradiated (20 krad) cercariae (VS). Binding of these sera was quantitated by counting the number of P388D/sub 1/ cells (a transformed, macrophage-like cell of mouse origin, bearing Fc receptors for IgG) binding to the parasite surface. Compared with schistosomula derived in vitro by mechanical transformation (MS), schistosomula recovered 3 hr after skin penetration in vitro (SS) showed a significant loss in surface binding of CIS. Schistosomula recovered 3 hr after skin penetration in vivo (SRS) showed even less binding, and this trend continued such that parasites recovered from the lungs 5 days after infection (LS) showed only minimal binding, and 10-day-old worms from the portal system showed no significant binding. In contrast, VS, which bound significantly less well to MS than CIS, showed enhanced binding to SS, and in the face of their declining antigenicity with respect to CIS, 3- to 24-hr SRS maintained this raised level of antigenicity. Although there appeared to be a decline in binding of VS thereafter, LS remained antigenic, still binding as many cells as MS did despite the fact that they also expressed host antigens detected usng antisera raised against mouse RBC. In spite of this persistence of VS binding up to the lung stage, resistance to eosinophil-mediated killing in vitro had developed by 48 hr post-infection, and LS were totally resistant to both eosinophil- and C-mediated killing.

  12. Minocycline attenuates HIV-1 infection and suppresses chronic immune activation in humanized NOD/LtsZ-scidIL-2Rγnull mice

    Science.gov (United States)

    Singh, Maneesh; Singh, Pratibha; Vaira, Dolores; Amand, Mathieu; Rahmouni, Souad; Moutschen, Michel

    2014-01-01

    More than a quarter of a century of research has established chronic immune activation and dysfunctional T cells as central features of chronic HIV infection and subsequent immunodeficiency. Consequently, the search for a new immunomodulatory therapy that could reduce immune activation and improve T-cell function has been increased. However, the lack of small animal models for in vivo HIV study has hampered progress. In the current study, we have investigated a model of cord blood haematopoietic progenitor cells (CB-HPCs) -transplanted humanized NOD/LtsZ-scidIL-2Rγnull mice in which progression of HIV infection is associated with widespread chronic immune activation and inflammation. Indeed, HIV infection in humanized NSG mice caused up-regulation of several T-cell immune activation markers such as CD38, HLA-DR, CD69 and co-receptor CCR5. T-cell exhaustion markers PD-1 and CTLA-4 were found to be significantly up-regulated on T cells. Moreover, increased plasmatic levels of lipopolysaccharide, sCD14 and interleukin-10 were also observed in infected mice. Treatment with minocycline resulted in a significant decrease of expression of cellular and plasma immune activation markers, inhibition of HIV replication and improved T-cell counts in HIV-infected humanized NSG mice. The study demonstrates that minocycline could be an effective, low-cost adjunctive treatment to regulate chronic immune activation and replication of HIV. PMID:24409837

  13. Investigation of genomic instability by assay of DNA fingerprint from the offspring of male mice exposed to chronic low-level γ-radiation

    International Nuclear Information System (INIS)

    By polymerase chain reaction with arbitrary primer (AP-PCR), the possibility of transmission of genome instability to somatic cells of the offspring (F1 generation) from male parents of mice exposed to chronic low-dose γ-radiation was studied. Male mice 15 days after exposure to 10-50 cGy were mated with unirradiated females. Biopsies were taken from tale tips of two month-old mice progeny for DNA separation. Primer in the AP-PCR was 20-mer oligonucleotide flanking the micro-satellite locus Atplb2 on chromosome 11 of the mouse. Comparative analysis of individual fingerprints of AP-PCR products on DNA-templates from the offspring of irradiated and unirradiated male mice revealed an increased variability of micro-satellite-associated sequences in the genome of the offspring of males exposed to 25 and 50 cGy. DNA-fingerprints of the offspring of male mice exposed to chronic irradiation doses 10 and 25 cGy. 15 days before fertilization (at the post-meiotic stage of spermatogenesis) showed an increased frequency of non-parent bands. Result of the study point to the possibility of transmission to the offspring somatic cells of changes increasing genome instability from male parents exposed to chronic low-dose radiation prior to fertilization

  14. Endothelial surface layer degradation by chronic hyaluronidase infusion induces proteinuria in apolipoprotein e-deficient mice

    OpenAIRE

    Meuwese, Marijn C.; Broekhuizen, Lysette N.; Mayella Kuikhoven; Sylvia Heeneman; Esther Lutgens; Marion J J Gijbels; Max Nieuwdorp; Peutz, Carine J; Stroes, Erik S.G.; Hans Vink; van den Berg, Bernard M.

    2010-01-01

    OBJECTIVE: Functional studies show that disruption of endothelial surface layer (ESL) is accompanied by enhanced sensitivity of the vasculature towards atherogenic stimuli. However, relevance of ESL disruption as causal mechanism for vascular dysfunction remains to be demonstrated. We examined if loss of ESL through enzymatic degradation would affect vascular barrier properties in an atherogenic model. METHODS: Eight week old male apolipoprotein E deficient mice on Western-type diet for 10 we...

  15. Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice.

    OpenAIRE

    Arbeit, J M; Howley, P M; Hanahan, D

    1996-01-01

    High-risk human papillomaviruses (HPVs), including type 16, have been identified as factors in cervical carcinogenesis. However, the presence and expression of the virus per se appear to be insufficient for carcinogenesis. Rather, cofactors most likely are necessary in addition to viral gene expression to initiate neoplasia. One candidate cofactor is prolonged exposure to sex hormones. To examine the possible effects of estrogen on HPV-associated neoplasia, we treated transgenic mice expressi...

  16. Major role for carbohydrate epitopes preferentially recognized by chronically infected mice in the determination of Schistosoma mansoni schistosomulum surface antigenicity

    International Nuclear Information System (INIS)

    A radioimmunoassay that makes use of whole Schistosomula and 125I-labeled protein A has been used to characterize and to quantify the binding of antisera to the surface of 3 hr mechanically transformed schistosomula of Schistosoma mansoni. This technique facilitates the determination of epitopes on the schistosomula in addition to those detected by surface labeling and immunoprecipitation. By using this technique, it has been demonstrated that there is a much greater binding to the parasite surface of antibodies from chronically infected mice (CMS) than of antibodies from mice infected with highly irradiated cercariae (VMS), and CMS recognizes epitopes that VMS does not. Treatment of the surface of the schistosomula with trifluoromethanesulphonic acid and sodium metaperiodate has suggested that the discrepancy of the binding between the two sera is due to the recognition of a large number of additional epitopes by CMS, which are carbohydrate in nature. Some of the carbohydrate epitopes are expressed on the previously described surface glycoprotein antigens of M/sub r/ 200,000, 38,000, and 17,000

  17. Major role for carbohydrate epitopes preferentially recognized by chronically infected mice in the determination of Schistosoma mansoni schistosomulum surface antigenicity

    Energy Technology Data Exchange (ETDEWEB)

    Omer-ali, P.; Magee, A.I.; Kelly, C.; Simpson, A.J.G.

    1986-12-01

    A radioimmunoassay that makes use of whole Schistosomula and /sup 125/I-labeled protein A has been used to characterize and to quantify the binding of antisera to the surface of 3 hr mechanically transformed schistosomula of Schistosoma mansoni. This technique facilitates the determination of epitopes on the schistosomula in addition to those detected by surface labeling and immunoprecipitation. By using this technique, it has been demonstrated that there is a much greater binding to the parasite surface of antibodies from chronically infected mice (CMS) than of antibodies from mice infected with highly irradiated cercariae (VMS), and CMS recognizes epitopes that VMS does not. Treatment of the surface of the schistosomula with trifluoromethanesulphonic acid and sodium metaperiodate has suggested that the discrepancy of the binding between the two sera is due to the recognition of a large number of additional epitopes by CMS, which are carbohydrate in nature. Some of the carbohydrate epitopes are expressed on the previously described surface glycoprotein antigens of M/sub r/ 200,000, 38,000, and 17,000.

  18. The toxic effects of a chronic administration of the gut-stimulating principle in Croton penduliflorus hutch. seeds in mice.

    Science.gov (United States)

    Asuzu, I U; Shetty, S N; Anika, S M

    1989-03-01

    Albino mice (8-10 wks) weighing between 14 and 25 g were divided into 2 groups and dosed orally once per week with 2 doses (7 mg/kg and 21 mg/kg) of the gut-stimulating principle in Croton penduliflorus seeds (CP crystals) for 12 weeks. Some mice (3-4) from each group were killed at 10 days intervals for the first 6 wks of the experiment and at 20 days intervals for the last 6 weeks. Gross and histopathological changes in the brain, heart, liver, kidney, adrenal, spleen, testis, lung and various segments of the gastrointestinal tract including the stomach, duodenum, ileum and colon were observed. The relative weights of the visceral organs were also recorded. Significant weight change in the spleen was evident. The congestion of the lung was the most common gross pathological observation made. Other observations were splenomegaly, enlarged heart, swollen uterine horns, etc. Histopathological changes observed included haemorrhages in the lungs, myocardium, liver, kidney, testis, brain etc. Goblet cell hyperplasia with mucin present in the lumen were observed in the jejunum, ileum and colon. In conclusion, CP crystals produced severe lesions in the visceral organs and the brain after chronic oral administration at low and high dosage levels which should indicate caution in administering the extract to humans. PMID:2714210

  19. The Role of Chronic Exposure to Amoxicillin/Clavulanic Acid on the Developmental Enamel Defects in Mice.

    Science.gov (United States)

    Mihalaş, Eugeniu; Matricala, Lavinia; Chelmuş, Alina; Gheţu, Nicolae; Petcu, Ana; Paşca, Sorin

    2016-01-01

    Amoxicillin used in early childhood may be associated with enamel hypomineralization. Our aim was to assess disturbances of amelogenesis in mice lower incisors induced by chronic administration of amoxicillin/clavulanic acid (AMC). Twenty-eight C57BL/6 male mice, of similar age, randomly divided into a control and 3 treatment groups (n = 7) received subcutaneous injection, once per day, for 60 days: 50, 100, and 150 mg/kg BW of AMC. Scanning electron microscopy/energy dispersive X-ray spectroscopy analysis in AMC treatment groups showed higher content in F and a decrease in P and Ca. Morphology changes ranged from scratched patterns, and small isolated pits-like enamel loss, to generalized demineralized enamel surface, giving a rough, foamy, scaly, or even cracked eggshell appearance to the affected areas. Histological analysis showed disturbances of maturation ameloblasts, which were less organized, with increased amounts of clear vacuoles in the cytoplasm and slightly more elongated and less condensed nucleus. Additionally, they were often detached from the enamel matrix. Transitional ameloblasts formed underlying the cysts of varied sizes. In conclusion, AMC dose-dependently affect ameloblast functions especially in the maturation phase, causing hypomineralized enamel formation with quantitative and/or qualitative defects. PMID:26534941

  20. Green Brazilian Propolis Action on Macrophages and Lymphoid Organs of Chronically Stressed Mice

    Directory of Open Access Journals (Sweden)

    Fabiane Missima

    2008-01-01

    Full Text Available Stress is a generic term that summarizes how psychosocial and environmental factors influence physical and mental well-being. The interaction between stress and immunity has been widely investigated, involving the neuroendocrine system and several organs. Assays using natural products in stress models deserve further investigation. Propolis immunomodulatory action has been mentioned and it has been the subject of scientific investigation in our laboratory. The aim of this study was to evaluate if and how propolis activated macrophages in BALB/c mice submitted to immobilization stress, as well as the histopathological analysis of the thymus, bone marrow, spleen and adrenal glands. Stressed mice showed a higher hydrogen peroxide (H2O2 generation by peritoneal macrophages, and propolis treatment potentiated H2O2 generation and inhibited nitric oxide (NO production by these cells. Histopathological analysis showed no alterations in the thymus, bone marrow and adrenal glands, but increased germinal centers in the spleen. Propolis treatment counteracted the alterations found in the spleen of stressed mice. New research is being carried out in order to elucidate propolis immunomodulatory action during stress.

  1. Commensal microbiota contributes to chronic endocarditis in TAX1BP1 deficient mice.

    Directory of Open Access Journals (Sweden)

    Satoko Nakano

    Full Text Available Tax1-binding protein 1 (Tax1bp1 negatively regulates NF-κB by editing the ubiquitylation of target molecules by its catalytic partner A20. Genetically engineered TAX1BP1-deficient (KO mice develop age-dependent inflammatory constitutions in multiple organs manifested as valvulitis or dermatitis and succumb to premature death. Laser capture dissection and gene expression microarray analysis on the mitral valves of TAX1BP1-KO mice (8 and 16 week old revealed 588 gene transcription alterations from the wild type. SAA3 (serum amyloid A3, CHI3L1, HP, IL1B and SPP1/OPN were induced 1,180-, 361-, 187-, 122- and 101-fold respectively. WIF1 (Wnt inhibitory factor 1 exhibited 11-fold reduction. Intense Saa3 staining and significant I-κBα reduction were reconfirmed and massive infiltration of inflammatory lymphocytes and edema formation were seen in the area. Antibiotics-induced 'germ free' status or the additional MyD88 deficiency significantly ameliorated TAX1BP1-KO mice's inflammatory lesions. These pathological conditions, as we named 'pseudo-infective endocarditis' were boosted by the commensal microbiota who are usually harmless by their nature. This experimental outcome raises a novel mechanistic linkage between endothelial inflammation caused by the ubiquitin remodeling immune regulators and fatal cardiac dysfunction.

  2. Radiation resistance in mice increased following chronic application of Li2CO3

    International Nuclear Information System (INIS)

    In experiments on strain H mice the increased radiation resistance of mice was analysed after three weeks' feeding with a diet including Li given as lithium carbonicum. The concentration of Li in the serum during the first three days of feeding was increased to 0.5 mmol/l and remained at that level to the end of feeding. The application of Li increased the overall number of stem cells in the spleen by 80 per cent compared with the control group. D0 of the line of dependence of the number of endogenous colonies on radiation dose increased following Li application by 1.2 Gy compared with controls. The proliferation activity of haemopoietic stem cells observed 90 min after injection of hydroxyurea was, after 21 days feeding with a mixture containing Li, increased by 200 per cent. The results support the idea that the increased radiation resistance of mice following feeding with Li salts before irradiation may be due to the increased content and resistance of the haemopoietic stem cells, as well as activation of granulopoiesis. (Auth.)

  3. A novel isoquinoline compound abolishes chronic unpredictable mild stress-induced depressive-like behavior in mice.

    Science.gov (United States)

    Pesarico, Ana Paula; Sartori, Gláubia; Brüning, César A; Mantovani, Anderson C; Duarte, Thiago; Zeni, Gilson; Nogueira, Cristina Wayne

    2016-07-01

    Chronic unpredictable mild stress (CUMS) elicits aspects of cognitive and behavioral alterations that can be used to model comparable aspects of depression in humans. The aim of the present study was to investigate the antidepressant-like potential of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a novel isoquinoline compound, in CUMS, a model that meets face, construct and predictive criteria for validity. Swiss mice were subjected to different stress paradigms daily for a period of 35 days to induce the depressive-like behavior. The animals received concomitant FDPI (0.1 and 1mg/kg, intragastric) or paroxetine (8mg/kg, intraperitoneal) and CUMS. The behavioral tests (splash test, tail suspension test, modified forced swimming test and locomotor activity) were performed. The levels of cytokines, corticosterone and adrenocorticotropic (ACTH) hormones were determined in the mouse prefrontal cortex and serum. The synaptosomal [(3)H] serotonin (5-HT) uptake, nuclear factor (NF)-κB, tyrosine kinase receptor (TrkB) and pro-brain-derived neurotrophic factor (BDNF) levels were determined in the mouse prefrontal cortex. CUMS induced a depressive-like behavior in mice, which was demonstrated in the modified forced swimming, tail suspension and splash tests. FDPI at both doses prevented depressive-like behavior induced by CUMS, without altering the locomotor activity of mice. FDPI at the highest dose prevented the increase in the levels of NF-kB, pro-inflammatory cytokines, corticosterone and ACTH and modulated [(3)H]5-HT uptake and the proBDNF/TrkB signaling pathway altered by CUMS. The present findings demonstrated that FDPI elicited an antidepressant-like effect in a model of stress-induced depression. PMID:27036647

  4. Crucial involvement of tumor-associated neutrophils in the regulation of chronic colitis-associated carcinogenesis in mice.

    Directory of Open Access Journals (Sweden)

    Kun Shang

    Full Text Available Ulcerative colitis (UC is a major form of chronic inflammation that can frequently progress to colon cancer. Several studies have demonstrated massive infiltration of neutrophils and macrophages into the lamina propria and submucosa in the progression of UC-associated colon carcinogenesis. Macrophages contribute to the development of colitis-associated colon cancer (CAC. However, the role of neutrophils is not well understood. To better understand the involvement of tumor-associated neutrophils (TANs in the regulation of CAC, we used a mouse CAC model produced by administering azoxymethane (AOM, followed by repeated dextran sulfate sodium (DSS ingestion. This causes severe colonic inflammation and subsequent development of multiple tumors in mice colon. We observed that colorectal mucosal inflammation became increasingly severe with AOM and DSS treatment. Macrophages infiltrated the lamina propria and submucosa, together with a marked increase in neutrophil infiltration. The chemokine CXCL2 increased in the lamina propria and submucosal regions of the colons of the treated mice, together with the infiltration of neutrophils expressing CXCR2, a specific receptor for CXCL2. This process was followed by neoplastic transformation. After AOM and DSS treatment, the mice showed enhanced production of metalloproteinase (MMP-9 and neutrophil elastase (NE, accompanied by excessive vessel generation and cell proliferation. Moreover, CXCL2 promoted neutrophil recruitment and induced neutrophils to express MMP-9 and NE in vitro. Furthermore, administration of neutrophil-neutralizing antibodies after the last DSS cycle markedly reduced the number and size of tumors and decreased the expression of CXCR2, CXCL2, MMP-9, and NE. These observations indicate a crucial role for TANs in the initiation and progression of CAC and suggest that the CXCL2-CXCR2 axis might be useful in reducing the risk of UC-associated colon cancer.

  5. Effect of Celastrus paniculatus seed oil (Jyothismati oil on acute and chronic immobilization stress induced in swiss albino mice

    Directory of Open Access Journals (Sweden)

    George Lekha

    2010-01-01

    Full Text Available Stress alters the homeostasis and is produced by several factors. Immobilization stress induced due to reduced floor area provided for the mobility results in the imbalance of oxidant and antioxidant status. The modern computer savvy world decreases human mobility in the working environment, leading to the formation of oxygen free radicals and if left untreated might result in severe health problems like hypertension, cardiovascular disease, premature aging and brain dysfunction. Hence, modern medicines rely upon the medicinal plants for some drugs with zero side effects. In this context, Jyothismati oil (JO, extracted from Celastrus paniculatus seeds, was used to treat acute and chronic immobilization induced experimentally. C. paniculatus plant is considered to be rich in antioxidant content and so the seed oil extract′s efficacy was tested against immobilization stress in albino mice. The animals were kept in a restrainer for short and long durations, grouped separately and fed with the drug. Animals were sacrificed and the samples were analyzed. The antioxidant enzyme levels of the animals regained and markedly increased in the acute and chronic immobilized groups, respectively. The results suggested that the extract of C. paniculatus seed was highly efficacious in reducing the stress induced by least mobility for hours.

  6. Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration.

    Science.gov (United States)

    Zanos, Panos; Georgiou, Polymnia; Metaxas, Athanasios; Kitchen, Ian; Winsky-Sommerer, Raphaelle; Bailey, Alexis

    2015-07-23

    Nicotine addiction is considered to be the main preventable cause of death worldwide. While growing evidence indicates that the neurohypophysial peptide oxytocin can modulate the addictive properties of several abused drugs, the regulation of the oxytocinergic system following nicotine administration has so far received little attention. Here, we examined the effects of long-term nicotine or saline administration on the central oxytocinergic system using [(125)I]OVTA autoradiographic binding in mouse brain. Male, 7-week old C57BL6J mice were treated with either nicotine (7.8 mg/kg daily; rate of 0.5 μl per hour) or saline for a period of 14-days via osmotic minipumps. Chronic nicotine administration induced a marked region-specific upregulation of the oxytocin receptor binding in the amygdala, a brain region involved in stress and emotional regulation. These results provide direct evidence for nicotine-induced neuroadaptations in the oxytocinergic system, which may be involved in the modulation of nicotine-seeking as well as emotional consequence of chronic drug use. PMID:26037668

  7. Chronic Inhibition of Dopamine β-Hydroxylase Facilitates Behavioral Responses to Cocaine in Mice

    OpenAIRE

    Gaval-Cruz, Meriem; Liles, Larry Cameron; Iuvone, Paul Michael; Weinshenker, David

    2012-01-01

    The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using...

  8. Chronic Non-Social Stress Affects Depressive Behaviors But Not Anxiety in Mice

    OpenAIRE

    Yoon, Sang Ho; Kim, Byung-Hak; Ye, Sang-Kyu; Kim, Myoung-Hwan

    2014-01-01

    The etiology of most psychiatric disorders is still incompletely understood. However, growing evidence suggests that stress is a potent environmental risk factor for depression and anxiety. In rodents, various stress paradigms have been developed, but psychosocial stress paradigms have received more attention than non-social stress paradigms because psychosocial stress is more prevalent in humans. Interestingly, some recent studies suggest that chronic psychosocial stress and social isolation...

  9. Chronic cellular imaging of entire cortical columns in awake mice using microprisms

    OpenAIRE

    Andermann, Mark L.; Gilfoy, Nathan B.; Goldey, Glenn J.; Sachdev, Robert N. S.; Wölfel, Markus; McCormick, David A.; Reid, R. Clay; Levene, Michael J.

    2013-01-01

    Two-photon imaging of cortical neurons in vivo has provided unique insights into the structure, function, and plasticity of cortical networks, but this method does not currently allow simultaneous imaging of neurons in the superficial and deepest cortical layers. Here, we describe a simple modification that enables simultaneous, long-term imaging of all cortical layers. Using a chronically implanted glass microprism in barrel cortex, we could image the same fluorescently labeled deeplayer pyr...

  10. Chronic exposure of Sk-1 hairless mice to narrow-band ultraviolet A (320-355 nm)

    International Nuclear Information System (INIS)

    Several recent investigations collectively suggest that the role of ultraviolet A (UVA) in chronic actinic skin damage may be greater than originally thought. In the present work, the output of a xenon-arc solar-simulator passed through a Bausch and Lomb monochromator in conjunction with a 2-mm Schott WG-320 filter produced narrow-band UVA centered at 338 nm, half-band width 24 nm, I0=3.4±0.3 mW/cm2. We chronically irradiated 10 SK-1 albino hairless mice 5 times per week for 18 weeks, starting with 1.25 J/cm2, for 33 irradiation days, sequentially followed by 1.50 J/cm2 (34 days), 1.8 J/cm2 (10 days), 2.0 J/cm2 (22 days) to afford a total UVA dose of 154.3 J/cm2 over 99 irradiation days. Erythema was noted clinically by day 6, which persisted throughout the irradiation. During the irradiation period, some scaling, consistent with mild epidermal hyperplasia was noted during irradiation days 37-56. This response later regressed despite continued chronic irradiation. Hematoxylin and eosin examination immediately after the final irradiation revealed a mild inflammatory response, with some dermal restructuring. At the end of the experiment, no significant signs of epidermal hyperplasia or (pre)malignant lesions were seen, although some stratum corneum thickening was noted. Marked dermal collagen damage and moderate elastosis was also evident. We believe that the observed differences in results reported in previous studies are in large part due to differences in light sources and irradiation protocols. (au)

  11. Chronic treatment with fluoxetine for more than 6 weeks decreases neurogenesis in the subventricular zone of adult mice

    Directory of Open Access Journals (Sweden)

    Ohira Koji

    2011-03-01

    Full Text Available Abstract Background Recent studies indicate that chronic treatment with serotonergic antidepressants upregulates adult neurogenesis of the dentate gyrus (DG. In contrast, some studies claimed that there was very little alteration of neurogenesis in the subventricular zone (SVZ by the antidepressants. Since almost all of those studies treated animals with drugs for 2 to 4 weeks as chronic treatment models of antidepressants, it is possible that antidepressant treatments for longer periods would affect adult neurogenesis in the SVZ. Results In the present study, we examined the effects of long-term (up to 9 weeks administration of fluoxetine (FLX, a selective serotonin reuptake inhibitor, on cell proliferation and survival in the DG and the SVZ of adult mice. As reported previously, in the DG of mice treated with FLX for 3, 6, or 9 weeks that were also injected with 5-bromodeoxyuridine (BrdU in the last 3 days before perfusion, the numbers of Ki67- and BrdU-positive cells, which are cell proliferation markers, were significantly upregulated even at 3 weeks after the onset of the FLX treatments, and these increases were sustained in mice treated with FLX for 9 weeks. On the other hand, in the SVZ, we found a small, insignificant decrease in the numbers of Ki67- and BrdU-positive cells at 3 weeks, followed by highly significant decreases in the numbers of Ki67- and BrdU-positive cells at both 6 and 9 weeks. Furthermore, among olfactory newly generated cells that survived for 3 weeks after BrdU injection, the number of new cells was decreased at 9 weeks of FLX treatment. Conclusions These results demonstrate that long-term (more than 6 weeks treatment with FLX has the opposite effect on neurogenesis in the SVZ than it does in the DG. The results also suggest that the decrease in neurogenesis in the SVZ might be involved in some aspects of the drugs' therapeutic effects on depression. In addition, our findings raise the possibility that some of the

  12. Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding

    Energy Technology Data Exchange (ETDEWEB)

    Kaphalia, Lata [Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Boroumand, Nahal [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Hyunsu, Ju [Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Kaphalia, Bhupendra S., E-mail: bkaphali@utmb.edu [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Calhoun, William J. [Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 775555 (United States)

    2014-06-01

    Consumption and over-consumption of alcoholic beverages are well-recognized contributors to a variety of pulmonary disorders, even in the absence of intoxication. The mechanisms by which alcohol (ethanol) may produce disease include oxidative stress and prolonged endoplasmic reticulum (ER) stress. Many aspects of these processes remain incompletely understood due to a lack of a suitable animal model. Chronic alcohol over-consumption reduces hepatic alcohol dehydrogenase (ADH), the principal canonical metabolic pathway of ethanol oxidation. We therefore modeled this situation using hepatic ADH-deficient deer mice fed 3.5% ethanol daily for 3 months. Blood ethanol concentration was 180 mg% in ethanol fed mice, compared to < 1.0% in the controls. Acetaldehyde (oxidative metabolite of ethanol) was minimally, but significantly increased in ethanol-fed vs. pair-fed control mice. Total fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) were 47.6 μg/g in the lungs of ethanol-fed mice as compared to 1.5 μg/g in pair-fed controls. Histological and immunohistological evaluation showed perivascular and peribronchiolar lymphocytic infiltration, and significant oxidative injury, in the lungs of ethanol-fed mice compared to pair-fed controls. Several fold increases for cytochrome P450 2E1, caspase 8 and caspase 3 found in the lungs of ethanol-fed mice as compared to pair-fed controls suggest role of oxidative stress in ethanol-induced lung injury. ER stress and unfolded protein response signaling were also significantly increased in the lungs of ethanol-fed mice. Surprisingly, no significant activation of inositol-requiring enzyme-1α and spliced XBP1 was observed indicating a lack of activation of corrective mechanisms to reinstate ER homeostasis. The data suggest that oxidative stress and prolonged ER stress, coupled with formation and accumulation of cytotoxic FAEEs may contribute to the pathogenesis of alcoholic lung disease. - Highlights: • Chronic

  13. Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding

    International Nuclear Information System (INIS)

    Consumption and over-consumption of alcoholic beverages are well-recognized contributors to a variety of pulmonary disorders, even in the absence of intoxication. The mechanisms by which alcohol (ethanol) may produce disease include oxidative stress and prolonged endoplasmic reticulum (ER) stress. Many aspects of these processes remain incompletely understood due to a lack of a suitable animal model. Chronic alcohol over-consumption reduces hepatic alcohol dehydrogenase (ADH), the principal canonical metabolic pathway of ethanol oxidation. We therefore modeled this situation using hepatic ADH-deficient deer mice fed 3.5% ethanol daily for 3 months. Blood ethanol concentration was 180 mg% in ethanol fed mice, compared to < 1.0% in the controls. Acetaldehyde (oxidative metabolite of ethanol) was minimally, but significantly increased in ethanol-fed vs. pair-fed control mice. Total fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) were 47.6 μg/g in the lungs of ethanol-fed mice as compared to 1.5 μg/g in pair-fed controls. Histological and immunohistological evaluation showed perivascular and peribronchiolar lymphocytic infiltration, and significant oxidative injury, in the lungs of ethanol-fed mice compared to pair-fed controls. Several fold increases for cytochrome P450 2E1, caspase 8 and caspase 3 found in the lungs of ethanol-fed mice as compared to pair-fed controls suggest role of oxidative stress in ethanol-induced lung injury. ER stress and unfolded protein response signaling were also significantly increased in the lungs of ethanol-fed mice. Surprisingly, no significant activation of inositol-requiring enzyme-1α and spliced XBP1 was observed indicating a lack of activation of corrective mechanisms to reinstate ER homeostasis. The data suggest that oxidative stress and prolonged ER stress, coupled with formation and accumulation of cytotoxic FAEEs may contribute to the pathogenesis of alcoholic lung disease. - Highlights: • Chronic

  14. Effects of Chronic Mild Stress on the Development of Atherosclerosis and Expression of Toll-Like Receptor 4 Signaling Pathway in Adolescent Apolipoprotein E Knockout Mice

    Directory of Open Access Journals (Sweden)

    Hongfeng Gu

    2009-01-01

    Full Text Available Here, we investigated the effect of chronic mild stress (CMS on the development of atherosclerosis as well as the expression of Toll-like receptors (TLRs signaling pathway in adolescent apolipoprotein E knockout (apoE-/- mice. Mice were subjected to daily CMS for 0, 4, and 12 weeks, respectively. To identify the expression of Toll-like receptor 4 signaling pathway in adolescent apolipoprotein E knockout mice subjected to CMS, we compared gene expression in aortas of stressed and unstressed mice using TLRs signaling pathway real-time PCR microarrays consisting of 87 genes. We found that atherosclerosis lesions both in aortic tress and sinuses of CMS mice were significantly increased linearly in response to duration of CMS exposure. Among 87 genes analyzed, 15 genes were upregulated in stressed mice, especially TLR4, myeloid differentiation factor 88 (MyD88, and IL-1β, and 28 genes were downregulated compared with nonstressed mice. CMS mice demonstrated markedly increased aortic atherosclerosis that were associated with significant increases in levels of expression of TLR4, MyD88, nuclear factor κB (NF-κB, MCP-1, IL-1β, TNF-α, and sICAM-1. Taken together, our results suggest an important role for TLR4 signaling pathway in atherosclerosis in a CMS mouse model.

  15. Stress response and humoral immune system alterations related to chronic hypergravity in mice.

    Science.gov (United States)

    Guéguinou, Nathan; Bojados, Mickaël; Jamon, Marc; Derradji, Hanane; Baatout, Sarah; Tschirhart, Eric; Frippiat, Jean-Pol; Legrand-Frossi, Christine

    2012-01-01

    Spaceflights are known to induce stress and immune dysregulation. Centrifugation, as hindlimb unloading, is a good ground based-model to simulate altered gravity which occurs during space missions. The aim of this study was to investigate the consequences of a long-term exposure to different levels of hypergravity on the stress response and the humoral immunity in a mouse model. For this purpose, adult C57Bl/6J male mice were subjected for 21 days either to control conditions or to 2G or 3G acceleration gravity forces. Corticosterone level and anxiety behavior revealed a stress response which was associated with a decrease of body weight, after 21-day of centrifugation at 3G but not at 2G. Spleen lymphocyte lipopolysaccharide (LPS) responsiveness was diminished by 40% in the 2G group only, whereas a decrease was noted when cells were stimulated with concanavalin A for both 2G and 3G groups (about 25% and 20%, respectively) compared to controls. Pro-inflammatory chemokines (MCP-1 and IP-10) and Th1 cytokines (IFNγ and IL2) were slightly decreased in the 2G group and strongly decreased in the 3G mouse group. Regarding Th2 cytokines (IL4, IL5) no further significant modification was observed, whereas the immunosuppressive cytokine IL10 was slightly increased in the 3G mice. Finally, serum IgG concentration was twice higher whereas IgA concentration was slightly increased (about 30%) and IgM were unchanged in 2G mice compared to controls. No difference was observed in the 3G group with these isotypes. Consequently, functional immune dysregulations and stress responses were dependent of the gravity level. PMID:21724335

  16. Distinct Effects of Chronic Dopaminergic Stimulation on Hippocampal Neurogenesis and Striatal Doublecortin Expression in Adult Mice

    Science.gov (United States)

    Salvi, Rachele; Steigleder, Tobias; Schlachetzki, Johannes C. M.; Waldmann, Elisabeth; Schwab, Stefan; Winner, Beate; Winkler, Jürgen; Kohl, Zacharias

    2016-01-01

    While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ), recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g., the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA) receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX), and Ropinirole (ROP), on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2′-deoxyuridine (BrdU) a proliferation paradigm was performed in which two BrdU injections (100 mg/kg) were applied intraperitoneally within 12 h after a 14-days-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS)-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and Neuronal Nuclei (NeuN) 32 days after the last of five BrdU injections (50 mg/kg) applied at the beginning of 14-days DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX) in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX+ neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active

  17. Distinct effects of chronic dopaminergic stimulation on hippocampal neurogenesis and striatal doublecortin expression in adult mice

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    Rachele eSalvi

    2016-03-01

    Full Text Available While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG and the subventricular zone (SVZ, recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g. the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX and Ropinirole (ROP, on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2'-deoxyuridine (BrdU a proliferation paradigm was performed in which two BrdU injections (100 mg/kg were applied intraperitoneally within 12 hours after a 14-day-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and NeuN 32 days after the last of five BrdU injections (50 mg/kg applied at the beginning of 14-day DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX+ neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active and

  18. Distinct Effects of Chronic Dopaminergic Stimulation on Hippocampal Neurogenesis and Striatal Doublecortin Expression in Adult Mice.

    Science.gov (United States)

    Salvi, Rachele; Steigleder, Tobias; Schlachetzki, Johannes C M; Waldmann, Elisabeth; Schwab, Stefan; Winner, Beate; Winkler, Jürgen; Kohl, Zacharias

    2016-01-01

    While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ), recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g., the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA) receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX), and Ropinirole (ROP), on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2'-deoxyuridine (BrdU) a proliferation paradigm was performed in which two BrdU injections (100 mg/kg) were applied intraperitoneally within 12 h after a 14-days-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS)-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and Neuronal Nuclei (NeuN) 32 days after the last of five BrdU injections (50 mg/kg) applied at the beginning of 14-days DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX) in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX(+) neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active

  19. Chronic minocycline treatment improves social recognition memory in adult male Fmr1 knockout mice.

    Science.gov (United States)

    Yau, Suk Yu; Chiu, Christine; Vetrici, Mariana; Christie, Brian R

    2016-10-01

    Fragile X syndrome (FXS) is caused by a mutation in the Fmr1 gene that leads to silencing of the gene and a loss of its gene product, Fragile X mental retardation protein (FMRP). Some of the key behavioral phenotypes for FXS include abnormal social anxiety and sociability. Here we show that Fmr1 knock-out (KO) mice exhibit impaired social recognition when presented with a novel mouse, and they display normal social interactions in other sociability tests. Administering minocycline to Fmr1 KO mice throughout critical stages of neural development improved social recognition memory in the novel mouse recognition task. To determine if synaptic changes in the prefrontal cortex (PFC) could have played a role in this improvement, we examined PSD-95, a member of the membrane-associated guanylate kinase family, and signaling molecules (ERK1/2, and Akt) linked to synaptic plasticity in the PFC. Our analyses indicated that while minocycline treatment can enhance behavioral performance, it does not enhance expression of PSD-95, ERK1/2 or Akt in the PFC. PMID:27291517

  20. Chronic Schistosoma japonicum infection reduces immune response to vaccine against hepatitis B in mice.

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    Lin Chen

    Full Text Available BACKGROUND: Hepatitis B and schistosomiasis are most prevalent in Africa and Asia, and co-infections of both are frequent in these areas. The immunomodulation reported to be induced by schistosome infections might restrict immune control of hepatitis B virus (HBV leading to more severe viral infection. Vaccination is the most effective measure to control and prevent HBV infection, but there is evidence for a reduced immune response to the vaccine in patients with chronic schistosomiasis japonica. METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we demonstrate in a mouse model that a chronic Schistosoma japonicum infection can inhibit the immune response to hepatitis B vaccine (HBV vaccine and lead to lower production of anti-HBs antibodies, interferon-γ (IFN-γ and interleukin-2 (IL-2. After deworming with Praziquantel (PZQ, the level of anti-HBs antibodies gradually increased and the Th2-biased profile slowly tapered. At 16 weeks after deworming, the levels of anti-HBs antibodies and Th1/Th2 cytokines returned to the normal levels. CONCLUSIONS/SIGNIFICANCE: The results suggest that the preexisting Th2-dominated immune profile in the host infected with the parasite may down-regulate levels of anti-HBs antibodies and Th1 cytokines. To improve the efficacy of HBV vaccination in schistosome infected humans it may be valuable to treat them with praziquantel (PZQ some time prior to HBV vaccination.

  1. Enhanced quantal release of excitatory transmitter in anterior cingulate cortex of adult mice with chronic pain

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    Zhao Ming-Gao

    2009-01-01

    Full Text Available Abstract The anterior cingulate cortex (ACC is a forebrain structure that plays important roles in emotion, learning, memory and persistent pain. Our previous studies have demonstrated that the enhancement of excitatory synaptic transmission was induced by peripheral inflammation and nerve injury in ACC synapses. However, little information is available on their presynaptic mechanisms, since the source of the enhanced synaptic transmission could include the enhanced probability of neurotransmitter release at existing release sites and/or increases in the number of available vesicles. The present study aims to perform quantal analysis of excitatory synapses in the ACC with chronic pain to examine the source of these increases. The quantal analysis revealed that both probability of transmitter release and number of available vesicles were increased in a mouse model of peripheral inflammation, whereas only probability of transmitter release but not number of available vesicles was enhanced in a mouse model of neuropathic pain. In addition, we compared the miniature excitatory postsynaptic potentials (mEPSCs in ACC synapses with those in other pain-related brain areas such as the amygdala and spinal cord. Interestingly, the rate and amplitude of mEPSCs in ACC synapses were significantly lower than those in the amygdala and spinal cord. Our studies provide strong evidences that chronic inflammatory pain increases both probability of transmitter release and number of available vesicles, whereas neuropathic pain increases only probability of transmitter release in the ACC synapses.

  2. Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines

    International Nuclear Information System (INIS)

    Purpose: To determine whether curcumin ameliorates acute and chronic radiation skin toxicity and to examine the expression of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-18, IL-1Ra, tumor necrosis factor [TNF]-α, and lymphotoxin-β) or fibrogenic cytokines (transforming growth factor [TGF]-β) during the same acute and chronic phases. Methods and Materials: Curcumin was given intragastrically or intraperitoneally to C3H/HeN mice either: 5 days before radiation; 5 days after radiation; or both 5 days before and 5 days after radiation. The cutaneous damage was assessed at 15-21 days (acute) and 90 days (chronic) after a single 50 Gy radiation dose was given to the hind leg. Skin and muscle tissues were collected for measurement of cytokine mRNA. Results: Curcumin, administered before or after radiation, markedly reduced acute and chronic skin toxicity in mice (p < 0.05). Additionally, curcumin significantly decreased mRNA expression of early responding cytokines (IL-1 IL-6, IL-18, TNF-α, and lymphotoxin-β) and the fibrogenic cytokine, TGF-β, in cutaneous tissues at 21 days postradiation. Conclusion: Curcumin has a protective effect on radiation-induced cutaneous damage in mice, which is characterized by a downregulation of both inflammatory and fibrogenic cytokines in irradiated skin and muscle, particularly in the early phase after radiation. These results may provide the molecular basis for the application of curcumin in clinical radiation therapy

  3. The catecholaminergic system in the hypothalamus of chronically gamma-irradiated mice

    International Nuclear Information System (INIS)

    Effect of continuous gamma-irradiation of rats at 1.1 and 2.1 cGy/day dose rate on the content of dopamine (DA) and noradrenaline (NA) in the hypothalamus responsible for relation between the nerve and endocrine systems playing very important role in genesis of many pathologic states in organism was studied. Abrupt changes of the content of catecholamines (DA and NA) in hypothalamus at 9-165 cGy dose range irradiation (dose rate constituted 1.1 cGy/day) and at 17-315 cGy dose range irradiation (dose rate - 2.1 cGy/day) were detected. Dose dependence of the effect was of non-monotonic nature. Conclusion was made as to high sensitivity of sympathetic-adrenal system to the effect of chronic low-dose gamma-irradiation

  4. Influence of KeGan Capsule to Mice with CC14 Chronic Hepatic Injury

    Institute of Scientific and Technical Information of China (English)

    XUYufang

    2004-01-01

    To study the action of KeGan capsule to resist injury of hepatic cells and fibrosis of liver. Methods Rephcate model of chronic hepatic injury with CC14, at the beginning of which KeGan capsule was applied; finishing experiment, respectively tested the level of liver fimction, TP,ALB, A/G, L-hydroxyproline and liver index and do pathologic examination to fiver. Results KeGan capsule can obviously reduce the degree of fibrosis of liver and the level of L - hydroxyproline, improve the fiver function. The histological examination showed that capsule has the action of protecting hepatic cells from injury and resisting fibrosis of fiver either. Conclusion For KeGan capsule has the action of resisting injury of liver cells and fibrosis of liver, it' s hoped to be applied in precaution and treatment of fibrosis of fiver.

  5. Deletion of GSTA4-4 results in increased mitochondrial post-translational modification of proteins by reactive aldehydes following chronic ethanol consumption in mice.

    Science.gov (United States)

    Shearn, Colin T; Fritz, Kristofer S; Shearn, Alisabeth H; Saba, Laura M; Mercer, Kelly E; Engi, Bridgette; Galligan, James J; Zimniak, Piotr; Orlicky, David J; Ronis, Martin J; Petersen, Dennis R

    2016-04-01

    Chronic alcohol consumption induces hepatic oxidative stress resulting in production of highly reactive electrophilic α/β-unsaturated aldehydes that have the potential to modify proteins. A primary mechanism of reactive aldehyde detoxification by hepatocytes is through GSTA4-driven enzymatic conjugation with GSH. Given reports that oxidative stress initiates GSTA4 translocation to the mitochondria, we hypothesized that increased hepatocellular damage in ethanol (EtOH)-fed GSTA4(-/-) mice is due to enhanced mitochondrial protein modification by reactive aldehydes. Chronic ingestion of EtOH increased hepatic protein carbonylation in GSTA4(-/-) mice as evidenced by increased 4-HNE and MDA immunostaining in the hepatic periportal region. Using mass spectrometric analysis of biotin hydrazide conjugated carbonylated proteins, a total of 829 proteins were identified in microsomal, cytosolic and mitochondrial fractions. Of these, 417 were novel to EtOH models. Focusing on mitochondrial fractions, 1.61-fold more carbonylated proteins were identified in EtOH-fed GSTA4(-)(/-) mice compared to their respective WT mice ingesting EtOH. Bioinformatic KEGG pathway analysis of carbonylated proteins from the mitochondrial fractions revealed an increased propensity for modification of proteins regulating oxidative phosphorylation, glucose, fatty acid, glutathione and amino acid metabolic processes in GSTA4(-/-) mice. Additional analysis revealed sites of reactive aldehyde protein modification on 26 novel peptides/proteins isolated from either SV/GSTA4(-/-) PF or EtOH fed mice. Among the peptides/proteins identified, ACSL, ACOX2, MTP, and THIKB contribute to regulation of fatty acid metabolism and ARG1, ARLY, and OAT, which regulate nitrogen and ammonia metabolism having direct relevance to ethanol-induced liver injury. These data define a role for GSTA4-4 in buffering hepatic oxidative stress associated with chronic alcohol consumption and that this GST isoform plays an important

  6. Deletion of GSTA4-4 results in increased mitochondrial post-translational modification of proteins by reactive aldehydes following chronic ethanol consumption in mice

    Directory of Open Access Journals (Sweden)

    Colin T. Shearn

    2016-04-01

    Full Text Available Chronic alcohol consumption induces hepatic oxidative stress resulting in production of highly reactive electrophilic α/β-unsaturated aldehydes that have the potential to modify proteins. A primary mechanism of reactive aldehyde detoxification by hepatocytes is through GSTA4-driven enzymatic conjugation with GSH. Given reports that oxidative stress initiates GSTA4 translocation to the mitochondria, we hypothesized that increased hepatocellular damage in ethanol (EtOH-fed GSTA4−/− mice is due to enhanced mitochondrial protein modification by reactive aldehydes. Chronic ingestion of EtOH increased hepatic protein carbonylation in GSTA4−/− mice as evidenced by increased 4-HNE and MDA immunostaining in the hepatic periportal region. Using mass spectrometric analysis of biotin hydrazide conjugated carbonylated proteins, a total of 829 proteins were identified in microsomal, cytosolic and mitochondrial fractions. Of these, 417 were novel to EtOH models. Focusing on mitochondrial fractions, 1.61-fold more carbonylated proteins were identified in EtOH-fed GSTA4−/− mice compared to their respective WT mice ingesting EtOH. Bioinformatic KEGG pathway analysis of carbonylated proteins from the mitochondrial fractions revealed an increased propensity for modification of proteins regulating oxidative phosphorylation, glucose, fatty acid, glutathione and amino acid metabolic processes in GSTA4−/− mice. Additional analysis revealed sites of reactive aldehyde protein modification on 26 novel peptides/proteins isolated from either SV/GSTA4−/− PF or EtOH fed mice. Among the peptides/proteins identified, ACSL, ACOX2, MTP, and THIKB contribute to regulation of fatty acid metabolism and ARG1, ARLY, and OAT, which regulate nitrogen and ammonia metabolism having direct relevance to ethanol-induced liver injury. These data define a role for GSTA4-4 in buffering hepatic oxidative stress associated with chronic alcohol consumption and that this GST

  7. Role of endogenous and exogenous female sex hormones in arthritis and osteoporosis development in B10.Q-ncf1*/* mice with collagen-induced chronic arthritis

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    Gjertsson Inger

    2010-12-01

    Full Text Available Abstract Background Collagen-induced arthritis (CIA is an often-used murine model for human rheumatoid arthritis (RA. Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM raloxifene in CIA in DBA/1-mice. B10.Q-ncf1*/*mice are B10.Q mice with a mutated Ncf1 gene. In B10.Q-ncf1*/*mice, CIA develops as a chronic relapsing disease, which more accurately mimics human RA. We investigated the role of endogenous and exogenous sex steroids and raloxifene in the course of this model of chronic arthritis. We also examined whether treatment would prevent the development of inflammation-triggered generalized osteoporosis. Methods Female B10.Q-ncf1*/*mice were sham-operated or ovariectomized, and CIA was induced. 22 days later, when 30% of the mice had developed arthritis, treatment with raloxifene, estradiol or vehicle was started, and the clinical disease was evaluated continuously. Treatment was continued until day 56 after immunization. At termination of the experiment (day 73, bone mineral density (BMD was analyzed, paws were collected for histological examination, and sera were analyzed for markers of cartilage turnover and pro-inflammatory cytokines. Results Raloxifene and estradiol treatment, as well as endogenous estrogen, decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis. These effects were associated with lower serum levels of the pro-inflammatory cytokine IL-6. Conclusions This is the first study to show that raloxifene and estradiol can ameliorate established erosive arthritis and inflammation-triggered osteoporosis in this chronic arthritis model. We propose that treatment with raloxifene could be a beneficial addition to the treatment of postmenopausal RA.

  8. Identification of surface antigens of schistosomula of Schistosoma mansoni recognized by antibodies from mice immunized by chronic infection and by exposure to highly irradiated cercariae

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    Simpson, A.J.; James, S.L.; Sher, A.

    1983-08-01

    Surface components of mechanically transformed schistosomula of Schistosoma mansoni were labeled by lactoperoxidase-catalyzed iodination. After solubilization with Triton X-100, antigens were identified by immunoprecipitation. Serum from chronically infected Swiss mice reproducibly precipitated seven major polypeptides with approximate molecular weights (X 10/sup 3/) of 94, 68, 45, 40 to 32, 22, and 16. The antigens of molecular weights (X 10/sup 3/) of 94, 40 to 32, 22, and 16 were shown to be exposed on the parasite surface by interaction of the antibodies with intact labeled schistosomula. Sera from several strains of infected inbred mice precipitated the same polypeptides. The antibodies produced during chronic infection were found to be stimulated by adult worms since sera from 6-week-infected animals precipitated none of the surface antigens, and the pattern produced by precipitation with antibodies from a mouse infected with male worms only was indistinguishable from the pattern obtained with sera from mice with bisexual infections. Antibodies from mice immunized with highly irradiated cercariae reproducibly precipitated major polypeptides of approximately (X 10/sup 3/) 94, 68, 45, 32, 22, 19, and 15 daltons. The antigens of (X 10/sup 3/) 94, 43, 32, 22, and 15 daltons were shown to be exposed on the parasite surface by interaction of the antibodies with intact labeled schistosomula. The 15 X 10(3)-dalton surface protein was recognized by sera from vaccinated, but not chronically infected, mice, suggesting that it represents a stage-specific immunogen present on schistosomula but not on adult worms. Sera from two inbred strains of mice which develop different degrees of immunity recognized the same antigens.

  9. Identification of surface antigens of schistosomula of Schistosoma mansoni recognized by antibodies from mice immunized by chronic infection and by exposure to highly irradiated cercariae

    International Nuclear Information System (INIS)

    Surface components of mechanically transformed schistosomula of Schistosoma mansoni were labeled by lactoperoxidase-catalyzed iodination. After solubilization with Triton X-100, antigens were identified by immunoprecipitation. Serum from chronically infected Swiss mice reproducibly precipitated seven major polypeptides with approximate molecular weights (X 103] of 94, 68, 45, 40 to 32, 22, and 16. The antigens of molecular weights (X 103] of 94, 40 to 32, 22, and 16 were shown to be exposed on the parasite surface by interaction of the antibodies with intact labeled schistosomula. Sera from several strains of infected inbred mice precipitated the same polypeptides. The antibodies produced during chronic infection were found to be stimulated by adult worms since sera from 6-week-infected animals precipitated none of the surface antigens, and the pattern produced by precipitation with antibodies from a mouse infected with male worms only was indistinguishable from the pattern obtained with sera from mice with bisexual infections. Antibodies from mice immunized with highly irradiated cercariae reproducibly precipitated major polypeptides of approximately (X 103] 94, 68, 45, 32, 22, 19, and 15 daltons. The antigens of (X 103] 94, 43, 32, 22, and 15 daltons were shown to be exposed on the parasite surface by interaction of the antibodies with intact labeled schistosomula. The 15 X 10(3)-dalton surface protein was recognized by sera from vaccinated, but not chronically infected, mice, suggesting that it represents a stage-specific immunogen present on schistosomula but not on adult worms. Sera from two inbred strains of mice which develop different degrees of immunity recognized the same antigens

  10. L-Tetrahydropalmatine alleviates mechanical hyperalgesia in models of chronic inflammatory and neuropathic pain in mice.

    Science.gov (United States)

    Zhou, Hai-Hui; Wu, Dan-Lian; Gao, Li-Yan; Fang, Yun; Ge, Wei-Hong

    2016-05-01

    Chronic pain is categorized as inflammatory and neuropathic, and there are common mechanisms underlying the generation of each pain state. Such pain is difficult to treat and the treatment at present is inadequate. Corydalis yanhusuo is a traditional Chinese medicine with demonstrated analgesic efficacy in humans. The potential antihyperalgesic effect of its active component is L-tetrahydropalmatine (L-THP). L-THP has been used for the treatment of headache and other mild pain. However, little is known about its analgesic effect on chronic pain and its mechanism. Here, we report that L-THP exerts remarkable antihyperalgesic effects on neuropathic and inflammatory pain in animal models. Neuropathic hypersensitivity was induced by segmental spinal nerve ligation and inflammatory hypersensitivity was induced by an intraplantar injection of complete Freund's adjuvant. To determine the receptor mechanism underlying the antihyperalgesic actions of L-THP, we used SCH23390, an antagonist of a dopamine D1 receptor, in an attempt to block the antihyperalgesic effects of L-THP. We found that L-THP (1-4 mg/kg, i.p.) produced a dose-dependent antihyperalgesic effect in spinal nerve ligation and complete Freund's adjuvant models. The antihyperalgesic effects of L-THP were abolished by a dopamine D1 receptor antagonist SCH23390 (0.02 mg/kg). Furthermore, L-THP (4 mg/kg, i.p.) did not influence motor function. These findings suggest that L-THP may ameliorate mechanical hyperalgesia by enhancing dopamine D1 receptor-mediated dopaminergic transmission. PMID:26981712

  11. Chronic oligodendrogenesis and remyelination after spinal cord injury in mice and rats.

    Science.gov (United States)

    Hesp, Zoe C; Goldstein, Evan Z; Goldstein, Evan A; Miranda, Carlos J; Kaspar, Brian K; Kaspar, Brain K; McTigue, Dana M

    2015-01-21

    Adult progenitor cells proliferate in the acutely injured spinal cord and their progeny differentiate into new oligodendrocytes (OLs) that remyelinate spared axons. Whether this endogenous repair continues beyond the first week postinjury (wpi), however, is unknown. Identifying the duration of this response is essential for guiding therapies targeting improved recovery from spinal cord injury (SCI) by enhancing OL survival and/or remyelination. Here, we used two PDGFRα-reporter mouse lines and rats injected with a GFP-retrovirus to assess progenitor fate through 80 d after injury. Surprisingly, new OLs were generated as late as 3 months after injury and their processes ensheathed axons near and distal to the lesion, colocalized with MBP, and abutted Caspr+ profiles, suggesting newly formed myelin. Semithin sections confirmed stereotypical thin OL remyelination and few bare axons at 10 wpi, indicating that demyelination is relatively rare. Astrocytes in chronic tissue expressed the pro-OL differentiation and survival factors CNTF and FGF-2. In addition, pSTAT3+ NG2 cells were present through at least 5 wpi, revealing active signaling of the Jak/STAT pathway in these cells. The progenitor cell fate genes Sox11, Hes5, Id2, Id4, BMP2, and BMP4 were dynamically regulated for at least 4 wpi. Collectively, these data verify that the chronically injured spinal cord is highly dynamic. Endogenous repair, including oligodendrogenesis and remyelination, continues for several months after SCI, potentially in response to growth factors and/or transcription factor changes. Identifying and understanding spontaneous repair processes such as these is important so that beneficial plasticity is not inadvertently interrupted and effort is not exerted to needlessly duplicate ongoing spontaneous repair. PMID:25609641

  12. Chronic 835-MHz radiofrequency exposure to mice hippocampus alters the distribution of calbindin and GFAP immunoreactivity.

    Science.gov (United States)

    Maskey, Dhiraj; Pradhan, Jonu; Aryal, Bijay; Lee, Chang-Min; Choi, In-Young; Park, Ki-Sup; Kim, Seok Bae; Kim, Hyung Gun; Kim, Myeung Ju

    2010-07-30

    Exponential interindividual handling in wireless communication system has raised possible doubts in the biological aspects of radiofrequency (RF) exposure on human brain owing to its close proximity to the mobile phone. In the nervous system, calcium (Ca(2+)) plays a critical role in releasing neurotransmitters, generating action potential and membrane integrity. Alterations in intracellular Ca(2+) concentration trigger aberrant synaptic action or cause neuronal apoptosis, which may exert an influence on the cellular pathology for learning and memory in the hippocampus. Calcium binding proteins like calbindin D28-K (CB) is responsible for the maintaining and controlling Ca(2+) homeostasis. Therefore, in the present study, we investigated the effect of RF exposure on rat hippocampus at 835 MHz with low energy (specific absorption rate: SAR=1.6 W/kg) for 3 months by using both CB and glial fibrillary acidic protein (GFAP) specific antibodies by immunohistochemical method. Decrease in CB immunoreactivity (IR) was noted in exposed (E1.6) group with loss of interneurons and pyramidal cells in CA1 area and loss of granule cells. Also, an overall increase in GFAP IR was observed in the hippocampus of E1.6. By TUNEL assay, apoptotic cells were detected in the CA1, CA3 areas and dentate gyrus of hippocampus, which reflects that chronic RF exposure may affect the cell viability. In addition, the increase of GFAP IR due to RF exposure could be well suited with the feature of reactive astrocytosis, which is an abnormal increase in the number of astrocytes due to the loss of nearby neurons. Chronic RF exposure to the rat brain suggested that the decrease of CB IR accompanying apoptosis and increase of GFAP IR might be morphological parameters in the hippocampus damages. PMID:20546709

  13. Chronic radiation injury with mice and dogs exposed to external whole-body irradiation at the Argonne National Laboratory

    International Nuclear Information System (INIS)

    This document describes studies on chronic radiation injury in experimental animals and the extrapolation of derived injury parameters to man. Most of the large studies have used mice given single, weekly, or continuous exposure to cobalt-60 gamma rays, or, more recently, single or weekly exposure to fission neutrons from the JANUS reactor. Primary measures of injury have been life shortening and the associated major pathological changes, particularly neoplastic diseases. Recent and ongoing studies compare the effects of extremely low neutron exposures with gamma irradiations delivered as a single dose or in 60 equal weekly increments. Total neutron doses range from 1 to 40 rads; gamma-ray doses range from 22.5 to 600 rads. Selected genetic studies are performed concurrently to provide a nearly complete matrix of somatic and genetic effects of these low exposures. Studies with the beagle have complemented those with mice and have shown a strong parallelism in the responses of the two species. Present exposures are at 0.3, 0.75, and 1.88 rads per day of continuous gamma irradiation to test a model for the prediction of life shortening in man which has evolved from Argonne's long-term studies. The dog offers the opportunity for longitudinal clinical evaluations that are not possible in the mouse, to develop a broader view of the neoplastic disease spectrum, and to study the mechanisms of radiation induction of leukemia. Diverse statistical approaches have been used to measure excess risk, dose-response functions, and rates of injury and repair. Actuarial statistical methods have been favored since they permit a more direct means of extrapolation to man. 50 refs., 4 figs

  14. Repeated Closed Head Injury in Mice Results in Sustained Motor and Memory Deficits and Chronic Cellular Changes

    Science.gov (United States)

    Bolton Hall, Amanda N.; Joseph, Binoy; Brelsfoard, Jennifer M.; Saatman, Kathryn E.

    2016-01-01

    Millions of mild traumatic brain injuries (TBIs) occur every year in the United States, with many people subject to multiple head injuries that can lead to chronic behavioral dysfunction. We previously reported that mild TBI induced using closed head injuries (CHI) repeated at 24h intervals produced more acute neuron death and glial reactivity than a single CHI, and increasing the length of time between injuries to 48h reduced the cumulative acute effects of repeated CHI. To determine whether repeated CHI is associated with behavioral dysfunction or persistent cellular damage, mice receiving either five CHI at 24h intervals, five CHI at 48h intervals, or five sham injuries at 24h intervals were evaluated across a 10 week period after injury. Animals with repeated CHI exhibited motor coordination and memory deficits, but not gait abnormalities when compared to sham animals. At 10wks post-injury, no notable neuron loss or glial reactivity was observed in the cortex, hippocampus, or corpus callosum. Argyrophilic axons were found in the pyramidal tract of some injured animals, but neither silver stain accumulation nor inflammatory responses in the injury groups were statistically different from the sham group in this region. However, argyrophilic axons, microgliosis and astrogliosis were significantly increased within the optic tract of injured animals. Repeated mild CHI also resulted in microgliosis and a loss of neurofilament protein 200 in the optic nerve. Lengthening the inter-injury interval from 24h to 48h did not effectively reduce these behavioral or cellular responses. These results suggest that repeated mild CHI results in persistent behavioral dysfunction and chronic pathological changes within the visual system, neither of which was significantly attenuated by lengthening the inter-injury interval from 24h to 48h. PMID:27427961

  15. Effect of recombinant human interleukin-2 on the course of experimental chronic respiratory tract infection caused by Klebsiella pneumoniae in mice.

    OpenAIRE

    Iizawa, Y; Nishi, T; Kondo, M.; Tsuchiya, K.; Imada, A

    1988-01-01

    The effect of recombinant human interleukin-2 (rIL-2) on the course of experimental chronic respiratory tract infection caused by Klebsiella pneumoniae in mice was examined. rIL-2 was administered subcutaneously once a day for 7 or 14 days, starting 2 weeks after the mice were infected. Administration of 2 or 20 micrograms of rIL-2 per mouse daily for 7 days reduced bacterial counts in the lungs dose dependently. At a dose of 0.2 microgram per day, proliferation of bacteria in the lungs was s...

  16. Long-Term Immunity to Lethal Acute or Chronic Type II Toxoplasma gondii Infection Is Effectively Induced in Genetically Susceptible C57BL/6 Mice by Immunization with an Attenuated Type I Vaccine Strain▿

    OpenAIRE

    Gigley, Jason P.; Fox, Barbara A.; Bzik, David J.

    2009-01-01

    C57BL/6 (B6) mice are genetically highly susceptible to chronic type II Toxoplasma gondii infections that invariably cause lethal toxoplasmic encephalitis. We examined the ability of an attenuated type I vaccine strain to elicit long-term immunity to lethal acute or chronic type II infections in susceptible B6 mice. Mice immunized with the type I cps1-1 vaccine strain were not susceptible to a lethal (100-cyst) challenge with the type II strain ME49. Immunized mice challenged with 10 ME49 cys...

  17. Chronic proliferative dermatitis in Sharpin null mice: development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling.

    Directory of Open Access Journals (Sweden)

    Christopher S Potter

    Full Text Available SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM, typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1(-/- mice, which lack mature B and T cells, were crossed with Sharpin(-/- mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra(-/- mice, unresponsive to both IL4 and IL13, were crossed with Sharpin(-/- mice. Double homozygous Sharpin(-/- , Il4ra(-/- mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin(-/- , Il4ra(-/- double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin(-/- , Il4ra(-/- mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin(-/- mice and this was maintained in Sharpin(-/- , Il4ra(-/- mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and IL13 signaling

  18. Repeated and chronic administration of Vardenafil or Sildenafil differentially affects emotional and socio-sexual behavior in mice.

    Science.gov (United States)

    Dadomo, H; Parmigiani, S; Nicolini, Y; Freschini, S; Gioiosa, L; Patrelli, T S; Palanza, P; Volpi, R

    2013-09-15

    Selective phosphodiesterases (PDEs) inhibitors have been widely studied as therapeutic agents for treatment of various human diseases, including cardiotonics, vasodilators, smooth muscle relaxants, antidepressants, antithrombotics, antiasthmatics, and agents for improving learning and memory. Although Sildenafil(®) and Vardenafil(®) have similar chemical formulae, the same target and interact with many of the same residues at the active site of phosphodiesterse-5 (PDE-5), they exhibit both in vitro and in vivo some important functional differences that could differentially affect behavior. Therefore we assessed whether repeated and chronic administration of Vardenafil and Sildenafil at a dose based upon human treatment can differentially affect aggressive, social, emotional and sexual behavior. To this aim, the effects of Sildenafil (10mg/kg) or Vardenafil (2mg/kg) (t.i.w., for 5 weeks) were observed in CD1 subordinate male mice in a low aggression and social subordination context. The results show that Sildenafil increased competitive aggression, environmental and social exploration, and reduced anxiety like behaviors as compared to controls, whereas Vardenafil had a significant major effect on appetitive and consummatory aspect of sexual behavior. This demonstrates that Sildenafil and Vardenafil, although being structurally and functionally similar, are characterized by different neuro-behavioral actions and can have differential therapeutic potentials. PMID:23850358

  19. Anti-nociceptive and anti-inflammatory effects of cyanocobalamin (vitamin B12) against acute and chronic pain and inflammation in mice.

    Science.gov (United States)

    Hosseinzadeh, H; Moallem, S A; Moshiri, M; Sarnavazi, M S; Etemad, L

    2012-07-01

    In this study, the anti-nociceptive and anti-inflammatory effects of cyanocobalamin (Vit B12) against acute and chronic pain and inflammation were evaluated in mice. Vit B12 (0.87, 1 and 1.77 mg/kg) were injected intraperitoneally. The anti-nociceptive effects against acute pain were examined using hot-plate and writhing tests. The chronic pain was examined 14 days after sciatic nerve ligation using the hot-plate test. Morphine (10 mg/kg) was used as a positive control. Anti-inflammatory effects of Vit B12 against acute and chronic inflammation were assessed using xylene-induced edema in ears and granuloma caused by compressed cotton implantation, respectively. In these tests, sodium diclofenac (15 mg/kg) was used as a positive control. Vit B12 showed a dose related effect in acute anti-nociceptive test and increased the anti-nociceptive effect of morphine in chronic treatment. Vit B12 demonstrated an anti-nociceptive effect in chronic studies as single or continues daily treatment and increased significantly the anti-nociceptive effect of morphine. All doses of Vit B12 significantly decreased xylene-induced ear edema. Maximum anti-inflammatory effect (37.5%) was obtained at dose of 1 mg/kg. In chronic inflammation, Vit B12 significantly decreased granuloma formation in mice. In conclusion our work presents some experimental evidence supporting the administration of cyanocobalamin in controlling acute and chronic neuropathic pain. Cyanocobalamin may have anti-inflammatory effect. It may reduce tolerance to anti-nociceptive effect of morphine as well. PMID:22588629

  20. Sex-specific effects of chronic fluoxetine treatment on neuroplasticity and pharmacokinetics in mice.

    Science.gov (United States)

    Hodes, Georgia E; Hill-Smith, Tiffany E; Suckow, Raymond F; Cooper, Thomas B; Lucki, Irwin

    2010-01-01

    Neurogenesis is a mechanism through which antidepressants may produce therapeutic effects. There is a dearth of information regarding the effects of antidepressants on neurogenesis and neurotrophin mobilization in females. This study examined sex differences in the alteration of cell proliferation and survival in multiple regions of the brain. Additional experiments examined brain-derived neurotrophic factor (BDNF) levels and pharmacokinetics of fluoxetine to determine whether they mediate sex differences. MRL/MpJ mice were treated with fluoxetine (5 and 10 mg/kg b.i.d.) for 21 days and received injections of 5-bromo-2'-deoxyuridine (200 mg/kg) to measure DNA synthesis. In the hippocampus, fluoxetine increased cell proliferation at both doses; females treated with 10 mg/kg produced more new cells than males. Fluoxetine did not alter survival in males, but 10 mg/kg reduced survival in females. In the frontal cortex, fluoxetine increased cell proliferation and survival in males treated with 10 mg/kg. In the cerebellum and amygdala, 10 mg/kg fluoxetine increased cell proliferation in both sexes but did not alter the incorporation of the new cells. Fluoxetine increased BDNF levels in the hippocampus of both sexes. BDNF levels correlated with cell proliferation in males but not females. Brain and plasma levels indicated that females metabolized fluoxetine faster than males and produced more of the metabolite norfluoxetine. These data suggest that fluoxetine acts on multiple areas of the brain to increase cell proliferation, and the pattern of activation differs between males and females. Sex-specific effects of fluoxetine on neurotrophin mobilization and pharmacokinetics may contribute to these differences in neural plasticity. PMID:19828877

  1. Physiological and neuroendocrine responses to chronic variable stress in male California mice (Peromyscus californicus): influence of social environment and paternal state

    OpenAIRE

    De Jong, TR; Harris, BN; Perea-Rodriguez, JP; Saltzman, W

    2013-01-01

    Social environment and parental state affect stress responses in mammals, but their impact may depend on the social and reproductive strategy of the species. The influences of cohabitation with a male or female conspecific, and the birth of offspring, on the physiological and endocrine responses to chronic variable stress were studied in the monogamous and biparental California mouse (Peromyscus californicus). Adult male California mice were housed either with a male cage ma...

  2. Effects of chronic expression of the HIV-induced protein, transactivator of transcription, on circadian activity rhythms in mice, with or without morphine

    OpenAIRE

    Duncan, Marilyn J.; Bruce-Keller, Annadora J.; Conner, Clayton; Knapp, Pamela E.; Xu, Ruquiang; Nath, Avindra; Hauser, Kurt F.

    2008-01-01

    Patients with human immunodeficiency virus (HIV) infection exhibit changes in sleep patterns, motor disorders, and cognitive dysfunction; these symptoms may be secondary to circadian rhythm abnormalities. Studies in mice have shown that intracerebral injection of an HIV protein, transactivator of transcription (Tat), alters the timing of circadian rhythms in a manner similar to light. Therefore, we tested the hypothesis that chronic Tat expression alters circadian rhythms, especially their en...

  3. Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men.

    Science.gov (United States)

    Ojo, Joseph O; Mouzon, Benoit C; Crawford, Fiona

    2016-01-01

    Chronic traumatic encephalopathy (CTE) is a neurological and psychiatric condition marked by preferential perivascular foci of neurofibrillary and glial tangles (composed of hyperphosphorylated-tau proteins) in the depths of the sulci. Recent retrospective case series published over the last decade on athletes and military personnel have added considerably to our clinical and histopathological knowledge of CTE. This has marked a vital turning point in the traumatic brain injury (TBI) field, raising public awareness of the potential long-term effects of mild and moderate repetitive TBI, which has been recognized as one of the major risk factors associated with CTE. Although these human studies have been informative, their retrospective design carries certain inherent limitations that should be cautiously interpreted. In particular, the current overriding issue in the CTE literature remains confusing in regard to appropriate definitions of terminology, variability in individual pathologies and the potential case selection bias in autopsy based studies. There are currently no epidemiological or prospective studies on CTE. Controlled preclinical studies in animals therefore provide an alternative means for specifically interrogating aspects of CTE pathogenesis. In this article, we review the current literature and discuss difficulties and challenges of developing in-vivo TBI experimental paradigms to explore the link between repetitive head trauma and tau-dependent changes. We provide our current opinion list of recommended features to consider for successfully modeling CTE in animals to better understand the pathobiology and develop therapeutics and diagnostics, and critical factors, which might influence outcome. We finally discuss the possible directions of future experimental research in the repetitive TBI/CTE field. PMID:26054886

  4. Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress.

    Science.gov (United States)

    Arp, J Marit; Ter Horst, Judith P; Loi, Manila; den Blaauwen, Jan; Bangert, Eline; Fernández, Guillén; Joëls, Marian; Oitzl, Melly S; Krugers, Harm J

    2016-09-01

    Early life adversity can have long-lasting impact on learning and memory processes and increase the risk to develop stress-related psychopathologies later in life. In this study we investigated (i) how chronic early life stress (ELS) - elicited by limited nesting and bedding material from postnatal day 2 to 9 - affects conditioned fear in adult mice and (ii) whether these effects can be prevented by blocking glucocorticoid receptors (GRs) at adolescent age. In adult male and female mice, ELS did not affect freezing behavior to the first tone 24h after training in an auditory fear-conditioning paradigm. Exposure to repeated tones 24h after training also resulted in comparable freezing behavior in ELS and control mice, both in males and females. However, male (but not female) ELS compared to control mice showed significantly more freezing behavior between the tone-exposures, i.e. during the cue-off periods. Intraperitoneal administration of the GR antagonist RU38486 during adolescence (on postnatal days 28-30) fully prevented enhanced freezing behavior during the cue-off period in adult ELS males. Western blot analysis revealed no effects of ELS on hippocampal expression of glucocorticoid receptors, neither at postnatal day 28 nor at adult age, when mice were behaviorally tested. We conclude that ELS enhances freezing behavior in adult mice in a potentially safe context after cue-exposure, which can be normalized by brief blockade of glucocorticoid receptors during the critical developmental window of adolescence. PMID:27246249

  5. Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice

    Directory of Open Access Journals (Sweden)

    Margarita Vida

    2015-07-01

    Full Text Available Interleukin-6 (IL-6 has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD in wild-type (WT and IL-6-deficient (IL-6−/− mice. Additionally, HFD-fed IL-6−/− mice were also chronically treated with recombinant IL-6 (rIL-6. Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1 and signal transducer and activator of transcription-3 (STAT3, increased AMP kinase phosphorylation (p-AMPK, and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS and stearoyl-CoA desaturase 1 (SCD1. The HFD-fed IL-6−/− mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β, FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6−/− mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.

  6. Polyclonal immunoglobulins from a chronic hepatitis C virus patient protect human liver-chimeric mice from infection with a homologous hepatitis C virus strain

    DEFF Research Database (Denmark)

    Vanwolleghem, Thomas; Bukh, Jens; Meuleman, Philip;

    2008-01-01

    chimeric mice, the inoculum was pre-incubated in vitro at an IgG concentration normally observed in humans. Conclusion: Polyclonal IgG from a patient with a long-standing HCV infection not only displays neutralizing activity in vitro using the HCVpp system, but also conveys sterilizing immunity toward the......The role of the humoral immune response in the natural course of hepatitis C virus (HCV) infection is widely debated. Most chronically infected patients have immunoglobulin G (IgG) antibodies capable of neutralizing HCV pseudoparticles (HCVpp) in vitro. It is, however, not clear whether these Ig......G can prevent a de novo HCV infection in vivo and contribute to the control of viremia in infected individuals. We addressed this question with homologous in vivo protection studies in human liver-urokinase-type plasminogen activator (uPA)(+/+) severe combined immune deficient (SCID) mice. Chimeric mice...

  7. Effects of estradiol-17β and bisphenol A administered chronically to mice throughout pregnancy and lactation on the male pups' reproductive system

    Institute of Scientific and Technical Information of China (English)

    Atsushi Okada; Osamu Kai

    2008-01-01

    Aim: To assess the effect of estradiol-17β(E2) and bisphenol A (BPA) administered chronically by implanting a silicone tube throughout pregnancy and lactation on male pups' reproductive system in ICR mice. Methods: Female mice were implanted with a tube filled with I0 ng, 500 ng, 1 μg, or 10 μg of E2, or 100 μg or 5 mg of BPA, before mating. The tube was kept in the mice throughout pregnancy and lactation, until the pups had weaned at 4 weeks of age. During the period, E2 was released from the tube at 120 pg or 6, 12 or 120 ng/day, and BPA at 1.2 or 60 μg/day. Results: Most of the mice given 1 μg and 10 μg of E2 did not maintain their pregnancy. However, the other groups showed high rates of birth, more than 70%. At age of 4 weeks, the male pups were killed. Body weight and reproductive organ weights (testes, epididymides and accessory reproductive glands) in the treated groups did not differ from the control values, whereas the percentage of seminiferous tubules in the testis with mature spermatids was significantly lower in the groups given 10 ng and 500 ng of E2 and 5 mg of BPA than that in the control. Conclusion: Chronic exposure to E2 and BPA might disrupt spermatogenesis in male pups.

  8. The flexDrive: An ultra-light implant for optical control and highly parallel chronic recording of neuronal ensembles in freely moving mice

    Directory of Open Access Journals (Sweden)

    Jakob eVoigts

    2013-05-01

    Full Text Available Electrophysiological recordings from ensembles of neurons in behaving mice are a central tool in the study of neural circuits. Despite the widespread use of chronic electrophysiology, the precise positioning of recording electrodes required for high-quality recordings remains a challenge, especially in behaving mice.The complexity of available drive mechanisms, combined with restrictions on implant weight tolerated by mice, limits current methods to recordings from no more than 4-8 electrodes in a single target area. We developed a highly miniaturized yet simple drive design that can be used to independently position 16 electrodes with up to 64 channels in a package that weighs approximately 2g. This advance over current designs is achieved by a novel spring-based drive mechanism that reduces implant weight and complexity. The device is easy to build and accommodates arbitrary spatial arrangements of electrodes. Multiple optical fibers can be integrated into the recording array and independently manipulated in depth. Thus, our novel design enables precise optogenetic control and highly parallel chronic recordings of identified single neurons throughout neural circuits in mice.

  9. Acute and chronic treatment with selective serotonin uptake inhibitors in mice: effects on nociceptive sensitivity and response to 5-methoxy-N,N-dimethyltryptamine.

    Science.gov (United States)

    Eide, P K; Hole, K

    1988-03-01

    The tail-flick and increasing temperature hot-plate tests were employed to study the effects of acute or chronic treatment with zimelidine, alaproclate or chlorimipramine on nociception and response to 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) in mice. A single dose of the serotonin (5-HT) uptake inhibitors produced antinociception in the hot-plate test but not in the tail-flick test. After chronic administration, reduced tail-flick latencies were demonstrated 24, 48, 72 and 144 h after withdrawal of zimelidine treatment, 48 h after withdrawal of alaproclate and 48 and 96 h after withdrawal of chlorimipramine treatment. The hot-plate response temperatures were slightly lowered after chronic zimelidine treatment but not after treatment with alaproclate or chlorimipramine. The response to 5-MeODMT was not altered by a single dose of the 5-HT uptake inhibitors, however, after withdrawal of chronic treatment this response was increased in the tail-flick test but not in the hot-plate test. It was concluded that acute and chronic treatment with 5-HT uptake inhibitors modulate nociception differently, and that chronic treatment induces supersensitivity of spinal postsynaptic 5-HT receptors. Different modulation of different 5-HT receptor subpopulations by these compounds may possibly contribute to the test-dependent results. PMID:2966334

  10. Regular moderate or intense exercise prevents depression-like behavior without change of hippocampal tryptophan content in chronically tryptophan-deficient and stressed mice.

    Directory of Open Access Journals (Sweden)

    Hosung Lee

    Full Text Available Regular exercise has an antidepressant effect in human subjects. Studies using animals have suggested that the antidepressant effect of exercise is attributable to an increase of brain 5-hydroxytryptamine (5-HT; however, the precise mechanism underlying the antidepressant action via exercise is unclear. In contrast, the effect of 5-HT on antidepressant activity has not been clarified, in part because the therapeutic response to antidepressant drugs has a time lag in spite of the rapid increase of brain 5-HT upon administration of these drugs. This study was designed to investigate the contribution of brain 5-HT to the antidepressant effect of exercise. Mice were fed a tryptophan-deficient diet and stressed using chronic unpredictable stress (CUS for 4 weeks with or without the performance of either moderate or intense exercise on a treadmill 3 days per week. The findings demonstrated that the onset of depression-like behavior is attributable not to chronic reduction of 5-HT but to chronic stress. Regular exercise, whether moderate or intense, prevents depression-like behavior with an improvement of adult hippocampal cell proliferation and survival and without the recovery of 5-HT. Concomitantly, the mice that exercised showed increased hippocampal noradrenaline. Regular exercise prevents the impairment of not long-term memory but short-term memory in a 5-HT-reduced state. Together, these findings suggest that: (1 chronic reduction of brain 5-HT may not contribute to the onset of depression-like behavior; (2 regular exercise, whether moderate or intense, prevents the onset of chronic stress-induced depression-like behavior independent of brain 5-HT and dependent on brain adrenaline; and (3 regular exercise prevents chronic tryptophan reduction-induced impairment of not long-term but short-term memory.

  11. Synergistic effects of celecoxib and bupropion in a model of chronic inflammation-related depression in mice.

    Directory of Open Access Journals (Sweden)

    Izaque S Maciel

    Full Text Available This study was aimed to characterize the depression-like behaviour in the classical model of chronic inflammation induced by Complete Freund's Adjuvant (CFA. Male Swiss mice received an intraplantar (i.pl. injection of CFA (50 µl/paw or vehicle. Behavioural and inflammatory responses were measured at different time-points (1 to 4 weeks, and different pharmacological tools were tested. The brain levels of IL-1β and BDNF, or COX-2 expression were also determined. CFA elicited a time-dependent edema formation and mechanical allodynia, which was accompanied by a significant increase in the immobility time in the tail suspension (TST or forced-swimming (FST depression tests. Repeated administration of the antidepressants imipramine (10 mg/kg, fluoxetine (20 mg/kg and bupropion (30 mg/kg significantly reversed depression-like behaviour induced by CFA. Predictably, the anti-inflammatory drugs dexamethasone (0.5 mg/kg, indomethacin (10 mg/kg and celecoxib (30 mg/kg markedly reduced CFA-induced edema. The oral treatment with the analgesic drugs dipyrone (30 and 300 mg/kg or pregabalin (30 mg/kg significantly reversed the mechanical allodyinia induced by CFA. Otherwise, either dipyrone or pregabalin (both 30 mg/kg did not significantly affect the paw edema or the depressive-like behaviour induced by CFA, whereas the oral treatment with dipyrone (300 mg/kg was able to reduce the immobility time in TST. Noteworthy, CFA-induced edema was reduced by bupropion (30 mg/kg, and depression behaviour was prevented by celecoxib (30 mg/kg. The co-treatment with bupropion and celecoxib (3 mg/kg each significantly inhibited both inflammation and depression elicited by CFA. The same combined treatment reduced the brain levels of IL-1β, as well as COX-2 immunopositivity, whilst it failed to affect the reduction of BDNF levels. We provide novel evidence on the relationship between chronic inflammation and depression, suggesting that combination of antidepressant and

  12. Neurogenomic Evidence for a Shared Mechanism of the Antidepressant Effects of Exercise and Chronic Fluoxetine in Mice

    OpenAIRE

    Huang, Guo-Jen; Ben-David, Eyal; Tort Piella, Agnès; Edwards, Andrew; Flint, Jonathan; Shifman, Sagiv

    2012-01-01

    Several different interventions improve depressed mood, including medication and environmental factors such as regular physical exercise. The molecular pathways underlying these effects are still not fully understood. In this study, we sought to identify shared mechanisms underlying antidepressant interventions. We studied three groups of mice: mice treated with a widely used antidepressant drug – fluoxetine, mice engaged in voluntary exercise, and mice living in an enriched environment. The ...

  13. Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice.

    Science.gov (United States)

    Rastellini, Cristiana; Han, Song; Bhatia, Vandanajay; Cao, Yanna; Liu, Ka; Gao, Xuxia; Ko, Tien C; Greeley, George H; Falzon, Miriam

    2015-10-01

    Chronic pancreatitis (CP) is a devastating disease with no treatments. Experimental models have been developed to reproduce the parenchyma and inflammatory responses typical of human CP. For the present study, one objective was to assess and compare the effects of pancreatic duct ligation (PDL) to those of repetitive cerulein (Cer)-induced CP in mice on pancreatic production of bone morphogenetic protein-2 (BMP2), apelin, and parathyroid hormone-related protein (PTHrP). A second objective was to determine the extent of cross talk among pancreatic BMP2, apelin, and PTHrP signaling systems. We focused on BMP2, apelin, and PTHrP since these factors regulate the inflammation-fibrosis cascade during pancreatitis. Findings showed that PDL- and Cer-induced CP resulted in significant elevations in expression and peptide/protein levels of pancreatic BMP2, apelin, and PTHrP. In vivo mouse and in vitro pancreatic cell culture experiments demonstrated that BMP2 stimulated pancreatic apelin expression whereas apelin expression was inhibited by PTHrP exposure. Apelin or BMP2 exposure inhibited PTHrP expression, and PTHrP stimulated upregulation of gremlin, an endogenous inhibitor of BMP2 activity. Transforming growth factor-β (TGF-β) stimulated PTHrP expression. Together, findings demonstrated that PDL- and Cer-induced CP resulted in increased production of the pancreatic BMP2, apelin, and PTHrP signaling systems and that significant cross talk occurred among pancreatic BMP2, apelin, and PTHrP. These results together with previous findings imply that these factors interact via a pancreatic network to regulate the inflammation-fibrosis cascade during CP. More importantly, this network communicated with TGF-β, a key effector of pancreatic pathophysiology. This novel network may be amenable to pharmacologic manipulations during CP in humans. PMID:26229008

  14. Unilateral Renal Ischemia-Reperfusion as a Robust Model for Acute to Chronic Kidney Injury in Mice.

    Directory of Open Access Journals (Sweden)

    Nathalie Le Clef

    Full Text Available Acute kidney injury (AKI is an underestimated, yet important risk factor for development of chronic kidney disease (CKD. Even after initial total recovery of renal function, some patients develop progressive and persistent deterioration of renal function and these patients are more likely to progress to end-stage renal disease (ESRD. Animal models are indispensable for unravelling the mechanisms underlying this progression towards CKD and ESRD and for the development of new therapeutic strategies in its prevention or treatment. Ischemia (i.e. hypoperfusion after surgery, bleeding, dehydration, shock, or sepsis is a major aetiology in human AKI, yet unilateral ischemia-reperfusion is a rarely used animal model for research on CKD and fibrosis. Here, we demonstrate in C57Bl/6J mice, by both histology and gene expression, that unilateral ischemia-reperfusion without contralateral nephrectomy is a very robust model to study the progression from acute renal injury to long-term tubulo-interstitial fibrosis, i.e. the histopathological hallmark of CKD. Furthermore, we report that the extent of renal fibrosis, in terms of Col I, TGFβ, CCN2 and CCN3 expression and collagen I immunostaining, increases with increasing body temperature during ischemia and ischemia-time. Thus, varying these two main determinants of ischemic injury allows tuning the extent of the long-term fibrotic outcome in this model. Finally, in order to cover the whole practical finesse of ischemia-reperfusion and allow model and data transfer, we provide a referenced overview on crucial technical issues (incl. anaesthesia, analgesia, and pre- and post-operative care with the specific aim of putting starters in the right direction of implementing ischemia in their research and stimulate them, as well as the community, to have a critical view on ischemic literature data.

  15. A long-lasting protective immunity against chronic toxoplasmosis in mice induced by recombinant rhoptry proteins encapsulated in poly (lactide-co-glycolide) microparticles.

    Science.gov (United States)

    Xu, Ying; Zhang, Nian-Zhang; Wang, Meng; Dong, Hu; Feng, Sheng-Yong; Guo, Hui-Chen; Zhu, Xing-Quan

    2015-11-01

    Toxoplasma gondii infection in humans and animals is a worldwide zoonosis. Prevention and control of toxoplasmosis based on vaccination is one of the promising strategies. In the present study, recombinant T. gondii rhoptry proteins 38 and 18 (TgROP38 and TgROP18) were encapsulated into poly (lactide-co-glycolide) (PLG) (1:1), respectively, to obtain the stable water-in-oil-in-water double emulsion. Female Kunming mice were then immunized with the protein vaccines twice at a 2-week interval. Eight weeks after the second immunization, 10 mice from each group were challenged with T. gondii PRU strain (genotype II). The entrapment rates of PLG-rROP38 and PLG-rROP18 ranged from 65.5 to 77.7% and 58.1 to 72.3%, respectively. Immunization of mice with rROP38 and rROP18 proteins encapsulated into PLG microparticles elicited strongly humoral and cell-mediated responses against T. gondii, associated with relatively high levels of total IgG, IgG2a isotype, and IFN-γ, as well as the mixed Th1/Th2 immunity responses. Immunization with various protein vaccines induced significant reduction of the brain cysts after chronic infection with the T. gondii PRU strain, and the most effective protection was achieved in the PLG-rROP38-rROP18-immunized mice, with a cyst reduction of 81.3%. The findings of the present study indicated that recombinant rhoptry antigens encapsulated in PLG could maintain the protein immunogenicity in an extended period and elicit effective protection against chronic T. gondii infection, which has implications for the development of long-lasting vaccines against chronic toxoplasmosis in animals. PMID:26243574

  16. Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress, arterial oxidation-specific epitopes, and atherogenesis in hypercholesterolemic mice

    Science.gov (United States)

    Napoli, Claudio; Ackah, Eric; de Nigris, Filomena; Del Soldato, Piero; D'Armiento, Francesco P.; Crimi, Ettore; Condorelli, Mario; Sessa, William C.

    2002-01-01

    The effects of chronic treatment with nitric oxide-containing aspirin (NO-aspirin, NCX-4016) in comparison with regular aspirin or placebo on the development of a chronic disease such as atherosclerosis were investigated in hypercholesterolemic low-density lipoprotein (LDL)-receptor-deficient mice. Male mice were assigned randomly to receive in a volume of 10 ml/kg either placebo (n = 10), 30 mg/kg/day NO-aspirin (n = 10), or 18 mg/kg/day of regular aspirin (n = 10). After 12 weeks of treatment, the computer-assisted imaging analysis revealed that NO-aspirin reduced the aortic cumulative lesion area by 39.8 ± 12.3% compared with that of the placebo (P < 0.001). Regular aspirin did not reduce significantly aortic lesions (−5.1 ± 2.3%) compared with the placebo [P = 0.867, not significant (NS)]. Furthermore, NO-aspirin reduced significantly plasma LDL oxidation compared with aspirin and placebo, as shown by the significant reduction of malondialdehyde content (P < 0.001) as well as by the prolongation of lag-time (P < 0.01). Similarly, systemic oxidative stress, measured by plasma isoprostanes, was significantly reduced by treatment with NCX-4016 (P < 0.05). More importantly, mice treated with NO-aspirin revealed by immunohistochemical analysis of aortic serial sections a significant decrease in the intimal presence of oxidation-specific epitopes of oxLDL (E06 monoclonal antibody, P < 0.01), and macrophages–derived foam cells (F4/80 monoclonal antibody, P < 0.05), compared with placebo or aspirin. These data indicate that enhanced NO release by chronic treatment with the NO-containing aspirin has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic mice. PMID:12209007

  17. The Effects of Sub-Chronic Treatment with Pioglitazone on the Septic Mice Mortality in the Model of Cecal Ligation and Puncture: Involvement of Nitric Oxide Pathway

    Directory of Open Access Journals (Sweden)

    Hamed Shafaroodi

    2015-10-01

    Full Text Available Sepsis is a systemic inflammatory response syndrome caused by an infection and remains as a major challenge in health care. Many studies have reported that pioglitazone may display anti-inflammatory effects. This study was designed to evaluate the effect of subchronic treatment with pioglitazone on high-grade septic mice survival and nitrergic system involvement. Diffused sepsis was induced by cecal ligation and puncture (CLP surgery in male NMRI mice (20-30 g. Pioglitazone (5,10 and 20 mg/kg was administered by gavage daily for 5 days prior to surgery. Nitric oxide involvement was assessed by sub-chronic administration of a non-selective nitric oxide synthase inhibitor, L-NAME and a selective inducible nitric oxide synthase inhibitor, aminoguanidine. TNF-α  and IL-1β plasma levels were measured by ELISA. Pioglitazone (10 and 20 mg/kg significantly improved survival rate in septic mice. The chronic intraperitoneally co-administration of L-NAME (0.5 mg/kg, daily or aminoguanidine (1 mg/kg, daily with a daily dose of pioglitazone, 5 mg/kg, significantly increased the survival rate. This survival improving effect was accompanied by a significant reduction in pro-inflammatory cytokines TNF-α and IL-1β plasma levels. In conclusion, sub-chronic pioglitazone treatment can improve survival in mouse sepsis model by CLP. Inhibition of nitric oxide release, probably through inducible nitric oxide synthase at least in part is responsible for this effect. Suppression of TNF-α and IL-1β could be another mechanism in pioglitazone-induced survival improving effect in septic mice.

  18. Long-lasting antidepressant action of ketamine, but not glycogen synthase kinase-3 inhibitor SB216763, in the chronic mild stress model of mice.

    Directory of Open Access Journals (Sweden)

    Xian-Cang Ma

    Full Text Available BACKGROUND: Clinical studies demonstrate that the N-methyl-D-aspartate (NMDA receptor antagonist, ketamine, induces rapid antidepressant effects in patients with refractive major depressive disorder and bipolar depression. This rapid onset of action makes ketamine a highly attractive drug for patients, particularly those who do not typically respond to therapy. A recent study suggested that glycogen synthase kinase (GSK-3 may underlie the rapid antidepressant action of ketamine, although the precise mechanisms are unclear. In this study, we examined the effects of ketamine and GSK-3 inhibitor SB216763 in the unpredictable, chronic mild stress (CMS mouse model of mice. METHODOLOGY/PRINCIPAL FINDINGS: Adult C57/B6 male mice were divided into 2 groups, a non-stressed control group and the unpredictable CMS (35 days group. Then, either vehicle, ketamine (10 mg/kg, or the established GSK-3 inhibitor, SB216763 (10 mg/kg, were administered into mice in the CMS group, while vehicle was administered to controls. In the open field test, there was no difference between the four groups (control+vehicle, CMS+vehicle, CMS+ketamine, CMS+SB216763. In the sucrose intake test, a 1% sucrose intake drop, seen in CMS mice, was significantly attenuated after a single dose of ketamine, but not SB216763. In the tail suspension test (TST and forced swimming test (FST, the increased immobility time seen in CMS mice was significantly attenuated by a single dose of ketamine, but not SB216763. Interestingly, the ketamine-induced increase in the sucrose intake test persisted for 8 days after a single dose of ketamine. Furthermore, a single administration of ketamine, but not SB216763, significantly attenuated the immobility time of the TST and FST in the control (non-stressed mice. CONCLUSIONS/SIGNIFICANCE: These findings suggest that a single administration of ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting antidepressant action in CMS model mice.

  19. Altered Anxiety-like Behavior and Long-term Potentiation in the Bed Nucleus of the Stria Terminalis in Adult Mice Exposed to Chronic Social Isolation, Unpredictable Stress and Ethanol Beginning in Adolescence

    OpenAIRE

    Conrad, Kelly L; Winder, Danny G.

    2010-01-01

    Alcohol and chronic stress exposure, especially during adolescence, can lead to an increased risk in adulthood of developing alcohol use disorders (AUDs). To date, however, no study has assessed the potential long-term effects of chronic intermittent and unpredictable ethanol (EtOH) exposure in mice chronically stressed beginning in adolescence on brain function and anxiety-like behaviors in adulthood. In particular, alterations in function of the bed nucleus of the stria terminalis (BNST), a...

  20. Pronounced susceptibility to infection by Salmonella enterica serovar Typhimurium in mice chronically exposed to lead correlates with a shift to Th2-type immune responses

    International Nuclear Information System (INIS)

    Persistent exposure to inorganic lead (Pb) is known to adversely affect the immune system. In the present study, we assessed the effect of chronic Pb exposure on susceptibility to infection by the facultative intracellular pathogen Salmonella enterica serovar Typhimurium. Mice were exposed to 10 mM Pb-acetate in drinking water for ∼ 16 weeks, resulting in a significant level of Pb in the blood (106.2 ± 8.9 μg/dl). Pb exposure rendered mice susceptible to Salmonella infection, manifested by increased bacterial burden in target organs and heightened mortality. Flow cytometric analysis of the splenic cellular composition in normal and Pb-exposed mice revealed no gross alteration in the ratios of B and T lymphocytes or myeloid cells. Similarly, the capacity of B and T cells to upregulate the expression of activation antigens in response to mitogenic or inflammatory stimuli was not hindered by Pb exposure. Analysis of the ability of ex vivo-cultured splenocytes to secrete cytokines demonstrated a marked reduction in IFN-γ and IL-12p40 production associated with Pb exposure. In contrast, secretion of IL-4 by splenocytes of Pb-treated mice was 3- to 3.6-fold higher than in normal mice. The increased capacity to produce IL-4 correlated with a shift in the in vivo anti-Salmonella antibody response from the protective IgG2a isotype to the Th2-induced IgG1 isotype. We conclude that chronic exposure to high levels of Pb results in a state of immunodeficiency which is not due to an overt cytotoxic or immunosuppressive mechanism, but rather is largely caused by a shift in immune responsiveness to Th2-type reactions

  1. Enhanced Expression of Contractile-Associated Proteins and Ion Channels in Preterm Delivery Model Mice With Chronic Odontogenic Porphyromonas Gingivalis Infection.

    Science.gov (United States)

    Miyoshi, Hiroshi; Konishi, Haruhisa; Teraoka, Yuko; Urabe, Satoshi; Furusho, Hisako; Miyauchi, Mutsumi; Takata, Takashi; Kudo, Yoshiki

    2016-07-01

    Inflammation and infection have been reported to induce preterm delivery. We have studied the relationship between inflammation and various ion channels, including the L-type Ca(2+) channel and P2X7 receptor, during acute inflammation of the pregnant rat uterus induced by lipopolysaccharides. Recently, we found that mice with odontogenic Porphyromonas gingivalis (P.g, an important odontogenic pathogen) infection delivered at day 18.3 of gestation (vs. day 20.5 in normal mice). The purpose of this study was to investigate the expression of myometrial contractile-associated proteins inducing contractions and confirm that these mice are useful as a model for preterm delivery induced by chronic inflammation. We examined the expression of the oxytocin receptor, connexin 43, prostaglandin F receptors, L-type Ca(2+) channel, and P2X7 receptor in the myometrium at day 18 of gestation by real-time PCR and western blot analyses. We also measured TNF-α and IL-1β levels in the blood serum, placenta, fetal membrane and myometrium on the same day. mRNA expression of the oxytocin receptor, connexin 43, prostaglandin F receptors, L-type Ca(2+) channel, and P2X7 receptor was elevated by 5.4, 3.2, 2.4, 2.5, and 1.7 fold, respectively, in the P.g-infected mice. Protein levels of the oxytocin receptor and connexin 43 also increased. Serum levels of TNF-α and IL-1β were elevated, showing that systemic inflammation continued during pregnancy. IL-1β levels in the placenta and fetal membrane also increased, suggesting inflammatory reactions were induced. Thus, mice with odontogenic infection may be useful as a model of chronic inflammation-induced preterm delivery. PMID:26692542

  2. Chronic low-level arsenic exposure causes gender-specific alterations in locomotor activity, dopaminergic systems, and thioredoxin expression in mice

    International Nuclear Information System (INIS)

    Arsenic (As) is a toxic metalloid widely present in the environment. Human exposure to As has been associated with the development of skin and internal organ cancers and cardiovascular disorders, among other diseases. A few studies report decreases in intelligence quotient (IQ), and sensory and motor alterations after chronic As exposure in humans. On the other hand, studies of rodents exposed to high doses of As have found alterations in locomotor activity, brain neurochemistry, behavioral tasks, and oxidative stress. In the present study both male and female C57Bl/6J mice were exposed to environmentally relevant doses of As such as 0.05, 0.5, 5.0, or 50 mg As/L of drinking water for 4 months, and locomotor activity was assessed every month. Male mice presented hyperactivity in the group exposed to 0.5 mg As/L and hypoactivity in the group exposed to 50 mg As/L after 4 months of As exposure, whereas female mice exposed to 0.05, 0.5, and 5.0 mg As/L exhibited hyperactivity in every monthly test during As exposure. Furthermore, striatal and hypothalamic dopamine content was decreased only in female mice. Also decreases in tyrosine hydroxylase (TH) and cytosolic thioredoxin (Trx-1) mRNA expression in striatum and nucleus accumbens were observed in male and female mice, respectively. These results indicate that chronic As exposure leads to gender-dependent alterations in dopaminergic markers and spontaneous locomotor activity, and down-regulation of the antioxidant capacity of the brain.

  3. Berberine ameliorates chronic relapsing dextran sulfate sodium-induced colitis in C57BL/6 mice by suppressing Th17 responses.

    Science.gov (United States)

    Li, Yan-Hong; Xiao, Hai-Tao; Hu, Dong-Dong; Fatima, Sarwat; Lin, Cheng-Yuan; Mu, Huai-Xue; Lee, Nikki P; Bian, Zhao-Xiang

    2016-08-01

    Ulcerative colitis (UC) is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment has fueled the search for alternative therapeutic strategies. In recent studies, berberine, a plant alkaloid with a long history of medicinal use in Chinese medicine, has shown beneficial effects against animal models of acute UC. However, UC usually presents as a chronic condition with frequent relapse in patients. How berberine will act on chronic UC remains unclear. In the present study, we adopted dextran sulfate sodium (DSS)-induced chronic relapsing colitis model to assess the ameliorating activity of berberine. Colitis was induced by two cycles of 2.0% DSS for five days followed by 14days of drinking water plus a third cycle consisting of DSS only for five days. The colitis mice were orally administered 20mg/kg berberine from day 13 onward for 30days and monitored daily. The body weight, stool consistency, and stool bleeding were recorded for determination of the disease activity index (DAI). At the end of treatment, animals were sacrificed and samples were collected and subjected to histological, RT-qPCR, Western blot, and LC-MS analyses. Lymphocytes were isolated from spleens and mesenteric lymph nodes (MLN) and cultured for flow cytometry analysis of IL-17 secretion from CD4(+) cells and the Th17 cell differentiation. Results showed that berberine significantly ameliorated the DAI, colon shortening, colon tissue injury, and reduction of colonic expression of tight junction (TJ) protein ZO-1 and occludin of colitis mice. Notably, berberine treatment pronouncedly reduced DSS-upregulated Th17-related cytokine (IL-17 and ROR-γt) mRNAs in the colon. Furthermore, the mRNA expression of IL-6 and IL-23, and the phosphorylation of STAT3 in colon tissues from DSS-treated mice were pronouncedly inhibited by berberine. Moreover, the up-regulation of IL-17 secretion from CD4(+) cells of spleens and MLNs caused by DSS were significantly

  4. [Changes in the Expression of Dopaminergic Genes in Brain Structures of Male Mice Exposed to Chronic Social Defeat Stress: An RNA-seq Study].

    Science.gov (United States)

    Kovalenko, I L; Smagin, D A; Galyamina, A G; Orlov, Yu L; Kudryavtseva, N N

    2016-01-01

    Whole-transcriptome analysis (RNA-seq) has been used to analyze changes in the expression of dopaminergic genes that encode proteins involved in the synthesis, inactivation, and neurotransmission of dopamine in the striatum, ventral tegmental area, raphe nuclei of the midbrain, hypothalamus, and hippocampus of male mice subjected to chronic social defeat. The expression of Th, Ddc, and Slc6A3 (Dat1) was upregulated, while that of Ppp1r1b and Sncg was downregulated in the ventral tegmental area; the expression of Th, Ddc, Drd2, and Sncg was downregulated in the raphe nuclei of midbrain; the expression of Th, Aldh2, and Ppp1r1b was upregulated, while that of Маоа was downregulated in the hypothalamus; Drd1 and Snca expression was downregulated and that of Sncb was upregulated in the striatum, and Sncb expression was upregulated in the hippocampus. There were no statistically significant changes in the expression of Comt, Maob, Drd3, Drd4, or Drd5 in the brain areas analyzed in stressed male mice (compared to control animals). Thus, the number of differentially expressed dopaminergic genes and the direction of expression changes in male mice experiencing chronic stress are specific to regions of the brain. PMID:27028825

  5. Chronic glucocorticoid exposure-induced epididymal adiposity is associated with mitochondrial dysfunction in white adipose tissue of male C57BL/6J mice.

    Directory of Open Access Journals (Sweden)

    Jie Yu

    Full Text Available Prolonged and excessive glucocorticoids (GC exposure resulted from Cushing's syndrome or GC therapy develops central obesity. Moreover, mitochondria are crucial in adipose energy homeostasis. Thus, we tested the hypothesis that mitochondrial dysfunction may contribute to chronic GC exposure-induced epididymal adiposity in the present study. A total of thirty-six 5-week-old male C57BL/6J mice (∼20 g were administrated with 100 µg/ml corticosterone (CORT or vehicle through drinking water for 4 weeks. Chronic CORT exposure mildly decreased body weight without altering food and water intake in mice. The epididymal fat accumulation was increased, but adipocyte size was decreased by CORT. CORT also increased plasma CORT, insulin, leptin, and fibroblast growth factor 21 concentrations as measured by RIA or ELISA. Interestingly, CORT increased plasma levels of triacylglycerols and nonesterified fatty acids, and up-regulated the expression of both lipolytic and lipogenic genes as determined by real-time RT-PCR. Furthermore, CORT impaired mitochondrial biogenesis and oxidative function in epididymal WAT. The reactive oxygen species production was increased and the activities of anti-oxidative enzymes were reduced by CORT treatment as well. Taken together, these findings reveal that chronic CORT administration-induced epididymal adiposity is, at least in part, associated with mitochondrial dysfunction in mouse epididymal white adipose tissue.

  6. N-Acetyl cysteine does not prevent liver toxicity from chronic low-dose plus subacute high-dose paracetamol exposure in young or old mice.

    Science.gov (United States)

    Kane, Alice Elizabeth; Huizer-Pajkos, Aniko; Mach, John; McKenzie, Catriona; Mitchell, Sarah Jayne; de Cabo, Rafael; Jones, Brett; Cogger, Victoria; Le Couteur, David G; Hilmer, Sarah Nicole

    2016-06-01

    Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute overexposures. The risk of hepatotoxicity from nonacute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine (NAC) for nonacute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and subacute paracetamol overexposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57BL/6 mice were fed a paracetamol-containing (1.33 g/kg food) or control diet for 6 weeks. Mice were then dosed orally eight times over 3 days with additional paracetamol (250 mg/kg) or saline, followed by either one or two doses of oral NAC (1200 mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase (ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Subacute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry (ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from subacute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for subacute paracetamol toxicity. PMID:26821200

  7. SUB CHRONIC TOXICITY TEST FROM ALKOHOL EXTRACT PALIASA LEAVES (Kleinhovia Hospita Linn TO HEPAR/LIVER AND KIDNEY OF EXPERIMENTAL MICE

    Directory of Open Access Journals (Sweden)

    Raflizar Raflizar

    2012-09-01

    Full Text Available Paliasa leaves used to be a traditional medicine for hepatic/ lever desease, so need to maintain the secure & health from the user of this medicine, the aim of the research is to find the dava of ub chronic toxicity from 70% alcohol extract paliasa leaves for experimental mice. The research use amount 30 of 40 months white male mice wistar strain, which have weight in average (SD about 208,75 ±17,47 gr. The extract was given by oral through the spuit for 12 weeks ( 3 months for every mice. After that, all of mice had been killed by ether liquid, andfor histology examination, the blood had been taken from the mice's heart, liver & kidney. The research had been conduct with completed random design includes 5 treatments & 6 repeats. Each treatment includes give the mice aquades with dosage 0 mg/kg body weight (control for 1st group paliasa leaves extract with dosage 250 mg/kg body weight for 2nd group, 3rd group with dosage 500 mg/kg body weight, 4th group with dosage 750 mb/kg body weight & for 5th group with dosage 1000 mg/kg body weight. SGOT, SGPT, Bilirubin direct& indirect, creatinin, ureum kidney & liver cell destruction had been measured from all of groups. The result shows that from eight parameters, in statistically, there are no significant differences between each treatment. The conclution is paliasa leaves extract still save in every treatment dosage. Key words : Toxicity, Electract Paliasa Leaves, Kidney

  8. Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein.

    Science.gov (United States)

    Wilson, Rona; Plinston, Chris; Hunter, Nora; Casalone, Cristina; Corona, Cristiano; Tagliavini, Fabrizio; Suardi, Silvia; Ruggerone, Margherita; Moda, Fabio; Graziano, Silvia; Sbriccoli, Marco; Cardone, Franco; Pocchiari, Maurizio; Ingrosso, Loredana; Baron, Thierry; Richt, Juergen; Andreoletti, Olivier; Simmons, Marion; Lockey, Richard; Manson, Jean C; Barron, Rona M

    2012-07-01

    The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans. PMID:22495232

  9. A CHRONIC INHALATION STUDY OF METHYL BROMIDE TOXICITY IN B6C3F1 MICE. (FINAL REPORT TO THE NATIONAL TOXICOLOGY PROGRAM)

    Energy Technology Data Exchange (ETDEWEB)

    HABER, S.B.

    1987-06-26

    This report provides a detailed account of a two year chronic inhalation study of methyl bromide toxicity in B6C3Fl mice conducted for the National Toxicology Program. Mice were randomized into three dose groups (10, 33 and 100 ppm methyl bromide) and one control group (0 ppm) per sex and exposed 5 days/week, 6 hours/day, for a total of 103 weeks. Endpoints included body weight; clinical signs and mortality, and at 6, 15 and 24 months of exposure, animals were sacrificed for organ weights, hematology and histopathology. In addition, a subgroup of animals in each dosage group was monitored for neurobehavioral and neuropathological changes. After only 20 weeks of exposure, 48% of the males and 12% of the females in the 100 ppm group had died. Exposures were terminated in that group and the surviving mice were observed for the duration of the study. Exposure of B6C3Fl mice to methyl bromide, even for only 20 weeks, produced significant changes in growth rate, mortality, organ weights and neurobehavioral functioning. These changes occurred in both males and females, but were more pronounced in males.

  10. Involvement of immune system in enhanced tumor rejection in mice by chronic low dose-rate irradiation

    International Nuclear Information System (INIS)

    In the previous study, I found that low dose-rate radiation, under certain irradiation conditions, enhanced the rejective response against tumor cells in irradiated C57BL/6N mice. To elucidate the involvement of immune system, I studied the rejective response against taking tumor cells in C57BL/6 mice and scid mice. The C57BL/6N mice have normal immune system, but the scid mice lack a functional immune system. The rejective response was analyzed by applying methods of TD50 assay. TD50 is the abbreviation for tumor dose 50 and indicates the number of cells required for successful transplantation to 50% of injected sites in the recipient animals. I transplanted the tumor cells prepared from a Methylcholanthrene-induced tumor (fibrosarcoma) in mice. The increase in the TD50 value suggests an enhancement of the rejective response against taking tumor cells. The TD50 in non-irradiated scid mice was smaller than that of non-irradiated C57BL/6N mice and the values were 7.6 x 102 and 1.01 x 104, respectively. Furthermore, the TD50 value in C57BL/6N mice irradiated with 250 mGy increased to 3.5 x 104. On the other hand, that in scid mice irradiated with the same total dose remained at low level and did riot change. These results suggest that the increase in TD50 value in mice by irradiation with 250 mGy needs normal immune system. The immune system is stimulated by transplantated tumor cells and induced the enhancement of the rejective response against taking tumor cells. (author)

  11. Dysfunction in Ribosomal Gene Expression in the Hypothalamus and Hippocampus following Chronic Social Defeat Stress in Male Mice as Revealed by RNA-Seq.

    Science.gov (United States)

    Smagin, Dmitry A; Kovalenko, Irina L; Galyamina, Anna G; Bragin, Anatoly O; Orlov, Yuriy L; Kudryavtseva, Natalia N

    2016-01-01

    Chronic social defeat stress leads to the development of anxiety- and depression-like states in male mice and is accompanied by numerous molecular changes in brain. The influence of 21-day period of social stress on ribosomal gene expression in five brain regions was studied using the RNA-Seq database. Most Rps, Rpl, Mprs, and Mprl genes were upregulated in the hypothalamus and downregulated in the hippocampus, which may indicate ribosomal dysfunction following chronic social defeat stress. There were no differentially expressed ribosomal genes in the ventral tegmental area, midbrain raphe nuclei, or striatum. This approach may be used to identify a pharmacological treatment of ribosome biogenesis abnormalities in the brain of patients with "ribosomopathies." PMID:26839715

  12. PBPK modeling/Monte Carlo simulation of methylene chloride kinetic changes in mice in relation to age and acute, subchronic, and chronic inhalation exposure.

    OpenAIRE

    Thomas, R S; Yang, R S; Morgan, D G; Moorman, M P; Kermani, H R; Sloane, R A; O'Connor, R W; Adkins, B; Gargas, M L; Andersen, M E

    1996-01-01

    During a 2-year chronic inhalation study on methylene chloride (2000 or 0 ppm; 6 hr/day, 5 days/week), gas-uptake pharmacokinetic studies and tissue partition coefficient determinations were conducted on female B6C3F1, mice after 1 day, 1 month, 1 year, and 2 years of exposure. Using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation and bootstrap resampling for data analyses, a significant induction in the mixed function oxidase (MFO) rate constant (Vma...

  13. Effects of Ning Shen Ling Granule(宁神灵冲剂)and Dehydroepiandrosterone on Cognitive Function in Mice Undergoing Chronic Mild Stress

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xiao; DONG Yi-long; YANG Nan; LIU Yan-yong; GAO Rui-feng; ZUO Ping-ping

    2007-01-01

    Objective:To investigate the changes of spontaneous and cognitive behavior,and cholinergic M receptors in the brain of mice subjected to chronic mild stress (CMS),and to determine the effect of Ning Shen Ling Granule (宁神灵冲剂,NSL) and dehydroepiandrosterone (DHEA) on them.Methods:CMS model mice were established by applying stress every day for 3 consecutive weeks with 7 kinds of unforeseeable stress sources,and they were medicated for 1 week beginning at the 3rd week of modeling.The changes in behavior were determined by Morris Water Maze and spontaneous movement test,and M-receptor binding activity in cerebral cortex,hippocampus and hypothalamus were measured by radioactive ligand assay with 3H-QNB.Results:(1)The spontaneous movement in CMS model mice was significantly reduced,with the latency for searching platform in Morris Water Maze obviously prolonged (P<0.01),and these abnormal changes in behavior were improved in those treated with NSL and DHEA.(2)The binding ability of M-receptor in cerebral cortex and hippocampus of CMS mice was significantly decreased as compared with those in the control group (P<0.05),but could be restored to the normal level after intervention with NSL or DHEA.Conclusion:The decline of spontaneous movement and spatial learning and memory ability could be induced in animals by chronic mild stress,and that may be related to the low activity of central cholinergic M-receptors.Both NSL and DHEA could effectively alleviate the above-mentioned changes.

  14. Effects of acamprosate on attentional set-shifting and cellular function in the prefrontal cortex of chronic alcohol-exposed mice

    Science.gov (United States)

    Hu, Wei

    Background: The medial prefrontal cortex (mPFC) inhibits impulsive and compulsive behaviors that characterize drug abuse and dependence. Acamprosate is the leading medication approved for the maintenance of abstinence, shown to reduce craving and relapse in animal models and human alcoholics. Whether acamprosate can modulate executive functions that are impaired by chronic ethanol exposure is unknown. Here we explored the effects of acamprosate on an attentional set-shifting task, and tested whether these behavioral effects are correlated with modulation of glutamatergic synaptic transmission and intrinsic excitability of mPFC neurons. Methods: We induced alcohol dependence in mice via chronic intermittent ethanol (CIE) exposure in vapor chambers and measured changes in alcohol consumption in a limited access 2-bottle choice paradigm. Impairments of executive function were assessed in an attentional set-shifting task. Acamprosate was applied subchronically for 2 days during withdrawal before the final behavioral test. Alcohol-induced changes in cellular function of layer 5/6 pyramidal neurons, and the potential modulation of these changes by acamprosate, were measured using patch clamp recordings in brain slices. Results: Chronic ethanol exposure impaired cognitive flexibility in the attentional set-shifting task. Acamprosate improved overall performance and reduced perseveration. Recordings of mPFC neurons showed that chronic ethanol exposure increased use-dependent presynaptic transmitter release and enhanced postsynaptic N-methyl-D-aspartate receptor (NMDAR) function. Moreover, CIE-treatment lowered input resistance, and decreased the threshold and the afterhyperpolarization (AHP) of action potentials, suggesting chronic ethanol exposure also impacted membrane excitability of mPFC neurons. However, acamprosate treatment did not reverse these ethanol-induced changes cellular function. Conclusion: Acamprosate improved attentional control of ethanol exposed animals

  15. Venlafaxine increases cell proliferation and regulates DISC1, PDE4B and NMDA receptor 2B expression in the hippocampus in chronic mild stress mice.

    Science.gov (United States)

    Zhang, Xinxin; Li, Xiaobai; Li, Min; Ren, Jintao; Yun, Ke; An, Yan; Lin, Lei; Zhang, Hailong

    2015-05-15

    Recent evidence has identified disrupted in schizophrenia-1 (DISC1) as an important genetic risk factor for the development of many psychiatric disorders, including major depressive disorders. In addition, studies using animal models have demonstrated that chronic stress affects hippocampal structure and function. However, the functional effects of chronic stress on DISC1 remain unknown. Using a chronic mild stress (CMS) paradigm, we investigated the effects of CMS on depressive-like behaviors, hippocampal cell proliferation, and hippocampal protein expression of DISC1, phosphodiesterase 4B (PDE4B) and N-methyl-d-aspartate receptor 2B subunit (NMDA receptor 2B), which may be involved in the regulation of DISC1 and neurogenesis. We also examined the effects and possible mechanisms of the antidepressant venlafaxine in CMS mice. CMS increased the expression of DISC1 and PDE4B. Chronic treatment with venlafaxine blocked the increases in these proteins, and also reversed the CMS-induced decrease in neurogenesis and NMDA receptor 2B protein in the hippocampus. These results suggest that DISC1 may play an important role in the etiology of depression and in the action of antidepressants. PMID:25769842

  16. Long-Term Immunity to Lethal Acute or Chronic Type II Toxoplasma gondii Infection Is Effectively Induced in Genetically Susceptible C57BL/6 Mice by Immunization with an Attenuated Type I Vaccine Strain▿

    Science.gov (United States)

    Gigley, Jason P.; Fox, Barbara A.; Bzik, David J.

    2009-01-01

    C57BL/6 (B6) mice are genetically highly susceptible to chronic type II Toxoplasma gondii infections that invariably cause lethal toxoplasmic encephalitis. We examined the ability of an attenuated type I vaccine strain to elicit long-term immunity to lethal acute or chronic type II infections in susceptible B6 mice. Mice immunized with the type I cps1-1 vaccine strain were not susceptible to a lethal (100-cyst) challenge with the type II strain ME49. Immunized mice challenged with 10 ME49 cysts exhibited significant reductions in brain cyst and parasite burdens compared to naive mice, regardless of the route of challenge infection. Remarkably, cps1-1 strain-immunized B6 mice chronically infected with ME49 survived for at least 12 months without succumbing to the chronic infection. Potent immunity to type II challenge infections persisted for at least 10 months after vaccination. While the cps1-1 strain-elicited immunity did not prevent the establishment of a chronic infection or clear established brain cysts, cps1-1 strain-elicited CD8+ immune T cells significantly inhibited recrudescence of brain cysts during chronic ME49 infection. In addition, we show that uracil starvation of the cps1-1 strain induces early markers of bradyzoite differentiation. Collectively, these results suggest that more effective immune control of chronic type II infection in the genetically susceptible B6 background is established by vaccination with the nonreplicating type I uracil auxotroph cps1-1 strain. PMID:19797073

  17. Long-term immunity to lethal acute or chronic type II Toxoplasma gondii infection is effectively induced in genetically susceptible C57BL/6 mice by immunization with an attenuated type I vaccine strain.

    Science.gov (United States)

    Gigley, Jason P; Fox, Barbara A; Bzik, David J

    2009-12-01

    C57BL/6 (B6) mice are genetically highly susceptible to chronic type II Toxoplasma gondii infections that invariably cause lethal toxoplasmic encephalitis. We examined the ability of an attenuated type I vaccine strain to elicit long-term immunity to lethal acute or chronic type II infections in susceptible B6 mice. Mice immunized with the type I cps1-1 vaccine strain were not susceptible to a lethal (100-cyst) challenge with the type II strain ME49. Immunized mice challenged with 10 ME49 cysts exhibited significant reductions in brain cyst and parasite burdens compared to naive mice, regardless of the route of challenge infection. Remarkably, cps1-1 strain-immunized B6 mice chronically infected with ME49 survived for at least 12 months without succumbing to the chronic infection. Potent immunity to type II challenge infections persisted for at least 10 months after vaccination. While the cps1-1 strain-elicited immunity did not prevent the establishment of a chronic infection or clear established brain cysts, cps1-1 strain-elicited CD8(+) immune T cells significantly inhibited recrudescence of brain cysts during chronic ME49 infection. In addition, we show that uracil starvation of the cps1-1 strain induces early markers of bradyzoite differentiation. Collectively, these results suggest that more effective immune control of chronic type II infection in the genetically susceptible B6 background is established by vaccination with the nonreplicating type I uracil auxotroph cps1-1 strain. PMID:19797073

  18. The effect of chronic exposure to highly aggressive mice on hippocampal gene expression of non-aggressive subordinates

    NARCIS (Netherlands)

    Feldker, DEM; Morsink, MC; Veenema, AH; Datson, NA; Proutski, [No Value; Lathouwers, D; de Kloet, ER; Vreugdenhil, E

    2006-01-01

    Exposure to a chronic psychosocial stressor changes the behavioral and neuroendocrine response pattern and causes structural changes in the rodent hippocampus. However, the underlying molecular mechanism of these changes induced by chronic stress is largely unknown. Recently, it was shown that expos

  19. Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice

    Science.gov (United States)

    Gavito, Ana Luisa; Bautista, Dolores; Suarez, Juan; Badran, Samir; Arco, Rocío; Pavón, Francisco Javier; Serrano, Antonia; Rivera, Patricia; Decara, Juan; Cuesta, Antonio Luis; Rodríguez-de-Fonseca, Fernando

    2016-01-01

    High-fat diet-induced obesity (DIO) is associated with fatty liver and elevated IL-6 circulating levels. IL-6 administration in rodents has yielded contradictory results regarding its effects on steatosis progression. In some models of fatty liver disease, high doses of human IL-6 ameliorate the liver steatosis, whereas restoration of IL-6 in DIO IL-6-/- mice up-regulates hepatic lipogenic enzymes and aggravates steatosis. We further examined the effects of chronic low doses of murine IL-6 on hepatic lipid metabolism in WT mice in DIO. IL-6 was delivered twice daily in C57BL/6J DIO mice for 15 days. The status and expression of IL-6-signalling mediators and targets were investigated in relation to the steatosis and lipid content in blood and in liver. IL-6 administration in DIO mice markedly raised circulating levels of lipids, glucose and leptin, elevated fat liver content and aggravated steatosis. Under IL-6 treatment there was hepatic Stat3 activation and increased gene expression of Socs3 and Tnf-alpha whereas the gene expression of endogenous IL-6, IL-6-receptor, Stat3, Cpt1 and the enzymes involved in lipogenesis was suppressed. These data further implicate IL-6 in fatty liver disease modulation in the context of DIO, and indicate that continuous stimulation with IL-6 attenuates the IL-6-receptor response, which is associated with high serum levels of leptin, glucose and lipids, the lowering levels of lipogenic and Cpt1 hepatic enzymes and with increased Tnf-alpha hepatic expression, a scenario evoking that observed in IL-6-/- mice exposed to DIO and in obese Zucker rats. PMID:27333268

  20. Similarities in the behavior and molecular deficits in the frontal cortex between the neurotensin receptor subtype 1 knockout mice and chronic phencyclidine-treated mice: relevance to schizophrenia

    OpenAIRE

    Li, Zhimin; Boules, Mona; Williams, Katrina; Gordillo, Andres; Li, Shuhua; Richelson, Elliott

    2010-01-01

    Much evidence suggests that targeting the neurotensin (NT) system may provide a novel and promising treatment for schizophrenia. Our recent work shows that: NTS1 knockout (NTS1−/−) mice may provide a potential animal model for studying schizophrenia by investigating the effect of deletion NTS1 receptor on amphetamine-induced hyperactivity and neurochemical changes. The data indicate a hyper-dopaminergic state similar to the excessive striatal DA activity reported in schizophrenia. The present...

  1. KM突变小鼠慢性炎症性皮肤病的免疫学改变%Immunological changes of chronic dermatitis in KM mutant mice

    Institute of Scientific and Technical Information of China (English)

    李彦红; 刘颖; 黄澜; 徐艳峰; 朱华; 马春梅; 秦川

    2012-01-01

    Objective To study the pathological and immunological changes of chronic dermatitis in KM mutant mice. Method The changes of external characteristics were observed by stereomicroscopy and optical microscopy, and the immune cells and inflammatory factors were observed using HE staining, immunohistochemistry and toluidine blue staining in 3-, 6-month old wild-type and KM mutant mice. Results The skin changes showed oligotrichia, scurf, rhicnosis and the histopathology showed epidermal cell necrosis, epithelial hyperkeratosis or parakeratosis, hypergranulosis, basal cell layer edema, dilatation of blood vessels in the superficial layer of dermis and infiltration of inflammation cells in the connective tissue; increase of cutaneous CD3+ and CD4+ T cells, macrophages and mast cells; and increase of inflammatory factors IL-6, IL-22, TNF-α, and lFN-γ in the 6-month old KM mutant mice and more severe in the 3-month old KM mutant mice . Conclusions The skin tissue of KM mutant mice shows chronic inflammatory changes in pathology and cell-molecular changes similar to that in human chronic inflammatory skin diseases. KM spontaneous mutant mice may become a novel animal model in research of of chronic dermatitis .%目的 观察KM突变小鼠皮肤慢性炎症的病理变化,探讨该小鼠皮肤免疫学改变.方法 通过外部特征、常规HE病理组织学、免疫组织化学、特染方法对3月龄、6月龄KM突变小鼠皮肤炎症细胞及炎症因子进行检测并与KM野生小鼠皮肤炎症细胞及炎症因子浸润进行比较.结果 KM突变小鼠皮肤毛稀、皮屑、皮皱等;组织病理表皮细胞坏死,上皮角化过度或不全,颗粒层增厚,基底细胞层水肿,真皮浅层血管扩张,结缔组织炎细胞浸润等,皮肤CD3+、CD4+T细胞、巨噬细胞、肥大细胞等增多,同时炎症因子IL-6、IL-22、TNF-α、IFN-γ等增多;且这些炎症细胞及炎症因子浸润3月龄较6月龄增多.结论 KM自发突变小鼠皮肤组

  2. CD11b+Ly6C++Ly6G- cells show distinct function in mice with chronic inflammation or tumor burden

    Directory of Open Access Journals (Sweden)

    Källberg Eva

    2012-12-01

    Full Text Available Abstract Background S100A9 has been shown to be important for the function of so called Myeloid Derived Suppressor Cells (MDSC. Cells with a similar phenotype are also involved in pro-inflammatory processes, and we therefore wanted to investigate the gene expression and function of these cells in animals that were either subjected to chronic inflammation, or inoculated with tumors. Methods CD11b+Ly6C++ and Ly6G+ cells were isolated from spleen, tumor tissue or inflammatory granulomas. S100A9, Arginase 1 and iNOS gene expression in the various CD11b+ cell populations was analyzed using Q-PCR. The suppressive activity of the CD11b+ cell populations from different donors was studied in co-culture experiments. Results S100A9 was shown to be expressed mainly in splenic CD11b+Ly6C+G+ cells both at the RNA and protein level. Arginase I and iNOS expression could be detected in both CD11b+Ly6C+Ly6G+ and CD11b+Ly6C+G-/C++G- derived from tumors or a site of chronic inflammation, but was very low in the same cell populations isolated from the spleen. CD11b+ cells isolated from mice with peritoneal chronic inflammation were able to stimulate T lymphocytes, while CD11b+ cells from mice with peritoneal tumors suppressed T cell growth. Conclusion An identical CD11b+Ly6C++G- cell population appears to have the ability to adopt immune stimulatory or immune suppressive functions dependent on the presence of a local inflammatory or tumor microenvironment. Thus, there is a functional plasticity in the CD11b+Ly6C++G- cell population that cannot be distinguished with the current molecular markers.

  3. Influence of Chronic Moderate Sleep Restriction and Exercise Training on Anxiety, Spatial Memory, and Associated Neurobiological Measures in Mice

    OpenAIRE

    Zielinski, Mark R.; Davis, J. Mark; Fadel, James R.; YOUNGSTEDT, SHAWN D.

    2013-01-01

    Sleep deprivation can have deleterious effects on cognitive function and mental health. Moderate exercise training has myriad beneficial effects on cognition and mental health. However, physiological and behavioral effects of chronic moderate sleep restriction and its interaction with common activities, such as moderate exercise training, have received little investigation. The aims of this study were to examine the effects of chronic moderate sleep restriction and moderate exercise training ...

  4. An Efficient Chronic Unpredictable Stress Protocol to Induce Stress-Related Responses in C57BL/6 Mice

    OpenAIRE

    Monteiro, Susana; Roque, Susana; de Sá-Calçada, Daniela; Sousa, Nuno; Correia-Neves, Margarida; Cerqueira, João José

    2015-01-01

    Exposure to chronic stress can have broad effects on health ranging from increased predisposition for neuropsychiatric disorders to deregulation of immune responses. The chronic unpredictable stress (CUS) protocol has been widely used to study the impact of stress exposure in several animal models and consists in the random, intermittent, and unpredictable exposure to a variety of stressors during several weeks. CUS has consistently been shown to induce behavioral and immunological alteration...

  5. Altered consolidation of extinction-like inhibitory learning in genotype-specific dysfunctional coping fostered by chronic stress in mice.

    Science.gov (United States)

    Campus, P; Maiolati, M; Orsini, C; Cabib, S

    2016-12-15

    Genetic and stress-related factors interact to foster mental disorders, possibly through dysfunctional learning. In a previous study we reported that a temporary experience of reduced food availability increases forced swim (FS)-induced helplessness tested 14days after a first experience in mice of the standard inbred C57BL/6(B6) strain but reduces it in mice of the genetically unrelated DBA/2J (D2) strain. Because persistence of FS-induced helplessness influences adaptive coping with stress challenge and involve learning processes the present study tested whether the behavioral effects of restricted feeding involved altered consolidation of FS-related learning. First, we demonstrated that restricted feeding does not influence behavior expressed on the first FS experience, supporting a specific effect on persistence rather then development of helplessness. Second, we found that FS-induced c-fos expression in the infralimbic cortex (IL) was selectively enhanced in food-restricted (FR) B6 mice and reduced in FR D2 mice, supporting opposite alterations of consolidation processes involving this brain area. Third, we demonstrated that immediate post-FS inactivation of IL prevents 24h retention of acquired helplessness by continuously free-fed mice of both strains, indicating the requirement of a functioning IL for consolidation of FS-related learning in either mouse strain. Finally, in line with the known role of IL in consolidation of extinction memories, we found that restricted feeding selectively facilitated 24h retention of an acquired extinction in B6 mice whereas impairing it in D2 mice. These findings support the conclusion that an experience of reduced food availability strain-specifically affects persistence of newly acquired passive coping strategies by altering consolidation of extinction-like inhibitory learning. PMID:27506654

  6. Effect of chronic khat (Catha edulis, Forsk) use on outcome of Plasmodium berghei ANKA infection in Swiss albino mice

    OpenAIRE

    Ketema, Tsige; Yohannes, Moti; Alemayehu, Esayas; Ambelu, Argaw

    2015-01-01

    Background The objective of this study was to explore effects of khat (Catha edulis) on outcome of rodent malaria infection and its anti-plasmodial activities on Plasmodium berghei ANKA (PbA). Methods Female Swiss albino mice were orally treated with crude khat (Catha edulis) extracts (100, 200 and 300 mg/kg) on a daily basis for 4 weeks prior to PbA infection. Physical, clinical, hematological, biochemical and histo-pathological features of the mice were assessed. In addition, in vivo anti-p...

  7. Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake.

    Science.gov (United States)

    Krishna, Saritha; Lin, Zhoumeng; de La Serre, Claire B; Wagner, John J; Harn, Donald H; Pepples, Lacey M; Djani, Dylan M; Weber, Matthew T; Srivastava, Leena; Filipov, Nikolay M

    2016-04-01

    High-fat diet (HFD) induced obesity is associated not only with metabolic dysregulation, e.g., impaired glucose homeostasis and insulin sensitivity, but also with neurological dysfunction manifested with aberrant behavior and/or neurotransmitter imbalance. Most studies have examined HFD's effects predominantly in male subjects, either in the periphery or on the brain, in isolation and after a finite feeding period. In this study, we evaluated the time-course of selected metabolic, behavioral, and neurochemical effects of HFD intake in parallel and at multiple time points in female (C57BL/6) mice. Peripheral effects were evaluated at three feeding intervals (short: 5-6 weeks, long: 20-22 weeks, and prolonged: 33-36 weeks). Central effects were evaluated only after long and prolonged feeding durations; we have previously reported those effects after the short (5-6 weeks) feeding duration. Ongoing HFD feeding resulted in an obese phenotype characterized by increased visceral adiposity and, after prolonged HFD intake, an increase in liver and kidney weights. Peripherally, 5 weeks of HFD intake was sufficient to impair glucose tolerance significantly, with the deleterious effects of HFD being greater with prolonged intake. Similarly, 5 weeks of HFD consumption was sufficient to impair insulin sensitivity. However, sensitivity to insulin after prolonged HFD intake was not different between control, low-fat diet (LFD) and HFD-fed mice, most likely due to age-dependent decrease in insulin sensitivity in the LFD-fed mice. HFD intake also induced bi-phasic hepatic inflammation and it increased gut permeability. Behaviorally, prolonged intake of HFD caused mice to be hypoactive and bury fewer marbles in a marble burying task; the latter was associated with significantly impaired hippocampal serotonin homeostasis. Cognitive (short-term recognition memory) function of mice was unaffected by chronic HFD feeding. Considering our prior findings of short-term (5-6 weeks) HFD

  8. Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation

    International Nuclear Information System (INIS)

    The biological and genetic effects of chronic low-dose radiation (LDR) exposure and its relationship to carcinogenesis have received a lot of attention in the recent years. For example, radiation-induced genome instability, which is thought to be a precursor of tumorogenesis, was shown to have a transgenerational nature. This indicates a possible involvement of epigenetic mechanisms in LDR-induced genome instability. Genomic DNA methylation is one of the most important epigenetic mechanisms. Existing data on radiation effects on DNA methylation patterns is limited, and no one has specifically studied the effects of the LDR. We report the first study of the effects of whole-body LDR exposure on global genome methylation in muscle and liver tissues of male and female mice. In parallel, we evaluated changes in promoter methylation and expression of the tumor suppressor gene p16INKa and DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). We observed different patterns of radiation-induced global genome DNA methylation in the liver and muscle of exposed males and females. We also found sex and tissue-specific differences in p16INKa promoter methylation upon LDR exposure. In male liver tissue, p16INKa promoter methylation was more pronounced than in female tissue. In contrast, no significant radiation-induced changes in p16INKa promoter methylation were noted in the muscle tissue of exposed males and females. Radiation also did not significantly affect methylation status of MGMT promoter. We also observed substantial sex differences in acute and chronic radiation-induced expression of p16INKa and MGMT genes. Another important outcome of our study was the fact that chronic low-dose radiation exposure proved to be a more potent inducer of epigenetic effects than the acute exposure. This supports previous findings that chronic exposure leads to greater genome destabilization than acute exposure

  9. Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation.

    Science.gov (United States)

    Kovalchuk, Olga; Burke, Paula; Besplug, Jill; Slovack, Mark; Filkowski, Jody; Pogribny, Igor

    2004-04-14

    The biological and genetic effects of chronic low-dose radiation (LDR) exposure and its relationship to carcinogenesis have received a lot of attention in the recent years. For example, radiation-induced genome instability, which is thought to be a precursor of tumorogenesis, was shown to have a transgenerational nature. This indicates a possible involvement of epigenetic mechanisms in LDR-induced genome instability. Genomic DNA methylation is one of the most important epigenetic mechanisms. Existing data on radiation effects on DNA methylation patterns is limited, and no one has specifically studied the effects of the LDR. We report the first study of the effects of whole-body LDR exposure on global genome methylation in muscle and liver tissues of male and female mice. In parallel, we evaluated changes in promoter methylation and expression of the tumor suppressor gene p16(INKa) and DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT). We observed different patterns of radiation-induced global genome DNA methylation in the liver and muscle of exposed males and females. We also found sex and tissue-specific differences in p16(INKa) promoter methylation upon LDR exposure. In male liver tissue, p16(INKa) promoter methylation was more pronounced than in female tissue. In contrast, no significant radiation-induced changes in p16(INKa) promoter methylation were noted in the muscle tissue of exposed males and females. Radiation also did not significantly affect methylation status of MGMT promoter. We also observed substantial sex differences in acute and chronic radiation-induced expression of p16(INKa) and MGMT genes. Another important outcome of our study was the fact that chronic low-dose radiation exposure proved to be a more potent inducer of epigenetic effects than the acute exposure. This supports previous findings that chronic exposure leads to greater genome destabilization than acute exposure. PMID:15063138

  10. Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Kovalchuk, Olga; Burke, Paula; Besplug, Jill; Slovack, Mark; Filkowski, Jody; Pogribny, Igor

    2004-04-14

    The biological and genetic effects of chronic low-dose radiation (LDR) exposure and its relationship to carcinogenesis have received a lot of attention in the recent years. For example, radiation-induced genome instability, which is thought to be a precursor of tumorogenesis, was shown to have a transgenerational nature. This indicates a possible involvement of epigenetic mechanisms in LDR-induced genome instability. Genomic DNA methylation is one of the most important epigenetic mechanisms. Existing data on radiation effects on DNA methylation patterns is limited, and no one has specifically studied the effects of the LDR. We report the first study of the effects of whole-body LDR exposure on global genome methylation in muscle and liver tissues of male and female mice. In parallel, we evaluated changes in promoter methylation and expression of the tumor suppressor gene p16{sup INKa} and DNA repair gene O{sup 6}-methylguanine-DNA methyltransferase (MGMT). We observed different patterns of radiation-induced global genome DNA methylation in the liver and muscle of exposed males and females. We also found sex and tissue-specific differences in p16{sup INKa} promoter methylation upon LDR exposure. In male liver tissue, p16{sup INKa} promoter methylation was more pronounced than in female tissue. In contrast, no significant radiation-induced changes in p16{sup INKa} promoter methylation were noted in the muscle tissue of exposed males and females. Radiation also did not significantly affect methylation status of MGMT promoter. We also observed substantial sex differences in acute and chronic radiation-induced expression of p16{sup INKa} and MGMT genes. Another important outcome of our study was the fact that chronic low-dose radiation exposure proved to be a more potent inducer of epigenetic effects than the acute exposure. This supports previous findings that chronic exposure leads to greater genome destabilization than acute exposure.

  11. Sex-specific differences in hyperoxic lung injury in mice: Implications for acute and chronic lung disease in humans

    International Nuclear Information System (INIS)

    Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72 h of hyperoxia (FiO2 > 0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF 2α) (LC–MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. Cytochrome P450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F > M) and VEGF (M > F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans. - Highlights: • Male mice were more susceptible to hyperoxic lung injury than females. • Sex differences in inflammatory markers were observed. • CYP1A expression was higher in females after hyperoxia exposure

  12. The bio-distribution of the antidepressant clomipramine is modulated by chronic stress in mice: Effects on behavior

    Directory of Open Access Journals (Sweden)

    Georgia eBalsevich

    2015-01-01

    Full Text Available Major depression is one of the most common psychiatric disorders, severely affecting the quality of life of millions of people worldwide. Despite the availability of several classes of antidepressants, treatment efficacy is still very variable and many patients do not respond to the treatment. Clomipramine (CMI, a classical and widely used antidepressant, shows widespread interindividual variability of efficacy, while the environmental factors contributing to such variability remain unclear. We investigated whether chronic stress modulates the bio-distribution of CMI, and as a result the behavioral response to CMI treatment in a mouse model of chronic social defeat stress. Our results show that stress exposure increased anxiety-like and depressive-like behaviors and altered the stress response. Chronic defeat stress furthermore significantly altered CMI bio-distribution. Interestingly, CMI bio-distribution highly correlated with anxiety-like and depressive-like behaviors only under basal conditions. Taken together, we provide first evidence demonstrating that chronic stress exposure modulates CMI bio-distribution and behavioral responses. This may contribute to CMI’s broad interindividual variability, and is especially relevant in clinical practice.

  13. Novel Epigallocatechin-3-Gallate (EGCG) Derivative as a New Therapeutic Strategy for Reducing Neuropathic Pain after Chronic Constriction Nerve Injury in Mice

    Science.gov (United States)

    Xifró, Xavier; Vidal-Sancho, Laura; Boadas-Vaello, Pere; Turrado, Carlos; Alberch, Jordi; Puig, Teresa; Verdú, Enrique

    2015-01-01

    Neuropathic pain is common in peripheral nerve injury and often fails to respond to ordinary medication. Here, we investigated whether the two novel epigallocatechin-3-gallate (EGCG) polyphenolic derivatives, compound 23 and 30, reduce the neuropathic pain in mice chronic constriction nerve injury (CCI). First, we performed a dose-response study to evaluate nociceptive sensation after administration of EGCG and its derivatives 23 and 30, using the Hargreaves test at 7 and 21 days after injury (dpi). We daily administered EGCG, 23 and 30 (10 to 100 mg/Kg; i.p.) during the first week post-CCI. None of the doses of compound 23 caused significant pain diminution, whereas 50mg/kg was optimal for both EGCG and 30 to delay the latency of paw withdrawal. With 50 mg/Kg, we showed that EGCC prevented the thermal hyperalgesia from 7 to 21 dpi and compound 30 from 14 to 56 dpi. To evaluate the molecular mechanisms underpinning why EGCG and compound 30 differentially prevented the thermal hyperalgesia, we studied several biochemical parameters in the dorsal horn of the spinal cord at 14 and 56 dpi. We showed that the effect observed with EGCG and compound 30 was related to the inhibition of fatty acid synthase (FASN), a known target of these polyphenolic compounds. Additionally, we observed that EGCG and compound 30 reduced the expression of CCI-mediated inflammatory proteins and the nuclear localization of nuclear factor-kappa B at 14 dpi, but not at 56 dpi. We also strongly detected a decrease of synaptic plasma membrane levels of N-methyl-D-asparte receptor 2B in CCI-mice treated with compound 30 at 56 dpi. Altogether, compound 30 reduced the chronic thermal hyperalgesia induced by CCI better than the natural compound EGCG. Thus, our findings provide a rationale for the preclinical development of compound 30 as an agent to treat neuropathic pain. PMID:25855977

  14. Chronic Angiotensin-(1-7) Improves Insulin Sensitivity in High-Fat Fed Mice Independent of Blood Pressure.

    Science.gov (United States)

    Williams, Ian M; Otero, Yolanda F; Bracy, Deanna P; Wasserman, David H; Biaggioni, Italo; Arnold, Amy C

    2016-05-01

    Angiotensin-(1-7) improves glycemic control in animal models of cardiometabolic syndrome. The tissue-specific sites of action and blood pressure dependence of these metabolic effects, however, remain unclear. We hypothesized that Ang-(1-7) improves insulin sensitivity by enhancing peripheral glucose delivery. Adult male C57BL/6J mice were placed on standard chow or 60% high-fat diet for 11 weeks. Ang-(1-7) (400 ng/kg per minute) or saline was infused subcutaneously during the last 3 weeks of diet, and hyperinsulinemic-euglycemic clamps were performed at the end of treatment. High-fat fed mice exhibited modest hypertension (systolic blood pressure: 137±3 high fat versus 123±5 mm Hg chow;P=0.001), which was not altered by Ang-(1-7) (141±4 mm Hg;P=0.574). Ang-(1-7) did not alter body weight or fasting glucose and insulin in chow or high-fat fed mice. Ang-(1-7) increased the steady-state glucose infusion rate needed to maintain euglycemia in high-fat fed mice (31±5 Ang-(1-7) versus 16±1 mg/kg per minute vehicle;P=0.017) reflecting increased whole-body insulin sensitivity, with no effect in chow-fed mice. The improved insulin sensitivity in high-fat fed mice was because of an enhanced rate of glucose disappearance (34±5 Ang-(1-7) versus 20±2 mg/kg per minute vehicle;P=0.049). Ang-(1-7) enhanced glucose uptake specifically into skeletal muscle by increasing translocation of glucose transporter 4 to the sarcolemma. Our data suggest that Ang-(1-7) has direct insulin-sensitizing effects on skeletal muscle, independent of changes in blood pressure. These findings provide new insight into mechanisms by which Ang-(1-7) improves insulin action, and provide further support for targeting this peptide in cardiometabolic disease. PMID:26975707

  15. Reduced response to chronic mild stress in PACAP mutant mice is associated with blunted FosB expression in limbic forebrain and brainstem centers.

    Science.gov (United States)

    Kormos, Viktória; Gáspár, László; Kovács, László Á; Farkas, József; Gaszner, Tamás; Csernus, Valér; Balogh, András; Hashimoto, Hitoshi; Reglődi, Dóra; Helyes, Zsuzsanna; Gaszner, Balázs

    2016-08-25

    Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in stress adaptation with potential relevance in mood disorder management. PACAP deficient (KO) mice on CD1 background were shown to have depression-like phenotype. Here we aimed at investigating effects of chronic variable mild stress (CVMS) in non-injected, vehicle and imipramine-treated KO mice vs. wildtype (WT) counterparts. We hypothesized reduced FosB neuronal activity in stress-related centers, altered activity and peptide/neurotransmitter content of corticotropin-releasing factor (CRF) cells of the oval (ovBST) bed nucleus of stria terminalis (BST), urocortin 1 (Ucn1) neurons of centrally projecting Edinger-Westphal nucleus (cpEW) and serotonin (5HT) cells of dorsal raphe (DR) in PACAP deficiency. CVMS caused decreased body weight and increased adrenal size, corticosterone (CORT) titers and depression-like behavior in WT mice, in contrast to KO animals. CVMS increased FosB in the central (CeA) and medial amygdala, dorsomedial (dmBST), ventral (vBST), ovBST, CA1 area, dentate gyrus (DG), ventral lateral septum, parvo- (pPVN) and magnocellular paraventricular nucleus, lateral periaqueductal gray, cpEW and DR. Lack of PACAP blunted the CVMS-induced FosB rise in the CeA, ovBST, dmBST, vBST, CA1 area, pPVN and DR. The CVMS-induced FosB expression in ovBST-CRF and cpEW-Ucn1 neurons was abolished in KO mice. Although CVMS did not induce FosB in 5HT-DR neurons, PACAP KO mice had increased 5HT cell counts and 5HT content. We conclude that PACAP deficiency affects neuronal reactivity in a brain area-specific manner in stress centers, as well as in ovBST-CRF, cpEW-Ucn1 and 5HT-DR neurons leading to reduced CVMS response and altered depression level. PMID:27282087

  16. Evolution of subpatent parasitaemia in Trypanosoma cruzi chronically infected mice with the help of a cyclophosphamide amplification transfer assay Evolução das parasitemias subpatentes na infecção crônica experimental pelo Trypanosoma cruzi através do ensaio de subinoculação modificado pelo tratamento com ciclofosfamida

    OpenAIRE

    Alvarez, José M.; Ayumi Oshima; Veronica Mozer; Liliane Guimarães; Hércules Menezes

    1991-01-01

    We have evaluated the sensitivity of the classical blood subinoculation method, modified through cyclophosphamide treatment of transferred mice, for the detection of occult parasitaemias in Trypanosoma cruzi chronically infected mice. Besides its simplicity, the method was shown to be highly sensitive for both the "chronic" phase parasites (99% of chronic cases were shown to harbour occult parasitaemias) and for the acute phase parasites (T. cruzi could be detected in 53.8% of animals transfe...

  17. Chronic Dosing with Membrane Sealant Poloxamer 188 NF Improves Respiratory Dysfunction in Dystrophic Mdx and Mdx/Utrophin-/- Mice.

    Directory of Open Access Journals (Sweden)

    Bruce E Markham

    Full Text Available Poloxamer 188 NF (national formulary (NF grade of P-188 improves cardiac muscle function in the mdx mouse and golden retriever muscular dystrophy models. However in vivo effects on skeletal muscle have not been reported. We postulated that P-188 NF might protect diaphragm muscle membranes from contraction-induced injury in mdx and mdx/utrophin-/- (dko muscular dystrophy models. In the first study 7-month old mdx mice were treated for 22 weeks with subcutaneous (s.c. injections of saline or P-188 NF at 3 mg/Kg. In the second, dkos were treated with saline or P-188 NF (1 mg/Kg for 8 weeks beginning at age 3 weeks. Prednisone was the positive control in both studies. Respiratory function was monitored using unrestrained whole body plethysmography. P-188 NF treatment affected several respiratory parameters including tidal volume/BW and minute volume/BW in mdx mice. In the more severe dko model, P-188 NF (1 mg/Kg significantly slowed the decline in multiple respiratory parameters compared with saline-treated dko mice. Prednisone's effects were similar to those seen with P-188 NF. Diaphragms from P-188 NF or prednisone treated mdx and dko mice showed signs of muscle fiber protection including less centralized nuclei, less variation in fiber size, greater fiber density, and exhibited a decreased amount of collagen deposition. P-188 NF at 3 mg/Kg s.c. also improved parameters of systolic and diastolic function in mdx mouse hearts. These results suggest that P-188 NF may be useful in treating respiratory and cardiac dysfunction, the leading causes of death in Duchenne muscular dystrophy patients.

  18. Chronic Endocannabinoid System Stimulation Induces Muscle Macrophage and Lipid Accumulation in Type 2 Diabetic Mice Independently of Metabolic Endotoxaemia

    OpenAIRE

    Geurts, Lucie; Muccioli, Giulio G.; Delzenne, Nathalie M.; Cani, Patrice D.

    2013-01-01

    Aims Obesity and type 2 diabetes are characterised by low-grade inflammation, metabolic endotoxaemia (i.e., increased plasma lipopolysaccharides [LPS] levels) and altered endocannabinoid (eCB)-system tone. The aim of this study was to decipher the specific role of eCB-system stimulation or metabolic endotoxaemia in the onset of glucose intolerance, metabolic inflammation and altered lipid metabolism. Methods Mice were treated with either a cannabinoid (CB) receptor agonist (HU210) or low-dose...

  19. Chronic endocannabinoid system stimulation induces muscle macrophage and lipid accumulation in type 2 diabetic mice independently of metabolic endotoxaemia

    OpenAIRE

    Geurts, Lucie; Muccioli, Giulio; Delzenne, Nathalie M.; Cani, Patrice D.

    2013-01-01

    AIMS: Obesity and type 2 diabetes are characterised by low-grade inflammation, metabolic endotoxaemia (i.e., increased plasma lipopolysaccharides [LPS] levels) and altered endocannabinoid (eCB)-system tone. The aim of this study was to decipher the specific role of eCB-system stimulation or metabolic endotoxaemia in the onset of glucose intolerance, metabolic inflammation and altered lipid metabolism. METHODS: Mice were treated with either a cannabinoid (CB) receptor agonist (HU210) or low-do...

  20. Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice

    OpenAIRE

    Amin, Ali; Choi, Soo-Kyoung; Galan, Maria; Kassan, Modar; Partyka, Megan; Kadowitz, Philip; Henrion, Daniel; Trebak, Mohamed; Belmadani, Souad; Matrougui, Khalid

    2012-01-01

    Endoplasmic reticulum (ER) stress and inflammation are important mechanisms that underlie many of the serious consequences of type II diabetes. However, the role of ER stress and inflammation in impaired ischaemia-induced neovascularization in type II diabetes is unknown. We studied ischaemia-induced neovascularization in the hind-limb of 4-week-old db−/db− mice and their controls treated with or without the ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) and interle...

  1. Chronic UVA (365-nm) irradiation induced scratching in hairless mice: dose-time dependency and the effect of ketanserin

    Energy Technology Data Exchange (ETDEWEB)

    Laat, J.M.T. de; Groenendijk, M.; Vloten, W.A. van; Gruijl, F.R. de [Univ. Hospital Utrecht, Dept. of Dermatology (Netherlands); Seite, S. [L`Oreal-Centre de Recherche Charles Zviak, Recherche Avancee Biologie (France)

    1997-12-31

    In a study on the dose-response relationship for longwave UVA (UVA1; 340-400 nm) carcinogenesis in hairless mice scratch marks appeared after months of daily exposure as an unwanted side effect. Tumor induction in the highest of the 4 tested dose groups (receiving a daily dose of 430 kJ/m{sup 2} of 365-nm radiation) could not be determined because extensive scarification occurred prior to the development of any tumors. The induction of scratch marks could be scored and quantified in all 4 dose groups tested. The UVA1 dose-dependencies for the induction of tumors and scratch marks were compared. We found that the induction of scratch marks depended mainly on the cumulative UVA1 exposure, whereas tumor induction showed a lesser dose-dependency. An attempt was made to prevent the apparent pruritogenic effect of UVA1 irradiation and to understand its mechanism. The influence of ketanserin, a serotonin/histamine antagonist, on the UVA1 induction of scratch marks was tested in groups of 8 mice daily irradiated with 430 kJ/m{sup 2}. No difference was found between treated and untreated animals. Histological examination of skin biopsies from irradiated mice from the 430-kJ/m{sup 2} dose group from the UVA1 carcinogenic experiment, showed no changes in numbers of mast cells or other inflammatory features when compared to skin biopsies from unirradiated control mice. This indicated that UVA1-induced scratching is not mediated through mast cell release of serotonin and/or histamine. An adequate therapeutic treatment which can prevent UVA1-induced scratching would enable us to test tumor induction with UVA1 over a larger dose range, and may provide additional insight in how this radiation damages the skin. It remains conjectural whether there exists and analogous UVA-induced pruritus in human skin. (au) 26 refs.

  2. Chronic hemodynamic unloading regulates the morphologic development of newborn mouse hearts transplanted into the ear of isogeneic adult mice.

    OpenAIRE

    Rossi, M. A.

    1992-01-01

    The morphologic development of newborn mouse hearts transplanted into the pinna of the ears of isogeneic adult mice was assessed in comparison to in situ ventricular myocardium of recipients. The grafted hearts became vascularized from the auricular artery at the base of the ear, and although these preparations appeared not to be intrinsically innervated, most of them showed grossly visible pulsatile activity. Since they were not subjected to hemodynamic load due to working against a pressure...

  3. Chronic UVA (365-nm) irradiation induced scratching in hairless mice: dose-time dependency and the effect of ketanserin

    International Nuclear Information System (INIS)

    In a study on the dose-response relationship for longwave UVA (UVA1; 340-400 nm) carcinogenesis in hairless mice scratch marks appeared after months of daily exposure as an unwanted side effect. Tumor induction in the highest of the 4 tested dose groups (receiving a daily dose of 430 kJ/m2 of 365-nm radiation) could not be determined because extensive scarification occurred prior to the development of any tumors. The induction of scratch marks could be scored and quantified in all 4 dose groups tested. The UVA1 dose-dependencies for the induction of tumors and scratch marks were compared. We found that the induction of scratch marks depended mainly on the cumulative UVA1 exposure, whereas tumor induction showed a lesser dose-dependency. An attempt was made to prevent the apparent pruritogenic effect of UVA1 irradiation and to understand its mechanism. The influence of ketanserin, a serotonin/histamine antagonist, on the UVA1 induction of scratch marks was tested in groups of 8 mice daily irradiated with 430 kJ/m2. No difference was found between treated and untreated animals. Histological examination of skin biopsies from irradiated mice from the 430-kJ/m2 dose group from the UVA1 carcinogenic experiment, showed no changes in numbers of mast cells or other inflammatory features when compared to skin biopsies from unirradiated control mice. This indicated that UVA1-induced scratching is not mediated through mast cell release of serotonin and/or histamine. An adequate therapeutic treatment which can prevent UVA1-induced scratching would enable us to test tumor induction with UVA1 over a larger dose range, and may provide additional insight in how this radiation damages the skin. It remains conjectural whether there exists and analogous UVA-induced pruritus in human skin. (au)

  4. Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress.

    Science.gov (United States)

    Sun, Jing; Wang, Fangyan; Hong, Guangliang; Pang, Mengqi; Xu, Hailing; Li, Haixiao; Tian, Feng; Fang, Renchi; Yao, Ye; Liu, Jiaming

    2016-04-01

    Sodium butyrate (NaB) has exhibited neuroprotective activity. This study aimed to explore that NaB exerts beneficial effects on chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and its possible mechanisms. The behavioral tests including sucrose preference test (SPT), open field test (OFT), tail suspension test (TST) and forced swimming test (FST) were to evaluate the antidepressant effects of NaB. Then changes of Nissl's body in the hippocampus, brain serotonin (5-HT) concentration, brain-derived neurotrophic factor (BDNF) and tight junctions (TJs) proteins level were assessed to explore the antidepressant mechanisms. Our results showed that CUMS caused significant depression-like behaviors, neuropathological changes, and decreased brain 5-HT concentration, TJs protein levels and BDNF expression in the hippocampus. However, NaB treatment significantly ameliorated behavioral deficits of the CUMS-induced mice, increased 5-HT concentration, increased BDNF expression, and up-regulated Occludin and zonula occludens-1(ZO-1) protein levels in the hippocampus, which demonstrated that NaB could partially restore CUMS-induced blood-brain barrier (BBB) impairments. Besides, the pathologic changes were alleviated. In conclusion, these results demonstrated that NaB significantly improved depression-like behaviors in CUMS-induced mice and its antidepressant actions might be related with, at least in part, the increasing brain 5-HT concentration and BDNF expression and restoring BBB impairments. PMID:26957230

  5. NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR-ABL-positive mice.

    Science.gov (United States)

    Chen, C I-U; Koschmieder, S; Kerstiens, L; Schemionek, M; Altvater, B; Pscherer, S; Gerss, J; Maecker, H T; Berdel, W E; Juergens, H; Lee, P P; Rossig, C

    2012-03-01

    Although BCR-ABL+ stem cells in chronic myeloid leukemia (CML) resist elimination by targeted pharmacotherapy in most patients, immunological graft-versus-leukemia effects can cure the disease. Besides cytotoxic T cells, natural killer (NK) cells may have a role in immune control of CML. Here, we explored the functionality of NK cells in CML patients and in a transgenic inducible BCR-ABL mouse model. Compared with controls, NK-cell proportions among lymphocytes were decreased at diagnosis of CML and did not recover during imatinib-induced remission for 10-34 months. Functional experiments revealed limited in vitro expansion of NK cells from CML patients and a reduced degranulation response to K562 target cells both at diagnosis and during imatinib therapy. Consistent with the results in human CML, relative numbers of NK1.1+ NK cells were reduced following induction of BCR-ABL expression in mice, and the defects persisted after BCR-ABL reversion. Moreover, target-induced degranulation by expanded BCR-ABL+ NK cells was compromised. We conclude that CML is associated with quantitative and functional defects within the NK-cell compartment, which is reproduced by induced BCR-ABL expression in mice. Further work will aim at identifying the mechanisms of NK-cell deficiency in CML and at developing strategies to exploit NK cells for immunotherapy. PMID:21904381

  6. Toxicological assessment of P-9801091 plant mixture extract after chronic administration in CBA/HZg mice--a biochemical and histological study.

    Science.gov (United States)

    Petlevski, Roberta; Hadzija, Mirko; Slijepcević, Milivoj; Juretić, Dubravka

    2008-06-01

    Acute, subchronic and chronic effects of the P-9801091 plant mixture extract at a dose of 20 mg/kg body mass were assessed in serum of healthy CBA/HZg mice at 24 hours, 7 days, 3 months and 6 months of treatment (experimental group), and compared with the values obtained in the control group of untreated healthy CBA/HZg mice. The P-9801091 plant mixture extract is an antihyperglycemic preparation containing Myrtilli folium (Vaccinium myrtillus L.), Taraxaci radix (Taraxacum officinale Web.), Cichorii radix (Cichorium intybus L.), Juniperi fructus (Juniperus communis L.), Centaurii herba (Centaurium umbellatum Gilib.), Phaseoli fructus sine semine (Phaseolus vulgaris L.), Millefolii herba (Achillea millefolium L.), Mori folium (Morus nigra L.), Valerianae radix (Valeriana officinalis L.) and Urticae herba et radix (Urtica dioica L). Toxic effect of the P-9801091 plant mixture extract was assessed by the following biochemical parameters: urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and cholesterol. Also, histopathological examination of the kidneys, liver, spleen, pancreas, testes and lungs was performed. Results of biochemical testing performed at specified time points generally showed no statistically significant differences from control values, with the only exception of the catalytic concentration of AST in the experimental group measured on day 7, which was significantly increased as compared with the control group (p<0.05). Pathohistological examination including characteristic organ and tissue structure, and parenchyma relationship to the adjacent blood vessels and connective tissue in the examined organs revealed no major pathologic changes. PMID:18756913

  7. Chronic up-regulation of the SHH pathway normalizes some developmental effects of trisomy in Ts65Dn mice.

    Science.gov (United States)

    Dutka, Tara; Hallberg, Dorothy; Reeves, Roger H

    2015-02-01

    Down Syndrome (DS) is a highly complex developmental genetic disorder caused by trisomy for human chromosome 21 (Hsa21). All individuals with DS exhibit some degree of brain structural changes and cognitive impairment; mouse models such as Ts65Dn have been instrumental in understanding the underlying mechanisms. Several phenotypes of DS might arise from a reduced response of trisomic cells to the Sonic Hedgehog (SHH) growth factor. If all trisomic cells show a similar reduced response to SHH, then up-regulation of the pathway in trisomic cells might ameliorate multiple DS phenotypes. We crossed Ptch1tm1Mps/+ mice, in which the canonical SHH pathway is expected to be up-regulated in every SHH-responsive cell due to the loss of function of one allele of the pathway suppressor, Ptch1, to the Ts65Dn DS model and assessed the progeny for possible rescue of multiple DS-related phenotypes. Down-regulation of Ptch produced several previously unreported effects on development by itself, complicating interpretation of some phenotypes, and a number of structural or behavioral effects of trisomy were not compensated by SHH signaling. However, a deficit in a nest-building task was partially restored in Ts;Ptch+/- mice, as were the structural anomalies of the cerebellum seen in Ts65Dn mice. These results extend the body of evidence indicating that reduced response to SHH in trisomic cells and tissues contributes to various aspects of the trisomic phenotype. PMID:25511459

  8. Chronic pyruvate supplementation increases exploratory activity and brain energy reserves in young and middle-aged mice

    Directory of Open Access Journals (Sweden)

    Hennariikka eKoivisto

    2016-03-01

    Full Text Available Numerous studies have reported neuroprotective effects of pyruvate when given in systemic injections. Impaired glucose uptake and metabolism are found in Alzheimer's disease (AD and in AD mouse models. We tested whether dietary pyruvate supplementation is able to provide added energy supply to brain and thereby attenuate aging- or AD-related cognitive impairment. Mice received ~ 800 mg/kg/day Na-pyruvate in their chow for 2- 6 months. In middle-aged wild-type mice and in 6.5-month-old APP/PS1 mice, pyruvate facilitated spatial learning and increased exploration of a novel odor. However, in passive avoidance task for fear memory, the treatment group was clearly impaired. Independent of age, long-term pyruvate increased explorative behavior, which likely explains the paradoxical impairment in passive avoidance. We also assessed pyruvate effects on body weight, muscle force and endurance, and found no effects. Metabolic post-mortem assays revealed increased energy compounds in nuclear magnetic resonance spectroscopy as well as increased brain glycogen storages in the pyruvate group. Pyruvate supplementation may counteract aging-related behavioral impairment but its beneficial effect seems related to increased explorative activity rather than direct memory enhancement.

  9. Influences of Chronic Mild Stress Exposure on Motor, Non-Motor Impairments and Neurochemical Variables in Specific Brain Areas of MPTP/Probenecid Induced Neurotoxicity in Mice.

    Directory of Open Access Journals (Sweden)

    Udaiyappan Janakiraman

    Full Text Available Parkinson's disease (PD is regarded as a movement disorder mainly affecting the elderly population and occurs due to progressive loss of dopaminergic (DAergic neurons in nigrostriatal pathway. Patients suffer from non-motor symptoms (NMS such as depression, anxiety, fatigue and sleep disorders, which are not well focussed in PD research. Depression in PD is a predominant /complex symptom and its pathology lies exterior to the nigrostriatal system. The main aim of this study is to explore the causative or progressive effect of chronic mild stress (CMS, a paradigm developed as an animal model of depression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg. body wt. with probenecid (250 mg/kg, s.c. (MPTP/p induced mice model of PD. After ten i.p. injections (once in 3.5 days for 5 weeks of MPTP/p or exposure to CMS for 4 weeks, the behavioural (motor and non-motor impairments, levels and expressions of dopamine (DA, serotonin (5-HT, DAergic markers such as tyrosine hydroxylase (TH, dopamine transporter (DAT, vesicular monoamine transporters-2 (VMAT 2 and α-synuclein in nigrostriatal (striatum (ST and substantia nigra (SN and extra-nigrostriatal (hippocampus, cortex and cerebellum tissues were analysed. Significantly decreased DA and 5-HT levels, TH, DAT and VMAT 2 expressions and increased motor deficits, anhedonia-like behaviour and α-synuclein expression were found in MPTP/p treated mice. Pre and/or post exposure of CMS to MPTP/p mice further enhanced the MPTP/p induced DA and 5-HT depletion, behaviour abnormalities and protein expressions. Our results could strongly confirm that the exposure of stress after MPTP/p injections worsens the symptoms and neurochemicals status of PD.

  10. Functionally deregulated AML1/RUNX1 cooperates with BCR-ABL to induce a blastic phase-like phenotype of chronic myelogenous leukemia in mice.

    Directory of Open Access Journals (Sweden)

    Kiyoko Yamamoto

    Full Text Available Patients in the chronic phase (CP of chronic myelogenous leukemia (CML have been treated successfully following the advent of ABL kinase inhibitors, but once they progress to the blast crisis (BC phase the prognosis becomes dismal. Although mechanisms underlying the progression are largely unknown, recent studies revealed the presence of alterations of key molecules for hematopoiesis, such as AML1/RUNX1. Our analysis of 13 BC cases revealed that three cases had AML1 mutations and the transcript levels of wild-type (wt. AML1 were elevated in BC compared with CP. Functional analysis of representative AML1 mutants using mouse hematopoietic cells revealed the possible contribution of some, but not all, mutants for the BC-phenotype. Specifically, K83Q and R139G, but neither R80C nor D171N mutants, conferred upon BCR-ABL-expressing cells a growth advantage over BCR-ABL-alone control cells in cytokine-free culture, and the cells thus grown killed mice upon intravenous transfer. Unexpectedly, wt.AML1 behaved similarly to K83Q and R139G mutants. In a bone marrow transplantation assay, K83Q and wt.AML1s induced the emergence of blast-like cells. The overall findings suggest the roles of altered functions of AML1 imposed by some, but not all, mutants, and the elevated expression of wt.AML1 for the disease progression of CML.

  11. The Effects of Taoren-Honghua Herb Pair on Pathological Microvessel and Angiogenesis-Associated Signaling Pathway in Mice Model of CCl4-Induced Chronic Liver Disease

    Directory of Open Access Journals (Sweden)

    Shengyan Xi

    2016-01-01

    Full Text Available Chronic liver disease is one of the most common diseases that threaten human health. Effective treatment is still lacking in western medicine. Semen Persicae (Taoren and Flos Carthami (Honghua are known to relieve acute hepatic injury and inflammation, improve microcirculation, and reduce tissue fiber. The aim of our study is to investigate the potential mechanisms of Taoren-Honghua Herb Pair (THHP in murine model of chronic liver disease caused by Carbon Tetrachloride (CCl4. Mice were randomly divided into seven groups: (1 blank, (2 model, (3 control (colchicine, 0.1 mg/kg, (4 THHP (5.53, 2.67, and 1.33 g/kg, and (5 Tao Hong Siwu Decoction (THSWD (8.50 g/kg. Histological change and microvessels density were examined by microscopy. Hepatic function, serum fibrosis related factors, and hepatic vascular endothelial growth factor (VEGF were measured with ELISA. VEGF, kinase insert domain-containing receptor (KDR, Flt-1, and Akt mRNA expression in hepatic tissue were determined with PCR. Tissues of Akt, pAkt, KDR, and Flt-1 were measured with western blotting. Data from this study showed that THHP improved hepatic function and restrained the hepatic inflammation and fibrosis. Its role in inhibiting pathological angiogenesis and hepatic fibrogenesis may be through affecting the angiogenesis-associated VEGF and its upstream and downstream signaling pathways.

  12. Spectral Confocal Imaging of Fluorescently tagged Nicotinic Receptors in Knock-in Mice with Chronic Nicotine Administration

    OpenAIRE

    Renda, Anthony; Nashmi, Raad

    2012-01-01

    Ligand-gated ion channels in the central nervous system (CNS) are implicated in numerous conditions with serious medical and social consequences. For instance, addiction to nicotine via tobacco smoking is a leading cause of premature death worldwide (World Health Organization) and is likely caused by an alteration of ion channel distribution in the brain1. Chronic nicotine exposure in both rodents and humans results in increased numbers of nicotinic acetylcholine receptors (nAChRs) in brain t...

  13. Sub-chronic exposure to the insecticide dimethoate induces a proinflammatory status and enhances the neuroinflammatory response to bacterial lypopolysaccharide in the hippocampus and striatum of male mice

    International Nuclear Information System (INIS)

    Dimethoate is an organophosphorus insecticide extensively used in horticulture. Previous studies have shown that the administration of dimethoate to male rats, at a very low dose and during a sub-chronic period, increases the oxidation of lipids and proteins, reduces the levels of antioxidants and impairs mitochondrial function in various brain regions. In this study, we have assessed in C57Bl/6 adult male mice, whether sub-chronic (5 weeks) intoxication with a low dose of dimethoate (1.4 mg/kg) affects the expression of inflammatory molecules and the reactivity of microglia in the hippocampus and striatum under basal conditions and after an immune challenge caused by the systemic administration of lipopolysaccharide. Dimethoate increased mRNA levels of tumor necrosis factor α (TNFα) and interleukin (IL) 6 in the hippocampus, and increased the proportion of Iba1 immunoreactive cells with reactive phenotype in dentate gyrus and striatum. Lipopolysaccharide caused a significant increase in the mRNA levels of IL1β, TNFα, IL6 and interferon-γ-inducible protein 10, and a significant increase in the proportion of microglia with reactive phenotype in the hippocampus and the striatum. Some of the effects of lipopolysaccharide (proportion of Iba1 immunoreactive cells with reactive phenotype and IL6 mRNA levels) were amplified in the animals treated with dimethoate, but only in the striatum. These findings indicate that a sub-chronic period of administration of a low dose of dimethoate, comparable to the levels of the pesticide present as residues in food, causes a proinflammatory status in the brain and enhances the neuroinflammatory response to the lipopolysaccharide challenge with regional specificity. - Highlights: • The dose of pesticide used was comparable to the levels of residues found in food. • Dimethoate administration increased cytokine expression and microglia reactivity. • Hippocampus and striatum were differentially affected by the treatment.

  14. Sub-chronic exposure to the insecticide dimethoate induces a proinflammatory status and enhances the neuroinflammatory response to bacterial lypopolysaccharide in the hippocampus and striatum of male mice

    Energy Technology Data Exchange (ETDEWEB)

    Astiz, Mariana, E-mail: marianaastiz@gmail.com; Diz-Chaves, Yolanda, E-mail: ydiz@cajal.csic.es; Garcia-Segura, Luis M., E-mail: lmgs@cajal.csic.es

    2013-10-15

    Dimethoate is an organophosphorus insecticide extensively used in horticulture. Previous studies have shown that the administration of dimethoate to male rats, at a very low dose and during a sub-chronic period, increases the oxidation of lipids and proteins, reduces the levels of antioxidants and impairs mitochondrial function in various brain regions. In this study, we have assessed in C57Bl/6 adult male mice, whether sub-chronic (5 weeks) intoxication with a low dose of dimethoate (1.4 mg/kg) affects the expression of inflammatory molecules and the reactivity of microglia in the hippocampus and striatum under basal conditions and after an immune challenge caused by the systemic administration of lipopolysaccharide. Dimethoate increased mRNA levels of tumor necrosis factor α (TNFα) and interleukin (IL) 6 in the hippocampus, and increased the proportion of Iba1 immunoreactive cells with reactive phenotype in dentate gyrus and striatum. Lipopolysaccharide caused a significant increase in the mRNA levels of IL1β, TNFα, IL6 and interferon-γ-inducible protein 10, and a significant increase in the proportion of microglia with reactive phenotype in the hippocampus and the striatum. Some of the effects of lipopolysaccharide (proportion of Iba1 immunoreactive cells with reactive phenotype and IL6 mRNA levels) were amplified in the animals treated with dimethoate, but only in the striatum. These findings indicate that a sub-chronic period of administration of a low dose of dimethoate, comparable to the levels of the pesticide present as residues in food, causes a proinflammatory status in the brain and enhances the neuroinflammatory response to the lipopolysaccharide challenge with regional specificity. - Highlights: • The dose of pesticide used was comparable to the levels of residues found in food. • Dimethoate administration increased cytokine expression and microglia reactivity. • Hippocampus and striatum were differentially affected by the treatment.

  15. Induction of Chronic Inflammation and Altered Levels of DNA Hydroxymethylation in Somatic and Germinal Tissues of CBA/CaJ Mice Exposed to (48)Ti Ions.

    Science.gov (United States)

    Rithidech, Kanokporn Noy; Jangiam, Witawat; Tungjai, Montree; Gordon, Chris; Honikel, Louise; Whorton, Elbert B

    2016-01-01

    Although the lung is one of the target organs at risk for cancer induction from exposure to heavy ions found in space, information is insufficient on cellular/molecular responses linked to increased cancer risk. Knowledge of such events may aid in the development of new preventive measures. Furthermore, although it is known that germinal cells are sensitive to X- or γ-rays, there is little information on the effects of heavy ions on germinal cells. Our goal was to investigate in vivo effects of 1 GeV/n (48)Ti ions (one of the important heavy ions found in the space environment) on somatic (lung) and germinal (testis) tissues collected at various times after a whole body irradiation of CBA/CaJ mice (0, 0.1, 0.25, or 0.5 Gy, delivered at 1 cGy/min). We hypothesized that (48)Ti-ion-exposure induced damage in both tissues. Lung tissue was collected from each mouse from each treatment group at 1 week, 1 month, and 6 months postirradiation. For the testis, we collected samples at 6 months postirradiation. Hence, only late-occurring effects of (48)Ti ions in the testis were studied. There were five mice per treatment group at each harvest time. We investigated inflammatory responses after exposure to (48)Ti ions by measuring the levels of activated nuclear factor kappa B and selected pro-inflammatory cytokines in both tissues of the same mouse. These measurements were coupled with the quantitation of the levels of global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Our data clearly showed the induction of chronic inflammation in both tissues of exposed mice. A dose-dependent reduction in global 5hmC was found in the lung at all time-points and in testes collected at 6 months postirradiation. In contrast, significant increases in global 5mC were found only in lung and testes collected at 6 months postirradiation from mice exposed to 0.5 Gy of 1 GeV/n (48)Ti ions. Overall, our data showed that (48)Ti ions may create health risks in both

  16. Prevention of Chronic Experimental Colitis Induced by Dextran Sulphate Sodium (DSS in Mice Treated with FR91

    Directory of Open Access Journals (Sweden)

    Valter R. M. Lombardi

    2012-01-01

    Full Text Available One of the main treatments currently used in humans to fight cancer is chemotherapy. A huge number of compounds with antitumor activity are present in nature, and many of their derivatives are produced by microorganisms. However, the search for new drugs still represents a main objective for cancer therapy, due to drug toxicity and resistance to multiple chemotherapeutic drugs. In animal models, a short-time oral administration of dextran sulfate sodium (DSS induces colitis, which exhibits several clinical and histological features similar to ulcerative colitis (UC. However, the pathogenic factors responsible for DSS-induced colitis and the subsequent colon cancer also remain unclear. We investigated the effect of FR91, a standardized lysate of microbial cells belonging to the Bacillus genus which has been previously shown to have significant immunomodulatory effects, against intestinal inflammation. Colitis was induced in mice during 5 weeks by oral administration 2% (DSS. Morphological changes in the colonic mucosa were evaluated by hematoxylin-eosin staining and immunohistochemistry methods. Adenocarcinoma and cryptal cells of the dysplastic epithelium showed cathenin-β, MLH1, APC, and p53 expression, together with increased production of IFN-γ. In our model, the optimal dose response was the 20% FR91 concentration, where no histological alterations or mild DSS-induced lesions were observed. These results indicate that FR91 may act as a chemopreventive agent against inflammation in mice DSS-induced colitis.

  17. Prolonged Pulmonary Exposure to Diesel Exhaust Particles Exacerbates Renal Oxidative Stress, Inflammation and DNA Damage in Mice with Adenine-Induced Chronic Renal Failure

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    Abderrahim Nemmar

    2016-05-01

    Full Text Available Background/Aims: Epidemiological evidence indicates that patients with chronic kidney diseases have increased susceptibility to adverse outcomes related to long-term exposure to particulate air pollution. However, mechanisms underlying these effects are not fully understood. Methods: Presently, we assessed the effect of prolonged exposure to diesel exhaust particles (DEP on chronic renal failure induced by adenine (0.25% w/w in feed for 4 weeks, which is known to involve inflammation and oxidative stress. DEP (0.5m/kg was intratracheally (i.t. instilled every 4th day for 4 weeks (7 i.t. instillation. Four days following the last exposure to either DEP or saline (control, various renal endpoints were measured. Results: While body weight was decreased, kidney weight increased in DEP+adenine versus saline+adenine or DEP. Water intake, urine volume, relative kidney weight were significantly increased in adenine+DEP versus DEP and adenine+saline versus saline. Plasma creatinine and urea increased and creatinine clearance decreased in adenine+DEP versus DEP and adenine+saline versus saline. Tumor necrosis factor α, lipid peroxidation and reactive oxygen species were significantly increased in adenine+DEP compared with either DEP or adenine+saline. The antioxidant calase was significantly decreased in adenine+DEP compared with either adenine+saline or DEP. Notably, renal DNA damage was significantly potentiated in adenine+DEP compared with either adenine+saline or DEP. Similarly, systolic blood pressure was increased in adenine+DEP versus adenine+saline or DEP, and in DEP versus saline. Histological evaluation revealed more collagen deposition, higher number of necrotic cell counts and dilated tubules, cast formation and collapsing glomeruli in adenine+DEP versus adenine+saline or DEP. Conclusion: Prolonged pulmonary exposure to diesel exhaust particles worsen renal oxidative stress, inflammation and DNA damage in mice with adenine-induced chronic

  18. 5-HT2A/2C receptor and 5-HT transporter densities in mice prone or resistant to chronic high-fat diet-induced obesity: a quantitative autoradiography study.

    Science.gov (United States)

    Huang, Xu-Feng; Huang, Xin; Han, Mei; Chen, Feng; Storlien, Len; Lawrence, Andrew J

    2004-08-27

    The present study examined the density of 5-HT2A/2C receptors and 5-HT transporters in the brains of chronic high-fat diet-induced obese (cDIO) and obese-resistant (cDR) mice. Thirty-five male mice were used in this study. Twenty-eight mice were fed with a high-fat diet (40% of calories from fat) for 6 weeks and then classified as the cDIO (n=8) or cDR (n=8) mice according to the highest and lowest body weight gainers. Seven mice were placed on a low-fat diet (LF: 10% of calories from fat) and were used as controls. After 20 weeks of feeding, the sum of epididymal, perirenal, omental and inguinal fat masses was 9.3+/-0.3 g in the cDIO group versus 3.1+/-0.5 g in the cDR (pcDIO mice had a significantly higher 5-HT2A/2C binding density in the anterior olfactory nucleus and ventromedial hypothalamic nucleus (VMH) compared to the cDR and LF mice (+39% and +47%, p=0.003 and 0.045, respectively), whereas the latter two groups did not differ. The density of 5-HT2A/2C receptors in the VMH was associated with total amount of fat mass (r=0.617, p=0.032). On the other hand, the cDR mice had significantly lower 5-HT transporter binding than the cDIO and LF mice, respectively, in the nucleus accumbens (-44%, -38%, both pcDIO and cDR mice. It provides neural anatomical bases by which genetic variability in 5-HT2A/2C receptors and 5-HT transporter may influence satiety and sensory aspects of energy balance. PMID:15276882

  19. Ageing and Chronic Administration of Serotonin-Selective Reuptake Inhibitor Citalopram Upregulate Sirt4 Gene Expression in the Preoptic Area of Male Mice

    Directory of Open Access Journals (Sweden)

    Wong eDutt Way

    2015-09-01

    Full Text Available Sexual dysfunction and cognitive deficits are markers of the ageing process. Mammalian sirtuins (SIRT, encoded by sirt 1-7 genes, are known as ageing molecules which are sensitive to serotonin (5-hydroxytryptamine, 5-HT. Whether the 5-HT system regulates SIRT in the preoptic area (POA, which could affect reproduction and cognition has not been examined. Therefore, this study was designed to examine the effects of citalopram (CIT, 10mg/kg for 4 weeks, wk, a potent selective-serotonin reuptake inhibitor and ageing on SIRT expression in the POA of male mice using real-time PCR and immunocytochemistry. Age-related increases of sirt1, sirt4, sirt5, and sirt7 mRNA levels were observed in the POA of 52 wk old mice. Furthermore, 4 wk of chronic CIT treatment started at 8 wk of age also increased sirt2 and sirt4 mRNA expression in the POA. Moreover, the number of SIRT4 immuno-reactive neurons increased with ageing in the medial septum area (12 wk = 1.00±0.15 vs 36 wk = 1.68±0.14 vs 52 wk = 1.54±0.11, p<0.05. In contrast, the number of sirt4-immunopositive cells did not show a statistically significant change with CIT treatment, suggesting that the increase in sirt4 mRNA levels may occur in cells in which sirt4 is already being expressed. Taken together, these studies suggest that CIT treatment and the process of ageing utilize the serotonergic system to up-regulate SIRT4 in the POA as a common pathway to deregulate social cognitive and reproductive functions.

  20. Chronic unpredictable stress (CUS) enhances the carcinogenic potential of 7,12-dimethylbenz(a)anthracene (DMBA) and accelerates the onset of tumor development in Swiss albino mice.

    Science.gov (United States)

    Suhail, Nida; Bilal, Nayeem; Hasan, Shirin; Ahmad, Ausaf; Ashraf, Ghulam Md; Banu, Naheed

    2015-11-01

    Social stressors evolving from individual and population interactions produce stress reactions in many organisms (including humans), influencing homeostasis, altering the activity of the immunological system, and thus leading to various pathological states including cancer and their progression. The present study sought to validate the effectiveness of chronic unpredictable stress (CUS) in cancer promotion and to assess oxidative stress outcomes in terms of various in vivo biochemical parameters, oxidative stress markers, DNA damage, and the development of skin tumors in Swiss albino mice. Animals were randomized into different groups based on their exposure to CUS alone, 7,12-dimethylbenz(a)anthracene (DMBA) alone (topical), and DMBA-12-O-tetradecanoylphorbol-13-acetate (TPA) (topical) and exposure to CUS prior to DMBA or DMBA-TPA treatments and sacrificed after 16 weeks of treatment. Prior exposure to CUS significantly increased the pro-oxidant effect of carcinogen, depicted by compromised levels of antioxidants in the circulation and skin, accompanied by enhanced lipid peroxidation, plasma corticosterone, and marker enzymes as compared to DMBA-alone or DMBA-TPA treatments. DNA damage results corroborated the above biochemical outcomes. Also, the development of skin tumors (in terms of their incidence, tumor yield, and tumor burden) in mice in the presence and absence of stress further strongly supported our above biochemical measurements. CUS may work as a promoter of carcinogenesis by enhancing the pro-oxidant potential of carcinogens. Further studies may be aimed at the development of interventions for disease prevention by identifying the relations between psychological factors and DNA damage. PMID:26272695

  1. Physiological and neuroendocrine responses to chronic variable stress in male California mice (Peromyscus californicus): Influence of social environment and paternal state.

    Science.gov (United States)

    De Jong, T R; Harris, B N; Perea-Rodriguez, J P; Saltzman, W

    2013-10-01

    Social environment and parental state affect stress responses in mammals, but their impact may depend on the social and reproductive strategy of the species. The influences of cohabitation with a male or female conspecific, and the birth of offspring, on the physiological and endocrine responses to chronic variable stress were studied in the monogamous and biparental California mouse (Peromyscus californicus). Adult male California mice were housed either with a male cage mate (virgin males, VM), a female cage mate (pair-bonded males, PBM), or a female cage mate and their first newborn litter (new fathers, NF). VM, PBM and NF underwent a 7-day chronic variable stress paradigm (CVS, three stressors per day at semi-random times, n=7-8 per housing condition). Compared to control males (CON, n=6-7 per housing condition), CVS caused loss of body mass, increased basal plasma corticosterone concentrations, and increased basal expression of arginine vasopressin (AVP) mRNA in the paraventricular nucleus of the hypothalamus (PVN). These effects were independent of housing condition. Neither CVS nor housing condition altered novel-stressor-induced corticosterone release, spleen or testis mass, or basal expression of corticotropin-releasing hormone (CRH) mRNA in the PVN. Although CVS appeared to increase adrenal mass and reduce thymus mass specifically in NF, these effects were explained by the lower adrenal mass and higher thymus mass of NF compared to PBM and VM under control conditions. These results suggest that neither engaging in a pair bond nor becoming a father attenuates typical responses to CVS, but that fatherhood may provide a buffer against transient mild stressors (i.e., weighing and blood sampling in the control groups) in this monogamous and biparental rodent. PMID:23582312

  2. Kinetics of Multiplication and Differentiation of Haemopoietic Progenitor Cells Transplanted into Irradiated Mice

    International Nuclear Information System (INIS)

    The growth of colony-forming units (CFU) was followed in the spleen of normal, polycythaemic and polycythaemic erythropoietin-treated test mice after irradiation and normal bone-marrow inoculation. The number of CFU was estimated at various time intervals after inoculation of bone-marrow by retransplantation of the test spleens in irradiated mice. The results indicate that in the spleen of polycythaemic animals the number of CFU is the same as in the normal animals up to day 4 after bone-marrow inoculation. At later times the content of CFU per spleen is about half of that in normal animals, although the CFU growth rate from day 6 to day 9 is comparable in both normal and polycythaemic animals. Erythropoietin injected daily in polycythaemic animals from day 3 after bone-marrow inoculation brings the CFU growth curve back to the level of normal animals. The 7-h uptake of 59Fe in the spleen of normal, polycythaemic and polycythaemic EPO-treated irradiated animals, at various times after bone-marrow inoculation, was also followed as a measure of CFU erythropoietic differentiation. The results are discussed in the light of the available information concerning growth and differentiation of spleen colony-formers. (author)

  3. GDNF在慢性应激和老化致小鼠行为与认知损伤中的作用%Role of GDNF in the behavior and cognitive impairment of mice induced by chronic stress and aging

    Institute of Scientific and Technical Information of China (English)

    李亚; 张亚楠; 陈亚静; 张冠雄; 史建勋

    2013-01-01

    Objective: To investigate the effects of chronic stress on the spatial learning-memory and the role of glial cell line-derived neurotrophic factor (GDNF) of prefrontal cortex (PFC) and hippocampus (HP) in different age mice. Methods: The chronic stress model mice in 21 days with multiple chronic unpredictable stressors were applied. The spontaneous behavior and spatial learning-memory ability of mice were tested, using Open field and Morris water maze task, and the expression of GDNF in HP and PFC were detected by immunohistoche-mical method. Results: Compared with young mice, the spontaneous behaviors were significantly decreased and the spatial learning-memory function were significantly decreased (P<0.05, P<0.01) in aged mice. The GDNF expression in the CA3, DG of HP and PFC were significantly reduced in aged mice (P<0.05, P<0.01). After chronic stress, the spontaneous behaviors were remarkably decreased and the ability of spatial learning-memory of the stress group mice were significantly decreased (P< 0.05, P<0.01) compared with those of the control group mice. The expression of GDNF in HP and PFC were remarkably reduced (P<0.05, P<0.01) in stress group mice. The aged stress mice had more serious changes after chronic stress. Conclusion: The brain aging and chronic stress in mice causes behavioral changes and the damage of spatial learning-memory function, and which may be nearly related to the expression of GDNF in HP and PFC.%目的:探讨慢性应激对不同月龄小鼠空间学习记忆功能的影响,以及小鼠前脑皮层和海马胶质细胞源性神经营养因子(GDNF)的作用.方法:采用多因素慢性应激动物模型,通过旷场试验和Morris水迷宫试验,检测不同月龄小鼠行为及空间学习记忆能力,并检测GDNF在小鼠脑海马和前脑皮层的表达.结果:与青年(2月龄)小鼠比较,老年(15月龄)小鼠的自发活动和探究行为明显减少,空间学习记忆能力明显降低(P<0.05,P<0.01),且海马CA3

  4. Chronic hyperbaric oxygen treatment elicits an anti-oxidant response and attenuates atherosclerosis in apoE knockout mice.

    Science.gov (United States)

    Kudchodkar, Bhalchandra J; Pierce, Anson; Dory, Ladislav

    2007-07-01

    We previously demonstrated that hyperbaric oxygen (HBO) treatment inhibits diet-induced atherosclerosis in New Zealand White rabbits. In the present study we investigate the mechanisms that might be involved in the athero-protective effect of HBO treatment in a well-accepted model of atherosclerosis, the apoE knockout (KO) mouse. We examine the effects of daily HBO treatment (for 5 and 10 weeks) on the components of the anti-oxidant defense mechanism and the redox state in blood, liver and aortic tissues and compare them to those of untreated apoE KO mice. HBO treatment results in a significant reduction of aortic cholesterol content and decreased fatty streak formation. These changes are accompanied by a significant reduction of autoantibodies against oxidatively modified LDL and profound changes in the redox state of the liver and aortic tissues. A 10-week treatment significantly reduces hepatic levels of TBARS and oxidized glutathione, while significantly increases the levels of reduced glutathione, glutathione reductase (GR), transferase, Se-dependent glutathione peroxidase and catalase (CAT). The effects of HBO treatment are similar in the aortic tissues. These observations provide evidence that HBO treatment has a powerful effect on the redox state of relevant tissues and produces an environment that inhibits oxidation. The anti-oxidant response may be the key to the anti-atherogenic effect of HBO treatment. PMID:16973170

  5. Growth and development of mice and rats conceived and reared at different G-intensities during chronic centrifugation

    Science.gov (United States)

    Oyama, J.; Solgaard, L.; Corrales, J.; Monson, C. B.

    1985-01-01

    Prenatal and postnatal growth of rats conceived and reared at different G-intensities from 1.0G (earth gravity) to a maximum of 2.03G were compared. Prenatal growth was not generally impaired but the lung/body mass ratio of 22-day old fetuses at 2.03G was decreased significantly compared to 1.06 controls. Survival of neonatal rats was substantially reduced at 1.71G and 2.03G. Postnatal growth was decreased at the higher G-intensities and showed smaller or no effects at the lower G-intensities. Comparisons of organ/body mass ratios of hyper-G and 1.0G rats at 9 wks of age showed relatively few differences at the lower G-intensities. Postnatal growth of mice at 2.03G was suppressed during the neonatal period but recovered later so that after 9 wks the body mass of females reached and of males approached controls. Results of this preliminary study clearly show the influence of body mass in scaling the effects of hyper-G on the growth and development of and between different animal species.

  6. Transcriptional changes associated with reduced spontaneous liver tumor incidence in mice chronically exposed to high dose arsenic

    International Nuclear Information System (INIS)

    Exposure of male C3H mice in utero (from gestational days 8-18) to 85 ppm sodium arsenite via the dams' drinking water has previously been shown to increase liver tumor incidence by 2 years of age. However, in our companion study (Ahlborn et al., 2009), continuous exposure to 85 ppm sodium arsenic (from gestational day 8 to postnatal day 365) did not result in increased tumor incidence, but rather in a significant reduction (0% tumor incidence). The purpose of the present study was to examine the gene expression responses that may lead to the apparent protective effect of continuous arsenic exposure. Genes in many functional categories including cellular growth and proliferation, gene expression, cell death, oxidative stress, protein ubiquitination, and mitochondrial dysfunction were altered by continuous arsenic treatment. Many of these genes are known to be involved in liver cancer. One such gene associated with rodent hepatocarcinogenesis, Scd1, encodes stearoyl-CoA desaturase and was down-regulated by continuous arsenic treatment. An overlap between the genes in our study affected by continuous arsenic exposure and those from the literature affected by long-term caloric restriction suggests that reduction in the spontaneous tumor incidence under both conditions may involve similar gene pathways such as fatty acid metabolism, apoptosis, and stress response.

  7. Dose-rate effects and chronological changes of chromosome aberration rates in spleen cells from mice that are chronically exposed to gamma-ray at low dose rates

    International Nuclear Information System (INIS)

    Dose-rate effects have not been examined in the low dose-rate regions of less than 60-600 mGy/h. Mice were chronically exposed to gamma-ray at 20 mGy/day (approximately 1 mGy/h) up to 700 days and at 1 mGy/day (approximately 0.05 mGy/h) for 500 days under SPF conditions. Chronological changes of chromosome aberration rates in spleen cells were observed along with accumulated doses at both low dose-rates. Unstable aberrations increased in a biphasic manner within 0-2 Gy and 4-14 Gy in 20 mGy/day irradiation. They slightly increased up to 0.5 Gy in 1 mGy/day irradiation. Chromosome aberration rates at 20 mGy/day and 1 mGy/day were compared at the same total doses of 0.5 Gy and 0.25 Gy. They were 2.0 vs. 0.53, and 1.0 vs. 0.47 respectively. Thus, dose-rate effects were observed in these low dose-rate regions. (author)

  8. Histomorphological study of the CBA line mice liver under combined chronic influence of the low dose γ--radiation and incorporated thorium nitrate

    International Nuclear Information System (INIS)

    The evaluation of the liver reaction on the external chronic impact of the low-intensity γ-radiation in combination with the thorium nitrate incorporation and application of morphophysiological and histomorphological evaluation criteria is carried out. The single-age nature mice males were exposed to the 226Ra (50 mR/h) source. Two series of experiments by the γ-radiation dose rate of 2 mR/h were performed in combination with the 232Th(NO3)2 incorporation. The total absorbed dose in the first series by the 30-day radiation dose constituted 14.4 cGy. The total absorbed dose in the second series by the 90-day radiation impact equaled 43.2 cGy. The increase in the animals liver mass and index, as compared to the control data, was noted in the first series of experiments. Such changes were not observed in the second series. The morphological indices (the number of two-nuclei and polyabsorbed hepatocytes, nucleoluses and also the square of contours of these cells and their nuclei and nucleoluses) testing to the intensity of energy balance in the liver

  9. Tests of induction in mice by acute and chronic ionizing radiation and ethylnitrosourea of dominant mutations that cause the more common skeletal anomalies

    International Nuclear Information System (INIS)

    Assessment-of-Dominant-Damage (ADD) experiments explored induction by proven specific-locus mutagens of dominant mutations that cause skeletal anomalies, cataracts, and stunted growth in offspring of mutagenized male mice. The data set reported here includes 6134 offspring. Mutagenic treatments included 600 R (i.e., approximately 6 Gy) of X-rays delivered in about 7 min, 600 R of gamma rays delivered over about 110 days, and four weekly intraperitoneal (i.p.) injections of 77.5 mg/kg of ethylnitrosourea (ENU). The results reported in this paper are restricted to mutations induced in stem-cell spermatogonia and to the 34 more common skeletal anomalies (i.e., those found in 0.5% or more of the control offspring). Mutation induction was demonstrated for eight anomalies in the acute X-ray experiment and for 17 anomalies (including those same eight anomalies) in the ENU experiment. In spite of the surprisingly high mutation rates found for these treatments, there was no hint of any induction of such dominant mutations by 600 R of chronic gamma radiation. Our results suggest that several anomalies related to variation in the sacralization pattern may be particularly useful for revealing induction of dominant mutations

  10. Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (6g on chronic unpredictable mild stress-induced changes in behavioural and brain oxidative stress parameters in mice

    Directory of Open Access Journals (Sweden)

    Shvetank Bhatt

    2014-01-01

    Full Text Available Aim: The aim of the study was to evaluate a novel 5 HT 3 receptor antagonist (6g on chronic stress induced changes in behavioural and brain oxidative stress parameter in mice. A complicated relationship exists among stressful stimuli, body′s reaction to stress and the onset of clinical depression. Chronic unpredictable stressors can produce a situation similar to human depression, and such animal models can be used for the preclinical evaluation of antidepressants. Materials and Methods: In the present study, a novel and potential 5-HT 3 receptor antagonist (4-benzylpiperazin-1-yl(3-methoxyquinoxalin-2-yl methanone (6g with good Log P (3.08 value and pA 2 (7.5 values, synthesized in our laboratory was investigated to study the effects on chronic unpredictable mild stress (CUMS-induced behavioural and biochemical alterations in mice. Mice were subjected to different stress paradigms daily for a period of 28 days to induce depressive-like behaviour. Results: The results showed that CUMS caused depression-like behaviour in mice, as indicated by the significant (P < 0.05 decrease in sucrose consumption and locomotor activity and increase in immobility the forced swim test. In addition, it was found that lipid peroxidation and nitrite levels were significantly (P < 0.05 increased, whereas glutathione levels, superoxide dismutase and catalase activities decreased in brain tissue of CUMS-treated mice. ′6g′ (1 and 2 mg/kg, p.o., 21 days and fluoxetine treatment (20 mg/kg, p.o., 21 days significantly (P < 0.05 reversed the CUMS-induced behavioural (increased immobility period, reduced sucrose preference and decreased locomotor activity and biochemical (increased lipid peroxidation; decreased glutathione levels, superoxide dismutase and catalase activities. However fluoxetine treatment (20 mg/kg, p.o., 21 days significantly decreased the nitrite level in the brain while ′6g′ (1 and 2 mg/kg, p.o., 21 days did not show significant (P < 0

  11. Association between repeated unpredictable chronic mild stress (UCMS procedures with a high fat diet: a model of fluoxetine resistance in mice.

    Directory of Open Access Journals (Sweden)

    Elsa Isingrini

    Full Text Available Major depressive disorder is a debilitating disease. Unfortunately, treatment with antidepressants (ADs has limited therapeutic efficacy since resistance to AD is common. Research in this field is hampered by the lack of a reliable natural animal model of AD resistance. Depression resistance is related to various factors, including the attendance of cardiovascular risk factors and past depressive episodes. We aimed to design a rodent model of depression resistance to ADs, associating cardiovascular risk factors with repeated unpredicted chronic mild stress (UCMS. Male BALB/c mice were given either a regular (4% fat or a high fat diet (45% fat and subjected to two 7-week periods of UCMS separated by 6 weeks. From the second week of each UCMS procedure, vehicle or fluoxetine (10 mg/kg, i.p. was administrated daily. The effects of the UCMS and fluoxetine in both diet conditions were assessed using physical (coat state and body weight and behavioural tests (the reward maze test and the splash test. The results demonstrate that during the second procedure, UCMS induced behavioural changes, including coat state degradation, disturbances in self-care behaviour (splash test and anhedonia (reward maze test and these were reversed by fluoxetine in the regular diet condition. In contrast, the high-fat diet regimen prevented the AD fluoxetine from abolishing the UCMS-induced changes. In conclusion, by associating UCMS-an already validated animal model of depression-with high-fat diet regimen, we designed a naturalistic animal model of AD resistance related to a sub-nosographic clinical entity of depression.

  12. Differential expression of dopamine D2 and D4 receptor and tyrosine hydroxylase mRNA in mice prone, or resistant, to chronic high-fat diet-induced obesity.

    Science.gov (United States)

    Huang, Xu-Feng; Yu, Yinghua; Zavitsanou, Katerina; Han, Mei; Storlien, Len

    2005-04-27

    The present study examined brain dopamine D2 and D4 receptor and tyrosine hydroxylase (TH) mRNA expression in chronic high-fat diet-induced obese (cDIO) and obese-resistant (cDR) mice. Twenty-eight mice were fed a high-fat diet (HF: 40% of calories from fat) for 6 weeks and then classified as cDIO (n = 8) or cDR (n = 8) mice according to the highest and lowest body weight gainers, respectively. Seven mice were fed a low-fat diet (LF: 10% of calories from fat) and used as controls. After 20 weeks of feeding, visceral fat per gram of initial body weight was significantly higher in the cDIO group (ratio: 0.25, 0.09, and 0.04; P cDIO vs. cDR and LF, respectively). Using quantitative in situ hybridization techniques, the levels of D2 and D4 receptor and tyrosine hydroxylase (TH) mRNAs were measured in multiple brain sections. The cDIO mice had a significantly higher level of D2 receptor mRNA expression in the core of the nucleus accumbens (AcbC, +16%) and ventral parts of caudate putamen (CPu, 21% and 24%) compared to the cDR and LF mice. The levels of D2 receptor mRNA expression in the AcbC and ventromedial part of the CPu were positively related to the final body weight. This study is the first to systematically examine the D4 mRNA expression in the mouse brain using in situ hybridization method. D4 receptor mRNA expression in the ventromedial hypothalamic nucleus (VMH) and the ventral part of the lateral septal nucleus were also significantly higher in the cDIO mice compared to the cDR and LF mice (+31% and +60%; P cDIO mice compared to cDR mice. In conclusion, this study has demonstrated differentially regulated levels of D2 and D4 receptor and TH mRNA expression in specific brain regions of cDIO and cDR mice. It provides evidence that D4 receptors may play an important role influencing satiety via the mesohypothalamic pathway while the D2 receptor may regulate reward and motor centers via mesolimbic and nigrostriatal pathways. These findings contribute to the

  13. 慢性应激对小鼠学习记忆功能影响及突触作用%Effects of chronic stress on spatial learning-memory function in mice and its synaptic mechanism

    Institute of Scientific and Technical Information of China (English)

    李亚; 陈亚静; 史建勋; 张冠雄

    2012-01-01

    目的 探讨慢性应激对不同月龄小鼠空间学习记忆功能影响以及前脑皮层和海马突触体膜流动性和突触体内游离Ca2+作用.方法 采用多因素慢性应激动物模型,通过Morris水迷宫测试小鼠空间学习记忆能力;检测突触体膜流动性和突触体内游离Ca2+浓度.结果 青年和老年对照组小鼠训练周期1逃避潜伏期、第一象限停留时间分别为(63.62 ±4.38)、(38.63 ±3.04)s和(76.46 ±3.32)、(36.24 ±2.65)s,老年小鼠空间学习记忆能力明显降低(P<0.05);老年小鼠前脑皮层和海马突触体膜r值分别为(0.1917±0.0015)、(0.1946±0.0012),均明显高于青年对照组(P<0.05);与青年对照组比较,老年小鼠突触体内游离Ca2+浓度明显增加(P<0.05);青年应激组小鼠训练周期1逃避潜伏期、第一象限停留时间分别为(64.32±4.56)、(34.56±2.83)s,空间学习记忆能力明显下降(P<0.05);前脑皮层和海马突触体膜r值分别为(0.184 6±0.000 8)、(0.188 8 ±0.001 0),均明显高于青年对照组(P<0.01);青年应激组小鼠突触体内游离Ca2浓度明显高于青年对照组(P<0.05);老年应激组小鼠变化更加明显.结论 衰老与慢性应激导致小鼠空间学习记忆功能损伤可能与突触体膜流动性和突触体内游离Ca2+浓度变化密切相关.%Objective To study the effect of chronic stress on spatial learning-memory and the role of membrane fluidity and free calcium concentrations([Ca2+ ]i) of prefrontal cortical and hippocampal synaptosomes in mice of different age. Methods The chronic stress model of mice was induced by stimulation of multiple stressors for 21 days. The spatial learning-memory ability of mice were tested using Morris water maze task. The changes of synaptosomal membrane fluidity and[Ca2 + ]i of prefrontal cortex (PFC) and hippocampus (HP) in mice brain were also examined. Results The escape latency and the swimming time of first quadrants in young and aged control mice

  14. Mice chronically exposed to low dose ionizing radiation possess splenocytes with elevated levels of HSP70 mRNA, HSC70 and HSP72 and with an increased capacity to proliferate

    International Nuclear Information System (INIS)

    The purpose of this study was to determine whether the enhanced proliferative activity of splenocytes induced by exposing mice to whole body, chronic, intermittent low doses of ionizing radiation is associated with an increase in the expression of stress protein genes. Mice were exposed to a γ-irradiation protocol of 0, 0.04 or 0.10 Gy/day for 5 consequent days/week, for 4 weeks. Splenocytes were then assessed for their levels of heat shock protein (HSP) 70 mRNA, glyceraldehyde 3-phosphate dehydrogenase (GAPD) mRNA, HSC70 (a constitutively-expressed isoform of HSP70) and HSP72 (an inducible isoform of HSP70), before and 1 day after mitogenic stimulation. (author)

  15. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

  16. Neuropathological Changes and Clinical Features of Autism Spectrum Disorder Participants Are Similar to that Reported in Congenital and Chronic Cerebral Toxoplasmosis in Humans and Mice

    Science.gov (United States)

    Prandota, Joseph

    2010-01-01

    Anatomic, histopathologic, and MRI/SPET studies of autistic spectrum disorders (ASD) patients' brains confirm existence of very early developmental deficits. In congenital and chronic murine toxoplasmosis several cerebral anomalies also have been reported, and worldwide, approximately two billion people are chronically infected with T. "gondii"…

  17. Chronic Caloric Restriction and Exercise Improve Metabolic Conditions of Dietary-Induced Obese Mice in Autophagy Correlated Manner without Involving AMPK

    Directory of Open Access Journals (Sweden)

    Mingxia Cui

    2013-01-01

    Full Text Available Aim. To investigate the role of AMPK activation and autophagy in mediating the beneficial effects of exercise and caloric restriction in obesity. Methods. Dietary-induced obesity mice were made and divided into 5 groups; one additional group of normal mice serves as control. Mice in each group received different combinations of interventions including low fat diet, caloric restriction, and exercise. Then their metabolic conditions were assessed by measuring serum glucose and insulin, serum lipids, and liver function. AMPK phosphorylation and autophagy activity were detected by western blotting. Results. Obese mice models were successfully induced by high fat diet. Caloric restriction consistently improved the metabolic conditions of the obese mice, and the effects are more prominent than the mice that received only exercise. Also, caloric restriction, exercise, and low fat diet showed a synergistic effect in the improvement of metabolic conditions. Western blotting results showed that this improvement was not related with the activation of AMPK in liver, skeletal muscle, or heart but correlates well with the autophagy activity. Conclusion. Caloric restriction has more prominent beneficial effects than exercise in dietary-induced obese mice. These effects are correlated with the autophagy activity and may be independent of AMPK activation.

  18. Chronic Diarrhea

    Science.gov (United States)

    ... infections that cause chronic diarrhea be prevented? Chronic Diarrhea What is chronic diarrhea? Diarrhea that lasts for more than 2-4 ... represent a life-threatening illness. What causes chronic diarrhea? Chronic diarrhea has many different causes; these causes ...

  19. Obesity-induced chronic inflammation in C57Bl6J mice, a novel risk factor in the progression of renal AA amyloidosis?

    NARCIS (Netherlands)

    Van Der Heijden, R.A.; Sheedfar, F.; Bijzet, J.; Hazenberg, B.P.; Koonen, D.P.; Heeringa, P.

    2015-01-01

    Background: Compelling evidence links obesity induced systemic inflammation to the development of chronic kidney disease (CKD). This systemic inflammation may result from exacerbated adipose inflammation. Besides the known detrimental effects of typical pro-inflammatory factors secreted by the adipo

  20. Chronic hypoxia induces the activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1ΔE9 transgenic mice in vivo

    Science.gov (United States)

    Varela-Nallar, Lorena; Rojas-Abalos, Macarena; Abbott, Ana C.; Moya, Esteban A.; Iturriaga, Rodrigo; Inestrosa, Nibaldo C.

    2014-01-01

    Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin, a key component of the canonical Wnt signaling pathway. Here we studied the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice in vivo. The hypoxia-inducible transcription factor-1α (HIF-1α) was analyzed as a molecular control of the physiological hypoxic response. Exposure to chronic hypoxia (10% oxygen for 6–72 h) stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, Bromodeoxyuridine (BrdU) incorporation and double labeling with doublecortin (DCX). Chronic hypoxia also induced neurogenesis in a double transgenic APPswe-PS1ΔE9 mouse model of Alzheimer’s disease (AD), which shows decreased levels of neurogenesis in the SGZ. Our results show for the first time that exposure to hypoxia in vivo can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorders associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired. PMID:24574965

  1. Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35-55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice.

    Science.gov (United States)

    Vandenbark, Arthur A; Rich, Cathleen; Mooney, Jeff; Zamora, Alex; Wang, Chunhe; Huan, Jianya; Fugger, Lars; Offner, Halina; Jones, Richard; Burrows, Gregory G

    2003-07-01

    In a previous study, we demonstrated that myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide could induce severe chronic experimental autoimmune encephalomyelitis (EAE) in HLA-DR2(+) transgenic mice lacking all mouse MHC class II genes. We used this model to evaluate clinical efficacy and mechanism of action of a novel recombinant TCR ligand (RTL) comprised of the alpha(1) and beta(1) domains of DR2 (DRB1*1501) covalently linked to the encephalitogenic MOG-35-55 peptide (VG312). We found that the MOG/DR2 VG312 RTL could induce long-term tolerance to MOG-35-55 peptide and reverse clinical and histological signs of EAE in a dose- and peptide-dependent manner. Some mice treated with lower doses of VG312 relapsed after cessation of daily treatment, but the mice could be successfully re-treated with a higher dose of VG312. Treatment with VG312 strongly reduced secretion of Th1 cytokines (TNF-alpha and IFN-gamma) produced in response to MOG-35-55 peptide, and to a lesser degree purified protein derivative and Con A, but had no inhibitory effect on serum Ab levels to MOG-35-55 peptide. Abs specific for both the peptide and MHC moieties of the RTLs were also present after treatment with EAE, but these Abs had only a minor enhancing effect on T cell activation in vitro. These data demonstrate the powerful tolerance-inducing therapeutic effects of VG312 on MOG peptide-induced EAE in transgenic DR2 mice and support the potential of this approach to inhibit myelin Ag-specific responses in multiple sclerosis patients. PMID:12816990

  2. Study of C57 mice depression model induced by chronic stress and separation%慢性应激联合孤养C57小鼠抑郁模型的研究

    Institute of Scientific and Technical Information of China (English)

    姚丽华; 陈建新; 王晓萍; 王惠玲; 王高华; 刘忠纯

    2014-01-01

    目的 探讨C57小鼠慢性不可预见性温和应激(chronic unpredictable mild stress,GUMS)联合孤养建立抑郁模型的可行性和有效性.方法 将30只雄性C57小鼠随机分为CUMS+孤养组、CUMS+孤养+氟西汀组、对照组各10只,前两组CUMS+孤养致抑郁模型3周,3周后对CUMS+孤养+氟西汀组进行氟西汀干预,观察小鼠应激前、应激后及干预后的摄食量/体质量、旷场实验和液体消耗实验变化.结果 与对照组比较,建模21d后CUMS+孤养组和CUMS+孤养+氟西汀组小鼠摄食量/体质量、糖水偏好、旷场总行程显著下降(P<0.05);经氟西汀干预14 d后摄食量/体质量、旷场总行程与对照组比较无明显差异(P>0.05),但糖水消耗量明显提高(P<0.05),与CUMS+孤养组比较也有明显改善(P<0.05).结论 C57小鼠CUMS联合孤养制作抑郁模型的效果肯定,是研究抑郁症较为理想的动物模型.%Objective To investigate the feasibility and effectiveness of C57 mice depression model established by chronic unpredictable mild stress (CUMS) and separation.Methods 30 male C57 mice were randomly divided into three groups:CUMS + separation group (group CS),CUMS + separation + fluoxetine group (group CSF),and control group (group C).The mice of group CS and group CSF were fed with chronic unpredictable mild stress (CUMS) and separation for 3 weeks.Then,the mice of group CSF were given fluoxetine.To record the food intake/body weight,liquid consumption and field test of the mice at relevant time point.Results Compared with control group,the food intake/body weight,total route in the field test,and the sucrose solution consumption in liquid consumption test of group CS and group CSF decreased significantly (P<0.05) at the 21th days.But after giving fluoxetine for 14 days,group CSF had no significant differences with group C except sucrose solution consumption.Although the difference of sucrose solution preferences was significant compared with

  3. Influence of long-term cadmium and selenite exposure on resistance to Listeria monocytogenes during acute and chronic infection in mice

    OpenAIRE

    Šimonytė, Sandrita; Plančiūnienė, Rita; Cherkashin, Gennadij; žekonis, Gediminas

    2006-01-01

    The aim of the present study was to evaluate the effect of long-term exposure to cadmium and selenite ions on the BALB/c mice resistance to experimental Listeria monocytogenes infection. A low-dose six-week exposure to cadmium ions (10 mg/ l in drinking water) decreased the clearance of listeria from mice liver and spleen at 24 h in the early phase of infection. Long-term treatment of mouse with selenite ions (0.15 mg/l) did not activate the elimination of bacteria from the organs. Eight week...

  4. Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer’s disease

    OpenAIRE

    Graham, Leah C.; Harder, Jeffrey M.; Ileana Soto; de Vries, Wilhelmine N.; Simon W M John; Gareth R Howell

    2016-01-01

    Studies have assessed individual components of a western diet, but no study has assessed the long-term, cumulative effects of a western diet on aging and Alzheimer’s disease (AD). Therefore, we have formulated the first western-style diet that mimics the fat, carbohydrate, protein, vitamin and mineral levels of western diets. This diet was fed to aging C57BL/6J (B6) mice to identify phenotypes that may increase susceptibility to AD, and to APP/PS1 mice, a mouse model of AD, to determine the e...

  5. Inhibition of Chronic Pancreatitis and Murine Pancreatic Intraepithelial Neoplasia by a Dual Inhibitor of c-RAF and Soluble Epoxide Hydrolase in LSL-KrasG¹²D/Pdx-1-Cre Mice.

    Science.gov (United States)

    Liao, Jie; Hwang, Sung Hee; Li, Haonan; Liu, Jun-Yan; Hammock, Bruce D; Yang, Guang-Yu

    2016-01-01

    Mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS) and chronic pancreatitis are the most common pathogenic events involved in human pancreatic carcinogenesis. In the process of long-standing chronic inflammation, aberrant metabolites of arachidonic acid play a crucial role in promoting carcinogenesis, in which the soluble epoxide hydrolase (sEH), as a pro-inflammatory enzyme, generally inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs). Herein, we determined the effect of our newly-synthesized novel compound trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide (t-CUPM), a dual inhibitor of sEH and RAF1 proto-oncogene serine/threonine kinase (c-RAF), on inhibiting the development of pancreatitis and pancreatic intraepithelial neoplasia (mPanIN) in LSL-Kras(G12D)/Pdx1-Cre mice. The results showed that t-CUPM significantly reduced the severity of chronic pancreatitis, as measured by the extent of acini loss, inflammatory cell infiltration and stromal fibrosis. The progression of low-grade mPanIN I to high-grade mPanIN II/III was significantly suppressed. Inhibition of mutant Kras-transmitted phosphorylation of mitogen-activated protein kinase's kinase/extracellular signal-regulated kinases was demonstrated in pancreatic tissues by western blots. Quantitative real-time polymerase chain reaction analysis revealed that t-CUPM treatment significantly reduced the levels of inflammatory cytokines including tumor necrosis facor-α, monocyte chemoattractant protein-1, as well as vascular adhesion molecule-1, and the levels of Sonic hedgehog and Gli transcription factor (Hedgehog pathway). Analysis of the eicosanoid profile revealed a significant increase of the EETs/dihydroxyeicosatrienoic acids ratio, which further confirmed sEH inhibition by t-CUPM. These results indicate that simultaneous inhibition of sEH and c-RAF by t-CUPM is important in preventing chronic pancreatitis and carcinogenesis

  6. Phenotypic assessment of pulmonary hypertension using high-resolution echocardiography is feasible in neonatal mice with experimental bronchopulmonary dysplasia and pulmonary hypertension: a step toward preventing chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Reynolds CL

    2016-07-01

    Full Text Available Corey L Reynolds,1 Shaojie Zhang,2 Amrit Kumar Shrestha,2 Roberto Barrios,3 Binoy Shivanna2 1Mouse Phenotyping Core, 2Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; 3Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA Abstract: Bronchopulmonary dysplasia (BPD and chronic obstructive pulmonary disease (COPD are chronic lung diseases of human infants and adults, respectively, that are characterized by alveolar simplification. One-third of the infants with severe BPD develop pulmonary hypertension (PH. More importantly, PH increases morbidity and mortality in BPD patients. Additionally, COPD is a common respiratory morbidity in former BPD patients. The lack of an appropriate small animal model wherein echocardiography (Echo can demonstrate PH is one of the major barriers to understand the molecular mechanisms of the disease and, thereby, develop rational therapies to prevent and/or treat PH in BPD patients. Thus, the goal of this study was to establish a model of experimental BPD and PH and investigate the feasibility of Echo to diagnose PH in neonatal mice. Since hyperoxia-induced oxidative stress and inflammation contributes to the development of BPD with PH, we tested the hypothesis that exposure of newborn C57BL/6J mice to 70% O2 (hyperoxia for 14 days leads to lung oxidative stress, inflammation, alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and Echo evidence of PH. Hyperoxia exposure caused lung oxidative stress and inflammation as evident by increased malondialdehyde adducts and inducible nitric oxide synthase, respectively. Additionally, hyperoxia exposure caused growth restriction, alveolar and pulmonary vascular simplification, and pulmonary vascular remodeling. At 14 days of age, Echo of these mice demonstrated that hyperoxia exposure decreased pulmonary acceleration time (PAT and PAT/ejection time ratio and increased

  7. Neurological Toxicity of Individual and Mixtures of Low Dose Arsenic, Mono and Di (n-butyl) Phthalates on Sub-Chronic Exposure to Mice.

    Science.gov (United States)

    Mao, Guanghua; Zhou, Zhaoxiang; Chen, Yao; Wang, Wei; Wu, Xueshan; Feng, Weiwei; Cobbina, Samuel Jerry; Huang, Jing; Zhang, Zhen; Xu, Hai; Yang, Liuqing; Wu, Xiangyang

    2016-03-01

    The objective of this study was to evaluate the toxicity of individual and mixtures of di(n-butyl) phthalates (DBP) and their active metabolite monobutyl phthalate (MBP) and arsenic (As) on spatial cognition associated with hippocampal apoptosis in mice. Mice were exposed, individually or in combination, to DBP (50 mg/kg body weight, intragastrically), MBP (50 mg/kg body weight, intragastrically), and As (10 mg/L, per os) for 8 weeks. The Morris water maze test showed that mice exposed to DBP/MBP combined with As exhibited longer escape latencies and the lower average number of crossing the platform. The As content in the hippocampus after As exposure increased as compared to those without As exposure. In mice exposed to DBP/MBP combined with As, pathological alterations and oxidative damage to the hippocampus were found. Expression of apoptosis-related protein: Bax and caspase-3 were significantly increased in the hippocampus, while there was no significant change in expression of Bcl-2. The results suggested that DBP and MBP combined with As can induce spatial cognitive deficits through altering the expression of apoptosis-related protein and As played a critical role in cognition impairments. And the joint exposure has antagonistic effect. PMID:26257159

  8. Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons.

    Science.gov (United States)

    Richter, Franziska; Gao, Fuying; Medvedeva, Vera; Lee, Patrick; Bove, Nicholas; Fleming, Sheila M; Michaud, Magali; Lemesre, Vincent; Patassini, Stefano; De La Rosa, Krystal; Mulligan, Caitlin K; Sioshansi, Pedrom C; Zhu, Chunni; Coppola, Giovanni; Bordet, Thierry; Pruss, Rebecca M; Chesselet, Marie-Françoise

    2014-09-01

    Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson's disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4months of age, approximately 10months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha

  9. Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress

    NARCIS (Netherlands)

    Marit Arp, J; Ter Horst, Judith P; Loi, Manila; den Blaauwen, Jan; Bangert, Eline; Fernández, Guillén; Joëls, Marian; Oitzl, Melly S; Krugers, Harm

    2016-01-01

    Early life adversity can have long-lasting impact on learning and memory processes and increase the risk to develop stress-related psychopathologies later in life. In this study we investigated i) how chronic early life stress (ELS) - elicited by limited nesting and bedding material from postnatal d

  10. Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis

    NARCIS (Netherlands)

    van der Heijden, Roel A.; Bijzet, Johan; Meijers, Wouter C.; Yakala, Gopala K.; Kleemann, Robert; Nguyen, Tri Q.; de Boer, Rudolf A.; Schalkwijk, Casper G.; Hazenberg, Bouke P. C.; Tietge, Uwe J. F.; Heeringa, Peter

    2015-01-01

    Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complicat

  11. Increased severity of experimental autoimmune encephalomyelitis, chronic macrophage/microglial reactivity, and demyelination in transgenic mice producing tumor necrosis factor-alpha in the central nervous system

    DEFF Research Database (Denmark)

    Taupin, V; Renno, T; Bourbonnière, L;

    1997-01-01

    are a target of immune attack. TNF-alpha also regulates macrophage activity which could contribute to autoimmune inflammation. We have expressed TNF-alpha at disease-equivalent levels in the central nervous system of transgenic mice, using a myelin basic protein (MBP) promoter. These mice were normal......Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine implicated in a number of autoimmune diseases. Apoptotic cell death is induced by TNF-alpha in vitro, and has been suggested as one cause of autoimmune pathology, including autoimmune demyelinating diseases where oligodendrocytes...... and showed no spontaneous pathology, but they developed experimental autoimmune encephalomyelitis (EAE) with greater severity than nontransgenic controls when immunized with MBP in adjuvant. Unlike nontransgenic controls, EAE then progressed to a nonabating demyelinating disease. Macrophage...

  12. Chronic nandrolone administration promotes oxidative stress, induction of pro-inflammatory cytokine and TNF-α mediated apoptosis in the kidneys of CD1 treated mice

    International Nuclear Information System (INIS)

    Nandrolone decanoate administration and strenuous exercise increase the extent of renal damage in response to renal toxic injury. We studied the role played by oxidative stress in the apoptotic response caused by nandrolone decanoate in the kidneys of strength-trained male CD1 mice. To measure cytosolic enzyme activity, glutathione peroxidase (GPx), glutathione reductase (GR) and malondialdehyde (MDA) were determined after nandrolone treatment. An immunohistochemical study and Western blot analysis were performed to evaluate cell apoptosis and to measure the effects of renal expression of inflammatory mediators (IL-1β, TNF-α) on the induction of apoptosis (HSP90, TUNEL). Dose-related oxidative damage in the kidneys of treated mice is shown by an increase in MDA levels and by a reduction of antioxidant enzyme GR and GPx activities, resulting in the kidney's reduced radical scavenging ability. Renal specimens of the treated group showed relevant glomeruli alterations and increased immunostaining and protein expressions, which manifested significant focal segmental glomerulosclerosis. The induction of proinflammatory cytokine expression levels was confirmed by Western blot analysis. Long-term administration of nandrolone promotes oxidative injury in the mouse kidneys. TNF-α mediated injury due to nandrolone in renal cells appears to play a role in the activation of both the intrinsic and extrinsic apoptosis pathways. - Highlights: • We analyze abuse of nandrolone decanoate in strength-trained male CD1 mice. • Nandrolone decanoate administration increases oxidative stress. • Increased cytokine expressions were observed. • Renal apoptosis was described. • Long-term administration of nandrolone promotes oxidative injury in mice kidney

  13. Effects of HIV/TAT protein expression and chronic selegiline treatment on spatial memory, reversal learning and neurotransmitter levels in mice.

    Science.gov (United States)

    Kesby, James P; Markou, Athina; Semenova, Svetlana

    2016-09-15

    Neurotoxic viral protein TAT may contribute to deficits in dopaminergic and cognitive function in individuals infected with human immunodeficiency virus. Transgenic mice with brain-specific doxycycline-induced TAT expression (TAT+, TAT- control) show impaired cognition. However, previously reported TAT-induced deficits in reversal learning may be compromised by initial learning deficits. We investigated the effects of TAT expression on memory retention/recall and reversal learning, and neurotransmitter function. We also investigated if TAT-induced effects can be reversed by improving dopamine function with selegiline, a monoamine oxidase inhibitor. Mice were tested in the Barnes maze and TAT expression was induced after the task acquisition. Selegiline treatment continued throughout behavioral testing. Dopamine, serotonin and glutamate tissue levels in the prefrontal/orbitofrontal cortex, hippocampus and caudate putamen were measured using high performance liquid chromatography. Neither TAT expression nor selegiline altered memory retention. On day 2 of reversal learning testing, TAT+ mice made fewer errors and used more efficient search strategies than TAT- mice. TAT expression decreased dopamine turnover in the caudate putamen, increased serotonin turnover in the hippocampus and tended to increase the conversion of glutamate to glutamine in all regions. Selegiline decreased dopamine and serotonin metabolism in all regions and increased glutamate levels in the caudate putamen. In the absence of impaired learning, TAT expression does not impair spatial memory retention/recall, and actually facilitates reversal learning. Selegiline-induced increases in dopamine metabolism did not affect cognitive function. These findings suggest that TAT-induced alterations in glutamate signaling, but not alterations in monoamine metabolism, may underlie the facilitation of reversal learning. PMID:27211061

  14. Chronic nandrolone administration promotes oxidative stress, induction of pro-inflammatory cytokine and TNF-α mediated apoptosis in the kidneys of CD1 treated mice

    Energy Technology Data Exchange (ETDEWEB)

    Riezzo, Irene; Turillazzi, Emanuela; Bello, Stefania; Cantatore, Santina [Department of Forensic Pathology, University of Foggia, Foggia (Italy); Cerretani, Daniela [Pharmacology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena (Italy); Di Paolo, Marco [Department of Forensic Pathology, University of Pisa, Pisa (Italy); Fiaschi, Anna Ida [Pharmacology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena (Italy); Frati, Paola [Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, University of Rome Sapienza, Viale Regina Elena 336, 00161 Rome (Italy); Neri, Margherita [Department of Forensic Pathology, University of Foggia, Foggia (Italy); Pedretti, Monica [Department of Forensic Pathology, University of Pisa, Pisa (Italy); Fineschi, Vittorio, E-mail: vfinesc@tin.it [Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, University of Rome Sapienza, Viale Regina Elena 336, 00161 Rome (Italy)

    2014-10-01

    Nandrolone decanoate administration and strenuous exercise increase the extent of renal damage in response to renal toxic injury. We studied the role played by oxidative stress in the apoptotic response caused by nandrolone decanoate in the kidneys of strength-trained male CD1 mice. To measure cytosolic enzyme activity, glutathione peroxidase (GPx), glutathione reductase (GR) and malondialdehyde (MDA) were determined after nandrolone treatment. An immunohistochemical study and Western blot analysis were performed to evaluate cell apoptosis and to measure the effects of renal expression of inflammatory mediators (IL-1β, TNF-α) on the induction of apoptosis (HSP90, TUNEL). Dose-related oxidative damage in the kidneys of treated mice is shown by an increase in MDA levels and by a reduction of antioxidant enzyme GR and GPx activities, resulting in the kidney's reduced radical scavenging ability. Renal specimens of the treated group showed relevant glomeruli alterations and increased immunostaining and protein expressions, which manifested significant focal segmental glomerulosclerosis. The induction of proinflammatory cytokine expression levels was confirmed by Western blot analysis. Long-term administration of nandrolone promotes oxidative injury in the mouse kidneys. TNF-α mediated injury due to nandrolone in renal cells appears to play a role in the activation of both the intrinsic and extrinsic apoptosis pathways. - Highlights: • We analyze abuse of nandrolone decanoate in strength-trained male CD1 mice. • Nandrolone decanoate administration increases oxidative stress. • Increased cytokine expressions were observed. • Renal apoptosis was described. • Long-term administration of nandrolone promotes oxidative injury in mice kidney.

  15. Chronic administration of Angelica sinensis polysaccharide effectively improves fatty liver and glucose homeostasis in high-fat diet-fed mice.

    Science.gov (United States)

    Wang, Kaiping; Cao, Peng; Wang, Hanxiang; Tang, Zhuohong; Wang, Na; Wang, Jinglin; Zhang, Yu

    2016-01-01

    This study aimed to investigate the therapeutic effects of Angelica sinensis polysaccharide (ASP), an active component derived from a water extract of Angelica sinensis, in high-fat diet (HFD)-fed BALB/c mice. The potential mechanisms underlying the activity of this compound were also considered. Specifically, serum and hepatic biochemical parameters were evaluated, and key proteins involved in the lipid/glucose metabolism were analyzed. Long-term feeding with a HFD induced severe fatty liver and hyperglycemia. Histological examination clearly showed that ASP reduced lipid accumulation in the liver and attenuated hepatic steatosis in HFD-fed mice. In addition, ASP markedly alleviated serum and liver lipid disorders and fatty liver via the upregulation of PPARγ expression and the activation of adiponectin-SIRT1-AMPK signaling. Furthermore, ASP also significantly relieved severe oxidative stress, demonstrating that ASP might attenuate nonalcoholic fatty liver disease via a "two-hit" mechanism. In addition, ASP reduced blood glucose levels and ameliorated insulin resistance via the regulation of related metabolic enzymes and by activating the PI3K/Akt pathway in HFD-fed mice. Our findings revealed that ASP might be used as an alternative dietary supplement or health care product to ameliorate metabolic syndrome in populations that consistently consume HFDs. PMID:27189109

  16. Chronic administration of the selective P2X3, P2X2/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice

    DEFF Research Database (Denmark)

    Hansen, RR; Nasser, A; Falk, S;

    2012-01-01

    The purinergic P2X3 and P2X2/3 receptors are in the peripheral nervous system almost exclusively confined to afferent sensory neurons, where they are found both at peripheral and central synapses. The P2X3 receptor is implicated in both neuropathic and inflammatory pain. However, the role of the ......X3 receptor in chronic cancer-induced bone pain is less known. Here we investigated the effect of systemic acute and chronic administration of the selective P2X3, P2X2/3 receptor antagonist (5-[[[(3-Phenoxyphenyl)methyl][(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl]-1...

  17. Virulence of catalase-deficient aspergillus nidulans in p47(phox)-/- mice. Implications for fungal pathogenicity and host defense in chronic granulomatous disease.

    OpenAIRE

    Chang, Y.C.; Segal, B.H.; Holland, S M; Miller, G.F.; Kwon-Chung, K. J.

    1998-01-01

    Chronic granulomatous disease (CGD) is a rare genetic disorder in which phagocytes fail to produce superoxide because of defects in one of several components of the NADPH oxidase complex. As a result, patients develop recurrent life-threatening bacterial and fungal infections. The organisms to which CGD patients are most susceptible produce catalase, regarded as an important factor for microbial pathogenicity in CGD. To test the role of pathogen-derived catalase in CGD directly, we have gener...

  18. Obesity-induced chronic inflammation in C57Bl6J mice, a novel risk factor in the progression of renal AA amyloidosis?

    OpenAIRE

    Heijden, R.A. van der; Sheedfar, F.; Bijzet, J; Hazenberg, B P; Koonen, D.P.; Heeringa, P.

    2015-01-01

    Background: Compelling evidence links obesity induced systemic inflammation to the development of chronic kidney disease (CKD). This systemic inflammation may result from exacerbated adipose inflammation. Besides the known detrimental effects of typical pro-inflammatory factors secreted by the adipose tissue (TNF-α, MCP-1 and IL-6) on the kidney, we hypothesize the enhanced obesity-induced secretion of serum amyloid A (SAA), an acute inflammatory protein, to play a key role in aggravating obe...

  19. The Effect of PPE-Induced Emphysema and Chronic LPS-Induced Pulmonary Inflammation on Atherosclerosis Development in APOE*3-LEIDEN Mice

    OpenAIRE

    Khedoe, P.P.S.J.; Wong, M C; Wagenaar, G.T.M.; Plomp, J. J.; Eck, M; Havekes, L. M.; Rensen, P.C.N.; Hiemstra, P. S.; Berbée, J.F.P.

    2013-01-01

    Background: Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation, airways obstruction and emphysema, and is a risk factor for cardiovascular disease (CVD). However, the contribution of these individual COPD components to this increased risk is unknown. Therefore, the aim of this study was to determine the contribution of emphysema in the presence or absence of pulmonary inflammation to the increased risk of CVD, using a mouse model for atherosclerosis. Becau...

  20. Larger adaptive response of 5-HT1A autoreceptors to chronic fluoxetine in a mouse model of depression than in healthy mice

    Institute of Scientific and Technical Information of China (English)

    N.FROGER; E.PALAZZO; T.RENOIR; M.MELFORT; N.BARDEN; M.HAMON; L.LANFUMEY

    2004-01-01

    Vulnerability to major depressive disorders, in particular depression, is often associated with both hypoactivity of the central serotoninergic (5-HT) system and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Extensive studies in normal healthy rodents showed that chronic treatment with SSRI antidepressants produced a marked functional desensitization of somatodendritic 5-HT1A autoreceptors, and this adaptive change has been claimed to play a key role in the therapeutic action of

  1. 5-(4-hydroxy-3-dimethoxybenzylidene)-rhodanine (RD-1)-improved mitochondrial function prevents anxiety- and depressive-like states induced by chronic corticosterone injections in mice.

    Science.gov (United States)

    Yang, Nan; Ren, Zhili; Zheng, Ji; Feng, Lu; Li, Dongmei; Gao, Kai; Zhang, Lianfeng; Liu, Yanyong; Zuo, Pingping

    2016-06-01

    Most current pharmacologic antidepressant treatments target monoaminergic systems confronts some problems such as low rate of remission and high risk for relapse indicating new therapeutic strategy is urgently need. Evidences showed that impairments in mitochondrial function were associated with the pathogenesis of mood disorders and improvement in its function may be a novel therapeutic choice. In the present study, effects of 5-(4-hydroxy-3-dimethoxybenzylidene)-2-thioxo-4-thiazolidinone (RD-1) were investigated in mice model of depression/anxiety induced by corticosterone (20 mg/kg) subcutaneously repeated injections in 5-week male BALB/c mice. Our results showed that five weeks of corticosterone administration induced anxiety/depressive-like behavioral changes, including decreased central activities in open field test, increased the immobility time in forced swimming test and the latency in the novelty-suppressed feeding test, as well as reduced bodyweight. Results showed that oral administration with RD-1 at the doses of 25, 50, and 100 mg/kg for five weeks significantly improved the anxiety/depressive-like behavioral changes induced by corticosterone. In glucose metabolism analysis by photon emission computed tomography/-computed tomography (PET/CT) imaging, corticosterone significantly deactivated the prefrontal cortex (PFC), temporal lobe and hippocampus. RD-1 treatment obviously improved the energy metabolism in the involved brain regions. In primary cultured hippocampal neuron, corticosterone reduced speed of anterograde transport, yet speed of retrograde transport was increased. Furthermore, RD-1 enhanced the mitochondrial anterograde transport to supply energy for the neurotransmitter release. In conclusion, RD-1 prevents anxiety/depressive-like behavior of mice induced by corticosterone repeated injections with novel mechanism of improvement in the mitochondrial function. PMID:26926430

  2. Gestational and Chronic Low-Dose PFOA Exposures and Mammary Gland Growth and Differentiation in Three Generations of CD-1 Mice

    OpenAIRE

    White, Sally S.; Stanko, Jason P.; Kato, Kayoko; Calafat, Antonia M.; Hines, Erin P.; Fenton, Suzanne E.

    2011-01-01

    Background: Prenatal exposure to perfluorooctanoic acid (PFOA), a ubiquitous industrial surfactant, has been reported to delay mammary gland development in female mouse offspring (F1) and the treated lactating dam (P0) after gestational treatments at 3 and 5 mg PFOA/kg/day. Objective: We investigated the consequences of gestational and chronic PFOA exposure on F1 lactational function and subsequent development of F2 offspring. Methods: We treated P0 dams with 0, 1, or 5 mg PFOA/kg/day on gest...

  3. Inhibitory Effects of Omacetaxine on Leukemic Stem Cells and BCR-ABL-Induced Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia in Mice

    OpenAIRE

    Chen, Yaoyu; Hu, Yiguo; Michaels, Shawnya; Segal, David; Brown, Dennis; Li, Shaoguang

    2009-01-01

    Omacetaxine mepesuccinate (formerly homoharringtonine) is a molecule with a mechanism of action that is different from tyrosine kinase inhibitors and its activity in chronic myeloid leukemia (CML) seems to be independent of BCR-ABL mutation status. Using BCR-ABL-expressing myelogenous and lymphoid cell lines and mouse models of CML and B cell acute lymphoblastic leukemia (B-ALL) induced by wild type BCR-ABL or T315I mutant-BCR-ABL, we evaluated the inhibitory effects of omacetaxine on CML and...

  4. Experimental study on influence of chronic stress on skin wound healing and skin graft survival time in mice%慢性应激对小鼠创面愈合及移植皮片存活时间影响的初步研究

    Institute of Scientific and Technical Information of China (English)

    杨震; 亓发芝; 曹小曼; 潘思璇

    2009-01-01

    Objective To investigate the influence of chronic stress on skin wound healing and skin graft survival time in mice. Methods In the study on skin wound healing,a full-thickness dermal wound on the hack of the female C57 BL/6J mice was made, then the mice were randomly divided into simple wound group and wound plus chronic stress group. The chronic stress was given in the latter group. The wound healing conditions of two groups were observed. Meanwhile, the female C57BL/6J mice were grafted with skin donated from the female BALB/C mice,and randomly divided into,the simple skin graft group and the skin graft plus chronic stress group. The chronic stress was given in the latter group. The skin graft survival time of two groups were observed. Re-sults Compared with simple wound group, the healing speed of the wound plus chronic stress group was notably lower, and the difference was significant (P0.05). Conclusion Chronic stress may delay wound healing. But there is no certain conclusion that whether chronic stress impact on skin graft survival time. We need further investigation.%目的 探讨慢性应激对小鼠创面愈合及移植皮片存活时间的影响.方法 在C57BL/6J小鼠背部形成创面,术后将小鼠随机分到单纯创面组和慢性应激创面组,慢性应激创面组给予慢性刺激,观察两组创面愈合伤口情况;同时取BALB/C小鼠背部皮肤移植于C57BL/6J小鼠创面,术后将小鼠随机分到单纯移植组和慢性应激植皮组2个组,观察移植皮片存活情况.结果 与单纯创面组相比,慢性应激创面组创面残余面积较大[第10天时分别为(20.33±0.38)%,(33.55±7.02)%],差异有显著性(P0.05).结论 慢性应激能够延缓创面愈合,而慢性应激对皮片移植影响则不明确,需要进一步研究.

  5. Induction of the interleukin 6/ signal transducer and activator of transcription pathway in the lungs of mice sub-chronically exposed to mainstream tobacco smoke

    Directory of Open Access Journals (Sweden)

    Williams Andrew

    2009-08-01

    Full Text Available Abstract Background Tobacco smoking is associated with lung cancer and other respiratory diseases. However, little is known about the global molecular changes that precede the appearance of clinically detectable symptoms. In this study, the effects of mainstream tobacco smoke (MTS on global transcription in the mouse lung were investigated. Methods Male C57B1/CBA mice were exposed to MTS from two cigarettes daily, 5 days/week for 6 or 12 weeks. Mice were sacrificed immediately, or 6 weeks following the last cigarette. High density DNA microarrays were used to characterize global gene expression changes in whole lung. Microarray results were validated by Quantitative real-time RT-PCR. Further analysis of protein synthesis and function was carried out for a select set of genes by ELISA and Western blotting. Results Globally, seventy nine genes were significantly differentially expressed following the exposure to MTS. These genes were associated with a number of biological processes including xenobiotic metabolism, redox balance, oxidative stress and inflammation. There was no differential gene expression in mice exposed to smoke and sampled 6 weeks following the last cigarette. Moreover, cluster analysis demonstrated that these samples clustered alongside their respective controls. We observed simultaneous up-regulation of interleukin 6 (IL-6 and its antagonist, suppressor of cytokine signalling (SOCS3 mRNA following 12 weeks of MTS exposure. Analysis by ELISA and Western blotting revealed a concomitant increase in total IL-6 antigen levels and its downstream targets, including phosphorylated signal transducer and activator of transcription 3 (Stat3, basal cell-lymphoma extra large (BCL-XL and myeloid cell leukemia 1 (MCL-1 protein, in total lung tissue extracts. However, in contrast to gene expression, a subtle decrease in total SOCS3 protein was observed after 12 weeks of MTS exposure. Conclusion Global transcriptional analysis identified a set

  6. Treatment with TUG891, a free fatty acid receptor 4 agonist, restores adipose tissue metabolic dysfunction following chronic sleep fragmentation in mice

    DEFF Research Database (Denmark)

    Gozal, D; Qiao, Z; Almendros, I;

    2016-01-01

    BACKGROUND: Sleep fragmentation (SF), a frequent occurrence in multiple sleep and other diseases leads to increased food intake and insulin resistance via increased macrophage activation and inflammation in visceral white adipose tissue (VWAT). Free fatty acid receptor 4 (FFA4) is reduced in pedi...... FFA4 activity may serve as potentially useful adjunctive therapies for sleep disorders accompanied by metabolic morbidity.International Journal of Obesity accepted article preview online, 16 March 2016. doi:10.1038/ijo.2016.37....... in pediatric sleep apnea patients and FFA4 agonists have been proposed in the treatment of obesity and metabolic dysfunction. METHODS: Male mice were subjected to SF exposures for 6 weeks, and treated during the last 2 weeks with either TUG891, a potent and selective FFA4 agonist, or vehicle (Veh). Glucose...

  7. Anti-inflammatory effects of a polyphenols-rich extract from tea (Camellia sinensis) flowers in acute and chronic mice models.

    Science.gov (United States)

    Chen, Bang-Tian; Li, Wei-Xi; He, Rong-Rong; Li, Yi-Fang; Tsoi, Bun; Zhai, Yu-Jia; Kurihara, Hiroshi

    2012-01-01

    While beneficial health properties of tea leaves have been extensively studied, less attention is paid to the flowers of tea. In this study, the anti-inflammatory effects of hot water extract of tea (Camellia sinensis) flowers were investigated. Pharmacological studies found that administration of tea flowers extract (TFE) could effectively inhibit croton oil-induced ear edema and carrageenin-induced paw edema. Furthermore, administration of TFE also protected against Propionibacterium acnes (P. ances) plus lipopolysaccharide-(LPS-) induced liver inflammation by reversing the histologic damage and plasma alanine aminotransferase (ALT) increase. Moreover, the levels of nitric oxide (NO), tumor necrosis factor-(TNF)-α and interleukin-(IL-) 1β mRNA in mouse liver were markedly suppressed after treatment with TFE in mice with immunological liver inflammation. These results indicated that tea flowers had potent anti-inflammatory effects on acute and immunological inflammation in vivo, and may be used as a functional natural food. PMID:22900128

  8. Anti-Inflammatory Effects of a Polyphenols-Rich Extract from Tea (Camellia sinensis Flowers in Acute and Chronic Mice Models

    Directory of Open Access Journals (Sweden)

    Bang-Tian Chen

    2012-01-01

    Full Text Available While beneficial health properties of tea leaves have been extensively studied, less attention is paid to the flowers of tea. In this study, the anti-inflammatory effects of hot water extract of tea (Camellia sinensis flowers were investigated. Pharmacological studies found that administration of tea flowers extract (TFE could effectively inhibit croton oil-induced ear edema and carrageenin-induced paw edema. Furthermore, administration of TFE also protected against Propionibacterium acnes (P. ances plus lipopolysaccharide-(LPS- induced liver inflammation by reversing the histologic damage and plasma alanine aminotransferase (ALT increase. Moreover, the levels of nitric oxide (NO, tumor necrosis factor-(TNF-α and interleukin-(IL- 1β mRNA in mouse liver were markedly suppressed after treatment with TFE in mice with immunological liver inflammation. These results indicated that tea flowers had potent anti-inflammatory effects on acute and immunological inflammation in vivo, and may be used as a functional natural food.

  9. Behavioural, biochemical and molecular changes induced by chronic crack-cocaine inhalation in mice: The role of dopaminergic and endocannabinoid systems in the prefrontal cortex.

    Science.gov (United States)

    Areal, Lorena B; Rodrigues, Livia C M; Andrich, Filipe; Moraes, Livia S; Cicilini, Maria A; Mendonça, Josideia B; Pelição, Fabricio S; Nakamura-Palacios, Ester M; Martins-Silva, Cristina; Pires, Rita G W

    2015-09-01

    Crack-cocaine addiction has increasingly become a public health problem worldwide, especially in developing countries. However, no studies have focused on neurobiological mechanisms underlying the severe addiction produced by this drug, which seems to differ from powder cocaine in many aspects. This study investigated behavioural, biochemical and molecular changes in mice inhaling crack-cocaine, focusing on dopaminergic and endocannabinoid systems in the prefrontal cortex. Mice were submitted to two inhalation sessions of crack-cocaine a day (crack-cocaine group) during 11 days, meanwhile the control group had no access to the drug. We found that the crack-cocaine group exhibited hyperlocomotion and a peculiar jumping behaviour ("escape jumping"). Blood collected right after the last inhalation session revealed that the anhydroecgonine methyl ester (AEME), a specific metabolite of cocaine pyrolysis, was much more concentrated than cocaine itself in the crack-cocaine group. Most genes related to the endocannabinoid system, CB1 receptor and cannabinoid degradation enzymes were downregulated after 11-day crack-cocaine exposition. These changes may have decreased dopamine and its metabolites levels, which in turn may be related with the extreme upregulation of dopamine receptors and tyrosine hydroxylase observed in the prefrontal cortex of these animals. Our data suggest that after 11 days of crack-cocaine exposure, neuroadaptive changes towards downregulation of reinforcing mechanisms may have taken place as a result of neurochemical changes observed on dopaminergic and endocannabinoid systems. Successive changes like these have never been described in cocaine hydrochloride models before, probably because AEME is only produced by cocaine pyrolysis and this metabolite may underlie the more aggressive pattern of addiction induced by crack-cocaine. PMID:25940765

  10. 慢性砷中毒对小鼠齿状回GFAP表达的影响%Effects of chronic arsenic poisoning on GFAP expression in the dentate gyms of adult mice

    Institute of Scientific and Technical Information of China (English)

    康朝胜; 孙宝飞; 余资江; 李玉飞

    2011-01-01

    Objective To investigate activation of glial fibrillary acidic protein (GFAP) in the dentate gyrus of adult mice after chronic arsenic poisoning. Methods 80 healthy adult Kunming mice, weighing 20-22g, were divided into four groups: the normal control group, the low-dose group, the medium-dose group and the high-dose group ( 10 males and 10 females in each group). Mice in the four groups were respectively fed with distilled water, 1/5 LD50, 1/10 LD50 and 1/40 LD50 AS2O3 for 3 months, and the dosage was adjusted according to changes of weight. Then ability of learning and memory was tested by a Y-maze, and expression of the GFAP protein in the dentate gyrus by Western blot and immunohistochemistry. Results Ability of learning and memory in the high-dose group was significantly lower than that in the normal control group ( P < 0.05 ). Immunohistochemical results showed that the number of GFAP-positive cells in the dentate gyrus was significantly more increased in the dose groups compared with the normal control group(P<0.01 ), and the average optical density was also increased (P <0.01 ). Western blot results showed the GFAP protein content increased with the dosage increasing (P <0.01 ). Conclusion Chronic arsenic poisoning might damage ability of learning and memory in mice, which may be related to proliferation of astroeytes and expression of GFAP in the dentate gyrus.%目的 研究砷中毒后小鼠齿状回胶质原纤维酸性蛋白(GFAP)的变化.方法 选取健康成年昆明小鼠80只,雌雄各半,分为对照组及慢性砷中毒高、中、低剂量组,每组20只,分别以蒸馏水、1/5 LD50、1/10 LD50、1/40LD50 As2O3连续灌胃3个月,根据其体质量变化随时调整用药剂量,采用Y-电迷宫检测各组小鼠学习记忆行为,采用免疫组织化学和蛋白印迹技术检测不同浓度砷中毒对小鼠齿状回部位GFAP表达的影响.结果 与正常对照组比较,高剂量砷中毒组学习、记忆Y-迷

  11. 慢性不可预知温和应激抑郁小鼠模型的建立%Establishment of Chronic Unpredictable Mild Stress Mice Model of Depression

    Institute of Scientific and Technical Information of China (English)

    张臣颢; 张曼芳; 谢青莲; 成志恒; 邹洪; 金玫蕾

    2011-01-01

    抑郁症是一种以情绪低落为主要症状的情感性精神障碍.利用慢性不可预知温和应激建立抑郁症小鼠模型,以蔗糖水消耗实验作为抑郁核心症状之一——快感缺乏的检测方法.将4周龄雄性小鼠(C57BL/6)持续6周暴露于一系列轻度应激中,每周检测蔗糖水消耗.应激包括:令小鼠恐惧的气味、噪音、饲养笼倾斜、潮湿的垫料、无垫料的新饲养笼、照明过夜以及短暂的同笼饲养.前3周模型组每天随机应用2个不同的应激,后3周应用3个不同的应激.结果:随着应激强度的增加,模型组对蔗糖水的摄取量显著低于对照组.由此表明,慢性不可预知性温和应激能导致小鼠出现对奖赏的反应性下降,快感缺乏等抑郁症状.%Depression is a chronic mental disorder mainly characterized by depressed mood. A series of chronic unpredictable mild stresses (CUMS) was used to set up a mice model of depression. And sucrose consumption test was adopted to estimate the anhedonia, one of the core symptoms of human depression. Mice (C57BL/6) were exposed to CUMS over 6 weeks, and anhedonia was evaluated by weekly monitoring sucrose intake. The stressors included that soiled cage with aversive odour, noise, cage tilt, damp bedding, illumination overnight, paired-housing. Week 1-3, two stressors was used daily. Week 4-6, three stressors was used. The results showed that, with the increasing of the stress frequency, sucrose consumption of the stress group was statistically decreased compared with the control group. This indicated that CUMS causes a decrease in responsiveness to rewards, which reflected the key symptom of depression-anhedonia.

  12. Liquiritigenin reverses depression-like behavior in unpredictable chronic mild stress-induced mice by regulating PI3K/Akt/mTOR mediated BDNF/TrkB pathway.

    Science.gov (United States)

    Tao, Weiwei; Dong, Yu; Su, Qiang; Wang, Hanqing; Chen, Yanyan; Xue, Wenda; Chen, Chang; Xia, Baomei; Duan, Jinao; Chen, Gang

    2016-07-15

    Major depression is a common long-lasting or recurrent psychiatric disease with high lifetime prevalence and high incidence of suicide. The main purpose of the current study was to verify whether liquiritigenin conferred an antidepressant-like effect on the depressive mouse model established by unpredictable chronic mild stress (UCMS) and explore its possible mechanism. The results of depression-related behaviors including sucrose preference test (SPT), open field test (OFT), forced swimming test (FST) and tail suspension test (TST) indicated that both liquiritigenin (7.5mg/kg, 15mg/kg) and fluoxetine (20mg/kg) dramatically improved the depression symptoms. Enzyme-linked immunosorbent assay (ELISA) revealed that treatment with liquiritigenin significantly reduced the concentrations of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α in serum and hippocampus. Compared with the UCMS group, the administrations of liquiritigenin, increased levels of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and decreased Malondialdehyde (MDA) content. Meanwhile, glucocorticoids (GC) content was reduced in the liquiritigenin group, which suggested that liquiritigenin exhibiting the ameliorative effect on activated hypothalamic-pituitary-adrenal (HPA) axis stimulated with UCMS. Mice treated with liquiritigenin showed restored levels of neurotransmitter norepinephrine (NE) and serotonin (5-HT). Western blot analysis displayed up-regulated expressions of p-phosphatidylinositol 3-kinase (PI3K), p-Akt, p- mammalian target of rapamycin (mTOR), p-tropomyosin-related kinase B (TrkB), brain-derived neurotrophic factor (BDNF). Thus, it was supposed that liquiritigenin might be useful for the treatment of chronic depression possibly through PI3K/Akt/mTOR mediated BDNF/TrkB pathway. PMID:27113683

  13. Positive environmental modification of depressive phenotype and abnormal hypothalamic-pituitary-adrenal axis activity in female C57BL/6J mice during abstinence from chronic ethanol consumption

    Directory of Open Access Journals (Sweden)

    Terence Y Pang

    2013-07-01

    Full Text Available Depression is a commonly reported co-morbidity during rehabilitation from alcohol use disorders and its presence is associated with an increased likelihood of relapse. Interventions which impede the development of depression could be of potential benefit if incorporated into treatment programs. We previously demonstrated an ameliorative effect of physical exercise on depressive behaviours in a mouse model of alcohol abstinence. Here, we show that environmental enrichment (cognitive and social stimulation has a similar beneficial effect. The hypothalamic-pituitary-adrenal (HPA axis is a key physiological system regulating stress responses and its dysregulation has been separably implicated in the pathophysiology of depression and addiction disorders. We performed a series of dexamethasone challenges and found that mice undergoing 2 weeks of alcohol abstinence had significantly greater corticosterone and ACTH levels following a DEX-CRH challenge compared to water controls. Environmental enrichment during alcohol abstinence corrected the abnormal DEX-CRH corticosterone response despite a further elevation of ACTH levels. Examination of gene expression revealed abstinence-associated alterations in glucocorticoid receptor (Gr, corticotrophin releasing hormone (Crh and pro-opiomelanocortin (Pomc1 mRNA levels which were differentially modulated by environmental enrichment. Overall, our study demonstrates a benefit of environmental enrichment on alcohol abstinence-associated depressive behaviours and HPA axis dysregulation.

  14. Central Agonism of GPR120 Acutely Inhibits Food Intake and Food Reward and Chronically Suppresses Anxiety-Like Behavior in Mice

    Science.gov (United States)

    Fisette, Alexandre; Fernandes, Maria F.; Hryhorczuk, Cécile; Poitout, Vincent; Alquier, Thierry; Fulton, Stephanie

    2016-01-01

    Background: GPR120 (FFAR4) is a G-protein coupled receptor implicated in the development of obesity and the antiinflammatory and insulin-sensitizing effects of omega-3 (ω-3) polyunsaturated fatty acids. Increasing central ω-3 polyunsaturated fatty acid levels has been shown to have both anorectic and anxiolytic actions. Despite the strong clinical interest in GPR120, its role in the brain is largely unknown, and thus we sought to determine the impact of central GPR120 pharmacological activation on energy balance, food reward, and anxiety-like behavior. Methods: Male C57Bl/6 mice with intracerebroventricular cannulae received a single injection (0.1 or 1 µM) or continuous 2-week infusion (1 µM/d; mini-pump) of a GPR120 agonist or vehicle. Free-feeding intake, operant lever-pressing for palatable food, energy expenditure (indirect calorimetry), and body weight were measured. GPR120 mRNA expression was measured in pertinent brain areas. Anxiety-like behavior was assessed in the elevated-plus maze and open field test. Results: GPR120 agonist injections substantially reduced chow intake during 4 hours postinjection, suppressed the rewarding effects of high-fat/-sugar food, and blunted approach-avoidance behavior in the open field. Conversely, prolonged central GPR120 agonist infusions reduced anxiety-like behavior in the elevated-plus maze and open field, yet failed to affect free-feeding intake, energy expenditure, and body weight on a high-fat diet. Conclusion: Acute reductions in food intake and food reward suggest that GPR120 could mediate the effects of central ω-3 polyunsaturated fatty acids to inhibit appetite. The anxiolytic effect elicited by GPR120 agonist infusions favors the testing of compounds that can enter the brain to activate GPR120 for the mitigation of anxiety. PMID:26888796

  15. Hepatic regeneration after partial hepatectomy in mice infected with Schistosoma mansoni, at the acute and chronic phases of the disease Regeneração hepática após hepatectomia parcial em camundongos infectados com Schistosoma mansoni, nas fases aguda e crônica da doença

    OpenAIRE

    Costa, G.(INFN Sezione di Milano, Milan, Italy); J.R. Cunha-Melo; AGUIAR B.G.; Gonçalves, S. C.; TOPPA N.H.; P. M. Z. Coelho

    1999-01-01

    Outbred male albino mice normal or infected with 30 cercariae of Schistosoma mansoni (LE strain) were submitted to 65% hepatectomy during the acute (70 days) and chronic phase (160 days) phases of the disease. A group of the infected animals was treated with 400 mg/kg of oxamniquine during the acute phase before hepatectomy. Non-infected, infected and treated but not hepatectomized animals were kept as controls. Hepatic regeneration was evaluated by incorporation of tritiated thymidine, intra...

  16. Sensitivity of the prefrontal GABAergic system to chronic stress in male and female mice: Relevance for sex differences in stress-related disorders.

    Science.gov (United States)

    Shepard, Ryan; Page, Chloe E; Coutellier, Laurence

    2016-09-22

    Stress-induced modifications of the prefrontal cortex (PFC) are believed to contribute to the onset of mood disorders, such as depression and anxiety, which are more prevalent in women. In depression, the PFC is hypoactive; however the origin of this hypoactivity remains unclear. Possibly, stress could impact the prefrontal GABAergic inhibitory system that, as a result, impairs the functioning of downstream limbic structures controlling emotions. Preclinical evidence indicates that the female PFC is more sensitive to the effects of stress. These findings suggest that exposure to stress could lead to sex-specific alterations in prefrontal GABAergic signaling, which contribute to sex-specific abnormal functioning of limbic regions. These limbic changes could promote the onset of depressive and anxiety behaviors in a sex-specific manner, providing a possible mechanism mediating sex differences in the clinical presentation of stress-related mood disorders. We addressed this hypothesis using a mouse model of stress-induced depressive-like behaviors: the unpredictable chronic mild stress (UCMS) paradigm. We observed changes in prefrontal GABAergic signaling after exposure to UCMS most predominantly in females. Increased parvalbumin (PV) expression and decreased prefrontal neuronal activity were correlated in females with severe emotionality deficit following UCMS, and with altered activity of the amygdala. In males, small changes in emotionality following UCMS were associated with minor changes in prefrontal PV expression, and with hypoactivity of the nucleus accumbens. Our data suggest that prefrontal hypoactivity observed in stress-related mood disorders could result from stress-induced increases in PV expression, particularly in females. This increased vulnerability of the female prefrontal PV system to stress could underlie sex differences in the prevalence and symptomatology of stress-related mood disorders. PMID:27365172

  17. Comparative Evaluation of Partial α2 -Adrenoceptor Agonist and Pure α2 -Adrenoceptor Antagonist on the Behavioural Symptoms of Withdrawal after Chronic Alcohol Administration in Mice.

    Science.gov (United States)

    Arora, Shivani; Vohora, Divya

    2016-08-01

    As an addictive drug, alcohol produces withdrawal symptoms if discontinued abruptly after chronic use. Clonidine (CLN), a partial α2 -adrenergic agonist, and mirtazapine (MRT), an antagonist of α2 -adrenoceptor, both clinically aid alcohol withdrawal. Considering different mechanisms of action of the two drugs, this study was designed to see how far these two mechanistically different drugs differ in their ability to decrease the severity of ethanol withdrawal syndrome. The effect of CLN and MRT on ethanol withdrawal-induced anxiety, depression and memory impairment was analysed using EPM, FST and PAR tests, respectively. Animals received distilled water, ethanol and/or either of the drugs (CLN and MRT) in different doses. Relapse to alcohol use was analysed by CPP test. Animals received ethanol as a conditioning drug and distilled water, CLN or MRT as test drug. CLN and MRT both alleviated anxiety in a dose-dependent manner. MRT (4 mg/kg) was more effective than CLN (0.1 mg/kg) in ameliorating the anxiogenic effect of alcohol withdrawal. However, CLN treatment increased depression. It significantly decreased swimming time and increased immobility time, whereas MRT treatment decreased immobility time and increased climbing and swimming time during abstinence. The effect was dose dependent for both drugs. The results of PAR test show that CLN treatment worsens working memory. Significant increase in SDE and TSZ and decrease in SDL were observed in CLN-treated animals. MRT treatment, on the other hand, improved working memory at both doses. Further, both CLN and MRT alleviated craving. A significant decrease in time spent in the ethanol-paired chamber was seen. MRT treatment at both doses showed better effect than CLN in preventing the development of preference in CPP test. These findings indicate a potential therapeutic use and better profile of mirtazapine over clonidine in improving memory, as well as in alleviating depression, anxiety and craving associated

  18. Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice.

    Directory of Open Access Journals (Sweden)

    Steven D Schutt

    Full Text Available Bruton's Tyrosine Kinase (BTK and IL-2 Inducible T-cell Kinase (ITK are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR signaling and T cell receptor (TCR signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD. We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT. We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD, where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.

  19. Tuberculosis Susceptibility of Diabetic Mice

    OpenAIRE

    Martens, Gregory W.; Arikan, Meltem Cevik; Lee, Jinhee; Ren, Fucheng; Greiner, Dale; Kornfeld, Hardy

    2007-01-01

    Increased susceptibility to infections, including tuberculosis (TB), is a major cause of morbidity and mortality in patients with diabetes. Despite the clinical importance of this problem, little is known about how diabetes impairs protective immunity. We modeled this phenomenon by infecting acute (⩽ 1 mo) or chronic (⩾ 3 mo) diabetic mice with a low aerosol dose of Mycobacterium tuberculosis (Mtb) Erdman. Diabetes was induced by streptozotocin (STZ) treatment of C57BL/6 mice, while another m...

  20. 四磨汤对慢性应激小鼠血清Leptin和MTL的影响%Effects of Simo Decoction on Leptin and Motilin in Serum of Mice with Chronic Stress

    Institute of Scientific and Technical Information of China (English)

    刘杰民; 蔺晓源; 蔡莹; 易健; 刘柏炎; 蔡光先

    2011-01-01

    Objective;To study the effect of Simo decoction on leptin and motilin(MTL) in serum of mice with chronic stress, and to explore the mechanism of Simo decoction on Functional dyspepsia(FD). Method:Fourty mice were randomized into normal group,model group,motilium group and Simo decoction group. The mice models were established by exerting the factors of irregular diet, reverse of day and night, binding and stimulating tails, then treated with distilled water, motilium and Simo decoction, respectively. The appetite and body weight of mice wereobserved. The contents of leptin and MTL were detected by enzyme-linked immunosorbent assay ( ELISA). Result; The appetite and body weight of model group were lower than normal group( P <0. 05) ,and the contents of leptin was increase and MTL deacreased in serum compared with the normal group ( P < 0. 05 ). Simo decoction group and motilium group increased the appetite, body weight and MTL with decreased leptin compared with the model group ( P < 0. 05 ). Simo decoction group had not statistically significant action compared with Motilium group. Conclusion; The therapeutic mechanism of Simo decoction for FD may probably lie in adjusting the secretionof leptin and MTL in serum.%目的:通过观察四磨汤对慢性应激小鼠血清瘦素(leptin)和胃动素(motilin,MTL)的影响,探讨四磨汤治疗功能性消化不良(FD)的作用机制.方法:40只小鼠随机分为正常组、模型组、吗丁啉3.78 mg·kg-1组及四磨汤7.56 g·kg-1组;采用饥饱失常、明暗颠倒以及束缚夹尾等多种应激法造模;模型成功后,分别给予蒸馏水、吗丁啉、四磨汤ig;观察小鼠的食量、体质量,酶联免疫吸附测定法(ELISA)检测血清中leptin和MTL的含量变化.结果:与正常组相比,模型组小鼠食量和体质量降低(P<0.05),血清中leptin含量升高,MTL含量降低(P<0.05);与模型组比较,四磨汤组和吗丁啉组小鼠食量、体质量

  1. Chronic Bronchitis

    Science.gov (United States)

    Bronchitis is an inflammation of the bronchial tubes, the airways that carry air to your lungs. It ... chest tightness. There are two main types of bronchitis: acute and chronic. Chronic bronchitis is one type ...

  2. Chronic gastritis

    OpenAIRE

    Sipponen, Pentti; Maaroos, Heidi-Ingrid

    2015-01-01

    Abstract Prevalence of chronic gastritis has markedly declined in developed populations during the past decades. However, chronic gastritis is still one of the most common serious pandemic infections with such severe killing sequelae as peptic ulcer or gastric cancer. Globally, on average, even more than half of people may have a chronic gastritis at present. Helicobacter pylori infection in childhood is the main cause of chronic gastritis, which microbial origin is the key for the understand...

  3. Chronic prostatitis

    OpenAIRE

    Erickson, Bradley A.; Schaeffer, Anthony J.; Le, Brian

    2008-01-01

    Chronic prostatitis can cause pain and urinary symptoms, and usually occurs without positive bacterial cultures from prostatic secretions (known as chronic abacterial prostatitis or chronic pelvic pain syndrome, CP/CPPS). Bacterial infection can result from urinary tract instrumentation, but the cause and natural history of CP/CPPS are unknown.

  4. Change of depression-like behavior in chronic alcoholism and withdrawal model, and co-mechanism of depression and chronic alcoholism in mice%小鼠慢性酒精中毒及戒断过程中抑郁样行为的改变及其共病机制

    Institute of Scientific and Technical Information of China (English)

    蒋曦; 田福荣; 赵应征

    2016-01-01

    目的:研究小鼠慢性酒精中毒及戒断过程中抑郁样行为的改变,进一步探讨酒精中毒与抑郁症的共病机制。方法:构建新型慢性酒精中毒小鼠模型;实验分为正常对照组及慢性酒精7 d、14 d、21 d和28 d组。在第6、13、20和27天分别进行酒精偏好度测试,测试后戒断酒精1 d,随后次日进行抑郁行为学测试,测试结束后处死小鼠取海马与额叶皮层,采用高效液相色谱法测定5-羟色胺(5-HT)及去甲肾上腺素(NE)含量,采用免疫印迹法测定cAMP反应元件结合蛋白( CREB)和脑源性神经营养因子( BDNF)的含量。结果:随着酒精饮酒天数及戒断次数的增加,小鼠表现出明显嗜酒现象,并且在强迫游泳和悬尾测试中,表现出明显的不动时间增加。7d组小鼠额叶皮层内5-HT水平升高(P<0.05),海马与额叶5-HT水平在21 d与28 d组降低(P<0.01);7 d和14 d组小鼠海马与额叶NE水平无明显变化,21 d和28 d组NE水平降低( P<0.05)。21 d和28 d组小鼠海马与额叶内p-CREB/CREB比值及BDNF表达水平明显下降( P<0.05),7 d与14 d组无明显变化。结论:酒精中毒、戒断阶段与抑郁的共病机制涉及5-HT。5-HT-cAMP-CREB-BDNF信号转导通路可能为酒精中毒与抑郁症的共病机制。%AIM: To investigate the behavior of depression in chronic alcoholism and withdrawal model of mice, and to explore the co-mechanism of alcoholism and depression.METHODS: A novel model of chronic alcoholism was constructed in this study.The animals were divided into normal control group, and alcohol 7 d, 14 d, 21 d and 28 d groups.The mice were given alcohol preference test on the 6th, 13th, 20th and 27th days.After the test, alcohol were withdrawn for 1 d, then the next day the mice were given behavior test of depression.After the test, the mice were sacri-ficed.The contents of 5-hydroxytryptamine (5-HT) and norepinephrine

  5. 芒果苷对慢性应激抑郁小鼠行为及海马脑源性神经营养因子表达的影响%The effects of mangiterin on the improvement of behavior and expression of brain-derived neurotrophic factor in the hippocampus of chronic stress-induced depression model mice

    Institute of Scientific and Technical Information of China (English)

    付燕燕; 宋远见; 杨宜华; 段静雨

    2013-01-01

    Objective To explore the effects of mangiterin on behaviors and brain-derived neurotrophic factor(BDNF) of hippocampus in chronic stress depression mice.Methods 60 male mice were randomly divided into normol control group,model group,fluoxetin control group and mangiterin groups (low,medium and high dose),10 mice in each group.All mice except normal control group were singly housed and subjected to chronic stress-induced depression model for 21 consecutive days.The behaviors of mice were detected by open-field test and tail-suspension test.The expression of BDNF in the hippocampus were assessed using western blot.Results Compared with the normal group,mice exposed chronic stress showed decreased body weight((5.33 ±1.20) g),crossing lines (102 ± 18) and distances ((3425 ± 112) mm) notably decreased in open-field behavior test.The duration of immobility during tail-suspension was increased significantly.BDNF expression in the hippocampus(0.45 ± 0.03) was downregulated significantly(P< 0.01),while it was upregulated in the groups of mangiterin(P < 0.01).Mangiterin group in high dose had the similar effects to fluoxetin group(P > 0.05).Conclusion Mangiterin can ameliorate behavior impairment of chronic stress induced-depression mice and it may be related to the upregulation of BDNF expression in the hippocampus.%目的 探讨芒果苷(Mangiterin)对慢性应激抑郁模型(chronic unpredictable stress,CUS)小鼠行为学的改善作用及对海马脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)表达的影响.方法 将大鼠随机分为正常对照组,慢性应激模型组,氟西汀组,芒果苷低、中和高剂量组,共6组,每组10只.采用慢性轻度不可预见性应激配合孤养复制抑郁模型,通过旷场及悬尾实验观察行为学改变,并运用免疫印迹检测海马BDNF的表达.结果 与正常对照组比,模型组体质量增长缓慢[(5.33±1.20)g],水平穿格次数减少[(102±18)次/5 min

  6. Chronic migraine.

    Science.gov (United States)

    Schwedt, Todd J

    2014-01-01

    Chronic migraine is a disabling neurologic condition that affects 2% of the general population. Patients with chronic migraine have headaches on at least 15 days a month, with at least eight days a month on which their headaches and associated symptoms meet diagnostic criteria for migraine. Chronic migraine places an enormous burden on patients owing to frequent headaches; hypersensitivity to visual, auditory, and olfactory stimuli; nausea; and vomiting. It also affects society through direct and indirect medical costs. Chronic migraine typically develops after a slow increase in headache frequency over months to years. Several factors are associated with an increased risk of transforming to chronic migraine. The diagnosis requires a carefully performed patient interview and neurologic examination, sometimes combined with additional diagnostic tests, to differentiate chronic migraine from secondary headache disorders and other primary chronic headaches of long duration. Treatment takes a multifaceted approach that may include risk factor modification, avoidance of migraine triggers, drug and non-drug based prophylaxis, and abortive migraine treatment, the frequency of which is limited to avoid drug overuse. This article provides an overview of current knowledge regarding chronic migraine, including epidemiology, risk factors for its development, pathophysiology, diagnosis, management, and guidelines. The future of chronic migraine treatment and research is also discussed. PMID:24662044

  7. 桂附地黄丸干预主要组织相容性复合物半相合移植小鼠慢性移植物抗宿主病的效应%Effect of Guifu rehmaniae bolus on preventing chronic graft versus host disease in major histocompatibilty complex halpo-identical bone marrow transplantation mice

    Institute of Scientific and Technical Information of China (English)

    吴顺杰; 梁凯雯; 吴远彬; 周健; 涂三芳

    2012-01-01

    BACKGROUND: At present, the method for the treatment of chronic graft versus host disease is not ideal due the adverse reactions, founding the traditional Chinese medicine for effective intervention and treatment of chronic graft versus host disease is one of the common focuses of attention for the transplant scholars. OBJECTIVE: To observe effect of Guifu rehmaniae bolus on preventing chronic graft versus host disease in major histocompatibilty complex halpo-identical bone marrow transplantation mice. METHODS: Transplantation models of major histocompatibilty complex halpo-identical hematopoietic stem cells transplantation mice were established by transplanting the hematopoietic stem cells of male Balb/cH-2d mice to female (Balb/cxC57BL/6) F1 H-2d/b (CB6F1) mice. After transplantation, 24 recipient mice were divided into two groups: Guifu rehmaniae bolus group and blank group, mice in the Guifu rehmaniae bolus group were lavaged from the first day after transplantation with 0.2 mL Guifu rehmaniae bolus liquid twice per day; mice in the blank group were lavaged with the same dose of normal saline and lasted for 100 days. RESULTS AND CONCLUSION: Five mice died in the Guifu rehmaniae bolus group, and all mice died in the blank group at 86 days after transplantation (P=0.004). The mice in the blank group depressed at 35 days after transplantation and the mice in the Guifu rehmaniae bolus group depressed at 45 days after transplantation, and the clinical score in the blank group was significantly higher than that in the Guifu rehmaniae bolus group (P < 0.05). Pathological observation showed that the mice with chronic graft versus host disease in Guifu rehmaniae bolus group mostly classified from 0 to 1 grade. Compared with blank group, the liver, skin and small intestine tissue of the mice in Guifu rehmaniae bolus group were improved. Guifu rehmaniae bolus can relieve symptoms of chronic graft versus host disease in major histocompatibilty complex halpo-identical bone

  8. Low chronic radiation doses

    International Nuclear Information System (INIS)

    In the context of the Chernobyl and Fukushima accidents where large territories have been contaminated durably and as consequence where local populations are submitted to chronic low radiation doses, IRSN (French institute for radiation protection and nuclear safety) has led various studies to assess the impact of chronic low doses. Studies about the effects of uranium on marine life show that the impact is strongly dependent on the initial state of the individual (zebra Danio rerio fish). The studies about the impact of chronic low doses due to cesium and strontium contamination show different bio-accumulations: 137Cs is found in the animal's whole body with higher concentrations in muscles and kidneys while 90Sr is found almost exclusively in bones and it accumulates more in female mice than in males. The study dedicated to the sanitary impact of chronic low doses on the workers of the nuclear industry shows a higher risk for developing a leukemia, a pleural cancer or a melanoma but no correlation appears between doses and the appearance of the pleural cancer or the melanoma. (A.C.)

  9. Chronic inflammatory polyneuropathy

    Science.gov (United States)

    Polyneuropathy - chronic inflammatory; CIDP; Chronic inflammatory demyelinating polyneuropathy ... of the body equally. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic neuropathy caused by ...

  10. Chronic pancreatitis

    OpenAIRE

    Kocher, Hemant M; Froeling, Fieke EM

    2008-01-01

    Chronic pancreatitis is characterised by long-standing inflammation of the pancreas owing to a wide variety of causes, including recurrent acute attacks of pancreatitis. Chronic pancreatitis affects 3–9 people in 100,000; 70% of cases are alcohol-induced.

  11. Chronic pancreatitis

    OpenAIRE

    Kocher, Hemant M; Kadaba, Raghu

    2011-01-01

    Chronic pancreatitis is characterised by long-standing inflammation of the pancreas due to a wide variety of causes, including recurrent acute attacks of pancreatitis. Chronic pancreatitis affects between 3 and 9 people in 100,000; 70% of cases are alcohol-induced.

  12. Phase-Dependent Roles of E-Selectin during Chronic Contact Hypersensitivity Responses

    OpenAIRE

    Fujita, Tomoyuki; Fujimoto, Manabu; Matsushita, Takashi; Shimada, Yuka; Hasegawa, Minoru; Kuwano, Yoshihiro; Ogawa, Fumihide; Takehara, Kazuhiko; Sato, Shinichi

    2007-01-01

    Chronic contact hypersensitivity (CH) models induced by repeated hapten exposure exhibit chronic dermatitis and immunological abnormalities resembling atopic dermatitis. To assess the contribution of endothelial selectins (P- and E-selectins) to cutaneous chronic inflammation, chronic CH responses were assessed in mice lacking P- or E-selectin. Elicitation with oxazolone on the ears of P-selectin−/− mice 7 days after the sensitization induced a typical delayed-type hypersensitivity response s...

  13. Regular physical activity prevents development of chronic pain and activation of central neurons

    OpenAIRE

    Sluka, Kathleen A; O'Donnell, James M.; DANIELSON, JESSICA; Rasmussen, Lynn A.

    2012-01-01

    Chronic musculoskeletal pain is a significant health problem and is associated with increases in pain during acute physical activity. Regular physical activity is protective against many chronic diseases; however, it is unknown if it plays a role in development of chronic pain. The current study induced physical activity by placing running wheels in home cages of mice for 5 days or 8 wk and compared these to sedentary mice without running wheels in their home cages. Chronic muscle pain was in...

  14. Chronic cholecystitis

    Science.gov (United States)

    ... foods may relieve symptoms in people. However, the benefit of a low-fat diet has not been proven. Alternative Names Cholecystitis - chronic Images Cholecystitis, CT scan Cholecystitis, cholangiogram Cholecystolithiasis Gallstones, cholangiogram Cholecystogram References Wang ...

  15. Chronic Pain

    Science.gov (United States)

    ... who have chronic pain may also have low self-esteem, depression, and anger. Causes & Risk Factors What causes ... as stretching and strengthening activities) and low-impact exercise (such as walking, swimming, or biking) can help ...

  16. Chronic Meningitis

    Science.gov (United States)

    ... School Lunch Lines FDA Cracks Down on Antibacterial Soaps Health Tip: Schedule a Back-to-School Dental ... the Professional Version Meningitis Introduction to Meningitis Acute Bacterial Meningitis Viral Meningitis Noninfectious Meningitis Recurrent Meningitis Chronic ...

  17. Chronic Pericarditis

    Science.gov (United States)

    ... Sugar Control Helps Fight Diabetic Eye Disease Are 'Workaholics' Prone to OCD, Anxiety? ALL NEWS > Resources First ... weeks after heart surgery) and is considered subacute. Causes Usually, the cause of chronic effusive pericarditis is ...

  18. Inhibition of Chronic Pancreatitis and Murine Pancreatic Intraepithelial Neoplasia by a Dual Inhibitor of c-RAF and Soluble Epoxide Hydrolase in LSL-KrasG12D/Pdx-1-Cre Mice

    OpenAIRE

    Liao, Jie; Hwang, Sung Hee; Li, Haonan; Liu, Jun-Yan; Hammock, Bruce D.; Yang, Guang-Yu

    2016-01-01

    Mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS) and chronic pancreatitis are the most common pathogenic events involved in human pancreatic carcinogenesis. In the process of long-standing chronic inflammation, aberrant metabolites of arachidonic acid play a crucial role in promoting carcinogenesis, in which the soluble epoxide hydrolase (sEH), as a pro-inflammatory enzyme, generally inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs). Herein, we determined the effect ...

  19. Clostridium difficile in gnotobiotic mice.

    OpenAIRE

    Onderdonk, A B; Cisneros, R L; Bartlett, J. G.

    1980-01-01

    Germfree mice associated with Clostridium difficile developed intestinal disease characterized by polymorphonuclear cell infiltration of the lamina propria, diarrhea, and cecal cytotoxin concentrations positive at a 10(-6) dilution. The numbers of viable bacteria never exceeded 10(10) colony-forming units per g (dry weight). Despite the high toxin levels and chronic inflammation over a 30-day period, the mortality rate was low (less than 2%). Daily treatment of these animals with two oral dos...

  20. 重组人甲状旁腺素对慢性苯中毒小鼠造血损伤的改善作用%Improving Effect of rhPTH on Hematopoietic Depression in Mice Caused by Chronic Benzene Poisoning

    Institute of Scientific and Technical Information of China (English)

    丁晓飞; 冯晓青; 胡志勇; 刘华清; 靳宗达; 杜厚兵; 李冰燕; 张增利

    2011-01-01

    [目的]研究重组人甲状旁腺素(rhPTH)对慢性苯中毒小鼠造血损伤的改善作用.[方法]皮下注射苯诱导小鼠造血系统损伤模型.将造模成功的30只慢性苯中毒小鼠随机分为3组:生理盐水治疗组、40μg/kg rhPTH治疗组、80μg/kg rhPTH治疗组.每周5次腹腔注射生理盐水或不同剂量rhPTH,治疗3周,间隔1周后取样,测定3组小鼠骨髓中的造血干细胞(外源性脾结节法)、造血祖细胞(集落培养)以及外周血细胞计数和脾脏系数.[结果]经rhPTH治疗的小鼠一般状况明显好于生理盐水治疗组;40 μg/kg rhPTH治疗组与80μg/kg rhPTH治疗组的造血干细胞数明显高于生理盐水治疗组(P<0.05),但两个剂量rhPTH治疗组间造血干细胞数差异无统计学意义;3组小鼠的造血祖细胞及外周血细胞计数均差异无统计学意义;两个rhPTH治疗组的脾脏系数均低于生理盐水治疗组(P<0.05).[结论]rhPTH可明显增加慢性苯中毒小鼠骨髓中造血干细胞数量.%[ Objective ] To explore the improving effect of recombinant human parathyroid hormone( rhPTH )on bone marrow hematopoietic depression in mice caused by chronic benzene poisoning. [ Methods ] The model mice of hematopoietic depression was established in a number of KM mice by subcutaneous administration of benzene. Established model mice were treated 5 times a week for 3 weeks intraperitoneally with normal saline( NS group ), 40 μg/kg rhPTH( 40PTH group ),and 80 μg/kg rhPTH ( 80PTH group ) separately. One week later, all mice in the three groups were sacrificed. The hematopoietic stem cell, hematopoietic progenitor cell, peripheral blood cell count, and spleen index were determined by routine methods.[ Results ] Mice in PTH-treated groups showed better general condition than mice in NS group. The hematopoietic stem cells in 40PTH group and 80PTH group were significantly increased than those in NS group ( P < 0.05 ). However, the hematopoietic progenitor cells

  1. T-Cell-Dependent Control of Acute Giardia lamblia Infections in Mice

    OpenAIRE

    Singer, Steven M.; Nash, Theodore E.

    2000-01-01

    We have studied immune mechanisms responsible for control of acute Giardia lamblia and Giardia muris infections in adult mice. Association of chronic G. lamblia infection with hypogammaglobulinemia and experimental infections of mice with G. muris have led to the hypothesis that antibodies are required to control these infections. We directly tested this hypothesis by infecting B-cell-deficient mice with either G. lamblia or G. muris. Both wild-type mice and B-cell-deficient mice eliminated t...

  2. Effects of magnesium valprote on behavior and lipid peroxidation of brain in chronic stress depression mice%丙戊酸镁对慢性应激抑郁小鼠行为及脑脂质过氧化的影响

    Institute of Scientific and Technical Information of China (English)

    王垣芳; 李祖成; 杨茗; 袁文丹

    2010-01-01

    目的 探讨丙戊酸镁对慢性应激抑郁小鼠行为及脑脂质过氧化的影响.方法 选择空旷分析法评分相近的雄性小鼠40只,分为正常对照组、模型组、阿米替林对照组和丙戊酸镁组.除正常对照组外,其余各组小鼠均单笼孤养,同时给予慢性不可预见性应激21 d,应激期间每天按时给药:阿米替林组每天灌胃阿米替林0.2 mg/10g体质量,丙戊酸镁组每天灌服丙戊酸镁0.8 mg/10g体质量,正常对照组和模型组在相同时间点灌服相同体积的生理盐水.于实验的第7,14,21d测定小鼠体质量的变化,应激结束后采用抖笼法和糖水消耗实验进行行为学检测,然后断头取脑.分光光度法测定脑匀浆超氧化物歧化酶(SOD)活力、谷胱甘肽过氧化物酶(GSH-Px)活力和丙二醛(MDA)含量.采用SPSS11.5统计学软件进行数据分析.结果 与模型组比较,丙戊酸镁组小鼠自主活动次增加[分别为(97.50±20.54)次,(302.30±39.04)次,t=31.1432,P<0.01],激惹次数减少[分别为(5.42±1.26)次,(1.54±0.53)次,t=17.1370,P<0.01],糖水消耗量增加[分别为(15.30±3.60)ml,(23.70±4.45)ml,t=9.8446,P<0.01],体质量的增长增加[21d体质量增长分别为(10.56±1.53)g,(12.63±2.12)g,t=5.3113,P=0.007],大脑组织SOD活力增加,GSH-Px活力增加(t=3.4143,P=0.007),MDA含量减少(t=11.0778,P=0.002),均差异有显著性.结论 丙戊酸镁能够改善慢性应激抑郁小鼠行为,抑制其脑脂质过氧化反应;丙戊酸镁的抗抑郁样作用机制可能与抑制脑脂质过氧化反应有关.%Objective To explore the effects of magnesium valprote on behaviors and lipid peroxidation of brain in chronic stress depression mice.Methods 40 male mice were randomly divided into normal control group,model group, amitriptyline control group and magnesium valprote group, and.10 mice each group.Except normal control group,other groups were separated one mouse in each box and exposed to 21 days chronic unpredictable

  3. Chronic myelogenous leukemia (CML)

    Science.gov (United States)

    CML; Chronic myeloid leukemia; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... nuclear disaster. It takes many years to develop leukemia from radiation exposure. Most people treated for cancer ...

  4. Chronic obstructive pulmonary disease

    Science.gov (United States)

    ... airways disease; Chronic obstructive lung disease; Chronic bronchitis; Emphysema; Bronchitis - chronic ... a protein called alpha-1 antitrypsin can develop emphysema. Other risk factors for COPD are: Exposure to ...

  5. Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary growth phase killing of P. aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr -/--mice

    DEFF Research Database (Denmark)

    Hoffmann, N.; Lee, Bao le ri; Hentzer, Morten;

    2007-01-01

    The consequences of O-acetylated alginate-producing Pseudomonas aeruginosa biofilms in the lungs of chronically infected cystic fibrosis (CF) patients are tolerance to both antibiotic treatments and effects on the innate and the adaptive defense mechanisms. In clinical trials, azithromycin (AZM) ...

  6. Effects of Yulangsan Polysaccharides on Behavior, Structure of Hippocampus in Mice with Chronic Stress-induced Depression%玉郎伞多糖对慢性应激抑郁小鼠行为学及海马结构的影响

    Institute of Scientific and Technical Information of China (English)

    陆玉丹; 黄仁彬; 何萍

    2013-01-01

    目的:观察玉郎伞多糖(YLSPA)对慢性应激抑郁小鼠行为学及海马结构的影响.方法:50只昆明种小鼠随机分为5组:正常对照组、模型组、氟西汀20 mg· kg-1组和YLSPA 1 200,600 mg· kg-1高、低剂量组,连续灌胃21 d,同期利用慢性不可预知温和应激加孤养模型建立小鼠抑郁症模型.采用蔗糖水消耗实验和小鼠自主活动记录仪进行行为学测定;采用脑组织切片HE染色观察海马结构的改变.结果:实验第22天,模型组小鼠的体重、活动站立次数、糖水偏爱度明显减少(与正常对照组比较,P<0.01或P<0.05),YLSPA高、低剂量组、氟西汀组均较模型组有所增加(P<0.01或P<0.05);观察HE染色切片可见慢性应激引起海马结构发生改变,细胞数量减少,玉郎伞多糖和氟西汀可对抗这种改变.结论:YLSPA具有抗抑郁作用,能改善慢性应激对小鼠海马神经元细胞的损伤.%Objective: To observe the effects of Yulangsan polysaccharides ( YLSPA ) on behavior, structure changes of hippocampus in mice with chronic stress-induced depression. Method: Fifty Kunming mice were randomly divided into 5 groups; normal control, animal model, fluoxetine 20 mg·kg-1 and YLSPA 1 200 mg · kg-1 , YLSPA 600 mg·kg-1 groups with continuous oral administration for 21 d, and chronic unpredictable mild stress ( CUMS) with isolated support was imposed simultaneously to establish mouse depression model. The behavior changes of mice were evaluated by sucrose water consumption and the spontaneous activity; the structure changes of hippocampus were detected by the brain tissue HE staining. Result: The weight, the number of active stand, the consumption and preference for sucrose solution of the animal model group were significantly decreased compared with normal control group (P <0. 01 or P < 0. 05 ) , and were increased in YLSPA group and fluoxetine group (P < 0. 01 or P <0. 05) . Chronic unpredictable mild stress with isolated

  7. Practical pathology of aging mice

    Directory of Open Access Journals (Sweden)

    Piper M. M. Treuting

    2011-06-01

    Full Text Available Old mice will have a subset of lesions as part of the progressive decline in organ function that defines aging. External and palpable lesions will be noted by the research, husbandry, or veterinary staff during testing, cage changing, or physical exams. While these readily observable lesions may cause alarm, not all cause undue distress or are life-threatening. In aging research, mice are maintained until near end of life that, depending on strain and genetic manipulation, can be upwards of 33 months. Aging research has unique welfare issues related to age-related decline, debilitation, fragility, and associated pain of chronic diseases. An effective aging research program includes the collaboration and education of the research, husbandry, and veterinary staff, and of the members of the institution animal care and use committee. This collaborative effort is critical to humanely maintaining older mice and preventing excessive censorship due to non-lethal diseases. Part of the educational process is becoming familiar with how old mice appear clinically, at necropsy and histopathologically. This baseline knowledge is important in making the determination of humane end points, defining health span, contributing causes of death and effects of interventions. The goal of this paper is to introduce investigators to age-associated diseases and lesion patterns in mice from clinical presentation to pathologic assessment. To do so, we present and illustrate the common clinical appearances, necropsy and histopathological lesions seen in subsets of the aging colonies maintained at the University of Washington.

  8. Low back pain - chronic

    Science.gov (United States)

    Nonspecific back pain; Backache - chronic; Lumbar pain - chronic; Pain - back - chronic; Chronic back pain - low ... Low back pain is common. Almost everyone has back pain at some time in their life. Often, the exact cause of ...

  9. Chronic Pelvic Pain

    Science.gov (United States)

    ... Events Advocacy For Patients About ACOG Chronic Pelvic Pain Home For Patients Search FAQs Chronic Pelvic Pain ... Pain FAQ099, August 2011 PDF Format Chronic Pelvic Pain Gynecologic Problems What is chronic pelvic pain? What ...

  10. Employees with Chronic Pain

    Science.gov (United States)

    ... Home | Accommodation and Compliance Series: Employees with Chronic Pain By Beth Loy, Ph.D. Preface Introduction Information ... at http://AskJAN.org/soar. Information about Chronic Pain How prevalent is chronic pain? Chronic pain has ...

  11. Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood status of STOP/MAP6 KO mice. : epothilone and fluoxetine improve STOP KO memory

    OpenAIRE

    Fournet, Vincent; De Lavilléon, Gaetan; Schweitzer, Annie; Giros, Bruno; Andrieux, Annie; Martres, Marie-Pascale

    2012-01-01

    International audience Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain...

  12. Chronic Exposure to Arsenic in Drinking Water Causes Alterations in Locomotor Activity and Decreases Striatal mRNA for the D2 Dopamine Receptor in CD1 Male Mice

    OpenAIRE

    Moreno Ávila, Claudia Leticia; Limón-Pacheco, Jorge H.; Giordano., Magda; Rodríguez, Verónica M.

    2016-01-01

    Arsenic exposure has been associated with sensory, motor, memory, and learning alterations in humans and alterations in locomotor activity, behavioral tasks, and neurotransmitters systems in rodents. In this study, CD1 mice were exposed to 0.5 or 5.0 mg As/L of drinking water for 6 months. Locomotor activity, aggression, interspecific behavior and physical appearance, monoamines levels, and expression of the messenger for dopamine receptors D1 and D2 were assessed. Arsenic exposure produced h...

  13. Chronic coughing

    International Nuclear Information System (INIS)

    Chronic coughing was acknowledged to result from pathological state of the respiratory organs. Cardiac diseases could be accompanied by coughing as well. It was recommended to perform x-ray examinations, including biomedical radiography of the chest, computerized tomography, scintiscanning with 67Ga-citrate, bronchi examination in order to exclude heart disease. The complex examination permitted to detect localization and type of the changes in the lungs and mediastinum, to distinguish benign tumor from malignant one

  14. Humanized mice

    OpenAIRE

    Macchiarini, Francesca; Manz, Markus G.; Palucka, A Karolina; Shultz, Leonard D.

    2005-01-01

    Animal models have been instrumental in increasing the understanding of human physiology, particularly immunity. However, these animal models have been limited by practical considerations and genetic diversity. The creation of humanized mice that carry partial or complete human physiological systems may help overcome these obstacles. The National Institute of Allergy and Infectious Diseases convened a workshop on humanized mouse models for immunity in Bethesda, MD, on June 13–14, 2005, during...

  15. MICE Overview

    OpenAIRE

    Coney, L

    2009-01-01

    Muon ionization cooling provides the only practical solution for preparing high brightness beams necessary for a neutrino factory or muon collider. The Muon Ionization Cooling Experiment (MICE) is under development at the Rutherford Appleton Laboratory (UK). It comprises a dedicated beam line designed to generate a range of input emittances and momenta with time-of-flight and Cherenkov detectors to select a pure muon beam. A first measurement of emittance is performed in the upstream magnetic...

  16. Inhibition of the Inflammasome NLRP3 by Arglabin Attenuates Inflammation, Protects Pancreatic β-Cells from Apoptosis, and Prevents Type 2 Diabetes Mellitus Development in ApoE2Ki Mice on a Chronic High-Fat Diet.

    Science.gov (United States)

    Abderrazak, Amna; El Hadri, Khadija; Bosc, Elodie; Blondeau, Bertrand; Slimane, Mohamed-Naceur; Büchele, Berthold; Simmet, Thomas; Couchie, Dominique; Rouis, Mustapha

    2016-06-01

    Intraperitoneal injection of arglabin (2.5 ng/g of body weight, twice daily, 13 weeks) into female human apolipoprotein E2 gene knock-in (ApoE2Ki) mice fed a high-fat Western-type diet (HFD) reduced plasma levels of glucose and insulin by ∼20.0% ± 3.5% and by 50.0% ± 2.0%, respectively, in comparison with vehicle-treated mice. Immunohistochemical analysis revealed the absence of active caspase-3 in islet sections from ApoE2Ki mice fed a HFD and treated with arglabin. In addition, arglabin reduced interleukin-1β (IL-1β) production in a concentration-dependent manner in Langerhans islets isolated from ApoE2Ki mice treated with lipopolysaccharide (LPS) and with cholesterol crystals. This inhibitory effect is specific for the inflammasome NOD-like receptor family, pyrin domain-containing 3 (NLRP3) because IL-1β production was abolished in Langerhans islets isolated from Nlrp3(-/-) mice. In the insulin-secreting INS-1 cells, arglabin inhibited, in a concentration-dependent manner, the maturation of pro-IL-1β into biologically active IL-1β probably through the inhibition of the maturation of procaspase-1 into active capsase-1. Moreover, arglabin reduced the susceptibility of INS-1 cells to apoptosis by increasing Bcl-2 levels. Similarly, autophagy activation by rapamycin decreased apoptosis susceptibility while autophagy inhibition by 3-methyladenin treatment promoted apoptosis. Arglabin further increased the expression of the autophagic markers Bcl2-interacting protein (Beclin-1) and microtubule-associated protein 1 light chain 3 II (LC3-II) in a concentration-dependent manner. Thus, arglabin reduces NLRP3-dependent inflammation as well as apoptosis in pancreatic β-cells in vivo and in the INS-1 cell line in vitro, whereas it increases autophagy in cultured INS-1 cells, indicating survival-promoting properties of the compound in these cells. Hence, arglabin may represent a new promising compound to treat inflammation and type 2 diabetes mellitus development

  17. 不同工艺白金胶囊对慢性不可预知应激所致小鼠抑郁症的影响%Effects of Different Processes ofBaijin Capsule on Treatment of Mice with Chronic

    Institute of Scientific and Technical Information of China (English)

    倪博然; 林龙飞; 张慧; 倪健

    2016-01-01

    目的:评价不同工艺制备的白金胶囊治疗慢性不可预知应激所致小鼠抑郁症的药效。方法采用慢性不可预知应激制备小鼠抑郁模型。实验小鼠按体质量随机分为模型组、阳性药组、工艺品1(传统工艺)大剂量组、工艺品1小剂量组、工艺品2(精制工艺)大剂量组、工艺品2小剂量组,各药物组小鼠予相应剂量灌胃给药。通过测定小鼠游泳不动时间、悬尾不动时间两个行为学指标考察白金胶囊传统工艺和精制工艺的抗抑郁作用;通过测定小鼠自主活动和体质量考察受试药物是否具有中枢兴奋性或改变动物机体的机能状态的作用。结果模型组和工艺品2大、小剂量组小鼠游泳不动时间分别为(138.27±40.70)s、(100.01±34.75)s、(88.15±30.62)s,差异有统计学意义(P<0.01);模型组和工艺品2小剂量组小鼠自主活动次数分别为(668±19)次、(705±24)次,差异有统计学意义(P<0.01);模型组和工艺品1大剂量组体质量分别为(28.14±1.25)g、(26.43±2.58)g,差异有统计学意义(P<0.05);模型组和工艺品2大剂量组小鼠悬尾不动时间时间分别为(98.29±36.90)s、(87.54±30.05)s,工艺品2大剂量组小鼠悬尾不动时间有缩短趋势,但差异无统计学意义。结论精制工艺白金胶囊用于治疗慢性不可预知应激所致小鼠抑郁症的药效优于传统工艺。%Objective To evaluate the efficacy of different processes ofBaijin Capsule to treatment of mice with chronic unpredictable stress-induced depression.Methods Chronic unpredictable stress was used to establish depression mice models. Experimental mice were divided into the following groups according to body mass: model group, positive medicine group, artware one (traditional process) high-dose and low-dose groups, and artware (refining process) two high-dose and low-dose groups. All medication

  18. Influence of chronic corticosterone injection on depression-like behavior and brain glycogen levels in mice%慢性皮质酮注射对小鼠抑郁样行为及脑糖原水平的影响

    Institute of Scientific and Technical Information of China (English)

    张绘宇; 赵玉男; 王中立

    2015-01-01

    AIM:To study the effect of chronic corticosterone ( CORT) injection on the depression-like behav-iors and the brain glycogen level in mice.METHODS:Male C57BL/6N mice (n=40) were randomly divided into nor-mal control group and model group.The mice in model group were subcutaneously consecutively injected with CORT for 4 weeks.The mouse model of chronic stress depression was constructed.The forced swim test and open field experiment were conducted to prove chronic stress model.The serum level of CORT in the mice was measured by radioimmunoassay.The protein levels of hippocampal synaptophysin ( SYP) and brain-derived neurotrophic factor ( BDNF) were detected by West-ern blot.Hippocampus glycogen, glycogen synthase and glycogen phosphorylase were determined by indirect fluorescence measurement.RESULTS:Compared with normal control group, the immobility time of the forced swim test in model group was significantly lengthened (P<0.01), and the ability of spontaneous activity was reduced (P<0.01), indicating that chronic CORT injection induced depression-like behaviors in mice.The CORT level increased significantly (P<0.01) in model group.CORT injection decreased the protein expression of hippocampal SYP and BDNF (P<0.01), reduced hipp-ocampal glycogen level (P<0.05) and glycogen synthase activity (P<0.05), and increased glycogen phosphorylase ac-tivity (P<0.05).CONCLUSION:Chronic CORT injection causes hippocampal neuron damage and induces the depres-sion-like behaviors of mice, which may be associated with decreasing hippocampal glycogen level by CORT.%目的:探讨慢性皮质酮注射对小鼠抑郁样行为以及脑糖原水平的影响。方法:将40只雄性C57 BL/6 N小鼠随机分为正常对照组与模型组,模型组小鼠连续4周给予皮质酮皮下注射,构建慢性应激抑郁障碍小鼠模型。采用强迫游泳实验和旷场实验验证慢性应激模型的建立;放免法测定小鼠血清中皮质酮( CORT)水平;采用蛋白免

  19. Effects of Chronic Administration of Green Tea on Anatomical Characters and the Expression of Taste Transduction Protein α-gustducin and PLCβ2 in Fungiform Taste Buds of the Mice%长期绿茶暴露改变小鼠菌状味蕾基础特征及味觉传导蛋白α-gustducin和PLCβ2的表达

    Institute of Scientific and Technical Information of China (English)

    熊艺姣; 秦玉梅; 郭会林; 段晖; 蔡雯雯; 邓少平

    2013-01-01

    以绿茶及绿茶中主要活性成分(咖啡因、茶多酚、茶氨酸)暴露成年ICR小鼠21天后,以小鼠的舌上皮为材料,运用舌上皮整体装片技术及免疫组化方法,实体显微镜和激光共聚焦显微镜下观察小鼠菌状味蕾基本解剖形态以及味觉信号传导关键蛋白α-味蛋白(α-gustducin)及磷脂酶Cβ2(phosphoinositide-specific phospholipase Cβ2,PLCβ2)的阳性细胞数量表达情况.与对照组小鼠相比,绿茶及绿茶中咖啡因+茶多酚刺激显著降低了菌状味蕾的数量;咖啡因+茶多酚与茶氨酸组显著降低了味细胞数量;而绿茶及其主要活性成分长期刺激后均显著降低了菌状味蕾的最大横截面积,同时免疫组化结果也表明,味觉信号传导关键蛋白α-味蛋白阳性细胞表达数量也显著降低;而磷脂酶Cβ2表达受绿茶和茶多酚+咖啡因影响最大.结果表明,绿茶及绿茶中各种主要活性成分的长期刺激会改变味觉感受的基础特征,而这些变化可能是长期茶叶摄入导致食物厌腻感或体重减轻的重要原因之一.%In this study,adult ICR mice are used and treated with the solution of green tea and its crucial active components for 21 days,including caffeine,tea polyphenols and L-theanine.Following forementioned chronic exposure,the anatomical characters of fungiform taste buds and the expressions of taste signal transduction proteins,α-gustducin and phospholipase Cβ2 (PLCβ2) in fungiform taste buds are detected by the methods of wholemount preparation of tongue epitheliums,immunohistochemistry and laser confocal scanning microscope.The results show that the mice treated by green tea and caffeine+tea polyphenols have less number of fungiform taste buds and PLCβ2-immunopositive cells per taste bud than that of control mice.The size of fungiform taste buds and the number of α-gustducin-immunopositive cells per taste bud have more significant reduction in all components treated mice

  20. Chronic Insomnia

    OpenAIRE

    Buysse, Daniel J.

    2008-01-01

    Ms. F, a 42-year-old divorced woman, presents for evaluation of chronic insomnia. She complains of difficulty falling asleep, often 30 minutes or longer, and difficulty maintaining sleep during the night, with frequent awakenings that often last 30 minutes or longer. These symptoms occur nearly every night, with only one or two “good” nights per month. She typically goes to bed around 10:00 p.m. to give herself adequate time for sleep, and she gets out of bed around 7:00 a.m. on work days and...

  1. Chronic anaemia, hyperbaric oxygen and tumour radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    McCormack, M.; Nias, A.H.W.; Smith, Eileen (Saint Thomas' Hospital, London (UK). Richard Dimbleby Research Lab.)

    1990-10-01

    The present study examined the relationship between anaemia and tumour response to radiation given in air or HPO in C{sub 3}H mice transplanted with a mammary adenocarcinoma using a growth delay assay to assess radiation response. Radiation studies with these anaemic mice demonstrated that the tumour radiosensitivity was decreased when treatment was given in air. HPO was successful in overcoming the increased radioresistance associated with anaemia. This result suggested that tumours grown in anaemic mice have a higher hypoxic fraction than those grown in control mice. Changes in host physiology with chronic anaemia may contribute to the benefit seen with HPO but such alterations per se may be inadequate to maintain tumour oxygenation when treatment is given in air. (author).

  2. Chronic Exposure to Arsenic in Drinking Water Causes Alterations in Locomotor Activity and Decreases Striatal mRNA for the D2 Dopamine Receptor in CD1 Male Mice

    Directory of Open Access Journals (Sweden)

    Claudia Leticia Moreno Ávila

    2016-01-01

    Full Text Available Arsenic exposure has been associated with sensory, motor, memory, and learning alterations in humans and alterations in locomotor activity, behavioral tasks, and neurotransmitters systems in rodents. In this study, CD1 mice were exposed to 0.5 or 5.0 mg As/L of drinking water for 6 months. Locomotor activity, aggression, interspecific behavior and physical appearance, monoamines levels, and expression of the messenger for dopamine receptors D1 and D2 were assessed. Arsenic exposure produced hypoactivity at six months and other behaviors such as rearing and on-wall rearing and barbering showed both increases and decreases. No alterations on aggressive behavior or monoamines levels in striatum or frontal cortex were observed. A significant decrease in the expression of mRNA for D2 receptors was found in striatum of mice exposed to 5.0 mg As/L. This study provides evidence for the use of dopamine receptor D2 as potential target of arsenic toxicity in the dopaminergic system.

  3. Chronic Exposure to Arsenic in Drinking Water Causes Alterations in Locomotor Activity and Decreases Striatal mRNA for the D2 Dopamine Receptor in CD1 Male Mice.

    Science.gov (United States)

    Moreno Ávila, Claudia Leticia; Limón-Pacheco, Jorge H; Giordano, Magda; Rodríguez, Verónica M

    2016-01-01

    Arsenic exposure has been associated with sensory, motor, memory, and learning alterations in humans and alterations in locomotor activity, behavioral tasks, and neurotransmitters systems in rodents. In this study, CD1 mice were exposed to 0.5 or 5.0 mg As/L of drinking water for 6 months. Locomotor activity, aggression, interspecific behavior and physical appearance, monoamines levels, and expression of the messenger for dopamine receptors D1 and D2 were assessed. Arsenic exposure produced hypoactivity at six months and other behaviors such as rearing and on-wall rearing and barbering showed both increases and decreases. No alterations on aggressive behavior or monoamines levels in striatum or frontal cortex were observed. A significant decrease in the expression of mRNA for D2 receptors was found in striatum of mice exposed to 5.0 mg As/L. This study provides evidence for the use of dopamine receptor D2 as potential target of arsenic toxicity in the dopaminergic system. PMID:27375740

  4. 香菇多糖对慢性应激抑郁模型小鼠的抗抑郁作用及可能机制研究%Antidepressant effect of lentinan in chronically stressed mice and its possible mechanism

    Institute of Scientific and Technical Information of China (English)

    马倩; 蒲燕; 袁文清; 吕路线; 杜志敏; 李万里

    2015-01-01

    Objective:By observing the hippocampus 5-HT1A receptor expression, MDA content and SOD activity and the effect of lentinan mouse model of chronic stress behavior,serum TNF-αand IL-6 content.To investigate the mechanism of antidepressant LNT.Methods:Healthy adult mice were 50,male,body weight (20 ±2) g,SPF grade,based on 1% sucrose water partial addicted degrees and were randomly divided into four groups,namely,normal control group (Normal controls,NG),model in the control group ( Model control,MG) ,LNT dose group ( L-LNT,2.5 mg/kg;H-LNT,5.0 mg/kg).Before the experiment began modeling 1 h daily oral administration,continuous administration 28 d, each experimental group administered according 1.0 ml/100 g weight.Application chronic unpredictable mild stress model of depression produced,and make improvements.Normal control group,not to stimulate,food and water properly.Model group and the experimental intervention group with the lone support,fasting,water deprivation (24 h),and accept the unpredictable stressors,the 28 d of the experiment,the animals were randomized to receive daily each only one stimulus, within five days after making the choreography the stimulus program was not repeated and unpredictable.Animals were observed daily behavior change,with a strange environment to start feeding feeding experimentally observed incubation period,forced swim stress test record swim immobility time,enzyme-linked immunosorbent assay of serum TNF-α,IL-6 content ,NBT assay of total SOD activity,thio-barbituric acid (thiobarbituric acid,TBA) MDA content assay,immune proteins mark (Western blot) to detect 5-HT1A receptor expression levels.Results:MG mice in an unfamiliar environment, feeding latency was significantly prolonged after giving LNT intervention can shorten lead to chronic stress in mice feeding latency in an unfamiliar environment,prolonged chronic stress leads to significantly reduce the stress in mice swimming in water immobility time extension,and 5-HT1A

  5. Virus-Induced Demyelination in Nude Mice Is Mediated by γδ T Cells

    OpenAIRE

    Dandekar, Ajai A.; Perlman, Stanley

    2002-01-01

    Infection of mice with mouse hepatitis virus (MHV), strain JHM, results in acute and chronic demyelination with many similarities to the human disease multiple sclerosis. This pathological process is primarily T cell-mediated and MHV infection of mice lacking B and T cells does not result in demyelination. In apparent contradiction to these results, robust demyelination is detected in MHV-infected young nude (athymic) mice. Herein, we show that demyelination in nude mice was mediated by γδ T ...

  6. Chronic Ethanol Feeding to Rats Decreases Adiponectin Secretion by Subcutaneous Adipocytes

    OpenAIRE

    Chen, Xiaocong; Sebastian, Becky M.; Nagy, Laura E.

    2006-01-01

    Chronic ethanol feeding to mice and rats decreases serum adiponectin concentration and adiponectin treatment attenuates chronic ethanol-induced liver injury. While it is clear that lowered adiponectin has pathophysiological importance, the mechanisms by which chronic ethanol decreases adiponectin are not known. Here we have investigated the impact of chronic ethanol feeding on adiponectin expression and secretion by adipose tissue. Rats were fed a 36% Lieber-DeCarli ethanol-containing liquid ...

  7. MICE Overview

    CERN Document Server

    Coney, L

    2009-01-01

    Muon ionization cooling provides the only practical solution for preparing high brightness beams necessary for a neutrino factory or muon collider. The Muon Ionization Cooling Experiment (MICE) is under development at the Rutherford Appleton Laboratory (UK). It comprises a dedicated beam line designed to generate a range of input emittances and momenta with time-of-flight and Cherenkov detectors to select a pure muon beam. A first measurement of emittance is performed in the upstream magnetic spectrometer with a scintillating fiber tracker. A cooling cell will then follow, alternating energy loss in liquid hydrogen and acceleration by RF cavities. A second spectrometer identical to the first and another particle identification system provide a measurement of the outgoing emittance. In late 2009, it is expected that the beam and many of the particle identification detectors will be in the final commissioning phase, and the first measurement of input beam emittance will take place in 2010. The steps of commissi...

  8. 克肝膠囊对CCI4慢性肝损伤大鼠的影响%Influence of KeGan Capsule to Mice with CCI4 Chronic Hepatic Injury

    Institute of Scientific and Technical Information of China (English)

    徐玉芳

    2004-01-01

    Objective To study the action of KeGan capsule to resist injury of hepatic cells and fibrosis of liver. Methods Replicate model of chronic hepatic injury with CCl4, at the beginning of which KeGan capsule was applied; finishing experiment, respectively tested the level of liver function, TP,ALB, A/G, L - hydroxyproline and liver index and do pathologic examination to liver. Results KeGan capsule can obviously reduce the degree of fibrosis of liver and the level of L - hydroxyproline, improve the liver function. The histological examination showed that capsule has the action of protecting hepatic cells from injury and resisting fibrosis of liver either. Conclusion For KeGan capsule has the action of resisting injury of liver cells and fibrosis of liver, it' s hoped to be applied in precaution and treatnent of fibrosis of liver.

  9. Atypical Chronic Myelogenous Leukemia

    Science.gov (United States)

    ... myeloproliferative neoplasms, leukemia , and other conditions . Chronic Myelomonocytic Leukemia Key Points Chronic myelomonocytic leukemia is a disease ... chance of recovery) and treatment options. Chronic myelomonocytic leukemia is a disease in which too many myelocytes ...

  10. Living with Chronic Bronchitis

    Science.gov (United States)

    ... from the NHLBI on Twitter. Living With Chronic Bronchitis If you have chronic bronchitis, you can take steps to control your symptoms. ... and a pneumonia vaccine. If you have chronic bronchitis, you may benefit from pulmonary rehabilitation (PR). PR ...

  11. Aorta Atherosclerosis Lesion Analysis in Hyperlipidemic Mice

    Science.gov (United States)

    Mohanta, Sarajo; Yin, Changjun; Weber, Christian; Hu, Desheng; Habenicht, Andreas JR

    2016-01-01

    Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries. Apolipoprotein E-deficient (ApoE-/-) mice are used as experimental models to study human atherosclerosis. ApoE-/- mice are constitutively hyperlipidemic and develop intima plaques that resemble human plaques. Various issues including experimental design for lesion analysis, dietary conditions, isolation of the aorta, staining methods, morphometry, group size, age, the location within the arterial tree, and statistical analyses are important parameters that need to be addressed to obtain robust data. Here, we provide detailed methods to quantify aorta atherosclerosis. PMID:27366759

  12. Chronic urticaria

    Directory of Open Access Journals (Sweden)

    Sandeep Sachdeva

    2011-01-01

    Full Text Available Chronic urticaria (CU is a disturbing allergic condition of the skin. Although frequently benign, it may sometimes be a red flag sign of a serious internal disease. A multitude of etiologies have been implicated in the causation of CU, including physical, infective, vasculitic, psychological and idiopathic. An autoimmune basis of most of the ′idiopathic′ forms is now hypothesized. Histamine released from mast cells is the major effector in pathogenesis and it is clinically characterized by wheals that have a tendency to recur. Laboratory investigations aimed at a specific etiology are not always conclusive, though may be suggestive of an underlying condition. A clinical search for associated systemic disease is strongly advocated under appropriate circumstances. The mainstay of treatment remains H1 antihistaminics. These may be combined with complementary pharmacopeia in the form of H2 blockers, doxepin, nifedipine and leukotriene inhibitors. More radical therapy in the form of immunoglobulins, plasmapheresis and cyclophosphamide may be required for recalcitrant cases. Autologous transfusion and alternative remedies like acupuncture have prospects for future. A stepwise management results in favorable outcomes. An update on CU based on our experience with patients at a tertiary care centre is presented.

  13. Lack of stress responses to long-term effects of corticosterone in Caps2 knockout mice.

    Science.gov (United States)

    Mishima, Yuriko; Shinoda, Yo; Sadakata, Tetsushi; Kojima, Masami; Wakana, Shigeharu; Furuichi, Teiichi

    2015-01-01

    Chronic stress is associated with anxiety and depressive disorders, and can cause weight gain. Ca(2+)-dependent activator protein for secretion 2 (CAPS2) is involved in insulin release. Caps2 knockout (KO) mice exhibit decreased body weight, reduced glucose-induced insulin release, and abnormal psychiatric behaviors. We chronically administered the stress hormone corticosterone (CORT), which induces anxiety/depressive-like behavior and normally increases plasma insulin levels, via the drinking water for 10 weeks, and we examined the stress response in KO mice. Chronic CORT exposure inhibited stress-induced serum CORT elevation in wild-type (WT) mice, but not in KO mice. Poor weight gain in CORT-treated animals was observed until week 6 in WT mice, but persisted for the entire duration of the experiment in KO mice, although there is no difference in drug*genotype interaction. Among KO mice, food consumption was unchanged, while water consumption was higher, over the duration of the experiment in CORT-treated animals, compared with untreated animals. Moreover, serum insulin and leptin levels were increased in CORT-treated WT mice, but not in KO mice. Lastly, both WT and KO mice displayed anxiety/depressive-like behavior after CORT administration. These results suggest that Caps2 KO mice have altered endocrine responses to CORT administration, while maintaining CORT-induced anxiety/depressive-like behavior. PMID:25754523

  14. Increased susceptibility of Cftr-/- mice to LPS-induced lung remodeling.

    Science.gov (United States)

    Bruscia, Emanuela M; Zhang, Ping-Xia; Barone, Christina; Scholte, Bob J; Homer, Robert; Krause, Diane S; Egan, Marie E

    2016-04-15

    Cystic fibrosis (CF) is caused by homozygous mutations of the CF transmembrane conductance regulator (CFTR) Cl(-) channel, which result in chronic pulmonary infection and inflammation, the major cause of morbidity and mortality. Although these processes are clearly related to each other, each is likely to contribute to the pathology differently. Understanding the contribution of each of these processes to the overall pathology has been difficult, because they are usually so intimately connected. Various CF mouse models have demonstrated abnormal immune responses compared with wild-type (WT) littermates when challenged with live bacteria or bacterial products acutely. However, these studies have not investigated the consequences of persistent inflammation on lung tissue in CF mice, which may better model the lung pathology in patients. We characterized the lung pathology and immune response of Cftr(-/-) (CF) and Cftr(+/+) (WT) mice to chronic administration of Pseudomonas aeruginosa lipopolysaccharide (LPS). We show that, after long-term repeated LPS exposure, CF mice develop an abnormal and persistent immune response, which is associated with more robust structural changes in the lung than those observed in WT mice. Although CF mice and their WT littermates develop lung pathology after chronic exposure to LPS, the inflammation and damage resolve in WT mice. However, CF mice do not recover efficiently, and, as a consequence of their chronic inflammation, CF mice are more susceptible to morphological changes and lung remodeling. This study shows that chronic inflammation alone contributes significantly to aspects of CF lung pathology. PMID:26851259

  15. Cholic acid induces a Cftr dependent biliary secretion and liver growth response in mice.

    Directory of Open Access Journals (Sweden)

    Frank A J A Bodewes

    Full Text Available The cause of Cystic fibrosis liver disease (CFLD, is unknown. It is well recognized that hepatic exposure to hydrophobic bile salts is associated with the development of liver disease. For this reason, we hypothesize that, CFTR dependent variations, in the hepatic handling of hydrophobic bile salts, are related to the development CFLD. To test our hypothesis we studied, in Cftr-/- and control mice, bile production, bile composition and liver pathology, in normal feeding condition and during cholate exposure, either acute (intravenous or chronic (three weeks via the diet. In Cftr-/- and control mice the basal bile production was comparable. Intravenous taurocholate increased bile production to the same extent in Cftr-/- and control mice. However, chronic cholate exposure increased the bile flow significantly less in Cftr-/- mice than in controls, together with significantly higher biliary bile salt concentration in Cftr-/- mice. Prolonged cholate exposure, however, did not induce CFLD like pathology in Cftr-/- mice. Chronic cholate exposure did induce a significant increase in liver mass in controls that was absent in Cftr-/- mice. Chronic cholate administration induces a cystic fibrosis-specific hepatobiliary phenotype, including changes in bile composition. These changes could not be associated with CFLD like pathological changes in CF mouse livers. However, chronic cholate administration induces liver growth in controls that is absent in Cftr-/- mice. Our findings point to an impaired adaptive homeotrophic liver response to prolonged hydrophobic bile salt exposure in CF conditions.

  16. 急、慢性束缚应激对小鼠情绪和学习记忆能力的不同影响%Different effects on emotion and cognition induced by acute restraint stress and chronic restraint stress in mice

    Institute of Scientific and Technical Information of China (English)

    周科成; 佳娜提; 吴黄辉; 王锋; 胡伟; 寇俊萍

    2013-01-01

    目的:观察急性束缚应激和慢性束缚应激对小鼠情绪和学习记忆能力的影响.方法:小鼠按体重和自发活动随机分成三组,即空白对照组,急性应激组和慢性应激组.采用束缚躯体的方法建立急慢性应激模型,并用自发活动实验检测小鼠的情绪状态,避暗实验检测小鼠的学习记忆能力.结果:自发活动实验中急性束缚应激组小鼠平均速度与空白组相比有显著增加(P<0.01),中央区活动时间和中央区活动路程百分比则显著增加(P<0.05),慢性应激组平均速度与空白组相比有显著减小(P<0.01),中央区活动时间和中央区活动路程百分比显著减小(P<0.05);避暗测试中急性应激组避暗潜伏期和错误次数没有改变,而慢性应激组潜伏期显著减小(P<0.05)、错误次数急显著增加(P<0.01).结论:急性束缚应激会使小鼠产生烦躁情绪、但不会改变其学习记忆能力;慢性束缚应激会使小鼠产生抑郁样情绪,会损害其学习记忆能力.%Objective: To investigate the effects of acute restraint stress (ARS) and chronic restraint stress (CRS) on the emotional change and cognitive ebility of mice. Methods: Mice were divided to three groups according body weight and spontaneous activity state i. e. control group, ARS and CRS. Acute restraint stress and chronic restraint stress animal models were established and changes of emotional and cognitive performances were examined by open field and step-through tests. Results: In open field test, ARS group showed lower mean velocity (P <0.01) , time in central zone (P <0. 05) and the percentage of distance in zone/total (P <0. 05) , while CRS group significantly reduced ( P <0. 05). There is no change of step-through latency and number of mistakes in ARS group, however, step-through latency significantly increased (P<0. 01) and number of mistakes deceased in CRS group (P<0. 05). Conclusion:The present results suggested that

  17. Protective effects of myricetin on chronic stress-induced cognitive deficits.

    Science.gov (United States)

    Wang, Qi-Min; Wang, Gui-Lin; Ma, Ze-Gang

    2016-06-15

    The aim of the present study is to investigate the possible effects of chronic administration of myricetin, a natural flavonoid, on chronic stress-induced learning and memory deficits in mice. The mice were restrained daily 4 h/day for 21 days in well-ventilated plexiglass tubes without access to food and water. These animals were injected with myricetin or vehicle 40 min before each restraint stress over a period of 21 days. Then, spatial learning and memory of the mice were evaluated by the Morris water maze task. We did not observe a significant difference in the escape latency in mice subjected to repeated restraint stress, which indicates that learning ability was not affected by restraint stress. However, the spatial memory ability was significantly impaired in the repeatedly restrained mice. Myricetin administration specifically increased the time spent in the target quadrant in mice exposed to chronic stress in the probe trial as tested in the Morris water maze task. Further studies showed that myricetin treatment decreased plasma adrenocorticotrophic hormone levels of those mice subjected to repeated restraint stress. The effect of myricetin on the levels of brain-derived neurotrophic factor (BDNF) in hippocampus was also investigated. The result showed that myricetin normalized the decreased BDNF levels in mice subjected to repeated restraint stress. These findings provide more evidence that chronic administration of myricetin improves spatial memory in repeatedly restrained mice and BDNF signaling in the hippocampus may be involved in the protective effects of myricetin. PMID:27171032

  18. Antidepressant activity of fingolimod in mice

    OpenAIRE

    di Nuzzo, Luigi; Orlando, Rosamaria; Tognoli, Cristina; Di Pietro, Paola; Bertini, Giuseppe; Miele, Jessica; Bucci, Domenico; Motolese, Marta; Scaccianoce, Sergio; Caruso, Alessandra; Mauro, Gianluca; De Lucia, Carmine; Battaglia, Giuseppe; Bruno, Valeria; Fabene, Paolo Francesco

    2015-01-01

    Recent findings indicate that fingolimod, the first oral drug approved for the treatment of multiple sclerosis (MS), acts as a direct inhibitor of histone deacetylases (HDACs) and enhances the production of brain-derived neurotrophic factor (BDNF) in the CNS. Both mechanisms are relevant to the pathophysiology and treatment of major depression. We examined the antidepressant activity of fingolimod in mice subjected to chronic unpredictable stress (CUS), a model of reactive depression endowed ...

  19. 骨髓间充质干细胞移植对慢性哮喘小鼠气道炎症及气道重塑的影响%Effects of Bone Marrow-Derived Mesenchymal Stem Cells on Airway Inflammation and Airway Remodeling in Chronic Asthmatic Mice

    Institute of Scientific and Technical Information of China (English)

    戈霞晖; 白冲; 陈若华; 胡珍丽; 朱天怡; 李强

    2011-01-01

    目的 探讨同种异体骨髓间充质干细胞(BMSC)移植对慢性哮喘小鼠气道炎症和气道重塑的影响.方法 40只雌性BALB/c小鼠随机分为正常对照组、BMSC对照组、哮喘模型组和BMSC治疗组.从雄性BALB/c小鼠分离BMSC.用卵白蛋白(OVA)制备慢性哮喘模型.观察BMSC移植对慢性哮喘小鼠气道炎症和气道重塑的影响,并采用流式细胞术检测BMSC对脾组织CD4+CD25+调节性T细胞比例的影响.结果 哮喘模型组支气管上皮黏膜脱落,上皮黏膜有杯状细胞增生,部分管腔内有黏液栓塞,气道、血管旁有大量炎件浸润,以及气道平滑肌细胞增生和肥大.正常对照组及BMSC对照组无气道炎症及气道重塑的表现,而BMSC治疗组气道炎症及气道重塑明显减轻.与BMSC对照组及正常对照组比较,哮喘模型组CD4+CD25+调节性T细胞占淋巴细胞的比例显著降低(P<0.05);与哮喘模型组比较,BMSC治疗组CD4+CD25+调节性T细胞占淋巴细胞的比例明显提高(P<0.05);BMSC治疗组与正常对照组及BMSC对照组无显著差异.结论 BMSC移植能明显减轻慢性哮喘小鼠气道炎症及气道重塑程度,并能上调外周CD4+CD25+调节性T细胞的比例.%Objective To investigate the effect of allogeneic bone marrow-derived mesenchymal stem cells (BMSCs) transplantation on the airway inflammation and airway remodeling in chronic asthmatic mice. Methods Forty female BALB/c mice were equally randomized into four groups,ie. a normal control group,a BMSCs control group,an asthma model group, and a BMSCs transplantation group. BMSCs were generated from male donor mice, then the mice in the asthma model group and the BMSCs transplantation group were sensitized and challenged with OVA to establish chronic asthmatic mice model. Hematoxylin and eosin staining and Alcian blue-periodic acid-Schiff staining were used to analyze the effects on airway inflammation and airway remodeling after BMSC engraftment. The number of

  20. Effects of bone marrow mesenchymal stem cells on the serum levels of interleukin-4 and interleukin-12 in chronic asthmatic