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Sample records for interleukin-10 agonist diminishes

  1. Interleukin-10

    NARCIS (Netherlands)

    de Waal Malefyt, R.; Yssel, H.; Roncarolo, M. G.; Spits, H.; de Vries, J. E.

    1992-01-01

    Despite the short history of interleukin-10, accumulated evidence indicates that this interleukin plays a major role in suppressing immune and inflammatory responses. Yet interleukin-10 also maintains cell viability and acts as a cofactor to promote the growth of lymphoid and myeloid cells in vitro.

  2. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    Science.gov (United States)

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. © 2010 American Academy of Forensic Sciences.

  3. The Toll-like receptor 1/2 agonists Pam(3) CSK(4) and human β-defensin-3 differentially induce interleukin-10 and nuclear factor-κB signalling patterns in human monocytes.

    Science.gov (United States)

    Funderburg, Nicholas T; Jadlowsky, Julie K; Lederman, Michael M; Feng, Zhimin; Weinberg, Aaron; Sieg, Scott F

    2011-10-01

    Human β-defensin 3 (hBD-3) activates antigen-presenting cells through Toll-like receptors (TLRs) 1/2. Several TLR1/2 agonists have been identified but little is known about how they might differentially affect cellular activation. We compared the effects of hBD-3 with those of another TLR1/2 agonist, Pam(3) CSK(4) , in human monocytes. Monocytes incubated with hBD-3 or Pam(3) CSK(4) produced interleukin-6 (IL-6), IL-8 and IL-1β, but only Pam(3) CSK(4) induced IL-10. The IL-10 induction by Pam(3) CSK(4) caused down-modulation of the co-stimulatory molecule, CD86, whereas CD86 expression was increased in monocytes exposed to hBD-3. Assessment of signalling pathways linked to IL-10 induction indicated that mitogen-activated protein kinases were activated similarly by hBD-3 or Pam(3) CSK(4) , whereas the non-canonical nuclear factor-κB pathway was only induced by Pam(3) CSK(4) . Our data suggest that the lack of non-canonical nuclear factor-κB signalling by hBD-3 could contribute to the failure of this TLR agonist to induce production of the anti-inflammatory cytokine, IL-10, in human monocytes. © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.

  4. Dopamine agonists diminish value sensitivity of the orbitofrontal cortex: a trigger for pathological gambling in Parkinson's disease?

    Science.gov (United States)

    van Eimeren, Thilo; Ballanger, Bénédicte; Pellecchia, Giovanna; Miyasaki, Janis M; Lang, Anthony E; Strafella, Antonio P

    2009-12-01

    The neurobehavioral underpinnings of pathological gambling are not well understood. Insight might be gained by understanding pharmacological effects on the reward system in patients with Parkinson's disease (PD). Treatment with dopamine agonists (DAs) has been associated with pathological gambling in PD patients. However, how DAs are involved in the development of this form of addiction is unknown. We tested the hypothesis that tonic stimulation of dopamine receptors specifically desensitizes the dopaminergic reward system by preventing decreases in dopaminergic transmission that occurs with negative feedback. Using functional magnetic resonance imaging, we studied PD patients during three sessions of a probabilistic reward task in random order: off medication, after levodopa (LD) treatment, and after an equivalent dose of DA (pramipexole). For each trial, a reward prediction error value was computed using outcome, stake, and probability. Pramipexole specifically changed activity of the orbitofrontal cortex (OFC) in two ways that were both associated with increased risk taking in an out-of-magnet task. Outcome-induced activations were generally higher with pramipexole compared with LD or off medication. In addition, only pramipexole greatly diminished trial-by-trial correlation with reward prediction error values. Further analysis yielded that this resulted mainly from impaired deactivation in trials with negative errors in reward prediction. We propose that DAs prevent pauses in dopamine transmission and thereby impair the negative reinforcing effect of losing. Our findings raise the question of whether pathological gambling may in part stem from an impaired capacity of the OFC to guide behavior when facing negative consequences.

  5. Interleukin-10 promoter polymorphisms in myasthenia gravis.

    Science.gov (United States)

    Alseth, Espen Homleid; Nakkestad, Hanne Linda; Aarseth, Jan; Gilhus, Nils Erik; Skeie, Geir Olve

    2009-05-29

    Interleukin 10 (IL-10) is secreted by several hemopoietic cells and suppresses the Th1 mediated immune response, while stimulating B cell differentiation and the humoral immune response. IL-10 expression in Con A-stimulated peripheral blood mononuclear cells is related to three polymorphisms in the promoter region of the IL-10 gene; G/A at position -1082, T/C at position -819 and A/C at position -592. We analyzed the distribution of these IL-10 polymorphisms in 64 MG patients and 87 healthy blood donors to determine any influence on MG susceptibility. MG patients had a significantly higher frequency of the ACC/ACC haplotype (12.5% vs 3.4% in controls), as had the subgroups with late onset MG and thymomatous MG (20.0% and 21.4%, respectively). Early onset MG patients had a high frequency of the ATA/ATA haplotype (19.2% vs 3.4% in controls). Titin Ab-positive MG patients had high ACC/ACC (20.0%). This study indicates a direct link between IL-10 and MG pathogenesis, although the complex role of this multi-faceted cytokine in vivo is as yet not fully elucidated.

  6. PPARγ agonists diminish serum VEGF elevation in diet-induced insulin resistant SD rats and ZDF rats

    International Nuclear Information System (INIS)

    Yang Baichun; Lin Peiyuan; Carrick, Kevin M.; McNulty, Judi A.; Clifton, Lisa G.; Winegar, Deborah A.; Strum, Jay C.; Stimpson, Stephen A.; Pahel, Greg L.

    2005-01-01

    We investigated the effect of peroxisome proliferator-activated receptor gamma (PPARγ) agonists on serum vascular endothelial growth factor (VEGF) in diet-induced insulin resistant SD rats and ZDF rats. SD rats fed a high fat/sucrose diet showed increases in serum insulin and VEGF (both p < 0.01). Treatment with a PPARγ agonist GI262570 normalized the diet-elevated insulin and VEGF (both p < 0.01). There was a positive correlation between serum insulin and VEGF (p < 0.05) in SD rats. ZDF rats had higher serum glucose, insulin, and VEGF than Zucker lean rats (all p < 0.01). Treatment of ZDF rats with PPARγ agonist pioglitazone decreased serum glucose and VEGF (both p < 0.01). There was a positive correlation between glucose and VEGF in ZDF rats (p < 0.05). In 3T3-L1 adipocytes, GI262570 did not affect insulin-stimulated VEGF secretion. These studies demonstrated that hyperinsulinemia in SD rats and hyperglycemia in ZDF rats were associated with increased serum VEGF; PPARγ agonists normalized serum insulin, glucose, and VEGF, but did not affect VEGF secretion in vitro

  7. Retigabine diminishes the effects of acetylcholine, adrenaline and adrenergic agonists on the spontaneous activity of guinea pig smooth muscle strips in vitro.

    Science.gov (United States)

    Apostolova, Elisaveta; Zagorchev, Plamen; Kokova, Vesela; Peychev, Lyudmil

    2017-03-01

    The aim of this study is to evaluate the effect of retigabine on the smooth muscle response to acetylcholine, adrenaline, α-and β-adrenoceptor agonists. We studied the change in the spontaneous smooth muscle contraction of guinea pig gastric corpus strips before and after 20-min treatment with 2μM retigabine. We also evaluated the effect of retigabine on the smooth muscle response to 10μM acetylcholine, 1 and 10μM adrenaline, 1μM methoxamine, 0.1μM p-iodoclonidine and 10μM isoproterenol. We observed a significant reduction in the effects of all studied mediators and agonists when they were added to organ baths in the presence of retigabine. Retigabine diminished the effect of acetylcholine on the spontaneous smooth muscle activity. The effect was fully antagonized by XE-991 (Kv7 channel blocker), which supports our hypothesis about the role of KCNQ channels in the registered changes. The increase in the contraction force after adding of 1μM adrenaline, methoxamine, and 0.1μM p-iodoclonidine was also significantly smaller in presence of retigabine. However, comparing the effect of 10μM adrenaline on the contractility before and after treatment with retigabine, we observed increased contractility when retigabine was present in the organ baths. A possible explanation for the observed diminished effects of mediators and receptor agonists is that the effect of retigabine on smooth muscle contractility is complex. The membrane hyperpolarization, the interaction between Kv7 channels and adrenoceptors, and the influence on signaling pathways may contribute to the summary smooth muscle response. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Analysis of Interleukin-10 polymorphic variants in Pakistani population

    African Journals Online (AJOL)

    use

    2011-12-14

    Dec 14, 2011 ... Boomsma DI, Vandenbroucke JP (1997). Genetic influence on cytokine production and fatal meningococcal disease. Lancet002C. 349: 170-3. Zhang X, Hei P, Deng L , Lin J (2006). Interleukin-10 gene promoter polymorphisms and their protein production in peritoneal fluid in patients with endometriosis.

  9. Tumour necrosis factor alpha and interleukin 10 gene ...

    Indian Academy of Sciences (India)

    Tumour necrosis factor alpha and interleukin 10 gene polymorphisms and the risk of ischemic stroke in south Indian population. Shehnaz Sultana Venkata K. Kolla Yasovanthi Jeedigunta Pranay K. Penagaluru Sindhu Joshi P. Usha Rani P. P. Reddy. Research Note Volume 90 Issue 2 August 2011 pp 361-364 ...

  10. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.

    Science.gov (United States)

    Glocker, Erik-Oliver; Kotlarz, Daniel; Boztug, Kaan; Gertz, E Michael; Schäffer, Alejandro A; Noyan, Fatih; Perro, Mario; Diestelhorst, Jana; Allroth, Anna; Murugan, Dhaarini; Hätscher, Nadine; Pfeifer, Dietmar; Sykora, Karl-Walter; Sauer, Martin; Kreipe, Hans; Lacher, Martin; Nustede, Rainer; Woellner, Cristina; Baumann, Ulrich; Salzer, Ulrich; Koletzko, Sibylle; Shah, Neil; Segal, Anthony W; Sauerbrey, Axel; Buderus, Stephan; Snapper, Scott B; Grimbacher, Bodo; Klein, Christoph

    2009-11-19

    The molecular cause of inflammatory bowel disease is largely unknown. We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease. We screened six additional patients with early-onset colitis for mutations in two candidate genes and carried out functional assays in patients' peripheral-blood mononuclear cells. We performed an allogeneic hematopoietic stem-cell transplantation in one patient. In four of nine patients with early-onset colitis, we identified three distinct homozygous mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a heterotetramer to make up the interleukin-10 receptor. The mutations abrogate interleukin-10-induced signaling, as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10. Consistent with this observation was the increased secretion of tumor necrosis factor alpha and other proinflammatory cytokines from peripheral-blood mononuclear cells from patients who were deficient in IL10R subunit proteins, suggesting that interleukin-10-dependent "negative feedback" regulation is disrupted in these cells. The allogeneic stem-cell transplantation performed in one patient was successful. Mutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis, involving hyperinflammatory immune responses in the intestine. Allogeneic stem-cell transplantation resulted in disease remission in one patient. 2009 Massachusetts Medical Society

  11. The dual nature of interleukin-10 in pemphigus vulgaris.

    Science.gov (United States)

    Cho, Michael Jeffrey; Ellebrecht, Christoph T; Payne, Aimee S

    2015-06-01

    The immunomodulatory cytokine interleukin-10 (IL-10) plays beneficial but also potentially detrimental roles in inflammation, infection, and autoimmunity. Recent studies suggest a regulatory role for IL-10-expressing B cells in the autoimmune blistering disease pemphigus vulgaris. Here we review the studies on IL-10 in pemphigus vulgaris and discuss the potential pathophysiological significance of these findings in comparison to prior studies of IL-10 in other human conditions. A better understanding of the complex roles of IL-10 in immune regulation may improve our understanding of pemphigus pathogenesis and treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Interleukin-10 and posttransplant lymphoproliferative disorder after kidney transplantation

    DEFF Research Database (Denmark)

    Birkeland, S.A.; Bendtzen, K.; Moller, B.

    1999-01-01

    , and the type and duration of immunosuppression. Interleukin-10 (IL-10) is a pleiotropic cytokine, produced primarily by T-helper 2 (Th2) lymphocytes in the later stages of T-cell activation, suggested to play a role in EBV-associated PTLD, We recently reported preliminary findings on IL-10 in relation...... human recombinant IL-10 was employed; the assay is specific for human natural and viral IL-10, Results, Three patients experienced primary EBV infection, five reactivated EBV infections, and one did not change EBV status. Three patients had a fulminant course and died with EBV-associated PTLD; confirmed...... immunosuppression and are now in a state of operational tolerance. In three of four cases with initial lymphoma, EBV infection (primary or reactivation) preceded the increase in IL-10, In all four cases, the IL-10 increase preceded the PTLD diagnosis. In six cases, IL-10 could be followed after treatment showing...

  13. Interleukin-10 promoter polymorphisms in patients with multiple sclerosis.

    Science.gov (United States)

    Myhr, Kjell-Morten; Vågnes, Kari S; Marøy, Tove H; Aarseth, Jan H; Nyland, Harald I; Vedeler, Christian A

    2002-10-15

    The expression level of interleukin-10 (IL-10) is related to polymorphisms -1082 (G/A), -819 (T/C) and -592 (A/C) in the promoter region of the IL-10 gene. The distribution of these polymorphisms was analyzed to determine whether they could influence disease susceptibility or clinical course in multiple sclerosis (MS). The -1082 (G/A), -819 (T/C) and -592 (A/C) genotypes were similarly distributed between MS patients and the controls. The primary progressive MS patients with the low IL-10 expression haplotype showed a trend towards a worse clinical outcome than did patients with medium- or high-expression haplotypes (P = 0.056). The polymorphisms did not influence the clinical course in patients with relapsing-remitting MS. Copyright 2002 Elsevier Science B.V.

  14. Piroxicam treatment augments bone abnormalities in interleukin-10 knockout mice

    DEFF Research Database (Denmark)

    Holgersen, Kristine; Dobie, Ross; Farquharson, Colin

    2015-01-01

    BACKGROUND: Osteoporosis and fractures are common complications of inflammatory bowel disease. The pathogenesis is multifactorial and has been partly attributed to intestinal inflammation. The aim of this study was to evaluate bone status and assess the association between bone loss and gut...... inflammation in an experimental colitis model. METHODS: Colitis was induced in interleukin-10 knockout mice (PAC IL-10 k.o.) by peroral administration of piroxicam for 12 days. The degree of colitis was assessed by clinical, macroscopic, and microscopic evaluation. Trabecular and cortical bone...... microarchitecture of tibia were determined using micro-computed tomography. Moreover, the serum levels of bone formation and bone resorption biomarkers were measured, and inflammatory protein profiling was performed on colons. RESULTS: PAC IL-10 k.o. mice developed severe colitis, characterized by hyperplasia...

  15. Effects of interleukin-10 on neonatal excitotoxic brain lesions in mice.

    Science.gov (United States)

    Mesples, Bettina; Plaisant, Frank; Gressens, Pierre

    2003-03-14

    Interleukin-10 markedly reduces production of proinflammatory cytokines by activated microglia or macrophages and downregulates the expression of activating molecules on these cells. In studies performed in adults or in cell cultures, interleukin-10 protected against hypoxic-ischemic neuronal death and against lipopolysaccharide-mediated oligodendrocyte cell death. Furthermore, it was recently shown that interleukin-10 counteracts metabolic and microcirculatory effects of hypoxia-ischemia in the perinatal pig brain. Intracerebral injection of the glutamatergic analogue ibotenate to newborn mice induces cortical plate and white matter lesions mimicking the brain damage associated with cerebral palsy, and pretreatment with proinflammatory cytokines such as interleukin-1-beta or with interleukin-9 significantly exacerbates these lesions. The present study evaluated the influence of interleukin-10 on ibotenate-induced brain lesions in newborn mice under basal conditions or after exposure to cytokines. Intraperitoneal injection of interleukin-10 for 3 days following ibotenate significantly reduced the size of excitotoxic brain lesions. Intraperitoneal injection of neutralizing anti-interleukin-10 antibody for 3 days following ibotenate had no detectable effect and no difference in ibotenate-induced brain lesion size was found between wild type pups and pups deleted for the interleukin-10 gene, suggesting that endogenous interleukin-10 in newborn mice may have limited effects. Co-administration of intracerebral ibotenate and interleukin-10 had no detectable effect, arguing against a direct neuroprotective effect of interleukin-10 on neurons. While pretreatment with intraperitoneal interleukin-10 alone had no detectable effect on excitotoxic brain lesions, interleukin-10 given with interleukin-1-beta pretreatment blunted the toxic effects of interleukin-1-beta. On the other hand, combined pretreatment with IL-9 and anti-IL-10 antibody largely reversed the exacerbating

  16. Interactions among the components of the interleukin-10 receptor complex.

    Science.gov (United States)

    Krause, Christopher D; Mei, Erwen; Mirochnitchenko, Olga; Lavnikova, Natasha; Xie, Junxia; Jia, Yiwei; Hochstrasser, Robin M; Pestka, Sidney

    2006-02-10

    We used fluorescence resonance energy transfer previously to show that the interferon-gamma (IFN-gamma) receptor complex is a preformed entity mediated by constitutive interactions between the IFN-gammaR2 and IFN-gammaR1 chains, and that this preassembled entity changes its structure after the treatment of cells with IFN-gamma. We applied this technique to determine the structure of the interleukin-10 (IL-10) receptor complex and whether it undergoes a similar conformational change after treatment of cells with IL-10. We report that, like the IFN-gamma receptor complex, the IL-10 receptor complex is preassembled: constitutive but weaker interactions occur between the IL-10R1 and IL-10R2 chains, and between two IL-10R2 chains. The IL-10 receptor complex undergoes no major conformational changes when cells are treated with cellular or Epstein-Barr viral IL-10. Receptor complex preassembly may be an inherent feature of Class 2 cytokine receptor complexes.

  17. Interleukin-10 serum level in acute coronary syndrome patients

    Directory of Open Access Journals (Sweden)

    Idrus Alwi

    2009-09-01

    Full Text Available Aim To compare plasma IL-10 concentrations in patients with Acute Coronary Syndrome (ACS with those in Coronary Artery Disease (CAD.Methods ACS patients hospitalized in intensive coronary care unit (ICCU of Cipto Mangunkusumo Hospital/Faculty of Medicine University of Indonesia (CMH/FMUI, Persahabatan Hospital, MMC Hospital, and Medistra Hospital, Jakarta, between May 2005 and May 2006, were included in this study. The ambulatory CAD patients were taken as comparator. The serum IL-10 level was measured by immunoassay method, and compared by using Independent Student’s t-test. To investigate whether IL-10 serum level could predict ACS, the sensitivity and specificity of this parameter towards ACS in various IL-10 serum levels were calculated as well.Results In this observational study, as many as 146 subjects were analyzed, consisting of 84 ACS patients, and 62 coronary artery disease (CAD. The IL-10 level was higher in the group of ACS patients (7.37 pg/mL + 7.81, CI 95% 5.68-9.07 than that in CAD patients (1.59 pg/mL + 1.55, CI 95% 1.2-1.98. The optimal cut-off point for serum IL-10level is >1.95 pg/mL, with 79.76 % sensitivity and 77.42 % specificity.Conclusion The IL-10 level was higher in the ACS patients compared to that in CAD patients. Serum IL-10 measurement is a quite superior method to distinguish acute and stable condition, eventhough it is not as good as hsCRP for the same purpose. (Med J Indones 2009;18:165-9Key words: Interleukin-10, acute coronary syndrome

  18. Piroxicam treatment augments bone abnormalities in interleukin-10 knockout mice.

    Science.gov (United States)

    Holgersen, Kristine; Dobie, Ross; Farquharson, Colin; vanʼt Hof, Rob; Ahmed, Syed Faisal; Hansen, Axel Kornerup; Holm, Thomas L

    2015-02-01

    Osteoporosis and fractures are common complications of inflammatory bowel disease. The pathogenesis is multifactorial and has been partly attributed to intestinal inflammation. The aim of this study was to evaluate bone status and assess the association between bone loss and gut inflammation in an experimental colitis model. Colitis was induced in interleukin-10 knockout mice (PAC IL-10 k.o.) by peroral administration of piroxicam for 12 days. The degree of colitis was assessed by clinical, macroscopic, and microscopic evaluation. Trabecular and cortical bone microarchitecture of tibia were determined using micro-computed tomography. Moreover, the serum levels of bone formation and bone resorption biomarkers were measured, and inflammatory protein profiling was performed on colons. PAC IL-10 k.o. mice developed severe colitis, characterized by hyperplasia and focal transmural inflammation, which was consistent with Crohn's disease-like pathology. The gut inflammation was accompanied by a 14% and 12% reduction in trabecular thickness relative to piroxicam-treated wild type and untreated wild type mice, respectively (P < 0.001). The trabecular bone structure was also changed in PAC IL-10 k.o. mice, whereas no differences in cortical bone geometry were observed. The trabecular thickness was inversely correlated with serum levels of CTX (r = -0.93, P = 0.006). Moreover, numerous inflammatory mediators, including RANKL and osteoprotegerin, were significantly increased in the colon of PAC IL-10 k.o. mice. PAC IL-10 k.o. mice develop bone loss and changed trabecular structure, as a result of increased bone resorption. Thus, the PAC IL-10 k.o. model could be a useful experimental model in preclinical research of inflammatory bowel disease-associated bone loss.

  19. Interleukin-10 haplotypes in Celiac Disease in the Spanish population.

    Science.gov (United States)

    Núñez, Concepción; Alecsandru, Diana; Varadé, Jezabel; Polanco, Isabel; Maluenda, Carlos; Fernández-Arquero, Miguel; de la Concha, Emilio G; Urcelay, Elena; Martínez, Alfonso

    2006-03-31

    Celiac disease (CD) is a chronic disorder characterized by a pathological inflammatory response after exposure to gluten in genetically susceptible individuals. The HLA complex accounts for less than half of the genetic component of the disease, and additional genes must be implicated. Interleukin-10 (IL-10) is an important regulator of mucosal immunity, and several reports have described alterations of IL-10 levels in celiac patients. The IL-10 gene is located on chromosome 1, and its promoter carries several single nucleotide polymorphisms (SNPs) and microsatellites which have been associated to production levels. Our aim was to study the role of those polymorphisms in susceptibility to CD in our population. A case-control and a familial study were performed. Positions -1082, -819 and -592 of the IL-10 promoter were typed by TaqMan and allele specific PCR. IL10R and IL10G microsatellites were amplified with labelled primers, and they were subsequently run on an automatic sequencer. In this study 446 patients and 573 controls were included, all of them white Spaniards. Extended haplotypes encompassing microsatellites and SNPs were obtained in families and estimated in controls by the Expectation-Maximization algorithm. No significant associations after Bonferroni correction were observed in the SNPs or any of the microsatellites. Stratification by HLA-DQ2 (DQA1*0501-DQB1*02) status did not alter the results. When extended haplotypes were analyzed, no differences were apparent either. The IL-10 polymorphisms studied are not associated with celiac disease. Our data suggest that the IL-10 alteration seen in patients may be more consequence than cause of the disease.

  20. Interleukin-10 haplotypes in Celiac Disease in the Spanish population

    Directory of Open Access Journals (Sweden)

    Fernández-Arquero Miguel

    2006-03-01

    Full Text Available Abstract Background Celiac disease (CD is a chronic disorder characterized by a pathological inflammatory response after exposure to gluten in genetically susceptible individuals. The HLA complex accounts for less than half of the genetic component of the disease, and additional genes must be implicated. Interleukin-10 (IL-10 is an important regulator of mucosal immunity, and several reports have described alterations of IL-10 levels in celiac patients. The IL-10 gene is located on chromosome 1, and its promoter carries several single nucleotide polymorphisms (SNPs and microsatellites which have been associated to production levels. Our aim was to study the role of those polymorphisms in susceptibility to CD in our population. Methods A case-control and a familial study were performed. Positions -1082, -819 and -592 of the IL-10 promoter were typed by TaqMan and allele specific PCR. IL10R and IL10G microsatellites were amplified with labelled primers, and they were subsequently run on an automatic sequencer. In this study 446 patients and 573 controls were included, all of them white Spaniards. Extended haplotypes encompassing microsatellites and SNPs were obtained in families and estimated in controls by the Expectation-Maximization algorithm. Results No significant associations after Bonferroni correction were observed in the SNPs or any of the microsatellites. Stratification by HLA-DQ2 (DQA1*0501-DQB1*02 status did not alter the results. When extended haplotypes were analyzed, no differences were apparent either. Conclusion The IL-10 polymorphisms studied are not associated with celiac disease. Our data suggest that the IL-10 alteration seen in patients may be more consequence than cause of the disease.

  1. The role of cortisol and interleukin-10 gene expression patterns in ...

    African Journals Online (AJOL)

    ... of interleukin-10 genes were up-regulated at 4 hours post exercise and sustained till 24 hours post exercise (χ² = 50, P = 0.000). Post exercise stress activates the release of cortisol, and interleukin-10 genes to reinstate homeostasis through modulation of the immune response. Keywords: Homeostasis, immune response, ...

  2. Protective role of interleukin-10 in Ozone-induced pulmonary inflammation**

    Science.gov (United States)

    Background: The mechanisms underlying ozone (03)-induced pulmonary inflammation remain unclear. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators. Objectives: We investigated the molecular mechanisms underlying interleuken-10...

  3. Diminished agonist-stimulated inositol trisphosphate generation blocks stimulus-secretion coupling in mouse pancreatic acini during diet-induced experimental pancreatitis

    International Nuclear Information System (INIS)

    Powers, R.E.; Saluja, A.K.; Houlihan, M.J.; Steer, M.L.

    1986-01-01

    Young female mice fed a choline-deficient, ethionine-supplemented (CDE) diet rapidly develop acute hemorrhagic pancreatitis. We have observed that pancreatic acini prepared from these mice are unable to secrete amylase in response to addition of the cholinergic agonist carbachol, although they retain the ability to secrete amylase in response to the Ca2+ ionophore A23187. The CDE diet does not alter the binding characteristics (Kd or the maximal number of binding sites) for muscarinic cholinergic receptors as tested using the antagonist [ 3 H]N-methylscopolamine nor the competition for this binding by carbachol. Addition of carbachol to acini prepared from mice fed the CDE diet does not result in as marked an increase in cytosolic free Ca2+ levels as that noted in control samples (evaluated using quin2 fluorescence). These observations indicate that the CDE diet interferes with stimulus-secretion coupling in mouse pancreatic acini at a step subsequent to hormone-receptor binding and prior to Ca2+ release. This conclusion is confirmed by our finding that the hormone-stimulated generation of [ 3 H]inositol phosphates (inositol trisphosphate, inositol bisphosphate, and inositol monophosphate) from acini labeled with [ 3 H]myoinositol is markedly reduced in acini prepared from mice fed the CDE diet. This reduction is not due to a decrease in phosphatidylinositol-4,5-bisphosphate. This communication represents the first report of a system in which a blockade of inositol phosphate generation can be related to a physiologic defect and pathologic lesion

  4. Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus

    Directory of Open Access Journals (Sweden)

    Fox Simon W

    2007-01-01

    Full Text Available Abstract Background IL-10 has a potent inhibitory effect on osteoclastogenesis. In vitro and in vivo studies confirm the importance of this cytokine in bone metabolism, for instance IL-10-deficient mice develop the hallmarks of osteoporosis. Although it is known that IL-10 directly inhibits osteoclastogenesis at an early stage, preventing differentiation of osteoclast progenitors to preosteoclasts, the precise mechanism of its action is not yet clear. Several major pathways regulate osteoclastogenesis, with key signalling genes such as p38, TRAF6, NF-κB and NFATc1 well established as playing vital roles. We have looked at gene expression in eleven of these genes using real-time quantitative PCR on RNA extracted from RANKL-treated RAW264.7 monocytes. Results There was no downregulation by IL-10 of DAP12, FcγRIIB, c-jun, RANK, TRAF6, p38, NF-κB, Gab2, Pim-1, or c-Fos at the mRNA level. However, we found that IL-10 significantly reduces RANKL-induced NFATc1 expression. NFATc1 is transcribed from two alternative promoters in Mus musculus and, interestingly, only the variant transcribed from promoter P1 and beginning with exon 1 was downregulated by IL-10 (isoform 1. In addition, immunofluorescence studies showed that IL-10 reduces NFATc1 levels in RANKL-treated precursors and suppresses nuclear translocation. The inhibitory effect of IL-10 on tartrate-resistant acid phosphatase-positive cell number and NFATc1 mRNA expression was reversed by the protein kinase C agonist phorbol myristate acetate, providing evidence that interleukin-10 disrupts NFATc1 activity through its effect on Ca2+ mobilisation. Conclusion IL-10 acts directly on mononuclear precursors to inhibit NFATc1 expression and nuclear translocation, and we provide evidence that the mechanism may involve disruption of Ca2+ mobilisation. We detected downregulation only of the NFATc1 isoform 1 transcribed from promoter P1. This is the first report indicating that one of the ways in which

  5. Low plasma concentrations of interleukin 10 in severe malarial anaemia compared with cerebral and uncomplicated malaria

    DEFF Research Database (Denmark)

    Kurtzhals, J A; Adabayeri, V; Goka, B Q

    1998-01-01

    BACKGROUND: Severe anaemia is a major complication of malaria but little is known about its pathogenesis. Experimental models have implicated tumour necrosis factor (TNF) in induction of bone-marrow suppression and eythrophagocytosis. Conversely, interleukin 10 (IL-10), which mediates feed...

  6. Low plasma concentrations of interleukin 10 in severe malarial anaemia compared with cerebral and uncomplicated malaria

    DEFF Research Database (Denmark)

    Kurtzhals, J A; Adabayeri, V; Goka, B Q

    1998-01-01

    BACKGROUND: Severe anaemia is a major complication of malaria but little is known about its pathogenesis. Experimental models have implicated tumour necrosis factor (TNF) in induction of bone-marrow suppression and eythrophagocytosis. Conversely, interleukin 10 (IL-10), which mediates feed-back r...

  7. Anti-inflammatory effect of interleukin-10 in rabbit immune complex-induced colitis

    NARCIS (Netherlands)

    Grool, TA; Van Dullemen, H; Meenan, J; Koster, F; ten Kate, F. J. W.; Lebeaut, A; Tytgat, GNJ; Van Deventer, SJH

    Background: Interleukin-10 (IL-10) is an anti-inflammatory cytokine that downregulates the secretion of pro-inflammatory cytokines and additionally induces the secretion of anti-inflammatory cytokines, thus possibly leading to reduction of chronic inflammation in inflammatory bowel disease. In this

  8. The role of cortisol and interleukin-10 gene expression patterns in ...

    African Journals Online (AJOL)

    defense mechanism when dealing with stress as well as being important in blood glucose regulation (Hackney and Walz, 2013). Interleukin 10 is known to play a significant role in immune regulation involving both T helper 2 (Th2) and T helper 1 (Th1), thereby enhancing normal tissue homeostasis. (Stenberg et al., 2000).

  9. Association of interleukin-10 (A1082G) gene polymorphism with oral ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 95; Issue 2. Association of interleukin-10 (A 10 8 2 G) gene ... Analysis of IL10 A1082G genotype in 232 OSCC cases and 221 healthy controls of comparable age, gender, smokers, tobacco chewing and alcohol consumption. IL10 A1082G status in cases and controls were ...

  10. Interleukin-10 and Fas polymorphisms and susceptibility for (pre)neoplastic cervical disease

    NARCIS (Netherlands)

    Zoodsma, M; Nolte, IM; Schipper, M; Oosterom, E; Van der Steege, G; De Vries, EGE; Te Meerman, GJ; Van der Zee, AGJ

    2005-01-01

    Infection with oncogenic types of human papillomavirus (HPV) is the main causal factor of cervical cancer and its precursor lesion (cervical intraepithelial neoplasia [CIN]). Cellular immunity may be critical in the elimination of HPV-harboring cells. Interleukin-10, a T-helper type 2 cytokine, has

  11. Study of interleukin-10 promoter region polymorphisms (−1082A/G ...

    Indian Academy of Sciences (India)

    Smeraldi R. and Momigliano-Richardi P. 2000 Systemic lupus erythematosus candidate genes in the Italian population: evi- dence for a significant association with interleukin-10. Arthri- tis Rheum. 43, 120–128. Erratum in: 2000 Arthritis Rheum. 43,. 1442. Eisenbarth G. S. 2005 Type 1 diabetes mellitus. In Joslin's diabetes.

  12. Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's disease. Crohn's Disease Study Group

    NARCIS (Netherlands)

    van Deventer, S. J.; Elson, C. O.; Fedorak, R. N.

    1997-01-01

    Interleukin 10 (IL-10) is a cytokine with immunosuppressive and anti-inflammatory activities. Gene-targeted IL-10-deficient mice develop a chronic intestinal inflammatory disease that is reminiscent of Crohn's disease. The present double-blind randomized multicenter trial was designed to evaluate

  13. Cerebral Edema and Cerebral Hemorrhages in Interleukin-10-Deficient Mice Infected with Plasmodium chabaudi

    OpenAIRE

    Sanni, Latifu A.; Jarra, William; Li, Ching; Langhorne, Jean

    2004-01-01

    During a Plasmodium chabaudi infection in interleukin-10 (IL-10) knockout mice, there is greater parasite sequestration, more severe cerebral edema, and a high frequency of cerebral hemorrhage compared with infection of C57BL/6 mice. Anti-tumor necrosis factor alpha treatment ameliorated both cerebral edema and hemorrhages, suggesting that proinflammatory responses contributed to cerebral complications in infected IL-10−/− mice.

  14. Immunological Priming Requires Tregs and Interleukin-10-Producing Macrophages to Accelerate Resolution from Severe Lung Inflammation

    Science.gov (United States)

    Eto, Yoshiki; Tripathi, Ashutosh; Mandke, Pooja; Mock, Jason R.; Garibaldi, Brian T.; Singer, Benjamin D.; Sidhaye, Venkataramana K.; Horton, Maureen R.; King, Landon S.; D'Alessio, Franco R.

    2014-01-01

    Overwhelming lung inflammation frequently occurs following exposure to both direct infectious and non-infectious agents, and is a leading cause of mortality world-wide. In that context, immunomodulatory strategies may be utilized to limit severity of impending organ damage. We sought to determine whether priming the lung by activating the immune system, or immunological priming, could accelerate resolution of severe lung inflammation. We assessed the importance of alveolar macrophages, regulatory T cells, and their potential interaction during immunological priming. We demonstrate that oropharyngeal delivery of low-dose lipopolysaccharide can immunologically prime the lung to augment alveolar macrophage production of interleukin-10 and enhance resolution of lung inflammation induced by a lethal dose of lipopolysaccharide or by pseudomonas bacterial pneumonia. Interleukin-10 deficient mice did not achieve priming and were unable to accelerate lung injury resolution. Depletion of lung macrophages or regulatory T cells during the priming response completely abrogated the positive effect of immunological priming on resolution of lung inflammation and significantly reduced alveolar macrophage interleukin-10 production. Finally, we demonstrated that oropharyngeal delivery of synthetic CpG-oligonucleotides elicited minimal lung inflammation compared to low-dose lipopolysaccharide, but nonetheless primed the lung to accelerate resolution of lung injury following subsequent lethal lipopolysaccharide exposure. Immunological priming is a viable immunomodulatory strategy used to enhance resolution in an experimental acute lung injury model with the potential for therapeutic benefit against a wide array of injurious exposures. PMID:24688024

  15. Expression of Tumor Necrosis Factor Receptor 2 Characterizes TLR9-Driven Formation of Interleukin-10-Producing B Cells

    Directory of Open Access Journals (Sweden)

    Olga Ticha

    2018-01-01

    Full Text Available B cell-derived interleukin-10 (IL-10 production has been described as a hallmark for regulatory function in B lymphocytes. However, there is an ongoing debate on the origin of IL-10-secreting B cells and lack of specific surface markers has turned into an important obstacle for studying human B regulatory cells. In this study, we propose that tumor necrosis factor receptor 2 (TNFR2 expression can be used for enrichment of IL-10-secreting B cells. Our data confirm that IL-10 production can be induced by TLR9 stimulation with CpG ODN and that IL-10 secretion accompanies differentiation of peripheral blood B cells into plasma blasts. We further show that CpG ODN stimulation induces TNFR2 expression, which correlates with IL-10 secretion and terminal differentiation. Indeed, flow cytometric sorting of TNFR2+ B cells revealed that TNFR2+ and TNFR2− fractions correspond to IL-10+ and IL-10− fractions, respectively. Furthermore, CpG-induced TNFR2+ B cells were predominantly found in the IgM+ CD27+ B cell subset and spontaneously released immunoglobulin. Finally, our data corroborate the functional impact of TNFR2 by demonstrating that stimulation with a TNFR2 agonist significantly augments IL-10 and IL-6 production in B cells. Altogether, our data highlight a new role for TNFR2 in IL-10-secreting human B lymphocytes along with the potential to exploit this finding for sorting and isolation of this currently ill-defined B cell subset.

  16. Modulation of the Host Environment by Human Cytomegalovirus with Viral Interleukin 10 in Peripheral Blood

    Science.gov (United States)

    Young, Vivian P.; Mariano, Margarette C.; Tu, Carolyn C.; Allaire, Kathryn M.; Avdic, Selmir; Slobedman, Barry

    2017-01-01

    Abstract Background. Human cytomegalovirus (HCMV) is a herpesvirus with both lytic and latent life cycles. Human cytomegalovirus encodes 2 viral cytokines that are orthologs of human cellular interleukin 10 (cIL-10). Both cytomegalovirus interleukin 10 (cmvIL-10) and Latency-associated cytomegalovirus interleukin 10 (LAcmvIL-10) (collectively vIL-10) are expressed during lytic infection and cause immunosuppressive effects that impede virus clearance. LAcmvIL-10 is also expressed during latent infection of myeloid progenitor cells and monocytes and facilitates persistence. Here, we investigated whether vIL-10 could be detected during natural infection. Methods. Plasma from healthy blood donors was tested by enzyme-linked immunosorbent assay for anti-HCMV immunoglobulin G and immunoglobulin M and for cIL-10 and vIL-10 levels using a novel vIL-10 assay that detects cmvIL-10 and LAcmvIL-10, with no cross-reactivity to cIL-10. Results. vIL-10 was evident in HCMV+ donors (n = 19 of 26), at levels ranging 31–547 pg/mL. By comparison, cIL-10 was detected at lower levels ranging 3–69 pg/mL. There was a strong correlation between vIL-10 and cIL-10 levels (P = .01). Antibodies against vIL-10 were also detected and neutralized vIL-10 activity. Conclusions. vIL-10 was detected in peripheral blood of healthy blood donors. These findings suggest that vIL-10 may play a key role in sensing or modifying the host environment during latency and, therefore, may be a potential target for intervention strategies. PMID:28453840

  17. High Serum Interleukin-10 and Tumor Necrosis Factor Alpha Levels in Chronic Paracoccidioidomycosis

    Science.gov (United States)

    Fornari, M. C.; Bava, A. J.; Guereño, M. T.; Berardi, V. E.; Silaf, M. R.; Negroni, R.; Diez, R. A.

    2001-01-01

    In patients with chronic paracoccidioidomycosis (n = 10), levels of tumor necrosis factor alpha, interleukin-10, and interleukin-2 in serum, measured by enzyme-linked immunosorbent assay (in picograms per milliliter, as mean ± standard error of the mean), were higher than in normal controls (n = 8): 186 ± 40 versus 40 ± 7 (P < 0.05), 203 ± 95 versus 20 ± 8 (P = 0.001), and 96.3 ± 78.57 versus 1.19 ± 1.19 (P = 0.045), respectively. Gamma interferon and interleukin-4 levels were similar in patients and controls. PMID:11527826

  18. [Serum values of interleukin-10, gamma-interferon and vitamin A in female adolescents].

    Science.gov (United States)

    Leal, Jorymar Y; Romero, Tania; Ortega, Pablo; Amaya, Daisy

    2007-09-01

    Many studies have demonstrated that vitamin A deficiency (VAD) affects the immunomodulated response mediated by cytokines. However, these studies are controversial. The purpose of the present study was to analyze Interleukin-10, gamma-Interferon and vitamin A serum concentrations in adolescents. Seventy three female, not pregnant adolescents (15.95 +/- 1.10 years old), of a low socioeconomic condition were studied. Serum retinol was determined by HPLC using the Bieri method. International reference standards were considered to define VAD (serum retinol 30 microg/dL). Serum concentrations of Interleukine-10 (IL-10) and gamma-Interferon (gamma-IFN) were detected by an ELISA method (pg/mL). The data were analyzed using the SAS/STAT statistical program; the results were presented as mean +/- Standard deviation and the differences between mean values were analyzed by the ANOVA test. The prevalence of VAD in adolescents was 6.85% (serum retinol <20 microg/dL) and 41.10% adolescents had VAD risk (20-30 microg/dL). Adolescents with VAD showed a significant increase of gamma-IFN serum concentration (p = 0.01). Correlation between serum retinol and gamma-IFN was r = -0.29 (p = 0.01). Adolescents represent a VAD risk group. Low serum levels of retinol were correlated with high levels of gamma-IFN, this cytokine has been associated with chronics inflammatory processes and it can contribute to increase the morbidity and mortality in this population.

  19. Interleukin 10 overexpression alters survival in the setting of gram-negative pneumonia following lung contusion.

    Science.gov (United States)

    Dolgachev, Vladislav A; Yu, Bi; Sun, Lei; Shanley, Thomas P; Raghavendran, Krishnan; Hemmila, Mark R

    2014-04-01

    Lung contusion injury produces a vulnerable window within the inflammatory defenses of the lung that predisposes the patient to pneumonia. Interleukin 10 (IL-10) is a known anti-inflammatory mediator produced by macrophages and capable of downregulating acute lung inflammation. We investigated the impact of increased levels of IL-10 within the lung on survival and the host response to trauma in the setting of lung contusion (LC) and gram-negative pneumonia. A bitransgenic, tetracycline-inducible, lung-specific human IL-10 overexpression (IL-10 OE) mouse model and single transgenic (TG-) control mice were used. Mice underwent LC injury or sham injury (sham) at time -6 h. At time 0, animals were inoculated intratracheally with 500 colony-forming units of Klebsiella pneumoniae (pneu). Bronchoalveolar lavage fluid, lung tissue specimens, or purified macrophages were collected. Lung tissue and blood bacteria levels were quantified. Cytokine levels were assayed by enzyme-linked immunosorbent assay, and gene expression levels were evaluated by real-time polymerase chain reaction. Cell-type identification and quantification were done using real-time polymerase chain reaction and flow cytometry. Interleukin 10 OE mice demonstrated decreased 5-day survival compared with TG- mice following LC + pneu (0 vs. 30%, P pneu animals (P < 0.05). Lung-specific IL-10 overexpression induces alternative activation of alveolar macrophages. This shift in macrophage phenotype decreases intracellular bacterial killing, resulting in a more pronounced bacteremia and accelerated mortality in a model of LC and pneumonia.

  20. Interleukin-10 and tumour necrosis factor-alpha serum levels in chronic Chagas disease patients.

    Science.gov (United States)

    Vasconcelos, R H T; Azevedo, E de A N; Diniz, G T N; Cavalcanti, M da G A de M; de Oliveira, W; de Morais, C N L; Gomes, Y de M

    2015-07-01

    In Chagas disease, chronically infected individuals may be asymptomatic or may present cardiac or digestive complications, and it is well known that the human immune response is related to different clinical manifestations. Different patterns of cytokine levels have been previously described in different clinical forms of this disease, but contradictory results are reported. Our aim was to evaluate the serum levels of interleukin-10 and tumour necrosis factor-alpha in patients with asymptomatic and cardiac Chagas disease. The serum interleukin-10 levels in patients with cardiomyopathy were higher than those in asymptomatic patients, mainly in those without heart enlargement. Although no significant difference was observed in serum tumour necrosis factor-alpha levels among the patients, we found that cardiac patients also present high levels of this cytokine, largely those with heart dilatation. Therefore, these cytokines play an important role in chronic Chagas disease cardiomyopathy. Follow-up investigations of these and other cytokines in patients with chronic Chagas disease need to be conducted to improve the understanding of the immunopathology of this disease. © 2015 John Wiley & Sons Ltd.

  1. [Plasma levels of interleukin-10 and nitric oxide in response to two different desflurane anesthesia flow rates].

    Science.gov (United States)

    Kalayci, Dilek; Dikmen, Bayazit; Kaçmaz, Murat; Taşpınar, Vildan; Ornek, Dilşen; Turan, Ozlem

    2014-01-01

    This study investigated interleukin-10 and nitric oxide plasma levels following surgery to determine whether there is a correlation between these two variables and if different desflurane anesthesia flow rates influence nitric oxide and interleukin-10 concentrations in circulation. Forty patients between 18 and 70 years and ASA I-II physical status who were scheduled to undergo thyroidectomy were enrolled in the study. Patients were allocated into two groups to receive two different desflurane anesthesia flow rates: high flow (Group HF) and low flow (Group LF). Blood samples were drawn at the beginning (t0) and end (t1) of the operation and after 24h (t2). Plasma interleukin-10 and nitric oxide levels were measured using an enzyme-linked-immunosorbent assay and a Griess reagents kit, respectively. Hemodynamic and respiratory parameters were assessed. There was no statistically significant difference between the two groups with regard to interleukin-10 levels at the times of measurement. Interleukin-10 levels were increased equally in both groups at times t1 and t2 compared with preoperative concentrations. For both groups, nitric oxide circulating concentrations were significantly reduced at times t1 and t2 compared with preoperative concentrations. However, the nitric oxide value was lower for Group HF compared to Group LF at t2. No correlation was found between the IL-10 and nitric oxide levels. Clinical usage of two different flow anesthesia forms with desflurane may increase interleukin-10 levels both in Group HF and Group LF; nitric oxide levels circulating concentrations were significantly reduced at times t1 and t2 compared with preoperative concentrations; however, at 24h postoperatively they were higher in Group LF compared to Group HF. No correlation was detected between interleukin-10 and nitric oxide levels. Copyright © 2013 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  2. Plasma levels of interleukin-10 and nitric oxide in response to two different desflurane anesthesia flow rates.

    Science.gov (United States)

    Kalaycı, Dilek; Dikmen, Bayazit; Kaçmaz, Murat; Taşpınar, Vildan; Ornek, Dilşen; Turan, Ozlem

    2014-01-01

    This study investigated interleukin-10 and nitric oxide plasma levels following surgery to determine whether there is a correlation between these two variables and if different desflurane anesthesia flow rates influence nitric oxide and interleukin-10 concentrations in circulation. Forty patients between 18 and 70 years and ASA I-II physical status who were scheduled to undergo thyroidectomy were enrolled in the study. Patients were allocated into two groups to receive two different desflurane anesthesia flow rates: high flow (Group HF) and low flow (Group LF). Blood samples were drawn at the beginning (t0) and end (t1) of the operation and after 24h (t2). Plasma interleukin-10 and nitric oxide levels were measured using an enzyme-linked-immunosorbent assay and a Griess reagents kit, respectively. Hemodynamic and respiratory parameters were assessed. There was no statistically significant difference between the two groups with regard to interleukin-10 levels at the times of measurement. Interleukin-10 levels were increased equally in both groups at times t1 and t2 compared with preoperative concentrations. For both groups, nitric oxide circulating concentrations were significantly reduced at times t1 and t2 compared with preoperative concentrations. However, the nitric oxide value was lower for Group HF compared to Group LF at t2. No correlation was found between the IL-10 and nitric oxide levels. Clinical usage of two different flow anesthesia forms with desflurane may increase interleukin-10 levels both in Group HF and Group LF; nitric oxide levels circulating concentrations were significantly reduced at times t1 and t2 compared with preoperative concentrations; however, at 24h postoperatively they were higher in Group LF compared to Group HF. No correlation was detected between interleukin-10 and nitric oxide levels. Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

  3. Plasma levels of interleukin-10 and nitric oxide in response to two different desflurane anesthesia flow rates

    Directory of Open Access Journals (Sweden)

    Dilek Kalayci

    2014-07-01

    Full Text Available OBJECTIVE: This study investigated interleukin-10 and nitric oxide plasma levels following surgery to determine whether there is a correlation between these two variables and if different desflurane anesthesia flow rates influence nitric oxide and interleukin-10 concentrations in circulation. MATERIALS AND METHODS: Forty patients between 18 and 70 years and ASA I-II physical status who were scheduled to undergo thyroidectomy were enrolled in the study. INTERVENTIONS: Patients were allocated into two groups to receive two different desflurane anesthesia flow rates: high flow (Group HF and low flow (Group LF. MEASUREMENTS: Blood samples were drawn at the beginning (t 0 and end (t 1 of the operation and after 24 h (t 2. Plasma interleukin-10 and nitric oxide levels were measured using an enzyme-linked-immunosorbent assay and a Griess reagents kit, respectively. Hemodynamic and respiratory parameters were assessed. RESULTS: There was no statistically significant difference between the two groups with regard to interleukin-10 levels at the times of measurement. Interleukin-10 levels were increased equally in both groups at times t 1 and t 2 compared with preoperative concentrations. For both groups, nitric oxide circulating concentrations were significantly reduced at times t 1 and t 2 compared with preoperative concentrations. However, the nitric oxide value was lower for Group HF compared to Group LF at t 2. No correlation was found between the IL-10 and nitric oxide levels. CONCLUSION: Clinical usage of two different flow anesthesia forms with desflurane may increase interleukin-10 levels both in Group HF and Group LF; nitric oxide levels circulating concentrations were significantly reduced at times t 1 and t 2 compared with preoperative concentrations; however, at 24 h postoperatively they were higher in Group LF compared to Group HF. No correlation was detected between interleukin-10 and nitric oxide levels.

  4. Role of interleukin-10 in prognosis of hepatitis B virus infection

    Directory of Open Access Journals (Sweden)

    WU Changhui

    2015-04-01

    Full Text Available Multiple etiological factors are integrally involved in the development of hepatitis B virus (HBV infection. Interleukin-10 (IL-10 is an essential cytokine of immune regulation, and IL-10 gene promoter polymorphism affects its mRNA transcription and serum level. IL-10 is related to the prognosis of HBV infection. This review briefly discusses the association of IL-10 gene polymorphism and its serum level with the prognosis of HBV infection, and summarizes the role of IL-10, as an anti-inflammatory cytokine, in host immune function, the prognosis and progression of HBV infection, and HBV-related complications. IL-10 gene polymorphism and its serum level are closely associated with inflammatory response after HBV infection, influence HBV clearance, and are related to the severity of HBV-related liver injury, liver cirrhosis, and hepatocellular carcinoma. The determination of IL-10 gene and serum levels may provide a predictive marker for the prognosis of HBV infection.

  5. Association of Interleukin-10 Gene Promoter Polymorphisms in Saudi Patients with Vitiligo

    Directory of Open Access Journals (Sweden)

    Abdullah Abanmi

    2008-01-01

    Full Text Available The promoter region of human Interleukin −10 gene is highly polymorphic and has been associated with numerous autoimmune diseases. Recent studies have linked vitiligo with defective autoimmune system. This study is aimed to explore a possible association between IL-10 gene polymorphism and vitiligo in Saudi population. This case control study consisted of 184 Saudi subjects including 83 vitiligo patients (40 males, 43 females mean age 27.85 ± 12.43 years and 101 matched controls. Genomic DNA was extracted from the blood samples of healthy controls and Vitiligo patients visiting out patient clinic of Department of Dermatology, Riyadh Armed Forces Hospital, using QIA ampR DNA mini kit (Qiagen CA, USA. Interleukin-10 gene was amplified by polymerase chain reaction (PCR using Arms primers to detect any polymorphism involved at positions −592, −819 and −1082.

  6. Interleukin 10 is an essential modulator of mucoid metaplasia in a mouse otitis media model

    Science.gov (United States)

    Tsuchiya, Katsuyuki; Komori, Masahiro; Zheng, Qing Yin; Ferrieri, Patricia; Lin, Jizhen

    2009-01-01

    Inflammatory cytokines are involved in the development of mucus cell metaplasia/hyperplasia (MCM) in otitis media (OM). However, which cytokines play an essential role in MCM OM is not clear at the moment. In this study, we hypothesized that interleukin-10 (IL-10) played an indispensable role in MCM of bacterial OM and used IL-10 knockout mice to test this hypothesis. In wild-type mice, both S. pneumoniae and H. influenzae triggered the development of MCM in the middle ear mucosa. In IL-10 knockout mice, the number of goblet cells and mucin-producing cells in the middle ear was significantly reduced after bacterial middle ear infection compared with that in wild-type mice. We, therefore, concluded that IL-10 plays an essential role in MCM of bacterial OM. IL-10 is a potential target for the treatment of MCM in OM. PMID:18771082

  7. Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance.

    Science.gov (United States)

    Dagdeviren, Sezin; Jung, Dae Young; Lee, Eunjung; Friedline, Randall H; Noh, Hye Lim; Kim, Jong Hun; Patel, Payal R; Tsitsilianos, Nicholas; Tsitsilianos, Andrew V; Tran, Duy A; Tsougranis, George H; Kearns, Caitlyn C; Uong, Cecilia P; Kwon, Jung Yeon; Muller, Werner; Lee, Ki Won; Kim, Jason K

    2016-12-01

    Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (M IL10 ). After 16 weeks of a high-fat diet (HFD), M IL10 mice became markedly obese but showed improved insulin action compared to that of wild-type mice, which was largely due to increased glucose metabolism and reduced inflammation in skeletal muscle. Since leptin regulates inflammation, the beneficial effects of interleukin-10 (IL-10) were further examined in leptin-deficient ob/ob mice. Muscle-specific overexpression of IL-10 in ob/ob mice (MCK-IL10 ob/ob ) did not affect spontaneous obesity, but MCK-IL10 ob/ob mice showed increased glucose turnover compared to that in ob/ob mice. Last, mice with muscle-specific ablation of IL-10 receptor (M-IL10R -/- ) were generated to determine whether IL-10 signaling in skeletal muscle is involved in IL-10 effects on glucose metabolism. After an HFD, M-IL10R -/- mice developed insulin resistance with reduced glucose metabolism compared to that in wild-type mice. Overall, these results demonstrate IL-10 effects to attenuate obesity-mediated inflammation and improve insulin sensitivity in skeletal muscle, and our findings implicate a potential therapeutic role of anti-inflammatory cytokines in treating insulin resistance and type 2 diabetes. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  8. Significant elevation of a Th2 cytokine, interleukin-10, in pelvic inflammatory disease.

    Science.gov (United States)

    Chen, Kuo-Shuen; Wang, Po-Hui; Yang, Shun-Fa; Lin, Ding-Bang; Lin, Yi-Jiun; Kuo, Dong-Yih; Lin, Long-Yau; Wu, Ming-Tsang; Lin, Chiao-Wen; Lee, Sheuan; Chou, Ming-Chih; Tsai, Hsiu-Ting; Hsieh, Yih-Shou

    2008-01-01

    We investigated the expressions and ratios of type 1 T helper cell (Th1) cytokines interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), as well as type 2 T helper cell (Th2) cytokines interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13) and interleukin-10 (IL-10) in pelvic inflammatory disease (PID) patients. The human cytokine LINCOplex multiplex bead array was used to measure the plasma levels of Th1 and Th2 cytokines in 50 healthy controls, as well as in 41 PID patients before and after routine protocol treatment. Significantly increased expressions of Th1 cytokine IFN-gamma (p=0.004), as well as Th2 cytokine IL-5 (p=0.001), and dramatically increased IL-10 (p=0.0001), but significantly decreased expression of Th1 cytokine IL-2 (p=0.029) in PID patients were found after comparison to the control group. The ratio of IFN-gamma to IL-13 showed a significant increase, but the ratios of IFN-gamma to IL-10 and IL-2 to IL-10 was significantly decreased in PID patients before treatment compared to after treatment and controls. The results indicate that the imbalance and cross-regulation between Th1 and Th2 cytokines pathways is probably contributed to the mechanism of PID.

  9. Genetically Modified Lactococcus lactis for Delivery of Human Interleukin-10 to Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Inge L. Huibregtse

    2012-01-01

    Full Text Available Interleukin-10 (IL-10 plays an indispensable role in mucosal tolerance by programming dendritic cells (DCs to induce suppressor Th-cells. We have tested the modulating effect of L. lactis secreting human IL-10 (L.  lactisIL-10 on DC function in vitro. Monocyte-derived DC incubated with L.  lactisIL-10 induced effector Th-cells that markedly suppressed the proliferation of allogenic Th-cells as compared to L. lactis. This suppressive effect was only seen when DC showed increased CD83 and CD86 expression. Furthermore, enhanced production of IL-10 was measured in both L.  lactisIL-10-derived DC and Th-cells compared to L. lactis-derived DC and Th-cells. Neutralizing IL-10 during DC-Th-cell interaction and coculturing L.  lactisIL-10-derived suppressor Th-cells with allogenic Th-cells in a transwell system prevented the induction of suppressor Th-cells. Only 130 pg/mL of bacterial-derived IL-10 and 40 times more exogenously added recombinant human IL-10 were needed during DC priming for the generation of suppressor Th-cells. The spatially restricted delivery of IL-10 by food-grade bacteria is a promising strategy to induce suppressor Th-cells in vivo and to treat inflammatory diseases.

  10. Interleukin-10 Inhibits Bone Resorption: A Potential Therapeutic Strategy in Periodontitis and Other Bone Loss Diseases

    Directory of Open Access Journals (Sweden)

    Qian Zhang

    2014-01-01

    Full Text Available Periodontitis and other bone loss diseases, decreasing bone volume and strength, have a significant impact on millions of people with the risk of tooth loss and bone fracture. The integrity and strength of bone are maintained through the balance between bone resorption and bone formation by osteoclasts and osteoblasts, respectively, so the loss of bone results from the disruption of such balance due to increased resorption or/and decreased formation of bone. The goal of therapies for diseases of bone loss is to reduce bone loss, improve bone formation, and then keep healthy bone density. Current therapies have mostly relied on long-term medication, exercise, anti-inflammatory therapies, and changing of the life style. However there are some limitations for some patients in the effective treatments for bone loss diseases because of the complexity of bone loss. Interleukin-10 (IL-10 is a potent anti-inflammatory cytokine, and recent studies have indicated that IL-10 can contribute to the maintenance of bone mass through inhibition of osteoclastic bone resorption and regulation of osteoblastic bone formation. This paper will provide a brief overview of the role of IL-10 in bone loss diseases and discuss the possibility of IL-10 adoption in therapy of bone loss diseases therapy.

  11. Interleukin-10 overexpression promotes Fas-ligand-dependent chronic macrophage-mediated demyelinating polyneuropathy.

    Directory of Open Access Journals (Sweden)

    Dru S Dace

    Full Text Available BACKGROUND: Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome or chronic forms. Interleukin-10 (IL-10, although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis. PRINCIPAL FINDINGS: Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammation-induced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL-mediated Schwann cell death. SIGNIFICANCE: These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP or Guillain-Barré syndrome.

  12. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis B to interferon alfa

    Directory of Open Access Journals (Sweden)

    Ma Weimin

    2011-01-01

    Full Text Available Abstract In order to examine whether variation in interleukin-10 promoter polymorphism would predict the likelihood of sustain response of chronic hepatitis B to treatment with interferon alfa (IFN-α, the inheritance of 3 biallelic polymorphisms in the IL-10 gene promoter in patients with 52 chronic hepatitis B were determined by polymerase chain reaction (PCR-bared techniques, restriction enzyme digestion or direct sequencing. The relationship to the outcome of antiviral therapy for chronic HBV infection was studied in 24 patients who had a virologically sustained response(SR and in 28 non-responder(NR to interferon alfa-2b and several IL-10 variants were more frequent among SR compared with NR. Carriage of the -592A allele, -592A/A genotype and -1082/-1819/-592 ATA haplotype was associated with SR. Our findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining the initial response of chronic hepatitis B to IFN-α therapy.

  13. Selective growth of silica nanowires using an Au catalyst for optical recognition of interleukin-10

    Energy Technology Data Exchange (ETDEWEB)

    Sekhar, Praveen K; Ramgir, Niranjan S; Joshi, Rakesh K; Bhansali, Shekhar [Bio-MEMS and Microfabrication Laboratory, Department of Electrical Engineering, University of South Florida, 4202 E Fowler Avenue, ENB 118, Tampa, FL 33620 (United States)], E-mail: bhansali@eng.usf.edu

    2008-06-18

    The vapor-liquid-solid (VLS) growth procedure has been extended for the selective growth of silica nanowires on SiO{sub 2} layer by using Au as a catalyst. The nanowires were grown in an open tube furnace at 1100 deg. C for 60 min using Ar as a carrier gas. The average diameter of these bottom-up nucleated wires was found to be 200 nm. Transmission electron microscopy analysis indicates the amorphous nature of these nanoscale wires and suggests an Si-silica heterostructure. The localized silica nanowires have been used as an immunoassay template in the detection of interleukin-10 which is a lung cancer biomarker. Such a nanostructured platform offered a tenfold enhancement in the optical response, aiding the recognition of IL-10 in comparison to a bare silica substrate. The role of nanowires in the immunoassay was verified through the quenching behavior in the photoluminescence (PL) spectra. Two orders of reduction in PL intensity have been observed after completion of the immunoassay with significant quenching after executing every step of the protocol. The potential of this site-specific growth of silica nanowires on SiO{sub 2} as a multi-modal biosensing platform has been discussed.

  14. Interleukin-10 inhibits lipopolysaccharide induced miR-155 precursor stability and maturation.

    Directory of Open Access Journals (Sweden)

    Sylvia T Cheung

    Full Text Available The anti-inflammatory cytokine interleukin-10 (IL-10 is essential for attenuating the inflammatory response, which includes reducing the expression of pro-inflammatory microRNA-155 (miR-155 in lipopolysaccharide (LPS activated macrophages. miR-155 enhances the expression of pro-inflammatory cytokines such as TNFα and suppresses expression of anti-inflammatory molecules such as SOCS1. Therefore, we examined the mechanism by which IL-10 inhibits miR-155. We found that IL-10 treatment did not affect the transcription of the miR-155 host gene nor the nuclear export of pre-miR-155, but rather destabilized both pri-miR-155 and pre-miR-155 transcripts, as well as interfered with the final maturation of miR-155. This inhibitory effect of IL-10 on miR-155 expression involved the contribution of both the STAT3 transcription factor and the phosphoinositol phosphatase SHIP1. This is the first report showing evidence that IL-10 regulates miRNA expression post-transcriptionally.

  15. Structural and Functional Characterization of Recombinant Interleukin-10 from Indian Major Carp Labeo rohita

    Directory of Open Access Journals (Sweden)

    Sweta Karan

    2016-01-01

    Full Text Available Interleukin-10, an important regulator of both the innate and adaptive immune systems, is a multifunctional major cytokine. Though it is one of the major cytokines, IL-10 from the Indian major carp, Labeo rohita, has not yet been characterized. In the present study, we report large scale production and purification of biologically active recombinant IL-10 of L. rohita (rLrIL-10 using a heterologous expression system and its biophysical and functional characterization. High yield (~70 mg/L of soluble rLrIL-10 was obtained at shake flask level. The rLrIL-10 was found to exist as a dimer. Far-UV CD spectroscopy showed presence of predominantly alpha helices. The tertiary structure of the purified rLrIL-10 was verified by fluorescence spectroscopy. Two-dimensional gel analysis revealed the presence of six isoforms of the rLrIL-10. The rLrIL-10 was biologically active and its administration significantly reduced serum proinflammatory cytokines, namely, interleukin 1β, TNFα, and IL-8, and augmented the NKEF transcript levels in spleen of L. rohita. Anti-inflammatory role of the rLrIL-10 was further established by inhibition of phagocytosis using NBT reduction assay in vitro. The data indicate that the dimeric alpha helical structure and function of IL-10 of L. rohita as a key regulator of anti-inflammatory response have remained conserved during evolution.

  16. Interleukin-10 inhibits bone resorption: a potential therapeutic strategy in periodontitis and other bone loss diseases.

    Science.gov (United States)

    Zhang, Qian; Chen, Bin; Yan, Fuhua; Guo, Jianbin; Zhu, Xiaofeng; Ma, Shouzhi; Yang, Wenrong

    2014-01-01

    Periodontitis and other bone loss diseases, decreasing bone volume and strength, have a significant impact on millions of people with the risk of tooth loss and bone fracture. The integrity and strength of bone are maintained through the balance between bone resorption and bone formation by osteoclasts and osteoblasts, respectively, so the loss of bone results from the disruption of such balance due to increased resorption or/and decreased formation of bone. The goal of therapies for diseases of bone loss is to reduce bone loss, improve bone formation, and then keep healthy bone density. Current therapies have mostly relied on long-term medication, exercise, anti-inflammatory therapies, and changing of the life style. However there are some limitations for some patients in the effective treatments for bone loss diseases because of the complexity of bone loss. Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine, and recent studies have indicated that IL-10 can contribute to the maintenance of bone mass through inhibition of osteoclastic bone resorption and regulation of osteoblastic bone formation. This paper will provide a brief overview of the role of IL-10 in bone loss diseases and discuss the possibility of IL-10 adoption in therapy of bone loss diseases therapy.

  17. Significant Association of Interleukin-10 Polymorphisms with Childhood Leukemia Susceptibility in Taiwan.

    Science.gov (United States)

    Lo, Wen-Jyi; Chang, Wen-Shin; Hsu, Han-Fang; Ji, Hong-Xue; Hsiao, Chieh-Lun; Tsai, Chia-Wen; Yeh, Su-Peng; Chen, Chuan-Mu; Bau, DA-Tian

    2016-01-01

    Mounting evidence supports the notion that inflammatory processes play a role in carcinogenesis, and interleukin-10 (IL10) is an important inflammatory cytokine. This study aimed to evaluate the contribution of IL10 A-1082G (rs1800896), T-819C (rs3021097) and A-592C (rs1800872) genotypes to the risk of childhood acute lymphoblastic leukemia (ALL) in Taiwan. Associations of these IL10 polymorphic genotypes with ALL risk were analyzed in 266 patients with childhood ALL patients and 266 non-cancer healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. The results showed that CC genotype carriers at IL10 T-819C were at lower risk for childhood ALL (odds ratio=0.33, 95% confidence interval=0.16-0.68). On the contrary, AC and CC genotype carriers at IL10 A-592C were at higher risk for childhood ALL (odds ratio=1.73 and 6.34, 95% confidence interval=1.19-2.51 and 3.16-12.72, respectively). There was no difference in the distribution of A-1082G genotypes between childhood ALL and control groups. The genotypes at IL10 T-819C and A-592C may serve as predictive biomarkers for childhood ALL in Taiwan. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  18. Association of interleukin 10 and transforming growth factor β gene polymorphisms with chronic idiopathic urticaria.

    Science.gov (United States)

    Tavakol, Marzieh; Movahedi, Masoud; Amirzargar, Ali Akbar; Aryan, Zahra; Bidoki, Alireza Zare; Heidari, Kimia; Soltani, Samaneh; Gharagozlou, Mohammad; Aghamohammadi, Asghar; Nabavi, Mohammad; Nasiri, Rasoul; Ahmadvand, Alireza; Rezaei, Nima

    2014-01-01

    Transforming growth factor β (TGF-β) and interleukin 10 (IL-10) are two anti-inflammatory cytokines that are implicated in the pathogenesis of urticaria. The goal of this study was to examine the possible association of polymorphisms of TGF-β and IL-10 genes with susceptibility to chronic idiopathic urticaria (CIU). This study was conducted on 90 patients with CIU. Polymerase chain reaction (PCR) was done to determine the genotype at 5 polymorphic sites; TGF-β (codon10C/T and codon25G/C) and IL-10 (-1082G/A, -819C/T, and -592C/A). The C allele at codon 25 of TGF-β was more prevalent in CIU patients compared to controls (OR = 9.5, 95% CI = 5.4-16.8, P<0.001). Genotypes of CT and CG at 10 and 25 codons of TGF-β gene, respectively, and AG, CT, and CA for loci of -1082, -819, and -592 of IL-10 gene were significantly higher in CIU patients (P<0.001). In haplotype analysis, frequency of TGF-β haplotypes differed between patients with CIU and controls; CC haplotype was overrepresented, while CG and TG haplotypes were underrepresented (P<0.001). These results suggest that TGF-β and IL-10 genetic variability could contribute to susceptibility to CIU. Additionally, patients with CIU seem to have genotypes leading to high production of TGF-β and IL-10.

  19. Anti-inflammatory cytokines in asthma and allergy: interleukin-10, interleukin-12, interferon-γ

    Directory of Open Access Journals (Sweden)

    Fan Chung

    2001-01-01

    Full Text Available Interleukin-10 (IL-10 is a cytokine derived from CD4+ T-helper type 2 (TH2 cells identified as a suppressor of cytokines from T-helper type 1(TH1 cells. Interleukin-12 (IL-12 is produced by B cells, macrophages and dendritic cells, and primarily regulates TH1 cell differentiation, while suppressing the expansion of TH2 cell clones. Interferon-γ (IFN-γ is a product of TH1 cells and exerts inhibitory effects on TH2 cell differentiation. These cytokines have been implicated in the pathogenesis of asthma and allergies. In this context, IL-12 and IFN-γ production in asthma have been found to be decreased, and this may reduce their capacity to inhibit IgE synthesis and allergic inflammation. IL-10 is a potent inhibitor of monocyte/macrophage function, suppressing the production of many pro-inflammatory cytokines. A relative underproduction of IL-10 from alveolar macrophages of atopic asthmatics has been reported. Therapeutic modulation of TH1/TH2 imbalance in asthma and allergy by mycobacterial vaccine, specific immunotherapy and cytoline-guanosine dinucleotide motif may lead to increases in IL-12 and IFN-γ production. Stimulation of IL-10 production by antigen-specific T-cells during immunotherapy may lead to anergy through inhibition of CD28-costimulatory molecule signalling by IL-10s anti-inflammatory effect on basophils, mast cells and eosinophils.

  20. Double blind, placebo controlled trial of two probiotic strains in interleukin 10 knockout mice and mechanistic link with cytokine balance

    NARCIS (Netherlands)

    McCarthy, J.; O'Mahony, L.; O'Callaghan, L.; Sheil, B.; Vaughan, E.E.; Fitzsimons, N.A.; Fitzgibbon, J.; O'Sullivan, G.C.; Kiely, B.; Collins, J.K.; Shanahan, F.

    2003-01-01

    Background: Prophylactic efficacy against colitis following lactobacillus consumption in interleukin 10 (IL-10) knockout ( KO) mice has been reported. Whether this applies equally to other probiotic strains is unknown, and the mechanism is unclear. Aims: ( 1) To compare the effect of feeding

  1. Interferon-gamma and interleukin-10 profile of children with tuberculosis in North Sumatera, Indonesia

    Science.gov (United States)

    Daulay, R. S.; Daulay, R. M.

    2018-03-01

    Cellular immunity was mediated the host immune response against Mycobacterium tuberculosis, in which cytokine and T-helper (Th) 1 cells play an important role. Interferon-gamma (IFN-γ) is a leading cytokine involved in the immune response of tuberculosis (TB).The primary function of IFN-γ is to activate macrophages in opposition Mycobacterium tuberculosis. Contrast from IFN-γ, interleukin-10 (IL-10) is considered inhibitory cytokine, important to an adequate balance between inflammatory responses. To analyze cytokine profile, particularly IFN-γ and IL-10 of the children with TB in Indonesia, a cross-sectional study was conducted at two general hospitals and seven primary health care located in Medan and Batubara, North Sumatera, Indonesia. Among 51 children with TB disease and 51 healthy children, found that IFN-γ and IL-10 levels were lower in TB patients compared to healthy children. Statistically significant decreased production of the IFN-γ levels (p=0.042) were found in TB patients 9.41 (1.10-28.06) pg/ml contrast to healthy children 6.30 (1.30-89.76) pg/ml. Homologue finding of the IL-10 levels were also found in TB patients 4.93 (0.22-48.01) pg/ml and 4.93 (0.07-81.60) pg/ml in healthy children, but not statistically significant (p=0.784). High levels of IL-10 were not proven to suppress the levels production of IFN-γ in TB patients.

  2. Interleukin-10 as a Marker of Disease Progression in Dengue Hemorrhagic Fever.

    Science.gov (United States)

    Tauseef, Ambreen; Umar, Naima; Sabir, Sana; Akmal, Ayesha; Sajjad, Saadia; Zulfiqar, Sibgha

    2016-03-01

    To evaluate the plasma interleukin-10 (IL-10) levels in patients suffering from dengue hemorrhagic fever between 4 to 7 days of onset of disease and 24 hours after the first sample, to find out the association of plasma IL-10 levels with the outcome. Analytical study. All major hospitals of Lahore, Pakistan, from August to November 2012. Participants included 50 registered patients of dengue hemorrhagic fever (DHF) aged between 15 - 50 years. Plasma IL-10 concentrations were measured on above stated day. Outcome was described as recovery and shock. Platelet count and hematocrit percentages were also recorded. Statistical analyses were done using SPSS version 19. Ap-value ≤0.05 was considered significant. Plasma IL-10 levels were found to be raised in DHF patients and were associated with fatal outcome (p=0.004). In recovered DHF patients, plasma IL-10 levels decreased after 24 hours (mean 26.54 ± 16.03 pg/ml) as compared to admission time (mean 74.39 ± 61.69 pg/ml) but in case of DHF patients suffering from shock, plasma IL-10 was found to be higher after 24 hours (mean 87.69 ± 7.77 pg/ml) as compared to levels at admission time (mean 42.56 ± 28.09 pg/ml). ROC curve analysis revealed a change (30 units pg/ml) of plasma IL-10 concentration, within 24 hours of admission, raised from the base line to be 105 times more critical for shock in DHF patients (100% sensitivity and 71.4% specificity, p < 0.001). Elevated plasma IL-10 is a potential predictor of disease severity and fatal outcome in DHF patients.

  3. Relationship Between HIV Coinfection, Interleukin 10 Production, and Mycobacterium tuberculosis in Human Lymph Node Granulomas.

    Science.gov (United States)

    Diedrich, Collin R; O'Hern, Jennifer; Gutierrez, Maximiliano G; Allie, Nafiesa; Papier, Patricia; Meintjes, Graeme; Coussens, Anna K; Wainwright, Helen; Wilkinson, Robert J

    2016-11-01

     Human immunodeficiency virus type 1 (HIV)-infected persons are more susceptible to tuberculosis than HIV-uninfected persons. Low peripheral CD4 + T-cell count is not the sole cause of higher susceptibility, because HIV-infected persons with a high peripheral CD4 + T-cell count and those prescribed successful antiretroviral therapy (ART) remain more prone to active tuberculosis than HIV-uninfected persons. We hypothesized that the increase in susceptibility is caused by the ability of HIV to manipulate Mycobacterium tuberculosis-associated granulomas.  We examined 71 excised cervical lymph nodes (LNs) from persons with HIV and M. tuberculosis coinfection, those with HIV monoinfection, and those with M. tuberculosis monoinfection with a spectrum of peripheral CD4 + T-cell counts and ART statuses. We quantified differences in M. tuberculosis levels, HIV p24 levels, cellular response, and cytokine presence within granulomas.  HIV increased M. tuberculosis numbers and reduced CD4 + T-cell counts within granulomas. Peripheral CD4 + T-cell depletion correlated with granulomas that contained fewer CD4 + and CD8 + T cells, less interferon γ, more neutrophils, more interleukin 10 (IL-10), and increased M. tuberculosis numbers. M. tuberculosis numbers correlated positively with IL-10 and interferon α levels and fewer CD4 + and CD8 + T cells. ART reduced IL-10 production.  Peripheral CD4 + T-cell depletion correlated with increased M. tuberculosis presence, increased IL-10 production, and other phenotypic changes within granulomas, demonstrating the HIV infection progressively changes these granulomas. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

  4. Meta-Analysis of Associations Between Interleukin-10 Polymorphisms and Susceptibility to Vasculitis.

    Science.gov (United States)

    Jung, Jae Hyun; Song, Gwan Gyu; Lee, Young Ho

    2015-01-01

    This study determined whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to vasculitis. A meta-analysis was conducted of the associations between the IL-10 -1082 G/A, -819 C/T, and -592 C/A polymorphisms and the haplotype of the IL-10-1082 G/A, -819 C/T, -592 C/A polymorphisms and vasculitis. A total of 21 comparative studies involving 4121 patients and 5504 controls were considered in the meta-analysis. Meta-analysis revealed no association between the IL-10-1082 G allele and vasculitis in all study subjects (OR = 0.927, 95% CI = 0.780-1.102, p = 0.389). However, disease-specific meta-analysis showed an association between Wegener's granulomatosis (WG) and the IL-10-1082 G allele (OR = 0.729, 95% CI = 0.547-0.971, p = 0.031). Meta-analysis revealed an association between vasculitis and the IL-10-819 C allele (OR = 0.804, 95% CI = 0.706-0.916, p = 0.001) in all study subjects and Behcet's disease (BD) (OR = 0.724, 95% CI = 0.679-0.781, p vasculitis in all study subjects (OR = 0.805, 95% CI = 0.619-0.938, p = 0.005) and BD (OR = 0.718, 95% CI = 0.661-0.781, p vasculitis in Europeans (OR = 1.239, 95% CI = 1.105-1.513, p = 0.035). This meta-analysis showed that IL-10 polymorphisms are associated with vasculitis susceptibility, especially in WG and BD.

  5. Interleukin-6 and interleukin-10 plasma levels and mRNA expression in polytrauma patients.

    Science.gov (United States)

    Sapan, Heber B; Paturusi, Idrus; Islam, Andi Asadul; Yusuf, Irawan; Patellongi, Ilhamjaya; Massi, Muhammmad Nasrum; Pusponegoro, Aryono D; Arief, Syafrie K; Labeda, Ibrahim; Rendy, Leo; Hatta, Mochammad

    2017-12-01

    Host response to polytrauma occasionally has unpredictable outcomes. Immune response is a major factor influencing patient's outcome. This study evaluated the interaction of two main cytokines in immune response after major trauma, specifically interleukin-6 (IL-6) and interleukin-10 (IL-10). Plasma level of these cytokines is determined by mRNA expression of these cytokines genes which may decide the outcome of polytrauma patients. This prospective multicenter trial held at four trauma centers enrolled 54 polytrauma patients [Injury Severity Score (ISS) ≥ 16]. Plasma levels and mRNA expression of IL-6 and IL-10 were measured for 5 days after trauma. Clinical evaluation was conducted to observe whether patients endured multiple organ dysfunction syndrome (MODS) and death. MODS evaluation was performed using sequential organ failure assessment (SOFA). Trauma load which in this study is represented with ISS, plasma level, expression of cytokine genes and patient's outcome were examined with correlation test and statistical analysis. The elevated IL-6/IL-10 ratio indicated increased activity of systemic inflammation response, especially pro-inflammation response which bears higher probability of progressing to MODS and death. The decline of IL-6/IL-10 ratio with heavy trauma load (ISS > 30) showed that compensatory anti-inflammation response syndrome (CARS) state was more dominant than systemic inflammatory response syndrome (SIRS), indicating that malfunction and failure of immune system eventually lead to MODS and deaths. The statistical significance in plasma level of cytokines was found in the outcome group which was defined as bearing a low trauma load but mortality. The pattern of cytokine levels in inflammation response has great impact on the outcome of polytrauma patients. Further study at the genetic level is needed to investigate inflammation process which may influence patient's outcome. Copyright © 2017 Daping Hospital and the Research Institute of

  6. Interleukin-10 as a Marker of Disease Progression in Dengue Hemorrhagic Fever

    International Nuclear Information System (INIS)

    Tauseef, A.; Akmal, A.; Umar, N.; Sabir, S.; Sajjad, S.; Zulfiqar, S.

    2016-01-01

    Objective: To evaluate the plasma interleukin-10 (IL-10) levels in patients suffering from dengue hemorrhagic fever between 4 to 7 days of onset of disease and 24 hours after the first sample, to find out the association of plasma IL-10 levels with the outcome. Study Design: Analytical study. Place and Duration of Study: All major hospitals of Lahore, Pakistan, from August to November 2012. Methodology: Participants included 50 registered patients of dengue hemorrhagic fever (DHF) aged between 15 - 50 years. Plasma IL-10 concentrations were measured on above stated day. Outcome was described as recovery and shock. Platelet count and hematocrit percentages were also recorded. Statistical analyses were done using SPSS version 19. A p-value 0.05 was considered significant. Results: Plasma IL-10 levels were found to be raised in DHF patients and were associated with fatal outcome (p=0.004). In recovered DHF patients, plasma IL-10 levels decreased after 24 hours (mean 26.54 ± 16.03 pg/ml) as compared to admission time (mean 74.39 ± 61.69 pg/ml) but in case of DHF patients suffering from shock, plasma IL-10 was found to be higher after 24 hours (mean 87.69 ± 7.77 pg/ml) as compared to levels at admission time (mean 42.56 ± 28.09 pg/ml). ROC curve analysis revealed a change (30 units pg/ml) of plasma IL-10 concentration, within 24 hours of admission, raised from the base line to be 105 times more critical for shock in DHF patients (100 percentage sensitivity and 71.4 percentage specificity, p < 0.001). Conclusion: Elevated plasma IL-10 is a potential predictor of disease severity and fatal outcome in DHF patients. (author)

  7. Effector CD8+T cell-derived interleukin-10 enhances acute liver immunopathology.

    Science.gov (United States)

    Fioravanti, Jessica; Di Lucia, Pietro; Magini, Diletta; Moalli, Federica; Boni, Carolina; Benechet, Alexandre Pierre; Fumagalli, Valeria; Inverso, Donato; Vecchi, Andrea; Fiocchi, Amleto; Wieland, Stefan; Purcell, Robert; Ferrari, Carlo; Chisari, Francis V; Guidotti, Luca G; Iannacone, Matteo

    2017-09-01

    Besides secreting pro-inflammatory cytokines, chemokines and effector molecules, effector CD8 + T cells that arise upon acute infection with certain viruses have been shown to produce the regulatory cytokine interleukin (IL)-10 and, therefore, contain immunopathology. Whether the same occurs during acute hepatitis B virus (HBV) infection and role that IL-10 might play in liver disease is currently unknown. Mouse models of acute HBV pathogenesis, as well as chimpanzees and patients acutely infected with HBV, were used to analyse the role of CD8 + T cell-derived IL-10 in liver immunopathology. Mouse HBV-specific effector CD8 + T cells produce significant amounts of IL-10 upon in vivo antigen encounter. This is corroborated by longitudinal data in a chimpanzee acutely infected with HBV, where serum IL-10 was readily detectable and correlated with intrahepatic CD8 + T cell infiltration and liver disease severity. Unexpectedly, mouse and human CD8 + T cell-derived IL-10 was found to act in an autocrine/paracrine fashion to enhance IL-2 responsiveness, thus preventing antigen-induced HBV-specific effector CD8 + T cell apoptosis. Accordingly, the use of mouse models of HBV pathogenesis revealed that the IL-10 produced by effector CD8 + T cells promoted their own intrahepatic survival and, thus supported, rather than suppressed liver immunopathology. Effector CD8 + T cell-derived IL-10 enhances acute liver immunopathology. Altogether, these results extend our understanding of the cell- and tissue-specific role that IL-10 exerts in immune regulation. Lay summary: Interleukin-10 is mostly regarded as an immunosuppressive cytokine. We show here that HBV-specific CD8 + T cells produce IL-10 upon antigen recognition and that this cytokine enhances CD8 + T cell survival. As such, IL-10 paradoxically promotes rather than suppresses liver disease. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  8. Role of Interleukin-10 on Nasal Polypogenesis in Patients with Chronic Rhinosinusitis with Nasal Polyps.

    Directory of Open Access Journals (Sweden)

    Jun Xu

    Full Text Available Interleukin 10 (IL-10 is a potent anti-inflammatory cytokine. The dysregulation of IL-10 is associated with an enhanced immunopathologic response to infection, as well as with an increased risk for developing numerous autoimmune diseases. In this study, we investigated IL-10 expression in chronic rhinosinusitis with nasal polyps (CRSwNP and assessed the possible role of IL-10 in the pathogenesis of CRSwNP.Thirty-five patients with CRSwNP, 12 patients with chronic rhinosinusitis without NP (CRSsNP and 10 control subjects were enrolled in this study. NP tissues and uncinated tissues (UT were collected for analysis. Dispersed NP cells (DNPCs were cultured in the presence or absence of IL-25 and IL-10, and a flow cytometric assay was performed to identify the constitutive cell populations of the DNPCs. Murine NP (n = 18 models were used for the in vivo experiments. Real-time PCR, immunohistochemistry, western blotting analysis and ELISA were performed to measure the expression levels of the selected inflammatory cytokines and inflammation-associated molecules.The mRNA expression levels of IL-10, IL-5, IL-17A, IL-25 and interferon gamma (IFN-γ were significantly higher in the NP tissues than in the UT tissues. Strong positive correlations were observed between IL-10 and a variety of inflammatory cytokines (IL-5, IL-17A, IL-25, IFN-γ and inflammation-associated molecules (B-cell activating factor; BAFF, CD19. Other than the IL-25 to IL-10 ratio, the expression ratios of the other measured inflammatory cytokines to IL-10 were significantly lower in the CRSwNP group than in the CRSsNP or control groups. Administrating IL-25 into the cultured DNPCs significantly increased the production of IL-10, but administrating IL-10 had no effect on the production of IL-25.Increased expression of IL-10, IL-10 related inflammatory cytokine, and IL-10 related B cell activation indicated that IL-10, a potent anti-inflammatory cytokine, has a pivotal role in the

  9. The structural network of Interleukin-10 and its implications in inflammation and cancer

    Science.gov (United States)

    2014-01-01

    Background Inflammation has significant roles in all phases of tumor development, including initiation, progression and metastasis. Interleukin-10 (IL-10) is a well-known immuno-modulatory cytokine with an anti-inflammatory activity. Lack of IL-10 allows induction of pro-inflammatory cytokines and hinders anti-tumor immunity, thereby favoring tumor growth. The IL-10 network is among the most important paths linking cancer and inflammation. The simple node-and-edge network representation is useful, but limited, hampering the understanding of the mechanistic details of signaling pathways. Structural networks complete the missing parts, and provide details. The IL-10 structural network may shed light on the mechanisms through which disease-related mutations work and the pathogenesis of malignancies. Results Using PRISM (a PRotein Interactions by Structural Matching tool), we constructed the structural network of IL-10, which includes its first and second degree protein neighbor interactions. We predicted the structures of complexes involved in these interactions, thereby enriching the available structural data. In order to reveal the significance of the interactions, we exploited mutations identified in cancer patients, mapping them onto key proteins of this network. We analyzed the effect of these mutations on the interactions, and demonstrated a relation between these and inflammation and cancer. Our results suggest that mutations that disrupt the interactions of IL-10 with its receptors (IL-10RA and IL-10RB) and α2-macroglobulin (A2M) may enhance inflammation and modulate anti-tumor immunity. Likewise, mutations that weaken the A2M-APP (amyloid precursor protein) association may increase the proliferative effect of APP through preventing β-amyloid degradation by the A2M receptor, and mutations that abolish the A2M-Kallikrein-13 (KLK13) interaction may lead to cell proliferation and metastasis through the destructive effect of KLK13 on the extracellular matrix

  10. Interleukin-10 Gene Polymorphisms are Associated With Freedom From Treatment Failure for Patients With Hodgkin Lymphoma

    Science.gov (United States)

    Schoof, Nils; Franklin, Jeremy; Fürst, Robert; Zander, Thomas; von Bonin, Frederike; Peyrade, Frederic; Trümper, Lorenz; Diehl, Volker; Engert, Andreas

    2013-01-01

    Background. Hodgkin lymphoma (HL) is a lymphoid malignancy characterized by the production of various cytokines possibly involved in immune deregulation. Interleukin-10 (IL-10) serum levels have been associated with clinical outcome in patients with HL. Because host genetic variations are known to alter the expression and function of cytokines and their receptors, we investigated whether genetic variations influence clinical outcome of patients with HL. Methods. A total of 301 patients with HL who were treated within randomized trials by the German Hodgkin Study Group were included in this exploratory retrospective study. Gene variations of IL-10 (IL-10-597AC, rs1800872; IL-10-824CT, rs1800871; IL-10-1087AG, rs1800896; IL-10-3538AT, rs1800890; IL-10-6208CG, rs10494879; IL-10-6752AT, rs6676671; IL-10-7400InDel), IL-13 (IL-13-1069CT, rs1800925; IL-13Q144R, rs20541), and IL-4R (IL-4RI75V, rs1805010; IL-4RQ576R, rs1801275) were genotyped. Results. Inferior freedom from treatment failure (FFTF) was found in patients harboring the IL-10-597AA, IL-10-824TT, or the IL-10-1087AA genotype. In contrast, the IL-10-1087G-824C-597C haplotype present in about 48% of analyzed HL patients is nominally significant for a better FFTF in a Cox-Regression model accounting for stage and treatment. No associations were observed between the other IL-10 gene variations, IL-13-1069CT, IL-13Q144R, IL-4RI75V, IL-4RQ576R and the clinical outcome of patients with HL. Conclusions. Our study provides further evidence that proximal IL-10 promoter gene variations are associated with clinical course of patients with HL. However, treatment success and survival rates are already at a very high rate, supporting the need to design studies focusing on identification of predictors to reduce the side effects of therapy. PMID:23299779

  11. Interleukin-10 Attenuates Hypochlorous Acid-Mediated Cytotoxicity to HEI-OC1 Cochlear Cells

    Directory of Open Access Journals (Sweden)

    Martin Mwangi

    2017-10-01

    Full Text Available Inflammatory reaction plays a crucial role in the pathophysiology of acquired hearing loss such as ototoxicity and labyrinthitis. In our earlier work, we showed the pivotal role of otic fibrocytes in cochlear inflammation and the critical involvement of proinflammatory cytokines in cisplatin ototoxicity. We also demonstrated that otic fibrocytes inhibit monocyte chemoattractant protein 1 (CCL2 upregulation in response to interleukin-10 (IL-10 via heme oxygenase 1 (HMOX1 signaling, resulting in suppression of cochlear inflammation. However, it is still unclear how IL-10 affects inflammation-mediated cochlear injury. Here we aim to determine how hypochlorous acid, a model inflammation mediator affects cochlear cell viability and how IL-10 affects hypochlorous acid-mediated cochlear cell injury. NaOCl, a sodium salt of hypochlorous acid (HOCl was found to induce cytotoxicity of HEI-OC1 cells in a dose-dependent manner. Combination of hydrogen peroxide and myeloperoxidase augmented cisplatin cytotoxicity, and this synergism was inhibited by N-Acetyl-L-cysteine and ML-171. The rat spiral ligament cell line (RSL appeared to upregulate the antioxidant response element (ARE activities upon exposure to IL-10. RSL cells upregulated the expression of NRF2 (an ARE ligand and NR0B2 in response to CoPP (a HMOX1 inducer, but not to ZnPP (a HMOX1 inhibitor. Adenovirus-mediated overexpression of NR0B2 was found to suppress CCL2 upregulation. IL-10-positive cells appeared in the mouse stria vascularis 1 day after intraperitoneal injection of lipopolysaccharide (LPS. Five days after injection, IL-10-positive cells were observed in the spiral ligament, spiral limbus, spiral ganglia, and suprastrial area, but not in the stria vascularis. IL-10R1 appeared to be expressed in the mouse organ of Corti as well as HEI-OC1 cells. HEI-OC1 cells upregulated Bcl-xL expression in response to IL-10, and IL-10 was shown to attenuate NaOCl-induced cytotoxicity. In addition, HEI

  12. Lipopolysaccharide treatment suppresses spontaneously developing ankylosing enthesopathy in B10.BR male mice: The potential role of interleukin-10

    Czech Academy of Sciences Publication Activity Database

    Čapková, Jana; Hrnčíř, Tomáš; Kubátová, Alena; Tlaskalová-Hogenová, Helena

    2012-01-01

    Roč. 13, č. 6 (2012) E-ISSN 1471-2474 R&D Projects: GA ČR(CZ) GAP304/11/1252; GA ČR GP310/09/P182; GA MŠk(CZ) 7E09091 Institutional research plan: CEZ:AV0Z50520701 Institutional support: RVO:61388971 Keywords : Ankylosing enthesopathy * Interleukin-10 * Lipopolysacharid * Cytokines Subject RIV: EC - Immunology Impact factor: 1.875, year: 2012

  13. Co-transfection of decorin and interleukin-10 modulates pro-fibrotic extracellular matrix gene expression in human tenocyte culture

    Science.gov (United States)

    Abbah, Sunny A.; Thomas, Dilip; Browne, Shane; O'Brien, Timothy; Pandit, Abhay; Zeugolis, Dimitrios I.

    2016-02-01

    Extracellular matrix synthesis and remodelling are driven by increased activity of transforming growth factor beta 1 (TGF-β1). In tendon tissue repair, increased activity of TGF-β1 leads to progressive fibrosis. Decorin (DCN) and interleukin 10 (IL-10) antagonise pathological collagen synthesis by exerting a neutralising effect via downregulation of TGF-β1. Herein, we report that the delivery of DCN and IL-10 transgenes from a collagen hydrogel system supresses the constitutive expression of TGF-β1 and a range of pro-fibrotic extracellular matrix genes.

  14. Predictive validity and immune cell involvement in the pathogenesis of piroxicam-accelerated colitis in interleukin-10 knockout mice

    DEFF Research Database (Denmark)

    Holgersen, Kristine; Kvist, Peter Helding; Hansen, Axel Jacob Kornerup

    2014-01-01

    Piroxicam administration is a method for induction of enterocolitis in interleukin-10 knockout (IL-10 k.o.) mice. The piroxicam-accelerated colitis (PAC) IL-10 k.o. model combines a dysregulated immune response against the gut microbiota with a decreased mucosal integrity. The predictive validity...... and pathogenic mechanisms of the model have not been thoroughly investigated. In this study, IL-10 k.o. mice received piroxicam in the chow, and model qualification was performed by examining the efficacy of prophylactic anti-IL-12/23p40 monoclonal antibody (mAb), anti-TNFαmAb, cyclosporine A (CsA) and oral...

  15. [Serum levels of interferon-gamma and interleukine-10 in anemic children with vitamin A deficiency].

    Science.gov (United States)

    Leal, Jorymar Y; Castejón, Haydée V; Romero, Tania; Ortega, Pablo; Gómez, Gisela; Amaya, Daysi; Estévez, Jesús

    2006-12-01

    Studies done with human and animals have shown that the diminished vitamin A intake can produce anemia, but the ethiopathogenic mechanism hasn't been known due to the few studies about the complex interactions between micronutrients deficiencies, immune system and cytokine productions. The objective of the present study was to analyze the serum concentration of IFN-gamma and IL-10 in anemic and non anemic children according to vitamin A nutritional status. A descriptive study of 53 euthrophic children, without infectious diseases (45-77 month old; 29 girls, 24 boys), living in a slum in Maracaibo-Venezuela. Anemia was evaluated by means of blood hemoglobin concentration analysis, standard WHO criteria for anemia were Hb 60 month old children. Vitamin A status was assessed by Conjunctival Impression Cytology (CIC) technique, which determines Normal CIC=Control or Abnormal CIC=VAD. The serum concentration of IFN-gamma and IL-10 (pg/mL; X +/- DE), was determined by the ELISA method. Statistical significance of differences was tested by ANOVA (p < 0.05). Prevalence of anemia was 75.50%; VAD 50.94% and anemia+VAD 35.86%. The anemic children with VAD showed significant serum values of IFN-gamma e IL-10 lower than in other groups. This alteration of the complex immunoregulatory mechanism could be responsible for dysfunction eritrhoid cell formation.

  16. Cissampelos sympodialis Eichl (Menispermaceae leaf extract induces interleukin-10-dependent inhibition of Trypanosoma cruzi killing by macrophages

    Directory of Open Access Journals (Sweden)

    Alexandre-Moreira M.S.

    2003-01-01

    Full Text Available The aqueous fraction of the ethanolic extract (AFL of Cissampelos sympodialis Eichl (Menispermaceae, popularly known as milona, has been shown to have both immunosuppressive and anti-inflammatory effects. In the present study we investigated the modulation of macrophage antimicrobicidal activity by in vitro treatment with the extract from C. sympodialis. Normal and thioglycolate-elicited mouse peritoneal macrophages were infected in vitro with the protozoan Trypanosoma cruzi DM28c clone. We observed that the AFL (used at doses ranging from 13 to 100 µg/ml increased T. cruzi growth and induced a 75% reduction in nitric oxide production. This inhibition could be mediated by the stimulation of macrophage interleukin-10 (IL-10 secretion since the in vitro treatment with the AFL stimulated IL-10 production by T. cruzi-infected macrophages. These results suggest that the anti-inflammatory effect of the AFL from C. sympodialis could be, at least in part, mediated by the inhibition of macrophage functions and that the inhibition of macrophage microbicidal activity induced by the C. sympodialis extract may be mediated by the decrease in macrophage function mediated by interleukin-10 production.

  17. Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10 Receptor-1 Mimetics.

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    Gloria Ruiz-Gómez

    Full Text Available Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1, which are relevant for its interaction with interleukin-10 (IL-10 has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands.

  18. [Changes in the interleukin-6 and interleukin-10 concentrations in the blood plasma of miners working in deep coal mines].

    Science.gov (United States)

    Plotkin, V Ia; Rebrov, B A; Belkina, E B

    2000-03-01

    Blood plasma levels of interleukin-6 (IL-6) and interleukin-10 (IL-10) were measured in 45 miners working in a deep coal mine immediately after work shift using an immunoenzyme technique. The highest IL-6 level was recorded in those miners engaged in hard work under most adverse conditions of underground workings--it was found to exceed the control values. The same group of workers demonstrated the lowest level of IL-10 that differed from the control value. Miners aged between 41 to 50 years working in a coal mine, their underground service duration 16 to 20 years, displayed a decline in the level of IL-6. The coal mine miners with the 11- to 15-year service duration revealed an increase in the level of IL-10.

  19. High leukocyte count and interleukin-10 predict high on-treatment-platelet-reactivity in patients treated with clopidogrel.

    Science.gov (United States)

    Osmancik, Pavel; Paulu, Petra; Tousek, Petr; Kocka, Viktor; Widimsky, Petr

    2012-05-01

    According to recent trials, a significant number of patients do not have a completely effective response to clopidogrel. The aim of the study was to evaluate the rate of clopidogrel resistance in the context of important clinical characteristics and to specifically determine the relation between clopidogrel efficacy and biomarkers of inflammation. Consecutive non-selected patients following PCI were enrolled into the study. All patients received a loading dose of 600 mg of clopidogrel. The effect of clopidogrel was assessed using the VerifyNow assay 24 h after clopidogrel administration, clopidogrel resistance was defined as PRU ≥ 240. At the same time, standard parameters of biochemistry and hematology, the concentration of anti-inflammatory cytokine interleukin-10 and of soluble CD40 ligand, were measured. 378 patients were enrolled. 243 (64.3%) patients were responders (R) and 135 patients (35.7%) were non-responders (NR). Non-responders were older (R 65.7 ± 13.3, NR 69.8 ± 11.5, P leukocyte count (R 9.8 ± 3.5, NR 11.7 ± 12.8, P leukocytes and IL-10 were associated with an increased risk for being a non-responder. Older, obese patients, especially women had a higher risk of high on-treatment-platelet-reactivity. Higher concentrations of leukocytes and interleukin-10 were also an important factor associated with the risk of low clopidogrel responsiveness.

  20. Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10

    Directory of Open Access Journals (Sweden)

    Flotte Terence R

    2005-02-01

    Full Text Available Abstract Despite many decades of drug development, effective therapies for neuropathic pain remain elusive. The recent recognition of spinal cord glia and glial pro-inflammatory cytokines as important contributors to neuropathic pain suggests an alternative therapeutic strategy; that is, targeting glial activation or its downstream consequences. While several glial-selective drugs have been successful in controlling neuropathic pain in animal models, none are optimal for human use. Thus the aim of the present studies was to explore a novel approach for controlling neuropathic pain. Here, an adeno-associated viral (serotype II; AAV2 vector was created that encodes the anti-inflammatory cytokine, interleukin-10 (IL-10. This anti-inflammatory cytokine is known to suppress the production of pro-inflammatory cytokines. Upon intrathecal administration, this novel AAV2-IL-10 vector was successful in transiently preventing and reversing neuropathic pain. Intrathecal administration of an AAV2 vector encoding beta-galactosidase revealed that AAV2 preferentially infects meningeal cells surrounding the CSF space. Taken together, these data provide initial support that intrathecal gene therapy to drive the production of IL-10 may prove to be an efficacious treatment for neuropathic pain.

  1. RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis.

    Science.gov (United States)

    Noto, Michael J; Becker, Kyle W; Boyd, Kelli L; Schmidt, Ann Marie; Skaar, Eric P

    2017-03-01

    The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor capable of recognizing multiple pathogen-associated and danger-associated molecular patterns that contributes to the initiation and potentiation of inflammation in many disease processes. During infection, RAGE functions to either exacerbate disease severity or enhance pathogen clearance depending on the pathogen studied. Acinetobacter baumannii is an opportunistic human pathogen capable of causing severe infections, including pneumonia and sepsis, in impaired hosts. The role of RAGE signaling in response to opportunistic bacterial infections is largely unknown. In murine models of A. baumannii pneumonia, RAGE signaling alters neither inflammation nor bacterial clearance. In contrast, RAGE -/- mice systemically infected with A. baumannii exhibit increased survival and reduced bacterial burdens in the liver and spleen. The increased survival of RAGE -/- mice is associated with increased circulating levels of the anti-inflammatory cytokine interleukin-10 (IL-10). Neutralization of IL-10 in RAGE -/- mice results in decreased survival during systemic A. baumannii infection that mirrors that of wild-type (WT) mice, and exogenous IL-10 administration to WT mice enhances survival in this model. These findings demonstrate the role for RAGE-dependent IL-10 suppression as a key modulator of mortality from Gram-negative sepsis. Copyright © 2017 American Society for Microbiology.

  2. Immunomodulatory role of interleukin-10 in visceral leishmaniasis: defective activation of protein kinase C-mediated signal transduction events.

    Science.gov (United States)

    Bhattacharyya, S; Ghosh, S; Jhonson, P L; Bhattacharya, S K; Majumdar, S

    2001-03-01

    Leishmania donovani, an intracellular protozoan parasite, challenges host defense mechanisms by impairing the signal transduction of macrophages. In this study we investigated whether interleukin-10 (IL-10)-mediated alteration of signaling events in a murine model of visceral leishmaniasis is associated with macrophage deactivation. Primary in vitro cultures of macrophages infected with leishmanial parasites markedly elevated the endogenous release of IL-10. Treatment with either L. donovani or recombinant IL-10 (rIL-10) inhibited both the activity and expression of the Ca2+-dependent protein kinase C (PKC) isoform. However, preincubation with neutralizing anti-IL-10 monoclonal antibody (MAb) restored the PKC activity in the parasitized macrophage. Furthermore, we observed that coincubation of macrophages with rIL-10 and L. donovani increased the intracellular parasite burden, which was abrogated by anti-IL-10 MAb. Consistent with these observations, generation of superoxide (O2-) and nitric oxide and the release of murine tumor necrosis factor-alpha were attenuated in response to L. donovani or rIL-10 treatment. On the other hand, preincubation of the infected macrophages with neutralizing anti-IL-10 MAb significantly blocked the inhibition of nitric oxide and murine tumor necrosis factor-alpha release by the infected macrophages. These findings imply that infection with L. donovani induces endogenous secretion of murine IL-10, which in turn facilitates the intracellular survival of the protozoan and orchestrates several immunomodulatory roles via selective impairment of PKC-mediated signal transduction.

  3. Bee Venom Acupuncture Reduces Interleukin-6, Increases Interleukin-10, and Induces Locomotor Recovery in a Model of Spinal Cord Compression.

    Science.gov (United States)

    Nascimento de Souza, Raquel; Silva, Fernanda Kohn; Alves de Medeiros, Magda

    2017-06-01

    Spinal cord injuries (SCIs) initiate a series of molecular and cellular events in which inflammatory responses can lead to major neurological dysfunctions. The present study aims to investigate whether bee venom (BV) acupuncture applied at acupoints ST36 (Zusanli) and GV3 (Yaoyangquan) could minimize locomotor deficits and the magnitude of neural tissue losses, and change the balance between pro- and anti-inflammatory cytokines after an SCI by compression. Wistar rats were subjected to an SCI model by compression in which a 2-French Fogarty embolectomy catheter was inflated in the extradural space. The effects of BV acupuncture, in which 20 μL of BV diluted in saline (0.08 mg/kg) was injected at acupoints GV3 and ST36 [BV(ST36+GV3)-SCI] was compared with BV injected at nonacupoints [BV(NP)-SCI] and with no treatment [group subjected only to SCI (CTL-SCI)]. The BV(ST36+GV3)-SCI group showed a significant improvement in the locomotor performance and a decrease of lesion size compared with the controls. BV acupuncture at the ST36 + GV3 increased the expression of interleukin-10 (anti-inflammatory) at 6 hours and reduced the expression of interleukin-6 (proinflammatory) at 24 hours after SCI compared with the controls. Our results suggest that BV acupuncture can reduce neuroinflammation and induce recovery in the SCI compression model. Copyright © 2017. Published by Elsevier B.V.

  4. The Effect of Levothyroxine on Serum Levels of Interleukin 10 and Interferon-gamma in Rat Model of Multiple Sclerosis

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    Cobra Payghani

    2017-01-01

    Full Text Available Background: There is an increase in inflammatory and a reduction in anti-inflammatory cytokines in multiple sclerosis (MS. Considering the role of thyroid hormones in the development and regulation of both neural and immune systems, the aim of this study was to evaluate the effects of levothyroxine on serum concentrations of interleukin-10 (IL-10 and interferon gamma (IFN-γ in animal models of MS. Materials and Methods: To induce demyelination in male Wistar rats, lysolecithin was injected into the optic chiasm. Then levothyroxine was injected intraperitoneally (20, 50, and 100 μg/kg for 21 days. Serum levels of cytokines were measured by enzyme-linked immunosorbent assay at 7, 14, and 21 days after that. Results: The results showed that injection of lysolecithin to the optic chiasm only increased serum concentrations of IL-10 compared to the sham group (P < 0.05 at 7th day, but this increase was prevented by all doses of levothyroxine. IFN-γ was decreased significantly (P < 0.001 21 days after. Comparing to the sham group at all sampling time and with respect to the MS group at the days 7 and 21, levothyroxine decreased serum concentrations of IFN-γ significantly. Conclusion: The results showed that thyroid hormones probably could produce protective effects against induced demyelination through affecting immune responses.

  5. Interleukin-10 Polymorphisms in Association with Prognosis in Patients with B-Cell Lymphoma Treated by R-CHOP

    Directory of Open Access Journals (Sweden)

    Min Kyeong Kim

    2016-12-01

    Full Text Available Interleukin-10 (IL10 plays an important role in initiating and maintaining an appropriate immune response to non-Hodgkin lymphoma (NHL. Previous studies have revealed that the transcription of IL10 mRNA and its protein expression may be infl uenced by several single-nucleotide polymorphisms in the promoter and intron regions, including rs1800896, rs1800871, and rs1800872. However, the impact of polymorphisms of the IL10 gene on NHL prognosis has not been fully elucidated. Here, we investigated the association between IL10 polymorphisms and NHL prognosis. This study involved 112 NHL patients treated at the National Cancer Center, Korea. The median age was 57 years, and 70 patients (62.5% were men. Clinical characteristics, including age, performance status, stage, and extra-nodal involvement, as well as cell lineage and International Prognostic Index (IPI, were evaluated. A total of four polymorphisms in IL10 with heterozygous alleles were analyzed for hazard ratios of overall survival (OS and progression-free survival (PFS using Cox proportional hazards regression analysis. Diffuse large B-cell lymphoma was the most common histologic type (n = 83, followed by T-cell lymphoma (n = 18, mantle cell lymphoma (n = 6, and others (n = 5. Cell lineage, IPI, and extra-nodal involvement were predictors of prognosis. In the additive genetic model results for each IL10 polymorphism, the rs1800871 and rs1800872 polymorphisms represented a marginal association with OS (p = 0.09 and p = 0.06 and PFS (p = 0.05 and p = 0.08 in B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP. These findings suggest that IL10 polymorphisms might be prognostic indicators for patients with B-cell NHL treated with R-CHOP.

  6. Interleukin 10-Dominant Immune Response and Increased Risk of Cutaneous Leishmaniasis After Natural Exposure to Lutzomyia intermedia Sand Flies.

    Science.gov (United States)

    Carvalho, Augusto M; Cristal, Juqueline R; Muniz, Aline C; Carvalho, Lucas P; Gomes, Regis; Miranda, José C; Barral, Aldina; Carvalho, Edgar M; de Oliveira, Camila I

    2015-07-01

    Leishmaniasis is caused by parasites transmitted to the vertebrate host by infected sand flies. During transmission, the vertebrate host is also inoculated with sand fly saliva, which exerts powerful immunomodulatory effects on the host's immune response. We conducted a prospective cohort analysis to characterize the human immune response to Lutzomyia intermedia saliva in 264 individuals, from an area for cutaneous leishmaniasis (CL) caused by Leishmania braziliensis. Antibodies were found in 150 individuals (56.8%); immunoglobulin G1 and G4 were the predominant subclasses. Recall responses to salivary gland sonicate showed elevated production of interleukin 10 (IL-10), interleukin 13, interferon γ, CXCL9, and CCL2 compared with controls. CD4(+)CD25(+) T cells, including Foxp3(+) cells, were the main source of IL-10. L. braziliensis replication was increased (P < .05) in macrophages cocultured with saliva-stimulated lymphocytes from exposed individuals and addition of anti-IL-10 reverted this effect. Positive correlation between antibody response to saliva and cellular response to Leishmania was not found. Importantly, individuals seropositive to saliva are 2.1 times more likely to develop CL (relative risk, 2.1; 95% confidence interval, 1.07-4.2; P < .05). Exposure to L. intermedia sand flies skews the human immune response, facilitating L. braziliensis survival in vitro, and increases the risk of developing CL. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Predictive validity and immune cell involvement in the pathogenesis of piroxicam-accelerated colitis in interleukin-10 knockout mice.

    Science.gov (United States)

    Holgersen, Kristine; Kvist, Peter Helding; Hansen, Axel Kornerup; Holm, Thomas Lindebo

    2014-07-01

    Piroxicam administration is a method for induction of enterocolitis in interleukin-10 knockout (IL-10 k.o.) mice. The piroxicam-accelerated colitis (PAC) IL-10 k.o. model combines a dysregulated immune response against the gut microbiota with a decreased mucosal integrity. The predictive validity and pathogenic mechanisms of the model have not been thoroughly investigated. In this study, IL-10 k.o. mice received piroxicam in the chow, and model qualification was performed by examining the efficacy of prophylactic anti-IL-12/23p40 monoclonal antibody (mAb), anti-TNFα mAb, cyclosporine A (CsA) and oral prednisolone treatment. To evaluate cell involvement in the disease pathogenesis, specific cell subsets were depleted by treatment with anti-CD4 mAb, anti-CD8 mAb or clodronate-encapsulated liposomes. T cell receptor co-stimulation was blocked by CTLA4-Ig. Cytokine profiling ELISAs and calprotectin immunohistochemistry were performed on colon tissue. Treatments with anti-IL-12/23p40 mAb and CsA prevented disease in PAC IL-10 k.o. mice and reduced IFNγ, IL-17A, MPO and calprotectin levels in colon. Anti-TNFα mAb treatment caused amelioration of selected clinical parameters. No effect of prednisolone was detected. Depletion of CD8(+) cells tended to increase mortality, whereas treatment with anti-CD4 mAb or CTLA4-Ig had no significant effect on disease development. Clodronate liposome treatment induced a loss of body weight; nevertheless macrophage depletion was associated with a significant reduction in colonic pathology. In conclusion, reference drugs with known efficacy in severe inflammatory bowel disease were efficacious in the PAC IL-10 k.o. model. Our data indicate that in this model macrophages are a main driver of colitis, whereas CD4(+) cells are not. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Design of a covalently linked human interleukin-10 fusion protein and its secretory expression in Escherichia coli.

    Science.gov (United States)

    Guggenbichler, Florian; Büttner, Carolin; Rudolph, Wolfram; Zimmermann, Kurt; Gunzer, Florian; Pöhlmann, Christoph

    2016-12-01

    Wild-type human interleukin-10 (hIL-10) is a non-covalent homodimer with a short half-life, thus limiting its therapeutic applications in vivo. To avoid loss of function due to dimer dissociation, we designed a synthetic hIL-10 analog by bridging both monomers via a 15 amino acid-long peptide spacer in a C-terminal to N-terminal fashion. For secretory expression in Escherichia coli, a 1156 bp fragment was generated from template vector pAZ1 by fusion PCR encoding a T7 promoter region and the signal sequence of the E. coli outer membrane protein F fused in frame to two tandem E. coli codon-optimized mature hIL-10 genes connected via a 45 nucleotide linker sequence. The construct was cloned into pUC19 for high-level expression in E. coli BL21 (DE3). The mean concentrations of hIL-10 fusion protein in the periplasm and supernatant of E. coli at 37 °C growth temperature were 130 ± 40 and 2 ± 1 ng/ml, respectively. The molecular mass of the recombinant protein was assessed via matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) analysis, indicating correct processing of the signaling sequence in E. coli. In vitro biological activity was shown by phosphorylation of signal transducer and activator of transcription protein 3 and suppression of tumor necrosis factor α secretion in lipopolysaccharide-stimulated macrophages.

  9. Preliminary characterisation of tumor necrosis factor alpha and interleukin-10 responses to Chlamydia pecorum infection in the koala (Phascolarctos cinereus.

    Directory of Open Access Journals (Sweden)

    Marina Mathew

    Full Text Available Debilitating infectious diseases caused by Chlamydia are major contributors to the decline of Australia's iconic native marsupial species, the koala (Phascolarctos cinereus. An understanding of koala chlamydial disease pathogenesis and the development of effective strategies to control infections continue to be hindered by an almost complete lack of species-specific immunological reagents. The cell-mediated immune response has been shown to play an influential role in the response to chlamydial infection in other hosts. The objective of this study, hence, was to provide preliminary data on the role of two key cytokines, pro-inflammatory tumour necrosis factor alpha (TNFα and anti-inflammatory interleukin 10 (IL10, in the koala Chlamydia pecorum response. Utilising sequence homology between the cytokine sequences obtained from several recently sequenced marsupial genomes, this report describes the first mRNA sequences of any koala cytokine and the development of koala specific TNFα and IL10 real-time PCR assays to measure the expression of these genes from koala samples. In preliminary studies comparing wild koalas with overt chlamydial disease, previous evidence of C. pecorum infection or no signs of C. pecorum infection, we revealed strong but variable expression of TNFα and IL10 in wild koalas with current signs of chlamydiosis. The description of these assays and the preliminary data on the cell-mediated immune response of koalas to chlamydial infection paves the way for future studies characterising the koala immune response to a range of its pathogens while providing reagents to assist with measuring the efficacy of ongoing attempts to develop a koala chlamydial vaccine.

  10. Preliminary characterisation of tumor necrosis factor alpha and interleukin-10 responses to Chlamydia pecorum infection in the koala (Phascolarctos cinereus).

    Science.gov (United States)

    Mathew, Marina; Beagley, Kenneth W; Timms, Peter; Polkinghorne, Adam

    2013-01-01

    Debilitating infectious diseases caused by Chlamydia are major contributors to the decline of Australia's iconic native marsupial species, the koala (Phascolarctos cinereus). An understanding of koala chlamydial disease pathogenesis and the development of effective strategies to control infections continue to be hindered by an almost complete lack of species-specific immunological reagents. The cell-mediated immune response has been shown to play an influential role in the response to chlamydial infection in other hosts. The objective of this study, hence, was to provide preliminary data on the role of two key cytokines, pro-inflammatory tumour necrosis factor alpha (TNFα) and anti-inflammatory interleukin 10 (IL10), in the koala Chlamydia pecorum response. Utilising sequence homology between the cytokine sequences obtained from several recently sequenced marsupial genomes, this report describes the first mRNA sequences of any koala cytokine and the development of koala specific TNFα and IL10 real-time PCR assays to measure the expression of these genes from koala samples. In preliminary studies comparing wild koalas with overt chlamydial disease, previous evidence of C. pecorum infection or no signs of C. pecorum infection, we revealed strong but variable expression of TNFα and IL10 in wild koalas with current signs of chlamydiosis. The description of these assays and the preliminary data on the cell-mediated immune response of koalas to chlamydial infection paves the way for future studies characterising the koala immune response to a range of its pathogens while providing reagents to assist with measuring the efficacy of ongoing attempts to develop a koala chlamydial vaccine.

  11. Interleukin-10 (IL-10) pathway: genetic variants and outcomes of HIV-1 infection in African American adolescents.

    Science.gov (United States)

    Shrestha, Sadeep; Wiener, Howard W; Aissani, Brahim; Song, Wei; Shendre, Aditi; Wilson, Craig M; Kaslow, Richard A; Tang, Jianming

    2010-10-14

    Immunological and clinical outcomes can vary considerably at the individual and population levels during both treated and untreated HIV-1 infection. Cytokines encoded by the interleukin-10 gene (IL10) family have broad immunomodulatory function in viral persistence, and several SNPs in the IL10 promoter sequence have been reported to influence pathogenesis or acquisition of HIV-1 infection. We examined 104 informative SNPs in IL10, IL19, IL20, IL24, IL10RA and IL10RB among 250 HIV-1 seropositive and 106 high-risk seronegative African American adolescents in the REACH cohort. In subsequent evaluation of five different immunological and virological outcomes related to HIV-1 infection, 25 SNPs were associated with a single outcome and three were associated with two different outcomes. One SNP, rs2243191 in the IL19 open reading frame (Ser to Phe substitution) was associated with CD4(+) T-cell increase during treatment. Another SNP rs2244305 in IL10RB (in strong linkage disequilibrium with rs443498) was associated with an initial decrease in CD4(+) T-cell by 23 ± 9% and 29 ± 9% every 3 months (for AA and AG genotypes, respectively, compared with GG) during ART-free period. These associations were reversed during treatment, as CD4(+) T-cell increased by 31 ± 0.9% and 17 ± 8% every 3 months for AA and AG genotype, respectively. In African Americans, variants in IL10 and related genes might influence multiple outcomes of HIV-1 infection, especially immunological response to HAART. Fine mapping coupled with analysis of gene expression and function should help reveal the immunological importance of the IL10 gene family to HIV-1/AIDS.

  12. Polymorphisms in the gene encoding bovine interleukin-10 receptor alpha are associated with Mycobacterium avium ssp. paratuberculosis infection status

    Directory of Open Access Journals (Sweden)

    Kelton David F

    2010-04-01

    Full Text Available Abstract Background Johne's disease is a chronic inflammatory bowel disease (IBD of ruminants caused by Mycobacterium avium ssp. paratuberculosis (MAP. Since this pathogen has been implicated in the pathogenesis of human IBDs, the goal of this study was to assess whether single nucleotide polymorphism (SNPs in several well-known candidate genes for human IBD are associated with susceptibility to MAP infection in dairy cattle. Methods The bovine candidate genes, interleukin-10 (IL10, IL10 receptor alpha/beta (IL10RA/B, transforming growth factor beta 1 (TGFB1, TGFB receptor class I/II (TGFBR1/2, and natural resistance-associated macrophage protein 1 (SLC11A1 were sequenced for SNP discovery using pooled DNA samples, and the identified SNPs were genotyped in a case-control association study comprised of 242 MAP negative and 204 MAP positive Holstein dairy cattle. Logistic regression was used to determine the association of SNPs and reconstructed haplotypes with MAP infection status. Results A total of 13 SNPs were identified. Four SNPs in IL10RA (984G > A, 1098C > T, 1269T > C, and 1302A > G were tightly linked, and showed a strong additive and dominance relationship with MAP infection status. Haplotypes AGC and AAT, containing the SNPs IL10RA 633C > A, 984G > A and 1185C > T, were associated with an elevated and reduced likelihood of positive diagnosis by serum ELISA, respectively. Conclusions SNPs in IL10RA are associated with MAP infection status in dairy cattle. The functional significance of these SNPs warrants further investigation.

  13. Canine Distemper Virus Infection Leads to an Inhibitory Phenotype of Monocyte-Derived Dendritic Cells In Vitro with Reduced Expression of Co-Stimulatory Molecules and Increased Interleukin-10 Transcription

    Science.gov (United States)

    Herder, Vanessa; Stein, Veronika M.; Tipold, Andrea; Urhausen, Carola; Günzel-Apel, Anne-Rose; Rohn, Karl; Baumgärtner, Wolfgang; Beineke, Andreas

    2014-01-01

    Canine distemper virus (CDV) exhibits a profound lymphotropism that causes immunosuppression and increased susceptibility of affected dogs to opportunistic infections. Similar to human measles virus, CDV is supposed to inhibit terminal differentiation of dendritic cells (DCs), responsible for disturbed repopulation of lymphoid tissues and diminished antigen presenting function in dogs. In order to testify the hypothesis that CDV-infection leads to an impairment of professional antigen presenting cells, canine DCs have been generated from peripheral blood monocytes in vitro and infected with CDV. Virus infection was confirmed and quantified by transmission electron microscopy, CDV-specific immunofluorescence, and virus titration. Flow cytometric analyses revealed a significant down-regulation of the major histocompatibility complex class II and co-stimulatory molecules CD80 and CD86 in CDV-infected DCs, indicative of disturbed antigen presenting capacity. Molecular analyses revealed an increased expression of the immune inhibitory cytokine interleukin-10 in DCs following infection. Results of the present study demonstrate that CDV causes phenotypical changes and altered cytokine expression of DCs, which represent potential mechanisms to evade host immune responses and might contribute to immune dysfunction and virus persistence in canine distemper. PMID:24769532

  14. Canine distemper virus infection leads to an inhibitory phenotype of monocyte-derived dendritic cells in vitro with reduced expression of co-stimulatory molecules and increased interleukin-10 transcription.

    Directory of Open Access Journals (Sweden)

    Visar Qeska

    Full Text Available Canine distemper virus (CDV exhibits a profound lymphotropism that causes immunosuppression and increased susceptibility of affected dogs to opportunistic infections. Similar to human measles virus, CDV is supposed to inhibit terminal differentiation of dendritic cells (DCs, responsible for disturbed repopulation of lymphoid tissues and diminished antigen presenting function in dogs. In order to testify the hypothesis that CDV-infection leads to an impairment of professional antigen presenting cells, canine DCs have been generated from peripheral blood monocytes in vitro and infected with CDV. Virus infection was confirmed and quantified by transmission electron microscopy, CDV-specific immunofluorescence, and virus titration. Flow cytometric analyses revealed a significant down-regulation of the major histocompatibility complex class II and co-stimulatory molecules CD80 and CD86 in CDV-infected DCs, indicative of disturbed antigen presenting capacity. Molecular analyses revealed an increased expression of the immune inhibitory cytokine interleukin-10 in DCs following infection. Results of the present study demonstrate that CDV causes phenotypical changes and altered cytokine expression of DCs, which represent potential mechanisms to evade host immune responses and might contribute to immune dysfunction and virus persistence in canine distemper.

  15. Serum profile of cytokines interferon gamma and interleukin-10 in ewes subjected to artificial insemination by cervical retraction.

    Science.gov (United States)

    Alvares, C T G; Cruz, J F; Romano, C C; Brandão, F Z

    2016-04-15

    This study evaluated the influence of artificial insemination (AI) by cervical retraction (CRI) on serum levels of interferon gamma (IFNγ) and interleukin-10 (IL-10) in ewes. Synchronized pluriparous Santa Inês ewes were subjected to natural mating (NM, n = 8) and AI, which was performed for a fixed time (55 ± 1 hour) by CRI (n = 8) or laparoscopy (n = 8). Ewes were classified as pregnant, with return to estrus (RE) or with embryonic loss (EL). Blood samples were collected on Day 0, Day 3, Day 5, Day 12, and Day 17 (Day 0 = AI/NM) for progesterone dosage and cytokines were quantified from Day 0 to Day 12. Progesterone levels were constant, except for a decrease in ewes with RE at Day 17 (P < 0.05). Regardless of the reproductive method used, there was no difference in the IFNγ and IL-10 levels at any time, with averages of 642.1, 713.2, and 741.2 pg/mL for IFNγ and 667.1, 616.8, and 721.1 pg/mL for IL-10 when using CRI, laproscopy, and NM, respectively. Regarding the physiological status, ewes with EL had lower serum levels of IFNγ and IL-10 than pregnant ewes and ewes with RE, regardless of the reproductive method used, with averages of 769.1, 714.9, and 555.7 pg/mL for IFNγ and 713.8, 699.3, and 578.7 pg/mL for IL-10 in pregnant ewes, ewes with RE and EL, respectively (P < 0.01). In conclusion, AI by CRI in Santa Inês ewes does not alter the profile of serum cytokines IFNγ and IL-10 and does not induce an inflammatory reaction that can compromise pregnancy. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. [Roles of interleukin-10 differentiated dendritic cell of allergic asthma patients in T-lymphocyte proliferation in vitro].

    Science.gov (United States)

    Tang, Jian-feng; Guan, Shu-hong; Wang, Zhi-gang

    2012-10-30

    To explore the roles of interleukin (IL)-10 differentiated peripheral blood monocyte-derived dendritic cell (DC-10) of allergic asthma patients in T-lymphocytes proliferation in vitro. From January to June 2011, 10 subjects with dust mite allergic asthma treated at Third Affiliated Hospital of Soochow University were enrolled. Their peripheral blood monocytes were isolated by Ficoll-Hypaque solution density gradient centrifugation and adherent method. And the adherent monocytes were routinely cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF)+interleukin-4 (IL-4)+tumor necrosis factor-alpha (TNF-α), stimulated with/without interleukin-10 (IL-10), pulsed with dust mite allergen and finally harvested. The cell surface molecules including CD80, CD83, CD86, human leukocyte antigen (HLA)-DR and immunoglobulin-like transcript 2 (ILT2) were detected by immunofluorescent labeling and flow cytometry. And cellular functions were estimated by detecting the capacities of DC uptake antigens with fluorescein isothiocyanate (FITC)-dextran capturing assay. The IL-10 differentiation DC (DC-10) were cultured with autologous peripheral T cells (DC-10 group), either alone (DC-TNF group) or together (combined group) with autologous immunostimulatory DC (DC-TNF). And the impact of this treatment on T-cell responses was assessed for each donor by 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) assay. The production of interferon-γ (IFN-γ), IL-4, interleukin-5 (IL-5) and interleukin-13 (IL-13) were measured with the quantification of enzyme linked immunosorbent assay (ELISA) kits. In DC-10, the levels of some mature DC's markers (CD80, CD83, CD86 & HLA-DR) decreased, ILT2 increased and there were the higher capacities of up-taking FITC-dextran particle (72.32%±2.93% vs 54.41%±2.95%, PDC-10 group (1.06±0.18) and that of the combined group (1.34±0.16) were significantly inhibited (PDC-10 group versus (3223±203), (149±19), (2465±183) and

  17. IgE mediates killing of intracellular Toxoplasma gondii by human macrophages through CD23-dependent, interleukin-10 sensitive pathway.

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    Ioannis Vouldoukis

    Full Text Available BACKGROUND: In addition to helminthic infections, elevated serum IgE levels were observed in many protozoal infections, while their contribution during immune response to these pathogens remained unclear. As IgE/antigen immune complexes (IgE-IC bind to human cells through FcεRI or FcεRII/CD23 surface molecules, the present study aimed to identify which functional receptor may be involved in IgE-IC interaction with human macrophages, the major effector cell during parasite infection. METHODOLOGY/PRINCIPAL FINDINGS: Human monocyte-derived macrophages were infected with Toxoplasma gondii before being incubated with IgE-IC. IgE receptors were then identified using appropriate blocking antibodies. The activation of cells and parasiticidal activity were evaluated by mediator quantification and direct counting of infected macrophages. RNAs were extracted and cell supernatants were also collected for their content in tumor necrosis factor (TNF-α, interleukin-10 (IL-10 and nitrites. Sera from symptomatic infected patients were also tested for their content of IgE, IL-10 and nitrites, and compared to values found in healthy donors. Results showed that IgE-IC induced intracellular elimination of parasites by human macrophages. IgE-mediated effect was FcεRI-independent, but required cross-linking of surface FcεRII/CD23, cell activation and the generation of nitric oxide (NO. Although TNF-α was shown to be produced during cell activation, this cytokine had minor contribution in this phenomenon while endogenous and exogenous IL-10 down-regulated parasite killing. Inverse relationship was found between IL-10 and NO expression by infected human macrophages at both mRNA and mediator levels. The relationship between these in vitro data and in vivo levels of various factors in T. gondii infected patients supports the involvement of CD23 antigen and IL-10 expression in disease control. CONCLUSION: Thus, IgE may be considered as immune mediator during

  18. Induction of Interleukin-10 Producing Dendritic Cells As a Tool to Suppress Allergen-Specific T Helper 2 Responses

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    Stefan Schülke

    2018-03-01

    Full Text Available Dendritic cells (DCs are gatekeepers of the immune system that control induction and polarization of primary, antigen-specific immune responses. Depending on their maturation/activation status, the molecules expressed on their surface, and the cytokines produced DCs have been shown to either elicit immune responses through activation of effector T cells or induce tolerance through induction of either T cell anergy, regulatory T cells, or production of regulatory cytokines. Among the cytokines produced by tolerogenic DCs, interleukin 10 (IL-10 is a key regulatory cytokine limiting und ultimately terminating excessive T-cell responses to microbial pathogens to prevent chronic inflammation and tissue damage. Because of their important role in preventing autoimmune diseases, transplant rejection, allergic reactions, or in controlling chronic inflammation DCs have become an interesting tool to modulate antigen-specific immune responses. For the treatment of allergic inflammation, the aim is to downregulate allergen-specific T helper 2 (Th2 responses and the associated clinical symptoms [allergen-driven Th2 activation, Th2-driven immunoglobulin E (IgE production, IgE-mediated mast cell and basophil activation, allergic inflammation]. Here, combining the presentation of allergens by DCs with a pro-tolerogenic, IL-10-producing phenotype is of special interest to modulate allergen-specific immune responses in the treatment of allergic diseases. This review discusses the reported strategies to induce DC-derived IL-10 secretion for the suppression of allergen-specific Th2-responses with a focus on IL-10 treatment, IL-10 transduction, and the usage of both whole bacteria and bacteria-derived components. Interestingly, while IL-10-producing DCs induced either by IL-10 treatment or IL-10 transduction are arrested in an immature/semi-mature state, treatment of DCs with live or killed bacteria as well as isolated bacterial components results in the induction of

  19. Correlation between serum levels of interleukins 10 and 12 and thrombocytopenia in hepatitis C cirrhotic (class A patients

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    N Abdallah

    2010-01-01

    Full Text Available Hepatitis C virus (HCV patients commonly have low platelet counts; however, the exact role of HCV infection in thrombocytopenia is unknown. This work aimed to study the serum levels of interleukins (IL 10 and 12 in patients with mild and moderate thrombocytopenia associated with chronic hepatitis C infection. Our study included 15 patients with chronic HCV infection and newly diagnosed isolated autoimmune thrombocytopenia (Group I and 15 patients with chronic HCV infection and normal platelet count as controls (Group II. All patients were examined for personal history and clinical aspects, complete blood count, bone marrow aspiration, liver function tests, HCV antibody assay by ELISA and polymerase chain reaction (PCR, abdominal ultrasound, Helicobacter pylori stool antigen test, evaluation of serum levels of IL-10, IL-12 and platelet specific antibodies. Our results revealed that eight patients from Group l had mild thrombocytopenia and seven patients had moderate thrombocytopenia. Serum IL-10 level was significantly elevated (t = 9.301, p < 0.001 while serum IL-12 showed a significant decrease (t = 6.502, p < 0.001 in Group I compared to the control group. No correlation was detected between platelet counts and the serum levels of either IL-10 [r = 0.454, p = 0.089 (Group I, r = 0.038, p = 0.89 (Group II] or IL-12 [r = 0.497, p = 0.06 (Group I, r = 0.499, p = 0.058 (Group II]. However, in Group I, a significant correlation was present only between moderate thrombocytopenia and serum levels of either IL-10 (r = 0.794, p = 0.033 or IL-12 (r = 0.967, p = 0.001, while no correlation was detected between these interleukin parameters and mild thrombocytopenia (r = 0.311 and p = 0.453 for IL-10 and r = -0.08 and p = 0.851 for IL-12. Based on our data, we may conclude that interleukins 10 and 12 are involved in low platelet levels.

  20. Association of interleukin-10 promoter haplotypes with disease susceptibility and IL-10 levels in Mexican patients with systemic lupus erythematosus.

    Science.gov (United States)

    Palafox-Sánchez, Claudia Azucena; Oregon-Romero, Edith; Salazar-Camarena, Diana Celeste; Valle, Yeminia Maribel; Machado-Contreras, Jesús René; Cruz, Alvaro; Orozco-López, Mariana; Orozco-Barocio, Gerardo; Vázquez-Del Mercado, Mónica; Muñoz-Valle, José Francisco

    2015-11-01

    Systemic lupus erythematosus (SLE) is the prototype autoimmune rheumatic disease. The etiology of this disease is incompletely understood; however, environmental factors and genetic predisposition are involved. Cytokine-mediated immunity plays a crucial role in the pathogenesis of SLE. We investigate the association of interleukin-10 (IL-10) promoter polymorphisms and their haplotypes in SLE patients from the western Mexico. One hundred and twenty-five SLE patients fulfilling the 1997 ACR criteria and 260 unrelated healthy subjects (HS), both Mexican mestizos, were genotyped for IL-10 -1082A>G, -819C>T, and -592C>A polymorphisms. Haplotypes were inferred using the expectation-maximization algorithm, then allele and haplotype distributions were compared between patients and HS, as well as patients with different clinical variables. We identified at -1082, -819, and -592 four predominant haplotypes ACC (43.70 % in patients vs 46.55 % in HS), ATA (21.45 vs 22.97 %), GCC (16.28 vs 14.21 %), and GTA (14.12 vs 14.12 %). The ATC haplotype was more frequent in SLE respect to HS, suggesting a risk effect (3.23 vs 1.05 %; OR 3.55, CI 1.14-11.11; p = 0.0293). SLE patient carriers of -592 CC genotype as well as the dominant model of inheritance showed higher sIL-10 respect to AA genotype, suggesting that -592 C allele is associated with increased production of the cytokine (p < 0.05). The ACC haplotype had higher IL-10 serum levels and higher values of Mexican version of the Systemic Lupus Erythematosus Disease Activity Index compared with the other haplotype carriers; however, no association was found regarding autoantibodies. Our data suggest that the IL-10 promoter haplotypes play an important role in the risk of developing SLE and influence the production of IL-10 in Mexican population. Nevertheless, further studies are required to analyze the expression of mRNA as well as to investigate the interacting epigenetic factors that could help to define the true contribution of

  1. Genome-Wide Association Study Identifies That the ABO Blood Group System Influences Interleukin-10 Levels and the Risk of Clinical Events in Patients with Acute Coronary Syndrome

    OpenAIRE

    Johansson, ?sa; Alfredsson, Jenny; Eriksson, Niclas; Wallentin, Lars; Siegbahn, Agneta

    2015-01-01

    Introduction Acute coronary syndrome (ACS) is a major cause of mortality worldwide. We have previously shown that increased interleukin-10 (IL-10) levels are associated with poor outcome in ACS patients. Method We performed a genome-wide association study in 2864 ACS patients and 408 healthy controls, to identify genetic variants associated with IL-10 levels. Then haplotype analyses of the identified loci were done and comparisons to levels of IL-10 and other known ACS related biomarkers. Res...

  2. Interleukin-10 increases reverse cholesterol transport in macrophages through its bidirectional interaction with liver X receptor α

    Energy Technology Data Exchange (ETDEWEB)

    Halvorsen, Bente, E-mail: Bente.Halvorsen@rr-research.no [Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo (Norway); Institute of Clinical Medicine, University of Oslo, Oslo (Norway); K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo (Norway); Holm, Sverre [Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo (Norway); Yndestad, Arne [Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo (Norway); Institute of Clinical Medicine, University of Oslo, Oslo (Norway); K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo (Norway); Scholz, Hanne [Section for Transplantation, Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo (Norway); Sagen, Ellen Lund [Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo (Norway); Nebb, Hilde [Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo (Norway); Institute of Clinical Medicine, University of Oslo, Oslo (Norway); Holven, Kirsten B. [Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo (Norway); Dahl, Tuva B. [Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo (Norway); Institute of Clinical Medicine, University of Oslo, Oslo (Norway); Aukrust, Pål [Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo (Norway); Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo (Norway); Institute of Clinical Medicine, University of Oslo, Oslo (Norway); K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo (Norway)

    2014-08-08

    Highlights: • IL-10 promotes reverse cholesterol efflux from lipid loaded macrophages. • IL-10 increases the expression of ABCA-1 and ABCG-1. • IL-10 exhibits cross-talk with the nuclear receptor LXRα. - Abstract: Interleukin (IL)-10 is a prototypical anti-inflammatory cytokine that has been shown to attenuate atherosclerosis development. In addition to its anti-inflammatory properties, the anti-atherogenic effect of IL-10 has recently also been suggested to reflect a complex effect of IL-10 on lipid metabolism in macrophages. In the present study we examined the effects of IL-10 on cholesterol efflux mechanism in lipid-loaded THP-1 macrophages. Our main findings were: (i) IL-10 significantly enhanced cholesterol efflux induced by fetal-calf serum, high-density lipoprotein (HDL){sub 2} and apolipoprotein A-1. (ii) The IL-10-mediated effects on cholesterol efflux were accompanied by an increased IL-10-mediated expression of the ATP-binding cassette transporters ABCA1 and ABCG1, that was further enhanced when the cells were co-activated with the liver X receptor (LXR)α agonist (22R)-hydroxycholesterol. (iii) The effect of LXRα activation on the IL-10-mediated effects on the ATP-binding cassette transporters seems to include enhancing effects on the IL-10 receptor 1 (IL10R1) expression and interaction with STAT-3 signaling. (iv) These enhancing effects on ABCA1 and ABCG1 was not seen when the cells were stimulated with the IL-10 family members IL-22 and IL-24. This study suggests that the anti-atherogenic properties of IL-10 may include enhancing effects on cholesterol efflux mechanism that involves cross-talk with LXRα activation.

  3. Interleukin-10 increases reverse cholesterol transport in macrophages through its bidirectional interaction with liver X receptor α

    International Nuclear Information System (INIS)

    Halvorsen, Bente; Holm, Sverre; Yndestad, Arne; Scholz, Hanne; Sagen, Ellen Lund; Nebb, Hilde; Holven, Kirsten B.; Dahl, Tuva B.; Aukrust, Pål

    2014-01-01

    Highlights: • IL-10 promotes reverse cholesterol efflux from lipid loaded macrophages. • IL-10 increases the expression of ABCA-1 and ABCG-1. • IL-10 exhibits cross-talk with the nuclear receptor LXRα. - Abstract: Interleukin (IL)-10 is a prototypical anti-inflammatory cytokine that has been shown to attenuate atherosclerosis development. In addition to its anti-inflammatory properties, the anti-atherogenic effect of IL-10 has recently also been suggested to reflect a complex effect of IL-10 on lipid metabolism in macrophages. In the present study we examined the effects of IL-10 on cholesterol efflux mechanism in lipid-loaded THP-1 macrophages. Our main findings were: (i) IL-10 significantly enhanced cholesterol efflux induced by fetal-calf serum, high-density lipoprotein (HDL) 2 and apolipoprotein A-1. (ii) The IL-10-mediated effects on cholesterol efflux were accompanied by an increased IL-10-mediated expression of the ATP-binding cassette transporters ABCA1 and ABCG1, that was further enhanced when the cells were co-activated with the liver X receptor (LXR)α agonist (22R)-hydroxycholesterol. (iii) The effect of LXRα activation on the IL-10-mediated effects on the ATP-binding cassette transporters seems to include enhancing effects on the IL-10 receptor 1 (IL10R1) expression and interaction with STAT-3 signaling. (iv) These enhancing effects on ABCA1 and ABCG1 was not seen when the cells were stimulated with the IL-10 family members IL-22 and IL-24. This study suggests that the anti-atherogenic properties of IL-10 may include enhancing effects on cholesterol efflux mechanism that involves cross-talk with LXRα activation

  4. Tr-1-like CD4+CD25-CD127-/lowFOXP3- cells are the main source of interleukin 10 in patients with cutaneous leishmaniasis due to Leishmania braziliensis.

    Science.gov (United States)

    Costa, Diego L; Cardoso, Tiago M; Queiroz, Adriano; Milanezi, Cristiane M; Bacellar, Olívia; Carvalho, Edgar M; Silva, João S

    2015-03-01

    CD4(+)CD25(+)FOXP3(+) regulatory T cells have long been shown to mediate susceptibility to Leishmania infection, mainly via interleukin 10 production. In this work, we showed that the main sources of interleukin 10 in peripheral blood mononuclear cells (PBMCs) from patients with cutaneous leishmaniasis due to Leishmania braziliensis are CD4(+)CD25(-)CD127(-/low)FOXP3(-) cells. Compared with uninfected controls, patients with CL had increased frequencies of circulating interleukin 10-producing CD4(+)CD25(-)CD127(-/low) cells, which efficiently suppressed tumor necrosis factor α production by the total PBMC population. Also, in CL lesions, interleukin 10 was mainly produced by CD4(+)CD25(-) cells, and interleukin 10 messenger RNA expression was associated with interleukin 27, interleukin 21, and interferon γ expression, rather than with FOXP3 or transforming growth factor β expressions. Active production of both interleukin 27 and interleukin 21, together with production of interferon γ and interleukin 10, was also detected in the lesions. Since these cytokines are associated with the differentiation and activity of Tr-1 cells, our results suggest that this cell population may play an important role in the immunomodulation of CL. Therefore, development of treatments that interfere with this pathway may lead to faster parasite elimination. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. Gene Expression Changes in the Colon Epithelium Are Similar to Those of Intact Colon during Late Inflammation in Interleukin-10 Gene Deficient Mice

    Science.gov (United States)

    Russ, Anna E.; Peters, Jason S.; McNabb, Warren C.; Barnett, Matthew P. G.; Anderson, Rachel C.; Park, Zaneta; Zhu, Shuotun; Maclean, Paul; Young, Wayne; Reynolds, Gordon W.; Roy, Nicole C.

    2013-01-01

    In addition to their role in absorption and secretion, epithelial cells play an important role in the protection of the colon mucosa from the resident microbiota and are important for the maintenance of homeostasis. Microarray analysis of intact colon samples is widely used to gain an overview of the cellular pathways and processes that are active in the colon during inflammation. Laser microdissection of colon epithelial cells allows a more targeted analysis of molecular pathways in the mucosa, preceding and during inflammation, with potentially increased sensitivity to changes in specific cell populations. The aim of this study was to investigate the molecular changes that occur in early and late inflammation stages in colon epithelium of a mouse model of inflammatory bowel diseases. Microarray analysis of intact colon samples and microdissected colon epithelial cell samples from interleukin-10 gene deficient and control mice at 6 and 12 weeks of age was undertaken. Results of gene set enrichment analysis showed that more immune-related pathways were identified between interleukin-10 gene deficient and control mice at 6 weeks of age in epithelial cells than intact colon. This suggests that targeting epithelial cells could increase sensitivity for detecting immune changes that occur early in the inflammatory process. However, in the later stages of inflammation, microarray analyses of intact colon and epithelium both provide a similar overview of gene expression changes in the colon mucosa at the pathway level. PMID:23700416

  6. Gene expression changes in the colon epithelium are similar to those of intact colon during late inflammation in interleukin-10 gene deficient mice.

    Directory of Open Access Journals (Sweden)

    Anna E Russ

    Full Text Available In addition to their role in absorption and secretion, epithelial cells play an important role in the protection of the colon mucosa from the resident microbiota and are important for the maintenance of homeostasis. Microarray analysis of intact colon samples is widely used to gain an overview of the cellular pathways and processes that are active in the colon during inflammation. Laser microdissection of colon epithelial cells allows a more targeted analysis of molecular pathways in the mucosa, preceding and during inflammation, with potentially increased sensitivity to changes in specific cell populations. The aim of this study was to investigate the molecular changes that occur in early and late inflammation stages in colon epithelium of a mouse model of inflammatory bowel diseases. Microarray analysis of intact colon samples and microdissected colon epithelial cell samples from interleukin-10 gene deficient and control mice at 6 and 12 weeks of age was undertaken. Results of gene set enrichment analysis showed that more immune-related pathways were identified between interleukin-10 gene deficient and control mice at 6 weeks of age in epithelial cells than intact colon. This suggests that targeting epithelial cells could increase sensitivity for detecting immune changes that occur early in the inflammatory process. However, in the later stages of inflammation, microarray analyses of intact colon and epithelium both provide a similar overview of gene expression changes in the colon mucosa at the pathway level.

  7. Effect of Nigella Sativa Extract on Inflammatory Cells, Interleukin-10, Interferon-γ and Histological of Kidney in Monosodium Glutamate-Induced Rats

    Directory of Open Access Journals (Sweden)

    Abdalrauf A Mahmud Yousif

    2016-04-01

    Full Text Available There is considerable evidence, suggest that, consumption of food additives monosodium glutamate (MSG, a flavor enhancer was unhealthy. Herbal medicine Nigella sativa (NS has antioxidant properties able to cure the toxic induced by MSG. This study aimed to evaluate the risks of excessive use of MSG and to study the role of NS to inhibit inflammation and renal damage. Treated rats (twenty four male wistar rats were divided into six group and analyzed by measuring the cells in blood, interleukin-10, interferon-γ serum levels by ELISA method and remove kidneys for histological examination. Histological of kidney for all groups except control, were showed different abnormalities include congestion of some blood vessels, hemorrhage between tubules, widening in the renal tubules, revealed severe dilatation of Bowman's capsule and shrinkage of glomeruli, and areas of huge vacuole, were observed compared with control. Interleukin-10 was reduced in Groups 2,3,4 and 5, whereas increase in NS group compared with control. Interferon-γ was increased in groups 2,3,4 and reduced in groups 5,6 compared with control. Eosinophil was increased in groups 2,5 and reduced in groups 3,4, 6 compared with control. This present study showed that administration of MSG to rats induced many changes effects on inflammatory cells, cytokines and histological of kidneys. NS has benefit in blood parameters, whereas harmful on kidney at these doses.

  8. Interaction between interleukin-10 (IL-10) polymorphisms and dietary fibre in relation to risk of colorectal cancer in a Danish case-cohort study

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Egeberg, Rikke; Tjonneland, Anne

    2012-01-01

    Background: More than 50% of the colorectal cancer (CRC) etiology has been attributed to diet. Established or suspected dietary factors modifying risk of CRC are red meat, cereals, fish, and fibre. Diet and lifestyle may be linked to cancer through inflammation. Interleukin-10 (IL-10) is an anti......-inflammatory cytokine. We wanted to test if dietary factors and IL10 polymorphisms interact in relation to colorectal carcinogenesis. Methods: The functional IL10 polymorphism C-592A (rs1800872) and the marker rs3024505 were assessed in relation to diet and lifestyle in a nested case-cohort study of 378 CRC cases...... and 775 randomly selected participants from a prospective study of 57,053 persons. Genotyping data on the IL10 polymorphism C-592A, smoking and nonsteroidal anti-inflammatory drugs (NSAID) was retrieved from Vogel et al. (Mutat Res, 2007; 624: 88). Incidence rate ratios (IRR) and 95% Confidence Interval...

  9. Electronic effects in emission of core/shell CdSe/ZnS quantum dots conjugated to anti-Interleukin 10 antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Quintos Vazquez, A.L. [ESIME—Instituto Politécnico Nacional, México D. F. 07738, México (Mexico); Torchynska, T.V., E-mail: ttorch@esfm.ipn.mx [ESFM–Instituto Politécnico Nacional, México D. F. 07738, México (Mexico); Casas Espinola, J.L. [ESFM–Instituto Politécnico Nacional, México D. F. 07738, México (Mexico); Jaramillo Gómez, J.A.; Douda, J. [UPIITA–Instituto Politécnico Nacional, México D. F. 07320, México (Mexico)

    2013-11-15

    The paper presents a comparative study of the photoluminescence (PL) and Raman scattering spectra of the core–shell CdSe/ZnS quantum dots (QDs) in nonconjugated states and after the conjugation to anti-Interleukin 10 antibodies (anti-IL10). All optical measurements are performed on the dried droplets of the original solution of nonconjugated and bioconjugated QDs located on the Si substrate. CdSe/ZnS QDs with emission at 605 and 655 nm have been used. PL spectra of nonconjugated QDs are characterized by one Gaussian shape PL band related to the exciton emission in the CdSe core. PL spectra of bioconjugated QDs have changed essentially: the core PL band shifts into the high energy spectral range (“blue” sift) and becomes asymmetric. Additionally two new PL bands appear. A set of physical reasons has been proposed for the “blue” shift explanation for the core PL band in bioconjugated QDs. Then Raman scattering spectra have been studied with the aim to analyze the impact of elastic strains or the oxidation process at the QD bioconjugation. The variation of PL spectra versus excitation light intensities has been studied to analyze the exciton emission via excited states in QDs. Finally the PL spectrum transformation for the core emission in bioconjugated QDs has been attributed to the electronic quantum confined effects stimulated by the electric charges of bioconjugated antibodies. -- Highlights: • The conjugation of CdSe/ZnS QDs to anti-Interleukin 10 antibodies has been studied. • PL shift to high energy is detected in bioconjugated CdSe/ZnS QDs. • The PL energy shift in bioconjugated QDs is stimulated by antibody electric charges. • The reasons of PL energy shift in bioconjugated QDs have been discussed.

  10. Interleukin-10 does not mediate the inhibitory effect of PDE-4 inhibitors and other cAMP-elevating drugs on lipopolysaccharide-induced tumors necrosis factor-alpha generation from human peripheral blood monocytes.

    Science.gov (United States)

    Seldon, P M; Barnes, P J; Giembycz, M A

    1998-01-01

    Lipopolysaccharide (LPS)-induced liver injury in mice and LPS-induced tumor necrosis factor-alpha (TNF-alpha) generation by murine macrophages and hepatocytes are suppressed markedly by agents that elevate intracellular cAMP. Phosphodiesterase (PDE)-4 inhibitors, beta 2-adrenoceptor agonists, and E-series prostaglandins also attenuate the induction of the TNF-alpha gene in human monocytes in response to bacterial LPS. The mechanism of action of cAMP is unclear, but in the mouse, is believed to involve the generation of this anti-inflammatory cytokine, interleukin-10 (IL-10). In this article, we describe the results of studies designed to determine the extent to which IL-10 contributes to the suppression of TNF-alpha generation from LPS-stimulated human monocytes evoked by 8-bromo cyclic AMP (8-Br-cAMP), rolipram, salbutamol, and prostaglandin E2 (PGE2). LPS evoked a time- and concentration-dependent generation of TNF-alpha (t1/2 = 4.5 h; EC50 = 273 pg/mL), which was inhibited by exogenous human recombinant (h) IL-10 (IC50 = 124 pg/mL), and by rolipram (EC50 = 420 nM), 8-Br-cAMP (EC50 = 77 (microM), PGE2 (EC50 = 15 nM) and salbutamol (EC50 = 20 nM). In addition, 8-Br-cAMP, PGE2; and salbutamol (but not rolipram) augmented significantly LPS-induced IL-10 production (two-to-fivefold) under identical experimental conditions. Pretreatment of monocytes with an anti-IL-10 monoclonal antibody (MAb) that abolished the inhibitory action of a maximally effective concentration of exogenous hrIL-10, failed to attenuate the inhibitory effect of rolipram, PGE2, salbutamol, and 8-Br-cAMP. Anti-IL-10 was similarly inactive when the number of monocytes seeded was increased from 0.5 to 4 x 10(6)/mL or when measurements were made at 42 h post-LPS, a time when the concentration of IL-10 released was maximal. Collectively, these data suggest that in contrast to murine hepatocytes and macrophages, IL-10 does not mediate the inhibitory effect of cAMP-elevating drugs on TNF

  11. Elements to diminish radioactive accidents

    International Nuclear Information System (INIS)

    Cortes I, M.E.; Ramirez G, F.P.

    1998-01-01

    In this work it is presented an application of the cause-effect diagram method or Ichikawa method identifying the elements that allow to diminish accidents when the radioactive materials are transported. It is considered the transport of hazardous materials which include radioactive materials in the period: December 1996 until March 1997. Among the identified elements by this method it is possible to mention: the road type, the radioactive source protection, the grade driver responsibility and the preparation that the OEP has in the radioactive material management. It is showed the differences found between the country inner roads and the Mexico City area. (Author)

  12. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  13. Antihyperglycemic effect of Sesbania grandiflora seed decoction on streptozotocin-induced diabetic mice: Inflammatory status and the role of interleukin-10

    Science.gov (United States)

    Zamroni, Ahmad; Widjanarko, Simon B.; Rifa'i, Muhaimin; Zubaidah, Elok

    2017-05-01

    Diabetes is one of the fastest growing diseases in the world: its prevalence is estimated to reach 642 million people, or one-tenth of adults will have diabetes by 2040. Traditional herbal exploration and investigation are needed in order to discover medicines that have potential anti-diabetic activity, with no or lower side effects than the medicines clinically used today. In this research, we investigated the anti-hyperglycemic activity of an aqueous decoction of Sesbania grandiflora seeds in streptozotocin-induced diabetic mice, and analyzed the immune responses that occurred during the counter balance process to reach blood glucose homeostasis. Our results revealed that administration of the aqueous decoction (2.5 g/kg BW) could lower the blood glucose levels of diabetic mice from an initial blood glucose level of 435 mg/dl to 213 mg/dl within 18 days of treatment. Analysis of inflammatory markers showed that there was no significant difference in the relative amounts of CD4+CD62L-, CD8+CD62L-, TNF-α or IFN-γ between the experimental groups, which revealed that there were no pro-inflammatory responses involved either in hyperglycemia or in the blood glucose lowering process. On the other hand, an increased amount of interleukin-10 in diabetic mice treated with an S. grandiflora seed decoction indicated a role for IL-10 in maintaining blood glucose homeostasis.

  14. A Glucuronoxylomannan-Associated Immune Signature, Characterized by Monocyte Deactivation and an Increased Interleukin 10 Level, Is a Predictor of Death in Cryptococcal Meningitis.

    Science.gov (United States)

    Scriven, James E; Graham, Lisa M; Schutz, Charlotte; Scriba, Thomas J; Wilkinson, Katalin A; Wilkinson, Robert J; Boulware, David R; Urban, Britta C; Lalloo, David G; Meintjes, Graeme

    2016-06-01

    Cryptococcal meningitis remains a significant cause of death among human immunodeficiency virus type 1 (HIV)-infected persons in Africa. We aimed to better understand the pathogenesis and identify immune correlates of mortality, particularly the role of monocyte activation. A prospective cohort study was conducted in Cape Town, South Africa. Patients with a first episode of cryptococcal meningitis were enrolled, and their immune responses were assessed in unstimulated and stimulated blood specimens, using flow cytometry and cytokine analysis. Sixty participants were enrolled (median CD4(+) T-cell count, 34 cells/µL). Mortality was 23% (14 of 60 participants) at 14 days and 39% (22 of 57) at 12 weeks. Nonsurvivors were more likely to have an altered consciousness and higher cerebrospinal fluid fungal burden at presentation. Principal component analysis identified an immune signature associated with early mortality, characterized by monocyte deactivation (reduced HLA-DR expression and tumor necrosis factor α response to lipopolysaccharide); increased serum interleukin 6, CXCL10, and interleukin 10 levels; increased neutrophil counts; and decreased T-helper cell type 1 responses. This immune signature remained an independent predictor of early mortality after adjustment for consciousness level and fungal burden and was associated with higher serum titers of cryptococcal glucuronoxylomannan. Cryptococcal-related mortality is associated with monocyte deactivation and an antiinflammatory blood immune signature, possibly due to Cryptococcus modulation of the host immune response. Validation in other cohorts is required. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

  15. Changes in composition of caecal microbiota associated with increased colon inflammation in interleukin-10 gene-deficient mice inoculated with Enterococcus species.

    Science.gov (United States)

    Bassett, Shalome A; Young, Wayne; Barnett, Matthew P G; Cookson, Adrian L; McNabb, Warren C; Roy, Nicole C

    2015-03-11

    Human inflammatory bowel disease (IBD) is a chronic intestinal disease where the resident microbiota contributes to disease development, yet the specific mechanisms remain unclear. Interleukin-10 gene-deficient (Il10-/-) mice develop inflammation similar to IBD, due in part to an inappropriate response to commensal bacteria. We have previously reported changes in intestinal morphology and colonic gene expression in Il10-/- mice in response to oral bacterial inoculation. In this study, we aimed to identify specific changes in the caecal microbiota associated with colonic inflammation in these mice. The microbiota was evaluated using pyrotag sequencing, denaturing gradient gel electrophoresis (DGGE) and quantitative real-time PCR. Microbiota profiles were influenced by genotype of the mice and by bacterial inoculation, and a strong correlation was observed between the microbiota and colonic inflammation scores. Although un-inoculated Il10-/- and C57 mice had similar microbiota communities, bacterial inoculation resulted in different changes to the microbiota in Il10-/- and C57 mice. Inoculated Il10-/- mice had significantly less total bacteria than un-inoculated Il10-/- mice, with a strong negative correlation between total bacterial numbers, relative abundance of Escherichia/Shigella, microbiota diversity, and colonic inflammation score. Our results show a putative causative role for the microbiota in the development of IBD, with potentially key roles for Akkermansia, or for Bacteroides, Helicobacter, Parabacteroides, and Alistipes, depending on the composition of the bacterial inoculum. These data support the use of bacterially-inoculated Il10-/- mice as an appropriate model to investigate human IBD.

  16. Interleukin 10–Dominant Immune Response and Increased Risk of Cutaneous Leishmaniasis After Natural Exposure to Lutzomyia intermedia Sand Flies

    Science.gov (United States)

    Carvalho, Augusto M.; Cristal, Juqueline R.; Muniz, Aline C.; Carvalho, Lucas P.; Gomes, Regis; Miranda, José C.; Barral, Aldina; Carvalho, Edgar M.; de Oliveira, Camila I.

    2015-01-01

    Background. Leishmaniasis is caused by parasites transmitted to the vertebrate host by infected sand flies. During transmission, the vertebrate host is also inoculated with sand fly saliva, which exerts powerful immunomodulatory effects on the host's immune response. Methods. We conducted a prospective cohort analysis to characterize the human immune response to Lutzomyia intermedia saliva in 264 individuals, from an area for cutaneous leishmaniasis (CL) caused by Leishmania braziliensis. Results. Antibodies were found in 150 individuals (56.8%); immunoglobulin G1 and G4 were the predominant subclasses. Recall responses to salivary gland sonicate showed elevated production of interleukin 10 (IL-10), interleukin 13, interferon γ, CXCL9, and CCL2 compared with controls. CD4+CD25+ T cells, including Foxp3+ cells, were the main source of IL-10. L. braziliensis replication was increased (P < .05) in macrophages cocultured with saliva-stimulated lymphocytes from exposed individuals and addition of anti–IL-10 reverted this effect. Positive correlation between antibody response to saliva and cellular response to Leishmania was not found. Importantly, individuals seropositive to saliva are 2.1 times more likely to develop CL (relative risk, 2.1; 95% confidence interval, 1.07–4.2; P < .05). Conclusions. Exposure to L. intermedia sand flies skews the human immune response, facilitating L. braziliensis survival in vitro, and increases the risk of developing CL. PMID:25596303

  17. In vitro infection of bovine monocytes with Mycoplasma bovis delays apoptosis and suppresses production of gamma interferon and tumor necrosis factor alpha but not interleukin-10.

    Science.gov (United States)

    Mulongo, Musa; Prysliak, Tracy; Scruten, Erin; Napper, Scott; Perez-Casal, Jose

    2014-01-01

    Mycoplasma bovis is one of the major causative pathogens of bovine respiratory complex disease (BRD), which is characterized by enzootic pneumonia, mastitis, pleuritis, and polyarthritis. M. bovis enters and colonizes bovine respiratory epithelial cells through inhalation of aerosol from contaminated air. The nature of the interaction between M. bovis and the bovine innate immune system is not well understood. We hypothesized that M. bovis invades blood monocytes and regulates cellular function to support its persistence and systemic dissemination. We used bovine-specific peptide kinome arrays to identify cellular signaling pathways that could be relevant to M. bovis-monocyte interactions in vitro. We validated these pathways using functional, protein, and gene expression assays. Here, we show that infection of bovine blood monocytes with M. bovis delays spontaneous or tumor necrosis factor alpha (TNF-α)/staurosporine-driven apoptosis, activates the NF-κB p65 subunit, and inhibits caspase-9 activity. We also report that M. bovis-infected bovine monocytes do not produce gamma interferon (IFN-γ) and TNF-α, although the level of production of interleukin-10 (IL-10) is elevated. Our findings suggest that M. bovis takes over the cellular machinery of bovine monocytes to prolong bacterial survival and to possibly facilitate subsequent systemic distribution.

  18. Cloning of Interleukin-10 from African Clawed Frog (Xenopus tropicalis, with the Finding of IL-19/20 Homologue in the IL-10 Locus

    Directory of Open Access Journals (Sweden)

    Zhitao Qi

    2015-01-01

    Full Text Available Interleukin-10 (IL-10 is a pleiotropic cytokine that plays an important role in immune system. In the present study, the IL-10 gene of African clawed frog (Xenopus tropicalis was first cloned, and its expression pattern and 3D structure were also analyzed. The frog IL-10 mRNA encoded 172 amino acids which possessed several conserved features found in IL-10s from other species, including five-exon/four-intron genomic structure, conserved four cysteine residues, IL-10 family motif, and six α-helices. Real-time PCR showed that frog IL-10 mRNA was ubiquitous expressed in all examined tissues, highly in some immune related tissues including kidney, spleen, and intestine and lowly in heart, stomach, and liver. The frog IL-10 mRNA was upregulated at 24 h after LPS stimulation, indicating that it plays a part in the host immune response to bacterial infection. Another IL, termed as IL-20, was identified from the frog IL-10 locus, which might be the homologue of mammalian IL-19/20 according to the analysis results of the phylogenetic tree and the sequence identities.

  19. STAT3 activation is associated with cerebrospinal fluid interleukin-10 (IL-10) in primary central nervous system diffuse large B cell lymphoma.

    Science.gov (United States)

    Mizowaki, Takashi; Sasayama, Takashi; Tanaka, Kazuhiro; Mizukawa, Katsu; Takata, Kumi; Nakamizo, Satoshi; Tanaka, Hirotomo; Nagashima, Hiroaki; Nishihara, Masamitsu; Hirose, Takanori; Itoh, Tomoo; Kohmura, Eiji

    2015-09-01

    Signal transducers and activators of transcription 3 (STAT3) are activated by various cytokines and oncogenes; however, the activity and pathogenesis of STAT3 in diffuse large B cell lymphoma of the central nervous system have not been thoroughly elucidated. We investigated the phosphorylation levels of STAT3 in 40 specimens of primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) and analyzed the association between phsopho-STAT3 (pSTAT3) expression and cerebrospinal fluid (CSF) concentration of interleukin-10 (IL-10) or IL-6. Immunohistochemistry and Western blot analysis revealed that most of the specimens in PCNS DLBCL expressed pSTST3 protein, and a strong phosphorylation levels of STAT3 was statistically associated with high CSF IL-10 levels, but not with CSF IL-6 levels. Next, we demonstrated that recombinant IL-10 and CSF containing IL-10 induced the phosphorylation of STAT3 in PCNS DLBCL cells. Furthermore, molecular subtype classified by Hans' algorithm was correlated with pSTAT3 expression levels and CSF IL-10 levels. These results suggest that the STAT3 activity is correlated with CSF IL-10 level, which is a useful marker for STAT3 activity in PCNS DLBCLs.

  20. Whole body hyperthermia treatment increases interleukin 10 and toll-like receptor 4 expression in patients with ankylosing spondylitis: a pilot study.

    Science.gov (United States)

    Zauner, Dorothea; Quehenberger, Franz; Hermann, Josef; Dejaco, Christian; Stradner, Martin H; Stojakovic, Tatjana; Angerer, Hannes; Rinner, Beate; Graninger, Winfried B

    2014-09-01

    Exposure to increased environmental temperatures is commonly used as a non-pharmacological treatment modality in ankylosing spondylitis (AS). We aimed to investigate systemic immunological effects of moderate whole body hyperthermia in patients with AS compared to healthy control subjects. Ten healthy control subjects and six AS patients underwent whole body hyperthermia treatment with 38.7-39 °C body core temperature over 60 min. Numbers of polymorphonuclear leucocytes and lymphocyte subsets, plasma concentrations of several acute phase reactants and cytokines, and gene expression levels of toll-like receptor 4 (TLR-4), interleukin 10 (IL-10) and heat shock protein beta 1 (HSPB1) were determined during and up to 24 h after treatment. TLR-4, IL-10 and HSPB1 gene expression increased significantly up to 3 h post treatment, with an earlier, higher and more pronounced increase of IL-10 in patients with AS. An increase of natural killer cells and CD8+ T lymphocytes was noted during active heating, with a subsequent decrease up to 2 h after treatment. CD4+ T lymphocytes showed a short increase during active treatment in AS patients, while decreasing immediately after start of treatment in control subjects. Neutrophil granulocytes increased significantly up to 3 h after treatment, monocytes and B lymphocytes remained unchanged. Likewise, no significant changes were found concerning systemic cytokine concentrations and acute phase reactants. Our data support the concept of systemic immunological effects of moderate whole body hyperthermia in patients with AS.

  1. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production.

    Science.gov (United States)

    Németh, Krisztián; Leelahavanichkul, Asada; Yuen, Peter S T; Mayer, Balázs; Parmelee, Alissa; Doi, Kent; Robey, Pamela G; Leelahavanichkul, Kantima; Koller, Beverly H; Brown, Jared M; Hu, Xuzhen; Jelinek, Ivett; Star, Robert A; Mezey, Eva

    2009-01-01

    Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCs -- also known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF) receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-alpha) reprogram macrophages by releasing prostaglandin E(2) that acts on the macrophages through the prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups.

  2. Changes of regulatory T cells, transforming growth factor-beta and interleukin-10 in patients with type 1 diabetes mellitus: A systematic review and meta-analysis.

    Science.gov (United States)

    Qiao, Yong-Chao; Shen, Jian; Hong, Xue-Zhi; Liang, Ling; Bo, Chao-Sheng; Sui, Yi; Zhao, Hai-Lu

    2016-09-01

    Regulatory T lymphocyte cells (Treg) associated with interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) have implicated in the development of type 1 diabetes mellitus (T1DM), yet the existing evidence remains unclear. Hereby we performed a systematic review and meta-analysis to characterize the changes in T1DM patients. A total of 1407 T1DM patients and 1373 healthy controls from 40 case-control studies were eventually included in the pooling analysis. Compared with the controls, T1DM patients had decreased frequency of CD4(+)CD25(+)Treg (p=0.0003), CD4(+)CD25(+)Foxp3(+)Treg (p=0.020), and the level of TGF-β (p=0.030). Decrease in IL-10 (p=0.14) was not significant. All the changes remained significant when the studies with low NOS scores and publication bias were excluded. In conclusion, peripheral Treg and serum TGF-β are reduced in type 1 diabetes mellitus whereas changes in serum IL-10 are not significant. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Association of interleukin 10 and interferon gamma gene polymorphisms with enterovirus 71 encephalitis in patients with hand, foot and mouth disease.

    Science.gov (United States)

    Yang, Jing; Zhao, Na; Su, Nai-Lun; Sun, Jian-Lan; Lv, Tie-Gang; Chen, Zong-Bo

    2012-06-01

    Enterovirus 71 (EV71) is one of the common causative agents of hand, foot and mouth disease (HFMD), and is associated with several outbreaks with neurological complications including encephalitis. This study investigated the polymorphisms of interferon gamma (IFN-γ)+874 T/A and interleukin 10 (IL-10)-1082 G/A in 65 Chinese patients with EV71 encephalitis and 113 Chinese HFMD patients without complications. The polymorphisms of IFN-γ+874 T/A and IL-10-1082 G/A were determined by polymerase chain reaction (PCR)-amplification refractory mutation system (ARMS) and PCR-sequence-specific primer (SSP) analysis, respectively. The IFN-γ + 874 A allele was observed with significantly greater frequency in patients with EV71 encephalitis (76.2%) compared with HFMD patients without complications (61.1%, p encephalitis (86.2%) compared with HFMD patients without complications (77.0%, p associated with susceptibility to EV71 encephalitis in Chinese patients.

  4. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  5. No Changes in Serum Concentrations of Interleukin 10 (IL-10 and Interferon γ (IF-γ Before and After Treatment of the Thyroid Eye Disease (TED

    Directory of Open Access Journals (Sweden)

    Nevenka Laban-Gučeva

    2008-11-01

    Full Text Available TED is a severe eye disease leading in rare cases to decrease of sight, optic nerve compression and blindness. Recently, significant progresses in understanding the disease have been done. Nevertheless, the treatment of the disease, especially in its severe form remains challenging. Glucocorticoids (GC have been the basis of the treatment for a long time. Orbital irradiation (OI and optical decompression (OD are also used in managing the severe forms of TED. Somatostatin, intravenous immunoglobulin have been also used, with conflicting results. Regarding the potential for the treatment of TED with cytokine antagonists, controlled clinical studies are not available. Since cytokines play an important role in the pathogenesis of the TED, they seemed to be logical choice for modern TED treatment. It has been shown that both Th1 (interleukin-2, tumor necrosis factor γ, interleukin γ and Th2 (interleukin-4,-5-,-10 profile T cells are activated in the TED. We therefore measured interleukin-γ, IF-γ and interleukin -10 (IL-10(Th1 and Th2 pattern to assess its relationship to the course of the disease. This paper shows that both Th1 (Il-2 and Th2 (If-γ pathways represented by those two cytokines are not involved (Il-10 before 2,29±5,23 and after treatment 3,77±8,44; IF γ before 0,50±0,24 and after treatment 0,35±0,19. No relationship to the response to treatment was found. GC resulted in positive response in 8/22 patients, OI (12 patients given after CS therapy, resulted in a response in all patients. Increase in proptosis, loss of visual acuity is spite of CS treatment prompted OD in two patients, who both recovered visual acuity and proptosis fell under 25mm Hertel.

  6. Effect of scaling and root planing on serum interleukin-10 levels and glycemic control in chronic periodontitis and type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Anirudh Balakrishna Acharya

    2015-01-01

    Full Text Available Aim: Chronic periodontal disease (CPD and type 2 diabetes mellitus (T2DM share common pathogenic pathways involving the cytokine network resulting in increased susceptibility to both diseases, leading to increased inflammatory destruction, insulin resistance, and poor glycemic control. Periodontal treatment may improve glycemic control. The aim of this study was to evaluate the effect of scaling and root planing (SRP of T2DM patients with CPD on hyperglycemia and the levels of serum interleukin-10 (IL-10. Materials and Methods: Forty-five subjects were divided into three groups comprising 15 subjects each as Group 1 (healthy controls, Group 2 (CPD patients, and Group 3 (T2DM patients with CPD. Plaque index, gingival index (GI, probing pocket depths (PPD, clinical attachment loss (AL, bleeding on probing (BoP, random blood sugar, glycosylated hemoglobin (HbA1C, and serum IL-10 were measured at baseline; SRP was performed on Groups 2 and 3 and the selected parameters recorded again at 6 months. Results: Statistically significant (P < 0.05 differences were observed in the variables at baseline and 6 months after SRP between the three groups using one-way ANOVA. The paired samples t-test for PPD and AL in Group 3 was statistically significant. Group 3 revealed positive correlations between PPD and HbA1C, BoP and IL-10, respectively, at 6 months and a predictable association of HbA1C with PPD and GI, and IL-10 levels with BoP, respectively, at 6 months. Conclusion: Scaling and root planing is effective in reducing blood glucose levels in T2DM patient with pocket depths and effective in elevating systemic IL-10 levels in CPD patients and CPD patients with T2DM.

  7. Interleukin-10 Production by T and B Cells Is a Key Factor to Promote Systemic Salmonella enterica Serovar Typhimurium Infection in Mice

    Directory of Open Access Journals (Sweden)

    Geraldyne A. Salazar

    2017-08-01

    Full Text Available Salmonella enterica serovar Typhimurium (S. Typhimurium is a Gram-negative bacterium that produces disease in numerous hosts. In mice, oral inoculation is followed by intestinal colonization and subsequent systemic dissemination, which leads to severe pathogenesis without the activation of an efficient anti-Salmonella immune response. This feature suggests that the infection caused by S. Typhimurium may promote the production of anti-inflammatory molecules by the host that prevent efficient T cell activation and bacterial clearance. In this study, we describe the contribution of immune cells producing the anti-inflammatory cytokine interleukin-10 (IL-10 to the systemic infection caused by S. Typhimurium in mice. We observed that the production of IL-10 was required by S. Typhimurium to cause a systemic disease, since mice lacking IL-10 (IL-10−/− were significantly more resistant to die after an infection as compared to wild-type (WT mice. IL-10−/− mice had reduced bacterial loads in internal organs and increased levels of pro-inflammatory cytokines in serum at 5 days of infection. Importantly, WT mice showed high bacterial loads in tissues and no increase of cytokines in serum after 5 days of S. Typhimurium infection, except for IL-10. In WT mice, we observed a peak of il-10 messenger RNA production in ileum, spleen, and liver after 5 days of infection. Importantly, the adoptive transfer of T or B cells from WT mice restored the susceptibility of IL-10−/− mice to systemic S. Typhimurium infection, suggesting that the generation of regulatory cells in vivo is required to sustain a systemic infection by S. Typhimurium. These findings support the notion that IL-10 production from lymphoid cells is a key process in the infective cycle of S. Typhimurium in mice due to generation of a tolerogenic immune response that prevents bacterial clearance and supports systemic dissemination.

  8. Formation of Foamy Macrophages by Tuberculous Pleural Effusions Is Triggered by the Interleukin-10/Signal Transducer and Activator of Transcription 3 Axis through ACAT Upregulation

    Directory of Open Access Journals (Sweden)

    Melanie Genoula

    2018-03-01

    Full Text Available The ability of Mycobacterium tuberculosis (Mtb to persist in its human host relies on numerous immune evasion strategies, such as the deregulation of the lipid metabolism leading to the formation of foamy macrophages (FM. Yet, the specific host factors leading to the foamy phenotype of Mtb-infected macrophages remain unknown. Herein, we aimed to address whether host cytokines contribute to FM formation in the context of Mtb infection. Our approach is based on the use of an acellular fraction of tuberculous pleural effusions (TB-PE as a physiological source of local factors released during Mtb infection. We found that TB-PE induced FM differentiation as observed by the increase in lipid bodies, intracellular cholesterol, and expression of the scavenger receptor CD36, as well as the enzyme acyl CoA:cholesterol acyl transferase (ACAT. Importantly, interleukin-10 (IL-10 depletion from TB-PE prevented the augmentation of all these parameters. Moreover, we observed a positive correlation between the levels of IL-10 and the number of lipid-laden CD14+ cells among the pleural cells in TB patients, demonstrating that FM differentiation occurs within the pleural environment. Downstream of IL-10 signaling, we noticed that the transcription factor signal transducer and activator of transcription 3 was activated by TB-PE, and its chemical inhibition prevented the accumulation of lipid bodies and ACAT expression in macrophages. In terms of the host immune response, TB-PE-treated macrophages displayed immunosuppressive properties and bore higher bacillary loads. Finally, we confirmed our results using bone marrow-derived macrophage from IL-10−/− mice demonstrating that IL-10 deficiency partially prevented foamy phenotype induction after Mtb lipids exposure. In conclusion, our results evidence a role of IL-10 in promoting the differentiation of FM in the context of Mtb infection, contributing to our understanding of how alterations of the host metabolic

  9. The Effect of an Eight-Week Rope Skipping Exercise Program on Interleukin-10 and C-Reactive Protein in Overweight and Obese Adolescents

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    Zakavi

    2015-08-01

    Full Text Available Background The different effects of exercise on obesity in obese adolescents have not sufficiently been studied. Objectives This study aimed to investigate the effect of an eight-week rope skipping exercise on interleukin-10 (IL-10 and C-reactive protein (CRP in obese and overweight adolescents. Patients and Methods In this semi-experimental study, using purposive convenience sampling 30 overweight and obese teens were randomly divided into two groups: the experimental (height 165.28 cm; weight 85.53 kg and age 13.73 years old and control (height 164.54 cm; weight 83.02 kg and age 13.93 years old groups. Then the experimental group performed the eight-week rope skipping exercise program while the control group did not receive any intervention and was only following up. Before and after the exercise, the variables including weight, fat percentage, body mass index (BMI and the maximum oxygen consumption (Vo2max in both groups were measured. To assess the amount of serum IL-10, CRP, 48 hours before and after the exercise, fasting blood samples were taken during the two-stage mode. The correlated t-test and the independent t-test were used to compare the intragroup and intergroup relationships, respectively. Results There was no significant change in the serum levels of IL-10 (P > 0.05; however, the intragroup comparison in the experimental group showed a significant increase in serum levels of IL.10 (P < 0.05. Moreover, the variables of the weight, BMI, fat percentage, V02max and CRP were significantly changed (P < 0.05. Conclusions A rope skipping protocol increases the anti-inflammatory index, reduces the risk of cardiovascular disease, and improves the body compounds and immune system of the obese and overweight teens.

  10. Genome-Wide Association Study Identifies That the ABO Blood Group System Influences Interleukin-10 Levels and the Risk of Clinical Events in Patients with Acute Coronary Syndrome.

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    Åsa Johansson

    Full Text Available Acute coronary syndrome (ACS is a major cause of mortality worldwide. We have previously shown that increased interleukin-10 (IL-10 levels are associated with poor outcome in ACS patients.We performed a genome-wide association study in 2864 ACS patients and 408 healthy controls, to identify genetic variants associated with IL-10 levels. Then haplotype analyses of the identified loci were done and comparisons to levels of IL-10 and other known ACS related biomarkers.Genetic variants at the ABO blood group locus associated with IL-10 levels (top SNP: rs676457, P = 4.4 × 10-10 were identified in the ACS patients. Haplotype analysis, using SNPs tagging the four main ABO antigens (A1, A2, B and O, showed that O and A2 homozygous individuals, or O/A2 heterozygotes have much higher levels of IL-10 compared to individuals with other antigen combinations. In the ACS patients, associations between ABO antigens and von Willebrand factor (VWF, P = 9.2 × 10-13, and soluble tissue factor (sTF, P = 8.6 × 10-4 were also found. In the healthy control cohort, the associations with VWF and sTF were similar to those in ACS patients (P = 1.2 × 10-15 and P = 1.0 × 10-5 respectively, but the healthy cohort showed no association with IL-10 levels (P>0.05. In the ACS patients, the O antigen was also associated with an increased risk of cardiovascular death, all causes of death, and recurrent myocardial infarction (odds ratio [OR] = 1.24-1.29, P = 0.029-0.00067.Our results suggest that the ABO antigens play important roles, not only for the immunological response in ACS patients, but also for the outcome of the disease.

  11. Genome-Wide Association Study Identifies That the ABO Blood Group System Influences Interleukin-10 Levels and the Risk of Clinical Events in Patients with Acute Coronary Syndrome.

    Science.gov (United States)

    Johansson, Åsa; Alfredsson, Jenny; Eriksson, Niclas; Wallentin, Lars; Siegbahn, Agneta

    2015-01-01

    Acute coronary syndrome (ACS) is a major cause of mortality worldwide. We have previously shown that increased interleukin-10 (IL-10) levels are associated with poor outcome in ACS patients. We performed a genome-wide association study in 2864 ACS patients and 408 healthy controls, to identify genetic variants associated with IL-10 levels. Then haplotype analyses of the identified loci were done and comparisons to levels of IL-10 and other known ACS related biomarkers. Genetic variants at the ABO blood group locus associated with IL-10 levels (top SNP: rs676457, P = 4.4 × 10-10) were identified in the ACS patients. Haplotype analysis, using SNPs tagging the four main ABO antigens (A1, A2, B and O), showed that O and A2 homozygous individuals, or O/A2 heterozygotes have much higher levels of IL-10 compared to individuals with other antigen combinations. In the ACS patients, associations between ABO antigens and von Willebrand factor (VWF, P = 9.2 × 10-13), and soluble tissue factor (sTF, P = 8.6 × 10-4) were also found. In the healthy control cohort, the associations with VWF and sTF were similar to those in ACS patients (P = 1.2 × 10-15 and P = 1.0 × 10-5 respectively), but the healthy cohort showed no association with IL-10 levels (P>0.05). In the ACS patients, the O antigen was also associated with an increased risk of cardiovascular death, all causes of death, and recurrent myocardial infarction (odds ratio [OR] = 1.24-1.29, P = 0.029-0.00067). Our results suggest that the ABO antigens play important roles, not only for the immunological response in ACS patients, but also for the outcome of the disease.

  12. Downregulation of the NHE3-binding PDZ-adaptor protein PDZK1 expression during cytokine-induced inflammation in interleukin-10-deficient mice.

    Directory of Open Access Journals (Sweden)

    Henrike Lenzen

    Full Text Available BACKGROUND: Impaired salt and water absorption is an important feature in the pathogenesis of diarrhea in inflammatory bowel disease (IBD. We analyzed the expression of proinflammatory cytokines in the infiltrating immune cells and the function and expression of the Na(+/H(+ exchanger isoform 3 (NHE3 and its regulatory PDZ-adaptor proteins NHERF1, NHERF2, and PDZK1 in the colon of interleukin-10-deficient (IL-10(-/- mice. METHODOLOGY/PRINCIPAL FINDINGS: Gene and protein expression were analyzed by real-time reverse transcription polymerase chain reaction (qRT-PCR, in situ RT-PCR, and immunohistochemistry. NHE3 activity was measured fluorometrically in apical enterocytes within isolated colonic crypts. Mice developed chronic colitis characterized by a typical immune cell infiltration composed of T-lymphocytes and macrophages, with high levels of gene and protein expression of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α. In parallel, inducible nitric oxide synthase expression was increased while procaspase 3 expression was unaffected. Interferon-γ expression remained low. Although acid-activated NHE3 activity was significantly decreased, the inflammatory process did not affect its gene and protein expression or its abundance and localization in the apical membrane. However, expression of the PDZ-adaptor proteins NHERF2 and PDZK1 was downregulated. NHERF1 expression was unchanged. In a comparative analysis we observed the PDZK1 downregulation also in the DSS (dextran sulphate sodium model of colitis. CONCLUSIONS/SIGNIFICANCE: The impairment of the absorptive function of the inflamed colon in the IL-10(-/- mouse, in spite of unaltered NHE3 expression and localization, is accompanied by the downregulation of the NHE3-regulatory PDZ adaptors NHERF2 and PDZK1. We propose that the downregulation of PDZ-adaptor proteins may be an important factor leading to NHE3 dysfunction and diarrhea in the course of the cytokine

  13. CXCR5+CD8+T cells present elevated capacity in mediating cytotoxicity toward autologous tumor cells through interleukin 10 in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Tang, Jiahong; Zha, Jie; Guo, Xutao; Shi, Pengcheng; Xu, Bing

    2017-09-01

    Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive subtype of non-Hodgkin's lymphomas, with limited treatment options in refractory and relapsed patients. Growing evidence supports the notion that CD8 + T cell immunity could be utilized to eliminate B cell lymphomas. CXCR5 + CD8 + T cell is a novel cell subtype and share CXCR5 expression with CD19 + tumor cells. In this study, we investigated the frequency and function of existing CXCR5 + CD8 + T cells in DLBCL patients. We found that DLBCL patients as a group demonstrated significantly higher level of CXCR5 + CD8 + T cells than healthy individuals, with huge variability in each patient. Using anti-CD3/CD28-stimulated CD8 + T cells as effector (E) cells and autologous CD19 + tumor cells as target (T) cells, at high E:T ratio, no difference between the intensities of CXCR5 + CD8 + T cell- and CXCR5 - CD8 + T cell-mediated cytotoxicity were observed. However, at intermediate and low E:T ratios, the CXCR5 + CD8 + T cells presented stronger cytotoxicity than CXCR5 - CD8 + T cells. The expressions of granzyme A, granzyme B, and perforin were significantly higher in CXCR5 + CD8 + T cells than in CXCR5 - CD8 + T cells, with no significant difference in the level of degranulation. Tumor cells in DLBCL were known to secrete high level of interleukin 10 (IL-10). We therefore blocked the IL-10/IL-10R pathway, and found that the expressions of granzyme A, granzyme B, and perforin by CXCR5 + CD8 + T cells were significantly elevated. Together, these results suggest that CXCR5 + CD8 + T cells are potential candidates of CD8 + T cell-based immunotherapies, could mediate elimination of autologous tumor cells in DLBCL patients, but are also susceptible to IL-10-mediated suppression. Copyright © 2017. Published by Elsevier B.V.

  14. Increased serum levels of interleukin-10 predict poor prognosis in extranodal natural killer/T-cell lymphoma patients receiving asparaginase-based chemotherapy

    Directory of Open Access Journals (Sweden)

    Wang H

    2015-09-01

    Full Text Available Hua Wang,1–3,* Liang Wang,1–3,* ZhiJun Wuxiao,4,* HuiQiang Huang,5 WenQi Jiang,5 ZhiMing Li,5 Yue Lu,1–3 ZhongJun Xia1–31Department of Hematological Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Guangzhou, People’s Republic of China; 3Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 4Department of Hematology & Oncology, The Affiliated Hospital, Hainan Medical College, Haikou, Hainan, People’s Republic of China; 5Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workAbstract: There are currently no prognostic biomarkers for extranodal natural killer/T-cell lymphoma (ENKTL patients receiving asparaginase-based chemotherapy. Interleukin-10 (IL-10 is a pleiotropic cytokine that is involved in the stimulation and suppression of immune responses and influences the prognosis of different subtypes of lymphoma. We retrospectively analyzed 98 newly diagnosed patients with ENKTL receiving asparaginase-based chemotherapy. Baseline serum IL-10 levels were tested with sandwich enzyme-linked immunosorbent assays. Patients with high IL-10 (≥12.28 pg/mL at diagnosis tended to have more adverse clinical features. Patients with low IL-10 (<12.28 pg/mL at diagnosis had better progression-free survival (PFS (P<0.001 and overall survival (OS (P<0.001. Multivariate analysis revealed that baseline serum IL-10 level ≥12.28 pg/mL, stage III/IV, elevated serum ferritin, and elevated serum Epstein–Barr virus DNA level at diagnosis were four adverse factors for PFS and OS. Based on these four independent prediction factors, we divided the patients into different subgroups as follows: group 1, no adverse factors; group 2, one factor; group 3, two factors; and group 4, three or four factors. Furthermore, significant

  15. Detection of levels of serum interleukin-10 and plasma endothelin in children with or without atopic asthma and their clinical significances

    International Nuclear Information System (INIS)

    Wang Xuehua; Liu Li; Qiao Hongmei; Li Ya'nan; Lu Qinghua; Cheng Huanji

    2012-01-01

    Objective: To observe the changes of the levels of serum interleukin-10 (Il-10), plasma endothelin (Et-1) and immunoglobulin E (IgE) in children with or without a topic asthma and to discuss their clinical significances. Methods: 60 asthma children conducted the Allergen skin prick tests and serum IgE measurement to determine a topic status at the same time, and they were divided into a topic asthma group (n=32) and non-a topic asthma group (n=28) according to the results. 30 normal healthy children were selected as control group. The expressions of Et-1 and IgE in the asthma children during attack period and remission phase and the children in control group were detected by radioimmunoassay and the levels of serum Il-10 were detected by the double antibody sandwich ELISA. Results: The level of serum Il-10 in the asthma children in the acute attack period was lower than those in control group (P<0.01), and the level of Et-1 was higher obviously than that in control group (P<0.05); the levels of IgE in the asthma children in the acute attack period and remission phase in asthma groups were obviously higher than that in control group (P<0.01). The levels of Et-1 and IgE of the a topic asthma children in acute attack period were higher than those of the atopic asthma children in remission phase, and the level of IL-10 was lower (P<0.01). The levels of serum IL-10 in atopic of the acute attack period was lower than that in non-atopic group (P<0.05), and the levels of the ET-1 and IgE of the patients in the acute attack period and remission phase in atopic group were higher than those in non-atopic group (P<0.05). The relationship between IL-10 level and ET-1 and IgE showed obviously negative correlations (r=-0.592, r=-0.894, P<0.05), and the relationship between ET-1 and IgE showed obviously positive correlation (r=-0.623, P<0.05). Conclusion: The levels of serum IL-10 and ET-1 perhaps take part in the pathologic and physiological process of the children's asthma

  16. Effects of bamboo vinegar powder on growth performance and mRNA expression levels of interleukin-10, interleukin-22, and interleukin-25 in immune organs of weaned piglets

    Directory of Open Access Journals (Sweden)

    Yongjiu Huo

    2016-06-01

    Full Text Available The aim of this study was to explore the effects of bamboo vinegar powder on growth performance, diarrhea situation and mRNA expression levels of cytokines i.e., interleukin-10 (IL-10, interleukin-22 (IL-22, and interleukin-25 (IL-25 in immune organs of weaned piglets, and to accumulate theoretical data for the application of bamboo vinegar powder in weaned piglet production. Forty-five crossbred (Duroc × Landrace × Yorkshire, all male weaned piglets with similar body weight (6.74 ± 0.17 kg at 31 days of age were randomly assigned to 5 treatments with 3 replicates per treatment and 3 piglets in each replicate. The five treatments were as follows: CON (a basal diet, ANT (the basal diet + 0.12% antibiotics, BV1 (the basal diet + 0.1% bamboo vinegar powder, BV5 (the basal diet + 0.5% bamboo vinegar powder, BV10 (the basal diet + 1.0% bamboo vinegar powder. This experiment lasted 35 days. The growth performance and diarrhea situation were recorded. The relative mRNA expression levels of IL-10, IL-22 and IL-25 in liver, spleen, duodenum and mesenteric lymph nodes were detected by real-time PCR. Feed: gain of BV5 was significantly lower than that of CON (P < 0.05. In comparison with CON, diarrhea rate and diarrhea index of BV1 and BV5 all tended to decrease (P < 0.1. Compared with CON, mRNA expression level of IL-10 in liver of ANT tended to be lower (P < 0.1 and these of BV1, BV5 and BV10 were significantly reduced (P < 0.05. The mRNA expression levels of IL-10 in duodenum of ANT, BV1, BV5 and BV10 were all lower than those of CON, of which BV10 had significantly decreased IL-10 mRNA expression in duodenum (P < 0.05. The mRNA expression levels of IL-22 in duodenum of ANT, BV1, BV5 and BV10 all tended to be inhibited compared with CON (P < 0.1. With the increase of bamboo vinegar powder dosage, mRNA expression levels of IL-25 in spleen and mesenteric lymph nodes of BV1, BV5 and BV10 tended to be up-regulated. Overall

  17. Expression of CD4+CD25+Foxp3+ Regulatory T Cells, Interleukin 10 and Transforming Growth Factor β in Newly Diagnosed Type 2 Diabetic Patients.

    Science.gov (United States)

    Yuan, Ning; Zhang, Hai-Feng; Wei, Qi; Wang, Ping; Guo, Wei-Ying

    2018-02-01

    Recent studies have shown that dysfunction and decrease of regulatory T cells (Tregs) correlates with insulin resistance (IR), one of the most significant mechanisms for type 2 diabetes mellitus (T2DM). To examine potential relationships among Tregs, IR, blood lipid content, and related cytokines, we investigated the frequency of CD4+CD25+Foxp3+ Tregs, as well as expression levels of interleukin 10 (IL-10) and transforming growth factor-β (TGF-β) in newly diagnosed T2DM patients. Fifty-one newly diagnosed T2DM patients and 55 control individuals were enrolled. According to body mass index (BMI), the T2DM patients were grouped into non-obese and obese groups. Blood was collected in ethylene diamine tetraacetic acid (EDTA) anticoagulant tubes for detection of CD4+CD25+Foxp3+ Tregs by flow cytometry. Serum was collected to quantify IL-10 and TGF-β levels by enzyme-linked immunosorbent assay (ELISA). By comparing percentages of Tregs between non-obese and obese groups, correlation with Treg frequency, homeostasis model assessment of insulin resistance (HOMA-IR), IL-10 and TGF-β was examined. The percentage of CD4+CD25+Foxp3+ Tregs in the newly diagnosed T2DM group was significantly lower than in the control group (P<0.01). Further, levels of IL-10 and TGF-β were also lower in the T2DM group (P<0.05). The level of IL-10 was remarkably lower in the obese group than in the non-obese and the control groups (P<0.01), but there was no significant difference between non-obese group and the control group. The level of TGF-β was lower in obese group than in the control group (P<0.05). There was no significant difference between non-obese group and the control group. The frequency of CD4+CD25+Foxp3+ Tregs in the obese group was significantly lower than in the non-obese group (P<0.05). In the obese group, the percentage of Tregs negatively correlated with HOMA-IR and positively correlated with TGF-β (P<0.05). There was no obvious correlation between Treg and HOMA-IR in the

  18. On convexity and Schoenberg's variation diminishing splines

    International Nuclear Information System (INIS)

    Feng, Yuyu; Kozak, J.

    1992-11-01

    In the paper we characterize a convex function by the monotonicity of a particular variation diminishing spline sequence. The result extends the property known for the Bernstein polynomial sequence. (author). 4 refs

  19. Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity

    Science.gov (United States)

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don; Hurd, Alexander; Aicher, Thomas D.; Toogood, Peter L.; Glick, Gary D.; Paulos, Chrystal M.; Zou, Weiping; Carter, Laura L.

    2016-01-01

    ABSTRACT RORγt is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are RORγ+ cells. To evaluate the role of RORγ in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate RORγ to a greater extent than the endogenous agonist desmosterol. These RORγ agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. RORγ agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of RORγ agonists were not observed in RORγ−/− T cells, underscoring the selective on-target activity of the compounds. In vitro treatment of tumor-specific T cells with RORγ agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1 in vivo. The in vitro effects of RORγ agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. RORγ agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, RORγ agonists represent a novel immunotherapy approach for cancer. PMID:28123897

  20. Effect of blood transfusion during radiotherapy on the immune function of patients with cancer of the uterine cervix: role of interleukin-10

    International Nuclear Information System (INIS)

    Santin, Alessandro D.; Bellone, Stefania; Palmieri, Michela; Bossini, Barbara; Dunn, Donna; Roman, Juan J.; Pecorelli, Sergio; Cannon, Martin; Parham, Groesbeck P.

    2002-01-01

    were noted in the percentage of CD4+ IFN-γ+ T cells and CD4+ IL-2+ T cells. The proportion of perforin-positive CD8+ and CD56+ cells was higher in the transfused group than in the untransfused group. However, CD56+ cells and CD8+ T cells from the transfused patients showed markedly diminished cytotoxic function. Finally, IL-10 was detected only in the plasma of the transfused patients. Conclusion: Blood transfusion during primary RT for cervical cancer profoundly alters the magnitude and characteristics of radiation-induced immunosuppression. Elevated serum IL-10 in transfused patients may play a role in the disregulation of lymphocyte function, in particular, the depression of NK- and T-cell cytotoxicity. Investigation of alternatives to blood transfusion during RT that do not diminish host immunity is warranted

  1. Comparison of efficacy of the disease-specific LOX1- and constitutive cytomegalovirus-promoters in expressing interleukin 10 through adeno-associated virus 2/8 delivery in atherosclerotic mice.

    Directory of Open Access Journals (Sweden)

    Hongqing Zhu

    Full Text Available The development of gene therapy vectors for treating diseases of the cardiovascular system continues at a steady pace. Moreover, in the field of gene therapy the utility of "disease-specific promoters" has strong appeal. Many therapeutic genes, including transforming growth factor beta 1 or interleukin 10, are associated to adverse effects. The use of a disease-specific promoter might minimize toxicity. The lectin-like oxidized low density lipoprotein receptor 1 is a marker of cardiovascular disease and a potential therapeutic target. The lectin-like oxidized low density lipoprotein receptor 1 is known to be up-regulated early during disease onset in a number of cell types at the sites where the disease will be clinically evident. In this study an adeno-associated virus-2 DNA vector (AAV2 using the AAV8 capsid, and containing the full length The lectin-like oxidized low density lipoprotein receptor 1 promoter, was generated and assayed for its ability to express human interleukin 10 in low density lipoprotein receptor knockout mice on high cholesterol diet. The cytomegalovirus early promoter was used for comparison in a similarly structured vector. The two promoters were found to have equal efficacy in reducing atherogenesis as measured by aortic systolic blood velocity, aortic cross sectional area, and aortic wall thickness. This is the first head-to-head comparison of a constitutive with a disease-specific promoter in a therapeutic context. These data strongly suggest that the use of a disease-specific promoter is appropriate for therapeutic gene delivery.

  2. Diminished ovarian reserve in patients with psoriasis

    Directory of Open Access Journals (Sweden)

    Burcu Tuğrul Ayanoğlu

    2018-04-01

    Full Text Available Objective: Psoriasis is a multi-systemic chronic inflammatory skin disease. Previous data suggests that women with some chronic inflammatory diseases have diminished ovarian reserve. This study explores ovarian reserve in patients with psoriasis. Materials and methods: We prospectively analyzed 14 female patients with psoriasis and 35 healthy age and body mass index matched controls. An interview explored demographic characteristics, obstetrical history and menstrual characteristics. Psoriatic area severity index (PASI in patients was assessed. Estrogen, follicle-stimulating hormone (FSH, luteinizing hormone (LH, thyroid stimulating hormone and with gynecologic ultrasonography, ovarian volume and antral follicular count (AFC were measured in both study and control groups. These values were analyzed with changes of the PASI in the patient group. Results: Patients with psoriasis had significantly higher levels of FSH and FSH/LH ratio than healthy controls (p = 0.039, p = 0.005 respectively. AFC of psoriasis patients were significantly lower than healthy controls (p = 0.002.There were no significant difference among other hormone levels and ovarian volumes (p > 0.05. The hormone levels, ovarian volume and AFC were not correlated with PASI of the patients. Conclusion: The results of the study suggest that patients with psoriasis may have diminished ovarian reserve. Keywords: Psoriasis, Ovarian reserve, Psoriatic area severity index, Antral follicular count, Follicle-stimulating hormone

  3. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...... presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide...... and liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  4. Evaluation of the adjuvant effect of agonists of toll-like receptor 4 and 7/8 in a vaccine against leishmaniasis in BALB/c mice.

    Science.gov (United States)

    Rostamian, Mosayeb; Niknam, Hamid M

    2017-11-01

    There is no effective vaccine against human leishmaniasis. Achieving successful vaccines seems to need powerful adjuvants. Separate or combined use of toll like receptor (TLR) agonists as adjuvant is a promising approach in Leishmania vaccine research. In present study, we evaluated adjuvant effect of separate or combined use of a TLR7/8 agonist, R848 and a TLR4 agonist, monophosphoryl lipid A (MPL) beside soluble Leishmania antigen (SLA) in BALB/c mice. Mice were vaccinated three times by SLA with separate or combined TLR7/8 and TLR4 agonists and were then challenged by Leishmania major. Delay type hypersensitivity, lesion development, parasite load, and cytokines (interferon gamma, and interleukin-10) response were assessed. Results showed: 1) MPL can slightly assist SLA in parasite load reduction, but it is not able to increase SLA ability in evoking DTH and cytokine responses or decreasing lesion diameter. 2) R848 does not affect the DTH response and parasite load of mice vaccinated with SLA, but it decreases/inhibits cytokine responses induced by SLA, leading to increase lesion diameter. 3) MPL neutralized inhibitory effect of R848. In overall, these data emphasize that MPL slightly assists SLA to make a more potent vaccine, but R848 is not a good adjuvant to induce T cell-dependent immune response in BALB/c mice, and therefore combination of these TLR agonists in the current formulation, is not recommended for making a more powerful adjuvant. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. The Effect of Turmeric (Curcuma longa Extract on the Functionality of the Solute Carrier Protein 22 A4 (SLC22A4 and Interleukin-10 (IL-10 Variants Associated with Inflammatory Bowel Disease

    Directory of Open Access Journals (Sweden)

    Mark J. McCann

    2014-10-01

    Full Text Available Inflammatory bowel disease (IBD is a chronic relapsing disease. Genetic predisposition to the disease reduces an individual’s capacity to respond appropriately to environmental challenges in the intestine leading to inappropriate inflammation. IBD patients often modify their diet to mitigate or reduce the severity of inflammation. Turmeric (Curcuma longa L., Zingiberaceae has historically been used in Chinese, Hindu, and Ayurvedic medicine over several centuries to treat inflammatory disorders. To understand how turmeric may influence the consequences of a genetic predisposition to inappropriate inflammation, we used HEK293 cells to examine the in vitro capacity of turmeric extract and fractions to affect the functionality of two gene variants, solute carrier protein 22 A4 (SLC22A4, rs1050152 and interleukin-10 (IL-10, rs1800896 associated with IBD. We found that a turmeric extract and several chromatographically separated fractions beneficially affected the variants of SLC22A4 and IL-10 associated with IBD, by reducing inappropriate epithelial cell transport (SLC22A4, 503F and increasing anti-inflammatory cytokine gene promoter activity (IL-10, −1082A. The effect of turmeric on the IL-10 variant was strongly associated with the curcumin content of the extract and its fractions.

  6. The effect of turmeric (Curcuma longa) extract on the functionality of the solute carrier protein 22 A4 (SLC22A4) and interleukin-10 (IL-10) variants associated with inflammatory bowel disease.

    Science.gov (United States)

    McCann, Mark J; Johnston, Sarah; Reilly, Kerri; Men, Xuejing; Burgess, Elaine J; Perry, Nigel B; Roy, Nicole C

    2014-10-13

    Inflammatory bowel disease (IBD) is a chronic relapsing disease. Genetic predisposition to the disease reduces an individual's capacity to respond appropriately to environmental challenges in the intestine leading to inappropriate inflammation. IBD patients often modify their diet to mitigate or reduce the severity of inflammation. Turmeric (Curcuma longa L., Zingiberaceae) has historically been used in Chinese, Hindu, and Ayurvedic medicine over several centuries to treat inflammatory disorders. To understand how turmeric may influence the consequences of a genetic predisposition to inappropriate inflammation, we used HEK293 cells to examine the in vitro capacity of turmeric extract and fractions to affect the functionality of two gene variants, solute carrier protein 22 A4 (SLC22A4, rs1050152) and interleukin-10 (IL-10, rs1800896) associated with IBD. We found that a turmeric extract and several chromatographically separated fractions beneficially affected the variants of SLC22A4 and IL-10 associated with IBD, by reducing inappropriate epithelial cell transport (SLC22A4, 503F) and increasing anti-inflammatory cytokine gene promoter activity (IL-10, -1082A). The effect of turmeric on the IL-10 variant was strongly associated with the curcumin content of the extract and its fractions.

  7. The Effect of Turmeric (Curcuma longa) Extract on the Functionality of the Solute Carrier Protein 22 A4 (SLC22A4) and Interleukin-10 (IL-10) Variants Associated with Inflammatory Bowel Disease

    Science.gov (United States)

    McCann, Mark J.; Johnston, Sarah; Reilly, Kerri; Men, Xuejing; Burgess, Elaine J.; Perry, Nigel B.; Roy, Nicole C.

    2014-01-01

    Inflammatory bowel disease (IBD) is a chronic relapsing disease. Genetic predisposition to the disease reduces an individual’s capacity to respond appropriately to environmental challenges in the intestine leading to inappropriate inflammation. IBD patients often modify their diet to mitigate or reduce the severity of inflammation. Turmeric (Curcuma longa L., Zingiberaceae) has historically been used in Chinese, Hindu, and Ayurvedic medicine over several centuries to treat inflammatory disorders. To understand how turmeric may influence the consequences of a genetic predisposition to inappropriate inflammation, we used HEK293 cells to examine the in vitro capacity of turmeric extract and fractions to affect the functionality of two gene variants, solute carrier protein 22 A4 (SLC22A4, rs1050152) and interleukin-10 (IL-10, rs1800896) associated with IBD. We found that a turmeric extract and several chromatographically separated fractions beneficially affected the variants of SLC22A4 and IL-10 associated with IBD, by reducing inappropriate epithelial cell transport (SLC22A4, 503F) and increasing anti-inflammatory cytokine gene promoter activity (IL-10, −1082A). The effect of turmeric on the IL-10 variant was strongly associated with the curcumin content of the extract and its fractions. PMID:25314644

  8. When will fossil fuel reserves be diminished?

    International Nuclear Information System (INIS)

    Shafiee, Shahriar; Topal, Erkan

    2009-01-01

    Crude oil, coal and gas are the main resources for world energy supply. The size of fossil fuel reserves and the dilemma that 'when non-renewable energy will be diminished' is a fundamental and doubtful question that needs to be answered. This paper presents a new formula for calculating when fossil fuel reserves are likely to be depleted and develops an econometrics model to demonstrate the relationship between fossil fuel reserves and some main variables. The new formula is modified from the Klass model and thus assumes a continuous compound rate and computes fossil fuel reserve depletion times for oil, coal and gas of approximately 35, 107 and 37 years, respectively. This means that coal reserves are available up to 2112, and will be the only fossil fuel remaining after 2042. In the Econometrics model, the main exogenous variables affecting oil, coal and gas reserve trends are their consumption and respective prices between 1980 and 2006. The models for oil and gas reserves unexpectedly show a positive and significant relationship with consumption, while presenting a negative and significant relationship with price. The econometrics model for coal reserves, however, expectedly illustrates a negative and significant relationship with consumption and a positive and significant relationship with price. Consequently, huge reserves of coal and low-level coal prices in comparison to oil and gas make coal one of the main energy substitutions for oil and gas in the future, under the assumption of coal as a clean energy source. (author)

  9. Diminished aversive classical conditioning in pathological gamblers.

    Science.gov (United States)

    Brunborg, Geir Scott; Johnsen, Bjørn Helge; Mentzoni, Rune Aune; Myrseth, Helga; Molde, Helge; Lorvik, Ingjerd Meen; Bu, Eli Torild Hellandsjø; Pallesen, Ståle

    2012-09-01

    Impaired ability to form associations between negative events in gambling and aversive somatic reactions may be a predisposing factor for pathological gambling. The current study investigated whether a group of pathological gamblers and a control group differed in aversive classical conditioning. A differential aversive classical conditioning paradigm, which consisted of three phases. In the habituation phase, one 850-Hz tone stimulus and one 1500-Hz tone stimulus were presented three times each in random order. In the acquisition phase, the two tones were presented 10 times each in random order, and one was always followed by a 100-dB burst of white noise. In the extinction phase the two tones were presented three times each without the white noise. University laboratory testing facilities and out-patient treatment facilities. Twenty pathological gamblers and 20 control participants. Duration of seven cardiac interbeat-intervals (IBIs) following tone offset, gambling severity, tobacco and alcohol use, anxiety and depression. No group differences were found in the habituation and acquisition phases. However, a significant group × stimuli × trials × IBIs interaction effect was found in the extinction phase (P classical conditioning, but that the control group did. Pathological gamblers have a diminished capacity to form associations between aversive events and stimuli that predict aversive events. Aversion learning is likely to be an ineffective treatment for pathological gamblers. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.

  10. Diminishing musyarakah investment model based on equity

    Science.gov (United States)

    Jaffar, Maheran Mohd; Zain, Shaharir Mohamad; Jemain, Abdul Aziz

    2017-11-01

    Most of the mudharabah and musyarakah contract funds are involved in debt financing. This does not support the theory that profit sharing contract is better than that of debt financing due to the sharing of risks and ownership of equity. Indeed, it is believed that Islamic banking is a financial model based on equity or musyarakah which emphasis on the sharing of risks, profit and loss in the investment between the investor and entrepreneur. The focus of this paper is to introduce the mathematical model that internalizes diminishing musyarakah, the sharing of profit and equity between entrepreneur and investor. The entrepreneur pays monthly-differed payment to buy out the equity that belongs to the investor (bank) where at the end of the specified period, the entrepreneur owns the business and the investor (bank) exits the joint venture. The model is able to calculate the amount of equity at any time for both parties and hence would be a guide in helping to estimate the value of investment should the entrepreneur or investor exit before the end of the specified period. The model is closer to the Islamic principles for justice and fairness.

  11. Effects of escitalopram, R-citalopram, and reboxetine on serum levels of tumor necrosis factor-α, interleukin-10, and depression-like behavior in mice after lipopolysaccharide administration.

    Science.gov (United States)

    Dong, Chao; Zhang, Ji-chun; Yao, Wei; Ren, Qian; Yang, Chun; Ma, Min; Han, Mei; Saito, Ryo; Hashimoto, Kenji

    2016-05-01

    Inflammation plays a role in the pathophysiology of depression. The purpose of this study is to examine whether the selective serotonin reuptake inhibitor (SSRI) escitalopram, its inactive enantiomer R-citalopram, and selective noradrenaline reuptake inhibitor (NRI) reboxetine, show anti-inflammatory and antidepressant effects in an inflammation-induced model of depression. Pretreatment with escitalopram (1, 3, or 10mg/kg, i.p.) markedly blocked an increase in the serum levels of pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), after a single administration of lipopolysaccharide (LPS; 0.5mg/kg). Furthermore, escitalopram (3 or 10mg/kg) significantly increased the serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) by a single administration of LPS. In contrast, pretreatment with R-citalopram (10mg/kg, i.p.) or reboxetine (10mg/kg, i.p.) did not affect the alterations in serum levels of TNF-α and IL-10 after LPS administration. Co-administration of reboxetine with escitalopram did not show anti-inflammatory effects. Pretreatment with escitalopram (10mg/kg) significantly attenuated LPS-induced increase of the immobility time in the tail-suspension test (TST) and forced swimming test (FST). In contrast, pretreatment with R-citalopram (10mg/kg), or reboxetine (10mg/kg) did not alter LPS-induced increase of immobility time of TST and FST. Interestingly, co-administration of reboxetine with escitalopram did not show antidepressant effect in this model. These findings suggest that escitalopram, but not R-citalopram and reboxetine, has anti-inflammatory and antidepressant effects in LPS-treated model of depression, and that reboxetine can antagonize the effects of escitalopram in the inflammation model. Therefore, it is likely that serotonergic system plays a key role in the pathophysiology of inflammation-induced depression. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Plasma concentrations and placental immunostaining of interleukin-10 and tumornecrosis factor-α as predictors of alterations in the embryo-fetal organism and the placental development of diabetic rats

    Directory of Open Access Journals (Sweden)

    Y.K. Sinzato

    2011-03-01

    Full Text Available Interleukin-10 (IL-10 appears to be the key cytokine for the maintenance of pregnancy and inhibits the secretion of inflammatory cytokines such as tumor necrosis factor-α (TNF-α. However, there are no studies evaluating the profile of these cytokines in diabetic rat models. Thus, our aim was to analyze IL-10 and TNF-α immunostaining in placental tissue and their respective concentrations in maternal plasma during pregnancy in diabetic rats in order to determine whether these cytokines can be used as predictors of alterations in the embryo-fetal organism and in placental development. These parameters were evaluated in non-diabetic (control; N = 15 and Wistar rats with streptozotocin (STZ-induced diabetes (N = 15. At term, the dams (100 days of life were killed under anesthesia and plasma and placental samples were collected for IL-10 and TNF-α determinations by ELISA and immunohistochemistry, respectively. The reproductive performance was analyzed. Plasma IL-10 concentrations were reduced in STZ rats compared to controls (7.6 ± 4.5 vs 20.9 ± 8.1 pg/mL. The placental scores of immunostaining intensity did not differ between groups (P > 0.05. Prevalence analysis showed that the IL-10 expression followed TNF-α expression, showing a balance between them. STZ rats also presented impaired reproductive performance and reduced plasma IL-10 levels related to damage during early embryonic development. However, the increased placental IL-10 as a compensatory mechanism for the deficit of maternal regulation permitted embryo development. Therefore, the data suggest that IL-10 can be used as a predictor of changes in the embryo-fetal organism and in placental development in pregnant diabetic rats.

  13. Polymorphisms of transporter associated with antigen presentation, tumor necrosis factor-α and interleukin-10 and their implications for protection and susceptibility to severe forms of dengue fever in patients in Sri Lanka

    Directory of Open Access Journals (Sweden)

    Anira N Fernando

    2015-01-01

    Full Text Available Context: To date, a clear understanding of dengue disease pathogenesis remains elusive. Some infected individuals display no symptoms while others develop severe life-threatening forms of the disease. It is widely believed that host genetic factors influence dengue severity. Aims: This study evaluates the relationship between certain polymorphisms and dengue severity in Sri Lankan patients. Settings and Design: Polymorphism studies are carried out on genes for; transporter associated with antigen presentation (TAP, promoter of tumor necrosis factor-α (TNF-α, and promoter of interleukin-10 (IL-10. In other populations, TAP1 (333, TAP2 (379, TNF-α (−308, and IL-10 (−1082, −819, −592 have been associated with dengue and a number of different diseases. Data have not been collected previously for these polymorphisms for dengue patients in Sri Lanka. Materials and Methods: The polymorphisms were typed by amplification refractory mutation system polymerase chain reaction in 107 dengue hemorrhagic fever (DHF patients together with 62 healthy controls. Statistical Analysis Used: Pearson′s Chi-square contingency table analysis with Yates′ correction. Results: Neither the TAP nor the IL-10 polymorphisms considered individually can define dengue disease outcome with regard to severity. However, the genotype combination, IL-10 (−592/−819/−1082 CCA/ATA was significantly associated with development of severe dengue in these patients, suggesting a risk factor to developing DHF. Also, identified is the genotype combination IL-10 (−592/−819/−1082 ATA/ATG which suggested a possibility for protection from DHF. The TNF-α (−308 GG genotype was also significantly associated with severe dengue, suggesting a significant risk factor. Conclusions: The results reported here are specific to the Sri Lankan population. Comparisons with previous reports imply that data may vary from population to population.

  14. Latency-Associated Viral Interleukin-10 (IL-10) Encoded by Human Cytomegalovirus Modulates Cellular IL-10 and CCL8 Secretion during Latent Infection through Changes in the Cellular MicroRNA hsa-miR-92a

    Science.gov (United States)

    Poole, Emma; Avdic, Selmir; Hodkinson, Jemima; Jackson, Sarah; Wills, Mark; Slobedman, Barry

    2014-01-01

    ABSTRACT The UL111A gene of human cytomegalovirus encodes a viral homologue of the cellular immunomodulatory cytokine interleukin 10 (cIL-10), which, due to alternative splicing, results in expression of two isoforms designated LAcmvIL-10 (expressed during both lytic and latent infection) and cmvIL-10 (identified only during lytic infection). We have analyzed the functions of LAcmvIL-10 during latent infection of primary myeloid progenitor cells and found that LAcmvIL-10 is responsible, at least in part, for the known increase in secretion of cellular IL-10 and CCL8 in the secretomes of latently infected cells. This latency-associated increase in CCL8 expression results from a concomitant LAcmvIL-10-mediated suppression of the expression of the cellular microRNA (miRNA) hsa-miR-92a, which targets CCL8 directly. Taking the data together, we show that the previously observed downregulation of hsa-miR-92a and upregulation of CCL8 during HCMV latent infection of myeloid cells are intimately linked via the latency-associated expression of LAcmvIL-10. IMPORTANCE HCMV latency causes significant morbidity and mortality in immunocompromised individuals, yet HCMV is carried silently (latently) in 50 to 90% of the population. Understanding how HCMV maintains infection for the lifetime of an infected individual is critical for the treatment of immunocompromised individuals suffering with disease as a result of HCMV. In this study, we analyze one of the proteins that are expressed during the “latent” phase of HCMV, LAcmvIL-10, and find that the expression of the gene modulates the microenvironment of the infected cell, leading to evasion of the immune system. PMID:25253336

  15. Dopamine agonists and Othello's syndrome

    Science.gov (United States)

    Graff-Radford, Jonathan; Ahlskog, J Eric.; Bower, James H.; Josephs, Keith A.

    2014-01-01

    Background Othello's syndrome (OS) is a delusion of infidelity. We describe seven cases of OS in Parkinson's disease (iPD) patients using dopamine agonists. Methods We searched the Mayo Clinic Medical Records System to identify all patients with OS. Clinical data abstracted include sex, age of onset of iPD, age of onset of OS, medications, effect of discontinuing the dopamine agonist, neuroimaging, and comorbidities. Results Seven non-demented iPD patients with dopamine agonist implementation time locked to the development and resolution of OS are reported. The average age of iPD onset was 46.6 years (Standard deviation: 5.0 years), and OS onset was 53.7 years (7.1 years). All seven patients had significant marital conflict as a result of the delusions. Conclusions OS can be associated with dopamine agonist use and can lead to serious consequences. Dopamine agonist cessation eliminates the delusion of infidelity and should be the first treatment option. PMID:20829092

  16. Interleukin 6, lipopolysaccharide-binding protein and interleukin 10 in the prediction of risk and etiologic patterns in patients with community-acquired pneumonia: results from the German competence network CAPNETZ

    Science.gov (United States)

    2012-01-01

    Background The aim of our study was to investigate the predictive value of the biomarkers interleukin 6 (IL-6), interleukin 10 (IL-10) and lipopolysaccharide-binding protein (LBP) compared with clinical CRB and CRB-65 severity scores in patients with community-acquired pneumonia (CAP). Methods Samples and data were obtained from patients enrolled into the German CAPNETZ study group. Samples (blood, sputum and urine) were collected within 24 h of first presentation and inclusion in the CAPNETZ study, and CRB and CRB-65 scores were determined for all patients at the time of enrollment. The combined end point representative of a severe course of CAP was defined as mechanical ventilation, intensive care unit treatment and/or death within 30 days. Overall, a total of 1,000 patients were enrolled in the study. A severe course of CAP was observed in 105 (10.5%) patients. Results The highest IL-6, IL-10 and LBP concentrations were found in patients with CRB-65 scores of 3-4 or CRB scores of 2-3. IL-6 and LBP levels on enrollment in the study were significantly higher for patients with a severe course of CAP than for those who did not have severe CAP. In receiver operating characteristic analyses, the area under the curve values for of IL-6 (0.689), IL-10 (0.665) and LPB (0.624) in a severe course of CAP were lower than that of CRB-65 (0.764) and similar to that of CRB (0.69). The accuracy of both CRB and CRB-65 was increased significantly by including IL-6 measurements. In addition, higher cytokine concentrations were found in patients with typical bacterial infections compared with patients with atypical or viral infections and those with infection of unknown etiology. LBP showed the highest discriminatory power with respect to the etiology of infection. Conclusions IL-6, IL-10 and LBP concentrations were increased in patients with a CRB-65 score of 3-4 and a severe course of CAP. The concentrations of IL-6 and IL-10 reflected the severity of disease in patients with CAP

  17. ASSOCIATION OF INTERLEUKIN-10 -1082 A/G (RS1800896) POLYMORPHISM WITH SUSCEPTIBILITY TO GASTRIC CANCER: META-ANALYSIS OF 6,101 CASES AND 8,557 CONTROLS.

    Science.gov (United States)

    Namazi, Abolfazl; Forat-Yazdi, Mohammad; Jafari, Mohammadali; Farahnak, Soudabeh; Nasiri, Rezvan; Foroughi, Elnaz; Abolbaghaei, Seyed Mojtaba; Neamatzadeh, Hossein

    2018-01-01

    The promoter -1082 A/G (rs1800896) polymorphism of Interleukin-10 (IL-10) gene have been widely reported and considered to have a significant role on gastric cancer risk, but the results are inconsistent. To clarify the association, we conducted a meta-analysis to investigate the associations IL-10 -1082 A/G polymorphism with gastric cancer. Eligible articles were identified by searching databases including PubMed, Web of Science, and Google Scholar up to August 03, 2017. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association. A total of 30 case-control studies with 6,101 cases and 8,557 controls were included in this meta-analysis. Overall, a significant association between IL-10 -1082 A/G polymorphism and gastric cancer risk was observed under the allele model (G vs A: OR=1.305, 95% CI=1.076-1.584; P=0.007), heterozygote model and (GA vs AA: OR=1.252, 95% CI=1.252-1.054; P=0.011) and dominant model (GG+GA vs AA: OR=1.264, 95% CI=1.053-1.516; P=0.012). In the subgroup analysis by ethnicity, increased gastric cancer risk were found in Asians under the allele model (G vs A: OR=1.520, 95% CI=1.172-1.973; P=0.002), homozygote model (GG+GA vs AA: OR=1.571, 95% CI=1.023-2.414; P= 0.039), heterozygote model (GA vs AA: OR=1.465, 95% CI=1.192-1.801; P≤0.001) and dominant model (GG+GA vs AA: OR=1.448, 95% CI=1.152-1.821; P=0.002), but not among Caucasian and Latinos populations. These results suggested that the IL-10 -1082 A/G (rs1800896) polymorphism might contribute to the gastric cancer susceptibility, especially among Asians.

  18. Resident Bacteria-Stimulated Interleukin-10-Secreting B Cells Ameliorate T-Cell-Mediated Colitis by Inducing T-Regulatory-1 Cells That Require Interleukin-27 SignalingSummary

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Mishima

    2015-05-01

    Full Text Available Background & Aims: The regulatory roles of interleukin-10 (IL10-producing B cells in colitis are not fully understood, so we explored the molecular mechanisms by which these cells modulate mucosal homeostasis. Methods: CD4+ T cells from wild-type (WT, Il10−/−, or Il27ra−/− mice were cotransferred with B cells from specific pathogen-free (SPF or germ-free (GF WT or Il10−/− mice into Rag2−/−Il10−/−(double-knockout mice, and the severity of colitis and intestinal regulatory T-cell populations were characterized. In vitro, WT or Il10−/− B cells were cocultured with unfractionated, naïve or regulatory T cells plus Il10−/− antigen-presenting cells and stimulated with cecal bacterial lysate (CBL with or without IL27 or anti-IL10R blockade. Gene expressions, cytokines in the supernatant and cell populations were assessed. Results: WT but not Il10−/− B cells attenuated T helper cell TH1/TH17-mediated colitis in double-knockout mice that also received WT but not Il10−/− T cells. In vitro, CBL-stimulated WT B cells secrete abundant IL10 and suppress interferon-γ (IFNγ and IL17a-production by T cells without requiring cell contact. Although both WT and Il10−/− B cells induced Foxp3+CD4+ T-regulatory cells, only WT B cells induced IL10-producing (Foxp3-negative T regulatory-1 (Tr-1 cells both in vivo and in vitro. However, IL10-producing B cells did not attenuate colitis or induce Tr-1 cells in the absence of T cell IL27 signaling in vivo. WT B cell-dependent Tr-1 induction and concomitant decreased IFNγ-secretion were also mediated by T-cell IL27-signaling in vitro. Conclusions: IL10-secreting B cells activated by physiologically relevant bacteria ameliorate T-cell-mediated colitis and contribute to intestinal homeostasis by suppressing effector T cells and inducing Tr-1 cells via IL27-signaling on T cells. Keywords: Experimental

  19. Hormones and β-Agonists

    NARCIS (Netherlands)

    Ginkel, van L.A.; Bovee, T.F.H.; Blokland, M.H.; Sterk, S.S.; Smits, N.G.E.; Pleadin, Jelka; Vulić, Ana

    2016-01-01

    This chapter provides some updated information on contemporary methods for hormone and β-agonist analyses. It deals with the classical approaches for the effective detection and identification of exogenous hormones. The chapter examines specific problems related to control strategies for natural

  20. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    and liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  1. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss

    DEFF Research Database (Denmark)

    Iepsen, E W; Lundgren, J; Dirksen, C

    2015-01-01

    of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor.......3 kg (95% CI=-0.6 to -4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI=-0.6 to -1)), P....3±0.1 mmol l(-1) to the level before weight loss (-0.5mmol l(-1) (95% CI=-0.1 to -0.9)), PMeal response of peptide PYY3-36 was higher at week 52 in the GLP-1RA group compared with the control group, P

  2. PPAR agonists stimulate adipogenesis at the expense of osteoblast differentiation while inhibiting osteoclast formation and activity.

    Science.gov (United States)

    Patel, Jessal J; Butters, Oliver R; Arnett, Timothy R

    2014-06-01

    Drugs used in the treatment of type 2 diabetes and cardiovascular disease, specifically peroxisome proliferator-activated receptor (PPAR) agonists, have been reported to affect bone cell function and fracture risk. In this study, we assessed the direct effects of PPAR-γ agonists (rosiglitazone and troglitazone), used in the treatment of diabetes, and a PPAR-α agonist (fenofibrate), used to treat hyperlipidaemia, on the function of primary osteoblasts and osteoclasts. Formation of 'trabecular' bone structures by rat calvarial osteoblasts was reduced by up to 85% in cultures treated with rosiglitazone and by 45% in troglitazone-treated or fenofibrate-treated cultures; at the same time, lipid droplet formation was increased by 40-70%. The expression of key osteogenic markers was similarly downregulated in cultures treated with PPAR agonists, whereas adipogenesis markers were upregulated. Formation of osteoclasts in cultures derived from mouse marrow diminished with fenofibrate treatment, whereas both glitazones reduced resorptive activity without affecting osteoclast number. Metformin, although not a PPAR agonist, is also commonly used in the treatment of type 2 diabetes. Here, metformin was found to have no effect on bone cell function. Taken together, these data suggest that PPAR-γ agonists may enhance bone loss via increased adipogenesis at the expense of osteoblast formation. In contrast, PPAR-α agonists may prevent bone loss. Given that the prevalence of diabetes and cardiovascular disease is expected to rise significantly, greater attention may need to be paid to the effects of PPAR agonists on bone homeostasis. Copyright © 2014 John Wiley & Sons, Ltd.

  3. Global smoothness preservation and the variation-diminishing property

    Directory of Open Access Journals (Sweden)

    Gavrea Ioan

    1999-01-01

    Full Text Available In the center of our paper are two counterexamples showing the independence of the concepts of global smoothness preservation and variation diminution for sequences of approximation operators. Under certain additional assumptions it is shown that the variation-diminishing property is the stronger one. It is also demonstrated, however, that there are positive linear operators giving an optimal pointwise degree of approximation, and which preserve global smoothness, monotonicity and convexity, but are not variation-diminishing.

  4. Reconstitution of high-affinity opioid agonist binding in brain membranes

    Energy Technology Data Exchange (ETDEWEB)

    Remmers, A.E.; Medzihradsky, F. (Univ. of Michigan Medical School, Ann Arbor (United States))

    1991-03-15

    In synaptosomal membranes from rat brain cortex, the {mu} selective agonist ({sup 3}H)dihydromorphine in the absence of sodium, and the nonselective antagonist ({sup 3}H)naltrexone in the presence of sodium, bound to two populations of opioid receptor sites with K{sub d} values of 0.69 and 8.7 nM for dihydromorphine, and 0.34 and 5.5 nM for naltrexone. The addition of 5 {mu}M guanosine 5{prime}-({gamma}-thio)triphosphate (GTP({gamma}S)) strongly reduced high-affinity agonist but not antagonist binding. Exposure of the membranes to high pH reduced the number of GTP({gamma}-{sup 35}S) binding sites by 90% and low K{sub m}, opioid-sensitive GTPase activity by 95%. In these membranes, high-affinity agonist binding was abolished and modulation of residual binding by GTP({gamma}S) was diminished. Alkali treatment of the glioma cell membranes prior to fusion inhibited most of the low K{sub m} GTPase activity and prevented the reconstitution of agonist binding. The results show that high-affinity opioid agonist binding reflects the ligand-occupied receptor - guanine nucleotide binding protein complex.

  5. Heart rate variability after BRL37344, a beta-3 agonist, in experimental bladder outlet obstruction

    Directory of Open Access Journals (Sweden)

    Łukasz Dobrek

    2013-08-01

    Full Text Available Introduction: Bladder overactivity symptoms accompany benign prostatic hyperplasia (BPH syndrome. The autonomic nervous system (ANS disturbances may be involved in bladder dysfunction. An ameliorating effect on bladder overactivity is being assigned to the currently investigated β-3 adrenoreceptor agonists. However, little is known about the influence of β-3 agonists on ANS activity. The aim of our study was to estimate ANS activity using heart rate variability (HRV in experimental model of bladder outlet obstruction (BOO, reflecting human BPH.Material/Methods: 30 female rats, divided into control, non-treated BOO (LLBOO, and β-3 agonist (BRL37344 BOO treated (LLBOO β3 agonist were studied. BOO was evoked by 5-week long partial proximal urethra ligation. Next, 20-minute resting HRV recordings were performed in each of the studied groups following i.p. administration of the vehicle (LLBOO or BRL37344 (LLBOO β3 agonist.Results: LLBOO rats were characterized by diminished NN range, SDNN, and rMSSD in time-domain analysis. Similarly, TP and non-normalized spectral HRV parameters were also decreased. Contrary to these findings, normalized spectral parameters were lower (nLF and higher (nHF. The animals treated with BRL37344 demonstrated no significant differences in time--domain HRV parameters. In spectral analysis, a decrease in LF and HF, together with a fall in TP, was found. Moreover, both nLF and nHF reached almost the same values in control and β-3 agonist treated rats.Disscussion: Our data indicates that BRL37344 is an agent abolishing the autonomic imbalance in experimental BOO, which may contribute to relieving the symptoms of bladder overactivity in β-3 agonists treated participants.

  6. Are there Diminishing Returns to R&D?

    DEFF Research Database (Denmark)

    Madsen, Jakob B.

    Semi-endogenous models and, to some extent, also Schumpeterian models are based on the assumption of diminishing returns to R&D. This paper shows that the null hypothesis of constant returns to R&D cannot be rejected for the OECD countries......Semi-endogenous models and, to some extent, also Schumpeterian models are based on the assumption of diminishing returns to R&D. This paper shows that the null hypothesis of constant returns to R&D cannot be rejected for the OECD countries...

  7. Effect of Yushen zhuyun decoction on rats with diminished ovarian ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of Yushen zhuyun decoction (YSZYF) on rats with diminished ovarian reserve (DOR). Methods: High-performance liquid chromatography (HPLC) was used to determine the major phytochemical constituents of YSZYF. Rats with DOR (DOR rats) were prepared by administration of ...

  8. Incidental finding of hypertension and diminished femoral pulses ...

    African Journals Online (AJOL)

    2012-06-08

    Jun 8, 2012 ... Case Study: Incidental finding of hypertension and diminished femoral pulses. 168. Vol 55 No 2. S Afr Fam Pract 2013. Introduction. Coarctation of the aorta is ... Surgery of the aorta and its branches. Philadelphia: WB Saunders Company, 2000; p. 3-10. 2. Rao PS. Coarctation of the aorta. Curr Cardiol Rep.

  9. Incidental finding of hypertension and diminished femoral pulses ...

    African Journals Online (AJOL)

    Incidental finding of hypertension and diminished femoral pulses: short-segment stenosis of the aorta just distal to the origin of the left subclavian artery. ... Young patients may present within the first few weeks of life with poor feeding, tachypnea and lethargy. They usually progress to overt congestive heart failure and shock.

  10. Is proprioception diminished in patients with patellar tendinopathy?

    NARCIS (Netherlands)

    Groot, H.E.; van der Worp, H.; Nijenbanning, L.; Diercks, R.L.; Zwerver, J.; van den Akker-Scheek, I.

    2016-01-01

    PURPOSE: Patellar tendinopathy is a highly prevalent overuse injury, and most treatments are only effective to some extent. This persistence of complaints could be linked to changed proprioception. One study showed diminished proprioception in athletes with lateral epicondylitis. Aim of this study

  11. Beta-agonists and animal welfare

    Science.gov (United States)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  12. GnRH agonist triggering

    DEFF Research Database (Denmark)

    Kol, Shahar; Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2013-01-01

    The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages......, including virtually complete prevention of ovarian hyperstimulation syndrome (OHSS), the introduction of a surge of FSH in addition to the LH surge and finally the possibility to individualize luteal-phase supplementation based on ovarian response to stimulation. We maintain that the automatic HCG...... triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients. Routinely, human chorionic gonadotrophin (HCG) is used to induce ovulation in fertility treatments. This approach deviates...

  13. Small Molecule Fluoride Toxicity Agonists

    Science.gov (United States)

    Nelson1, James W.; Plummer, Mark S.; Blount, Kenneth F.; Ames, Tyler D.; Breaker, Ronald R.

    2015-01-01

    SUMMARY Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch-reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. PMID:25910244

  14. Effects of trypan blue on the action of adrenergic agonists in the guinea-pig isolated atrium.

    Science.gov (United States)

    Mahmoudian, M; Ziai, S A

    1998-01-01

    It has been reported that trypan blue, a diazo dye with polyamphipathic structure, can inhibit the coupling of receptors to G-proteins. The present study was carried out to investigate the effect of trypan blue on the actions of adrenoceptor agonists in the guinea-pig atrium. Trypan blue (10 and 100 microM) antagonized the positive inotropic effects of isoprenaline and dobutamine by shifting their concentration-response curves to the right. With the selective beta 2-adrenoceptor agonist, salbutamol, there was a reduction of response in the presence of trypan blue. Therefore, we concluded that trypan blue diminish the response to beta-adrenoceptor agonists possibly via decoupling receptors from Gs. Trypan blue and similar agents, due to their unique mode of action, can be used as tools for the investigation of the mechanism of receptor-G protein coupling in the whole tissue preparation.

  15. On the Issue of Age Diminished Responsibility in Criminal Law

    Directory of Open Access Journals (Sweden)

    Kuznetsova I. A.

    2014-04-01

    Full Text Available The analysis of standards of the criminal law regulating questions of age diminished responsibility is presented in article. The points of view of scientists in the field of criminal law and criminology are analysed. The problem question of a ratio of provisions of Art. 20 and Art. 22 of the criminal code of Russian Federation is designated. The option of permission of a problem question is offered

  16. Literature of Diminishment: American Regionalism and the Writing of Nature

    OpenAIRE

    Chow, Juliana

    2015-01-01

    Literature of Diminishment redefines regionalism as a philosophical approach that prefers a partial view of oneself and of others, whether human or nonhuman, rather than the comprehensive view pursued by nineteenth-century science. I show how American regionalist writings from the 1820s to 1910s adapt scientific techniques of observation to the aesthetics of the regionalist sketch. Their "sketchy" view of Nature highlights the deficiencies of knowing and nonetheless opens out to a view of bio...

  17. Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia.

    Science.gov (United States)

    Shukla, Surendra K; Gebregiworgis, Teklab; Purohit, Vinee; Chaika, Nina V; Gunda, Venugopal; Radhakrishnan, Prakash; Mehla, Kamiya; Pipinos, Iraklis I; Powers, Robert; Yu, Fang; Singh, Pankaj K

    2014-01-01

    Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in view the significant role of metabolic alterations in cancer, we hypothesized that a ketogenic diet may diminish glycolytic flux in tumor cells to alleviate cachexia syndrome and, hence, may provide an efficient therapeutic strategy. We observed reduced glycolytic flux in tumor cells upon treatment with ketone bodies. Ketone bodies also diminished glutamine uptake, overall ATP content, and survival in multiple pancreatic cancer cell lines, while inducing apoptosis. A decrease in levels of c-Myc, a metabolic master regulator, and its recruitment on glycolytic gene promoters, was in part responsible for the metabolic phenotype in tumor cells. Ketone body-induced intracellular metabolomic reprogramming in pancreatic cancer cells also leads to a significantly diminished cachexia in cell line models. Our mouse orthotopic xenograft models further confirmed the effect of a ketogenic diet in diminishing tumor growth and cachexia. Thus, our studies demonstrate that the cachectic phenotype is in part due to metabolic alterations in tumor cells, which can be reverted by a ketogenic diet, causing reduced tumor growth and inhibition of muscle and body weight loss.

  18. Organizational Friction: Urban Crime Control Diminish Effect Theory

    Science.gov (United States)

    2010-12-10

    titled, the Urban Crime Control Diminish Effect Theory v ACKNOWLEDGMENTS I acknowledge the almighty God the steward of all guidance. I thank my...able to use impersonators to infiltrate the Police Department simply by gaining access to their uniform. He further commented that with his... impersonate a genuine member of the police department for a considerable period of time. An opinion poll was conducted following the discovery of the

  19. Endogenous Receptor Agonists: Resolving Inflammation

    Directory of Open Access Journals (Sweden)

    Gerhard Bannenberg

    2007-01-01

    Full Text Available Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and ω-3 polyunsaturated fatty acids (PUFA–derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS–based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA. These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution.

  20. Dopamine Agonists and Pathologic Behaviors

    Directory of Open Access Journals (Sweden)

    Brendan J. Kelley

    2012-01-01

    Full Text Available The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

  1. β2-Agonist clenbuterol hinders human monocyte differentiation into dendritic cells.

    Science.gov (United States)

    Giordani, Luciana; Cuzziol, Noemi; Del Pinto, Tamara; Sanchez, Massimo; Maccari, Sonia; Massimi, Alessia; Pietraforte, Donatella; Viora, Marina

    2015-12-10

    Clenbuterol (CLB) is a beta2-adrenergic agonist commonly used in asthma therapy, but is also a non-steroidal anabolic drug often abused in sport doping practices. Here we evaluated the in vitro impact of CLB on the physiology and function of human monocytes and dendritic cells (DCs), instrumental in the development of immune responses. We demonstrate that CLB inhibits the differentiation of monocytes into DCs and this effect is specific and dependent on β2-adrenergic receptor (AR) activation. We found that CLB treatment reduced the percentage of CD1a(+) immature DCs, while increasing the frequency of monocytes retaining CD14 surface expression. Moreover, CLB inhibited tumor necrosis factor-alpha (TNF-alpha) enhanced IL-(interleukin)-10 and IL-6 production. In contrast, CLB did not modulate the phenotypic and functional properties of monocytes and DCs, such as the surface expression of HLA-DR, CD83, CD80 and CD86 molecules, cytokine production, immunostimulatory activity and phagocytic activity. Moreover, we found that CLB did not modulate the activation of NF-kB in DCs. Moreover, we found that the differentiation of monocytes into DCs was associated with a significant decrease of β2-ARs mRNA expression. These results provide new insights on the effect of CLB on monocyte differentiation into DCs. Considering the frequent illegal use of CLB in doping, our work suggests that this drug is potentially harmful to immune responses decreasing the supply of DCs, thus subverting immune surveillance. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Elements to diminish radioactive accidents; Elementos para disminuir accidentes radiactivos

    Energy Technology Data Exchange (ETDEWEB)

    Cortes I, M.E.; Ramirez G, F.P. [Instituto Mexicano del Petroleo, Eje Central Lazaro Cardenas 152, C.P. 07730 Mexico D.F. (Mexico)

    1998-12-31

    In this work it is presented an application of the cause-effect diagram method or Ichikawa method identifying the elements that allow to diminish accidents when the radioactive materials are transported. It is considered the transport of hazardous materials which include radioactive materials in the period: December 1996 until March 1997. Among the identified elements by this method it is possible to mention: the road type, the radioactive source protection, the grade driver responsibility and the preparation that the OEP has in the radioactive material management. It is showed the differences found between the country inner roads and the Mexico City area. (Author)

  3. Multi-layered see-through movie in diminished reality

    Science.gov (United States)

    Uematsu, Yuko; Hashimoto, Takanori; Inoue, Takuya; Shimizu, Naoki; Saito, Hideo

    2012-03-01

    This paper presents generating a multi-layered see-through movie for an auto-stereoscopic display. This work is based on Diminished Reality (DR), which is one of the research fields of Augmented Reality (AR). In the usual AR, some virtual objects are added on the real world. On the other hand, DR removes some real objects from the real world. Therefore, the background is visualized instead of the real objects (obstacles) to be removed. We use multiple color cameras and one TOF depth camera. The areas of obstacles are defined by using the depth camera based on the distance of obstacles. The background behind the obstacles is recovered by planarprojection of multiple cameras. Then, the recovered background is overlaid onto the removed obstacles. For visualizing it through the auto-stereoscopic display, the scene is divided into multiple layers such as obstacles and background. The pixels corresponding to the obstacles are not visualized or visualized semi-transparently at the center viewpoints. Therefore, we can see that the obstacles are diminished according to the viewpoints.

  4. Apoptosis inhibitor of macrophage (AIM) diminishes lipid droplet-coating proteins leading to lipolysis in adipocytes

    International Nuclear Information System (INIS)

    Iwamura, Yoshihiro; Mori, Mayumi; Nakashima, Katsuhiko; Mikami, Toshiyuki; Murayama, Katsuhisa; Arai, Satoko; Miyazaki, Toru

    2012-01-01

    Highlights: ► AIM induces lipolysis in a distinct manner from that of hormone-dependent lipolysis. ► AIM ablates activity of peroxisome proliferator-activated receptor in adipocytes. ► AIM reduces mRNA levels of lipid-droplet coating proteins leading to lipolysis. -- Abstract: Under fasting conditions, triacylglycerol in adipose tissue undergoes lipolysis to supply fatty acids as energy substrates. Such lipolysis is regulated by hormones, which activate lipases via stimulation of specific signalling cascades. We previously showed that macrophage-derived soluble protein, AIM induces obesity-associated lipolysis, triggering chronic inflammation in fat tissue which causes insulin resistance. However, the mechanism of how AIM mediates lipolysis remains unknown. Here we show that AIM induces lipolysis in a manner distinct from that of hormone-dependent lipolysis, without activation or augmentation of lipases. In vivo and in vitro, AIM did not enhance phosphorylation of hormone-sensitive lipase (HSL) in adipocytes, a hallmark of hormone-dependent lipolysis activation. Similarly, adipose tissue from obese AIM-deficient and wild-type mice showed comparable HSL phosphorylation. Consistent with the suppressive effect of AIM on fatty acid synthase activity, the amount of saturated and unsaturated fatty acids was reduced in adipocytes treated with AIM. This response ablated transcriptional activity of peroxisome proliferator-activated receptor (PPARγ), leading to diminished gene expression of lipid-droplet coating proteins including fat-specific protein 27 (FSP27) and Perilipin, which are indispensable for triacylglycerol storage in adipocytes. Accordingly, the lipolytic effect of AIM was overcome by a PPARγ-agonist or forced expression of FSP27, while it was synergized by a PPARγ-antagonist. Overall, distinct modes of lipolysis appear to take place in different physiological situations; one is a supportive response against nutritional deprivation achieved by

  5. Automatic needle insertion diminishes pain during growth hormone injection

    DEFF Research Database (Denmark)

    Main, K M; Jørgensen, J T; Hertel, N T

    1995-01-01

    Non-compliance in children receiving growth hormone (GH) treatment is often caused by pain on injection and difficulties in administration of GH. It has been suggested that automatic needle insertion diminishes pain perception. We quantitatively measured pain intensity on injection with two...... prototype pens for GH administration, providing either manual or automatic sc needle insertion, using a combined visual analogue/facial scale and a five-item scale in 18 children. With the automatic pen there was a significantly lower maximum pain score compared with the manual pen (median 28.5 versus 52.......0 mm) as well as a lower mean pain score (mean 13.7 versus 23.5 mm). The five-item scale revealed that automatic needle insertion was significantly less painful than manual insertion and 13 patients chose to continue treatment with the automatic pen. In conclusion, pain during GH injection can...

  6. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels

    2015-01-01

    to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...... antagonists and describes the development of potent antagonists from partial agonists originally derived from the potent GABAAR agonist muscimol. In this process, several heterocyclic aromatic systems have been used in combination with structural models in order to map the orthosteric binding site...... and to reveal structural details to be used for obtaining potency and subtype selectivity. The challenges connected to functional characterization of orthosteric GABAAR partial agonists and antagonists, especially with regard to GABAAR stoichiometry and alternative binding sites are discussed. GABAAR...

  7. Peroxisome Proliferator-Activated Receptorα Agonists Differentially Regulate Inhibitor of DNA Binding Expression in Rodents and Human Cells

    Directory of Open Access Journals (Sweden)

    María del Carmen González

    2012-01-01

    Full Text Available Inhibitor of DNA binding (Id2 is a helix-loop-helix (HLH transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPARα activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPARα. In order to determine whether the fibrate effects were mediated by PPARα, wild-type mice and PPARα-null mice were treated with Wy-14,643 (WY. WY reduced Id2 expression in wild-type mice without an effect in PPARα-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2. MK-886, a PPARα antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARα-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARα agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V, the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARα agonists have different effects in rodents and humans.

  8. Overeducation and depressive symptoms: diminishing mental health returns to education.

    Science.gov (United States)

    Bracke, Piet; Pattyn, Elise; von dem Knesebeck, Olaf

    2013-11-01

    In general, well-educated people enjoy better mental health than those with less education. As a result, some wonder whether there are limits to the mental health benefits of education. Inspired by the literature on the expansion of tertiary education, this article explores marginal mental health returns to education and studies the mental health status of overeducated people. To enhance the validity of the findings we use two indicators of educational attainment - years of education and ISCED97 categories - and two objective indicators of overeducation (the realised matches method and the job analyst method) in a sample of the working population of 25 European countries (unweighted sample N = 19,089). Depression is measured using an eight-item version of the CES-D scale. We find diminishing mental health returns to education. In addition, overeducated people report more depression symptoms. Both findings hold irrespective of the indicators used. The results must be interpreted in the light of the enduring expansion of education, as our findings show that the discussion of the relevance of the human capital perspective, and the diploma disease view on the relationship between education and modern society, is not obsolete. © 2013 The Authors. Sociology of Health & Illness © 2013 Foundation for the Sociology of Health & Illness/John Wiley & Sons Ltd.

  9. Ambient groundwater flow diminishes nitrogen cycling in streams

    Science.gov (United States)

    Azizian, M.; Grant, S. B.; Rippy, M.; Detwiler, R. L.; Boano, F.; Cook, P. L. M.

    2017-12-01

    Modeling and experimental studies demonstrate that ambient groundwater reduces hyporheic exchange, but the implications of this observation for stream N-cycling is not yet clear. We utilized a simple process-based model (the Pumping and Streamline Segregation or PASS model) to evaluate N- cycling over two scales of hyporheic exchange (fluvial ripples and riffle-pool sequences), ten ambient groundwater and stream flow scenarios (five gaining and losing conditions and two stream discharges), and three biogeochemical settings (identified based on a principal component analysis of previously published measurements in streams throughout the United States). Model-data comparisons indicate that our model provides realistic estimates for direct denitrification of stream nitrate, but overpredicts nitrification and coupled nitrification-denitrification. Riffle-pool sequences are responsible for most of the N-processing, despite the fact that fluvial ripples generate 3-11 times more hyporheic exchange flux. Across all scenarios, hyporheic exchange flux and the Damkohler Number emerge as primary controls on stream N-cycling; the former regulates trafficking of nutrients and oxygen across the sediment-water interface, while the latter quantifies the relative rates of organic carbon mineralization and advective transport in streambed sediments. Vertical groundwater flux modulates both of these master variables in ways that tend to diminish stream N-cycling. Thus, anthropogenic perturbations of ambient groundwater flows (e.g., by urbanization, agricultural activities, groundwater mining, and/or climate change) may compromise some of the key ecosystem services provided by streams.

  10. COMBATING CYBERBULLYING AS STRATEGY TO DIMINISH THE STUDENTS’ AGGRESSIVENESS

    Directory of Open Access Journals (Sweden)

    Ali ABU RIA

    2018-03-01

    Full Text Available This article addresses the relationship between cyberbullying and students’ behaviors. At present, cyber security is one of the most discussed topics in most countries of the world. Cyber space is characterized by lack of borders, dynamism and anonymity, generating both opportunities for the development of the information society and risks to its functioning and its beneficiaries. Noting the noxious impact of cyberbullying on youth behaviors, we propose tackling cyberbullying as a strategy to diminish students' aggressiveness in the school.COMBATEREA BULLYING-ULUI CIBERNETIC CA STRATEGIE DE DIMINUARE A AGRESIVITĂȚII ELEVILORÎn articol este abordată relația dintre bullying-ul cibernetic și comportamentele elevilor. La etapa actuală, securitatea cibernetică este unul dintre cele mai discutate subiecte în majoritatea țărilor lumii. Spaţiul cibernetic se caracterizează prin lipsa frontierelor, dinamism şi anonimat, generând atât oportunităţi de dezvoltare a societăţii informaţionale, cât şi riscuri la adresa funcţionării acesteia și a beneficiarilor săi. Constatând impactul nociv al bullying-ului cibernetic asupra comportamentelor tinerilor, propunem abordarea combaterii bullying-ului cibernetic ca strategie de diminuare a agresi­vității elevilor în școală.

  11. Is proprioception diminished in patients with patellar tendinopathy?

    Science.gov (United States)

    Groot, H E; van der Worp, H; Nijenbanning, L; Diercks, R L; Zwerver, J; van den Akker-Scheek, I

    2016-03-01

    Patellar tendinopathy is a highly prevalent overuse injury, and most treatments are only effective to some extent. This persistence of complaints could be linked to changed proprioception. One study showed diminished proprioception in athletes with lateral epicondylitis. Aim of this study was to determine differences in proprioception, by measuring threshold to detect passive motion (TTDPM) between recreational athletes diagnosed with patellar tendinopathy and healthy controls. The TTDPM as measure of proprioception was determined in 22 recreational athletes with patellar tendinopathy and 22 healthy recreational athletes using a validated instrument. Amount of knee flexion and extension before the movement was noticed by the subject was determined. 80 measurements per athlete (left and right leg, towards extension and flexion and with two starting angles of 20° and 40° flexion) were performed. Mean TTDPM was compared between groups and among the injured recreational athletes between the affected and unaffected knee. No significant difference in TTDPM was found between recreational athletes with patellar tendinopathy and healthy controls. We did find a significant difference between the injured and non-injured knee in recreational athletes with patellar tendinopathy; mean TTDPM was 0.02° higher in the injured knee (p=0.044). No difference was found in proprioception between recreational athletes with patellar tendinopathy and healthy recreational athletes. It is unclear whether such a small difference in TTDPM between affected and unaffected knee is important in clinical setting. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Normal aging selectively diminishes alpha lateralization in visual spatial attention.

    Science.gov (United States)

    Hong, Xiangfei; Sun, Junfeng; Bengson, Jesse J; Mangun, George R; Tong, Shanbao

    2015-02-01

    EEG studies of cue-induced visual alpha power (8-13 Hz) lateralization have been conducted on young adults without examining differences that may develop as a consequence of normal aging. Here, we examined age-related differences in spatial attention by comparing healthy older and younger adults. Our key finding is that cue-induced alpha power lateralization was observed in younger, but not older adults, even though both groups exhibited classic event-related potential signatures of spatial orienting. Specifically, both younger and older adults showed significant early directing-attention negativity (EDAN), anterior directing-attention negativity (ADAN), late directing-attention positivity (LDAP) and contingent negative variation (CNV). Furthermore, target-evoked sensory components were enhanced for attended relative to unattended targets in both younger and older groups. This pattern of results suggests that although older adults can successfully allocate spatial attention, they do so without the lateralization of alpha power that is commonly observed in younger adults. Taken together, our findings demonstrate that younger and older adults might engage different neural mechanisms for attentional orienting, and that alpha power lateralization during visual spatial attention is a phenomenon that diminishes during normal aging. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Overexpression of Catalase Diminishes Oxidative Cysteine Modifications of Cardiac Proteins.

    Directory of Open Access Journals (Sweden)

    Chunxiang Yao

    Full Text Available Reactive protein cysteine thiolates are instrumental in redox regulation. Oxidants, such as hydrogen peroxide (H2O2, react with thiolates to form oxidative post-translational modifications, enabling physiological redox signaling. Cardiac disease and aging are associated with oxidative stress which can impair redox signaling by altering essential cysteine thiolates. We previously found that cardiac-specific overexpression of catalase (Cat, an enzyme that detoxifies excess H2O2, protected from oxidative stress and delayed cardiac aging in mice. Using redox proteomics and systems biology, we sought to identify the cysteines that could play a key role in cardiac disease and aging. With a 'Tandem Mass Tag' (TMT labeling strategy and mass spectrometry, we investigated differential reversible cysteine oxidation in the cardiac proteome of wild type and Cat transgenic (Tg mice. Reversible cysteine oxidation was measured as thiol occupancy, the ratio of total available versus reversibly oxidized cysteine thiols. Catalase overexpression globally decreased thiol occupancy by ≥1.3 fold in 82 proteins, including numerous mitochondrial and contractile proteins. Systems biology analysis assigned the majority of proteins with differentially modified thiols in Cat Tg mice to pathways of aging and cardiac disease, including cellular stress response, proteostasis, and apoptosis. In addition, Cat Tg mice exhibited diminished protein glutathione adducts and decreased H2O2 production from mitochondrial complex I and II, suggesting improved function of cardiac mitochondria. In conclusion, our data suggest that catalase may alleviate cardiac disease and aging by moderating global protein cysteine thiol oxidation.

  14. Overexpression of Catalase Diminishes Oxidative Cysteine Modifications of Cardiac Proteins.

    Science.gov (United States)

    Yao, Chunxiang; Behring, Jessica B; Shao, Di; Sverdlov, Aaron L; Whelan, Stephen A; Elezaby, Aly; Yin, Xiaoyan; Siwik, Deborah A; Seta, Francesca; Costello, Catherine E; Cohen, Richard A; Matsui, Reiko; Colucci, Wilson S; McComb, Mark E; Bachschmid, Markus M

    2015-01-01

    Reactive protein cysteine thiolates are instrumental in redox regulation. Oxidants, such as hydrogen peroxide (H2O2), react with thiolates to form oxidative post-translational modifications, enabling physiological redox signaling. Cardiac disease and aging are associated with oxidative stress which can impair redox signaling by altering essential cysteine thiolates. We previously found that cardiac-specific overexpression of catalase (Cat), an enzyme that detoxifies excess H2O2, protected from oxidative stress and delayed cardiac aging in mice. Using redox proteomics and systems biology, we sought to identify the cysteines that could play a key role in cardiac disease and aging. With a 'Tandem Mass Tag' (TMT) labeling strategy and mass spectrometry, we investigated differential reversible cysteine oxidation in the cardiac proteome of wild type and Cat transgenic (Tg) mice. Reversible cysteine oxidation was measured as thiol occupancy, the ratio of total available versus reversibly oxidized cysteine thiols. Catalase overexpression globally decreased thiol occupancy by ≥1.3 fold in 82 proteins, including numerous mitochondrial and contractile proteins. Systems biology analysis assigned the majority of proteins with differentially modified thiols in Cat Tg mice to pathways of aging and cardiac disease, including cellular stress response, proteostasis, and apoptosis. In addition, Cat Tg mice exhibited diminished protein glutathione adducts and decreased H2O2 production from mitochondrial complex I and II, suggesting improved function of cardiac mitochondria. In conclusion, our data suggest that catalase may alleviate cardiac disease and aging by moderating global protein cysteine thiol oxidation.

  15. Diminishing self-disclosure to maintain security in partners' care.

    Science.gov (United States)

    Lemay, Edward P; Melville, Michael C

    2014-01-01

    Six studies demonstrate that perceivers' desire to bond with targets motivates perceivers to misconstrue their own self-disclosure in ways that maintain perceivers' security in targets' care and commitment. Perceivers who strongly valued relationships with targets reported high levels of global self-disclosure, consistent with many findings suggesting salutary effects of disclosure. However, these same perceivers reported low self-disclosure of needs and desires in hypothetical (Study 1) and actual (Study 2) situations characterized by targets' unresponsive behavior. Similarly, in daily report (Study 3) and behavioral observation (Study 4) studies, perceivers who valued relationships with targets perceived high levels of self-disclosure when targets were responsive, but they perceived low self-disclosure when targets were unresponsive, and these perceptions seemed partly illusory. In turn, these perceptions of low self-disclosure in situations characterized by partners' unresponsive behavior predicted decreased perceptions of diagnosticity of targets' behavior (Studies 1-3) and buffered the negative affective and interpersonal effects of unresponsive behavior (Study 4). Experimental manipulations (Studies 5 and 6) demonstrated the motivational nature of perceived self-disclosure. Collectively, the results suggest that a desire to bond with targets motivates perceivers to downplay the diagnosticity of targets' unresponsive behavior through diminishing their self-disclosure, in turn preserving perceivers' trust in targets' care and commitment.

  16. Measuring mental illness stigma with diminished social desirability effects.

    Science.gov (United States)

    Michaels, Patrick J; Corrigan, Patrick W

    2013-06-01

    For persons with mental illness, stigma diminishes employment and independent living opportunities as well as participation in psychiatric care. Public stigma interventions have sought to ameliorate these consequences. Evaluation of anti-stigma programs' impact is typically accomplished with self-report questionnaires. However, cultural mores encourage endorsement of answers that are socially preferred rather than one's true belief. This problem, social desirability, has been circumvented through development of faux knowledge tests (KTs) (i.e., Error-Choice Tests); written to assess prejudice. Our KT uses error-choice test methodology to assess stigmatizing attitudes. Test content was derived from review of typical KTs for façade reinforcement. Answer endorsement suggests bias or stigma; such determinations were based on the empirical literature. KT psychometrics were examined in samples of college students, community members and mental health providers and consumers. Test-retest reliability ranged from fair (0.50) to good (0.70). Construct validity analyses of public stigma indicated a positive relationship with the Attribution Questionnaire and inverse relationships with Self-Determination and Empowerment Scales. No significant relationships were observed with self-stigma measures (recovery, empowerment). This psychometric evaluation study suggests that a self-administered questionnaire may circumvent social desirability and have merit as a stigma measurement tool.

  17. FXR agonist activity of conformationally constrained analogs of GW 4064

    Energy Technology Data Exchange (ETDEWEB)

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  18. Gonadotropin releasing hormone agonists: Expanding vistas

    Directory of Open Access Journals (Sweden)

    Navneet Magon

    2011-01-01

    Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

  19. Tumour necrosis factor alpha and interleukin 10 gene ...

    Indian Academy of Sciences (India)

    2011-08-19

    Aug 19, 2011 ... Hypertension was defined according to Joint National Committee VI–VII, as a systolic blood pressure >140 mm Hg and/or a diastolic blood pressure. >90 mm Hg based on the average of two blood pressure measurements. Diabetes was diagnosed if fasting plasma glucose was >126 mg/dL, in accordance ...

  20. Interleukin-10 gene promoter polymorphism as a potential host ...

    African Journals Online (AJOL)

    10) gene have been associated with altered levels of circulating IL-10, a Th2 cytokine that plays a key role in the pathogenesis of TB. We analyzed the frequencies of IL-10 promoter polymorphisms in 82 TB patients and 99 healthy Pakistani ...

  1. Interleukin 10 gene promoter polymorphism and risk of diffuse large ...

    African Journals Online (AJOL)

    Purpose: Given the importance of understanding the genetic variations involved in the pathogenesis of non-Hodgkin's lymphoma (NHL), this work was designed to study the impact of IL-10 (1082 G/A; rs1800896 and 819 C/T; rs1800871) gene promoter polymorphism on susceptibility of Egyptians to diffuse large B cell ...

  2. Interleukin-10 gene promoter polymorphism as a potential host ...

    African Journals Online (AJOL)

    ajl yemi

    2011-10-26

    Oct 26, 2011 ... Muhammad Sohail Afzal, Sadia Anjum, Amna Salman, Sajjad Ashraf, Zia Ur Rehman Farooqi,. Tahir Ahmed, Yasir waheed and Ishtiaq Qadri. Center of Virology and Immunology (NCVI), National University of Science and Technology (NUST), Sec H-12,. Islamabad, Pakistan. Accepted 9 September, 2011.

  3. Association assessment of Interleukine-10 gene polymorphism and ...

    African Journals Online (AJOL)

    Seyedeh Zahra Mousavi

    eral factors increase the risk of CAD such as age, gender, heredity, smoking, high blood cholesterol, high blood pressure, physical inactivity, and obesity. These factors make people prone to the coronary heart disease [3]. The cytokines are potent inflammatory factors that regulate each stage of atherosclerosis and leading ...

  4. Interleukin-10 regulates hepcidin in Plasmodium falciparum malaria

    KAUST Repository

    Huang, Honglei

    2014-02-10

    Background: Acute malarial anemia remains a major public health problem. Hepcidin, the major hormone controlling the availability of iron, is raised during acute and asymptomatic parasitemia. Understanding the role and mechanism of raised hepcidin and so reduced iron availability during infection is critical to establish evidence-based guidelines for management of malaria anemia. Our recent clinical evidence suggests a potential role of IL-10 in the regulation of hepcidin in patients with acute P. falciparum malaria. Methods: We have measured secretion of hepcidin by primary macrophages and the hepatoma cell line HepG2 stimulated with IL-10, IL-6 and Plasmodium falciparum-infected erythrocytes. Findings: We have observed that IL-10 and IL-6 production increased in primary macrophages when these cells were co-cultured with Plasmodium falciparum-infected erythrocytes. We found that IL-10 induced hepcidin secretion in primary macrophages in a dose-dependent manner but not in HepG2 cells. These effects were mediated through signal transducer and activator of transcription (STAT) 3-phosphorylation and completely abrogated by a specific STAT3 inhibitor. Conclusion: IL-10 can directly regulate hepcidin in primary macrophages but not in HepG2 cells. This effect can be modulated by Plasmodium falciparum. The results are consistent with a role for IL-10 in modulating iron metabolism during acute phase of infection. 2014 Huang et al.

  5. Interleukin 10 gene promoter polymorphism and risk of diffuse large ...

    African Journals Online (AJOL)

    Roba M. Talaat

    2013-10-09

    23]. The same result was found in-L-. 10 (А1082) which is consistent with those presented by Ghiel- mini and Mora [24] where the frequency of the IL-10 (А1082). G allele was not significantly different in DLBCL patients ver-.

  6. Tumour necrosis factor alpha and interleukin 10 gene ...

    Indian Academy of Sciences (India)

    2011-08-19

    Aug 19, 2011 ... TNF(-308) promoter polymorphism and stroke risk in children with sickle cell anemia. Stroke 38, 2241–2246. Karahan Z. C., Deda G., Sipahi T., Elhan A. H. and Akar N. 2005. TNF-alpha -308G/A and IL-6 -174 G/C polymorphisms in the. Turkish pediatric stroke patients. Thromb. Res. 115, 393–398. Koch W.

  7. Sports doping: Emerging designer and therapeutic B2-agonists

    NARCIS (Netherlands)

    Fragkaki, A.G.; Georgakopoulos, C.; Sterk, S.S.; Nielen, M.W.F.

    2013-01-01

    Beta2-adrenergic agonists, or ß2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of ß2-agonists is prohibited in sports by the World Anti-Doping

  8. Loneliness in older adults is associated with diminished cortisol output.

    Science.gov (United States)

    Schutter, N; Holwerda, T J; Stek, M L; Dekker, J J M; Rhebergen, D; Comijs, H C

    2017-04-01

    Loneliness in older adults has been associated with increased mortality and health problems. One of the assumed underlying mechanisms is dysregulation of the hypothalamic-pituitary-adrenocortical axis (HPA-axis). The purpose of this study was to investigate whether loneliness in older adults is associated with HPA-axis dysregulation and whether this association differs between depressed and non-depressed persons. Cross-sectional data of 426 lonely and non-lonely older adults in the Netherlands Study of Depression in Older Persons (NESDO) were used. Linear regression analyses and multinominal logistic regression analyses were performed to examine the association between loneliness and morning cortisol, cortisol awakening response, diurnal slope and dexamethasone suppression ratio. In all analyses, confounders were introduced. In order to examine whether the association between loneliness and cortisol measures is different in depressed versus non-depressed persons, an interaction term for loneliness x depression diagnosis was tested. Cortisol output in the first hour after awakening and dexamethasone suppression ratio was lower in lonely participants. There were no significant interactions between loneliness and depression diagnosis in the association with the cortisol measures. This study is the first to investigate the association between the HPA-axis and loneliness in a large group of older adults aged 60-93years. We found lower cortisol output in the first hour after awakening and lower dexamethasone suppression ratio in lonely older depressed and non-depressed adults. Whether diminished cortisol output is the underlying mechanism that leads to health problems in lonely older adults is an interesting object for further study. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. The Fate of Aspen in a World with Diminishing Snowpacks

    Science.gov (United States)

    Kavanagh, K.; Link, T. E.; Seyfried, M. S.; Kemp, K. B.

    2010-12-01

    Aspen (Populus tremuloides) productivity is tightly coupled with soil moisture. In the mountainous regions of the western USA, annual replenishment of soil moisture commonly occurs during snowmelt. Therefore, snow pack depth and duration can play an important role in sustaining aspen productivity. The presence of almost 50 years of detailed climate data across an elevational transect in the Reynolds Creek Experimental Watershed (RCEW) in southwestern Idaho offers a novel opportunity to better understand the role of shifting precipitation patterns on aspen productivity. Over the past 50 years, the proportion of the precipitation falling in the form of snow decreased by almost a factor of 2 at mid to low elevations in the RCEW, coupled with a roughly four week advance of snow ablation, and decline of large snow drifts that release moisture into the early summer. Results from growth ring increment, stable isotope analysis, sapflux and a process model (Biome BGC), will be used to determine the impact of shifting precipitation patterns on tree productivity along this transect over the past 50 years. Aspen trees located on moist microsites continue to transpire water and maintain high stomatal conductance 21 days later in the growing season relative to individuals on drier microsites. Predictions of net primary productivity (NPP) in aspen are very sensitive to precipitation patterns. NPP becomes negative as early as day 183 (90 days post budbreak) for years with little winter and spring precipitation whereas, in years with ample winter and spring precipitation, NPP remains positive until day 260 when leaf fall occurs. These results give unique insight into the conditions that deciduous tree species will encounter in a warming climate where snow water equivalent continues to diminish and soil moisture declines soon after budbreak occurs.

  10. Apoptosis inhibitor of macrophage (AIM) diminishes lipid droplet-coating proteins leading to lipolysis in adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Iwamura, Yoshihiro; Mori, Mayumi; Nakashima, Katsuhiko [Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Mikami, Toshiyuki; Murayama, Katsuhisa [Genomic Science Laboratories, Dainippon Sumitomo Pharma Co. Ltd., 3-1-98 Kasugadenaka, Konohana-ku, Osaka 554-0022 (Japan); Arai, Satoko [Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Miyazaki, Toru, E-mail: tm@m.u-tokyo.ac.jp [Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)

    2012-06-08

    Highlights: Black-Right-Pointing-Pointer AIM induces lipolysis in a distinct manner from that of hormone-dependent lipolysis. Black-Right-Pointing-Pointer AIM ablates activity of peroxisome proliferator-activated receptor in adipocytes. Black-Right-Pointing-Pointer AIM reduces mRNA levels of lipid-droplet coating proteins leading to lipolysis. -- Abstract: Under fasting conditions, triacylglycerol in adipose tissue undergoes lipolysis to supply fatty acids as energy substrates. Such lipolysis is regulated by hormones, which activate lipases via stimulation of specific signalling cascades. We previously showed that macrophage-derived soluble protein, AIM induces obesity-associated lipolysis, triggering chronic inflammation in fat tissue which causes insulin resistance. However, the mechanism of how AIM mediates lipolysis remains unknown. Here we show that AIM induces lipolysis in a manner distinct from that of hormone-dependent lipolysis, without activation or augmentation of lipases. In vivo and in vitro, AIM did not enhance phosphorylation of hormone-sensitive lipase (HSL) in adipocytes, a hallmark of hormone-dependent lipolysis activation. Similarly, adipose tissue from obese AIM-deficient and wild-type mice showed comparable HSL phosphorylation. Consistent with the suppressive effect of AIM on fatty acid synthase activity, the amount of saturated and unsaturated fatty acids was reduced in adipocytes treated with AIM. This response ablated transcriptional activity of peroxisome proliferator-activated receptor (PPAR{gamma}), leading to diminished gene expression of lipid-droplet coating proteins including fat-specific protein 27 (FSP27) and Perilipin, which are indispensable for triacylglycerol storage in adipocytes. Accordingly, the lipolytic effect of AIM was overcome by a PPAR{gamma}-agonist or forced expression of FSP27, while it was synergized by a PPAR{gamma}-antagonist. Overall, distinct modes of lipolysis appear to take place in different physiological

  11. How to diminish calcium loss and muscle atrophy in space

    Science.gov (United States)

    Gorgolewski, S.

    perfect relaxation when asleep or awake. We have to check in space if we can thus diminish the use of medicaments or even eliminate them. Slow Yoga exercises decrease also the amount on food required because life is not so energy demanding in space as it is here under the earth's gravitation. We can stay lean and healthy with such static yet most effective physical exercises. In addition it gives us for free a vegetarian life style, just another benefit so useful in space travel.

  12. Diminished Baroreflex Control of Forearm Vascular Resistance Following Training

    Science.gov (United States)

    Mack, G. W.; Thompson, C. A.; Doerr, D. F.; Nadel, E. R.; Convertino, V. A.

    1991-01-01

    The stimulus-response characteristics of cardiopulmonary baroreflex control of forearm vascular resistance (FVR units in mm Hg x min x I00 ml/ml) were studied in 14 volunteers before and after 10 wk of endurance training. We assessed the relationship betaleen reflex stimulus (changes in central venous pressure, CVP) and response (FVR) during unloading of cardiopulmonary baroreceptors with lower body negative pressure (LBNP, 0 to - 2O mm Hg). Changes in CVP during LBNP were estimated from pressure changes in a large peripheral vein in the dependent arm of the subject in the right lateral decubitus position. Maximal oxygen uptake (VO(sub 2max)) and total blood volume increased with endurance training from 37.8 +/- 1.4 ml/min x kg and 63.6 +/- 2.1 ml/kg to 45.3 +/- 1.4 ml/ min x kg and 69.3 +/- 2.8 ml/kg respectively (P less than 0.05). Reflex forearm vasoconstriction occurred in response to a reduction in estimated CVP, and the absolute change in FVR per unit of CVP was reduced from -5.96 +/- 0.79 to -4.06 +/- 0.52 units x mm/ Hg (P less than 0.05) following exercise training but was unchanged from -6.10 to 0.57 to -6.22 +/- 0.94 units x mm/ Hg for the time control group (N = 7). Resting values for FVR were similar before and after exercise training; however, resting estimated CVP was elevated from 9.5 +/- 0.5 mm x Hg before training to 11.3 +/- 0.6 mm x Hg after training. The reduction in sensitivity of the cardiopulmonary baroreflex control of FVR was linearly related to the increase in blood volume (r = 0.65, P less than 0.05). suggesting that diminished cardiopulmonary baroreflex control of FVR in physically fit individuals is related, in part, to a training-induced blood volume expansion.

  13. Subtype selective kainic acid receptor agonists

    DEFF Research Database (Denmark)

    Bunch, Lennart; Krogsgaard-Larsen, Povl

    2009-01-01

    (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (m......GluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists...

  14. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists.

    Science.gov (United States)

    Stahn, Cindy; Löwenberg, Mark; Hommes, Daniel W; Buttgereit, Frank

    2007-09-15

    Glucocorticoids (GC) are the most common used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic and other inflammatory diseases. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused by the cytosolic glucocorticoid receptor (cGCR); secondary non-genomic effects which are also initiated by the cGCR; membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects; non-specific, non-genomic effects caused by interactions with cellular membranes. The classical, genomic mechanism of GC-action can be divided into two processes: "transrepression", which is responsible for a large number of desirable anti-inflammatory and immunomodulating effects, and "transactivation" which is associated with frequently occurring side effects as well as with some immunosuppressive activities [Ehrchen, J., Steinmuller, L., Barczyk, K., Tenbrock, K., Nacken, W., Eisenacher, M., Nordhues, U., Sorg, C., Sunderkotter, C., Roth, J., 2007. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood 109, 1265-1274]. Great efforts have been made to diminish glucocorticoid-induced adverse effects, but the improvement of conventional glucocorticoids has almost reached its limits. As a consequence, new variations of the conventional "good old drugs" are being tested and nitro-steroids and long circulating liposomal glucocorticoids indeed show promising results. Nevertheless, crux of the matter should be the design of qualitatively new drugs, such as selective glucocorticoid receptor agonists (SEGRAs). These innovative steroidal or non-steroidal molecules induce transrepression, while transactivation processes are less affected. First reports on two different GCR ligands, A276575 and ZK216348, show promising results. Here, we review the above-mentioned mechanisms of glucocorticoid action and give particular attention

  15. Adverse Effects of GLP-1 Receptor Agonists

    OpenAIRE

    Filippatos, Theodosios D.; Panagiotopoulou, Thalia V.; Elisaf, Moses S.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of ...

  16. Agonist trigger: what is the best approach? Agonist trigger and low dose hCG

    DEFF Research Database (Denmark)

    Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2012-01-01

    Low-dose hCG supplementation after GnRH agonist trigger may normalize reproductive outcome while minimizing the occurrence of OHSS in high risk IVF patients. (Fertil Steril (R) 2012;97:529-30. (C) 2012 by American Society for Reproductive Medicine.)......Low-dose hCG supplementation after GnRH agonist trigger may normalize reproductive outcome while minimizing the occurrence of OHSS in high risk IVF patients. (Fertil Steril (R) 2012;97:529-30. (C) 2012 by American Society for Reproductive Medicine.)...

  17. Sphingosine-1-Phosphate Receptor-1 Selective Agonist Enhances Collateral Growth and Protects against Subsequent Stroke.

    Directory of Open Access Journals (Sweden)

    Masahiko Ichijo

    CCAO. Administration of the S1PR1 selective agonist significantly increased cerebral blood flow (CBF and the diameter of leptomeningeal collateral vessels (42.9 ± 2.6 μm compared with the controls (27.6 ± 5.7 μm; P < 0.01. S1PR1 inverse agonist administration diminished the effect of the S1PR1 agonist (P < 0.001. After pMCAO, S1PR1 agonist pretreated animals showed significantly smaller infarct volume (17.5% ± 4.0% vs. 7.7% ± 4.0%, P < 0.01 and better functional recovery than vehicle-treated controls.These results suggest that S1PR1 is one of the principal regulators of leptomeningeal collateral recruitment at the site of increased shear stress and provide evidence that an S1PR1 selective agonist has a role in promoting collateral growth and preventing of ischemic damage and neurological dysfunction after subsequent stroke in patients with intracranial major artery stenosis or occlusion.

  18. Complementary anti-inflammatory actions of the β₂-adrenoceptor agonist clenbuterol and the glucocorticoid dexamethasone in rat brain.

    Science.gov (United States)

    Ryan, Katie J; Griffin, Eadaoin W; Connor, Thomas J

    2011-03-01

    Systemic administration of the β(2)-adrenoceptor agonist clenbuterol induces expression of IL-1β and its negative regulators, interleukin-1 receptor antagonist (IL-1ra) and the interleukin-1 type II decoy receptor (IL-1RII) in rat brain. Clenbuterol also increases central expression of the broad spectrum anti-inflammatory cytokine interleukin-10 (IL-10) and its downstream signalling molecule, suppressor of cytokine signalling-3 (SOCS-3). Here we examine the impact of combined treatment with clenbuterol (0.5mg/kg) and the glucocorticoid dexamethasone (1mg/kg) on mRNA expression of IL-1β and the IL-1β-inducible gene iNOS, on IκBα mRNA expression and NFκB activation, and on mRNA expression of the anti-inflammatory molecules IL-1ra, IL-1RII, IL-10 and SOCS-3 in rat cortex, striatum and hippocampus. Dexamethasone inhibited induction of IL-1β and iNOS mRNA expression by clenbuterol in all three brain regions, without altering its ability to induce IL-1ra mRNA expression. In the case of IL-1RII, dexamethasone further augmented clenbuterol-induced IL-1RII mRNA expression in hippocampus and striatum. These data highlight a mechanistic dissociation between the ability of β(2)-adrenoceptor activation to induce expression of IL-1β, and its negative regulators IL-1ra and IL-1RII in the brain. Treatment with either dexamethasone or clenbuterol alone independently induced IκBα mRNA expression, and elicited a concomitant decrease in the DNA binding of NFκB in all three brain regions. In the hippocampus and striatum dexamethasone treatment did not influence the ability of clenbuterol to induce IL-10 mRNA expression. In contrast in the cortex, induction of IL-10 and SOCS-3 mRNA expression by clenbuterol administered in combination with dexamethasone was less than induced by clenbuterol alone. Overall these data indicate that combined treatment with dexamethasone and the β(2)-adrenoceptor agonist clenbuterol elicit complementary anti-inflammatory actions in the CNS

  19. Sports doping: emerging designer and therapeutic β2-agonists.

    Science.gov (United States)

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future. © 2013.

  20. GLP-1 agonists for type 2 diabetes

    DEFF Research Database (Denmark)

    Jespersen, Maria J; Knop, Filip K; Christensen, Mikkel

    2013-01-01

    and safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches...... and obesity. The difference in chemical structure have strong implications for key pharmacokinetic parameters such as absorption and clearance, and eventually the safety and efficacy of the individual GLP-1-RA. The main safety concerns are pancreatitis and neoplasms, for which there are no identifiable...

  1. Dopamine agonist: pathological gambling and hypersexuality.

    Science.gov (United States)

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication.

  2. Neurotensin agonists block the prepulse inhibition deficits produced by a 5-HT2A and an alpha1 agonist.

    Science.gov (United States)

    Shilling, P D; Melendez, G; Priebe, K; Richelson, E; Feifel, D

    2004-09-01

    Neurotensin (NT) agonists have been proposed as potential antipsychotics based exclusively upon their ability to inhibit dopamine-2 (D2) receptor transmission. Several other pharmacological mechanisms have been implicated in enhancing the antipsychotic profile produced by D2 inhibition alone. These include inhibition of 5-HT2A and alpha1-adrenoceptors. Recently, we reported that systemic administration of the neurotensin agonist PD149163 blocks deficits in prepulse inhibition (PPI) of the startle reflex produced by the 5-HT2A receptor agonist DOI. This suggested that NT agonists could inhibit 5-HT2A modulation of neurotransmission. To determine if other peripherally administered NT agonists shared this effect, we examined the effects of NT69L, another NT agonist, on DOI-induced PPI deficits. In addition, to determine if NT agonists also inhibit alpha1-adrenoceptor neurotransmission, we examined the effects of PD149163 and NT69L on PPI deficits induced by the alpha1-adrenoceptor agonist, cirazoline. In the NT69L/DOI study, rats received subcutaneous (SC) injections of NT69L (0, 0.1, 1, or 2 mg/kg) followed 30 min later by SC saline or DOI (0.5 mg/kg). In the NT agonist/cirazoline studies, animals received SC injections of either PD149163 (0, 0.01, 0.1, or 1 mg/kg) or NT69L (0, 0.01, 0.1, or 1 mg/kg) followed 30 min later by SC saline or cirazoline (0.7 mg/kg). Animals were tested in startle chambers 20 min later. In all three experiments the PPI disruption produced by DOI and cirazoline was blocked by the NT agonists. These findings provide strong evidence that NT agonists inhibit 5-HT2A and alpha1-adrenoceptor modulation of neurotransmission, pharmacological effects that, in conjunction with their known inhibition of dopamine transmission, strengthen the antipsychotic potential of NT agonists.

  3. FIR Filter Implementation Based on the RNS with Diminished-1 Encoded Channel

    Directory of Open Access Journals (Sweden)

    Dragana Uros Zivaljevic

    2013-03-01

    Full Text Available A technique, based on the residue number system (RNS with diminished-1 encoded channel, has being used for implementing a finite impulse response (FIR digital filter. The proposed RNS architecture of the filter consists of three main blocks: forward and reverse converter and arithmetic processor for each channel. Architecture for residue to binary (reverse convertor with diminished-1 encoded channel has been proposed. Besides, for all RNS channels, the systolic design is used for the efficient  realization of FIR filter. A numerical example illustrates the principles of diminished-1 residue arithmetic, signal processing, and decoding for FIR filters.

  4. Chamomile Flower, Myrrh, and Coffee Charcoal, Components of a Traditional Herbal Medicinal Product, Diminish Proinflammatory Activation in Human Macrophages.

    Science.gov (United States)

    Vissiennon, Cica; Hammoud, Dima; Rodewald, Steffen; Fester, Karin; Goos, Karl-Heinz; Nieber, Karen; Arnhold, Jürgen

    2017-07-01

    A traditional herbal medicinal product, containing myrrh, chamomile flower, and coffee charcoal, has been used in Germany for the relief of gastrointestinal complaints for decades. Clinical studies suggest its use in the maintenance therapy of inflammatory bowel disease. However, the pharmacological mechanisms underlying the clinical effects are not yet fully understood.The present study aims to elucidate immunopharmacological activities of myrrh, chamomile flower, and coffee charcoal by studying the influence of each plant extract on gene expression and protein release of activated human macrophages.The plant extracts effect on gene and protein expression of activated human monocyte-derived macrophages was investigated by microarray gene expression analysis and assessment of the release of pro- and anti-inflammatory mediators (TNF α , chemokine CXCL13, and interleukin-10) using an ELISA test system.The extracts of myrrh, chamomile flower, and coffee charcoal influenced gene expression of activated human macrophages within the cytokine/chemokine signaling pathway. Particularly, chemokine gene expression was suppressed. Subsequently, the production of CXCL13 and, to a minor extent, cytokine TNF α was inhibited by all herbal extracts. Chamomile flower and coffee charcoal extracts enhanced interleukin-10 release from activated macrophages. The observed effects on protein release were comparable to the effect of budesonide, which decreased TNF α and CXCL13 and enhanced interleukin-10 release.The components of the herbal medicinal product influence the activity of activated human macrophages on both gene and protein level. The induced alterations within chemokine/cytokine signaling could contribute to a positive effect on the immunological homeostasis, which is disturbed in patients with chronic intestinal inflammation. Georg Thieme Verlag KG Stuttgart · New York.

  5. The importance of β2-agonists in myocardial infarction

    DEFF Research Database (Denmark)

    Rørth, Rasmus; Fosbøl, Emil L; Mogensen, Ulrik M

    2016-01-01

    PURPOSE: β2-Agonists are widely used for relief of respiratory symptoms. Studies so far have reported conflicting results regarding use of β2-agonists and risk of myocardial infarction (MI). Yet, coronary angiographical data and longitudinal outcomes data are sparse and could help explain...

  6. Agonist induction, conformational selection, and mutant receptors.

    Science.gov (United States)

    Giraldo, Jesús

    2004-01-02

    Current models of receptor activation are based on either of two basic mechanisms: agonist induction or conformational selection. The importance of one pathway relative to the other is controversial. In this article, the impossibility of distinguishing between the two mechanisms under a thermodynamic approach is shown. The effect of receptor mutation on the constants governing ligand-receptor equilibria is discussed. The two-state model of agonism both in its original formulation (one cycle) and including multiple active states (multiple cycles) is used. Pharmacological equations for the double (two cycles) two-state model are derived. The simulations performed suggest that the double two-state model of agonism can be a useful model for assessing quantitatively the changes in pharmacological activity following receptor mutation.

  7. Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

    DEFF Research Database (Denmark)

    Maolanon, Alex R.; Risgaard, Rune; Wang, Shuang Yan

    2017-01-01

    A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist...... efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit......-selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission....

  8. Biased μ-opioid receptor agonists diversely regulate lateral mobility and functional coupling of the receptor to its cognate G proteins.

    Science.gov (United States)

    Melkes, Barbora; Hejnova, Lucie; Novotny, Jiri

    2016-12-01

    There are some indications that biased μ-opioid ligands may diversely affect μ-opioid receptor (MOR) properties. Here, we used confocal fluorescence recovery after photobleaching (FRAP) to study the regulation by different MOR agonists of receptor movement within the plasma membrane of HEK293 cells stably expressing a functional yellow fluorescent protein (YFP)-tagged μ-opioid receptor (MOR-YFP). We found that the lateral mobility of MOR-YFP was increased by (D-Ala 2 ,N-MePhe 4 ,Gly 5 -ol)-enkephalin (DAMGO) and to a lesser extent also by morphine but decreased by endomorphin-2. Interestingly, cholesterol depletion strongly enhanced the ability of morphine to elevate receptor mobility but significantly reduced or even eliminated the effect of DAMGO and endomorphin-2, respectively. Moreover, the ability of DAMGO and endomorphin-2 to influence MOR-YFP movement was diminished by pertussis toxin treatment. The results obtained by agonist-stimulated [ 35 S]GTPγS binding assays indicated that DAMGO exhibited higher efficacy than morphine and endomorphin-2 did and that the efficacy of DAMGO, contrary to the latter agonists, was enhanced by cholesterol depletion. Overall, our study provides clear evidence that biased MOR agonists diversely affect receptor mobility in plasma membranes as well as MOR/G protein coupling and that the regulatory effect of different ligands depends on the membrane cholesterol content. These findings help to delineate the fundamental properties of MOR regarding their interaction with biased MOR ligands and cognate G proteins.

  9. Adenosine receptor agonists modulate visceral hyperalgesia in the rat.

    Science.gov (United States)

    Sohn, Chong-Il; Park, Hyo Jin; Gebhart, G F

    2008-06-01

    Adenosine is an endogenous modulator of nociception. Its role in visceral nociception, particularly in visceral hyperalgesia, has not been studied. The aim of this study was to determine the effects of adenosine receptor agonists in a model of visceral hyperalgesia. The visceromotor response (VMR) in rats to colorectal distension (CRD; 80 mmHg, 20 seconds) was quantified by electromyographic recordings from the abdominal musculature. Three hours after the intracolonic administration of zymosan (25 mg/mL, 1 mL), VMRs to CRD were measured before and after either subcutaneous or intrathecal administration of an adenosine receptor agonist. Subcutaneous injection of 5'-N-ethylcarboxyamidoadenosine (NECA; an A1 and A2 receptor agonist), R(-)-N6-(2-phenylisopropyl)-adenosine (R-PIA; a selective A1 receptor agonist), or CGS-21680 hydrochloride (a selective A2a receptor agonist) dose-dependently (10-100 mg/kg) attenuated the VMR to CRD, although hindlimb weakness occurred at the higher doses tested. Intrathecal administration of NECA or R-PIA dose-dependently (0.1-1.0 microg/kg) decreased the VMR, whereas CGS-21680 hydrochloride was ineffective over the same concentration range. Higher intrathecal doses of the A1/A2 receptor agonist NECA produced motor weakness. Adenosine receptor agonists are antihyperalgesic, but also produce motor weakness at high doses. However, activation of the spinal A1 receptor significantly attenuates the VMR to CRD without producing motor weakness.

  10. Dopamine agonist withdrawal syndrome: implications for patient care.

    Science.gov (United States)

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper.

  11. Synthetic ROR? agonists regulate multiple pathways to enhance antitumor immunity

    OpenAIRE

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don

    2016-01-01

    ABSTRACT ROR?t is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are ROR?+ cells. To evaluate the role of ROR? in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate ROR? to a greater extent than the endogenous agonist desmosterol. These ROR? agonists enhance effector function of Type 17...

  12. Problematic gambling on dopamine agonists: Not such a rarity.

    Science.gov (United States)

    Grosset, Katherine A; Macphee, Graeme; Pal, Guru; Stewart, David; Watt, Andrew; Davie, Jim; Grosset, D G

    2006-12-01

    Excessive gambling is recognized with dopamine agonist therapy, but the prevalence is unknown. We assessed the prevalence of excess gambling by specific prospective enquiry in Parkinson's disease patients attending six West Scotland movement disorder clinics. Of 388 patients taking anti-Parkinson medication, 17 (4.4%) developed pathological gambling, all of whom were prescribed dopamine agonists. Thus, 8% of patients taking dopamine agonists had pathological gambling. Pathological gambling is not uncommon, and patients should be made aware of this potential adverse effect. Copyright 2006 Movement Disorder Society.

  13. Nicotine receptor partial agonists for smoking cessation.

    Science.gov (United States)

    Cahill, Kate; Stead, Lindsay F; Lancaster, Tim

    2012-04-18

    Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation. We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in December 2011. We also searched online clinical trials registers. We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up.The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model. Two recent cytisine trials (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled RR of

  14. Albiglutide: a unique GLP-1 receptor agonist.

    Science.gov (United States)

    Rendell, Marc S

    2016-12-01

    Albiglutide is a long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection. Area covered: The pharmacokinetic and pharmacodynamic properties of albiglutide and its clinical effects are discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents. Expert opinion: Albiglutide has a chemical structure quite distinct from that of other marketed GLP-1 RAs. The agent has less gastrointestinal side effects than other comparable GLP-1 RAs and is safe in patients with renal failure. As a sole treatment for diabetes and used with other hypoglycemic agents, it achieves a lowering of HbA1c of up to 1%, less than several competitor GLP-1 RAs. The benefit on weight reduction is minimal compared to other GLP-1 RAs. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long term study now underway will determine if albiglutide, with its lower level of GI intolerance, has a place in the treatment of patients with increased risk of cardiovascular events.

  15. Nicotine receptor partial agonists for smoking cessation

    Directory of Open Access Journals (Sweden)

    Kate Cahill

    Full Text Available BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist and reducing smoking satisfaction (acting as an antagonist. OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist' in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialized register was in December 2011. We also searched online clinical trials registers. SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up. The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs, using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: Two recent cytisine trials (937 people

  16. Development of a radioreceptor assay for β2 adrenergic agonists

    International Nuclear Information System (INIS)

    Helbo, V.; Vandenbroeck, M.; Maghuin-Rogister, G.

    1994-01-01

    Several β 2 adrenergic agonists are illegally used as growth promoters in meat production. We have developed and evaluated a radioreceptor assay for the multianalyte detection of these compounds. The method is based on a competition for binding with receptors (plasma membranes prepared from bovine teat muscles) between a radioactive tracer ( 3 H-dihydroalprenolol) and β 2 agonist residues present in the samples. The method has been validated for three β 2 agonists (clenbuterol, mabuterol and cimaterol) in bovine urine samples. The detection limit (mean of ''blank'' values + 3 SEM) in urine was 2.4 ppb clenbuterol. Using this procedure, samples containing at least 5 ppb of clenbuterol, mabuterol or cimaterol could be identified as positive for the presence of β 2 agonists. (orig.) [de

  17. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    Directory of Open Access Journals (Sweden)

    Akinori Hirashima

    2003-04-01

    Full Text Available The compounds 1-(2,6-diethylphenylimidazolidine-2-thione and 2-(2,6-diethylphenylimidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor.

  18. MELATONIN DAN MELATONIN RECEPTOR AGONIST SEBAGAI PENANGANAN INSOMNIA PRIMER KRONIS

    Directory of Open Access Journals (Sweden)

    Ni Luh Putu Ayu Maha Iswari

    2013-04-01

    Full Text Available Melatonin is a hormone that has an important role in the mechanism of sleep. Hypnotic effects of melatonin and melatonin receptor agonist are mediated via MT1 and MT2 receptors, especially in circadian rhythm pacemaker, suprachiasmatic nucleus, which is worked on the hypothalamic sleep switch. This mechanism is quite different with the GABAergic drugs such as benzodiazepine. Agonist melatonin triggers the initiation of sleep and normalize circadian rhythms so that makes it easier to maintain sleep. The main disadvantage of melatonin in helping sleep maintenance on primary insomnia is that the half life is very short. The solution to this problem is the use of prolonged-release melatonin and melatonin receptor agonist agents such as ramelteon. Melatoninergic agonist does not cause withdrawal effects, dependence, as well as cognitive and psychomotor disorders as often happens on the use of benzodiazepine.  

  19. Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches.

    Science.gov (United States)

    Vallée, Alexandre; Lecarpentier, Yves; Guillevin, Rémy; Vallée, Jean-Noël

    2018-04-16

    Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4⁺ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4⁺ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4⁺ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.

  20. Division of Work and Fragmented Information: An Explanation for the Diminishing Marginal Product of Labor

    OpenAIRE

    Harashima, Taiji

    2014-01-01

    In this paper, an explanation for the diminishing marginal product of labor is demonstrated in a model that incorporates the concept of entropy from information theory. First, I introduce the concept of “division of work” and argue that the division of work (i.e., the allocation of tasks in the production process) and not the division of labor (i.e., worker specialization) is the source of the diminishing marginal product of labor. Division of work results in a fragmentation of the informatio...

  1. Sleep attacks in patients taking dopamine agonists: review.

    Science.gov (United States)

    Homann, Carl Nikolaus; Wenzel, Karoline; Suppan, Klaudia; Ivanic, Gerd; Kriechbaum, Norbert; Crevenna, Richard; Ott, Erwin

    2002-06-22

    To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinson's disease. 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinson's disease. Prospective population based studies are needed to provide this information.

  2. Biological evaluation and molecular docking studies of AA3052, a compound containing a μ-selective opioid peptide agonist DALDA and d-Phe-Phe-d-Phe-Leu-Leu-NH2, a substance P analogue.

    Science.gov (United States)

    Kowalczyk, Agnieszka; Kleczkowska, Patrycja; Rękawek, Monika; Kulik, Kamila; Lesniak, Anna; Erdei, Anna; Borics, Attila; Martin, Charlotte; Pawlik, Karolina; Lipkowski, Andrzej W; Benyhe, Sándor; Makulska-Nowak, Helena; Ballet, Steven; Bujalska-Zadrozny, Magdalena

    2016-10-10

    The design of novel drugs for pain relief with improved analgesic properties and diminished side effect induction profile still remains a challenging pursuit. Tolerance is one of the most burdensome phenomena that may hamper ongoing opioid therapy, especially in chronic pain patients. Therefore, a promising strategy of hybridizing two pharmacophores that target distinct binding sites involved in pain modulation and transmission was established. Previous studies have led to the development of opioid agonist/NK1 agonist hybrids that produce sufficient analgesia and also suppress opioid-induced tolerance development. In our present investigation we assessed the antinociceptive potency of a new AA3052 chimera comprised of a potent MOR selective dermorphin derivative (DALDA) and an NK1 agonist, a stabilized substance P analogue. We have shown that AA3052 significantly prolonged responses to both mechanical and noxious thermal stimuli in rats after intracerebroventricular administration. Additionally, AA3052 did not trigger the development of tolerance in a 6-day daily injection paradigm nor did it produce any sedative effects, as assessed in the rotarod performance test. However, the antinociceptive effect of AA3052 was independent of opioid receptor stimulation by the DALDA pharmacophore as shown in the agonist-stimulated G-protein assay. Altogether the current results confirm the antinociceptive effectiveness of a novel opioid/SP hybrid agonist, AA3052, and more importantly its ability to inhibit the development of tolerance. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. A step ahead of PPARγ full agonists to PPARγ partial agonists: therapeutic perspectives in the management of diabetic insulin resistance.

    Science.gov (United States)

    Chigurupati, Sridevi; Dhanaraj, Sokkalingam A; Balakumar, Pitchai

    2015-05-15

    Described since long as a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptors (PPARs) regulate the gene expression of proteins involved in glucose and lipid metabolism. PPARs indeed regulate several physiologic processes, including lipid homeostasis, adipogenesis, inflammation, and wound healing. PPARs bind natural or synthetic PPAR ligands can function as cellular sensors to regulate the gene transcription. Dyslipidemia, and type 2 diabetes mellitus (T2DM) with insulin resistance are treated using agonists of PPARα and PPARγ, respectively. The PPARγ is a key regulator of insulin sensitization and glucose metabolism, and therefore is considered as an imperative pharmacological target to combat diabetic metabolic disease and insulin resistance. Of note, currently available PPARγ full agonists like rosiglitazone display serious adverse effects such as fluid retention/oedema, weight gain, and increased incidence of cardiovascular events. On the other hand, PPARγ partial agonists are being suggested to devoid or having less incidence of these undesirable events, and are under developmental stages. Current research is on the way for the development of novel PPARγ partial agonists with enhanced therapeutic efficacy and reduced adverse effects. This review sheds lights on the current status of development of PPARγ partial agonists, for the management of T2DM, having comparatively less or no adverse effects to that of PPARγ full agonists. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Less Guilty by Reason of Adolescence: Developmental Immaturity, Diminished Responsibility, and the Juvenile Death Penalty

    Science.gov (United States)

    Steinberg, Laurence; Scott, Elizabeth S.

    2003-01-01

    The authors use a developmental perspective to examine questions about the criminal culpability of juveniles and the juvenile death penalty. Under principles of criminal law, culpability is mitigated when the actor's decision-making capacity is diminished, when the criminal act was coerced, or when the act was out of character. The authors argue…

  5. Nonsuicidal self-injury and diminished pain perception: the role of emotion dysregulation

    NARCIS (Netherlands)

    Franklin, J.C.; Aaron, R.V.; Arthur, M.S.; Shorkey, S.P.; Prinstein, M.J.

    2012-01-01

    Nonsuicidal self-injury (NSSI) is the deliberate destruction of one's own body tissue in the absence of suicidal intent (e.g., cutting or burning the skin). Previous studies have found that people with a history of NSSI display diminished pain perception. However, it remains unclear why this effect

  6. Can Using Human Examples Diminish the Number of Misconceptions Held Concerning Mendelian Genetics Concepts?

    Science.gov (United States)

    Moore, John M.

    2000-01-01

    Explores high school biology and the teaching of genetics. The question is asked, Can the use of relevant, meaningful human genetics concepts diminish the number of misconceptions formed between new and existing concepts? Can the application of the Ausubelian learning theory also decrease the acquisition of misconceptions? (SAH)

  7. Does too much work hamper innovation? Evidence for diminishing returns of work hours for patent grants

    NARCIS (Netherlands)

    Celbis, M.G.; Turkeli, S.

    2014-01-01

    This study suggests that individual time is an important factor that needs to be considered in innovation research. We define two types of time: work time and free time. We find that work time has a positive but diminishing effect on innovative output such that after a certain point the

  8. Socioeconomic Status and Self-Rated Oral Health; Diminished Return among Hispanic Whites.

    Science.gov (United States)

    Assari, Shervin

    2018-04-24

    Background. An extensive body of knowledge has documented weaker health effects of socio-economic status (SES) for Blacks compared to Whites, a phenomenon also known as Blacks’ diminished return. It is, however, unknown whether the same diminished return also holds for other ethnic minorities such as Hispanics or not. Aim. Using a nationally representative sample, the current study aimed to compare Non-Hispanic and Hispanic Whites for the effects of SES on self-rated oral health. Methods. For the current cross-sectional study, we used data from the Collaborative Psychiatric Epidemiology Surveys (CPES), 2001⁻2003. With a nationally representative sampling, CPES included 11,207 adults who were either non-Hispanic Whites ( n = 7587) or Hispanic Whites ( n = 3620. The dependent variable was self-rated oral health, treated as dichotomous measure. Independent variables were education, income, employment, and marital status. Ethnicity was the focal moderator. Age and gender were covariates. Logistic regressions were used for data analysis. Results. Education, income, employment, and marital status were associated with oral health in the pooled sample. Although education, income, employment, and marital status were associated with oral health in non-Hispanic Whites, none of these associations were found for Hispanic Whites. Conclusion. In a similar pattern to Blacks’ diminished return, differential gain of SES indicators exists between Hispanic and non-Hispanic Whites, with a disadvantage for Hispanic Whites. Diminished return of SES should be regarded as a systemically neglected contributing mechanism behind ethnic oral health disparities in the United States. Replication of Blacks’ diminished return for Hispanics suggests that these processes are not specific to ethnic minority groups, and non-White groups gain less because they are not enjoying the privilege and advantage of Whites.

  9. Effects of selective beta 1- and beta 2-adrenoreceptor agonists and antagonists on intraocular pressure in the cat.

    Science.gov (United States)

    Colasanti, B K; Trotter, R R

    1981-01-01

    Ocular tension of cats was measured after topical administration of the selective beta 1-adrenergic agonist CGP 7760B, the selective beta 1-adrenergic antagonist atenolol, the selective beta 2-adrenergic agonist salbutamol, the selective beta 2-adrenergic antagonist H 35/25, and the mixed beta 1- and beta 2-adrenergic antagonist timolol. Although atenolol did not alter intraocular pressure, CGP 7760B produced a modest decrease amounting to 3 to 4 mm Hg. Salbutamol, H 35/25, and timolol each produced a dose-dependent lowering of ocular tension, with maximal reductions amounting to 7, 5, and 5 mm Hg, respectively. Sympathetically denervated cat eyes showed supersensitivity to the pressure-lowering effect of salbutamol. In contrast, sympathectomy markedly reduced the effects of H 35/25 and timolol on ocular tension. Eyes rendered subsensitive to the pressure-lowering effects of cholinomimetics by chronic echothiophate treatment likewise showed diminished responsiveness to H 35/25 and timolol. Pretreatment with timolol (3 hr) completely abolished the pressure-lowering effect of salbutamol, and pretreatment with atenolol likewise completely antagonized the effect of CGP 7760B. These results suggest that beta-adrenergic receptors in the anterior segment of the cat eye are predominantly beta 2. Although beta-adrenergic antagonists apparently exert their effects on ocular tension by action at beta-adrenergic receptors, a cholinergic mechanism may be involved as well.

  10. Ecdysone Agonist: New Insecticides with Novel Mode of Action

    Directory of Open Access Journals (Sweden)

    Y. Andi Trisyono

    2002-12-01

    Full Text Available Development of insect resistance to insecticide has been the major driving force for the development of new insecticides. Awareness and demand from public for more environmentally friendly insecticides have contributed in shifting the trend from using broad spectrum to selective insecticides. As a result, scientists have looked for new target sites beyond the nervous system. Insect growth regulators (IGRs are more selective insecticides than conventional insecticides, and ecdysone agonists are the newest IGRs being commercialized, e.g. tebufenozide, methoxyfenozide, and halofenozide. Ecdysone agonists bind to the ecdysteroid receptors, and they act similarly to the molting hormone 20-hydroxyecdysone. The binding provides larvae or nymphs with a signal to enter a premature and lethal molting cycle. In addition, the ecdysone agonists cause a reduction in the number of eggs laid by female insects. The ecdysone agonists are being developed as selective biorational insecticides. Tebufenozide and methoxyfenozide are used to control lepidopteran insect pests, whereas halofenozide is being used to control coleopteran insect pests. Their selectivity is due to differences in the binding affinity between these compounds to the receptors in insects from different orders. The selectivity of these compounds makes them candidates to be used in combinations with other control strategies to develop integrated pest management programs in agricultural ecosystems. Key words: new insecticides, selectivity, ecdysone agonists

  11. Modification of opiate agonist binding by pertussis toxin

    Energy Technology Data Exchange (ETDEWEB)

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  12. Agonistic behavior enhances adult neurogenesis in male Acheta domesticus crickets.

    Science.gov (United States)

    Ghosal, Kaushik; Gupta, Mohit; Killian, Kathleen A

    2009-07-01

    We examined the effect of agonistic behavior on cell proliferation and neurogenesis in the central nervous system (CNS) of adult male Acheta domesticus crickets. We combined 5-bromo,2'deoxyuridine (BrdU)-labeling of dividing cells with immunocytochemical detection of the neuronal marker horseradish peroxidase to examine the proliferation of progenitor cells and the survival of newborn neurons. In crickets, the mushroom bodies of the brain contain clusters of proliferative cells that divide and generate new neurons in adulthood. Pairs of male crickets were allowed to fight and establish social rank and were then injected with BrdU. Proliferation of mushroom body neurogenic cluster cells was unaffected by agonistic interactions; 24 h after a fight, the number of BrdU positive cells in fought and un-fought males did not significantly differ. However, agonistic interactions did influence cell survival. Two weeks after an agonistic interaction, fought males had more newborn neurons than males that did not fight. There was also a rank-specific effect because dominant males had significantly more new neurons than subordinates. We also report for the first time that neurogenesis in adult crickets can occur in other regions of the brain and in other CNS ganglia, including the terminal abdominal ganglion (TAG). Agonistic interactions enhanced the proliferation of these distributed precursor cells but did not increase the survival of the newborn neurons generated by these cells.

  13. Unique interaction pattern for a functionally biased ghrelin receptor agonist

    DEFF Research Database (Denmark)

    Sivertsen, Bjørn Behrens; Lang, Manja; Frimurer, Thomas M.

    2011-01-01

    Based on the conformationally constrained D-Trp-Phe-D-Trp (wFw) core of the prototype inverse agonist [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]substance P, a series of novel, small, peptide-mimetic agonists for the ghrelin receptor were generated. By using various simple, ring-constrained spacers...... connecting the D-Trp-Phe-D-Trp motif with the important C-terminal carboxyamide group, 40 nm agonism potency was obtained and also in one case (wFw-Isn-NH(2), where Isn is isonipecotic acid) ~80% efficacy. However, in contrast to all previously reported ghrelin receptor agonists, the piperidine-constrained w......Fw-Isn-NH(2) was found to be a functionally biased agonist. Thus, wFw-Isn-NH(2) mediated potent and efficacious signaling through the Ga(q) and ERK1/2 signaling pathways, but in contrast to all previous ghrelin receptor agonists it did not signal through the serum response element, conceivably the Ga(12...

  14. Modification of opiate agonist binding by pertussis toxin

    International Nuclear Information System (INIS)

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-01-01

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in 3 (H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding

  15. Tactical Approaches to Interconverting GPCR Agonists and Antagonists.

    Science.gov (United States)

    Dosa, Peter I; Amin, Elizabeth Ambrose

    2016-02-11

    There are many reported examples of small structural modifications to GPCR-targeted ligands leading to major changes in their functional activity, converting agonists into antagonists or vice versa. These shifts in functional activity are often accompanied by negligible changes in binding affinity. The current perspective focuses on outlining and analyzing various approaches that have been used to interconvert GPCR agonists, partial agonists, and antagonists in order to achieve the intended functional activity at a GPCR of therapeutic interest. An improved understanding of specific structural modifications that are likely to alter the functional activity of a GPCR ligand may be of use to researchers designing GPCR-targeted drugs and/or probe compounds, specifically in cases where a particular ligand exhibits good potency but not the preferred functional activity at the GPCR of choice.

  16. Pharmacophore-driven identification of PPARγ agonists from natural sources

    DEFF Research Database (Denmark)

    Petersen, R. K.; Christensen, Kathrine Bisgaard; Assimopoulou, A. N.

    2011-01-01

    mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while......In a search for more effective and safe anti-diabetic compounds, we developed a pharmacophore model based on partial agonists of PPARγ. The model was used for the virtual screening of the Chinese Natural Product Database (CNPD), a library of plant-derived natural products primarily used in folk...... medicine. From the resulting hits, we selected methyl oleanonate, a compound found, among others, in Pistacia lentiscus var. Chia oleoresin (Chios mastic gum). The acid of methyl oleanonate, oleanonic acid, was identified as a PPARγ agonist through bioassay-guided chromatographic fractionations of Chios...

  17. Principles of agonist recognition in Cys-loop receptors

    Directory of Open Access Journals (Sweden)

    Timothy eLynagh

    2014-04-01

    Full Text Available Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine and GABA. After the term chemoreceptor emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands.

  18. GnRH antagonist versus long agonist protocols in IVF

    DEFF Research Database (Denmark)

    Lambalk, C B; Banga, F R; Huirne, J A

    2017-01-01

    was not the only variable between the compared study arms. OBJECTIVE AND RATIONALE: The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. SEARCH......BACKGROUND: Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist...... METHODS: The Cochrane Menstrual Disorders and Subfertility Review Group specialized register of controlled trials and Pubmed and Embase databases were searched from inception until June 2016. Eligible trials were those that compared GnRH antagonist protocols and standard long GnRH agonist protocols...

  19. TPO receptor agonist for chronic idiopathic thrombocytopenic purpura.

    Science.gov (United States)

    Zeng, Yan; Duan, Xin; Xu, Jiajun; Ni, Xun

    2011-07-06

    Chronic idiopathic thrombocytopenic purpura (ITP) is an acquired autoimmune disorder that is characterized predominantly by a low platelet count. Thrombopoietin (TPO) receptor agonists increase production of platelets by stimulating the TPO receptor in people with chronic ITP. To determine the efficacy and safety of TPO receptor agonists in chronic ITP patients. We searched MEDLINE (from 1950 to March 2011), EMBASE (from 1974 to March 2011), and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3) to identify all randomized trials in chronic ITP. We also contacted authors of included studies and TPO receptor agonists manufacturers. Randomized controlled trials (RCTs) comparing TPO receptor agonists alone, or in combination with other drugs, to placebo, no treatment, other drugs, splenectomy or another TPO receptor agonist in patients with chronic ITP. Two review authors independently screened papers, extracted data and assessed the risk of bias in the included studies. Six trials with 808 patients were included. Five studies compared TPO receptor agonists with placebo (romiplostim: 100, eltrombopag: 299, placebo: 175); one study compared TPO receptor agonists with standard of care (SOC) (romiplostim: 157; SOC: 77). SOC included a variety of therapies, such as glucocorticoid, anti-D immune globulin, intravenous immune globulin, rituximab, azathioprine, and so on. Overall survival, one of our primary outcomes, was not studied by these RCTs and we could not estimate number needed to treat (NNT). Another primary outcome, improving significant bleeding events, did not reveal any significant differences between the TPO receptor agonists group and the control group (placebo or SOC) (versus placebo risk ratio (RR) 0.48, 95% confidence interval (CI) 0.20 to 1.15; versus SOC RR 0.49, 95% CI 0.15 to 1.63).For secondary outcomes, TPO receptor agonists statistically significantly improved overall platelet response (versus placebo RR

  20. Diminishing Marginal Returns From Genomic Selection As More Selection Candidates Are Phenotyped

    DEFF Research Database (Denmark)

    Okeno, Tobias O; Henryon, Mark; Sørensen, Anders Christian

    We used stochastic simulation to test hypotheses that, (i) phenotyping proportion of high ranking selection candidates based on estimated breeding values (EBV) before genotyping could realize as much genetic gains as phenotyping all candidates, and (ii) there is diminishing return to selection...... as more candidates are phenotyped in genomic breeding programs. Three phenotyping criteria, namely, random (RS), EBV and true breeding value (TBV) were investigated under two schemes (across-population and within-litter) using traditional-BLUP and genomic-BLUP models. The EBV ranked above RS and realized...... maximum achievable gains in the breeding program at 80% phenotyping. There was diminishing return to selection as more candidates were phenotyped; indicating that information content is not so large in the last candidate compared to the first candidate phenotyped. These findings demonstrate the need...

  1. Fiberotomy enhances orthodontic tooth movement and diminishes relapse in a rat model.

    Science.gov (United States)

    Young, L; Binderman, I; Yaffe, A; Beni, L; Vardimon, A D

    2013-08-01

    Accelerated orthodontic tooth movement is triggered by procedures that include mucoperiosteum flap surgery and surgical scarring of cortical bone. Our aim was to test whether fiberotomy by itself will accelerate orthodontic tooth movement and diminish relapse. In 34 Wistar rats, alveolar bone resorption and molar tooth movement were measured after fiberotomy, apical full-thickness flap without detachment of gingiva from the roots, or no surgery. Orthodontic appliance was installed at time of surgery and activated for 14 days, generating movement of the first maxillary molar buccal and then removed. Percent of sections in which alveolar bone resorption was detected was significantly higher (p accelerated orthodontic tooth movement and diminished relapse. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Repeated exposure to media violence is associated with diminished response in an inhibitory frontolimbic network.

    Science.gov (United States)

    Kelly, Christopher R; Grinband, Jack; Hirsch, Joy

    2007-12-05

    Media depictions of violence, although often claimed to induce viewer aggression, have not been shown to affect the cortical networks that regulate behavior. Using functional magnetic resonance imaging (fMRI), we found that repeated exposure to violent media, but not to other equally arousing media, led to both diminished response in right lateral orbitofrontal cortex (right ltOFC) and a decrease in right ltOFC-amygdala interaction. Reduced function in this network has been previously associated with decreased control over a variety of behaviors, including reactive aggression. Indeed, we found reduced right ltOFC responses to be characteristic of those subjects that reported greater tendencies toward reactive aggression. Furthermore, the violence-induced reduction in right ltOFC response coincided with increased throughput to behavior planning regions. These novel findings establish that even short-term exposure to violent media can result in diminished responsiveness of a network associated with behaviors such as reactive aggression.

  3. Impact of a program to diminish gender insensitivity and sexual harassment at a medical school.

    Science.gov (United States)

    Jacobs, C D; Bergen, M R; Korn, D

    2000-05-01

    To measure the effect of an intervention to reduce gender insensitivity and sexual harassment at one medical school. Stanford University School of Medicine undertook a multifaceted program to educate faculty and students regarding gender issues and to diminish sexual harassment. The authors developed a survey instrument to assess the faculty's perceptions regarding environment (five scales) and incidences of sexual harassment. Faculty were surveyed twice during the interventions (1994 and 1995). Between the two years, the authors measured significant improvements in mean ratings for positive climate (p = .004) and cohesion (p = .006) and decreases in the faculty's perceptions of sexual harassment (p = 0006), gender insensitivity (p = .001), and gender discrimination (p = .004). The faculty also reported fewer observations of harassing behavior during the study period. An intervention program to diminish gender insensitivity and sexual harassment can measurably improve a medical school's environment.

  4. Diminished levels of the soluble form of RAGE are related to poor survival in malignant melanoma.

    Science.gov (United States)

    Wagner, Nikolaus B; Weide, Benjamin; Reith, Maike; Tarnanidis, Kathrin; Kehrel, Coretta; Lichtenberger, Ramtin; Pflugfelder, Annette; Herpel, Esther; Eubel, Jana; Ikenberg, Kristian; Busch, Christian; Holland-Letz, Tim; Naeher, Helmut; Garbe, Claus; Umansky, Viktor; Enk, Alexander; Utikal, Jochen; Gebhardt, Christoffer

    2015-12-01

    RAGE is a central driver of tumorigenesis by sustaining an inflammatory tumor microenvironment. This study links the soluble forms of RAGE (sRAGE and esRAGE) with clinical outcome of melanoma patients. Moreover, tissue expression of RAGE was analyzed using immunohistochemistry on two independent tissue microarrays (TMA) containing 35 or 257 primary melanomas, and 41 or 22 benign nevi, respectively. Serum concentrations of sRAGE and esRAGE were measured in 229 Stage III-IV patients using ELISA and plasma concentrations of sRAGE were analyzed in an independent second cohort with 173 samples of Stage I-IV patients. In this cohort, three well-described SNPs in the RAGE gene were analyzed. RAGE protein expression was highly upregulated in primary melanomas compared to benign nevi in the two TMA (p melanomas (p = 0.046). sRAGE and esRAGE were identified as prognostic markers for survival as diminished sRAGE (p = 0.034) and esRAGE (p = 0.012) serum levels correlated with poor overall survival (OS). Multivariate Cox regression analysis showed that diminished serum sRAGE was independently associated with poor survival (p = 0.009). Moreover, diminished sRAGE was strongly associated with impaired OS in the second cohort (p forms of RAGE and variants in its genetic locus are prognostic markers for survival in melanoma patients with high risk for progression. © 2015 UICC.

  5. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    Science.gov (United States)

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  6. Use of ß-adrenergic agonists in hybrid catfish

    Science.gov (United States)

    Ractopamine hydrochloride (RH) is a potent ß-adrenergic agonist that has been used in some species of fish to improve growth performance and dress out characteristics. While this metabolic modifier has been shown to have positive effects on growth of fish, little research has focused on the mechani...

  7. Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Due-Hansen, Maria E; Urban, Christian

    2012-01-01

    FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metabolic...

  8. Glucagon-like peptide 1 receptor agonist (GLP-1 RA)

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Hansen, Tine Willum; Goetze, Jens Peter

    2015-01-01

    AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim...

  9. Beta2-adrenoceptors: mechanisms of action of beta2-agonists.

    Science.gov (United States)

    Johnson, M

    2001-03-01

    The human beta2-adrenoceptor is a member of the 7 transmembrane family of receptors. It is encoded by a gene on chromosome 5 and is widely distributed in the respiratory tract. Following beta2-adrenoceptor activation, intracellular signalling is mainly produced by inducing cyclic AMP. This produces airway relaxation through phosphorylation of muscle regulatory proteins and modification of cellular Ca2+concentrations. Beta2-agonists have been characterised into those which directly activate the receptor (salbutamol/terbutaline), those which are taken up into a membrane depot (formoterol) and those which interact with a receptor-specific, auxiliary binding site (salmeterol). These differences in mechanism of action are reflected in the kinetics of airway smooth muscle relaxation and bronchodilation in asthmatic patients. Beta-adrenoceptor desensitisation is associated with beta2-agonist activation and differs depending on the cell type. It is reflected in the different profiles of clinical tolerance to chronic beta2-agonist therapy. A number of polymorphisms of the beta2-receptor have been described which appear to alter the behaviour of the receptor, including the degree of downregulation and response to beta2-agonists.

  10. Innovations in agonist maintenance treatment of opioid-dependent patients

    NARCIS (Netherlands)

    Haasen, Christian; van den Brink, Wim

    2006-01-01

    PURPOSE OF REVIEW: To provide an overview of published studies on agonist maintenance treatment options for opioid-dependent patients. RECENT FINDINGS: The recent publication of controlled trials confirms earlier clinical evidence of the efficacy of diamorphine (heroin) in the treatment of opioid

  11. The elusive endogenous adipogenic PPARγ agonists: Lining up the suspects

    DEFF Research Database (Denmark)

    Hallenborg, Philip; Petersen, Rasmus K.; Kouskoumvekaki, Irene

    2016-01-01

    and their derivatives are known to bind to and activate PPARγ, the identity of the ligand(s) responsible for initiating adipocyte differentiation is still a matter of debate. Here we review recent data on pathways involved in ligand production as well as possible endogenous, adipogenic PPARγ agonists....

  12. Dopamine agonists and risk: impulse control disorders in Parkinson's disease.

    Science.gov (United States)

    Voon, Valerie; Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J; Hallett, Mark

    2011-05-01

    Impulse control disorders are common in Parkinson's disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a 'Sure' choice and a 'Gamble' choice of moderate risk. To commence each trial, in the 'Gain' condition, individuals started at $0 and in the 'Loss' condition individuals started at -$50 below the 'Sure' amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk ('Gamble Risk'). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the 'Gain' relative to the 'Loss' condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.

  13. Dopamine agonists and risk: impulse control disorders in Parkinson's; disease

    Science.gov (United States)

    Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J.; Hallett, Mark

    2011-01-01

    Impulse control disorders are common in Parkinson's; disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's; disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a ‘Sure’ choice and a ‘Gamble’ choice of moderate risk. To commence each trial, in the ‘Gain’ condition, individuals started at $0 and in the ‘Loss’ condition individuals started at −$50 below the ‘Sure’ amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk (‘Gamble Risk’). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's; disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the ‘Gain’ relative to the ‘Loss’ condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's; disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's; disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals. PMID:21596771

  14. Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling.

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E; Zarnke, Allison L; Laine, Muriel; Al Abosy, Rose; Chang, Ya-Fang; Dembo, Anna G; Schoenfelt, Kelly; Vadhi, Raga; Qiu, Xintao; Rao, Prakash; Santhamma, Bindu; Nair, Hareesh B; Nickisch, Klaus J; Long, Henry W; Becker, Lev; Brown, Myles; Greene, Geoffrey L

    2018-01-12

    Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR

  15. Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E.; Zarnke, Allison L.; Laine, Muriel; Al Abosy, Rose; Chang, Ya-Fang; Dembo, Anna G.; Schoenfelt, Kelly; Vadhi, Raga; Qiu, Xintao; Rao, Prakash; Santhamma, Bindu; Nair, Hareesh B.; Nickisch, Klaus J.; Long, Henry W.; Becker, Lev; Brown, Myles; Greene, Geoffrey L.

    2018-01-01

    Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR

  16. The TP73 gene polymorphism (rs4648551, A>G is associated with diminished ovarian reserve.

    Directory of Open Access Journals (Sweden)

    Laura Diniz Vagnini

    Full Text Available It's known that the members of the TP53 family are involved in the regulation of female reproduction. Studies in mice showed that the TP73 gene (member of this family plays a role in the size of follicular pool, ovulation rate and maintenance of genomic stability. In the present study we analyzed data from 605 patients with ≤ 37 years attending their first intracytoplasmic sperm injection (ICSI. The association between the TP73 polymorphism (rs4648551, A>G and the following parameters related to ovarian reserve, like age, antral follicular count (AFC, anti-Mullerian hormone levels (AMH and ovarian response prediction index (ORPI was evaluated. Our results showed an association of the AA genotype with diminished ovarian reserve (AMH <1, AFC ≤9. Women presenting the AA genotype had a 2.0-fold increased risk for having AMH <1 and AFC ≤9 (OR 2.0, 95% CI 1.23-3.31, P = 0.005. Patients presenting AA genotype had the lowest levels of AMH (P = 0.02, the lowest number of antral follicles (P = 0.01 and the lowest ORPI (P = 0.007. Analyzing the alleles, we can see an enrichment of the A allele in the group of diminished ovarian reserve (OR 1.4, 95%CI 1.02-1.83, P = 0.04. To the best of our knowledge, the present study is the first to analyze this polymorphism in humans for assessing the numbers of ovarian follicles and AMH levels and, therefore, the ovarian reserve. Our findings can contribute to the use of this polymorphism as a potential marker of diminished ovarian reserve.

  17. Diminished functional connectivity on the road to child sexual abuse in pedophilia.

    Science.gov (United States)

    Kärgel, Christian; Massau, Claudia; Weiß, Simone; Walter, Martin; Kruger, Tillmann H C; Schiffer, Boris

    2015-03-01

    Pedophilia is a disorder recognized for its impairment to the individual and for the harm it may cause to others. However, the neurobiology of pedophilia and a possible propensity to sexually abuse children are not well understood. In this study, we thus aimed at providing new insights in how functional integration of brain regions may relate to pedophilia or child sexual abuse (CSA). By using functional magnetic resonance imaging (fMRI) technique, we compared functional connectivity at rest (RSFC) between pedophiles who engaged (P+CSA; N = 12) or did not engage (P-CSA; N = 14) in CSA and healthy controls (HCs; N = 14) within two networks: (i) the default mode network and (ii) the limbic network that has been linked to pedophilia before. Pedophiles who engaged in CSA show diminished RSFC in both networks compared with HC and P-CSA. Most importantly, they showed diminished RSFC between the left amygdala and orbitofrontal as well as anterior prefrontal regions. Though significant age differences between groups could not be avoided, correlation control analysis did not provide evidence for the assumption that the RSFC effects were related to age differences. We found significantly diminished RSFC in brain networks critically involved in widespread motivational and socio-emotional processes. These results extend existing models of the functional neuroanatomy of pedophilia and CSA as altered RSFC between these regions were related to CSA rather than pedophilia and thus may account for an increased propensity to engage in CSA in people suffering from pedophilia. © 2015 International Society for Sexual Medicine.

  18. Agonists and inverse agonists for the herpesvirus 8-encoded constitutively active seven-transmembrane oncogene product, ORF-74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Bräuner-Osborne, Hans

    1999-01-01

    , whereas IP-10 and stromal cell-derived factor-1alpha surprisingly acted as inverse agonists. These peptides had similar pharmacological properties with regard to enhancing or inhibiting, respectively, the stimulatory effect of ORF-74 on NIH-3T3 cell proliferation. Construction of a high affinity zinc...

  19. Agonist signalling properties of radiotracers used for imaging of dopamine D2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, Jan-Peter; Michel, Martin C.; Janssen, Henk M.; Janssen, Anton G.; Elsinga, Philip H.; Booij, Jan

    2014-01-01

    Dopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists are more

  20. Agonist signalling properties of radiotracers used for imaging of dopamine D-2/3 receptors

    NARCIS (Netherlands)

    van Wieringen, Jan-Peter; Michel, Martin C.; Janssen, Henk M.; Janssen, Anton G.; Elsinga, Philip H.; Booij, Jan

    2014-01-01

    Background: Dopamine D-2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists

  1. Symptoms of Diminished Autonomy over Cigarettes with Non-Daily Use

    Directory of Open Access Journals (Sweden)

    Judith A. Savageau

    2008-12-01

    Full Text Available Data from a nationally representative sample of smokers (ages 12-22 years, n=2,091 was examined to investigate the prevalence of symptoms of diminished autonomy over cigarettes. Six symptoms were assessed: failed cessation, smoking despite a desire to quit, and a need or urge to smoke, irritability, restlessness, or disrupted concentration attributed to nicotine withdrawal. One or more of the six symptoms were present in 18.9% of subjects who smoked less often than once per week. Among subjects who had not smoked 20 cigarettes in their lifetime, 12.6% had symptoms of nicotine withdrawal, and 25% had made an unsuccessful quit attempt.

  2. Agonists and partial agonists of rhodopsin: retinal polyene methylation affects receptor activation.

    Science.gov (United States)

    Vogel, Reiner; Lüdeke, Steffen; Siebert, Friedrich; Sakmar, Thomas P; Hirshfeld, Amiram; Sheves, Mordechai

    2006-02-14

    Using Fourier transform infrared (FTIR) difference spectroscopy, we have studied the impact of sites and extent of methylation of the retinal polyene with respect to position and thermodynamic parameters of the conformational equilibrium between the Meta I and Meta II photoproducts of rhodopsin. Deletion of methyl groups to form 9-demethyl and 13-demethyl analogues, as well as addition of a methyl group at C10 or C12, shifted the Meta I/Meta II equilibrium toward Meta I, such that the retinal analogues behaved like partial agonists. This equilibrium shift resulted from an apparent reduction of the entropy gain of the transition of up to 65%, which was only partially offset by a concomitant reduction of the enthalpy increase. The analogues produced Meta II photoproducts with relatively small alterations, while their Meta I states were significantly altered, which accounted for the aberrant transitions to Meta II. Addition of a methyl group at C14 influenced the thermodynamic parameters but had little impact on the position of the Meta I/Meta II equilibrium. Neutralization of the residue 134 in the E134Q opsin mutant increased the Meta II content of the 13-demethyl analogue, but not of the 9-demethyl analogue, indicating a severe impairment of the allosteric coupling between the conserved cytoplasmic ERY motif involved in proton uptake and the Schiff base/Glu 113 microdomain in the 9-demethyl analogue. The 9-methyl group appears therefore essential for the correct positioning of retinal to link protonation of the cytoplasmic motif with protonation of Glu 113 during receptor activation.

  3. Diminished Antimicrobial Peptide and Antifungal Antibiotic Activities against Candida albicans in Denture Adhesive

    Directory of Open Access Journals (Sweden)

    Amber M. Bates

    2017-02-01

    Full Text Available The underlying causes of denture stomatitis may be related to the long-term use of adhesives, which may predispose individuals to oral candidiasis. In this study, we hypothesize that antimicrobial peptides and antifungal antibiotics have diminished anti-Candida activities in denture adhesive. To show this, nine antimicrobial peptides and five antifungal antibiotics with and without 1.0% denture adhesive were incubated with Candida albicans strains ATCC 64124 and HMV4C in radial diffusion assays. In gels with 1.0% adhesive, HNP-1, HBD2, HBD3, IP-10, LL37 (only one strain, histatin 5 (only one strain, lactoferricin B, and SMAP28 showed diminished activity against C. albicans. In gels with 1.0% adhesive, amphotericin B and chlorhexidine dihydrochloride were active against both strains of C. albicans. These results suggest that denture adhesive may inactivate innate immune mediators in the oral cavity increasing the risk of C. albicans infections, but inclusion of antifungal antibiotics to denture adhesive may aid in prevention or treatment of Candida infections and denture stomatitis.

  4. When is diminishment a form of enhancement? Rethinking the enhancement debate in biomedical ethics

    Science.gov (United States)

    Earp, Brian D.; Sandberg, Anders; Kahane, Guy; Savulescu, Julian

    2014-01-01

    The enhancement debate in neuroscience and biomedical ethics tends to focus on the augmentation of certain capacities or functions: memory, learning, attention, and the like. Typically, the point of contention is whether these augmentative enhancements should be considered permissible for individuals with no particular “medical” disadvantage along any of the dimensions of interest. Less frequently addressed in the literature, however, is the fact that sometimes the diminishment of a capacity or function, under the right set of circumstances, could plausibly contribute to an individual's overall well-being: more is not always better, and sometimes less is more. Such cases may be especially likely, we suggest, when trade-offs in our modern environment have shifted since the environment of evolutionary adaptation. In this article, we introduce the notion of “diminishment as enhancement” and go on to defend a welfarist conception of enhancement. We show how this conception resolves a number of definitional ambiguities in the enhancement literature, and we suggest that it can provide a useful framework for thinking about the use of emerging neurotechnologies to promote human flourishing. PMID:24550792

  5. Changes in Global Monsoon Circulations: Evidence of a diminishing global hydrological cycle?

    Science.gov (United States)

    Chase, T. N.; Knaff, J. A.; Pielke, R. A.

    2001-05-01

    We examined changes in several independent intensity indices of four major tropical monsoonal circulations from approximately 1950-1998. These intensity indices included upper-level divergence at several standard levels, land surface precipitation in the monsoon regions and ocean surface pressure. These values were averaged seasonally over appropriate regions of southeastern Asian, western Africa, eastern Africa and Australia/Maritime continent and adjacent ocean areas. As a consistency check we also examined two secondary indices: mean sea level pressure trends averaged over each monsoon region and low level convergence at several levels both from the NCEP reanalysis. We find that in each of the four regions examined, a consistent picture emerges indicating significantly diminished monsoonal circulations over the period of record, evidence of a diminished global hydrological cycle since 1950. Trends since 1978, the period of strongest surface warming, are insignificant and uncorrelated with the surface warming. When strong ENSO years are removed from the time series the trends still show a general, significant reduction of monsoon intensity indicating that ENSO variability is not the direct cause for the observed weakening. A comparison with general circulation model simulations of the effects of rising CO2 shows an increase in monsoonal activity with rising global surface temperature except in the case of the Australian/Maritime continent monsoon. When the effects of aerosols are included the simulated southeastern Asian summer monsoon is also reduced in intensity.

  6. Ski diminishes TGF-β1-induced myofibroblast phenotype via up-regulating Meox2 expression.

    Science.gov (United States)

    Chen, Zhaowei; Li, Wenjing; Ning, Yan; Liu, Tong; Shao, Jingxiang; Wang, Yaojun

    2014-12-01

    The aim of the present work was to investigate the mechanism of transforming growth factor (TGF)-β1 and Sloan-Kettering Institute (Ski) in the pathogenesis of hypertrophic scars (HS). Wound healing is an inherent process, but the aberrant wound healing of skin injury may lead to HS. There has been growing evidence suggesting a role for TGF-β1 and Ski in the pathogenesis of fibrosis. The MTT assay was used to detect the cell proliferation induced by TGF-β1. The Ski gene was transduced into cells with an adenovirus, and then the function of Ski in cell proliferation and differentiation was observed. Ski mRNA levels were measured by RT-PCR. Western blotting was used to detect the protein expression of α-SMA, E-cadherin, Meox1, Meox2, Zeb1 and Zeb2. TGF-β1 can promote human skin fibroblast (HSF) cell proliferation in a time-dependent manner, but the promoting effect could be suppressed by Ski. TGF-β1 also induces the formation of the myofibroblast phenotype and the effect of TGF-β1 could be diminished by Ski. Also, Ski modulates the cardiac myofibroblast phenotype and function through suppression of Zeb2 by up-regulating the expression of Meox2. Ski diminishes the myofibroblast phenotype induced by TGF-β1 through the suppression of Zeb2 by up-regulating the expression of Meox2. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Poor sleep quality diminishes cognitive functioning independent of depression and anxiety in healthy young adults.

    Science.gov (United States)

    Benitez, Andreana; Gunstad, John

    2012-01-01

    Sufficient sleep is essential for optimum cognitive and psychological functioning. Diminished sleep quality is associated with depression and anxiety, but the extent to which poor sleep quality uniquely impacts attention and executive functions independent of the effects of the common underlying features of depression and anxiety requires further exploration. Here 67 healthy young adults were given the Minnesota Multiphasic Personality Inventory, second edition (MMPI-2), the Pittsburgh Sleep Quality Index (PSQI), and tests of attention and executive functions. Similar to findings from a previous study with healthy community-based older adults (Nebes, Buysse, Halligan, Houck, & Monk, 2009), participants who reported poor sleep quality on the PSQI endorsed significantly greater scores on MMPI-2 Restructured Clinical scales related to depression and anxiety (Cohen's d = 0.77-1.05). In addition, PSQI component scores indexing poor sleep quality, duration, and medication use were associated with diminished attention and executive functions, even after controlling for emotional reactivity or demoralization (rs = 0.21-0.27). These results add to the concurrent validity of the PSQI, and provide further evidence for subtle cognitive decrements related to insufficient sleep even in healthy young adults. Future extension of these findings is necessary with larger samples and clinical comparison groups, and using objective indices of sleep dysfunction such as polysomnography.

  8. Epstein-Barr virus reactivation associated with diminished cell-mediated immunity in antarctic expeditioners

    Science.gov (United States)

    Mehta, S. K.; Pierson, D. L.; Cooley, H.; Dubow, R.; Lugg, D.

    2000-01-01

    Epstein-Barr virus (EBV) reactivation and cell-mediated immune (CMI) responses were followed in 16 Antarctic expeditioners during winter-over isolation at 2 Australian National Antarctic Research Expedition stations. Delayed-type hypersensitivity (DTH) skin testing was used as an indicator of the CMI response, that was evaluated 2 times before winter isolation and 3 times during isolation. At all 5 evaluation times, 8 or more of the 16 subjects had a diminished CMI response. Diminished DTH was observed on every test occasion in 4/16 subjects; only 2/16 subjects exhibited normal DTH responses for all 5 tests. A polymerase chain reaction (PCR) assay was used to detect EBV DNA in saliva specimens collected before, during, and after the winter isolation. EBV DNA was present in 17% (111/642) of the saliva specimens; all 16 subjects shed EBV in their saliva on at least 1 occasion. The probability of EBV shedding increased (P = 0.013) from 6% before or after winter isolation to 13% during the winter period. EBV appeared in saliva during the winter isolation more frequently (P viruses.

  9. Diminished Auditory Responses during NREM Sleep Correlate with the Hierarchy of Language Processing.

    Directory of Open Access Journals (Sweden)

    Meytal Wilf

    Full Text Available Natural sleep provides a powerful model system for studying the neuronal correlates of awareness and state changes in the human brain. To quantitatively map the nature of sleep-induced modulations in sensory responses we presented participants with auditory stimuli possessing different levels of linguistic complexity. Ten participants were scanned using functional magnetic resonance imaging (fMRI during the waking state and after falling asleep. Sleep staging was based on heart rate measures validated independently on 20 participants using concurrent EEG and heart rate measurements and the results were confirmed using permutation analysis. Participants were exposed to three types of auditory stimuli: scrambled sounds, meaningless word sentences and comprehensible sentences. During non-rapid eye movement (NREM sleep, we found diminishing brain activation along the hierarchy of language processing, more pronounced in higher processing regions. Specifically, the auditory thalamus showed similar activation levels during sleep and waking states, primary auditory cortex remained activated but showed a significant reduction in auditory responses during sleep, and the high order language-related representation in inferior frontal gyrus (IFG cortex showed a complete abolishment of responses during NREM sleep. In addition to an overall activation decrease in language processing regions in superior temporal gyrus and IFG, those areas manifested a loss of semantic selectivity during NREM sleep. Our results suggest that the decreased awareness to linguistic auditory stimuli during NREM sleep is linked to diminished activity in high order processing stations.

  10. Medical treatment in Cushing's syndrome: dopamine agonists and cabergoline.

    Science.gov (United States)

    Petrossians, Patrick; Thonnard, Anne-Sophie; Beckers, Albert

    2010-01-01

    Dopamine (DA) is a catecholamine with a wide range of functions and whose five subtype receptors are found in different organs where they exert a mainly inhibitory action. Since this action may also appear in a number of secretory tumors in various locations, DA agonists have elicited some interest as a medical treatment for hypercorticism. Non-iatrogenic Cushing's syndromes are due in 70% of the cases to a pituitary adrenocorticotropic hormone (ACTH)-producing adenoma, and, less frequently, to an adrenal adenoma or an ectopic ACTH secretion by a neuroendocrine tumor. First-line treatment in Cushing's syndrome consists of the surgical removal of the secreting tumor. However, surgery may not achieve a complete cure in a number of cases, hence emphasizing the potential benefit of a medical complementary treatment, which could also benefit patients as an alternative approach, either when waiting for, or when the patient is not eligible for surgery. Studies of corticotropic adenomas have shown that 80% of these tumors express D2 receptors. Clinical trials of DA agonists in Cushing's disease have shown an inhibitory effect of these drugs with an inhibition of ACTH secretion and/or a decrease of tumor size. There are only a few cases of documented use of DA agonists in ectopic ACTH secretion, but when the tumor expresses DA receptors, DA agonists may represent a useful complementary treatment. DA receptors are also expressed in normal and tumoral adrenals, suggesting a potential use of DA agonists in Cushing's syndrome secondary to adrenal tumors. However, clinical data regarding this specific situation are very scarce, maybe due to the relatively high rate of surgical cure of adrenal adenomas. In conclusion, DA agonists represent a potential preparatory or complementary treatment for endogenous Cushing's syndrome, especially in Cushing's disease. These compounds may be underused as suggested by the scarce number of publication and case reports in the literature. In the

  11. Diminished thrombogenic responses by deletion of the Podocalyxin Gene in mouse megakaryocytes.

    Directory of Open Access Journals (Sweden)

    Miguel Pericacho

    Full Text Available Podocalyxin (Podxl is a type I membrane sialoprotein of the CD34 family, originally described in the epithelial glomerular cells of the kidney (podocytes in which it plays an important function. Podxl can also be found in megakaryocytes and platelets among other extrarenal places. The surface exposure of Podxl upon platelet activation suggested it could play some physiological role. To elucidate the function of Podxl in platelets, we generated mice with restricted ablation of the podxl gene in megakaryocytes using the Cre-LoxP gene targeting methodology. Mice with Podxl-null megakaryocytes did not show any apparent phenotypical change and their rates of growth, life span and fertility did not differ from the floxed controls. However, Podxl-null mice showed prolonged bleeding time and decreased platelet aggregation in response to physiological agonists. The number, size-distribution and polyploidy of Podxl-null megakaryocytes were similar to the floxed controls. Podxl-null platelets showed normal content of surface receptors and normal activation by agonists. However, the mice bearing Podxl-null platelets showed a significant retardation in the ferric chloride-induced occlusion of the carotid artery. Moreover, acute thrombosis induced by the i.v. injection of sublethal doses of collagen and phenylephrine produced a smaller fall in the number of circulating platelets in Podxl-null mice than in control mice. In addition, perfusion of uncoagulated blood from Podxl-null mice in parallel flow chamber showed reduced adhesion of platelets and formation of aggregates under high shear stress. It is concluded that platelet Podxl is involved in the control of hemostasis acting as a platelet co-stimulator, likely due to its pro-adhesive properties.

  12. Produção de interleucina-10 na gestação reduz a taxa de replicação do HIV-1 em culturas de linfócitos maternos Interleukin-10 production during pregnancy reduces HIV-1 replicaction in cultures of maternal lymphocytes

    Directory of Open Access Journals (Sweden)

    Bruno Monção Paolino

    2005-07-01

    . In some experiments we added anti-IL-10 monoclonal antibody. The plasma samples and supernatants from cell cultures were stored to determine both peripheral cytokine levels, by ELISA sandwich, and viral load, by RT-PCR. RESULTS: the results showed that the lymphoproliferative response was smaller in cultures obtained from HIV-1-infected women than in control cultures [4.2±0.37 vs 2.4±0.56 (x 10(6 cell/mL, p<0.005]. In both control and infected pregnant women who had low plasma viral load, the level of IL-10 was higher than in those with high viral replication (9.790±3.224 vs 1.256±350 pg/mL, p=0.002. The elevated TNF-alpha production detected in serum (7.200±2.440 pg/mL and supernatants (21.350±15.230 pg/mL was associated with higher plasma viral loads and vertical infection. The IL-10 blockade by anti-IL-10 antibodies augmented viral replication in the cell cultures. CONCLUSION: these results indicate that IL-10 production exerts a negative influence on virus replication, diminishing the probability of intrauterine HIV-1 infection.

  13. Identification and predictive value of interleukin-6+ interleukin-10+ and interleukin-6-interleukin-10+ cytokine patterns in st-elevation acute myocardial infarction

    KAUST Repository

    Ammirati, Enrico

    2012-08-29

    RATIONALE: At the onset of ST-elevation acute myocardial infarction (STEMI), patients can present with very high circulating interleukin-6 (IL-6) levels or very low-IL-6 levels. OBJECTIVE: We compared these 2 groups of patients to understand whether it is possible to define specific STEMI phenotypes associated with outcome based on the cytokine response. METHODS AND RESULTS: We compared 109 patients with STEMI in the top IL-6 level (median, 15.6 pg/mL; IL-6 STEMI) with 96 in the bottom IL-6 level (median, 1.7 pg/mL; IL-6 STEMI) and 103 matched controls extracted from the multiethnic First Acute Myocardial Infarction study. We found minimal clinical differences between IL-6 STEMI and IL-6 STEMI. We assessed the inflammatory profiles of the 2 STEMI groups and the controls by measuring 18 cytokines in blood samples. We exploited clustering analysis algorithms to infer the functional modules of interacting cytokines. IL-6 STEMI patients were characterized by the activation of 2 modules of interacting signals comprising IL-10, IL-8, macrophage inflammatory protein-1α, and C-reactive protein, and monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and monokine induced by interferon-γ. IL-10 was increased both in IL-6 STEMI and IL-6 STEMI patients compared with controls. IL-6IL-10 STEMI patients had an increased risk of systolic dysfunction at discharge and an increased risk of death at 6 months in comparison with IL-6IL-10 STEMI patients. We combined IL-10 and monokine induced by interferon-γ (derived from the 2 identified cytokine modules) with IL-6 in a formula yielding a risk index that outperformed any single cytokine in the prediction of systolic dysfunction and death. CONCLUSIONS: We have identified a characteristic circulating inflammatory cytokine pattern in STEMI patients, which is not related to the extent of myocardial damage. The simultaneous elevation of IL-6 and IL-10 levels distinguishes STEMI patients with worse clinical outcomes from other STEMI patients. These observations could have potential implications for risk-oriented patient stratification and immune-modulating therapies. © 2012 American Heart Association, Inc.

  14. Diminishing-cues retrieval practice: A memory-enhancing technique that works when regular testing doesn't.

    Science.gov (United States)

    Fiechter, Joshua L; Benjamin, Aaron S

    2017-08-28

    Retrieval practice has been shown to be a highly effective tool for enhancing memory, a fact that has led to major changes to educational practice and technology. However, when initial learning is poor, initial retrieval practice is unlikely to be successful and long-term benefits of retrieval practice are compromised or nonexistent. Here, we investigate the benefit of a scaffolded retrieval technique called diminishing-cues retrieval practice (Finley, Benjamin, Hays, Bjork, & Kornell, Journal of Memory and Language, 64, 289-298, 2011). Under learning conditions that favored a strong testing effect, diminishing cues and standard retrieval practice both enhanced memory performance relative to restudy. Critically, under learning conditions where standard retrieval practice was not helpful, diminishing cues enhanced memory performance substantially. These experiments demonstrate that diminishing-cues retrieval practice can widen the range of conditions under which testing can benefit memory, and so can serve as a model for the broader application of testing-based techniques for enhancing learning.

  15. Investigating the Efficacy of Novel TrkB Agonists to Augment Stroke Recovery

    Science.gov (United States)

    Warraich, Zuha

    Stroke remains the leading cause of adult disability in developed countries. Most survivors live with residual motor impairments that severely diminish independence and quality of life. After stroke, the only accepted treatment for these patients is motor rehabilitation. However, the amount and kind of rehabilitation required to induce clinically significant improvements in motor function is rarely given due to the constraints of our current health care system. Research reported in this dissertation contributes towards developing adjuvant therapies that may augment the impact of motor rehabilitation and improve functional outcome. These studies have demonstrated reorganization of maps within motor cortex as a function of experience in both healthy and brain-injured animals by using intracortical microstimulation technique. Furthermore, synaptic plasticity has been identified as a key neural mechanism in directing motor map plasticity, evidenced by restoration of movement representations within the spared cortical tissue accompanied by increase in synapse number translating into motor improvement after stroke. There is increasing evidence that brain-derived neurotrophic factor (BDNF) modulates synaptic and morphological plasticity in the developing and mature nervous system. Unfortunately, BDNF itself is a poor candidate because of its short half-life, low penetration through the blood brain barrier, and activating multiple receptor units, p75 and TrkB on the neuronal membrane. In order to circumvent this problem efficacy of two recently developed novel TrkB agonists, LM22A-4 and 7,8-dihydroxyflavone, that actively penetrate the blood brain barrier and enhance functional recovery. Findings from these dissertation studies indicate that administration of these pharmacological compounds, accompanied by motor rehabilitation provide a powerful therapeutic tool for stroke recovery.

  16. Beta-adrenergic agonists as additive in beef cattle

    Directory of Open Access Journals (Sweden)

    Marcelo Vedovatto

    2014-10-01

    Full Text Available The agonists receptor beta-adrenergic (β-AA are present in virtually all types of mammalian cells and are stimulated by catecholamines (epinephrine and norepinephrine produced by the organism itself. The β-AA agonists are synthetic substances with similar structure to these amines. When provided in the diet they alter the body composition of animals, affecting the distribution of nutrients toward to protein deposition, and decreasing lipogenesis. Although the mechanisms of action are not fully understood, these may cause morphological and physiological changes such as increased blood flow decrease in plasma insulin, decreased lipogenesis, and muscle hypertrophy mainly in type II fibers. We also observed changes in motility and secretions grastointestinal tract, beyond the direct influence on the rumen bacteria, altering the digestibility of the diet. The β-AA agonists released in some countries for use in beef cattle are ractopamine hydrochloride and zilpaterol hydrochloride. According to literature data, the inclusion of these additives in the diet of feedlot cattle has been associated with an increase infeed efficiency with the increase in daily weight gain and with equal or lower feed intake. Carcass characteristics improvement was verified in carcass weight, and increased loin eye area, but with the possibility to decrease the subcutaneous fat thickness and marbling. Reviews in sensory panel of meat from animals consuming β-AA agonists showed decreased tenderness and juiciness. Thus β-AA improve performance and carcass characteristics, but more studies are needed to confirm whether they have negative influence on the organoleptic characteristics of the meat.

  17. Newspapers and Newspaper Ink Contain Agonists for the Ah Receptor

    Science.gov (United States)

    Bohonowych, Jessica E. S.; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T.; Denison, Michael S.

    2010-01-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [3H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed. PMID:18203687

  18. Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

    Science.gov (United States)

    2010-05-01

    agents histamine and cowhage activate separate populations of Ko and Naughtonto antinociceptive effects of spinally administered mor- phine or/and NOP...similar to other opioid receptor agonists at the cellular level (Meunier et al., 1995; Rizzi et al., 2007). However, the effects of NOP receptor...the hypotheses that in the non-human primate (1) the functions and behavioral effects of the NOP receptor are independent of classical opioid receptors

  19. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    Energy Technology Data Exchange (ETDEWEB)

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K. (GSKPA)

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  20. GnRH agonist for triggering of final oocyte maturation

    DEFF Research Database (Denmark)

    Al Humaidan, Peter Samir Heskjær; Kol, S; Papanikolaou, E G

    2011-01-01

    GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase...... deficiency. Therefore, the challenge has been to rescue the luteal phase. Studies now report a luteal phase rescue, with a reproductive outcome comparable to that seen after hCG triggering....

  1. State Estimation For An Agonistic-Antagonistic Muscle System

    OpenAIRE

    Nguyen, Thang; Warner, Holly; La, Hung; Mohammadi, Hanieh; Simon, Dan; Richter, Hanz

    2017-01-01

    Research on assistive technology, rehabilitation, and prosthesis requires the understanding of human machine interaction, in which human muscular properties play a pivotal role. This paper studies a nonlinear agonistic-antagonistic muscle system based on the Hill muscle model. To investigate the characteristics of the muscle model, the problem of estimating the state variables and activation signals of the dual muscle system is considered. In this work, parameter uncertainty and unknown input...

  2. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    Science.gov (United States)

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline.

  3. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond.

    Science.gov (United States)

    Xia, Yang; Kellems, Rodney E

    2013-06-21

    Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These

  4. Structure of the agonist-bound neurotensin receptor.

    Science.gov (United States)

    White, Jim F; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G; Grisshammer, Reinhard

    2012-10-25

    Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8 Å resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.

  5. Pyrazolodiazepine derivatives with agonist activity toward Drosophila RYamide receptor.

    Science.gov (United States)

    Yoon, Yeu Kyung; Kim, Jung Ha; Kim, Jeong-Hyun; Kwon, Jae-Young; Kim, Yong-Chul; Kim, Young-Joon; Park, Zee-Yong

    2016-10-15

    The neuropeptide Y (NPY)-like signaling is conserved broadly in many animal species, and implicated in diverse biological functions, particularly those associated with feeding and metabolism. In Drosophila, three G protein coupled receptors (GPCRs) are closely related to the vertebrate NPY receptors: RYamide receptor (RYa-R) CG5811, neuropeptide F receptor (NPFR) CG1147 and short neuropeptide F receptor (sNPF-R) CG7395. Here, we screened 442 compounds of the pyrazolodiazepine analogs library, and identified four synthetic small compounds that activate the RYa-R, but not other two receptors. Their maximum activity is about 40% of the endogenous ligand, Drosophila RYamide-1, indicating they are partial agonists. Structural comparisons of these agonists identified an active core structure, characterized by phenylalanine and lysine fused pyrazolodiazepine skeletons, which can be utilized as a lead structure for further development of more potent drugs active on mammalian NPYRs. Identification of small compound agonists selective on RYa-R of the genetically amenable insect model will facilitate future efforts to understand biological functions of RYa-R, a GPCR conserved in many species. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Suppression of atherosclerosis by synthetic REV-ERB agonist

    International Nuclear Information System (INIS)

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2015-01-01

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization

  7. Suppression of atherosclerosis by synthetic REV-ERB agonist

    Energy Technology Data Exchange (ETDEWEB)

    Sitaula, Sadichha [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Billon, Cyrielle [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States); Kamenecka, Theodore M.; Solt, Laura A. [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Burris, Thomas P., E-mail: burristp@slu.edu [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States)

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  8. Fluorescent agonists for the Torpedo nicotinic acetylcholine receptor.

    Science.gov (United States)

    Krieger, Florian; Mourot, Alexandre; Araoz, Romulo; Kotzyba-Hibert, Florence; Molgó, Jordi; Bamberg, Ernst; Goeldner, Maurice

    2008-05-05

    We have synthesized a series of fluorescent acylcholine derivatives carrying different linkers that vary in length and structure and connect the acylcholine unit to the environment-sensitive fluorophores 7-(diethylamino)coumarin-3-carbonyl (DEAC) or N-(7-nitrobenz-2-oxa-1,3-diazol-yl) (NBD). The pharmacological properties of the fluorescent analogues were investigated on heterologously expressed nicotinic acetylcholine receptor (nAChR) from Torpedo californica and on oocytes transplanted with nAChR-rich Torpedo marmorata membranes. Agonist action strongly depends on the length and the structure of the linker. One particular analogue, DEAC-Gly-C6-choline, showed partial agonist behavior with about half of the maximum response of acetylcholine, which is at least 20 times higher than those observed with previously described fluorescent dansyl- and NBD-acylcholine analogues. Binding of DEAC-Gly-C6-choline to Torpedo nAChR induces a strong enhancement of fluorescence intensity. Association and displacement kinetic experiments revealed dissociation constants of 0.5 nM for the alphadelta-binding site and 15.0 nM for the alphagamma-binding site. Both the pharmacological and the spectroscopic properties of this agonist show great promise for characterizing the allosteric mechanism behind the function of the Torpedo nAChR, as well as for drug-screening studies.

  9. Development of specific dopamine D-1 agonists and antagonists

    International Nuclear Information System (INIS)

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo[a,d]cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo[1,2]cyclohepta[3,4,5d,e]isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC 50 of compound 11 for displacement of 3 H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of 3 H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor

  10. PPAR Agonists and Metabolic Syndrome: An Established Role?

    Directory of Open Access Journals (Sweden)

    Margherita Botta

    2018-04-01

    Full Text Available Therapeutic approaches to metabolic syndrome (MetS are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs, blood glucose, and abdominal adiposity. PPARs may be classified into the α, β/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate and omega-3 fatty acids, are powerful TG-lowering agents. They mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (HDL-C. PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α/δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD which is closely associated with the MetS. The PPAR system thus offers an important hope in the management of atherogenic dyslipidemias, although concerns regarding potential adverse events such as the rise of plasma creatinine, gallstone formation, drug–drug interactions (i.e., gemfibrozil and myopathy should also be acknowledged.

  11. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    Science.gov (United States)

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes. Copyright © 2013 John Wiley & Sons, Ltd.

  12. Effects of the cannabinoid CB1agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs.

    Science.gov (United States)

    Berger, Joel I; Coomber, Ben; Hill, Samantha; Alexander, Steve P H; Owen, William; Palmer, Alan R; Wallace, Mark N

    2017-12-01

    Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2'-chloroethylamide (ACEA), a highly-selective CB 1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB 1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  13. Diminished neural resources allocation to time processing in Autism Spectrum Disorders

    Directory of Open Access Journals (Sweden)

    Anna Lambrechts

    2018-01-01

    Results: Our results suggest that compared to TDC individuals, individuals with ASD are less able to predict the duration of the standard tone accurately, affecting the sensitivity of the comparison process. In addition, contrary to TDC individuals who allocate resources at different times depending on the nature of the task (pitch or duration discrimination, individuals with ASD seem to engage less resources for the Duration task than for the Pitch task regardless of the context. Although individuals with ASD showed top-down adaptation to the context of the task, this neuronal strategy reflects a bias in the readiness to perform different types of tasks, and in particular a diminished allocation of resources to duration processing which could have cascading effect on learning and development of other cognitive functions.

  14. Diminished exercise capacity and mitochondrial bc1 complex deficiency in tafazzin-knockdown mice.

    Directory of Open Access Journals (Sweden)

    Corey ePowers

    2013-04-01

    Full Text Available The phospholipid, cardiolipin, is essential for maintaining mitochondrial structure and optimal function. Cardiolipin-deficiency in humans, Barth syndrome, is characterized by exercise intolerance, dilated cardiomyopathy, neutropenia and 3-methyl-glutaconic aciduria. The causative gene is the mitochondrial acyl-transferase, tafazzin that is essential for remodeling acyl chains of cardiolipin. We sought to determine metabolic rates in tafazzin-deficient mice during resting and exercise, and investigate the impact of cardiolipin deficiency on mitochondrial respiratory chain activities. Tafazzin knockdown in mice markedly impaired oxygen consumption rates during an exercise, without any significant effect on resting metabolic rates. CL-deficiency resulted in significant reduction of mitochondrial respiratory reserve capacity in neonatal cardiomyocytes that is likely to be caused by diminished activity of complex-III, which requires CL for its assembly and optimal activity. Our results may provide mechanistic insights of Barth syndrome pathogenesis.

  15. Acute hyperinsulinemia decreases plasma osteoprotegerin with diminished effect in type 2 diabetes and obesity

    DEFF Research Database (Denmark)

    Jørgensen, Gitte Maria; Vind, Birgitte; Nybo, Mads

    2009-01-01

    the acute effects of insulin on plasma OPG concentrations in individuals with type 2 diabetes and obese individuals compared with lean controls. DESIGN: The study population consisted of ten type 2 diabetic, ten obese subjects, and ten lean subjects with no family history of diabetes. METHODS: All subjects...... infusion decreased plasma OPG concentrations in all groups (Pobese and type 2 diabetic individuals (P=0.007). Baseline OPG correlated with fasting insulin, baseline lactate, and low density lipoprotein cholesterol in the diabetic group, and with baseline FFA...... in the lean group. The relative change of OPG in response to insulin correlated inversely with HbA1c and baseline FFA in the lean group. CONCLUSIONS: Acute hyperinsulinemia decreases plasma OPG, but with diminished effect in individuals with type 2 diabetes and obesity. Increased levels of OPG in arteries...

  16. SAT predicts GPA better for high ability subjects: Implications for Spearman's Law of Diminishing Returns.

    Science.gov (United States)

    Coyle, Thomas; Snyder, Anissa; Pillow, David; Kochunov, Peter

    2011-04-01

    This research examined the predictive validity of the SAT (formerly, the Scholastic Aptitude Test) for high and low ability groups. SAT scores and college GPAs were obtained from the 1997 National Longitudinal Survey of Youth. Subjects were classified as high or low ability by g factor scores from the Armed Services Vocational Aptitude Battery. SAT correlations with GPA were higher for high than low ability subjects. SAT g loadings (i.e., SAT correlations with g) were equivalent for both groups. This is the first study to show that the predictive validity of the SAT varies for ability groups that differ in g. The results contradict a presumption, based on Spearman's Law of Diminishing Returns, that a test's predictive validity should be lower for high ability subjects. Further research is needed to identify factors that contribute to the predictive validity of the SAT for groups that differ in g.

  17. Diminishing Risk for Age-Related Macular Degeneration with Nutrition: A Current View

    Directory of Open Access Journals (Sweden)

    Allen Taylor

    2013-07-01

    Full Text Available Age-related macular degeneration (AMD is the leading cause of blindness in the elderly. Clinical hallmarks of AMD are observed in one third of the elderly in industrialized countries. Preventative interventions through dietary modification are attractive strategies, because they are more affordable than clinical therapies, do not require specialists for administration and many studies suggest a benefit of micro- and macro-nutrients with respect to AMD with few, if any, adverse effects. The goal of this review is to provide information from recent literature on the value of various nutrients, particularly omega-3 fatty acids, lower glycemic index diets and, perhaps, some carotenoids, with regard to diminishing risk for onset or progression of AMD. Results from the upcoming Age-Related Eye Disease Study (AREDS II intervention trial should be particularly informative.

  18. Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone

    Science.gov (United States)

    Zhao, Liangliang; Hadziahmetovic, Majda; Wang, Chenguang; Xu, Xueying; Song, Ying; Jinnah, H.A.; Wodzinska, Jolanta; Iacovelli, Jared; Wolkow, Natalie; Krajacic, Predrag; Weissberger, Alyssa Cwanger; Connelly, John; Spino, Michael; Lee, Michael K.; Connor, James; Giasson, Benoit; Harris, Z. Leah; Dunaief, Joshua L.

    2016-01-01

    Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons. PMID:26303407

  19. Use of the radio mutagenesis gamma to diminish the germinative periods of the seeds

    International Nuclear Information System (INIS)

    Ramos Espinosa, K.A.; Damera Martinez, A.; Benito Zamora, E.; Vazquez Hernandez, L.

    2001-01-01

    Among the nuclear techniques that have been used in Cuba in to feasible way for their it lives it uses in the agriculture it dog think about that the radio mutagenesis is that of advance it lives. In this address the fundamental problem consists in that to the being to casuistically method forces to uses to great initial population. The Fruit Bomb Net Maradol was studied and it was obtained to diminish its germination period in 12 days without affecting the quality of the cultivation. The seeds were irradiated with an irradiator with source of Co-60, originator of radiations a (gamma) with to power of dose of 2,76 kGy/h and to half energy of 1,25 MeV. The dose range applied to the seeds was among 50 - 250 Gy

  20. Characterizing and Diminishing Autofluorescence in Formalin-fixed Paraffin-embedded Human Respiratory Tissue

    Science.gov (United States)

    Davis, A. Sally; Richter, Anke; Becker, Steven; Moyer, Jenna E.; Sandouk, Aline; Skinner, Jeff

    2014-01-01

    Tissue autofluorescence frequently hampers visualization of immunofluorescent markers in formalin-fixed paraffin-embedded respiratory tissues. We assessed nine treatments reported to have efficacy in reducing autofluorescence in other tissue types. The three most efficacious were Eriochrome black T, Sudan black B and sodium borohydride, as measured using white light laser confocal Λ2 (multi-lambda) analysis. We also assessed the impact of steam antigen retrieval and serum application on human tracheal tissue autofluorescence. Functionally fitting this Λ2 data to 2-dimensional Gaussian surfaces revealed that steam antigen retrieval and serum application contribute minimally to autofluorescence and that the three treatments are disparately efficacious. Together, these studies provide a set of guidelines for diminishing autofluorescence in formalin-fixed paraffin-embedded human respiratory tissue. Additionally, these characterization techniques are transferable to similar questions in other tissue types, as demonstrated on frozen human liver tissue and paraffin-embedded mouse lung tissue fixed in different fixatives. PMID:24722432

  1. A short educational intervention diminishes causal illusions and specific paranormal beliefs in undergraduates.

    Science.gov (United States)

    Barberia, Itxaso; Tubau, Elisabet; Matute, Helena; Rodríguez-Ferreiro, Javier

    2018-01-01

    Cognitive biases such as causal illusions have been related to paranormal and pseudoscientific beliefs and, thus, pose a real threat to the development of adequate critical thinking abilities. We aimed to reduce causal illusions in undergraduates by means of an educational intervention combining training-in-bias and training-in-rules techniques. First, participants directly experienced situations that tend to induce the Barnum effect and the confirmation bias. Thereafter, these effects were explained and examples of their influence over everyday life were provided. Compared to a control group, participants who received the intervention showed diminished causal illusions in a contingency learning task and a decrease in the precognition dimension of a paranormal belief scale. Overall, results suggest that evidence-based educational interventions like the one presented here could be used to significantly improve critical thinking skills in our students.

  2. Discovery and Computational Rationalization of Diminishing Alternation in [n]Dendralenes.

    Science.gov (United States)

    Saglam, Mehmet F; Fallon, Thomas; Paddon-Row, Michael N; Sherburn, Michael S

    2016-01-27

    The [n]dendralenes are a family of acyclic hydrocarbons which, by virtue of their ability to rapidly generate structural complexity, have attracted significant recent synthetic attention. [3]Dendralene through [8]dendralene have been previously prepared but no higher member of the family has been reported to date. Here, we describe the first chemical syntheses of the "higher" dendralenes, [9]dendralene through [12]dendralene. We also report a detailed investigation into the spectroscopic properties and chemical reactivity of the complete family of fundamental hydrocarbons, [3]dendralene to [12]dendralene. These studies reveal the first case of diminishing alternation in behavior in a series of related structures. We also report a comprehensive series of computational studies, which trace this dampening oscillatory effect in both spectroscopic measurements and chemical reactivity to conformational preferences.

  3. Diminished macrophage apoptosis and reactive oxygen species generation after phorbol ester stimulation in Crohn's disease.

    Directory of Open Access Journals (Sweden)

    Christine D Palmer

    2009-11-01

    Full Text Available Crohn's Disease (CD is a chronic relapsing disorder characterized by granulomatous inflammation of the gastrointestinal tract. Although its pathogenesis is complex, we have recently shown that CD patients have a systemic defect in macrophage function, which results in the defective clearance of bacteria from inflammatory sites.Here we have identified a number of additional macrophage defects in CD following diacylglycerol (DAG homolog phorbol-12-myristate-13-acetate (PMA activation. We provide evidence for decreased DNA fragmentation, reduced mitochondrial membrane depolarization, impaired reactive oxygen species production, diminished cytochrome c release and increased IL-6 production compared to healthy subjects after PMA exposure. The observed macrophage defects in CD were stimulus-specific, as normal responses were observed following p53 activation and endoplasmic reticulum stress.These findings add to a growing body of evidence highlighting disordered macrophage function in CD and, given their pivotal role in orchestrating inflammatory responses, defective apoptosis could potentially contribute to the pathogenesis of CD.

  4. Vision-guided ocular growth in a mutant chicken model with diminished visual acuity.

    Science.gov (United States)

    Ritchey, Eric R; Zelinka, Christopher; Tang, Junhua; Liu, Jun; Code, Kimberly A; Petersen-Jones, Simon; Fischer, Andy J

    2012-09-01

    Visual experience is known to guide ocular growth. We tested the hypothesis that vision-guided ocular growth is disrupted in a model system with diminished visual acuity. We examine whether ocular elongation is influenced by form-deprivation (FD) and lens-imposed defocus in the Retinopathy, Globe Enlarged (RGE) chicken. Young RGE chicks have poor visual acuity, without significant retinal pathology, resulting from a mutation in guanine nucleotide-binding protein β3 (GNB3), also known as transducin β3 or Gβ3. The mutation in GNB3 destabilizes the protein and causes a loss of Gβ3 from photoreceptors and ON-bipolar cells (Ritchey et al., 2010). FD increased ocular elongation in RGE eyes in a manner similar to that seen in wild-type (WT) eyes. By comparison, the excessive ocular elongation that results from hyperopic defocus was increased, whereas myopic defocus failed to significantly decrease ocular elongation in RGE eyes. Brief daily periods of unrestricted vision interrupting FD prevented ocular elongation in RGE chicks in a manner similar to that seen in WT chicks. Glucagonergic amacrine cells differentially expressed the immediate early gene Egr1 in response to growth-guiding stimuli in RGE retinas, but the defocus-dependent up-regulation of Egr1 was lesser in RGE retinas compared to that of WT retinas. We conclude that high visual acuity, and the retinal signaling mediated by Gβ3, is not required for emmetropization and the excessive ocular elongation caused by FD and hyperopic defocus. However, the loss of acuity and Gβ3 from RGE retinas causes enhanced responses to hyperopic defocus and diminished responses to myopic defocus. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Overlapping binding site for the endogenous agonist, small-molecule agonists, and ago-allosteric modulators on the ghrelin receptor

    DEFF Research Database (Denmark)

    Holst, Birgitte; Frimurer, Thomas M; Mokrosinski, Jacek

    2008-01-01

    secretagogue GHRP-6) plus four nonpeptide agonists-the original benzolactam L-692,429 [3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5-yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamide], the spiroindoline sulfonamide MK-677 [N-[1(R)-1, 2-dihydro-1-ethanesulfonylspiro-3H...

  6. Problems of normative strenght and critique within the concept of agonistic participation: Towards the complementarity of agonistic and participatory democracy

    Directory of Open Access Journals (Sweden)

    Đorđević Biljana

    2014-01-01

    Full Text Available In this article I argue that there are grounds for considering agonistic democracy and participatory democracy complementarity in order to institutionalize agonism which has thus far lacked an elaborate articulation of its institutional dimension. The two democratic theories share a commitment toward widening the scope of the political as a way of inclusion of citizens and their subsequent political subjectivation and empowerment. Furthermore, there are authors on both sides who think democracy does not need foundations. Agonistic participation and contestation, on the one hand, and the broadening and strengthening of various sectors of political participation, on the other, both open up new possibilities for critique and change, but also create new risks. Building on a redefinition of agonisitic participation, I aim to attenuate an objection that agonism is normatively weak in terms of lacking resources to motivate citizens and justify their critique of practices of domination and oppression. The article concludes that we need to embrace agonistic participation as a means towards the development of democratic political judgement, as there are no other guarantees, i.e. secure foundations, for our ability to distinguish between democratic and non-democratic agon. [Projekat Ministarstva nauke Republike Srbije, br. 47026: Konstitucionalizam i vladavina prava u izgradnji nacionalne države - slučaj Srbije

  7. The treatment of Parkinson's disease with dopamine agonists

    Directory of Open Access Journals (Sweden)

    Frank, Wilhelm

    2008-06-01

    Full Text Available Parkinson’s disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body. The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system. A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen. Since the introduction of L-Dopa in the 1960´s it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors, monoaminoxydase-inhibitors (MAO-inhibitors and NMDA-antagonists (N-Methyl-d-aspartat-antagonists. In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia. The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine

  8. Synthetic and computer assisted analysis of the pharmacophore for agonists at benzodiazepine receptors.

    Science.gov (United States)

    Diaz-Arauzo, H; Koehler, K F; Hagen, T J; Cook, J M

    1991-01-01

    In order to employ rational drug design in the discovery of selective benzodiazepine receptor agonists and inverse agonists, pharmacophore/receptor models for both these activities must first be established. Recently, a pharmacophore for the inverse agonist site has been formulated employing the most recent receptor mapping techniques (22). The continuation of this approach to the pharmacophore for agonist ligands has permitted a definition of this site independently of the inverse agonist model. The agonist pharmacophore/receptor contains two hydrogen bond donating sites of interaction (H1 and H2) located about 6.5 A from each other, as well as three areas of lipophilic interaction (L1-L3). The areas L1 and L2 are critical for agonist activity; moreover, some ligands also require an interaction in a third lipophilic area termed L3. This is in agreement with previous work (12-23). In addition, an area of negative steric interaction (S1) between the ligand and receptor-binding protein is defined. In regard to the pharmacophore, it was established that the alignment rule for agonist beta-carbolines is different from that which elicits inverse agonist activity. Consideration of the pharmacophore has resulted in the synthesis of a new beta-carboline 16 which elicits agonist activity. This ligand 16 not only satisfied the requirements of the pharmacophore, but more importantly it elicited both anticonvulsant and anxiolytic activity, but was devoid of the myorelaxant/ataxic properties associated with the benzodiazepines.

  9. Lipid- and polyion complex-based micelles as agonist platforms for TNFR superfamily receptors.

    Science.gov (United States)

    Gilbreth, Ryan N; Novarra, Shabazz; Wetzel, Leslie; Florinas, Stelios; Cabral, Horacio; Kataoka, Kazunori; Rios-Doria, Jonathan; Christie, Ronald J; Baca, Manuel

    2016-07-28

    Receptor clustering is important for signaling among the therapeutically relevant TNFR superfamily of receptors. In nature, this clustering is driven by trimeric ligands often presented in large numbers as cell surface proteins. Molecules capable of driving similar levels of clustering could make good agonists and hold therapeutic value. However, recapitulating such extensive clustering using typical biotherapeutic formats, such as antibodies, is difficult. Consequently, generating effective agonists of TNFR superfamily receptors is challenging. Toward addressing this challenge we have used lipid- and polyion complex-based micelles as platforms for presenting receptor-binding biologics in a multivalent format that facilitates receptor clustering and imparts strong agonist activity. We show that receptor-binding scFvs or small antibody mimetics that have no agonist activity on their own can be transformed into potent agonists through multivalent presentation on a micelle surface and that the activity of already active multivalent agonists can be enhanced. Using this strategy, we generated potent agonists against two different TNFR superfamily receptors and mouse tumor model studies demonstrate that these micellar agonists have therapeutic efficacy in vivo. Due to its ease of implementation and applicability independent of agonist molecular format, we anticipate that this strategy could be useful for developing agonists to a variety of receptors that rely on clustering to signal. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Inhibition of K+ permeability diminishes alpha 2-adrenoceptor mediated effects on norepinephrine release

    International Nuclear Information System (INIS)

    Zimanyi, I.; Folly, G.; Vizi, E.S.

    1988-01-01

    The effect of two different potassium channel blockers, 4-aminopyridine (4-AP) and quinine, on the alpha 2-adrenoceptor mediated modulation of norepinephrine (NE) release was investigated. Pairs of mouse vasa deferentia were loaded with 3 H-norepinephrine ( 3 H-NE), superfused continuously, and stimulated electrically. 4-AP (5.3 x 10(-4) M), and quinine (10(-5) M) enhanced the stimulation-evoked release of tritium significantly. The electrically induced release of radioactivity was reduced by alpha 2-adrenoceptor agonists (1-NE and xylazine) and enhanced by the alpha 2-adrenoceptor antagonist yohimbine. Both effects were affected markedly by 4-AP or quinine: the depressant action of 1-NA and xylazine was partially antagonized and the facilitatory effect of yohimbine was completely abolished during the blockade of the potassium channels. It is suggested that the blockade of the potassium permeability counteracts negative feedback modulation; therefore, it seems likely that the stimulation of alpha 2-adrenoceptors leads to an enhanced potassium permeability and hyperpolarization of varicose axon terminals

  11. Application of numerical method in calculating the internal rate of return of joint venture investment using diminishing musyarakah model

    Science.gov (United States)

    Ruslan, Siti Zaharah Mohd; Jaffar, Maheran Mohd

    2017-05-01

    Islamic banking in Malaysia offers variety of products based on Islamic principles. One of the concepts is a diminishing musyarakah. The concept of diminishing musyarakah helps Muslims to avoid transaction which are based on riba. The diminishing musyarakah can be defined as an agreement between capital provider and entrepreneurs that enable entrepreneurs to buy equity in instalments where profits and losses are shared based on agreed ratio. The objective of this paper is to determine the internal rate of return (IRR) for a diminishing musyarakah model by applying a numerical method. There are several numerical methods in calculating the IRR such as by using an interpolation method and a trial and error method by using Microsoft Office Excel. In this paper we use a bisection method and secant method as an alternative way in calculating the IRR. It was found that the diminishing musyarakah model can be adapted in managing the performance of joint venture investments. Therefore, this paper will encourage more companies to use the concept of joint venture in managing their investments performance.

  12. Smoking Through a Topography Device Diminishes Some of the Acute Rewarding Effects of Smoking.

    Science.gov (United States)

    Ross, Kathryn C; Juliano, Laura M

    2016-05-01

    Smoking topography (ST) devices are an important methodological tool for quantifying puffing behavior (eg, puff volume, puff velocity) as well as identifying puffing differences across individuals and situations. Available ST devices are designed such that the smoker's mouth and hands have direct contact with the device rather than the cigarette itself. Given the importance of the sensorimotor aspects of cigarette smoking in smoking reward, it is possible that ST devices may interfere with the acute rewarding effects of smoking. Despite the methodological importance of this issue, few studies have directly compared subjective reactions to smoking through a topography device to naturalistic smoking. Smokers (N = 58; 38% female) smoked their preferred brand of cigarettes one time through a portable topography device and one time naturalistically, in counterbalanced order across two laboratory sessions. Smoking behavior (eg, number of puffs) and subjective effects (eg, urge reduction, affect, smoking satisfaction) were assessed. Negative affect reduction was greater in the natural smoking condition relative to the topography condition, but differences were not significant on measures of urge, withdrawal, or positive affect. Self-reported smoking satisfaction, enjoyment of respiratory tract sensations, psychological reward, craving reduction, and other rewarding effects of smoking were also significantly greater in the naturalistic smoking condition. The effects of using a ST device on the smoking experience should be considered when it is used in research as it may diminish some of the rewarding effects of smoking. When considering the inclusion of a smoking topography device in one's research, it is important to know if use of that device will alter the smoker's experience. This study assessed affective and subjective reactions to smoking through a topography device compared to naturalistic smoking. We found that smoking satisfaction, psychological reward, enjoyment

  13. Vitamin D Levels in Patients with Autoimmune Thyroiditis with Diminished Thyroid Function

    Directory of Open Access Journals (Sweden)

    V.V. Povoroznyuk

    2014-08-01

    Full Text Available The study examined vitamin D levels in 75 patients with autoimmune thyroiditis (AIT with diminished thyroid function. The objective of the study — to determine the content of 25(OHD in patients with overt and subclinical hypothyroidism on the background of AIT. Materials and Methods. 75 patients (59 women and 16 men and 25 apparently healthy subjects (matched for age and sex were followed. The levels of thyroid stimulating hormone (TSH, free thyroxine (fT4, free triiodothyronine (fT3, antibodies to thyroid peroxidase (TPO, and the content of 25(OHD in the blood serum were determined. Results. Patients with AІT were divided according to the levels of TSH and thyroid hormones into the group with subclinical (n = 21 and overt (n = 54 hypothyroidism. TSH level was significantly higher in the group with subclinical (6.80 ± 1.84 mcU/ml and overt hypothyroidism (11.38 ± 2.16 mcU/ml compared with the control group (2.11 ± 0.37 mcU/ml (p < 0.05. The level of antibodies to TPO was 312.83 ± 7.19 U/ml in subclinical hypothyroidism and 546.29 ± 9.81 U/ml — in overt hypothyroidism. 25(OHD level in blood serum was significantly lower in subclinical (18.8 ± 1.2 nmol/l and overt hypothyroidism (21.7 ± 1.3 nmol/l compared with the control group (27.3 ± 1.4 nmol/l (p < 0.05. Highly reliable negative correlation was established between the level of TSH, antibodies to TPO and vitamin D (p < 0.001. Also highly reliable positive correlation was established between the levels of serum 25(OHD and fT4 content (p < 0.001, between TSH and TPO antibody levels (p < 0.05. Conclusions. Vitamin D deficiency is combined with the presence of AIT with diminished thyroid function (in subclinical and overt hypothyroidism. Further studies are needed to determine vitamin D deficiency as a causal factor of AIT.

  14. α7 nicotinic receptor agonist reactivates neurogenesis in adult brain.

    Science.gov (United States)

    Narla, Sridhar; Klejbor, Ilona; Birkaya, Barbara; Lee, Yu-Wei; Morys, Janusz; Stachowiak, Ewa K; Terranova, Christopher; Bencherif, Merouane; Stachowiak, Michal K

    2013-10-15

    Reactivation of neurogenesis by endogenous Neural Stem/Progenitor Cells (NS/PC) in the adult brain or spinal cord holds the key for treatment of CNS injuries as well as neurodegenerative disorders, which are major healthcare issues for the world's aging population. Recent studies show that targeting the α7 nicotinic acetylcholine receptors (α7nAChR) with a specific TC-7020 agonist inhibits proliferation and stimulates neuronal differentiation of NS/PC in subventricular zone (SVZ) in the adult mouse brain. TC-7020-induced neuronogenesis is observed in different brain regions, including: (1) βIII Tubulin-expressing cortical neurons, (2) calretinin expressing hippocampal neurons and (3) cells in substantia nigra (SN) expressing predopaminergic Nurr1+phenotype. Reactivation of developmental integrative nuclear FGFR1 signaling (INFS), via gene transfection reinstates neurogenesis in the adult brain by promoting neuronal differentiation of brain NS/PC. TC-7020 neuronogenic effect is associated with a robust accumulation of endogenous FGFR1 in the nuclei of differentiating cells. Furthermore, direct in vitro stimulation of neural stem/progenitor cells with α7nAChR agonist activates INFS and neuronal-like differentiation and activation of neuronal genes. The α7nAChR upregulation of early neuronal βIII-Tubulin gene involves neurogenic FGFR1-Nur signaling and direct FGFR1 interaction with the gene promoter. The reactivation of developmental INFS and neurogenesis in adult brain by the α7nAChR agonist may offer new strategy to treat brain injuries, neurodegenerative and neurodevelopmental diseases. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Metabolic effects of beta2-agonists in relation to exercise performance

    DEFF Research Database (Denmark)

    Kalsen, Anders

    2015-01-01

    athletes. The present PhD thesis is based on four manuscripts in which the acute effects of beta2-agonists on exercise performance were investigated. The aims were 1) to investigate whether supratherapeutic inhalation of beta2-agonists enhances muscle strength, anaerobic performance and aerobic performance...... that supratherapeutic inhalation of beta2-agonists increases muscle strength and improves performance during maximal sprinting lasting up to ~ 60 s, whereas no effect was observed on exercise lasting more than ~ 180 s. The ergogenic effects of beta2-agonists on power output during maximal sprinting requires......Beta2-agonists are frequently used in the treatment of asthma and exercise-induced bronchoconstriction in elite athletes. However, aside from a bronchodilatory effect, beta2-agonists have also been shown to improve exercise performance, which makes these substances subjected to misuse by elite...

  16. Metabolic effects of beta2-agonists in relation to exercise performance

    DEFF Research Database (Denmark)

    Kalsen, Anders

    2015-01-01

    Beta2-agonists are frequently used in the treatment of asthma and exercise-induced bronchoconstriction in elite athletes. However, aside from a bronchodilatory effect, beta2-agonists have also been shown to improve exercise performance, which makes these substances subjected to misuse by elite...... athletes. The present PhD thesis is based on four manuscripts in which the acute effects of beta2-agonists on exercise performance were investigated. The aims were 1) to investigate whether supratherapeutic inhalation of beta2-agonists enhances muscle strength, anaerobic performance and aerobic performance...... that supratherapeutic inhalation of beta2-agonists increases muscle strength and improves performance during maximal sprinting lasting up to ~ 60 s, whereas no effect was observed on exercise lasting more than ~ 180 s. The ergogenic effects of beta2-agonists on power output during maximal sprinting requires...

  17. Cardiovascular safety and benefits of GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Dalsgaard, Niels B; Brønden, Andreas; Lauritsen, Tina Vilsbøll

    2017-01-01

    INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss...... and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients...

  18. Potent small molecule Hedgehog agonists induce VEGF expression in vitro.

    Science.gov (United States)

    Seifert, Katrin; Büttner, Anita; Rigol, Stephan; Eilert, Nicole; Wandel, Elke; Giannis, Athanassios

    2012-11-01

    Here, we describe the synthesis, SAR studies as well as biological investigations of the known Hedgehog signaling agonist SAG and a small library of its analogues. The SAG and its derivatives were analyzed for their potency to activate the expression of the Hh target gene Gli1 in a reporter gene assay. By analyzing SAR important molecular descriptors for Gli1 activation have been identified. SAG as well as compound 10c proven to be potent activators of VEGF expression in cultivated dermal fibroblasts. Importantly and in contrast to SAG, derivative 10c displayed no toxicity in concentrations up to 250 μm. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Clenbuterol, a beta(2)-agonist, retards atrophy in denervated muscles

    Science.gov (United States)

    Zeman, Richard J.; Ludemann, Robert; Etlinger, Joseph D.

    1987-01-01

    The effects of a beta(2) agonist, clenbuterol, on the protein content as well as on the contractile strength and the muscle fiber cross-sectional area of various denervated muscles from rats were investigated. It was found that denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, of rats treated for 2-3 weeks with clenbuterol contained 95-110 percent more protein than denervated controls. The twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area.

  20. Long-acting β2-agonists in asthma

    DEFF Research Database (Denmark)

    Jacobson, Glenn A; Raidal, Sharanne; Hostrup, Morten

    2018-01-01

    Long-acting β2-agonists (LABAs) such as formoterol and salmeterol are used for prolonged bronchodilatation in asthma, usually in combination with inhaled corticosteroids (ICSs). Unexplained paradoxical asthma exacerbations and deaths have been associated with LABAs, particularly when used without...... ICS. LABAs clearly demonstrate effective bronchodilatation and steroid-sparing activity, but long-term treatment can lead to tolerance of their bronchodilator effects. There are also concerns with regard to the effects of LABAs on bronchial hyperresponsiveness (BHR), where long-term use is associated...

  1. Plasma membrane cholesterol level and agonist-induced internalization of δ-opioid receptors; colocalization study with intracellular membrane markers of Rab family.

    Science.gov (United States)

    Brejchova, Jana; Vosahlikova, Miroslava; Roubalova, Lenka; Parenti, Marco; Mauri, Mario; Chernyavskiy, Oleksandr; Svoboda, Petr

    2016-08-01

    Decrease of cholesterol level in plasma membrane of living HEK293 cells transiently expressing FLAG-δ-OR by β-cyclodextrin (β-CDX) resulted in a slight internalization of δ-OR. Massive internalization of δ-OR induced by specific agonist DADLE was diminished in cholesterol-depleted cells. These results suggest that agonist-induced internalization of δ-OR, which has been traditionally attributed exclusively to clathrin-mediated pathway, proceeds at least partially via membrane domains. Identification of internalized pools of FLAG-δ-OR by colocalization studies with proteins of Rab family indicated the decreased presence of receptors in early endosomes (Rab5), late endosomes and lysosomes (Rab7) and fast recycling vesicles (Rab4). Slow type of recycling (Rab11) was unchanged by cholesterol depletion. As expected, agonist-induced internalization of oxytocin receptors was totally suppressed in β-CDX-treated cells. Determination of average fluorescence lifetime of TMA-DPH, the polar derivative of hydrophobic membrane probe diphenylhexatriene, in live cells by FLIM indicated a significant alteration of the overall PM structure which may be interpreted as an increased "water-accessible space" within PM area. Data obtained by studies of HEK293 cells transiently expressing FLAG-δ-OR by "antibody feeding" method were extended by analysis of the effect of cholesterol depletion on distribution of FLAG-δ-OR in sucrose density gradients prepared from HEK293 cells stably expressing FLAG-δ-OR. Major part of FLAG-δ-OR was co-localized with plasma membrane marker Na,K-ATPase and β-CDX treatment resulted in shift of PM fragments containing both FLAG-δ-OR and Na,K-ATPase to higher density. Thus, the decrease in content of the major lipid constituent of PM resulted in increased density of resulting PM fragments.

  2. Innate Immune Responses to TLR2 and TLR4 Agonists Differ between Baboons, Chimpanzees and Humans

    Science.gov (United States)

    Brinkworth, Jessica F.; Pechenkina, Ekaterina A.; Silver, Jack; Goyert, Sanna M.

    2012-01-01

    Background African catarrhine primates differ in bacterial disease susceptibility. Methods Human, chimpanzee, and baboon blood was stimulated with TLR-detected bacterial agonists and cytokine/chemokine induction assessed by real-time pcr. Results Humans and chimpanzees shared similar cytokine/chemokine responses, while baboon cytokine/chemokine induction differed. Generally, responses were agonist-independent. Conclusions These primates tend to generate species rather than agonist–specific responses to bacterial agonists. PMID:22978822

  3. Glucagon-Like Peptide-1 Receptor Agonists: Beta-Cell Protection or Exhaustion?

    Science.gov (United States)

    van Raalte, Daniël H; Verchere, C Bruce

    2016-07-01

    Glucagon-like peptide (GLP)-1 receptor agonists enhance insulin secretion and may improve pancreatic islet cell function. However, GLP-1 receptor (GLP-1R) agonist treatment may have more complex, and sometimes deleterious, effects on beta cells. We discuss the concepts of beta cell protection versus exhaustion for different GLP-1R agonists based on recent data. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Efficacy and safety of the PPARγ partial agonist balaglitazone compared with pioglitazone and placebo

    DEFF Research Database (Denmark)

    Henriksen, Kim; Byrjalsen, Inger; Qvist, Per

    2011-01-01

    Treatment of patients with perioxisome proliferator-activated receptor-¿ full agonists are associated with weight gain, heart failure, peripheral oedema, and bone loss. However, the safety of partial perioxisome proliferator-activated receptor-¿ agonists has not been established in a clinical tri....... The BALaglitazone glucose Lowering Efficacy Trial aimed to establish the glucose-lowering effects and safety parameters of the perioxisome proliferator-activated receptor-¿ partial agonist balaglitazone in diabetic patients on stable insulin therapy....

  5. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

    Energy Technology Data Exchange (ETDEWEB)

    Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  6. Diminished facial emotion expression and associated clinical characteristics in Anorexia Nervosa.

    Science.gov (United States)

    Lang, Katie; Larsson, Emma E C; Mavromara, Liza; Simic, Mima; Treasure, Janet; Tchanturia, Kate

    2016-02-28

    This study aimed to investigate emotion expression in a large group of children, adolescents and adults with Anorexia Nervosa (AN), and investigate the associated clinical correlates. One hundred and forty-one participants (AN=66, HC= 75) were recruited and positive and negative film clips were used to elicit emotion expressions. The Facial Activation Coding system (FACES) was used to code emotion expression. Subjective ratings of emotion were collected. Individuals with AN displayed less positive emotions during the positive film clip compared to healthy controls (HC). There was no significant difference between the groups on the Positive and Negative Affect Scale (PANAS). The AN group displayed emotional incongruence (reporting a different emotion to what would be expected given the stimuli, with limited facial affect to signal the emotion experienced), whereby they reported feeling significantly higher rates of negative emotion during the positive clip. There were no differences in emotion expression between the groups during the negative film clip. Despite this individuals with AN reported feeling significantly higher levels of negative emotions during the negative clip. Diminished positive emotion expression was associated with more severe clinical symptoms, which could suggest that these individuals represent a group with serious social difficulties, which may require specific attention in treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Application of the Diminishing Returns Concept in the Hydroecologic Restoration of Riverscapes

    International Nuclear Information System (INIS)

    Diefenderfer, Heida L.; Johnson, Gary E.; Skalski, John R.; Breithaupt, Stephen A.; Coleman, Andre M.

    2012-01-01

    Principles for optimizing the number and placement of ecological restoration actions on rivers and coasts would be useful in project engineering design and program planning. This study demonstrated that the yield of inundated floodplain habitat area from dike breaching conforms to a diminishing returns model. The aggregate effects of establishing hydrologic connections between a tidally influenced main stem river and the floodplain were experimentally examined using a hydrodynamic model. Restoration clusters of size 1, 4, 8, and more, replicated and randomized within the landscape, yielded average wetted floodplain area conforming with an exponential rise to maximum curve2(0.99)r=. Analysis of the average incremental change in floodplain inundation produced per breach showed that opening 25 % of the channels crossing the dike provided the maximum return on investment as measured by wetted area. Midstream breaches yielded 60 % and upstream breaches 2 % of the wetted area produced by downstream breaches. Dike-breach restoration programs therefore can be optimized by strategic determination of the spatial configuration and number of demolitions, though biological factors such as the accessibility of floodplain habitat and total length of channels connected also need to be considered. These findings have implications for cost-benefit analyses in restoration program planning.

  8. Failure to demonstrate that playing violent video games diminishes prosocial behavior.

    Directory of Open Access Journals (Sweden)

    Morgan J Tear

    Full Text Available BACKGROUND: Past research has found that playing a classic prosocial video game resulted in heightened prosocial behavior when compared to a control group, whereas playing a classic violent video game had no effect. Given purported links between violent video games and poor social behavior, this result is surprising. Here our aim was to assess whether this finding may be due to the specific games used. That is, modern games are experienced differently from classic games (more immersion in virtual environments, more connection with characters, etc. and it may be that playing violent video games impacts prosocial behavior only when contemporary versions are used. METHODS AND FINDINGS: Experiments 1 and 2 explored the effects of playing contemporary violent, non-violent, and prosocial video games on prosocial behavior, as measured by the pen-drop task. We found that slight contextual changes in the delivery of the pen-drop task led to different rates of helping but that the type of game played had little effect. Experiment 3 explored this further by using classic games. Again, we found no effect. CONCLUSIONS: We failed to find evidence that playing video games affects prosocial behavior. Research on the effects of video game play is of significant public interest. It is therefore important that speculation be rigorously tested and findings replicated. Here we fail to substantiate conjecture that playing contemporary violent video games will lead to diminished prosocial behavior.

  9. Application of the Diminishing Returns Concept in the Hydroecologic Restoration of Riverscapes

    Energy Technology Data Exchange (ETDEWEB)

    Diefenderfer, Heida L.; Johnson, Gary E.; Skalski, John R.; Breithaupt, Stephen A.; Coleman, Andre M.

    2012-03-17

    Principles for optimizing the number and placement of ecological restoration actions on rivers and coasts would be useful in project engineering design and program planning. This study demonstrated that the yield of inundated floodplain habitat area from dike breaching conforms to a diminishing returns model. The aggregate effects of establishing hydrologic connections between a tidally influenced main stem river and the floodplain were experimentally examined using a hydrodynamic model. Restoration clusters of size 1, 4, 8, and more, replicated and randomized within the landscape, yielded average wetted floodplain area conforming with an exponential rise to maximum curve2(0.99)r=. Analysis of the average incremental change in floodplain inundation produced per breach showed that opening 25 % of the channels crossing the dike provided the maximum return on investment as measured by wetted area. Midstream breaches yielded 60 % and upstream breaches 2 % of the wetted area produced by downstream breaches. Dike-breach restoration programs therefore can be optimized by strategic determination of the spatial configuration and number of demolitions, though biological factors such as the accessibility of floodplain habitat and total length of channels connected also need to be considered. These findings have implications for cost-benefit analyses in restoration program planning.

  10. No Spearman’s Law of Diminishing Returns for the working memory and intelligence relationship

    Directory of Open Access Journals (Sweden)

    Kroczek Bartłomiej

    2016-04-01

    Full Text Available Spearman’s Law of Diminishing Returns (SLODR holds that correlation between general (g/fluid (Gf intelligence factor and other cognitive abilities weakens with increasing ability level. Thus, cognitive processing in low ability people is most strongly saturated by g/Gf, whereas processing in high ability people depends less on g/Gf. Numerous studies demonstrated that low g is more strongly correlated with crystallized intelligence/creativity/processing speed than is high g, however no study tested an analogous effect in the case of working memory (WM. Our aim was to investigate SLODR for the relationship between Gf and WM capacity, using a large data set from our own previous studies. We tested alternative regression models separately for three types of WM tasks that tapped short-term memory storage, attention control, and relational integration, respectively. No significant SLODR effect was found for any of these tasks. Each task shared with Gf virtually the same amount of variance in the case of low- and high-ability people. This result suggests that Gf and WM rely on one and the same (neurocognitive mechanism.

  11. Do online reviews diminish physician authority? The case of cosmetic surgery in the U.S.

    Science.gov (United States)

    Menon, Alka V

    2017-05-01

    This article analyzes the substance and perception of online physician reviews, which are qualitative and quantitative assessments of physicians written and shared by patients, in the case of U.S. cosmetic surgery. Like other cash-pay medical specialties, cosmetic surgery is elective and paid for largely out of pocket, with patients having latitude in their choice of surgeon. Drawing on qualitative data from interviews, observations of an American Society of Aesthetic Plastic Surgery professional meeting, and online reviews from the platforms RealSelf and Yelp, I identify two interdependent contributors to physician authority: reputation and expertise. I argue that surgeons see reviews overwhelmingly as a threat to their reputation, even as actual review content often positively reinforces physician expertise and enhances physician reputation. I show that most online reviews linked to interview participants are positive, according considerable deference to surgeons. Reviews add patients' embodied and consumer expertise as a circumscribed supplement to surgeons' technical expertise. Moreover, reviews change the doctor-patient relationship by putting it on display for a larger audience of prospective patients, enabling patients and review platforms to affect physician reputation. Surgeons report changing how they practice to establish and maintain their reputations. This research demonstrates how physician authority in medical consumerist contexts is a product of reputation as well as expertise. Consumerism changes the doctor-patient relationship and makes surgeons feel diminished authority by dint of their reputational vulnerability to online reviews. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Estrogen receptor diminishes DNA-binding activities of chicken GATA-1 and CACCC-binding proteins.

    Science.gov (United States)

    Holth, L T; Sun, J M; Coutts, A S; Murphy, L C; Davie, J R

    1997-12-01

    The estrogen receptor (ER) repressed erythroid differentiation and erythroid-specific gene expression. In this study, we investigated the effect of ER alpha (referred to throughout as ER) on DNA-binding activities of transcription factors involved in regulating the expression of erythroid-specific genes, and, in particular, the histone H5 gene. Using electrophoretic mobility shift assays, we found that in the presence of rabbit reticulocyte lysate, human ER reduced the binding activities of chicken immature erythrocyte nuclear extracted proteins to GATA and CACCC sites in the H5 promoter and enhancer. In contrast, the binding activities of NF1 and Sp1 were not affected by ER. Binding of ER to an estrogen response element was enhanced by addition of rabbit reticulocyte lysate. This lysate was also necessary for ER to diminish the DNA-binding activity of GATA-1. These results suggest that additional factor(s) are necessary for full ER function. Both GATA-1 and CACCC-binding proteins are critical for the developmentally regulated expression of erythroid-specific genes. We hypothesize that interference in DNA-binding activities of GATA-1 and CACCC-binding proteins is the mechanism by which the ER inhibits regulation of these genes.

  13. Failure to Demonstrate That Playing Violent Video Games Diminishes Prosocial Behavior

    Science.gov (United States)

    Tear, Morgan J.; Nielsen, Mark

    2013-01-01

    Background Past research has found that playing a classic prosocial video game resulted in heightened prosocial behavior when compared to a control group, whereas playing a classic violent video game had no effect. Given purported links between violent video games and poor social behavior, this result is surprising. Here our aim was to assess whether this finding may be due to the specific games used. That is, modern games are experienced differently from classic games (more immersion in virtual environments, more connection with characters, etc.) and it may be that playing violent video games impacts prosocial behavior only when contemporary versions are used. Methods and Findings Experiments 1 and 2 explored the effects of playing contemporary violent, non-violent, and prosocial video games on prosocial behavior, as measured by the pen-drop task. We found that slight contextual changes in the delivery of the pen-drop task led to different rates of helping but that the type of game played had little effect. Experiment 3 explored this further by using classic games. Again, we found no effect. Conclusions We failed to find evidence that playing video games affects prosocial behavior. Research on the effects of video game play is of significant public interest. It is therefore important that speculation be rigorously tested and findings replicated. Here we fail to substantiate conjecture that playing contemporary violent video games will lead to diminished prosocial behavior. PMID:23844191

  14. Increased conformity offers diminishing returns for reducing total knee replacement wear.

    Science.gov (United States)

    Fregly, Benjamin J; Marquez-Barrientos, Carlos; Banks, Scott A; DesJardins, John D

    2010-02-01

    Wear remains a significant problem limiting the lifespan of total knee replacements (TKRs). Though increased conformity between TKR components has the potential to decrease wear, the optimal amount and planes of conformity have not been investigated. Furthermore, differing conformities in the medial and lateral compartments may provide designers the opportunity to address both wear and kinematic design goals simultaneously. This study used a computational model of a Stanmore knee simulator machine and a previously validated wear model to investigate this issue for simulated gait. TKR geometries with different amounts and planes of conformity on the medial and lateral sides were created and tested in two phases. The first phase utilized a wide range of sagittal and coronal conformity combinations to blanket a physically realistic design space. The second phase performed a focused investigation of the conformity conditions from the first phase to which predicted wear volume was sensitive. For the first phase, sagittal but not coronal conformity was found to have a significant effect on predicted wear volume. For the second phase, increased sagittal conformity was found to decrease predicted wear volume in a nonlinear fashion, with reductions gradually diminishing as conformity increased. These results suggest that TKR geometric design efforts aimed at minimizing wear should focus on sagittal rather than coronal conformity and that at least moderate sagittal conformity is desirable in both compartments.

  15. Recovery of diminished mealtime-associated anticipatory behavior by aniracetam in aged rats.

    Science.gov (United States)

    Tanaka, Y; Kurasawa, M; Nakamura, K

    2000-08-01

    Disease- or age-related neuropsychiatric symptoms and cognitive and chronobiological impairments greatly aggravate the activities of daily living (ADL) in patients. The present study evaluates the effects of aniracetam on a decline in mealtime-associated anticipatory behavior in aged rats, as an animal model of temporally regulated behaviors or habitual daily activities. Aged rats showed a lower but typical nocturnal motor activity rhythm than young rats when the animals were fed ad lib. Mealtime-associated anticipatory behavior emerged in young rats when the rats were fed at a fixed time for 6 days, but the activity in aged rats was diminished. Repeated administration of aniracetam (100 mg/kg PO) or physostigmine (0.1 mg/kg SC) for 7 days ameliorated the impaired anticipatory behavior in aged rats. Nefiracetam (10 mg/kg PO) was ineffective. All compounds tested had no effect on appetite or motor ability. These results indicate that aging disturbs the timing or temporal regulation of anticipatory behavior, probably resulting from dysfunction in a food-entrainable oscillator linked to central cholinergic systems. The restoration of the time-keeping ability by aniracetam may be mediated by the facilitation of reticulothalamic cholinergic neurotransmission, and the action may lead to the improvement of declined ADL in stroke patients.

  16. Ambient groundwater flow diminishes nitrate processing in the hyporheic zone of streams

    Science.gov (United States)

    Azizian, Morvarid; Boano, Fulvio; Cook, Perran L. M.; Detwiler, Russell L.; Rippy, Megan A.; Grant, Stanley B.

    2017-05-01

    Modeling and experimental studies demonstrate that ambient groundwater reduces hyporheic exchange, but the implications of this observation for stream N-cycling is not yet clear. Here we utilize a simple process-based model (the Pumping and Streamline Segregation or PASS model) to evaluate N-cycling over two scales of hyporheic exchange (fluvial ripples and riffle-pool sequences), ten ambient groundwater and stream flow scenarios (five gaining and losing conditions and two stream discharges), and three biogeochemical settings (identified based on a principal component analysis of previously published measurements in streams throughout the United States). Model-data comparisons indicate that our model provides realistic estimates for direct denitrification of stream nitrate, but overpredicts nitrification and coupled nitrification-denitrification. Riffle-pool sequences are responsible for most of the N-processing, despite the fact that fluvial ripples generate 3-11 times more hyporheic exchange flux. Across all scenarios, hyporheic exchange flux and the Damköhler Number emerge as primary controls on stream N-cycling; the former regulates trafficking of nutrients and oxygen across the sediment-water interface, while the latter quantifies the relative rates of organic carbon mineralization and advective transport in streambed sediments. Vertical groundwater flux modulates both of these master variables in ways that tend to diminish stream N-cycling. Thus, anthropogenic perturbations of ambient groundwater flows (e.g., by urbanization, agricultural activities, groundwater mining, and/or climate change) may compromise some of the key ecosystem services provided by streams.

  17. Inhibition of the Pim1 oncogene results in diminished visual function.

    Directory of Open Access Journals (Sweden)

    Jun Yin

    Full Text Available Our objective was to profile genetic pathways whose differential expression correlates with maturation of visual function in zebrafish. Bioinformatic analysis of transcriptomic data revealed Jak-Stat signalling as the pathway most enriched in the eye, as visual function develops. Real-time PCR, western blotting, immunohistochemistry and in situ hybridization data confirm that multiple Jak-Stat pathway genes are up-regulated in the zebrafish eye between 3-5 days post-fertilisation, times associated with significant maturation of vision. One of the most up-regulated Jak-Stat genes is the proto-oncogene Pim1 kinase, previously associated with haematological malignancies and cancer. Loss of function experiments using Pim1 morpholinos or Pim1 inhibitors result in significant diminishment of visual behaviour and function. In summary, we have identified that enhanced expression of Jak-Stat pathway genes correlates with maturation of visual function and that the Pim1 oncogene is required for normal visual function.

  18. The relative effectiveness of extinction and counter-conditioning in diminishing children's fear.

    Science.gov (United States)

    Newall, Carol; Watson, Tiffany; Grant, Kerry-Ann; Richardson, Rick

    2017-08-01

    Two behavioural strategies for reducing learned fear are extinction and counter-conditioning, and in this study we compared the relative effectiveness of the two procedures at diminishing fear in children. Seventy-three children aged 7-12 years old (M = 9.30, SD = 1.62) were exposed to pictures of two novel animals on a computer screen during the fear acquisition phase. One of these animals was paired with a picture of a scared human face (CS+) while the other was not (CS-). The children were then randomly assigned to one of three conditions: counter-conditioning (animal paired with a happy face), extinction (animal without scared face), or control (no fear reduction procedure). Changes in fear beliefs and behavioural avoidance of the animal were measured. Counter-conditioning was more effective at reducing fear to the CS + than extinction. The findings are discussed in terms of implications for behavioural treatments of childhood anxiety disorders. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  19. Diminished osmotic fragility of mouse erythrocytes following intravenous injection of polymeric plutonium

    International Nuclear Information System (INIS)

    Joshima, Hisamasa; Kashima, Masatoshi; Matsuoka, Osamu

    1984-01-01

    Changes in the osmotic fragility and the mean corpuscular diameter of erythrocytes in CFNo.1/Nrs male mice caused by internal irradiation with polymeric 239 Pu at the dose levels of 15 μCi/kg, 10 μCi/kg and 5 μCi/kg were studied at 28 and 56 days after intravenous injection of plutonium. At 56 days after injection of plutonium, osmotic fragility curves were found to shift toward lower NaCl concentration in proportion to the amount of plutonium injected, which indicated the reduction of osmotic fragility. The size distribution curves of erythrocytes were slightly shifted toward larger size, depending on the amount of plutonium injected. Mean corpuscular diameter of erythrocytes in the highest dose group was significantly larger than that of control group. Mean corpuscular thickness of erythrocytes in plutonium injected groups was not different from that of control group. The increase in the mean corpuscular diameter-to-thickness ratio might allow the erythrocyte to accumulate a larger volume of water in a hypotonic environment before reaching the critical hemolytic volume. In the present study, it was concluded that the increased diameter-to-thickness ratio of erythrocytes could be related to the diminished osmotic fragility of erythrocytes in animals given polymeric plutonium. (author)

  20. Confronting diminished epistemic privilege and epistemic injustice in pregnancy by challenging a "panoptics of the womb".

    Science.gov (United States)

    Freeman, Lauren

    2015-02-01

    This paper demonstrates how the problematic kinds of epistemic power that physicians have can diminish the epistemic privilege that pregnant women have over their bodies and can put them in a state of epistemic powerlessness. This result, I argue, constitutes an epistemic injustice for many pregnant women. A reconsideration of how we understand and care for pregnant women and of the physician-patient relationship can provide us with a valuable context and starting point for helping to alleviate the knowledge/power problems that are symptomatic of the current system and structure of medicine. I suggest that we can begin to confront this kind of injustice if medicine adopts a more phenomenological understanding of bodies and if physicians and patients--in this case, pregnant women--become what I call "epistemic peers." © The Author 2014. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. Metabolic Evidence of Diminished Lipid Oxidation in Women With Polycystic Ovary Syndrome

    Science.gov (United States)

    Whigham, Leah D.; Butz, Daniel E.; Dashti, Hesam; Tonelli, Marco; Johnson, LuAnn K.; Cook, Mark E.; Porter, Warren P.; Eghbalnia, Hamid R.; Markley, John L.; Lindheim, Steven R.; Schoeller, Dale A.; Abbott, David H.; Assadi-Porter, Fariba M.

    2014-01-01

    Polycystic ovary syndrome (PCOS), a common female endocrinopathy, is a complex metabolic syndrome of enhanced weight gain. The goal of this pilot study was to evaluate metabolic differences between normal (n=10) and PCOS (n=10) women via breath carbon isotope ratio, urinary nitrogen and nuclear magnetic resonance (NMR)-determined serum metabolites. Breath carbon stable isotopes measured by cavity ring down spectroscopy (CRDS) indicated diminished (p<0.030) lipid use as a metabolic substrate during overnight fasting in PCOS compared to normal women. Accompanying urinary analyses showed a trending correlation (p<0.057) between overnight total nitrogen and circulating testosterone in PCOS women, alone. Serum analyzed by NMR spectroscopy following overnight, fast and at 2 h following an oral glucose tolerance test showed that a transient elevation in blood glucose levels decreased circulating levels of lipid, glucose and amino acid metabolic intermediates (acetone, 2-oxocaporate, 2-aminobutyrate, pyruvate, formate, and sarcosine) in PCOS women, whereas the 2 h glucose challenge led to increases in the same intermediates in normal women. These pilot data suggest that PCOS-related inflexibility in fasting-related switching between lipid and carbohydrate/protein utilization for carbon metabolism may contribute to enhanced weight gain. PMID:24765590

  2. The addition of body armor diminishes dynamic postural stability in military soldiers.

    Science.gov (United States)

    Sell, Timothy C; Pederson, Jonathan J; Abt, John P; Nagai, Takashi; Deluzio, Jennifer; Wirt, Michael D; McCord, Larry J; Lephart, Scott M

    2013-01-01

    Poor postural stability has been identified as a risk factor for lower extremity musculoskeletal injury. The additional weight of body armor carried by Soldiers alters static postural stability and may predispose Soldiers to lower extremity musculoskeletal injuries. However, static postural stability tasks poorly replicate the dynamic military environment, which places considerable stress on the postural control system during tactical training and combat. Therefore, the purpose of this study was to examine the effects of body armor on dynamic postural stability during single-leg jump landings. Thirty-six 101st Airborne Division (Air Assault) Soldiers performed single-leg jump landings in the anterior direction with and without wearing body armor. The dynamic postural stability index and the individual stability indices (medial-lateral stability index, anterior-posterior stability index, and vertical stability index) were calculated for each condition. Paired sample t-tests were performed to determine differences between conditions. Significant differences existed for the medial-lateral stability index, anterior-posterior stability index, vertical stability index, and dynamic postural stability index (p armor resulted in diminished dynamic postural stability, which may result in increased lower extremity injuries. Training programs should address the altered dynamic postural stability while wearing body armor in attempts to promote adaptations that will result in safer performance during dynamic tasks.

  3. Diminished neural responses predict enhanced intrinsic motivation and sensitivity to external incentive.

    Science.gov (United States)

    Marsden, Karen E; Ma, Wei Ji; Deci, Edward L; Ryan, Richard M; Chiu, Pearl H

    2015-06-01

    The duration and quality of human performance depend on both intrinsic motivation and external incentives. However, little is known about the neuroscientific basis of this interplay between internal and external motivators. Here, we used functional magnetic resonance imaging to examine the neural substrates of intrinsic motivation, operationalized as the free-choice time spent on a task when this was not required, and tested the neural and behavioral effects of external reward on intrinsic motivation. We found that increased duration of free-choice time was predicted by generally diminished neural responses in regions associated with cognitive and affective regulation. By comparison, the possibility of additional reward improved task accuracy, and specifically increased neural and behavioral responses following errors. Those individuals with the smallest neural responses associated with intrinsic motivation exhibited the greatest error-related neural enhancement under the external contingency of possible reward. Together, these data suggest that human performance is guided by a "tonic" and "phasic" relationship between the neural substrates of intrinsic motivation (tonic) and the impact of external incentives (phasic).

  4. A change will do us good: threats diminish typical preferences for male leaders.

    Science.gov (United States)

    Brown, Elizabeth R; Diekman, Amanda B; Schneider, Monica C

    2011-07-01

    The current research explores role congruity processes from a new vantage point by investigating how the need for change might shift gender-based leadership preferences. According to role congruity theory, favorability toward leaders results from alignment between what is desired in a leadership role and the characteristics stereotypically ascribed to the leader. Generally speaking, these processes lead to baseline preferences for male over female leaders. In this research, the authors propose that a shift in gender-based leadership preferences will emerge under conditions of threat. Because the psychological experience of threat signals a need for change, individuals will favor candidates who represent new directions in leadership rather than consistency with past directions in leadership. Specifically, they find that threat evokes an implicit preference for change over stability (Experiment 1) and gender stereotypes align women with change but men with stability (Experiments 2a and 2b). Consequently, the typical preference for male leaders is diminished, or even reversed, under threat (Experiments 3 and 4). Moreover, the shift away from typical gender-based leadership preferences occurs especially among individuals who highly legitimize the sociopolitical system (Experiment 4), suggesting that these preference shifts might serve to protect the underlying system. © 2011 by the Society for Personality and Social Psychology, Inc

  5. Diminished epinephrine response to hypoglycemia despite enlarged adrenal medulla in trained rats

    DEFF Research Database (Denmark)

    Stallknecht, B; Kjaer, M; Mikines, K J

    1990-01-01

    Studies in humans have indicated that trained athletes compared with sedentary subjects have an increased capacity to secrete epinephrine. To investigate whether this is due to an adaptation induced by physical training or a selection phenomenon, rats were swim trained (T) 10 wk for 6 h/day or se...... nervous system to reduced blood glucose levels induced by repeated exercise bouts, the epinephrine response to insulin-induced hypoglycemia is markedly diminished after training.......)]. Cold stress or sham swim training did not increase adrenal weight or volume of adrenal medulla (P greater than 0.05). To stimulate adrenal medulla secretion, rats had an insulin-induced hypoglycemia. Insulin dose needed to suppress plasma glucose below 4.0 mM was four times greater in sedentary...... compared with trained rats. During hypoglycemia the epinephrine response was much smaller in trained than in untrained rats (P less than 0.05). In conclusion, in rats strenuous endurance training causes an enlargement of the adrenal medulla. However, possibly reflecting an adaptation within the central...

  6. Diminished whole-brain but enhanced peri-sylvian connectivity in absolute pitch musicians.

    Science.gov (United States)

    Jäncke, Lutz; Langer, Nicolas; Hänggi, Jürgen

    2012-06-01

    Several anatomical studies have identified specific anatomical features within the peri-sylvian brain system of absolute pitch (AP) musicians. In this study we used graph theoretical analysis of cortical thickness covariations (as indirect indicator of connectivity) to examine whether AP musicians differ from relative pitch musicians and nonmusicians in small-world network characteristics. We measured "local connectedness" (local clustering = γ), "global efficiency of information transfer" (path length = λ), "small-worldness" (σ = γ/λ), and "degree" centrality as measures of connectivity. Although all groups demonstrated typical small-world features, AP musicians showed significant small-world alterations. "Degree" as a measure of interconnectedness was globally significantly decreased in AP musicians. These differences let us suggest that AP musicians demonstrate diminished neural integration (less connections) among distant brain regions. In addition, AP musicians demonstrated significantly increased local connectivity in peri-sylvian language areas of which the planum temporale, planum polare, Heschl's gyrus, lateral aspect of the superior temporal gyrus, STS, pars triangularis, and pars opercularis were hub regions. All of these brain areas are known to be involved in higher-order auditory processing, working or semantic memory processes. Taken together, whereas AP musicians demonstrate decreased global interconnectedness, the local connectedness in peri-sylvian brain areas is significantly higher than for relative pitch musicians and nonmusicians.

  7. Akt1 deficiency diminishes skeletal muscle hypertrophy by reducing satellite cell proliferation.

    Science.gov (United States)

    Moriya, Nobuki; Miyazaki, Mitsunori

    2018-02-14

    Skeletal muscle mass is determined by the net dynamic balance between protein synthesis and degradation. Although the Akt/mechanistic target of rapamycin (mTOR)-dependent pathway plays an important role in promoting protein synthesis and subsequent skeletal muscle hypertrophy, the precise molecular regulation of mTOR activity by the upstream protein kinase Akt is largely unknown. In addition, the activation of satellite cells has been indicated as a key regulator of muscle mass. However, the requirement of satellite cells for load-induced skeletal muscle hypertrophy is still under intense debate. In this study, female germline Akt1 knockout (KO) mice were used to examine whether Akt1 deficiency attenuates load-induced skeletal muscle hypertrophy through suppressing mTOR-dependent signaling and satellite cell proliferation. Akt1 KO mice showed a blunted hypertrophic response of skeletal muscle, with a diminished rate of satellite cell proliferation following mechanical overload. In contrast, Akt1 deficiency did not affect the load-induced activation of mTOR signaling and the subsequent enhanced rate of protein synthesis in skeletal muscle. These observations suggest that the load-induced activation of mTOR signaling occurs independently of Akt1 regulation and that Akt1 plays a critical role in regulating satellite cell proliferation during load-induced muscle hypertrophy.

  8. Marriage of scintillator and semiconductor for synchronous radiotherapy and deep photodynamic therapy with diminished oxygen dependence.

    Science.gov (United States)

    Zhang, Chen; Zhao, Kuaile; Bu, Wenbo; Ni, Dalong; Liu, Yanyan; Feng, Jingwei; Shi, Jianlin

    2015-02-02

    Strong oxygen dependence and limited penetration depth are the two major challenges facing the clinical application of photodynamic therapy (PDT). In contrast, ionizing radiation is too penetrative and often leads to inefficient radiotherapy (RT) in the clinic because of the lack of effective energy accumulation in the tumor region. Inspired by the complementary advantages of PDT and RT, we present herein the integration of a scintillator and a semiconductor as an ionizing-radiation-induced PDT agent, achieving synchronous radiotherapy and depth-insensitive PDT with diminished oxygen dependence. In the core-shell Ce(III)-doped LiYF4@SiO2@ZnO structure, the downconverted ultraviolet fluorescence from the Ce(III)-doped LiYF4 nanoscintillator under ionizing irradiation enables the generation of electron-hole (e(-)-h(+)) pairs in ZnO nanoparticles, giving rise to the formation of biotoxic hydroxyl radicals. This process is analogous to a type I PDT process for enhanced antitumor therapeutic efficacy. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Failure to demonstrate that playing violent video games diminishes prosocial behavior.

    Science.gov (United States)

    Tear, Morgan J; Nielsen, Mark

    2013-01-01

    Past research has found that playing a classic prosocial video game resulted in heightened prosocial behavior when compared to a control group, whereas playing a classic violent video game had no effect. Given purported links between violent video games and poor social behavior, this result is surprising. Here our aim was to assess whether this finding may be due to the specific games used. That is, modern games are experienced differently from classic games (more immersion in virtual environments, more connection with characters, etc.) and it may be that playing violent video games impacts prosocial behavior only when contemporary versions are used. Experiments 1 and 2 explored the effects of playing contemporary violent, non-violent, and prosocial video games on prosocial behavior, as measured by the pen-drop task. We found that slight contextual changes in the delivery of the pen-drop task led to different rates of helping but that the type of game played had little effect. Experiment 3 explored this further by using classic games. Again, we found no effect. We failed to find evidence that playing video games affects prosocial behavior. Research on the effects of video game play is of significant public interest. It is therefore important that speculation be rigorously tested and findings replicated. Here we fail to substantiate conjecture that playing contemporary violent video games will lead to diminished prosocial behavior.

  10. Reducing the Polluting Emissions. A Source for Diminishing the Climate Changes

    Directory of Open Access Journals (Sweden)

    Emilian M. DOBRESCU

    2009-06-01

    Full Text Available The USA and the Western Europe are responsible for 2/3 of the CO2 emissions accumulated until today. On the other hand, Africa has produced only 3% of polluting emission since 1900 until today, by burning mineral fuels. Since 1992, the most industrialized countries have promised to help ôthe most vulnerable nations face the adverse consequences of climate changesö by supporting the costs of adaptation. The commitment was included in the convention frame that gave birth to the Kyoto Treaty, which was rejected by the George W. Bush Administration, even though the initial document, issued in 1992, had been signed by George Bush. The industrialized countries that signed the Kyoto Treaty have decided to create a special fund for ôclimate adaptationö. Hundreds of millions of dollars had to be used in order to diminish the impact of the global warming in the most exposed areas.Lately, maybe because the CO2 emissions increase due to human activities, the planet climate has changed for worse. 2007 was a key year in evaluating the reply the planet would give to the global overheating, mainly caused by the green-house effect and worsen by El Nino oceanic stream. This superposition of climate factors made 2007 to be one of the warmest years ever registered.

  11. A diminished aortic-cardiac reflex during hypotension in aerobically fit young men

    Science.gov (United States)

    Shi, X.; Crandall, C. G.; Potts, J. T.; Williamson, J. W.; Foresman, B. H.; Raven, P. B.

    1993-01-01

    We compared the aortic-cardiac baroreflex sensitivity in eight average fit (AF: VO2max = 44.7 +/- 1.3 ml.kg-1 x min-1) and seven high fit (HF: VO2max = 64.1 +/- 1.7 ml.min-1 x kg-1) healthy young men during hypotension elicited by steady state sodium nitroprusside (SN) infusion. During SN mean arterial pressure (MAP) was similarly decreased in AF (-12.6 +/- 1.0 mm Hg) and HF (-12.1 +/- 1.1 mm Hg). However, the increases in heart rate (HR) were less (P 0.05) was applied to counteract the decreased carotid sinus transmural pressure during SN, thereby isolating the aortic baroreceptors, the increased HR remained less (P baroreflex sensitivity (i.e., the gain difference between the stage SN and SN + NS) was not different between AF (0.7 +/- 0.2 bpm.mm Hg-1) and HF (0.6 +/- 0.1 bpm.mm Hg-1). These data indicated that the aortic-cardiac baroreflex sensitivity during hypotension was significantly diminished with endurance exercise training.

  12. A legal-ethical analysis of reproductive endocrinologists' right to refuse ovulation induction to patients with diminished ovarian reserve.

    Science.gov (United States)

    Karipcin, Fethiye Sinem; Hossain, Amjad; Phelps, John Y

    2011-11-01

    Review of the legal and ethical basis for reproductive endocrinologists to refuse ovulation induction to patients with diminished ovarian reserve. The Lexis-Nexis search engine was used to perform a legal review pertaining to refusal of treatment. Ethical opinions of medical organizations were also reviewed. Federal antidiscrimination laws provide legal recourse for patients with diminished ovarian reserve who are denied ovulation induction. However, the same laws also permit refusal of care when there is bona fide medical justification to decline services. In addition, the codes of ethics for relevant professional organizations support physicians' decisions to refuse treatment when treatment is futile. Although it is ethically and legally permissible to deny ovulation induction to patients with diminished ovarian reserve when medically justified, refusal may invite retaliatory litigation. Counseling remains a cornerstone in directing these patients to options with more potential for success, such as donor eggs and adoption.

  13. Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Payton-Stewart, Florastina [Department of Chemistry, College of Arts and Sciences, Xavier University of Louisiana, New Orleans, LA (United States); Tilghman, Syreeta L. [Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA (United States); Williams, LaKeisha G. [Division of Clinical and Administrative Sciences, College of Pharmacy Xavier University of Louisiana, New Orleans, LA (United States); Winfield, Leyte L., E-mail: lwinfield@spelman.edu [Department of Chemistry, Spelman College, Atlanta, GA (United States)

    2014-08-08

    Highlights: • The methyl-substituted benzimidazole was more effective at inhibiting growth in MDA-MB 231 cells. • The naphthyl-substituted benzimidazole was more effective at inhibiting growth in MCF-7 cells than ICI. • The benzimidazole molecules demonstrated a dose-dependent reduction in ERE transcriptional activity. • The benzimidazole molecules had binding mode in ERα and ERβ comparable to that of the co-crystallized ligand. - Abstract: Estrogen receptors (ERα and ERβ) are members of the nuclear receptor superfamily. They regulate the transcription of estrogen-responsive genes and mediate numerous estrogen related diseases (i.e., fertility, osteoporosis, cancer, etc.). As such, ERs are potentially useful targets for developing therapies and diagnostic tools for hormonally responsive human breast cancers. In this work, two benzimidazole-based sulfonamides originally designed to reduce proliferation in prostate cancer, have been evaluated for their ability to modulate growth in estrogen dependent and independent cell lines (MCF-7 and MDA-MB 231) using cell viability assays. The molecules reduced growth in MCF-7 cells, but differed in their impact on the growth of MDA-MB 231 cells. Although both molecules reduced estrogen response element (ERE) transcriptional activity in a dose dependent manner, the contrasting activity in the MDA-MB-231 cells seems to suggest that the molecules may act through alternate ER-mediated pathways. Further, the methyl analog showed modest selectivity for the ERβ receptor in an ER gene expression array panel, while the naphthyl analog did not significantly alter gene expression. The molecules were docked in the ligand binding domains of the ERα-antagonist and ERβ-agonist crystal structures to evaluate the potential of the molecules to interact with the receptors. The computational analysis complimented the results obtained in the assay of transcriptional activity and gene expression suggesting that the molecules

  14. The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex.

    Science.gov (United States)

    Ogbonmwan, Yvonne E; Sciolino, Natale R; Groves-Chapman, Jessica L; Freeman, Kimberly G; Schroeder, Jason P; Edwards, Gaylen L; Holmes, Philip V; Weinshenker, David

    2015-07-01

    Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex. © 2014 Society for the Study of Addiction.

  15. Structure-activity relationships for the irreversible blockade of nicotinic receptor agonist sites by lophotoxin and congeneric diterpene lactones

    Energy Technology Data Exchange (ETDEWEB)

    Culver, P.; Burch, M.; Potenza, C.; Wasserman, L.; Fenical, W.; Taylor, P.

    1985-11-01

    Lophotoxin, a diterpene lactone paralytic toxin from gorgonian corals of the genus Lophogorgia, inhibits ( SVI)-alpha-toxin binding to surface nicotinic receptors of BC3H-1 cells by irreversible occupation of the primary agonist sites. In contrast, receptor-bearing membrane fragments or detergent-solubilized receptors prepared from BC3H-1 cells are not susceptible to lophotoxin block. Thus, lophotoxin inhibition requires intact cells. However, when intact cells were incubated with lophotoxin, subsequent membrane-fragment preparation or detergent solubilization of the receptors did not diminish lophotoxin occupation of ( SVI)-alpha-toxin-binding sites, indicating that lophotoxin binds very tightly to nicotinic receptors. These studies further demonstrate that both surface and nonsurface nicotinic receptors of BC3H-1 cells are susceptible to irreversible occupation by lophotoxin, indicating that the lipophilic toxin freely permeates intact cells. The authors also examined several structural analogs of lophotoxin, one of which was equipotent with lophotoxin for inhibition of ( SVI)-alpha-toxin binding to intact cells and, notably, also blocked alpha-toxin binding to detergent-extracted receptor.

  16. Long-acting beta(2)-agonists in management of childhood asthma

    DEFF Research Database (Denmark)

    Bisgaard, H

    2000-01-01

    This review assesses the evidence regarding the use of long-acting beta(2)-agonists in the management of pediatric asthma. Thirty double-blind, randomized, controlled trials on the effects of formoterol and salmeterol on lung function in asthmatic children were identified. Single doses of inhaled......, long-acting beta(2)-agonists provide effective bronchodilatation and bronchoprotection when used as intermittent, single-dose treatment of asthma in children, but not when used as regular treatment. Future studies should examine the positioning of long-acting beta(2)-agonists as an "as needed" rescue...... medication instead of short-acting beta(2)-agonists for pediatric asthma management....

  17. Agonist signalling properties of radiotracers used for imaging of dopamine D2/3 receptors.

    Science.gov (United States)

    van Wieringen, Jan-Peter; Michel, Martin C; Janssen, Henk M; Janssen, Anton G; Elsinga, Philip H; Booij, Jan

    2014-01-01

    Dopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists are more sensitive to detect dopamine release than antagonist radiopharmaceuticals, but this theory has been challenged. Interestingly, not all agonists similarly activate the classic cyclic adenosine mono phosphate (cAMP) and the ?-arrestin-2 pathway, some stimulate preferentially one of these pathways; a phenomenon called biased agonism. Because these pathways can be affected separately by pathologies or drugs (including dopamine releasers), it is important to know how agonist radiotracers act on these pathways. Therefore, we characterized the intracellular signalling of the well-known D2/3R agonist radiopharmaceuticals NPA and PHNO and of several novel D2/3R agonists. cAMP accumulation and ?-arrestin-2 recruitment were measured on cells expressing human D2R. All tested agonists showed (almost) full agonism in both pathways. The tested D2/3R agonist radiopharmaceuticals did not exhibit biased agonism in vitro. Consequently, it is likely that drugs (including psychostimulants like amphetamines) and/or pathologies that influence the cAMP and/or the ?-arrestin-2 pathway may influence the binding of these radiopharmaceuticals.

  18. Agonists and inverse agonists for the herpesvirus 8-encoded constitutively active seven-transmembrane oncogene product, ORF-74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Bräuner-Osborne, Hans

    1999-01-01

    A number of CXC chemokines competed with similar, nanomolar affinity against 125I-interleukin-8 (IL-8) binding to ORF-74, a constitutively active seven-transmembrane receptor encoded by human herpesvirus 8. However, in competition against 125I-labeled growth-related oncogene (GRO)-alpha, the ORF-74...... receptor was highly selective for GRO peptides, with IL-8 being 10,000-fold less potent. The constitutive stimulating activity of ORF-74 on phosphatidylinositol turnover was not influenced by, for example, IL-8 binding. In contrast, GRO peptides acted as potent agonists in stimulating ORF-74 signaling...

  19. How does agonistic behaviour differ in albino and pigmented fish?

    Science.gov (United States)

    Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics. PMID:27114883

  20. AMP is an adenosine A1 receptor agonist.

    Science.gov (United States)

    Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J

    2012-02-17

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

  1. Mood Disorders, Circadian Rhythms, Melatonin and Melatonin Agonists

    Directory of Open Access Journals (Sweden)

    M.A. Quera Salva

    2012-04-01

    Full Text Available Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC. Melatonin (N-acetyl-5-hydroxytryptamine is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse.

  2. GLP-1 receptor agonist-induced polyarthritis: a case report.

    Science.gov (United States)

    Ambrosio, Maria Luisa; Monami, Matteo; Sati, Lavinia; Marchionni, Niccolò; Di Bari, Mauro; Mannucci, Edoardo

    2014-08-01

    Occasional cases of bilateral, symmetrical, seronegative polyarthritis have been reported in patients treated with dipeptidyl peptidase-4 inhibitors (Crickx et al. in Rheumatol Int, 2013). We report here a similar case observed during treatment with a GLP-1 receptor agonist. A 42-year-old man with type 2 diabetes treated with metformin 1,500 mg/day and liraglutide 1.8 mg/day. After 6 months from the beginning of treatment, the patient complained of bilateral arthralgia (hands, feet, ankles, knees, and hips). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and leukocytes were increased. Rheumatoid factor, anticyclic citrullinated protein antibody, antinuclear antibodies, anti-Borrelia, and burgdorferi antibodies were all negative, and myoglobin and calcitonin were normal. Liraglutide was withdrawn, and the symptoms completely disappeared within 1 week, with normalization of ESR, CRP, fibrinogen, and leukocytes. Previously described cases of polyarthritis associated with DPP4 inhibitors had been attributed to a direct effect of the drugs on inflammatory cells expressing the enzyme. The present case, occurred during treatment with a GLP-1 receptor agonists, suggests a possibly different mechanism, mediated by GLP-1 receptor stimulation, which deserved further investigation.

  3. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    Science.gov (United States)

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

  4. Cold suppresses agonist-induced activation of TRPV1.

    Science.gov (United States)

    Chung, M-K; Wang, S

    2011-09-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

  5. Toll-Like Receptor 9 Agonists for Cancer Therapy

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    Davide Melisi

    2014-08-01

    Full Text Available The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

  6. Toll-Like Receptor 9 Agonists for Cancer Therapy.

    Science.gov (United States)

    Melisi, Davide; Frizziero, Melissa; Tamburrino, Anna; Zanotto, Marco; Carbone, Carmine; Piro, Geny; Tortora, Giampaolo

    2014-08-04

    The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs) have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC) and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs) have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

  7. Cannabidiol, a novel inverse agonist for GPR12.

    Science.gov (United States)

    Brown, Kevin J; Laun, Alyssa S; Song, Zhao-Hui

    2017-11-04

    GPR12 is a constitutively active, G s protein-coupled receptor that currently has no confirmed endogenous ligands. GPR12 may be involved in physiological processes such as maintenance of oocyte meiotic arrest and brain development, as well as pathological conditions such as metastatic cancer. In this study, the potential effects of various classes of cannabinoids on GPR12 were tested using a cAMP accumulation assay. Our data demonstrate that cannabidiol (CBD), a major non-psychoactive phytocannabinoid, acted as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR12. Thus, GPR12 is a novel molecular target for CBD. The structure-activity relationship studies of CBD indicate that both the free hydroxyl and the pentyl side chain are crucial for the effects of CBD on GPR12. Furthermore, studies using cholera toxin, which blocks G s protein and pertussis toxin, which blocks G i protein, revealed that G s , but not G i is involved in the inverse agonism of CBD on GPR12. CBD is a promising novel therapeutic agent for cancer, and GPR12 has been shown to alter viscoelasticity of metastatic cancer cells. Since we have demonstrated that CBD is an inverse agonist for GPR12, this provides novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. How does agonistic behaviour differ in albino and pigmented fish?

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    Ondřej Slavík

    2016-04-01

    Full Text Available In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics.

  9. NKT-cell glycolipid agonist as adjuvant in synthetic vaccine.

    Science.gov (United States)

    Liu, Zheng; Guo, Jun

    2017-11-27

    NKT cells are CD1d-restricted, glycolipid antigen-reactive, immunoregulatory T lymphocytes that can serve as a bridge between the innate and adaptive immunities. NKT cells have a wide range of therapeutic application in autoimmunity, transplant biology, infectious disease, cancer, and vaccinology. Rather than triggering "danger signal" and eliciting an innate immune response, αGalCer-based NKT-cell agonist act via a unique mechanism, recruiting NKT cells which play a T helper-like role even without peptide as Th epitope. Importantly, the non-polymorphism of CD1d render glycolipid a universal helper epitope, offering the potential to simplify the vaccine construct capable of eliciting consistent immune response in different individuals. This review details recent advances in the design of synthetic vaccines using NKT-cell agonist as adjuvant, highlighting the role of organic synthesis and conjugation technique to enhance the immunological actives and to simplify the vaccine constructs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets

    International Nuclear Information System (INIS)

    Schaechter, M.; Godfrey, P.P.; Minchin, M.C.W.; McClue, S.J.; Young, M.M.

    1985-01-01

    The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with [ 3 H]-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT 2 antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT 2 type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors. 30 references, 4 figures

  11. Diminished Alternative Reinforcement as a Mechanism Underlying Socioeconomic Disparities in Adolescent Substance Use

    Science.gov (United States)

    Leventhal, Adam M.; Bello, Mariel S.; Unger, Jennifer B.; Strong, David R.; Kirkpatrick, Matthew G.; Audrain-McGovern, Janet

    2015-01-01

    OBJECTIVE This study examined socioeconomic disparities in adolescent substance use utilizing a behavioral economic theoretical framework. We tested the hypothesis that teens of lower (vs. higher) socioeconomic status (SES) are vulnerable to substance use because they engage in fewer pleasurable substance-free activities that provide reinforcement and may deter substance use. METHOD In a cross-sectional correlational design, 9th grade students (N=2,839; mean age=14.1 years) in Los Angeles, California, USA completed surveys in Fall 2013 measuring SES (i.e., parental education), alternative reinforcement (engagement in pleasurable substance-free activities, e.g., hobbies), substance use susceptibility, initiation, and frequency, and other factors. RESULTS For multi-substance composite outcomes, lower parental education was associated with greater likelihood of substance use initiation in the overall sample, frequency of use among lifetime substance users, and susceptibility to substance use in never users. Substance-specific analyses revealed that lower parental education was associated with higher likelihood of initiating cigarettes, alcohol, and marijuana use as well as greater susceptibility to use cigarettes in never smokers. Each inverse association between parental education and substance-related outcomes was statistically mediated by diminished alternative reinforcement; lower parental education was associated with lower engagement in alternative reinforcers, which, in turn, was associated with greater substance use susceptibility, initiation, and frequency. CONCLUSION These results point to a behavioral economic interpretation for socioeconomic disparities in adolescent substance use. Replication and extension of these findings would suggest that prevention programs that increase access to and engagement in healthy and fun activities may reduce youth socioeconomic health disparities related to substance use. PMID:26051200

  12. Food image-induced brain activation is not diminished by insulin infusion.

    Science.gov (United States)

    Belfort-DeAguiar, R; Seo, D; Naik, S; Hwang, J; Lacadie, C; Schmidt, C; Constable, R T; Sinha, R; Sherwin, R

    2016-11-01

    The obesity epidemic appears to be driven in large part by our modern environment inundated by food cues, which may influence our desire to eat. Although insulin decreases food intake in both animals and humans, the effect of insulin on motivation for food in the presence of food cues is not known. Therefore, the aim of this study was to evaluate the effect of an intravenous insulin infusion on the brain response to visual food cues, hunger and food craving in non-obese human subjects. Thirty-four right-handed healthy non-obese subjects (19F/15M, age: 29±8 years.; BMI: 23.1±2.1 kg m -2 ) were divided in two groups matched by age and BMI; the insulin group (18 subjects) underwent a hyperinsulinemic-euglycemic-clamp, and the control group (16 subjects) received an intravenous saline infusion, while viewing high and low-calorie food and non-food pictures during a functional MRI scan. Motivation for food was determined via analog scales for hunger, wanting and liking ratings. Food images induced brain responses in the hypothalamus, striatum, amygdala, insula, ventromedial prefrontal cortex (PFC), dorsolateral PFC and occipital lobe (whole brain correction, Pinsulin and saline infusion groups. Hunger ratings increased throughout the MRI scan and correlated with preference for high-calorie food pictures (r=0.70; Pbrain activity nor food cravings were affected by hyperinsulinemia or hormonal status (leptin and ghrelin levels) (P=NS). Our data demonstrate that visual food cues induce a strong response in motivation/reward and cognitive-executive control brain regions in non-obese subjects, but that these responses are not diminished by hyperinsulinemia per se. These findings suggest that our modern food cue saturated environment may be sufficient to overpower homeostatic hormonal signals, and thus contribute to the current obesity epidemic.

  13. Mycobacterium tuberculosis has diminished capacity to counteract redox stress induced by elevated levels of endogenous superoxide.

    Science.gov (United States)

    Tyagi, Priyanka; Dharmaraja, Allimuthu T; Bhaskar, Ashima; Chakrapani, Harinath; Singh, Amit

    2015-07-01

    Mycobacterium tuberculosis (Mtb) has evolved protective and detoxification mechanisms to maintain cytoplasmic redox balance in response to exogenous oxidative stress encountered inside host phagocytes. In contrast, little is known about the dynamic response of this pathogen to endogenous oxidative stress generated within Mtb. Using a noninvasive and specific biosensor of cytoplasmic redox state of Mtb, we for first time discovered a surprisingly high sensitivity of this pathogen to perturbation in redox homeostasis induced by elevated endogenous reactive oxygen species (ROS). We synthesized a series of hydroquinone-based small molecule ROS generators and found that ATD-3169 permeated mycobacteria to reliably enhance endogenous ROS including superoxide radicals. When Mtb strains including multidrug-resistant (MDR) and extensively drug-resistant (XDR) patient isolates were exposed to this compound, a dose-dependent, long-lasting, and irreversible oxidative shift in intramycobacterial redox potential was detected. Dynamic redox potential measurements revealed that Mtb had diminished capacity to restore cytoplasmic redox balance in comparison with Mycobacterium smegmatis (Msm), a fast growing nonpathogenic mycobacterial species. Accordingly, Mtb strains were extremely susceptible to inhibition by ATD-3169 but not Msm, suggesting a functional linkage between dynamic redox changes and survival. Microarray analysis showed major realignment of pathways involved in redox homeostasis, central metabolism, DNA repair, and cell wall lipid biosynthesis in response to ATD-3169, all consistent with enhanced endogenous ROS contributing to lethality induced by this compound. This work provides empirical evidence that the cytoplasmic redox poise of Mtb is uniquely sensitive to manipulation in steady-state endogenous ROS levels, thus revealing the importance of targeting intramycobacterial redox metabolism for controlling TB infection. Copyright © 2015 The Authors. Published by

  14. Exposure to Porphyromonas gingivalis LPS during macrophage polarisation leads to diminished inflammatory cytokine production.

    Science.gov (United States)

    Belfield, Louise A; Bennett, Jon H; Abate, Wondwossen; Jackson, Simon K

    2017-09-01

    The objective of the present study was to determine the effects of concurrent LPS and cytokine priming, reflective of the in vivo milieu, on macrophage production of key periodontitis associated cytokines TNF, IL-1β and IL-6. THP-1 cells were pre-treated with combinations of Porphyromonas gingivalis and Escherichia coli lipopolysaccharide (LPS), concurrently with polarising cytokines IFNγ and IL-4, or PMA as a non-polarised control. Production of key periodontitis associated cytokines in response to subsequent LPS challenge were measured by enzyme - linked immunosorbent assay. Compared with cells incubated with IFNγ or IL-4 alone in the "polarisation" phase, macrophages that were incubated with LPS during the first 24h displayed a down-regulation of TNF and IL-1β production upon secondary LPS treatment in the "activation" phase. In all three macrophage populations (M0, M1 and M2), pre-treatment with P. gingivalis LPS during the polarisation process led to a significant decrease in TNF production in response to subsequent activation by LPS (p=0.007, p=0.002 and p=0.004, respectively). Pre-treatment with E. coli LPS also led to a significant down-regulation in TNF production in all three macrophage populations (pLPS during polarisation also led to the down-regulation of IL-1β in the M1 population (pLPS challenge, whereby production of key periodontitis associated cytokines TNF and IL-1β is reduced after exposure to LPS during the polarisation phase, even in the presence of inflammatory polarising cytokines. This diminished cytokine response may lead to the reduced ability to clear infection and transition to chronic inflammation seen in periodontitis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Diminished neural resources allocation to time processing in Autism Spectrum Disorders.

    Science.gov (United States)

    Lambrechts, Anna; Falter-Wagner, Christine M; van Wassenhove, Virginie

    2018-01-01

    Interval timing, the ability to judge the duration of short events, has been shown to be compromised in Autism Spectrum Disorders (ASD). Timing abilities are ubiquitous and underlie behaviours as varied as sensory integration, motor coordination or communication. It has been suggested that atypical temporal processing in ASD could contribute to some of the disorder's symptoms, in particular motor clumsiness and difficulties in social interaction and communication. Recent behavioural investigations have suggested that interval timing in ASD is characterised by intact sensitivity but reduced precision in duration judgements. In this study we investigated the processing of duration as compared to pitch in a group of high-functioning individuals with ASD using magnetoencephalography (MEG). 18 adolescents and adults with ASD and 18 age- and IQ-matched typically-developing control (TDC) individuals compared two consecutive tones according to their duration or pitch in separate experimental blocks. The analysis was carried out exclusively on physically identical stimuli (500 Hz tones lasting 600 ms), which served, according to instruction, as standard or probe in a Duration or Pitch task respectively. Our results suggest that compared to TDC individuals, individuals with ASD are less able to predict the duration of the standard tone accurately, affecting the sensitivity of the comparison process. In addition, contrary to TDC individuals who allocate resources at different times depending on the nature of the task (pitch or duration discrimination), individuals with ASD seem to engage less resources for the Duration task than for the Pitch task regardless of the context. Although individuals with ASD showed top-down adaptation to the context of the task, this neuronal strategy reflects a bias in the readiness to perform different types of tasks, and in particular a diminished allocation of resources to duration processing which could have cascading effect on learning and

  16. Diminished telomeric 3' overhangs are associated with telomere dysfunction in Hoyeraal-Hreidarsson syndrome.

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    Noa Lamm

    Full Text Available BACKGROUND: Eukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC and its severe form Hoyeraal-Hreidarsson Syndrome (HHS are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency. METHODOLOGY/PRINCIPAL FINDINGS: We studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3' overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types. CONCLUSIONS/SIGNIFICANCE: Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres

  17. Diminished Telomeric 3′ Overhangs Are Associated with Telomere Dysfunction in Hoyeraal-Hreidarsson Syndrome

    Science.gov (United States)

    Lamm, Noa; Ordan, Elly; Shponkin, Rotem; Richler, Carmelit; Aker, Memet; Tzfati, Yehuda

    2009-01-01

    Background Eukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR) and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC) and its severe form Hoyeraal-Hreidarsson Syndrome (HHS) are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency. Methodology/Principal Findings We studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3′ overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types. Conclusions/Significance Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it

  18. Associations between postpartum depressive symptoms and childhood asthma diminish with child age.

    Science.gov (United States)

    Kozyrskyj, A L; Letourneau, N L; Kang, L J; Salmani, M

    2017-03-01

    Affecting 19% of women, postpartum depression is a major concern to the immediate health of mothers and infants. In the long-term, it has been linked to the development of early-onset asthma at school entry, but only if the depression persists beyond the postnatal period. No studies have tested whether associations with postpartum depressive symptoms and early-onset asthma phenotypes persist into later school age. To determine associations between maternal postpartum depressive symptoms and childhood asthma between the ages of 5-10 by using a nested longitudinal design. Data were drawn from the 1994-2004 administrations of the Canadian National Longitudinal Survey of Children and Youth, which tracks the health of a nationally representative sample of children in Canada. Child asthma was diagnosed by a health professional, and maternal depressive symptoms were assessed by the Centre for Epidemiological Studies Depression scale. Analyses were conducted by using a multilevel modelling approach, in which longitudinal assessments of asthma in 1696 children were nested within the exposure of postpartum depression. Postpartum depressive symptoms had a 1.5-fold significant association with childhood asthma between the ages 6-8. This was independent of male sex, maternal asthma, non-immigrant status, low household socioeconomic status, being firstborn, low birthweight, low family functioning and urban-rural residence, of which the first 4 covariates elevated the risk of asthma. Statistical significance was lost at age 8 when maternal prenatal smoking replaced urban-rural residence as a covariate. At ages 9-10, an association was no longer evident. Women affected by postpartum depressive symptoms are concerned about long-term health effects of their illness on their infants. Although postpartum depressive symptoms were associated with school-age asthma at ages 6 and 7, this association diminished later. Both home and school life stress should be considered in future studies

  19. Diminishing returns from increased percent Bt cotton: the case of pink bollworm.

    Directory of Open Access Journals (Sweden)

    Yunxin Huang

    Full Text Available Regional suppression of pests by transgenic crops producing insecticidal proteins from Bacillus thuringiensis (Bt has been reported in several cropping systems, but little is known about the functional relationship between the ultimate pest population density and the pervasiveness of Bt crops. Here we address this issue by analyzing 16 years of field data on pink bollworm (Pectinophora gossypiella population density and percentage of Bt cotton in the Yangtze River Valley of China. In this region, the percentage of cotton hectares planted with Bt cotton increased from 9% in 2000 to 94% in 2009 and 2010. We find that as the percent Bt cotton increased over the years, the cross-year growth rate of pink bollworm from the last generation of one year to the first generation of the next year decreased. However, as the percent Bt cotton increased, the within-year growth rate of pink bollworm from the first to last generation of the same year increased, with a slope approximately opposite to that of the cross-year rates. As a result, we did not find a statistically significant decline in the annual growth rate of pink bollworm as the percent Bt cotton increased over time. Consistent with the data, our modeling analyses predict that the regional average density of pink bollworm declines as the percent Bt cotton increases, but the higher the percent Bt cotton, the slower the decline in pest density. Specifically, we find that 95% Bt cotton is predicted to cause only 3% more reduction in larval density than 80% Bt cotton. The results here suggest that density dependence can act against the decline in pest density and diminish the net effects of Bt cotton on suppression of pink bollworm in the study region. The findings call for more studies of the interactions between pest density-dependence and Bt crops.

  20. Diminished androgen and estrogen receptors and aromatase levels in hypogonadal diabetic men: reversal with testosterone.

    Science.gov (United States)

    Ghanim, Husam; Dhindsa, Sandeep; Abuaysheh, Sanaa; Batra, Manav; Kuhadiya, Nitesh D; Makdissi, Antoine; Chaudhuri, Ajay; Dandona, Paresh

    2018-03-01

    One-third of males with type 2 diabetes (T2DM) have hypogonadism, characterized by low total and free testosterone concentrations. We hypothesized that this condition is associated with a compensatory increase in the expression of androgen receptors (AR) and that testosterone replacement reverses these changes. We also measured estrogen receptor and aromatase expression. This is a randomized double-blind placebo-controlled trial. Thirty-two hypogonadal and 32 eugonadal men with T2DM were recruited. Hypogonadal men were randomized to receive intramuscular testosterone or saline every 2 weeks for 22 weeks. We measured AR, ERα and aromatase expression in peripheral blood mononuclear cells (MNC), adipose tissue and skeletal muscle in hypogonadal and eugonadal males with T2DM at baseline and after 22 weeks of treatment in those with hypogonadism. The mRNA expression of AR, ERα (ESR1) and aromatase in adipose tissue from hypogonadal men was significantly lower as compared to eugonadal men, and it increased significantly to levels comparable to those in eugonadal patients with T2DM following testosterone treatment. AR mRNA expression was also significantly lower in MNC from hypogonadal patients compared to eugonadal T2DM patients. Testosterone administration in hypogonadal patients also restored AR mRNA and nuclear extract protein levels from MNC to that in eugonadal patients. In the skeletal muscle, AR mRNA and protein expression are lower in men with hypogonadism. Testosterone treatment restored AR expression levels to that comparable to levels in eugonadal men. We conclude that, contrary to our hypothesis, the expression of AR, ERα and aromatase is significantly diminished in hypogonadal men as compared to eugonadal men with type 2 diabetes. Following testosterone replacement, there is a reversal of these deficits. © 2018 European Society of Endocrinology.

  1. The diminished expression of proangiogenic growth factors and their receptors in gastric ulcers of cirrhotic patients.

    Science.gov (United States)

    Luo, Jiing-Chyuan; Peng, Yen-Ling; Hou, Ming-Chih; Huang, Kuang-Wei; Huang, Hui-Chun; Wang, Ying-Wen; Lin, Han-Chieh; Lee, Fa-Yauh; Lu, Ching-Liang

    2013-01-01

    The pathogenesis of the higher occurrence of peptic ulcer disease in cirrhotic patients is complex. Platelets can stimulate angiogenesis and promote gastric ulcer healing. We compared the expressions of proangiogenic growth factors and their receptors in the gastric ulcer margin between cirrhotic patients with thrombocytopenia and those of non-cirrhotic patients to elucidate possible mechanisms. Eligible cirrhotic patients (n = 55) and non-cirrhotic patients (n = 55) who had gastric ulcers were enrolled. Mucosa from the gastric ulcer margin and non-ulcer areas were sampled and the mRNA expressions of the proangiogenic growth factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF], basic fibroblast growth factor [bFGF]) and their receptors (VEGFR1, VEGFR2, PDGFRA, PDGFRB, FGFR1, FGFR2) were measured and compared. Platelet count and the expressions of these growth factors and their receptors were correlated with each other. The two groups were comparable in terms of gender, ulcer size and infection rate of Helicobacter pylori. However, the cirrhotic group were younger in age, had a lower platelet count than those in the non-cirrhotic group (pexpressions of PDGFB, VEGFR2, FGFR1, and FGFR2 in gastric ulcer margin when compared with those of the non-cirrhotic patients (pexpressions of PDGFB and VEGFR2, FGFR1, and FGFR2 were well correlated with the degree of thrombocytopenia in these cirrhotic patients (ρ>0.5, pimplied that diminished activity of proangiogenic factors and their receptors may contribute to the pathogenesis of gastric ulcers in cirrhotic patients.

  2. Lentinan diminishes apoptotic bodies in the ileal crypts associated with S-1 administration.

    Science.gov (United States)

    Suga, Yasuyo; Takehana, Kenji

    2017-09-01

    S-1 is an oral agent containing tegafur (a prodrug of 5-fluorouracil) that is used to treat various cancers, but adverse effects are frequent. Two pilot clinical studies have suggested that lentinan (LNT; β-1,3-glucan) may reduce the incidence of adverse effects caused by S-1 therapy. In this study, we established a murine model for assessment of gastrointestinal toxicity associated with S-1 and studied the effect of LNT. S-1 was administered orally to BALB/c mice at the effective dose (8.3mg/kg, as tegafur equivalent) once daily (5days per week) for 3weeks. Stool consistency and intestinal specimens were examined. We investigated the effect of combined intravenous administration of LNT at 0.1mg, which is an effective dose in murine tumor models. We also investigated the effect of a single administration of S-1. During long-term administration of S-1, some mice had loose stools and an increase in apoptotic bodies was observed in the ileal crypts. An increase in apoptotic bodies was also noted after a single administration of S-1 (15mg/kg). Prior or concomitant administration of LNT inhibited the increase in apoptotic bodies in both settings. Administration of LNT also increased the accumulation of CD11b + TIM-4 + cells in the ileum, while depletion of these cells by liposomal clodronate diminished the inhibitory effect of LNT on S-1 toxicity. Combined administration of LNT with S-1 led to a decrease in apoptotic bodies in the ileal crypts, possibly because LNT promoted phagocytosis of damaged cells by CD11b + TIM-4 + cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Diminished Wastewater Treatment: Evaluation of Septic System Performance Under a Climate Change Scenario

    Science.gov (United States)

    Cooper, J.; Loomis, G.; Kalen, D.; Boving, T. B.; Morales, I.; Amador, J.

    2015-12-01

    The effects of climate change are expected to reduce the ability of soil-based onsite wastewater treatment systems (OWTS), to treat domestic wastewater. In the northeastern U.S., the projected increase in atmospheric temperature, elevation of water tables from rising sea levels, and heightened precipitation will reduce the volume of unsaturated soil and oxygen available for treatment. Incomplete removal of contaminants may lead to transport of pathogens, nutrients, and biochemical oxygen demand (BOD) to groundwater, increasing the risk to public health and likelihood of eutrophying aquatic ecosystems. Advanced OWTS, which include pre-treatment steps and provide unsaturated drainfields of greater volume relative to conventional OWTS, are expected to be more resilient to climate change. We used intact soil mesocosms to quantify water quality functions for two advanced shallow narrow drainfield types and a conventional drainfield under a current climate scenario and a moderate climate change scenario of 30 cm rise in water table and 5°C increase in soil temperature. While no fecal coliform bacteria (FCB) was released under the current climate scenario, up to 109 CFU FCB/mL (conventional) and up to 20 CFU FCB/mL (shallow narrow) were released under the climate change scenario. Total P removal rates dropped from 100% to 54% (conventional) and 71% (shallow narrow) under the climate change scenario. Total N removal averaged 17% under both climate scenarios in the conventional, but dropped from 5.4% to 0% in the shallow narrow under the climate change scenario, with additional leaching of N in excess of inputs indicating release of previously held N. No significant difference was observed between scenarios for BOD removal. The initial data indicate that while advanced OWTS retain more function under the climate change scenario, all three drainfield types experience some diminished treatment capacity.

  4. Achievement of the charge exchange work diminishing of an internal combustion engine in part load

    Directory of Open Access Journals (Sweden)

    Stefan POSTRZEDNIK

    2012-01-01

    Full Text Available Internal combustion engines, used for driving of different cars, occurs not only at full load, but mostly at the part load. The relative load exchange work at the full (nominal engine load is significantly low. At the part load of the IC engine its energy efficiency ηe is significantly lower than in the optimal (nominal field range of the performance parameters. One of the numerous reasons of this effect is regular growing of the relative load exchange work of the IC engine. It is directly connected with the quantitative regulation method commonly used in the IC engines. From the thermodynamic point of view - the main reason of this effect is the throttling process (causing exergy losses occurring in the inlet and outlet channels. The known proposals for solving of this problem are based on applying of the fully electronic control of the motion of inlet, outlet valves and new reference cycles.The idea presented in the paper leads to diminishing the charge exchange work of the IC engines. The problem can be solved using presented in the paper a new concept of the reference cycle (called as eco-cycle of IC engine. The work of the engine basing on the eco-cycle occurs in two 3-stroke stages; the fresh air is delivered only once for both stages, but in range of each stage a new portion of fuel is burned. Normally the charge exchange occurs once during each engine cycle realized. Elaborated proposition bases on the elimination of chosen charge exchange processes and through this the dropping of the charge exchange work can be achieved.

  5. Upper gastrointestinal dysmotility after spinal cord injury: Is diminished vagal sensory processing one culprit?

    Directory of Open Access Journals (Sweden)

    Gregory M Holmes

    2012-07-01

    Full Text Available Despite the widely recognized prevalence of gastric, colonic and anorectal dysfunction after SCI, significant knowledge gaps persist regarding the mechanisms leading to post-SCI gastrointestinal (GI impairments. Briefly, the regulation of GI function is governed by a mix of parasympathetic, sympathetic and enteric neurocircuitry. Unlike the intestines, the stomach is dominated by parasympathetic (vagal control whereby gastric sensory information is transmitted via the afferent vagus nerve to neurons of the nucleus tractus solitarius (NTS. The NTS integrates this sensory information with signals from throughout the CNS. Glutamatergic and GABAergic NTS neurons project to other nuclei, including the preganglionic parasympathetic neurons of the dorsal motor nucleus of the vagus (DMV. Finally, axons from the DMV project to gastric myenteric neurons, again, through the efferent vagus nerve. SCI interrupts descending input to the lumbosacral spinal cord neurons that modulate colonic motility and evacuation reflexes. In contrast, vagal neurocircuitry remains anatomically intact after injury. This review presents evidence that unlike the post-SCI loss of supraspinal control which leads to colonic and anorectal dysfunction, gastric dysmotility occurs as an indirect or secondary pathology following SCI. Specifically, emerging data points toward diminished sensitivity of vagal afferents to GI neuroactive peptides, neurotransmitters and, possibly, macronutrients. The neurophysiological properties of rat vagal afferent neurons are highly plastic and can be altered by injury or energy balance. A reduction of vagal afferent signaling to NTS neurons may ultimately bias NTS output toward unregulated GABAergic transmission onto gastric-projecting DMV neurons. The resulting gastroinhibitory signal may be one mechanism leading to upper GI dysmotility following SCI.

  6. Ageing diminishes the modulation of human brain responses to visual food cues by meal ingestion.

    Science.gov (United States)

    Cheah, Y S; Lee, S; Ashoor, G; Nathan, Y; Reed, L J; Zelaya, F O; Brammer, M J; Amiel, S A

    2014-09-01

    Rates of obesity are greatest in middle age. Obesity is associated with altered activity of brain networks sensing food-related stimuli and internal signals of energy balance, which modulate eating behaviour. The impact of healthy mid-life ageing on these processes has not been characterised. We therefore aimed to investigate changes in brain responses to food cues, and the modulatory effect of meal ingestion on such evoked neural activity, from young adulthood to middle age. Twenty-four healthy, right-handed subjects, aged 19.5-52.6 years, were studied on separate days after an overnight fast, randomly receiving 50 ml water or 554 kcal mixed meal before functional brain magnetic resonance imaging while viewing visual food cues. Across the group, meal ingestion reduced food cue-evoked activity of amygdala, putamen, insula and thalamus, and increased activity in precuneus and bilateral parietal cortex. Corrected for body mass index, ageing was associated with decreasing food cue-evoked activation of right dorsolateral prefrontal cortex (DLPFC) and precuneus, and increasing activation of left ventrolateral prefrontal cortex (VLPFC), bilateral temporal lobe and posterior cingulate in the fasted state. Ageing was also positively associated with the difference in food cue-evoked activation between fed and fasted states in the right DLPFC, bilateral amygdala and striatum, and negatively associated with that of the left orbitofrontal cortex and VLPFC, superior frontal gyrus, left middle and temporal gyri, posterior cingulate and precuneus. There was an overall tendency towards decreasing modulatory effects of prior meal ingestion on food cue-evoked regional brain activity with increasing age. Healthy ageing to middle age is associated with diminishing sensitivity to meal ingestion of visual food cue-evoked activity in brain regions that represent the salience of food and direct food-associated behaviour. Reduced satiety sensing may have a role in the greater risk of

  7. Diminished metal accumulation in riverine fishes exposed to acid mine drainage over five decades.

    Directory of Open Access Journals (Sweden)

    Ross A Jeffree

    Full Text Available Bony bream (Nematalosa erebi and black catfish (Neosilurus ater were sampled from the fresh surface waters of the Finniss River in tropical northern Australia, along a metal pollution gradient draining the Rum Jungle copper/uranium mine, a contaminant source for over five decades. Paradoxically, populations of both fish species exposed to the highest concentrations of mine-related metals (cobalt, copper, lead, manganese, nickel, uranium and zinc in surface water and sediment had the lowest tissue (bone, liver and muscle concentrations of these metals. The degree of reduction in tissue concentrations of exposed populations was also specific to each metal and inversely related to its degree of environmental increase above background. Several explanations for diminished metal bioaccumulation in fishes from the contaminated region were evaluated. Geochemical speciation modeling of metal bioavailability in surface water showed no differences between the contaminated region and the control sites. Also, the macro-nutrient (calcium, magnesium and sodium water concentrations, that may competitively inhibit metal uptake, were not elevated with trace metal contamination. Reduced exposure to contaminants due to avoidance behavior was unlikely due to the absence of refugial water bodies with the requisite metal concentrations lower than the control sites and very reduced connectivity at time of sampling. The most plausible interpretation of these results is that populations of both fish species have modified kinetics within their metal bioaccumulation physiology, via adaptation or tolerance responses, to reduce their body burdens of metals. This hypothesis is consistent with (i reduced tissue concentrations of calcium, magnesium and sodium (macro-nutrients, in exposed populations of both species, (ii experimental findings for other fish species from the Finniss River and other contaminated regions, and (iii the number of generations exposed to likely

  8. Diminished Neural Processing of Aversive and Rewarding Stimuli During Selective Serotonin Reuptake Inhibitor Treatment

    Science.gov (United States)

    McCabe, Ciara; Mishor, Zevic; Cowen, Philip J.; Harmer, Catherine J.

    2010-01-01

    Background Selective serotonin reuptake inhibitors (SSRIs) are popular medications for anxiety and depression, but their effectiveness, particularly in patients with prominent symptoms of loss of motivation and pleasure, has been questioned. There are few studies of the effect of SSRIs on neural reward mechanisms in humans. Methods We studied 45 healthy participants who were randomly allocated to receive the SSRI citalopram, the noradrenaline reuptake inhibitor reboxetine, or placebo for 7 days in a double-blind, parallel group design. We used functional magnetic resonance imaging to measure the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste) on the final day of drug treatment. Results Citalopram reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex. In contrast, reboxetine did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward. Citalopram also decreased neural responses to the aversive stimuli conditions in key “punishment” areas such as the lateral orbitofrontal cortex. Reboxetine produced a similar, although weaker effect. Conclusions Our findings are the first to show that treatment with SSRIs can diminish the neural processing of both rewarding and aversive stimuli. The ability of SSRIs to decrease neural responses to reward might underlie the questioned efficacy of SSRIs in depressive conditions characterized by decreased motivation and anhedonia and could also account for the experience of emotional blunting described by some patients during SSRI treatment. PMID:20034615

  9. Diminishing returns from increased percent Bt cotton: the case of pink bollworm.

    Science.gov (United States)

    Huang, Yunxin; Wan, Peng; Zhang, Huannan; Huang, Minsong; Li, Zhaohua; Gould, Fred

    2013-01-01

    Regional suppression of pests by transgenic crops producing insecticidal proteins from Bacillus thuringiensis (Bt) has been reported in several cropping systems, but little is known about the functional relationship between the ultimate pest population density and the pervasiveness of Bt crops. Here we address this issue by analyzing 16 years of field data on pink bollworm (Pectinophora gossypiella) population density and percentage of Bt cotton in the Yangtze River Valley of China. In this region, the percentage of cotton hectares planted with Bt cotton increased from 9% in 2000 to 94% in 2009 and 2010. We find that as the percent Bt cotton increased over the years, the cross-year growth rate of pink bollworm from the last generation of one year to the first generation of the next year decreased. However, as the percent Bt cotton increased, the within-year growth rate of pink bollworm from the first to last generation of the same year increased, with a slope approximately opposite to that of the cross-year rates. As a result, we did not find a statistically significant decline in the annual growth rate of pink bollworm as the percent Bt cotton increased over time. Consistent with the data, our modeling analyses predict that the regional average density of pink bollworm declines as the percent Bt cotton increases, but the higher the percent Bt cotton, the slower the decline in pest density. Specifically, we find that 95% Bt cotton is predicted to cause only 3% more reduction in larval density than 80% Bt cotton. The results here suggest that density dependence can act against the decline in pest density and diminish the net effects of Bt cotton on suppression of pink bollworm in the study region. The findings call for more studies of the interactions between pest density-dependence and Bt crops.

  10. Do β-adrenoceptor agonists induce homologous or heterologous desensitization in rat urinary bladder?

    Science.gov (United States)

    Michel, Martin C

    2014-03-01

    β3-Adrenoceptor agonists have recently been introduced for the symptomatic treatment of the overactive bladder syndrome. As such treatment is not curative, long-term treatment is anticipated to be required. As the susceptibility of β3-adrenoceptors to undergo agonist-induced desensitization is cell type- and tissue-dependent, we have explored whether pre-treatment with a β-adrenoceptor agonist will attenuate subsequent relaxation responses to freshly added agonist using rat urinary bladder as a model. We have used the prototypical β-adrenoceptor agonist isoprenaline, the β2-selective fenoterol and the β3-selective CL 316,243 and mirabegron as well as the receptor-independent bladder relaxant forskolin. We show that a 6-h pre-treatment with agonist can significantly reduce subsequent relaxation against KCl-induced smooth muscle tone, but agonist-induced desensitization was also observed with longer pre-treatments or against passive tension. The agonist-induced desensitization was prominent for the β2 component of rat bladder relaxation but much weaker or even absent for the β3 component. Moreover, β-adrenoceptor agonist pre-treatment reduced contractile responses to the muscarinic agonist carbachol and the receptor-independent stimulus KCl. Taken together these data do not support the hypothesis that the long-term clinical efficacy of β3-adrenoceptor agonists in the treatment of the overactive bladder syndrome will be limited by receptor desensitization. Rather they raise the possibility that such treatment may not only cause smooth muscle relaxation but also may attenuate hyper-contractility of the bladder.

  11. Conversion of chronic pain patients from full-opioid agonists to sublingual buprenorphine.

    Science.gov (United States)

    Daitch, Jonathan; Frey, Michael E; Silver, David; Mitnick, Carol; Daitch, Danielle; Pergolizzi, Joseph

    2012-07-01

    Sublingual buprenorphine-naloxone (buprenorphine SL) is a preparation that is used to treat opioid dependence. In addition, the Drug Enforcement Administration (DEA) has acknowledged the legality of an off-label use to treat pain with a sublingual buprenorphine preparation. Buprenorphine SL is unique among the opioid class of analgesics; this compound has a high affinity for the mu-receptor, yet only partially activates it. Thus, buprenorphine SL can provide analgesia, yet minimize opioid side effects. Many patients on high doses of traditional opioid medication develop tolerance. Despite escalating medication dosage, a subset of patients had a paradoxical increase in pain, which has been characterized as opioid-induced hyperalgesia (OIH).  Buprenorphine SL, on the other hand, may even be anti-hyperalgesic and may have utility in treating these challenging patients. To determine the effectiveness of converting patients from traditional full agonist opioid medication to sublingual buprenorphine, as well as to identify patient groups that are most likely to benefit from this therapy. Patients who underwent conversion either had developed tolerance with diminished analgesia or were experiencing side effects on their opioid medications. An observational report of outcomes assessment. An interventional pain management practice setting in the United States. Retrospective data from clinical records was compiled on 104 de-identified chronic pain patients whose personal information had been redacted (60 men and 44 women, aged 21-78) and who had previously been treated with opioid-agonist drugs; they were converted to buprenorphine SL in tablet form during the study. Chronic pain was defined as persistent pain for at least 6 months. Data collected from patient profiles included age, sex, diagnosis, medication history, pre-induction opioid intake, reason for detoxification, pre-induction Clinical Opiate Withdrawal Score (COWS), and if applicable, cause of buprenorphine SL

  12. Spearman's "law of diminishing returns" and the role of test reliability investigated in a large sample of Danish military draftees

    DEFF Research Database (Denmark)

    Teasdale, Thomas William; Hartmann, P.

    2005-01-01

    The present article investigates Spearman's "Law of Diminishing Returns" (SLODR), which hypothesizes that the g saturation for cognitive tests is lower for high ability subjects than for low ability subjects. This hypothesis was tested in a large sample of Danish military draftees (N = 6757) who ...

  13. Night sweats, sleep disturbance, and depression associated with diminished libido in late menopausal transition and early postmenopause

    Science.gov (United States)

    Reed, Susan D.; Newton, Katherine M.; LaCroix, Andrea Z.; Grothaus, Lou C.; Ehrlich, Kelly

    2007-01-01

    Objective To evaluate the association of depression, sleep disturbance and menopausal symptoms with diminished libido. Study Design Data from a 2001-2002 baseline survey of 341 peri- and postmenopausal women, ages 45-55, participating in a randomized trial was analyzed. Eligibility included at least two hot flashes and/or night sweats per day and no hormone therapy for at least the prior 3 months. The survey evaluated sexual function, depression, sleep and vasomotor symptoms. We examined the association between these factors, using multivariate regression models. Results Of 341 women, 64% had diminished libido, 18% had moderate-severe depression, and 43% had poor sleep quality. Women averaged 4.6 hot flashes and 1.9 night sweats per day. Depressive symptoms (P=0.003), poor sleep (P=0.02), and night sweats (P=0.04), were significantly associated with diminished libido. Conclusions Factors associated with diminished libido in midlife are complex but include depression, disturbed sleep and night sweats, all common symptoms of the menopausal transition and early menopause. PMID:17547910

  14. PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

    Directory of Open Access Journals (Sweden)

    Monica Puligheddu

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα, nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p. or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2% for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.. Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key

  15. The 5-HT(1F) receptor agonist lasmiditan as a potential treatment of migraine attacks

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer C; Olesen, Jes

    2012-01-01

    Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo...

  16. Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists

    DEFF Research Database (Denmark)

    Palmer, Daniel; Gonçalves, Juliana P.L.; Hansen, Louise V.

    2017-01-01

    were synthesized by solid phase click chemistry to develop novel, potent, selective MC4R agonists. Using cAMP measurements and a transcriptional reporter assay, we observed that several constrained agonists generated by a cycloaddition reaction displayed high selectivity (223- to 467-fold) toward MC4R...

  17. Low-dose add-back therapy during postoperative GnRH agonist treatment

    Directory of Open Access Journals (Sweden)

    Hsiao-Wen Tsai

    2016-02-01

    Conclusion: Low dose add-back therapy could effectively ameliorate hypoestrogenic side effects and simultaneously maintain the therapeutic response of GnRH agonist treatment. The treatment dropout was lower compared with a regular dose. Therefore, low dose add-back therapy can be considered a treatment choice during postoperative GnRH agonist treatment.

  18. Trialkyltin rexinoid-X receptor agonists selectively potentiate thyroid hormone induced programs of xenopus laevis metamorphosis

    NARCIS (Netherlands)

    Mengeling, Brenda J.; Murk, Albertinka J.; Furlow, J.D.

    2016-01-01

    The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3.TRE-Luc. The prevalence of TBT and TPT in the

  19. Major drawbacks and additional benefits of agonist trigger--not ovarian hyperstimulation syndrome related

    DEFF Research Database (Denmark)

    Shapiro, Bruce S; Andersen, Claus Yding

    2015-01-01

    The GnRH agonist trigger alters traditional IVF paradigms when compared with hCG-only triggers. The agonist trigger induces rapid luteolysis and therefore separates the oocyte maturation aspect of LH from the luteal support previously afforded by lingering hCG. This might allow customized and mor...

  20. A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites

    DEFF Research Database (Denmark)

    Kongsbak, Kristine Grønning; Bergmann, Rikke; Sørensen, Pernille Louise

    2013-01-01

    We present a full-length a1b2c2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate...

  1. Effects of â2-agonist therapy on blood pressure, glycaemic control ...

    African Journals Online (AJOL)

    Introduction: the blood pressure, glycaemic control and electrolyte concentrations are influenced by autonomic nervous system and are expected to be affected by beta-2 agonist medications commonly used by asthmatic patients. Objective:The objective of this study is to detect the possible effects of beta-2 agonist ...

  2. Structure and function of an irreversible agonist-β(2) adrenoceptor complex

    DEFF Research Database (Denmark)

    Rosenbaum, Daniel M; Zhang, Cheng; Lyons, Joseph A

    2011-01-01

    G-protein-coupled receptors (GPCRs) are eukaryotic integral membrane proteins that modulate biological function by initiating cellular signalling in response to chemically diverse agonists. Despite recent progress in the structural biology of GPCRs, the molecular basis for agonist binding and all...

  3. PPAR Agonists: Potential as Therapeutics for Neovascular Retinopathies

    Directory of Open Access Journals (Sweden)

    Harrihar A. Pershadsingh

    2008-01-01

    Full Text Available The angiogenic, neovascular proliferative retinopathies, proliferative diabetic retinopathy (PDR, and age-dependent macular degeneration (AMD complicated by choroidal neovascularization (CNV, also termed exudative or “wet” AMD, are common causes of blindness. The antidiabetic thiazolidinediones (TZDs, rosiglitazone, and troglitazone are PPAR agonists with demonstrable antiproliferative, and anti-inflammatory effects, in vivo, were shown to ameliorate PDR and CNV in rodent models, implying the potential efficacy of TZDs for treating proliferative retinopathies in humans. Activation of the angiotensin II type 1 receptor (AT1-R propagates proinflammatory and proliferative pathogenic determinants underlying PDR and CNV. The antihypertensive dual AT1-R blocker (ARB, telmisartan, recently was shown to activate PPAR and improve glucose and lipid metabolism and to clinically improve PDR and CNV in rodent models. Therefore, the TZDs and telmisartan, clinically approved antidiabetic and antihypertensive drugs, respectively, may be efficacious for treating and attenuating PDR and CNV humans. Clinical trials are needed to test these possibilities.

  4. Emerging corticosteroid agonists for the treatment of asthma

    DEFF Research Database (Denmark)

    Westergaard, Christian G; Porsbjerg, Celeste; Backer, Vibeke

    2015-01-01

    approved ICS show improved pharmocodynamic properties. Nevertheless, emerging drugs acting on the same receptor as the ICS, glucocorticoid receptor agonists (GRAs), are under current research. These drugs exhibit selective action on the glucocorticoid receptor (GR), which may improve their adverse effect...... profile, compared to the currently approved ICS that act unselectively on the GR. AREAS COVERED: The present article reviews emerging GRAs for the treatment of asthma. Furthermore, the more recently approved ICS with improved safety profiles are reviewed. EXPERT OPINION: Compared with drugs acting...... on other pathological pathways, research in GRAs for asthma is sparse. However, a few promising agents acting selectively on the GR are currently under investigation and may reach approval for asthma treatment. These drugs exhibit improved pharmacodynamic properties due to selectivity in the mechanism...

  5. Use of thrombopoietin receptor agonists in childhood immune thrombocytopenia

    Directory of Open Access Journals (Sweden)

    Angelica Maria Garzon

    2015-08-01

    Full Text Available Most children with immune thrombocytopenia (ITP will have spontaneous remission regardless of therapy, while about 20% will go on to have chronic ITP. In those children with chronic ITP who need treatment, standard therapies for acute ITP may have adverse effects that complicate their long term use. Thus, alternative treatment options are needed for children with chronic ITP. Thrombopoietin receptor agonists (TPO-RA have been shown to be safe and efficacious in adults with ITP, and represent a new treatment option for children with chronic ITP. One TPO-RA, eltrombopag, is now approved for children. Clinical trials in children are ongoing and data is emerging on safety and efficacy. This review will focus on the physiology of TPO-RA, their clinical use in children, as well as the long term safety issues that need to be considered when using these agents

  6. [Safety and tolerability of GLP-1 receptor agonists].

    Science.gov (United States)

    Soldevila, Berta; Puig-Domingo, Manel

    2014-09-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  7. Kangaroo mother care diminishes pain from heel lance in very preterm neonates: A crossover trial

    Directory of Open Access Journals (Sweden)

    McNaughton Kathryn

    2008-04-01

    Full Text Available Abstract Background Skin-to-skin contact, or kangaroo mother care (KMC has been shown to be efficacious in diminishing pain response to heel lance in full term and moderately preterm neonates. The purpose of this study was to determine if KMC would also be efficacious in very preterm neonates. Methods Preterm neonates (n = 61 between 28 0/7 and 31 6/7 weeks gestational age in three Level III NICU's in Canada comprised the sample. A single-blind randomized crossover design was employed. In the experimental condition, the infant was held in KMC for 15 minutes prior to and throughout heel lance procedure. In the control condition, the infant was in prone position swaddled in a blanket in the incubator. The primary outcome was the Premature Infant Pain Profile (PIPP, which is comprised of three facial actions, maximum heart rate, minimum oxygen saturation levels from baseline in 30-second blocks from heel lance. The secondary outcome was time to recover, defined as heart rate return to baseline. Continuous video, heart rate and oxygen saturation monitoring were recorded with event markers during the procedure and were subsequently analyzed. Repeated measures analysis-of-variance was employed to generate results. Results PIPP scores at 90 seconds post lance were significantly lower in the KMC condition (8.871 (95%CI 7.852–9.889 versus 10.677 (95%CI 9.563–11.792 p CI 103–142 versus 193 seconds (95%CI 158–227. Facial actions were highly significantly lower across all points in time reaching a two-fold difference by 120 seconds post-lance and heart rate was significantly lower across the first 90 seconds in the KMC condition. Conclusion Very preterm neonates appear to have endogenous mechanisms elicited through skin-to-skin maternal contact that decrease pain response, but not as powerfully as in older preterm neonates. The shorter recovery time in KMC is clinically important in helping maintain homeostasis. Trial Registration (Current

  8. Furosemide diminishes {sup 18}F-fluoroethylcholine uptake in prostate cancer in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Rischke, H.C. [University of Freiburg, Department of Radiation Oncology, Freiburg (Germany); University of Freiburg, Department of Nuclear Medicine, Freiburg (Germany); Beck, Teresa; Wieser, Gesche; Meyer, Philipp T. [University of Freiburg, Department of Nuclear Medicine, Freiburg (Germany); Vach, Werner [University of Freiburg, Department of Clinical Epidemiology, Department of Medical Biometry and Medical Informatics, Freiburg (Germany); Grosu, Anca L. [University of Freiburg, Department of Radiation Oncology, Freiburg (Germany); Schultze-Seemann, Wolfgang; Jilg, Cordula A. [University of Freiburg, Department of Urology, Freiburg (Germany)

    2014-11-15

    choline uptake in tumour lesions, especially significant in pelvic lymph node metastases. Although furosemide administration improved image quality, optimal image quality may also be obtained by adequate hydration without the risk of diminishing choline uptake in PCa lesions. Therefore a controlled hydration protocol seems more appropriate than administration of furosemide. (orig.)

  9. Diminished forearm vasomotor response to central hypervolemic loading in aerobically fit individuals

    Science.gov (United States)

    Shi, X.; Gallagher, K. M.; SMith, S. A.; Bryant, K. H.; Raven, P. B.; Blomqvist, C. G. (Principal Investigator)

    1996-01-01

    The aim of this study was to test the hypothesis that cardiopulmonary baroreflex control of forearm vascular resistance (FVR) during central hypervolemic loading was less sensitive in exercise trained high fit individuals (HF) compared to untrained average fit individuals (AF). Eight AF (age: 24 +/- 1 yr and weight: 78.9 +/- 1.7 kg) and eight HF (22 +/- 1 yr 79.5 +/- 2.4 kg) voluntarily participated in the investigation. Maximal aerobic power (determined on a treadmill), plasma volume and blood volume (Evans blue dilution method) were significantly greater in the HF than AF (60.8 +/- 0.7 vs. 41.2 +/- 1.9 ml.kg-1.min-1, 3.96 +/- 0.17 vs 3.36 +/- 0.08 1, and 6.33 +/- 0.23 vs 5.28 +/- 0.13 1). Baseline heart rate (HR), central venous pressure (CVP), mean arterial pressure (MAP, measured by an intraradial catheter or a Finapres finger cuff), forearm blood flow (FBF, plethysmography), and FVR, calculated from the ratio (MAP-CVP)/FBF, were not different between the HF and the AF. Lower body negative pressure (LBNP, -5, -10, -15, and -20 torr) and passive leg elevation (LE, 50 cm) combined with lower body positive pressure (LBPP, +5, +10, and +20 torr) were utilized to elicit central hypovolemia and hypervolemia, respectively. Range of CVP (from LBNP to LE+LBPP) was similar in the AF (from -3.9 to +1.9 mm Hg) and HF (from -4.0 to +2.2 mm Hg). However, FVR/CVP was significantly less in the HF (-1.8 +/- 0.1 unit.mm Hg-1) than AF (-34 +/- 0.1 unit.mm Hg-1). The FVR decrease in response to increase in CVP was significantly diminished in the HF (-1.46 +/- 0.45 unit.mm Hg-1) compared to the AF (-4.40 +/- 0.97 unit.mm Hg-1), and during LBNP induced unloading the FVR/CVP of the HF (-2.01 +/- 0.49 unit.mm Hg-1) was less (P training.

  10. Inverse agonistic activity of antihistamines and suppression of histamine H1 receptor gene expression.

    Science.gov (United States)

    Mizuguchi, Hiroyuki; Ono, Shohei; Hattori, Masashi; Fukui, Hiroyuki

    2012-01-01

    Histamine H(1) receptor (H1R) expression influences the severity of allergy symptoms. We examined the effect of inverse agonists on H1R gene expression. Two inverse agonists (carebastine and mepyramine), but not the neutral antagonist oxatomide, decreased inositol phosphate accumulation. The inverse agonists also decreased H1R gene expression and down-regulated H1R mRNA below basal expression, while basal H1R mRNA expression was maintained after oxatomide treatment. These results suggest that inverse agonists more potently alleviate allergy symptoms by not only inhibiting stimulus-induced up-regulation of H1R gene expression but also by suppressing basal histamine signaling through their inverse agonistic activity.

  11. Could dopamine agonists aid in drug development for anorexia nervosa?

    Science.gov (United States)

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  12. AMP Is an Adenosine A1 Receptor Agonist*

    Science.gov (United States)

    Rittiner, Joseph E.; Korboukh, Ilia; Hull-Ryde, Emily A.; Jin, Jian; Janzen, William P.; Frye, Stephen V.; Zylka, Mark J.

    2012-01-01

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5′-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5′-monophosphonate, ACP) directly activated the adenosine A1 receptor (A1R). In contrast, AMP only activated the adenosine A2B receptor (A2BR) after hydrolysis to adenosine by ecto-5′-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A1R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A1R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A1R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A1R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine. PMID:22215671

  13. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Science.gov (United States)

    Frank, Guido K. W.

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  14. Theory of partial agonist activity of steroid hormones

    Directory of Open Access Journals (Sweden)

    Carson C. Chow

    2015-04-01

    Full Text Available The different amounts of residual partial agonist activity (PAA of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system, we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site, relative to a concentration limited step (CLS, which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally, the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus, this theory now makes it possible to predict how different cofactors modulate antisteroid PAA, which should be invaluable in developing more selective antagonists.

  15. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Directory of Open Access Journals (Sweden)

    Guido eFrank

    2014-11-01

    Full Text Available Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  16. Study of interleukin-10 promoter region polymorphisms (−1082A/G ...

    Indian Academy of Sciences (India)

    (−1082A/G, −819T/C and −592A/C) in type 1 diabetes mellitus in Turkish population. HASSAN MOHEBBATIKALJAHI1∗, SEVDA MENEVSE1, ILHAN YETKIN2 and HUSEYIN DEMIRCI2. 1Department of Medical Biology and Genetics, 2Department of Internal Medicine, Gazi University. Faculty of Medicine, 06500 Ankara, ...

  17. Serum level of interleukin-10 with its gene polymorphism can be ...

    African Journals Online (AJOL)

    10) gene polymorphism and its serum level in predicting response to treatment in patients with chronic hepatitis C virus. Patients and methods: This study was carried out on 35 Egyptian patients with chronic HCV (Hepatitis C Virus) and 15 age- ...

  18. The Dynamics of Interleukin-10-Afforded Protection during Dextran Sulfate Sodium-Induced Colitis

    Directory of Open Access Journals (Sweden)

    Ana Cardoso

    2018-03-01

    Full Text Available Inflammatory bowel disease encompasses a group of chronic-inflammatory conditions of the colon and small intestine. These conditions are characterized by exacerbated inflammation of the organ that greatly affects the quality of life of patients. Molecular mechanisms counteracting this hyperinflammatory status of the gut offer strategies for therapeutic intervention. Among these regulatory molecules is the anti-inflammatory cytokine interleukin (IL-10, as shown in mice and humans. Indeed, IL-10 signaling, particularly in macrophages, is essential for intestinal homeostasis. We sought to investigate the temporal profile of IL-10-mediated protection during chemical colitis and which were the underlying mechanisms. Using a novel mouse model of inducible IL-10 overexpression (pMT-10, described here, we show that mice preconditioned with IL-10 for 8 days before dextran sulfate sodium (DSS administration developed a milder colitic phenotype. In IL-10-induced colitic mice, Ly6C cells isolated from the lamina propria showed a decreased inflammatory profile. Because our mouse model leads to transcription of the IL-10 transgene in the bone marrow and elevated seric IL-10 concentration, we investigated whether IL-10 could imprint immune cells in a long-lasting way, thus conferring sustained protection to colitis. We show that this was not the case, as IL-10-afforded protection was only observed if IL-10 induction immediately preceded DSS-mediated colitis. Thus, despite the protection afforded by IL-10 in colitis, novel strategies are required, specifically to achieve long-lasting protection.

  19. Interleukin-6 and interleukin-10 plasma levels and mRNA expression in polytrauma patients

    Directory of Open Access Journals (Sweden)

    Heber B. Sapan

    2017-12-01

    Conclusion: The pattern of cytokine levels in inflammation response has great impact on the outcome of polytrauma patients. Further study at the genetic level is needed to investigate inflammation process which may influence patient's outcome.

  20. Distinct cytokines balance the development of regulatory T cells and interleukin-10-producing regulatory B cells

    Czech Academy of Sciences Publication Activity Database

    Holáň, Vladimír; Zajícová, Alena; Javorková, Eliška; Trošan, Peter; Chudíčková, Milada; Pavlíková, M.; Krulová, Magdaléna

    2014-01-01

    Roč. 141, č. 4 (2014), s. 577-586 ISSN 0019-2805 R&D Projects: GA MZd(CZ) NT14102; GA ČR(CZ) GAP301/11/1568; GA ČR GAP304/11/0653 Institutional support: RVO:68378041 Keywords : Autoregulation * B cells * Cytokines Subject RIV: FF - HEENT, Dentistry Impact factor: 3.795, year: 2014

  1. Disease protection and interleukin-10 induction by endogenous interferon-β in multiple sclerosis?

    DEFF Research Database (Denmark)

    Hesse, D.; Krakauer, M.; Lund, H

    2011-01-01

    with increased spontaneous MX1 expression also had increased expression of other genes induced by regular IFN-ß treatment of MS. MX1 expression correlated with FOXP3 and IL10 expression, and IL10 expression correlated negatively with disease activity on magnetic resonance imaging. Further, in vivo IL10...... expression was lower in NAb-positive patients than in untreated patients with MS and healthy controls. Finally, ex vivo treatment of mononuclear blood cells with IFN-ß induced the expression of IL10, and this was blocked by the addition of serum from NAb-positive patients with MS. CONCLUSION: Our findings...... suggest that endogenous IFN-ß may induce the expression of immunoregulatory IL10 in MS and that this might be associated with dampening of inflammatory disease activity....

  2. The role of the interleukin-10 subfamily members in immunoglobulin production by human B cells

    DEFF Research Database (Denmark)

    Hummelshoj, L; Ryder, L P; Poulsen, Lars K.

    2006-01-01

    Interleukin (IL)-10 has been shown to have various effects on B cells, including positively affecting the production of immunoglobulin A (IgA) and IgG. Several human IL-10-related molecules have been identified. These include IL-19, IL-20, IL-22, IL-24, IL-26, IL-28 and IL-29. To determine...... the effects of the IL-10 analogues on the class switch recombination in B cells, we analysed Ig production from naïve B cells stimulated with these cytokines in the presence of anti-CD40. None of the cytokines were found to induce Ig production by themselves in the presence of anti-CD40 Ab. However, all...... cytokines inhibited the production of IgA and IgG induced by anti-CD40 Ab alone. In combination with anti-CD40 Ab and IL-4, IgG4 were inhibited in cultures stimulated with IL-20, IL-22, IL-26, IL-28 and IL-29 compared with IL-4 and anti-CD40 Ab alone, whereas all IL-10 analogues increased the production...

  3. Characterisation of enterocolitis in the piroxicam-accelerated interleukin-10 knock out mouse

    DEFF Research Database (Denmark)

    Holgersen, Kristine; Kvist, Peter Helding; Markholst, Helle

    2014-01-01

    Background: In inflammatory bowel disease a defective mucosal barrier, a dysregulated immune response and an excessive reactivity against the gut microbiota are assumed to cause a breakdown of the intestinal homeostasis and lead to chronic inflammation. Piroxicam treatment is a method for induction...... of colitis in IL-10 k.o. mice, which integrates a dysfunction of both the intestinal barrier and the immune system. However, the translational value of this model has not been thoroughly clarified. Aim: To characterise the piroxicam-accelerated colitis (PAC) IL-10 k.o. model with respect to clinical features...

  4. Interleukin-10 Inhibits Bone Resorption: A Potential Therapeutic Strategy in Periodontitis and Other Bone Loss Diseases

    OpenAIRE

    Zhang, Qian; Chen, Bin; Yan, Fuhua; Guo, Jianbin; Zhu, Xiaofeng; Ma, Shouzhi; Yang, Wenrong

    2014-01-01

    Periodontitis and other bone loss diseases, decreasing bone volume and strength, have a significant impact on millions of people with the risk of tooth loss and bone fracture. The integrity and strength of bone are maintained through the balance between bone resorption and bone formation by osteoclasts and osteoblasts, respectively, so the loss of bone results from the disruption of such balance due to increased resorption or/and decreased formation of bone. The goal of therapies for diseases...

  5. Interleukin 10 gene promoter polymorphism and risk of diffuse large B cell lymphoma (DLBCL

    Directory of Open Access Journals (Sweden)

    Roba M. Talaat

    2014-01-01

    Conclusions: Taken together, our findings demonstrated that IL-10 promoter gene polymorphism (−1082 and −819 may not have an influence on the clinical outcome of DLBCL, especially in terms of overall secretion level. Further investigations of other cytokine gene polymorphisms will lead to a better understanding of the disease’s biological background.

  6. Generation of regulatory gut-homing human T lymphocytes using ex vivo interleukin 10 gene transfer

    NARCIS (Netherlands)

    van Montfrans, Catherine; Hooijberg, Erik; Rodriguez Pena, Maria Sol; de Jong, Esther C.; Spits, Hergen; te Velde, Anje A.; van Deventer, Sander J. H.

    2002-01-01

    Background & Aims: Systemic treatment of Crohn's disease patients using recombinant interleukin (rIL)-10 has not resulted in significant therapeutic benefit presumably because of limited bioavailability and unexpected proinflammatory effects of high-dose rIL-10. Ex vivo gene transfer of the

  7. Interleukin 10 modulation of pathogenic Th17 cells during fatal alphavirus encephalomyelitis.

    Science.gov (United States)

    Kulcsar, Kirsten A; Baxter, Victoria K; Greene, Ivorlyne P; Griffin, Diane E

    2014-11-11

    Mosquito-borne alphaviruses are important causes of epidemic encephalomyelitis. Neuronal cell death during fatal alphavirus encephalomyelitis is immune-mediated; however, the types of cells involved and their regulation have not been determined. We show that the virus-induced inflammatory response was accompanied by production of the regulatory cytokine IL-10, and in the absence of IL-10, paralytic disease occurred earlier and mice died faster. To determine the reason for accelerated disease in the absence of IL-10, immune responses in the CNS of IL-10(-/-) and wild-type (WT) mice were compared. There were no differences in the amounts of brain inflammation or peak virus replication; however, IL-10(-/-) animals had accelerated and increased infiltration of CD4(+)IL-17A(+) and CD4(+)IL-17A(+)IFNγ(+) cells compared with WT animals. Th17 cells infiltrating the brain demonstrated a pathogenic phenotype with the expression of the transcription factor, Tbet, and the production of granzyme B, IL-22, and GM-CSF, with greater production of GM-CSF in IL-10(-/-) mice. Therefore, in fatal alphavirus encephalomyelitis, pathogenic Th17 cells enter the CNS at the onset of neurologic disease and, in the absence of IL-10, appear earlier, develop into Th1/Th17 cells more often, and have greater production of GM-CSF. This study demonstrates a role for pathogenic Th17 cells in fatal viral encephalitis.

  8. Mesenchymal Stem Cells Overexpressing Interleukin-10 Promote Neuroprotection in Experimental Acute Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Masataka Nakajima

    2017-09-01

    Full Text Available Interleukin (IL-10 is a contributing factor to neuroprotection of mesenchymal stem cell (MSC transplantation after ischemic stroke. Our aim was to increase therapeutic effects by combining MSCs and ex vivo IL-10 gene transfer with an adeno-associated virus (AAV vector using a rat transient middle cerebral artery occlusion (MCAO model. Sprague-Dawley rats underwent 90 min MCAO followed by intravenous administration of MSCs alone or IL-10 gene-transferred MSCs (MSC/IL-10 at 0 or 3 hr after ischemia reperfusion. Infarct lesions, neurological deficits, and immunological analyses were performed within 7 days after MCAO. 0-hr transplantation of MSCs alone and MSC/IL-10 significantly reduced infarct volumes and improved motor function. Conversely, 3-hr transplantation of MSC/IL-10, but not MSCs alone, significantly reduced infarct volumes (p < 0.01 and improved motor function (p < 0.01 compared with vehicle groups at 72 hr and 7 days after MCAO. Immunological analysis showed that MSC/IL-10 transplantation significantly inhibits microglial activation and pro-inflammatory cytokine expression compared with MSCs alone. Moreover, overexpressing IL-10 suppressed neuronal degeneration and improved survival of engrafted MSCs in the ischemic hemisphere. These results suggest that overexpressing IL-10 enhances the neuroprotective effects of MSC transplantation by anti-inflammatory modulation and thereby supports neuronal survival during the acute ischemic phase.

  9. Interleukin 10: A new risk marker for the development of restenosis after percutaneous coronary intervention

    NARCIS (Netherlands)

    Monraats, P.S.; Kurreeman, F.A.S.; Pons, D.; Sewgobind, V.D.K.D.; Vries, F.R. de; Zwinderman, A.H.; Maat, M.P.M. de; Doevendans, P.A.; Winter, R.J. de; Tio, R.A.; Waltenberger, J.; Huizinga, T.W.J.; Eefting, D.; Quax, P.H.A.; Frants, R.R.; Laarse, A. van der; Wall, E.E. van der; Jukema, J.W.

    2007-01-01

    Genetic factors appear to be important in the process of restenosis after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. An important mediator in the inflammatory response is interleukin (IL)-10. Our aim was to study whether genetic variants in

  10. Interleukin-10 rs2227307 and CXCR2 rs1126579 polymorphisms modulate the predisposition to septic shock

    Directory of Open Access Journals (Sweden)

    Cristina Padre Cardoso

    2015-06-01

    Full Text Available Despite major improvements in its treatment and diagnosis, sepsis is still a leading cause of death and admittance to the intensive care unit (ICU. Failure to identify patients at high risk of developing septic shock contributes to an increase in the sepsis burden and rapid molecular tests are currently the most promising avenue to aid in patient risk determination and therapeutic anticipation. The primary goal of this study was to evaluate the genetic susceptibility that affects sepsis outcome in 72 sepsis patients admitted to the ICU. Seven polymorphisms were genotyped in key inflammatory response genes in sepsis, including tumour necrosis factor-α, interlelukin (IL-1β, IL-10, IL-8, Toll-like receptor 4, CXCR1 and CXCR2. The primary finding showed that patients who were homozygous for the major A allele in IL-10 rs1800896 had almost five times higher chance to develop septic shock compared to heterozygotes. Similarly, selected clinical features and CXCR2 rs1126579 single nucleotide polymorphisms modulated septic shock susceptibility without affecting survival. These data support the hypothesis that molecular testing has clinical usefulness to improve sepsis prognostic models. Therefore, enrichment of the ICU portfolio by including these biomarkers will aid in the early identification of sepsis patients who may develop septic shock.

  11. Micro RNA-98 suppresses interleukin-10 in peripheral B cells in patient post-cardio transplantation.

    Science.gov (United States)

    Song, Jiangping; Su, Wenjun; Chen, Xiao; Zhao, Qian; Zhang, Ningning; Li, Mao-Gang; Yang, Ping-Chang; Wang, Liqing

    2017-04-25

    The immune tolerance to the transplant heart survival is critical. Regulatory B cells are one of the major immune regulatory cell populations in the immune tolerance. Micro RNAs (miR) can regulate the activities of immune cells, such as the expression of interleukin (IL)-10 by B cells. This study tests a hypothesis that micro RNA (miR)-98 plays a role in the regulation of interleukin (IL)-10 expression in B cells (B10 cell) after heart transplantation. In this study, the peripheral blood samples were collected from patients before and after heart transplantation. The expression of miR-98 and IL-10 in B cells was assessed by real time RT-PCR. An allograft heart transplantation mouse model was developed. We observed that after heart transplantation, the frequency of peripheral B10 cell and the IL-10 mRNA levels in peripheral B cells were significantly decreased, the levels of miR-98 were increased in peripheral B cells and the serum levels of cortisol were increased in the patients. Treating naive B cells with cortisol in the culture suppressed the expression of IL-10 in B cells, which was abolished by knocking down the miR-98 gene. Administration with anti-miR-98, or cortisol inhibitor, or adoptive transfer with B10 cells, significantly enhanced the survival rate and time of mice received allograft heart transplantation. In conclusion, the enhancement of serum cortisol affects the immune tolerant feature of B cells, which can be attenuated by anti-miR-98-carrying liposomes.

  12. Interleukin 10 Level in the Cerebrospinal Fluid as a Possible Biomarker for Lymphomatosis Cerebri.

    Science.gov (United States)

    Hashiguchi, Shunta; Momoo, Takayuki; Murohashi, Yoko; Endo, Masanao; Shimamura, Megumi; Kawasaki, Takashi; Kanada, Sachie; Nozawa, Akinori; Tada, Mikiko; Koyano, Shigeru; Tanaka, Fumiaki

    2015-01-01

    A 71-year-old immunocompetent man developed cognitive decline and gait disturbance. Brain magnetic resonance imaging (MRI) revealed bilateral diffuse leukoencephalopathy without a mass lesion. An analysis of the cerebrospinal fluid (CSF) showed elevated levels of interleukin (IL)-10. The condition of the patient progressively deteriorated, and intravenous high-dose steroids proved ineffective. Detection of non-destructive, diffusely infiltrating, large B-cell lymphoma in biopsy and autopsy specimens led to a diagnosis of lymphomatosis cerebri (LC). On serial MRI, the basal ganglia and white matter lesions increased in parallel with the levels of IL-10. These findings suggest that the IL-10 level in the CSF may represent a potentially useful biomarker for the early diagnosis and monitoring of the disease progression in LC.

  13. Sequence and functional analysis of a homolog of interleukin-10 encoded by the parapoxvirus orf virus.

    Science.gov (United States)

    Fleming, S B; Haig, D M; Nettleton, P; Reid, H W; McCaughan, C A; Wise, L M; Mercer, A

    2000-01-01

    Orf virus is a large DNA virus and is the type species of the Parapoxvirus genus of the family Poxviridae. Orf virus infects the epithelium of sheep and goats and is transmissible to humans. Recently we discovered a gene in orf virus that encodes a polypeptide with remarkable homology to mammalian interleukin (IL-10) and viral encoded IL-10s of herpes viruses. The predicted polypeptide sequence shows high levels of amino acid identity to IL-10 of sheep (80%), cattle (75%), humans (67%) and mice (64%), as well as IL-10-like proteins of Epstein-Barr virus (63%) and equine herpes virus (67%). The C-terminal region, comprising two-thirds of the orf virus protein, is identical to ovine IL-10 which suggests that this gene has been captured from its host sheep during the evolution of orf virus. In contrast the N-terminal region shows little homology with cellular IL10s and in this respect resembles other viral IL-10s. IL-10 is a pleiotrophic cytokine that can exert either immunostimulatory or immunosuppressive effects on many cell types. IL-10 is a potent anti-inflammatory cytokine with inhibitory effects on non-specific immunity in particular macrophage function and Thl effector function. Our studies so far, indicate, that the functional activities of orf virus IL-10 are the same as ovine IL-10. Orf virus IL-10 stimulates mouse thymocyte proliferation and inhibits cytokine synthesis in lipopolysaccharide-activated ovine macrophages, peripheral blood monocytes and keratinocytes. Infection of sheep with an IL-10 deletion mutant of orf virus has shown that interferon-gamma levels are higher in tissue infected with the mutant virus than the parent virus. The functional activities of IL-10 and our data on orf virus IL-10 suggest a role in immune evasion.

  14. Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

    Science.gov (United States)

    Gill, JasKiran K.; Savolainen, Mari; Young, Gareth T.; Zwart, Ruud; Sher, Emanuele; Millar, Neil S.

    2011-01-01

    Conventional nicotinic acetylcholine receptor (nAChR) agonists, such as acetylcholine, act at an extracellular “orthosteric” binding site located at the interface between two adjacent subunits. Here, we present evidence of potent activation of α7 nAChRs via an allosteric transmembrane site. Previous studies have identified a series of nAChR-positive allosteric modulators (PAMs) that lack agonist activity but are able to potentiate responses to orthosteric agonists, such as acetylcholine. It has been shown, for example, that TQS acts as a conventional α7 nAChR PAM. In contrast, we have found that a compound with close chemical similarity to TQS (4BP-TQS) is a potent allosteric agonist of α7 nAChRs. Whereas the α7 nAChR antagonist metyllycaconitine acts competitively with conventional nicotinic agonists, metyllycaconitine is a noncompetitive antagonist of 4BP-TQS. Mutation of an amino acid (M253L), located in a transmembrane cavity that has been proposed as being the binding site for PAMs, completely blocks agonist activation by 4BP-TQS. In contrast, this mutation had no significant effect on agonist activation by acetylcholine. Conversely, mutation of an amino acid located within the known orthosteric binding site (W148F) has a profound effect on agonist potency of acetylcholine (resulting in a shift of ∼200-fold in the acetylcholine dose-response curve), but had little effect on the agonist dose-response curve for 4BP-TQS. Computer docking studies with an α7 homology model provides evidence that both TQS and 4BP-TQS bind within an intrasubunit transmembrane cavity. Taken together, these findings provide evidence that agonist activation of nAChRs can occur via an allosteric transmembrane site. PMID:21436053

  15. Combining a GLP-1 receptor agonist and basal insulin: study evidence and practical considerations.

    Science.gov (United States)

    Carris, Nicholas W; Taylor, James R; Gums, John G

    2014-12-01

    Most patients with diabetes mellitus require multiple medications to achieve glycemic goals. Considering this and the increasing incidence of type 2 diabetes worldwide, the need for effective combination therapy is pressing. Basal insulin and glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes. Though both classes of medication are exclusively injectable, which may cause initial hesitation from providers, evidence for their combined use is substantial. This review summarizes the theoretical benefit, supporting evidence, and implementation of a combined basal insulin-GLP-1 receptor agonist regimen. Basal insulin added to a GLP-1 receptor agonist reduces hemoglobin A1c (HbA1c) without weight gain or significantly increased hypoglycemia. A GLP-1 receptor agonist added to basal insulin reduces HbA1c and body weight. Compared with the addition of meal-time insulin to basal insulin, a GLP-1 receptor agonist produces similar or greater reduction in HbA1c, weight loss instead of weight gain, and less hypoglycemia. Gastrointestinal adverse events are common with GLP-1 receptor agonists, especially during initiation and titration. However, combination with basal insulin is not expected to augment expected adverse events that come with using a GLP-1 receptor agonist. Basal insulin can be added to a GLP-1 receptor agonist with a slow titration to target goal fasting plasma glucose. In patients starting a GLP-1 receptor agonist, the dose of basal insulin should be decreased by 20 % in patients with an HbA1c ≤8 %. The evidence from 15 randomized prospective studies supports the combined use of a GLP-1 receptor agonist with basal insulin in a broad range of patients with uncontrolled type 2 diabetes.

  16. Association Between Benzodiazepine Receptor Agonists and Snoring Among Women in the Nurses' Health Study.

    Science.gov (United States)

    Lin, Brian M; Hu, Frank B; Curhan, Gary C

    2017-02-01

    Snoring is highly prevalent among adults. The use of benzodiazepine receptor agonists is also common, with higher prevalence of use with more advanced age. Benzodiazepine receptor agonists cause muscle relaxation, which may affect muscle tone and airway dynamics and thereby increase snoring. Previous studies examining the association between use of benzodiazepine receptor agonists and snoring were underpowered to detect clinically meaningful differences or did not report the magnitude of association. To investigate the association between use of benzodiazepine receptor agonists and snoring in women. Women aged 62 to 86 years provided information on snoring and covariates of interest in the 2008 survey of the Nurses' Health Study, a cross-sectional cohort study of female registered nurses in the United States. Potential effect modification of the association between use of benzodiazepine receptor agonists and snoring by age, body mass index, waist circumference, smoking, alcohol consumption, and physical activity was explored. Logistic regression was used to adjust for potential confounders. Data analysis was conducted from November 2015 to March 2016. Self-reported habitual snoring, defined as a few nights a week or more. Of 52 504 participants (mean [SD] age, 72.4 [6.7] years), 14 831 (28.2%) reported habitual snoring. There was a slightly higher prevalence of benzodiazepine receptor agonist use among habitual snorers (11.4%) compared with nonhabitual snorers (10.6%) (absolute difference, 0.8%; 95% CI, 0.2%-1.4%). After multivariable adjustment, use of benzodiazepine receptor agonists was not associated with snoring (odds ratio, 1.01; 95% CI, 0.95-1.07) compared with women who did not use benzodiazepine receptor agonists. Although there was no significant interaction with smoking, there were higher odds of snoring with use of benzodiazepine receptor agonists among current smokers (odds ratio, 1.34; 95% CI, 1.04-1.73). Use of benzodiazepine receptor agonists is

  17. Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells.

    Science.gov (United States)

    Pan, Shi; Sharma, Pawan; Shah, Sushrut D; Deshpande, Deepak A

    2017-07-01

    Airway remodeling, including increased airway smooth muscle (ASM) mass, is a hallmark feature of asthma and COPD. We previously identified the expression of bitter taste receptors (TAS2Rs) on human ASM cells and demonstrated that known TAS2R agonists could promote ASM relaxation and bronchodilation and inhibit mitogen-induced ASM growth. In this study, we explored cellular mechanisms mediating the antimitogenic effect of TAS2R agonists on human ASM cells. Pretreatment of ASM cells with TAS2R agonists chloroquine and quinine resulted in inhibition of cell survival, which was largely reversed by bafilomycin A1, an autophagy inhibitor. Transmission electron microscope studies demonstrated the presence of double-membrane autophagosomes and deformed mitochondria. In ASM cells, TAS2R agonists decreased mitochondrial membrane potential and increased mitochondrial ROS and mitochondrial fragmentation. Inhibiting dynamin-like protein 1 (DLP1) reversed TAS2R agonist-induced mitochondrial membrane potential change and attenuated mitochondrial fragmentation and cell death. Furthermore, the expression of mitochondrial protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) and mitochondrial localization of DLP1 were significantly upregulated by TAS2R agonists. More importantly, inhibiting Bnip3 mitochondrial localization by dominant-negative Bnip3 significantly attenuated cell death induced by TAS2R agonist. Collectively the TAS2R agonists chloroquine and quinine modulate mitochondrial structure and function, resulting in ASM cell death. Furthermore, Bnip3 plays a central role in TAS2R agonist-induced ASM functional changes via a mitochondrial pathway. These findings further establish the cellular mechanisms of antimitogenic effects of TAS2R agonists and identify a novel class of receptors and pathways that can be targeted to mitigate airway remodeling as well as bronchoconstriction in obstructive airway diseases. Copyright © 2017 the American Physiological

  18. Reconciling the Mitscherlich's law of diminishing returns with Liebig's law of the minimum. Some results on crop modeling.

    Science.gov (United States)

    Ferreira, Iuri E P; Zocchi, Silvio S; Baron, Daniel

    2017-11-01

    Reliable fertilizer recommendations depend on the correctness of the crop production models fitted to the data, but generally the crop models are built empirically, neglecting important physiological aspects related with response to fertilizers, or they are based in laws of plant mineral nutrition seen by many authors as conflicting theories: the Liebig's Law of the Minimum and Mitscherlich's Law of Diminishing Returns. We developed a new approach to modelling the crop response to fertilizers that reconcile these laws. In this study, the Liebig's Law is applied at the cellular level to explain plant production and, as a result, crop models compatible with the Law of Diminishing Returns are derived. Some classical crop models appear here as special cases of our methodology, and a new interpretation for Mitscherlich's Law is also provided. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Diminished insulin-mediated forearm blood flow and muscle glucose uptake in young men with low birth weight

    DEFF Research Database (Denmark)

    Sonne, M P; Højbjerre, L; Alibegovic, A C

    2009-01-01

    with venous occlusion plethysmography and intra-arterial infusions of adenosine and acetylcholine, before and during a hyperinsulinemic isoglycemic clamp. RESULTS: Forearm blood flow response to systemic hyperinsulinemia was diminished in LBW compared to controls (p Fractional arteriovenous glucose...... extraction was similar, and consequently insulin-stimulated forearm glucose clearance was diminished in LBW compared with controls (0.8 +/- 0.09 vs. 1.4 +/- 0.36 ml x 100 ml(-1) x min(-1), respectively, p blood flow response to adenosine and acetylcholine with or without insulin stimulation...... did not differ between groups. Whole-body glucose uptake was lower in LBW than controls (8.7 +/- 0.5 and 9.1 +/- 0.6 mg x min(-1) x kg(-1) lean body mass); however, this was not significant. CONCLUSIONS: Forearm blood flow response to insulin is impaired in LBW, whereas the response to adenosine...

  20. The emergence of devastating impulse control disorders during dopamine agonist therapy of the restless legs syndrome.

    Science.gov (United States)

    Dang, Dien; Cunnington, David; Swieca, John

    2011-01-01

    The Restless Legs Syndrome is a common sensorimotor disorder, typically amenable to treatment with dopamine agonist therapy. Dopamine agonists have been associated with emergent impulse control disorders (ICDs) when used in patients with Parkinson disease, and ICDs have now been reported in individuals with RLS on dopamine agonist therapy. Our aim was to characterize cases of emergent ICDs in Australian patients with focus on the dopamine agonists implicated and the social significance of ICDs. A series of RLS patients on dopamine agonist therapy were identified with ICDs over a 2-year period. Additional cases of ICDs were found using a mailout questionnaire designed to capture those with high impulsivity. These patients were assessed using the Barratt Impulsiveness Scale, Version 11, and a modified Minnesota Impulse Disorders Interview. Case records and medication schedules were evaluated. Twelve cases of patients with de novo ICDs were found with a range of impulsive behaviors including pathological gambling, kleptomania, compulsive shopping, and hypersexuality. Criminality, suicidality, and marital discord also were featured. These occurred over a wide range of latencies and l-dopa exposures. This group of Australian RLS patients with ICDs display high levels of impulsivity and is the first to use the BIS-11 questionnaire in this setting. Impulse control disorders can occur over a wide range of dopamine agonist therapy types and dose exposures. Impulse control disorder tendencies may persist, despite withdrawal of dopamine agonists. The emergence of ICDs needs careful consideration in light of their potentially devastating financial, social, and marital consequences.

  1. Association of dopamine agonist use with impulse control disorders in Parkinson disease.

    Science.gov (United States)

    Weintraub, Daniel; Siderowf, Andrew D; Potenza, Marc N; Goveas, Joseph; Morales, Knashawn H; Duda, John E; Moberg, Paul J; Stern, Matthew B

    2006-07-01

    To determine the frequency and correlates of impulse control disorders (ICDs) in Parkinson disease (PD). An unstructured screening interview for ICDs (compulsive gambling, buying, and sexual behavior) followed by a telephone-administered structured interview for screen-positive patients. Two university-affiliated movement disorders centers. A convenience sample of 272 patients with idiopathic PD who were screened for psychiatric complications. Presence of compulsive gambling, buying, or sexual behavior as assessed by the Minnesota Impulsive Disorders Interview. Eighteen patients (6.6%) with PD met criteria for an ICD at some point during the course of PD, including 11 (4.0%) with an active ICD. Compulsive gambling and compulsive sexual behavior were equally common. In a multivariate model, treatment with a dopamine agonist (P = .01) and a history of ICD symptoms prior to PD onset (P = .02) predicted current ICD. There were no differences between the dopamine agonists in their association with ICDs (P = .21), and daily doses of dopamine agonists were higher in patients with an ICD than in dopamine agonist-treated patients without an ICD (P < .001). Patients with PD treated with a dopamine agonist should be made aware of the risk of developing an ICD and monitored clinically. Because dopamine agonists are increasingly being used for other indications, future research should assess the dopamine agonist-associated risk for ICDs in other populations.

  2. Dopamine Agonist Use is Associated with Impulse Control Disorders in Parkinson’s Disease

    Science.gov (United States)

    Weintraub, Daniel; Siderowf, Andrew D.; Potenza, Marc N.; Goveas, Joseph; Morales, Knashawn H.; Duda, John E.; Moberg, Paul J.; Stern, Matthew B.

    2006-01-01

    Objective To determine the frequency and correlates of impulse control disorders (ICDs) in Parkinson’s disease (PD). Design An unstructured screening interview for ICDs (compulsive gambling, buying, and sexual behavior) followed by a telephone-administered structured interview for screen-positive patients. Setting Two university-affiliated movement disorders centers. Participants A convenience sample of 272 patients with idiopathic PD who were screened for psychiatric complications. Main Outcome Measures Presence of compulsive gambling, buying, or sexual behavior as assessed by the Minnesota Impulsive Disorders Interview. Results Eighteen (6.6%) PD patients met criteria for an ICD at some point during the course of PD, including 11 (4.0%) with an active ICD. Compulsive gambling and compulsive sexual behavior were equally common. In a multivariate model, treatment with a dopamine agonist (P = .01) and a history of ICD symptomatology prior to PD onset (P = .02) predicted current ICD. There were no differences between the dopamine agonists in their association with ICDs (P = .21), and daily doses of dopamine agonists were higher in patients with an ICD than in dopamine agonist-treated patients without an ICD (P < .001). Conclusions PD patients treated with a dopamine agonist should be made aware of the risk of developing an ICD and monitored clinically. As dopamine agonists are increasing being used for other indications, future research should assess the dopamine agonist-associated risk for ICDs in other populations. PMID:16831966

  3. Serotonin 2A receptor agonist binding in the human brain with [C]Cimbi-36

    DEFF Research Database (Denmark)

    Ettrup, A.; da Cunha-Bang, S.; McMahon, Barry P.

    2014-01-01

    [C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely ....... Thus, we here describe [C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT receptors in the human brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 30 April 2014; doi:10.1038/jcbfm.2014.68.......[C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely...... than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT receptors with [C]Cimbi-36 PET. The two-tissue compartment model using arterial input...

  4. The Role of Agonistic Striving in the Association Between Cortisol and High Blood Pressure.

    Science.gov (United States)

    Ewart, Craig K; Elder, Gavin J; Jorgensen, Randall S; Fitzgerald, Sheila T

    2017-05-01

    A social action theory of chronic stress proposes that agonistic striving (seeking to influence or control others) impairs cardiovascular health by magnifying the impact of high adversity-induced cortisol levels on blood pressure. We tested three predictions of social action theory: (1) the social action theory taxonomy of regulatory strivings characterizes young adults from high-adversity neighborhoods; (2) high cortisol levels predict high blood pressure more reliably in the subgroup with the agonistic striving profile than in subgroups with other profiles; (3) the association of higher cortisol and higher blood pressure with agonistic striving is not explained by negative affect (depressive symptoms/dysphoria, anger, hostility). Participants were young adults (N = 198, mean [SD] age = 32 [3.4] years); 71% female; 65% black) from disadvantaged urban neighborhoods. Motive profiles (including agonistic strivings) were assessed using the Social Competence Interview. Cortisol levels were derived from saliva samples; blood pressure level was obtained during two days of ambulatory monitoring. Psychological measures of negative affect were assessed using questionnaires. The predicted taxonomy of regulatory strivings was replicated in this sample; the interaction between cortisol and motive profile was significant (F(2, 91) = 6.72, p = .002); analyses of simple effects disclosed that higher cortisol levels predicted higher ambulatory blood pressure only in individuals who exhibited agonistic striving. Depressive symptoms/dysphoria, trait anger, and hostility were not correlated with agonistic striving, cortisol, or blood pressure. Agonistic striving may represent a distinctive (and novel) social-cognitive mechanism of toxic stress and cardiovascular risk.

  5. The Effect of PPAR Agonists on the Migration of Mature and Immature Eosinophils

    Directory of Open Access Journals (Sweden)

    Steven G. Smith

    2012-01-01

    Full Text Available PPARγ agonists can either enhance or inhibit eosinophil migration, which is a sum of directional migration (chemotaxis and random cell movement (chemokinesis. To date, the effects of PPAR agonists on chemokinesis have not been examined. This study investigates the effects of PPARα, δ, and γ agonists on eosinophil migration and chemokinesis. Eosinophils purified from blood of atopic donors were preincubated with rosiglitazone (PPARγ agonist, GW9578 (PPARα agonist, GW501516 (PPARδ agonist, or diluent. The effects of PPAR agonists were examined on eosinophil chemokinesis, eotaxin-induced migration of eosinophils, and migration of IL-5Rα+ CD34+ cells. Expressions of CCR3, phospho-p38, phospho-ERK, and calcium release were also measured in eosinophils after rosiglitazone treatment. Low concentrations of rosiglitazone, but not GW9578 or GW501516, increased chemokinesis of eosinophils (P=0.0038, and SDF-1α-induced migration of immature eosinophils (P=0.0538. Rosiglitazone had an effect on eosinophil calcium flux but had no effect on expression of CCR3 or phosphorylation of p38 or ERK. In contrast, high concentrations of rosiglitazone inhibited eosinophil migration (P=0.0042. The effect of rosiglitazone on eosinophil migration and chemokinesis appears to be through modification of calcium signaling, which alludes to a novel PPAR-mediated mechanism to modulate eosinophil function.

  6. Ascorbic acid enables reversible dopamine receptor 3H-agonist binding

    International Nuclear Information System (INIS)

    Leff, S.; Sibley, D.R.; Hamblin, M.; Creese, I.

    1981-01-01

    The effects of ascorbic acid on dopaminergic 3 H-agonist receptor binding were studied in membrane homogenates of bovine anterior pituitary and caudate, and rat striatum. In all tissues virtually no stereospecific binding (defined using 1uM (+)butaclamol) of the 3 H-agonists N-propylnorapomorphine (NPA), apomorphine, or dopamine could be demonstrated in the absence of ascorbic acid. Although levels of total 3 H-agonist binding were three to five times greater in the absence than in the presence of 0.1% ascorbic acid, the increased binding was entirely non-stereospecific. Greater amounts of dopamine-inhibitable 3 H-NPA binding could be demonstrated in the absence of 0.1% ascorbic acid, but this measure of ''specific binding'' was demonstrated not to represent dopamine receptor binding since several other catecholamines and catechol were equipotent with dopamine and more potent than the dopamine agonist (+/-)amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) in inhibiting this binding. High levels of dopamine-displaceable 3 H-agonist binding were detected in fresh and boiled homogenates of cerebellum, an area of brain which receives no dopaminergic innervation, further demonstrating the non-specific nature of 3 H-agonist binding in the absence of ascorbic acid. These studies emphasize that under typical assay conditions ascorbic acid is required in order to demonstrate reversible and specific 3 H-agonist binding to dopamine receptors

  7. Usefulness of HeLa cells to evaluate inverse agonistic activity of antihistamines.

    Science.gov (United States)

    Mizuguchi, Hiroyuki; Ono, Shohei; Hattori, Masashi; Sasaki, Yohei; Fukui, Hiroyuki

    2013-03-01

    Antihistamines are thought to antagonize histamine and prevent it from binding to the histamine H1 receptor (H1R). However, recent studies indicate that antihistamines are classified into two groups, i.e., inverse agonists and neutral antagonists on the basis of their ability to down-regulate the constitutive activity of H1R. As H1R is an allergy-sensitive gene whose expression influences the severity of allergic symptoms, inverse agonists should more potently alleviate allergic symptoms than neutral antagonists by inhibiting H1R constitutive activity. Therefore, it is important to assess inverse agonistic activity of antihistamines. Here we report a novel assay method using HeLa cells expressing H1R endogenously for evaluation of inverse agonistic activity of antihistamines. Pretreatment with inverse agonists down-regulated H1R gene expression below to its basal level. On the other hand, basal H1R mRNA expression was unchanged by neutral antagonist pretreatment. Both inverse agonists and neutral antagonists suppressed histamine-induced H1R mRNA elevation. Classification of antihistamines on the basis of their suppressive activity of basal H1R gene expression was consistent with that of inositol phosphate accumulation in H1R-overexpressed cells. Our data suggest that the assay method using HeLa cells is more convenient and useful than the existing methods and may contribute to develop new antihistamines with inverse agonistic activity. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Chronic treatment with Tempol during acquisition or withdrawal from CPP abolishes the expression of cocaine reward and diminishes oxidative damage

    OpenAIRE

    Beiser, Tehila; Numa, Ran; Kohen, Ron; Yaka, Rami

    2017-01-01

    In previous studies, we reported that pretreatment with the antioxidant Tempol attenuated the development and expression of cocaine-induced psychomotor sensitization in rats and diminished cocaine-induced oxidative stress (OS) in the prefrontal cortex (PFC) and nucleus accumbens (NAc), suggesting a potential role for Tempol in interfering with cocaine-related psychomotor sensitization. The aim of the current study was to examine the role of Tempol in reward and reinforcement using the conditi...

  9. Diminished alternative reinforcement as a mechanism linking conduct problems and substance use in adolescence: a longitudinal examination.

    Science.gov (United States)

    Khoddam, Rubin; Cho, Junhan; Jackson, Nicholas J; Leventhal, Adam M

    2018-01-14

    To determine whether diminished alternative reinforcement (i.e. engagement and enjoyment from substance-free activities) mediated the longitudinal association of conduct problems with substance use in early-mid-adolescence. Structural equation modeling tested whether the association between wave 1 (baseline) conduct problems and wave 3 (24-month follow-up) substance use outcomes was mediated by diminished alternative reinforcement at wave 2 (12-month follow-up). Additional analyses tested whether sex and socio-economic status moderated this association. Ten high schools in Los Angeles, CA, USA, 2013-15. Students (n = 3396, 53.5% female, mean [standard deviation (SD)] age at wave 1 baseline = 14.1 (0.42) years). Self-reported conduct problems (11-item questionnaire), alternative reinforcement (44-item questionnaire) and use of alcohol, marijuana and combustible cigarettes during the past 6 months (yes/no) and the past 30 days (nine-level ordinal response based on days used in past 30 days). Significant associations of wave 1 conduct problems with wave 3 marijuana use during the past 6 months (β = 0.25) and past 30 days (β = 0.26) were mediated by wave 2 diminished alternative reinforcement (β indirect effect : 6 months = 0.013, 30 days = 0.017, Ps conduct problems with alcohol or combustible cigarette use were not mediated by alternative reinforcement. All associations did not differ by sex and socio-economic status. Diminished alternative reinforcement may be a modifiable mechanism linking early adolescent conduct problems and subsequent marijuana use that could be targeted in prevention programs to offset the adverse health and social sequelae associated with comorbid conduct problems and marijuana use in early-mid adolescence. © 2018 Society for the Study of Addiction.

  10. Diet-related modification of cuticular hydrocarbon profiles of the Argentine ant, Linepithema humile, diminishes intercolony aggression.

    Science.gov (United States)

    Buczkowski, Grzegorz; Kumar, Ranjit; Suib, Steven L; Silverman, Jules

    2005-04-01

    Territorial boundaries between conspecific social insect colonies are maintained through a highly developed nestmate recognition system modulated by heritable and, in some instances, nonheritable cues. Argentine ants, Linepithema humile, use both genetic and environmentally derived cues to discriminate nestmates from nonnestmates. We explored the possibility that intraspecific aggression in the Argentine ant might diminish when colonies shared a common diet. After segregating recently field-collected colony pairs into high or moderate aggression categories, we examined the effect of one of three diets: two hydrocarbon-rich insect prey, Blattella germanica and Supella longipalpa, and an artificial (insect-free) diet, on the magnitude of aggression loss. Aggression diminished between colony pairs that were initially moderately aggressive. However, initially highly aggressive colony pairs maintained high levels of injurious aggression throughout the study, independent of diet type. Each diet altered the cuticular hydrocarbon profile by contributing unique, diet-specific cues. We suggest that acquisition of common exogenous nestmate recognition cues from shared food sources may diminish aggression and promote fusion in neighboring colonies of the Argentine ant.

  11. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    Energy Technology Data Exchange (ETDEWEB)

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi, E-mail: kumamote@cc.saga-u.ac.jp

    2013-04-26

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  12. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    International Nuclear Information System (INIS)

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-01-01

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC 50 values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC 50 = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other

  13. Regulation of ventilation and oxygen consumption by delta- and mu-opioid receptor agonists.

    Science.gov (United States)

    Schaeffer, J I; Haddad, G G

    1985-09-01

    To study the effect of endorphins on metabolic rate and on the relationship between O2 consumption (VO2) and ventilation, we administered enkephalin analogues (relatively selective delta-receptor agonists) and a morphiceptin analogue (a highly selective mu-receptor agonist) intracisternally in nine unanesthetized chronically instrumented adult dogs. Both delta- and mu-agonists decreased VO2 by 40-60%. delta-Agonists induced a dose-dependent decrease in mean instantaneous minute ventilation (VT/TT) associated with periodic breathing. The decrease in VT/TT started and resolved prior to the decrease and returned to baseline of VO2, respectively. In contrast, the mu-agonists induced an increase in VT/TT associated with rapid shallow breathing. Arterial PCO2 increased and arterial PO2 decreased after both delta- and mu-agonists. Low doses of intracisternal naloxone (0.002-2.0 micrograms/kg) reversed the opioid effect on VT/TT but not on VO2; higher doses of naloxone (5-25 micrograms/kg) reversed both. Naloxone administered alone had no effect on VT/TT or VO2. These data suggest that 1) both delta- and mu-agonists induce alveolar hypoventilation despite a decrease in VO2, 2) this hypoventilation results from a decrease in VT/TT after delta-agonists but an increase in dead space ventilation after mu-agonists, and 3) endorphins do not modulate ventilation and metabolic rate tonically, but we speculate that they may do so in response to stressful stimulation.

  14. TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors

    Directory of Open Access Journals (Sweden)

    Teagan R. Wall

    2017-09-01

    Full Text Available (E-5-(Pyrimidin-5-yl-1,2,3,4,7,8-hexahydroazocine (TC299423 is a novel agonist for nicotinic acetylcholine receptors (nAChRs. We examined its efficacy, affinity, and potency for α6β2∗ (α6β2-containing, α4β2∗, and α3β4∗ nAChRs, using [125I]-epibatidine binding, whole-cell patch-clamp recordings, synaptosomal 86Rb+ efflux, [3H]-dopamine release, and [3H]-acetylcholine release. TC299423 displayed an EC50 of 30–60 nM for α6β2∗ nAChRs in patch-clamp recordings and [3H]-dopamine release assays. Its potency for α6β2∗ in these assays was 2.5-fold greater than that for α4β2∗, and much greater than that for α3β4∗-mediated [3H]-acetylcholine release. We observed no major off-target binding on 70 diverse molecular targets. TC299423 was bioavailable after intraperitoneal or oral administration. Locomotor assays, measured with gain-of-function, mutant α6 (α6L9′S nAChR mice, show that TC299423 elicits α6β2∗ nAChR-mediated responses at low doses. Conditioned place preference assays show that low-dose TC299423 also produces significant reward in α6L9′S mice, and modest reward in WT mice, through a mechanism that probably involves α6(non-α4β2∗ nAChRs. However, TC299423 did not suppress nicotine self-administration in rats, indicating that it did not block nicotine reinforcement in the dosage range that was tested. In a hot-plate test, TC299423 evoked antinociceptive responses in mice similar to those of nicotine. TC299423 and nicotine similarly inhibited mouse marble burying as a measure of anxiolytic effects. Taken together, our data suggest that TC299423 will be a useful small-molecule agonist for future in vitro and in vivo studies of nAChR function and physiology.

  15. T151. APATHY AND DIMINISHED EXPRESSION ARE NOT ASSOCIATED WITH VENTRAL OR DORSAL STRIATUM VOLUME IN SCHIZOPHRENIA

    Science.gov (United States)

    Burrer, Achim; Kirschner, Matthias; Seifritz, Erich; Stefan, Kaiser

    2018-01-01

    Abstract Background Negative symptoms are core features of schizophrenia and can be grouped into two domains. These are apathy including anhedonia, avolition and asocialty as well as diminished expression including blunted affect and alogia. A large body of research found that ventral striatal hypoactivation is linked to negative symptoms. In particular, it has been shown that this neural correlate is specific for apathy but not diminished expression. Here, we investigated whether this dissociation can also be found in ventral striatum volume. Methods We included brain structural T1 MRI data of 60 patients diagnosed with schizophrenia (SZ) and 58 healthy controls (HC). Negative symptoms in these groups have been assessed using the Brief Negative Symptom Scale (BNSS). We performed voxel-based morphometry (VBM) using the statistical parametric mapping package (SPM 12; Wellcome Trust Centre for Neuroimaging, London). We performed a region of interest (ROI) analysis of ventral and dorsal striatal volume between patients with schizophrenia and healthy controls. Furthermore, we analyzed the correlation of right and left ventral striatal volume with apathy and diminished expression in patients with schizophrenia. Moreover, we analyzed potential group differences in gray matter volume in an exploratory whole-brain analysis. Finally, we performed an exploratory whole-brain linear regression to identify potential correlations between the two negative symptom dimensions and gray matter volume. (cluster-defining threshold of p < 0.001, cluster-level pFWE < 0.05) Results Patients with schizophrenia showed no differences in ventral striatal volume compared to healthy controls. Apathy or diminished expression did not correlate with ventral or dorsal striatal gray matter volume in patients with schizophrenia. In the exploratory whole-brain analysis we found significant less gray matter volume in the right insula of schizophrenia patients compared to healthy controls (cluster

  16. SENESCENCE-ASSOCIATED DECLINE IN HEPATIC PEROXISOMAL ENZYME ACTIVITIES CORRESPONDS WITH DIMINISHED LEVELS OF RETINOID X RECEPTOR ALPHA, BUT NOT PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA1

    Science.gov (United States)

    AbstractAging is associated with alterations in hepatic peroxisomal metabolism and susceptibility to hepatocarcinogenecity produced by agonists of peroxisome proliferator-activated receptor alpha (PPARa). Mechanisms involved in these effects are not well understood. Howev...

  17. Neurotensin Agonist Attenuates Nicotine Potentiation to Cocaine Sensitization

    Directory of Open Access Journals (Sweden)

    Paul Fredrickson

    2014-01-01

    Full Text Available Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a “gateway drug”. Neurotensin (NT is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13 analog, blocks behavioral sensitization (an animal model for psychostimulant addiction to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine.

  18. Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis

    Directory of Open Access Journals (Sweden)

    Fabrizio Fierro

    2017-09-01

    Full Text Available Human G-protein coupled receptors (hGPCRs constitute a large and highly pharmaceutically relevant membrane receptor superfamily. About half of the hGPCRs' family members are chemosensory receptors, involved in bitter taste and olfaction, along with a variety of other physiological processes. Hence these receptors constitute promising targets for pharmaceutical intervention. Molecular modeling has been so far the most important tool to get insights on agonist binding and receptor activation. Here we investigate both aspects by bioinformatics-based predictions across all bitter taste and odorant receptors for which site-directed mutagenesis data are available. First, we observe that state-of-the-art homology modeling combined with previously used docking procedures turned out to reproduce only a limited fraction of ligand/receptor interactions inferred by experiments. This is most probably caused by the low sequence identity with available structural templates, which limits the accuracy of the protein model and in particular of the side-chains' orientations. Methods which transcend the limited sampling of the conformational space of docking may improve the predictions. As an example corroborating this, we review here multi-scale simulations from our lab and show that, for the three complexes studied so far, they significantly enhance the predictive power of the computational approach. Second, our bioinformatics analysis provides support to previous claims that several residues, including those at positions 1.50, 2.50, and 7.52, are involved in receptor activation.

  19. PPAR and Agonists against Cancer: Rational Design of Complementation Treatments

    Directory of Open Access Journals (Sweden)

    Dorina Veliceasa

    2008-01-01

    Full Text Available PPAR is a member of the ligand-activated nuclear receptor superfamily: its ligands act as insulin sensitizers and some are approved for the treatment of metabolic disorders in humans. PPAR has pleiotropic effects on survival and proliferation of multiple cell types, including cancer cells, and is now subject of intensive preclinical cancer research. Studies of the recent decade highlighted PPAR role as a potential modulator of angiogenesis in vitro and in vivo. These observations provide an additional facet to the PPAR image as potential anticancer drug. Currently PPAR is regarded as an important target for the therapies against angiogenesis-dependent pathological states including cancer and vascular complications of diabetes. Some of the studies, however, identify pro-angiogenic and tumor-promoting effects of PPAR and its ligands pointing out the need for further studies. Below, we summarize current knowledge of PPAR regulatory mechanisms and molecular targets, and discuss ways to maximize the beneficial activity of the PPAR agonists.

  20. PPAR agonists, - Could tissue targeting pave the way?

    Science.gov (United States)

    Bugge, Anne; Holst, Dorte

    2017-05-01

    Over the last couple of decades, the PPAR family of transcription factors has received much attention from the pharmaceutical industry due to their profound ability to improve glucose and lipid metabolism upon agonist activation. However, more recently the interest in these nuclear receptors has faded because several clinical trials have shown that it is difficult to develop a ligand that significantly ameliorates glucose and lipid metabolism disorders without concomitantly inducing unacceptable side-effects. Nevertheless, the data also suggests that tissue specific targeting could pave the way to renewed interest and clinical use of PPAR ligands. In this review we summarize the results and learnings from the clinical trials on PPAR agonism and discuss the possibilities for tissue targeting of PPAR ligands by using state of the art technology to fuse them to peptides homing selectively to tissues expressing the cognate surface receptor. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  1. Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist.

    Science.gov (United States)

    Bandholtz, Sebastian; Erdmann, Sarah; von Hacht, Jan Lennart; Exner, Samantha; Krause, Gerd; Kleinau, Gunnar; Grötzinger, Carsten

    2016-11-23

    This study investigated the role of individual U-II amino acid positions and side chain characteristics important for U-IIR activation. A complete permutation library of 209 U-II variants was studied in an activity screen that contained single substitution variants of each position with one of the other 19 proteinogenic amino acids. Receptor activation was measured using a cell-based high-throughput fluorescence calcium mobilization assay. We generated the first complete U-II substitution map for U-II receptor activation, resulting in a detailed view into the structural features required for receptor activation, accompanied by complementary information from receptor modeling and ligand docking studies. On the basis of the systematic SAR study of U-II, we created 33 further short and linear U-II variants from eight to three amino acids in length, including d- and other non-natural amino acids. We identified the first high-potency linear U-II analogues. Urolinin, a linear U-II agonist (nWWK-Tyr(3-NO 2 )-Abu), shows low nanomolar potency as well as improved metabolic stability.

  2. Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin-1 receptor in the grey squirrel (Sciurus carolinensis).

    Science.gov (United States)

    McRobie, Helen R; King, Linda M; Fanutti, Cristina; Symmons, Martyn F; Coussons, Peter J

    2014-06-27

    The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1RΔ24) variant. We demonstrate that the MC1RΔ24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RΔ24. We conclude that the deletion in the MC1RΔ24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  3. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

    Science.gov (United States)

    Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

    2013-01-01

    This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

  4. Comparison of Agonist vs. Antagonist Stimulation on Triceps Surae Spasticity in Spinal Cord

    Directory of Open Access Journals (Sweden)

    Sneha Khanna

    2017-06-01

    Discussion: This study provides evidence that both agonist electrical stimulation and antagonist electrical stimulations are equally effective in reducing spasticity in triceps surae muscle in patients with spinal cord injury.

  5. Minimal_Set_of_In_Vitro_ER_Agonist_Assays_Selection_RegToxPharm_Data

    Data.gov (United States)

    U.S. Environmental Protection Agency — A dataset for the manuscript which demonstrates that it is possible to achieve levels of performance equivalent to the full 16 assay ER agonist model against both in...

  6. Agonists of fibroblast growth factor receptor induce neurite outgrowth and survival of cerebellar granule neurons

    DEFF Research Database (Denmark)

    Li, Shizhong; Christensen, Claus; Køhler, Lene B

    2009-01-01

    Fibroblast growth factor receptor (FGFR) signaling is pivotal in the regulation of neurogenesis, neuronal differentiation and survival, and synaptic plasticity both during development and in adulthood. In order to develop low molecular weight agonists of FGFR, seven peptides, termed hexafins...

  7. Crystal structure of the GLP-1 receptor bound to a peptide agonist.

    Science.gov (United States)

    Jazayeri, Ali; Rappas, Mathieu; Brown, Alastair J H; Kean, James; Errey, James C; Robertson, Nathan J; Fiez-Vandal, Cédric; Andrews, Stephen P; Congreve, Miles; Bortolato, Andrea; Mason, Jonathan S; Baig, Asma H; Teobald, Iryna; Doré, Andrew S; Weir, Malcolm; Cooke, Robert M; Marshall, Fiona H

    2017-06-08

    Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an α-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.

  8. Structure and biological activity of endogenous and synthetic agonists of GPR119

    Science.gov (United States)

    Tyurenkov, I. N.; Ozerov, A. A.; Kurkin, D. V.; Logvinova, E. O.; Bakulin, D. A.; Volotova, E. V.; Borodin, D. D.

    2018-02-01

    A G-protein-coupled receptor, GPR119, is a promising pharmacological target for a new class of hypoglycaemic drugs with an original mechanism of action, namely, increase in the glucose-dependent incretin and insulin secretion. In 2005, the first ligands were found and in the subsequent years, a large number of GPR119 agonists were synthesized in laboratories in various countries; the safest and most promising agonists have entered phase I and II clinical trials as agents for the treatment of type 2 diabetes mellitus and obesity. The review describes the major endogenous GPR119 agonists and the main trends in the design and modification of synthetic structures for increasing the hypoglycaemic activity. The data on synthetic agonists are arranged according to the type of the central core of the molecules. The bibliography includes 104 references.

  9. Dopamine D1 receptor agonist treatment attenuates extinction of morphine conditioned place preference while increasing dendritic complexity in the nucleus accumbens core.

    Science.gov (United States)

    Kobrin, Kendra L; Arena, Danielle T; Heinrichs, Stephen C; Nguyen, Olivia H; Kaplan, Gary B

    2017-03-30

    The dopamine D1 receptor (D1R) has a role in opioid reward and conditioned place preference (CPP), but its role in CPP extinction is undetermined. We examined the effect of D1R agonist SKF81297 on the extinction of opioid CPP and associated dendritic morphology in the nucleus accumbens (NAc), a region involved with reward integration and its extinction. During the acquisition of morphine CPP, mice received morphine and saline on alternate days; injections were given immediately before each of eight daily conditioning sessions. Mice subsequently underwent six days of extinction training designed to diminish the previously learned association. Mice were treated with either 0.5mg/kg SKF81297, 0.8mg/kg SKF81297, or saline immediately after each extinction session. There was a dose-dependent effect, with the highest dose of SKF81297 attenuating extinction, as mice treated with this dose had significantly higher CPP scores than controls. Analysis of medium spiny neuron morphology revealed that in the NAc core, but not in the shell, dendritic arbors were significantly more complex in the morphine conditioned, SKF81297-treated mice compared to controls. In separate experiments using mice conditioned with only saline, SKF81297 administration after extinction sessions had no effect on CPP and produced differing effects on dendritic morphology. At the doses used in our experiments, SKF81297 appears to maintain previously learned opioid conditioned behavior, even in the face of new information. The D1R agonist's differential, rather than unidirectional, effects on dendritic morphology in the NAc core suggests that it may be involved in encoding reward information depending on previously learned behavior. Published by Elsevier B.V.

  10. The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor.

    Science.gov (United States)

    Westaway, Susan M; Brown, Samantha L; Conway, Elizabeth; Heightman, Tom D; Johnson, Christopher N; Lapsley, Kate; Macdonald, Gregor J; MacPherson, David T; Mitchell, Darren J; Myatt, James W; Seal, Jon T; Stanway, Steven J; Stemp, Geoffrey; Thompson, Mervyn; Celestini, Paolo; Colombo, Andrea; Consonni, Alessandra; Gagliardi, Stefania; Riccaboni, Mauro; Ronzoni, Silvano; Briggs, Michael A; Matthews, Kim L; Stevens, Alexander J; Bolton, Victoria J; Boyfield, Izzy; Jarvie, Emma M; Stratton, Sharon C; Sanger, Gareth J

    2008-12-15

    Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.

  11. Improvement in psoriasis after treatment with the glucagon-like peptide-1 receptor agonist liraglutide

    DEFF Research Database (Denmark)

    Faurschou, A; Knop, F K; Thyssen, J P

    2011-01-01

    A 59-year old man with moderate and stable psoriasis through 15 years was admitted to our Department with inadequately controlled type 2 diabetes. Treatment was initiated with the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide. The patient experienced marked improvement in his...... improvement in comorbidities such as overweight. Randomized clinical trials are needed to reveal whether GLP-1R agonists represent a new therapeutic option for psoriasis....

  12. Terguride, a dopamine D(2) partial agonist, as a discriminative stimulus in rats.

    Science.gov (United States)

    Yamaguchi, M.; Kimura-Iwasaki, K.; Akai, T.; Nakada, Y.; Nakagawa, H.

    1991-06-01

    Drug discrimination training with terguride, a 9, 10-transdihydrogenated derivative of lisuride, was carried out using a two-lever food-reinforced procedure (FR 10) in rats, to investigate its influence on central dopaminergic (DA) and serotonergic (5-HT) functions. The terguride (0.05mg/kg, i.p.) discrimination was established within 64 +/- 5 training sessions (mean +/- S.E.) and was stably maintained thereafter. Higher doses of terguride could not be used for discriminative training due to response disruption. In generalization tests with terguride, drug-appropriate responding increased dose-dependently and reached levels of 45 and 99% at 0.01 and 0.05mg/kg i.p. The D(2) agonist lisuride at low doses and the DA autoreceptor agonist (-)-3-PPP substituted for terguride. The DA agonist apomorphine and the 5-HT agonist 5-MeO-DMT produced dose-dependent but incomplete substitution. The D(1) agonist SKF38393, the DA antagonist haloperidol, the D(2) antagonist sulpiride, the D(1) antagonist SCH23390, the 5-HT(1A) agonist 8-OH-DPAT, the 5-HT(1B) agonist m-CPP and the 5-HT(2) agonist DOI were not generalized. In antagonism tests, sulpride completely blocked the terguride-appropriate response, but SCH23390 and the 5-HT antagonist methysergide did not. These results indicate that discriminative stimulus properties of terguride in rats are mediated primarily by activation of receptors with characteristics similar to those of presynaptic D(2) autoreceptors.

  13. Effect of ventilation pressure on alveolar fluid clearance and beta-agonist responses in mice.

    Science.gov (United States)

    Yu, Erin N Z; Traylor, Zachary P; Davis, Ian C

    2009-10-01

    High tidal volume ventilation is detrimental to alveolar fluid clearance (AFC), but effects of ventilation pressure (P) on AFC are unknown. In anesthetized BALB/c mice ventilated at constant tidal volume (8 ml/kg), mean AFC rate was 12.8% at 6 cmH(2)O P, but increased to 37.3% at 18 cmH(2)O P. AFC rate declined at 22 cmH(2)O P, which also induced lung damage. Increased AFC at 18 cmH(2)O P did not result from elevated plasma catecholamines, hypercapnia, or hypocapnia, but was due to augmented Na(+) and Cl(-) absorption. PKA agonists and beta-agonists stimulated AFC at 10 cmH(2)O P by upregulating amiloride-sensitive Na(+) transport. However, at 18 cmH(2)O P, PKA agonists and beta-agonists reduced AFC. At 15 cmH(2)O P, the AFC rate was intermediate (mean 26.6%), and forskolin and beta-agonists had no effect. Comparable P dependency of AFC and beta-agonist responsiveness was found in C57BL/6 mice. The effect on AFC of increasing P to 18 cmH(2)O was blocked by adenosine deaminase or an A(2b)-adenosine receptor antagonist, and could be mimicked by adenosine in mice ventilated at 10 cmH(2)O P. Modulation of adenosine signaling also resulted in altered responsiveness to beta-agonists. These findings indicate that, in the normal mouse lung, basal AFC rates and responses to beta-agonists are impacted by ventilation pressure in an adenosine-dependent manner.

  14. An Overview of the CNS-Pharmacodynamic Profiles of Nonselective and Selective GABA Agonists

    Directory of Open Access Journals (Sweden)

    Xia Chen

    2012-01-01

    Full Text Available Various 2,3 subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are expected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines. Several 2,3 subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery addressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2 mg was the comparator in three studies. Three 2,3-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498, one 1-selective GABAA agonists (zolpidem, and another full agonist (alprazolam were examined. Pharmacological selectivity was assessed by determination of regression lines for the change from baseline of saccadic-peak-velocity- (ΔSPV- relative effect, relative to changes in different pharmacodynamic endpoints (ΔPD. SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes of the ΔSPV-ΔPD relations were consistently lower with the 2,3 selective GABA-A agonists than with lorazepam, indicating that their PD effects are less than their SPV-effects. The ΔSPV-ΔPD relations of lorazepam were comparable to alprazolam. Zolpidem showed relatively higher impairments in ΔPD relative to ΔSPV, but did not significantly differ from lorazepam. These PD results support the pharmacological selectivity of the 2,3-selective GABA-A agonists, implying an improved therapeutic window.

  15. Hierarchical Phosphorylation of δ-Opioid Receptor Regulates Agonist-induced Receptor Desensitization and Internalization*

    OpenAIRE

    Maestri-El Kouhen, Odile; Wang, Guilin; Solberg, Jonathan; Erickson, Laurie J.; Law, Ping-Yee; Loh, Horace H.

    2000-01-01

    Treatment of HEK293 cells expressing the δ-opioid receptor with agonist [d-Pen2,5]enkephalin (DPDPE) resulted in the rapid phosphorylation of the receptor. We constructed several mutants of the potential phosphorylation sites (Ser/Thr) at the carboxyl tail of the receptor in order to delineate the receptor phosphorylation sites and the agonist-induced desensitization and internalization. The Ser and Thr were substituted to alanine, and the corresponding mutants were transiently and stably exp...

  16. Discovery of Azetidinone Acids as Conformationally-Constrained Dual PPARalpha/gamma Agonists

    Energy Technology Data Exchange (ETDEWEB)

    Wang, W.; Devasthale, P; Farrelly, D; Gu, L; Harrity, T; Cap, M; Chu, C; Kunselman, L; Morgan, N; et. al.

    2008-01-01

    A novel class of azetidinone acid-derived dual PPAR{alpha}/{gamma} agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARa and PPAR? receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

  17. Evaluation of the Tolerability of Switching Patients on Chronic Full ?-Opioid Agonist Therapy to Buccal Buprenorphine

    OpenAIRE

    Webster, Lynn; Gruener, Daniel; Kirby, Todd; Xiang, Qinfang; Tzanis, Evan; Finn, Andrew

    2016-01-01

    Objective?Assess whether patients with chronic pain receiving 80 to 220?mg oral morphine sulfate equivalent of a full ?-opioid agonist could be transitioned to buccal buprenorphine at approximately 50% of their full dose without inducing opioid withdrawal or sacrificing analgesic efficacy. Methods.?A randomized, double-blind, double-dummy, active-controlled, two-period crossover study in adult patients receiving around-the-clock full opioid agonist therapy and confirmed to be opioid dependent...

  18. TRPA1 agonist activity of probenecid desensitizes channel responses: consequences for screening.

    Science.gov (United States)

    McClenaghan, Conor; Zeng, Fanning; Verkuyl, Jan Martin

    2012-12-01

    The transient receptor potential channel subtype A member 1 (TRPA1) is a nonselective cation channel widely viewed as having therapeutic potential, particularly for pain-related indications. Realization of this potential will require potent, selective modulators; however, currently the pharmacology of TRPA1 is poorly defined. As TRPA1 is calcium permeable, calcium indicators offer a simple assay format for high-throughput screening. In this report, we show that probenecid, a uricosuric agent used experimentally in screening to increase loading of calcium-sensitive dyes, activates TRPA1. Prolonged probenecid incubation during the dye-loading process reduces agonist potency upon subsequent challenge. When Chinese Hamster Ovary (CHO)-hTRPA1 or STC-1 cells, which endogenously express TRPA1, were dye loaded in the presence of 2 mM probenecid TRPA1, agonists appeared less potent; EC(50) for allyl isothiocyante agonists in CHO-hTRPA1 was increased from 1.5±0.19 to 7.32±1.20 μM (P<0.01). No significant effect on antagonist potency was observed when using the agonist EC(80) concentration determined under the appropriate dye-loading conditions. We suggest an alternative protocol for calcium imaging using another blocker of anion transport, sulfinpyrazone. This blocker significantly augments indicator dye loading and the screening window, but is not a TRPA1 agonist and has no effect on agonist potency.

  19. In vitro effects of Beta-2 agonists on skeletal muscle differentiation, hypertrophy, and atrophy.

    Science.gov (United States)

    Wannenes, Francesca; Magni, Loretta; Bonini, Matteo; Dimauro, Ivan; Caporossi, Daniela; Moretti, Costanzo; Bonini, Sergio

    2012-06-01

    : Beta-2 agonists are widely used in the treatment of asthma and chronic obstructive pulmonary disease for their effect on airway smooth muscle relaxation. They also act on skeletal muscle, although their reported ergogenic effect is controversial. : To evaluate the in vitro effects of short-acting and long-acting beta-2 agonists on adrenergic receptor (ADR) expression, hypertrophy, and atrophy markers, in a skeletal muscle cell line. : The C2C12 cell line was used as a model of skeletal muscle differentiation. ADR messenger RNA expression was evaluated in proliferating myoblasts, committed cells, and differentiated myotubes, in basal conditions and after treatment with 10 M clenbuterol, salbutamol, salmeterol, and formoterol. Effect of beta-2 agonists on gene and protein expression of hypertrophy and atrophy markers was assessed in differentiated myotubes. : Our study shows that beta-2 ADR messenger RNA was expressed and progressively increased during cell differentiation. Beta-2 agonist treatment did not affect its expression. Skeletal muscle hypertrophy markers (fast and slow myosin, myogenin) were not modulated by any of the beta-2 agonists evaluated. However, clenbuterol induced a significant, dose-dependent downregulation of skeletal muscle atrophy genes (atrogin-1, MuRF-1, and cathepsin L). : The reported ergogenic effect of beta-2 agonists, if any, should be considered as drug-specific and not class-specific and that of clenbuterol is mediated by the inhibition of the atrophic pathway.

  20. Effects of cannabinoid and vanilloid receptor agonists and their interaction on learning and memory in rats.

    Science.gov (United States)

    Shiri, Mariam; Komaki, Alireza; Oryan, Shahrbanoo;