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Sample records for auranofin inhibit selenoprotein

  1. Selective inhibition of endogenous antioxidants with Auranofin causes mitochondrial oxidative stress which can be countered by selenium supplementation.

    Science.gov (United States)

    Radenkovic, Filip; Holland, Olivia; Vanderlelie, Jessica J; Perkins, Anthony V

    2017-12-15

    Auranofin is a thiol-reactive gold (I)-containing compound with potential asa chemotherapeutic. Auranofin has the capacity to selectively inhibit endogenous antioxidant enzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx), resulting in oxidative stress and the initiation of a pro-apoptotic cascade. The effect of Auranofin exposure on TrxR and GPx, and the potential for cellular protection through selenium supplementation was examined in the non-cancerous human cell line Swan-71. Auranofin exposure resulted in a concentration dependent differential inhibition of selenoprotein antioxidants. Significant inhibition of TrxR was observed at 20nM Auranofin with inhibition of GPx from 10µM. Significant increases in reactive oxygen species (ROS) were associated with antioxidant inhibition at Auranofin concentrations of 100nM (TrxR inhibition) and 10µM (TrxR and GPx inhibition), respectively. Evaluation of mitochondrial respiration demonstrated significant reductions in routine and maximal respiration at both 100nM and 10μM Auranofin. Auranofin treatment at concentrations of 10μM and higher concentrations resulted in a ∼68% decrease in cellular viability and was associated with elevations in pro-apoptotic markers cytochrome c flux control factor (FCFc) at concentration of 100nM and mitochondrial Bax at 10μM. The supplementation of selenium (100nM) prior to treatment had a generalized protective affect through the restoration of antioxidant activity with a significant increase in TrxR and GPx activity, a significant reduction in ROS and associated improvement in mitochondrial respiration and cellular viability (10µM ∼48% increase). Selenium supplementation reduced the FCFc at low doses of Auranofin (<10μM) however no effect was noted on either FCFc or Bax at concentrations above 10μM. The inhibition of antioxidant systems in non-cancerous cells by Auranofin is strongly dose dependent, and this inhibition can be altered by selenium exposure

  2. Investigation of a potential mechanism for the inhibition of SmTGR by Auranofin and its implications for Plasmodium falciparum inhibition

    KAUST Repository

    Caroli, Antonia

    2012-01-01

    Schistosoma mansoni and Plasmodium falciparum are pathogen parasites that spend part of their lives in the blood stream of the human host and are therefore heavily exposed to fluxes of toxic reactive oxygen species (ROS). SmTGR, an essential enzyme of the S. mansoni ROS detoxification machinery, is known to be inhibited by Auranofin although the inhibition mechanism has not been completely clarified. Auranofin also kills P. falciparum, even if its molecular targets are unknown. Here, we used computational and docking techniques to investigate the molecular mechanism of interaction between SmTGR and Auranofin. Furthermore, we took advantage of the homology relationship and of docking studies to assess if PfTR, the SmTGR malaria parasite homologue, can be a putative target for Auranofin. Our findings support a recently hypothesized molecular mechanism of inhibition for SmTGR and suggest that PfTR is indeed a possible and attractive drug target in P. falciparum. © 2011 Elsevier Inc.

  3. Auranofin Inhibits the Enzyme Activity of Pasteurella multocida Toxin PMT in Human Cells and Protects Cells from Intoxication

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    Stefan Carle

    2017-01-01

    Full Text Available The AB-type protein toxin from Pasteurella multocida (PMT contains a functionally important disulfide bond within its catalytic domain, which must be cleaved in the host cell cytosol to render the catalytic domain of PMT into its active conformation. Here, we found that the reductive potential of the cytosol of target cells, and more specifically, the activity of the thioredoxin reductase (TrxR is crucial for this process. This was demonstrated by the strong inhibitory effect of the pharmacological TrxR inhibitor auranofin, which inhibited the intoxication of target cells with PMT, as determined by analyzing the PMT-catalyzed deamidation of GTP-binding proteins (G-proteins in the cytosol of cells. The amount of endogenous substrate levels modified by PMT in cells pretreated with auranofin was reduced compared to cells treated with PMT alone. Auranofin had no inhibitory effect on the activity of the catalytic domain of constitutively active PMT in vitro, demonstrating that auranofin did not directly inhibit PMT activity, but interferes with the mode of action of PMT in cells. In conclusion, the results show that TrxR is crucial for the mode of action of PMT in mammalian cells, and that the drug auranofin can serve as an efficient inhibitor, which might be a starting point for novel therapeutic options against toxin-associated diseases.

  4. Auranofin Inhibits the Enzyme Activity of Pasteurella multocida Toxin PMT in Human Cells and Protects Cells from Intoxication.

    Science.gov (United States)

    Carle, Stefan; Brink, Thorsten; Orth, Joachim H C; Aktories, Klaus; Barth, Holger

    2017-01-13

    The AB-type protein toxin from Pasteurella multocida (PMT) contains a functionally important disulfide bond within its catalytic domain, which must be cleaved in the host cell cytosol to render the catalytic domain of PMT into its active conformation. Here, we found that the reductive potential of the cytosol of target cells, and more specifically, the activity of the thioredoxin reductase (TrxR) is crucial for this process. This was demonstrated by the strong inhibitory effect of the pharmacological TrxR inhibitor auranofin, which inhibited the intoxication of target cells with PMT, as determined by analyzing the PMT-catalyzed deamidation of GTP-binding proteins (G-proteins) in the cytosol of cells. The amount of endogenous substrate levels modified by PMT in cells pretreated with auranofin was reduced compared to cells treated with PMT alone. Auranofin had no inhibitory effect on the activity of the catalytic domain of constitutively active PMT in vitro, demonstrating that auranofin did not directly inhibit PMT activity, but interferes with the mode of action of PMT in cells. In conclusion, the results show that TrxR is crucial for the mode of action of PMT in mammalian cells, and that the drug auranofin can serve as an efficient inhibitor, which might be a starting point for novel therapeutic options against toxin-associated diseases.

  5. A proof-of-concept trial of protein kinase C iota inhibition with auranofin for the paclitaxel-induced acute pain syndrome.

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    Jatoi, Aminah; Grudem, Megan E; Dockter, Travis J; Block, Matthew S; Villasboas, Jose C; Tan, Angelina; Deering, Erin; Kasi, Pashtoon M; Mansfield, Aaron S; Botero, Juliana Perez; Okuno, Scott H; Smith, Deanne R; Fields, Alan P

    2017-03-01

    Paclitaxel causes the paclitaxel-induced acute pain (PIAP) syndrome. Based on preclinical data, we hypothesized that the protein kinase C (PKC) iota inhibitor, auranofin (a gold salt used for other pain conditions), palliates this pain. In a randomized, double-blinded manner, patients who had suffered this syndrome were assigned a one-time dose of auranofin 6 mg orally on day #2 of the chemotherapy cycle (post-paclitaxel) versus placebo. Patients completed the Brief Pain Inventory and a pain diary on days 2 through 8 and at the end of the cycle. The primary endpoint was pain scores, as calculated by area under the curve, in response to "Please rate your pain by circling the one number that best describes your pain at its worse in the last 24 hours." Thirty patients were enrolled. For the primary endpoint, mean area under the curve of 55 units (standard deviation 19) and 61 units (standard deviation 22) were observed in auranofin-treated and placebo-exposed patients, respectively (p = 0.44). On day 8 and at the end of the cycle, pain scores in auranofin-treated patients were more favorable, although differences were not statistically significant. In the dose schedule studied, auranofin did not palliate the PIAP syndrome, but delayed beneficial trends suggest further study for this indication.

  6. Deficiency in the 15 kDa Selenoprotein Inhibits Human Colon Cancer Cell Growth

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    Ryuta Tobe

    2011-09-01

    Full Text Available Selenium is an essential micronutrient for humans and animals, and is thought to provide protection against some forms of cancer. These protective effects appear to be mediated, at least in part, through selenium-containing proteins (selenoproteins. Recent studies in a mouse colon cancer cell line have shown that the 15 kDa selenoprotein (Sep15 may also play a role in promoting colon cancer. The current study investigated whether the effects of reversing the cancer phenotype observed when Sep15 was removed in mouse colon cancer cells, were recapitulated in HCT116 and HT29 human colorectal carcinoma cells. Targeted down-regulation of Sep15 using RNAi technology in these human colon cancer cell lines resulted in similarly decreased growth under anchorage-dependent and anchorage-independent conditions. However, the magnitude of reduction in cell growth was much less than in the mouse colon cancer cell line investigated previously. Furthermore, changes in cell cycle distribution were observed, indicating a delayed release of Sep15 deficient cells from the G0/G1 phase after synchronization. The potential mechanism by which human colon cancer cells lacking Sep15 revert their cancer phenotype will need to be explored further.

  7. Auranofin inactivates Trichomonas vaginalis thioredoxin reductase and is effective against trichomonads in vitro and in vivo.

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    Hopper, Melissa; Yun, Jeong-Fil; Zhou, Bianhua; Le, Christine; Kehoe, Katelin; Le, Ryan; Hill, Ryan; Jongeward, Gregg; Debnath, Anjan; Zhang, Liangfang; Miyamoto, Yukiko; Eckmann, Lars; Land, Kirkwood M; Wrischnik, Lisa A

    2016-12-01

    Trichomoniasis, caused by the protozoan parasite Trichomonas vaginalis, is the most common, non-viral, sexually transmitted infection in the world, but only two closely related nitro drugs are approved for its treatment. New antimicrobials against trichomoniasis remain an urgent need. Several organic gold compounds were tested for activity against T. vaginalis thioredoxin reductase (TrxR) in cell-free systems as well as for activity against different trichomonads in vitro and in a murine infection model. The organic gold(I) compounds auranofin and chloro(diethylphenylphosphine)gold(I) inhibited TrxR in a concentration-dependent manner in assays with recombinant purified reductase and in cytoplasmic extracts of T. vaginalis transfected with a haemagglutinin epitope-tagged form of the reductase. Auranofin potently suppressed the growth of three independent clinical T. vaginalis isolates as well as several strains of another trichomonad (Tritrichomonas foetus) in a 24 h-assay, with 50% inhibitory concentrations of 0.7-2.5 µM and minimum lethal concentrations of 2-6 µM. The drug also compromised the ability of the parasite to overcome oxidant stress, supporting the notion that auranofin acts, in part, by inactivating TrxR-dependent antioxidant defences. Chloro(diethylphenylphosphine)gold(I) was 10-fold less effective against T. vaginalis in vitro than auranofin. Oral administration of auranofin for 4 days cleared the parasites in a murine model of vaginal T. foetus infection without displaying any apparent adverse effects. The approved human drug auranofin may be a promising agent as an alternative treatment of trichomoniasis in cases when standard nitro drug therapies have failed. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  8. Salsalate and Adiponectin Improve Palmitate-Induced Insulin Resistance via Inhibition of Selenoprotein P through the AMPK-FOXO1α Pathway.

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    Jung, Tae Woo; Choi, Hae Yoon; Lee, So Young; Hong, Ho Cheol; Yang, Sae Jeong; Yoo, Hye Jin; Youn, Byung-Soo; Baik, Sei Hyun; Choi, Kyung Mook

    2013-01-01

    Selenoprotein P (SeP) was recently identified as a hepatokine that induces insulin resistance (IR) in rodents and humans. Recent clinical trials have shown that salsalate, a prodrug of salicylate, significantly lowers blood glucose levels and increases adiponectin concentrations. We examined the effects of salsalate and full length-adiponectin (fAd) on the expression of SeP under hyperlipidemic conditions and explored their regulatory mechanism on SeP. In palmitate-treated HepG2 cells as well as high fat diet (HFD)-fed male Spraque Dawley (SD) rats and male db/db mice, SeP expression and its regulatory pathway, including AMPK-FOXO1α, were evaluated after administration of salsalate and salicylate. Palmitate treatment significantly increased SeP expression and aggravated IR, while knock-down of SeP by siRNA restored these changes in HepG2 cells. Palmitate-induced SeP expression was inhibited by both salsalate and salicylate, which was mediated by AMPK activation, and was blocked by AMPK siRNA or an inhibitor of AMPK. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift (EMSA) assay showed that salsalate suppressed SeP expression by AMPK-mediated phosphorylation of FOXO1α. Moreover, fAd also reduced palmitate-induced SeP expression through the activation of AMPK, which results in improved IR. Both salsalate and salicylate treatment significantly improved glucose intolerance and insulin sensitivity, accompanied by reduced SeP mRNA and protein expression in HFD-fed rats and db/db mice, respectively. Taken together, we found that salsalate and adiponectin ameliorated palmitate-induced IR in hepatocytes via SeP inhibition through the AMPK-FOXO1α pathway. The regulation of SeP might be a novel mechanism mediating the anti-diabetic effects of salsalate and adiponectin.

  9. Salsalate and Adiponectin Improve Palmitate-Induced Insulin Resistance via Inhibition of Selenoprotein P through the AMPK-FOXO1α Pathway.

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    Tae Woo Jung

    Full Text Available Selenoprotein P (SeP was recently identified as a hepatokine that induces insulin resistance (IR in rodents and humans. Recent clinical trials have shown that salsalate, a prodrug of salicylate, significantly lowers blood glucose levels and increases adiponectin concentrations. We examined the effects of salsalate and full length-adiponectin (fAd on the expression of SeP under hyperlipidemic conditions and explored their regulatory mechanism on SeP. In palmitate-treated HepG2 cells as well as high fat diet (HFD-fed male Spraque Dawley (SD rats and male db/db mice, SeP expression and its regulatory pathway, including AMPK-FOXO1α, were evaluated after administration of salsalate and salicylate. Palmitate treatment significantly increased SeP expression and aggravated IR, while knock-down of SeP by siRNA restored these changes in HepG2 cells. Palmitate-induced SeP expression was inhibited by both salsalate and salicylate, which was mediated by AMPK activation, and was blocked by AMPK siRNA or an inhibitor of AMPK. Chromatin immunoprecipitation (ChIP and electrophoretic mobility shift (EMSA assay showed that salsalate suppressed SeP expression by AMPK-mediated phosphorylation of FOXO1α. Moreover, fAd also reduced palmitate-induced SeP expression through the activation of AMPK, which results in improved IR. Both salsalate and salicylate treatment significantly improved glucose intolerance and insulin sensitivity, accompanied by reduced SeP mRNA and protein expression in HFD-fed rats and db/db mice, respectively. Taken together, we found that salsalate and adiponectin ameliorated palmitate-induced IR in hepatocytes via SeP inhibition through the AMPK-FOXO1α pathway. The regulation of SeP might be a novel mechanism mediating the anti-diabetic effects of salsalate and adiponectin.

  10. Selenoprotein-Transgenic Chlamydomonas reinhardtii

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    Jiazuan Ni

    2013-02-01

    Full Text Available Selenium (Se deficiency is associated with the occurrence of many diseases. However, excessive Se supplementation, especially with inorganic Se, can result in toxicity. Selenoproteins are the major forms of Se in vivo to exert its biological function. Expression of those selenoproteins, especially with the application of a newly developed system, is thus very important for studying the mechanism of Se in nutrition. The use of Chlamydomonas reinhardtii (C. reinhardtii as a biological vector to express an heterogeneous protein is still at the initial stages of development. In order to investigate the possibility of using this system to express selenoproteins, human 15-KDa selenoprotein (Sep15, a small but widely distributed selenoprotein in mammals, was chosen for the expression platform test. Apart from the wild-type human Sep15 gene fragment, two Sep15 recombinants were constructed containing Sep15 open reading frame (ORF and the selenocysteine insertion sequence (SECIS element from either human Sep15 or C. reinhardtii selenoprotein W1, a highly expressed selenoprotein in this alga. Those Sep15-containing plasmids were transformed into C. reinhardtii CC-849 cells. Results showed that Sep15 fragments were successfully inserted into the nuclear genome and expressed Sep15 protein in the cells. The transgenic and wild-type algae demonstrated similar growth curves in low Se culture medium. To our knowledge, this is the first report on expressing human selenoprotein in green alga.

  11. Selenium, selenoproteins and vision.

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    Flohé, Leopold

    2005-01-01

    Selenium biochemistry is reviewed in respect to its presumed relevance to age-related ocular diseases. Selenium is an essential trace element that exerts its physiological role as selenocysteine residue in at least 25 distinct selenoenzymes in mammals. Lack of GPx-1 due to alimentary selenium deprivation has been inferred to induce cataract in rats and was demonstrated to cause cataracts in mice by targeted gene disruption. The role of other selenoproteins in the eye remains to be worked out. Selenium in excess of the tiny amounts required for selenoprotein synthesis is toxic in general and causes cataracts in experimental animals. Clinical evidence for a protective role of selenium in the development of cataract, macula degeneration, retinitis pigmentosa or any other ocular disease is not available, likely because suboptimum selenium intake, as it may result from unbalanced diet, does not cause any pathologically relevant selenium deficiency in the eye. At present, there is neither theoretical nor an empirical basis to expect beneficial effects of selenium supplementation beyond the dietary reference intakes of 55 microg/day in the context of ocular diseases.

  12. Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.

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    Christina A Bulman

    2015-02-01

    Full Text Available Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC, and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.

  13. Evolution of selenoproteins in the metazoan

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    Jiang Liang

    2012-09-01

    Full Text Available Abstract Background The selenocysteine (Sec containing proteins, selenoproteins, are an important group of proteins present throughout all 3 kingdoms of life. With the rapid progression of selenoprotein research in the post-genomic era, application of bioinformatics methods to the identification of selenoproteins in newly sequenced species has become increasingly important. Although selenoproteins in human and other vertebrates have been investigated, studies of primitive invertebrate selenoproteomes are rarely reported outside of insects and nematodes. Result A more integrated view of selenoprotein evolution was constructed using several representative species from different evolutionary eras. Using a SelGenAmic-based selenoprotein identification method, 178 selenoprotein genes were identified in 6 invertebrates: Amphimedon queenslandica, Trichoplax adhaerens, Nematostella vectensis, Lottia gigantean, Capitella teleta, and Branchiostoma floridae. Amphioxus was found to have the most abundant and variant selenoproteins of any animal currently characterized, including a special selenoprotein P (SelP possessing 3 repeated Trx-like domains and Sec residues in the N-terminal and 2 Sec residues in the C-terminal. This gene structure suggests the existence of two different strategies for extension of Sec numbers in SelP for the preservation and transportation of selenium. In addition, novel eukaryotic AphC-like selenoproteins were identified in sponges. Conclusion Comparison of various animal species suggests that even the most primitive animals possess a selenoproteome range and variety similar to humans. During evolutionary history, only a few new selenoproteins have emerged and few were lost. Furthermore, the massive loss of selenoproteins in nematodes and insects likely occurred independently in isolated partial evolutionary branches.

  14. Auranofin efficacy against MDR Streptococcus pneumoniae and Staphylococcus aureus infections.

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    Aguinagalde, Leire; Díez-Martínez, Roberto; Yuste, Jose; Royo, Inmaculada; Gil, Carmen; Lasa, Íñigo; Martín-Fontecha, Mar; Marín-Ramos, Nagore Isabel; Ardanuy, Carmen; Liñares, Josefina; García, Pedro; García, Ernesto; Sánchez-Puelles, José M

    2015-09-01

    Auranofin is an FDA-approved, gold-containing compound in clinical use for the oral treatment of rheumatoid arthritis and has been recently granted by the regulatory authorities due to its antiprotozoal properties. A reprofiling strategy was performed with a Streptococcus pneumoniae phenotypic screen and a proprietary library of compounds, consisting of both FDA-approved and unapproved bioactive compounds. Two different multiresistant S. pneumoniae strains were employed in a sepsis mouse model of infection. In addition, an MRSA strain was tested using both the thigh model and a mesh-associated biofilm infection in mice. The repurposing approach showed the high potency of auranofin against multiresistant clinical isolates of S. pneumoniae and Staphylococcus aureus in vitro and in vivo. Efficacy in the S. pneumoniae sepsis model was obtained using auranofin by the oral route in the dose ranges used for the treatment of rheumatoid arthritis. Thioglucose replacement by alkyl chains showed that this moiety was not essential for the antibacterial activity and led to the discovery of a new gold derivative (MH05) with remarkable activity in vitro and in vivo. Auranofin and the new gold derivative MH05 showed encouraging in vivo activity against multiresistant clinical isolates of S. pneumoniae and S. aureus. The clinical management of auranofin, alone or in combination with other antibiotics, deserves further exploration before use in patients presenting therapeutic failure caused by infections with multiresistant Gram-positive pathogens. Decades of clinical use mean that this compound is safe to use and may accelerate its evaluation in humans. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action.

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    Parsonage, Derek; Sheng, Fang; Hirata, Ken; Debnath, Anjan; McKerrow, James H; Reed, Sharon L; Abagyan, Ruben; Poole, Leslie B; Podust, Larissa M

    2016-05-01

    The anti-arthritic gold-containing drug Auranofin is lethal to the protozoan intestinal parasite Entamoeba histolytica, the causative agent of human amebiasis, in both culture and animal models of the disease. A putative mechanism of Auranofin action proposes that monovalent gold, Au(I), released from the drug, can bind to the redox-active dithiol group of thioredoxin reductase (TrxR). Au(I) binding in the active site is expected to prevent electron transfer to the downstream substrate thioredoxin (Trx), thus interfering with redox homeostasis in the parasite. To clarify the molecular mechanism of Auranofin action in more detail, we determined a series of atomic resolution X-ray structures for E. histolytica thioredoxin (EhTrx) and thioredoxin reductase (EhTrxR), the latter with and without Auranofin. Only the disulfide-bonded form of the active site dithiol (Cys(140)-Cys(143)) was invariably observed in crystals of EhTrxR in spite of the addition of reductants in various crystallization trials, and no gold was found associated with these cysteines. Non-catalytic Cys(286) was identified as the only site of modification, but further mutagenesis studies using the C286Q mutant demonstrated that this site was not responsible for inhibition of EhTrxR by Auranofin. Interestingly, we obtained both of the catalytically-relevant conformations of this bacterial-like, low molecular weight TrxR in crystals without requiring an engineered disulfide linkage between Cys mutants of TrxR and Trx (as was originally done with Escherichia coli TrxR and Trx). We note that the -CXXC- catalytic motif, even if reduced, would likely not provide space sufficient to bind Au(I) by both cysteines of the dithiol group. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin

    Energy Technology Data Exchange (ETDEWEB)

    Oommen, Deepu [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom); Yiannakis, Dennis [Plymouth Oncology Centre, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth PL6 8DH (United Kingdom); Jha, Awadhesh N., E-mail: a.jha@plymouth.ac.uk [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom)

    2016-02-15

    Highlights: • BRCA1 deficient cancer cells exhibit increased DNA damage upon auranofin treatment. • Auranofin induces apoptosis in BRCA1 deficient cancer cells despite the activation of Nrf2. • Antioxidant protects BRCA1 deficient cancer cells from auranofin. - Abstract: Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2—related factor 2 (Nrf2) via direct protein–protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.

  17. Analysis of Conserved Structural Features of Selenoprotein K | Al ...

    African Journals Online (AJOL)

    Selenium plays important roles in human health and these roles may be exerted through its presence in selenoproteins. Among the 25 selenoproteins in human is selenoprotein K (SelK) whose exact function is still unclear. Here, we investigated the conserved structural features of SelK using bioinformatics as an approach ...

  18. Selenium, selenoproteins and neurodegenerative diseases.

    Science.gov (United States)

    Cardoso, Bárbara Rita; Roberts, Blaine R; Bush, Ashley I; Hare, Dominic J

    2015-08-01

    It is unsurprising that our understanding of the role of selenium in neurological function is somewhat immature, considering its relatively recent discovery as an essential element to human health. Selenocysteine, the 21st amino acid, is the defining feature of the 25 selenoprotein-encoding genes so far discovered within the human genome. The low abundance of these proteins in the brain belies the integral role they play in normal neurological function, from well-characterised antioxidant activity in the periphery to poorly understood mechanisms that modulate mitochondrial function and response to brain pathology. Selenium has been identified as playing a role in several neurodegenerative disorders, including Alzheimer's and Parkinson's disease, though its function as a 'cause or effect' of disease process remains unclear. This review discusses selenium metabolism in detail, specifically with regard to the role it plays within the central nervous system, and examines the most current literature investigating how selenium may be involved in chronic diseases of the central nervous system.

  19. A new look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases

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    Jocelyn M Madeira

    2015-01-01

    Full Text Available Neurodegenerative disorders including Alzheimer′s disease are characterized by chronic inflammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise another class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neurodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.

  20. Ebola viral selenoproteins: a metallomics analysis

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    Somsri Wiwanitkit

    2015-01-01

    Full Text Available Ebola virus infection is the present public health problem. The trend of worldwide epidemic becomes the serious consideration for this infection. The Ebola virus infection has main clinical manifestation as acute febrile illness with hemorrhagic episode. The problem of hemostatic disturbance can be seen. Focusing on the pathophysiology, selenium plays an important role in the blood clotting regulation. The study on the selenoprotein of the Ebola virus can be useful for further understanding on the pathology of the infection. Here, the authors use metallomics analysis for assessment of Ebola virus genome. According to this study, the selenoprotein portion within Ebola virus genome can be detected at position 1046-1115.

  1. Auranofin-loaded nanoparticles as a new therapeutic tool to fight streptococcal infections

    National Research Council Canada - National Science Library

    Díez-Martínez, Roberto; García-Fernández, Esther; Manzano, Miguel; Martínez, Ángel; Domenech, Mirian; Vallet-Regí, María; García, Pedro

    2016-01-01

    .... We have loaded auranofin, a gold compound traditionally used for treatment of rheumatoid arthritis, into PLGA NPs and their efficiency as antibacterial agent against two Gram-positive pathogens...

  2. Auranofin protects against cocaine-induced hepatic injury through induction of heme oxygenase-1.

    Science.gov (United States)

    Ashino, Takashi; Sugiuchi, Jinko; Uehara, Junna; Naito-Yamamoto, Yumiko; Kenmotsu, Sachiyo; Iwakura, Yoichiro; Shioda, Seiji; Numazawa, Satoshi; Yoshida, Takemi

    2011-10-01

    Auranofin, a disease-modifying gold compound, has been empirically applying to the management of rheumatoid arthritis. We investigated a protective effect of auranofin against hepatic injury induced by cocaine. Cocaine (75 mg/kg) markedly increased serum alanine amino transferase (ALT) (4,130 IU/l) and aspartate amino transferase (AST) (1,730 IU/l) activities at 16 hr after treatment, and induced hepatic necrosis surrounding central veins in mice. Concurrently, overexpression of heme oxygenase-1 (HO-1), a rate-limiting enzyme for heme degradation and an oxidative stress marker, was identified at the edges of cocaine-mediated necrotic area. Auranofin (10 mg/ml, i.p.) significantly induced hepatic HO-1 protein in mice from 12 hr after treatment. Interestingly, pretreatment with auranofin resulted in the prevention of the increase of serum ALT and AST activities in a dose-dependent manner. On the other hand, although cocaine increased tumor necrosis factor α (TNFα) gene expression in mouse livers, cocaine-induced liver injury was observed in TNFα deficient mice as well as wild-type mice. Auranofin-inducted HO-1 gene expression was observed in human primary hepatocytes as well as mouse primary hepatocytes. The present findings suggest that auranofin is effective in preventing cocaine-induced hepatic injury, and HO-1 may contribute to protect against chemically-induced cytotoxicity.

  3. The 15kDa selenoprotein and thioredoxin reductase 1 promote colon cancer by different pathways.

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    Petra A Tsuji

    Full Text Available Selenoproteins mediate much of the cancer-preventive properties of the essential nutrient selenium, but some of these proteins have been shown to also have cancer-promoting effects. We examined the contributions of the 15kDa selenoprotein (Sep15 and thioredoxin reductase 1 (TR1 to cancer development. Targeted down-regulation of either gene inhibited anchorage-dependent and anchorage-independent growth and formation of experimental metastases of mouse colon carcinoma CT26 cells. Surprisingly, combined deficiency of Sep15 and TR1 reversed the anti-cancer effects observed with down-regulation of each single gene. We found that inflammation-related genes regulated by Stat-1, especially interferon-γ-regulated guanylate-binding proteins, were highly elevated in Sep15-deficient, but not in TR1-deficient cells. Interestingly, components of the Wnt/β-catenin signaling pathway were up-regulated in cells lacking both TR1 and Sep15. These results suggest that Sep15 and TR1 participate in interfering regulatory pathways in colon cancer cells. Considering the variable expression levels of Sep15 and TR1 found within the human population, our results provide insights into new roles of selenoproteins in cancer.

  4. Selenium and selenoprotein deficiencies induce widespread pyogranuloma formation in mice, while high levels of dietary selenium decrease liver tumor size driven by TGFα.

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    Mohamed E Moustafa

    Full Text Available Changes in dietary selenium and selenoprotein status may influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. To characterize such outcomes in a defined setting, we undertook a controlled hepatocarcinogenesis study involving varying levels of dietary selenium and altered selenoprotein status using mice carrying a mutant (A37G selenocysteine tRNA transgene (Trsp(tG37 and/or a cancer driver TGFα transgene. The use of Trsp(tG37 altered selenoprotein expression in a selenoprotein and tissue specific manner and, at sufficient dietary selenium levels, separate the effect of diet and selenoprotein status. Mice were maintained on diets deficient in selenium (0.02 ppm selenium or supplemented with 0.1, 0.4 or 2.25 ppm selenium or 30 ppm triphenylselenonium chloride (TPSC, a non-metabolized selenium compound. Trsp(tG37 transgenic and TGFα/Trsp(tG37 bi-transgenic mice subjected to selenium-deficient or TPSC diets developed a neurological phenotype associated with early morbidity and mortality prior to hepatocarcinoma development. Pathology analyses revealed widespread disseminated pyogranulomatous inflammation. Pyogranulomas occurred in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes in these transgenic and bi-transgenic mice. The incidence of liver tumors was significantly increased in mice carrying the TGFα transgene, while dietary selenium and selenoprotein status did not affect tumor number and multiplicity. However, adenoma and carcinoma size and area were smaller in TGFα transgenic mice that were fed 0.4 and 2.25 versus 0.1 ppm of selenium. Thus, selenium and selenoprotein deficiencies led to widespread pyogranuloma formation, while high selenium levels inhibited the size of TGFα-induced liver tumors.

  5. Selenium and Selenoprotein Deficiencies Induce Widespread Pyogranuloma Formation in Mice, while High Levels of Dietary Selenium Decrease Liver Tumor Size Driven by TGFα

    Science.gov (United States)

    Zhong, Nianxin; Ward, Jerrold M.; Perella, Christine M.; Hoffmann, Victoria J.; Rogers, Keith; Combs, Gerald F.; Schweizer, Ulrich; Merlino, Glenn; Gladyshev, Vadim N.; Hatfield, Dolph L.

    2013-01-01

    Changes in dietary selenium and selenoprotein status may influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. To characterize such outcomes in a defined setting, we undertook a controlled hepatocarcinogenesis study involving varying levels of dietary selenium and altered selenoprotein status using mice carrying a mutant (A37G) selenocysteine tRNA transgene (TrsptG37) and/or a cancer driver TGFα transgene. The use of TrsptG37 altered selenoprotein expression in a selenoprotein and tissue specific manner and, at sufficient dietary selenium levels, separate the effect of diet and selenoprotein status. Mice were maintained on diets deficient in selenium (0.02 ppm selenium) or supplemented with 0.1, 0.4 or 2.25 ppm selenium or 30 ppm triphenylselenonium chloride (TPSC), a non-metabolized selenium compound. TrsptG37 transgenic and TGFα/TrsptG37 bi-transgenic mice subjected to selenium-deficient or TPSC diets developed a neurological phenotype associated with early morbidity and mortality prior to hepatocarcinoma development. Pathology analyses revealed widespread disseminated pyogranulomatous inflammation. Pyogranulomas occurred in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes in these transgenic and bi-transgenic mice. The incidence of liver tumors was significantly increased in mice carrying the TGFα transgene, while dietary selenium and selenoprotein status did not affect tumor number and multiplicity. However, adenoma and carcinoma size and area were smaller in TGFα transgenic mice that were fed 0.4 and 2.25 versus 0.1 ppm of selenium. Thus, selenium and selenoprotein deficiencies led to widespread pyogranuloma formation, while high selenium levels inhibited the size of TGFα–induced liver tumors. PMID:23460847

  6. Relaxation of selective constraints causes independent selenoprotein extinction in insect genomes.

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    Charles E Chapple

    Full Text Available BACKGROUND: Selenoproteins are a diverse family of proteins notable for the presence of the 21st amino acid, selenocysteine. Until very recently, all metazoan genomes investigated encoded selenoproteins, and these proteins had therefore been believed to be essential for animal life. Challenging this assumption, recent comparative analyses of insect genomes have revealed that some insect genomes appear to have lost selenoprotein genes. METHODOLOGY/PRINCIPAL FINDINGS: In this paper we investigate in detail the fate of selenoproteins, and that of selenoprotein factors, in all available arthropod genomes. We use a variety of in silico comparative genomics approaches to look for known selenoprotein genes and factors involved in selenoprotein biosynthesis. We have found that five insect species have completely lost the ability to encode selenoproteins and that selenoprotein loss in these species, although so far confined to the Endopterygota infraclass, cannot be attributed to a single evolutionary event, but rather to multiple, independent events. Loss of selenoproteins and selenoprotein factors is usually coupled to the deletion of the entire no-longer functional genomic region, rather than to sequence degradation and consequent pseudogenisation. Such dynamics of gene extinction are consistent with the high rate of genome rearrangements observed in Drosophila. We have also found that, while many selenoprotein factors are concomitantly lost with the selenoproteins, others are present and conserved in all investigated genomes, irrespective of whether they code for selenoproteins or not, suggesting that they are involved in additional, non-selenoprotein related functions. CONCLUSIONS/SIGNIFICANCE: Selenoproteins have been independently lost in several insect species, possibly as a consequence of the relaxation in insects of the selective constraints acting across metazoans to maintain selenoproteins. The dispensability of selenoproteins in insects may

  7. Lokalisation und Verteilung von Selenoprotein P im humanen Gehirn

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    M. Scharpf

    2015-02-01

    Full Text Available Selenoprotein P ist ein überwiegend hepatisch synthetisiertes Protein, welches Selen im menschlichen Körper transportiert. Außer in der Leber findet man die mRNA in einer Vielzahl von weiteren Geweben, in denen Selenoprotein P wahrscheinlich weitere Funktionen erfüllt. Die vorliegenden Untersuchungen wurden mit der Zielsetzung durchgeführt, einen besseren Überblick über die Verteilung im gesunden sowie erkrankten menschlichen Gehirn zu bekommen.

  8. Selenoproteins are essential for proper keratinocyte function and skin development.

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    Aniruddha Sengupta

    2010-08-01

    Full Text Available Dietary selenium is known to protect skin against UV-induced damage and cancer and its topical application improves skin surface parameters in humans, while selenium deficiency compromises protective antioxidant enzymes in skin. Furthermore, skin and hair abnormalities in humans and rodents may be caused by selenium deficiency, which are overcome by dietary selenium supplementation. Most important biological functions of selenium are attributed to selenoproteins, proteins containing selenium in the form of the amino acid, selenocysteine (Sec. Sec insertion into proteins depends on Sec tRNA; thus, knocking out the Sec tRNA gene (Trsp ablates selenoprotein expression. We generated mice with targeted removal of selenoproteins in keratin 14 (K14 expressing cells and their differentiated descendents. The knockout progeny had a runt phenotype, developed skin abnormalities and experienced premature death. Lack of selenoproteins in epidermal cells led to the development of hyperplastic epidermis and aberrant hair follicle morphogenesis, accompanied by progressive alopecia after birth. Further analyses revealed that selenoproteins are essential antioxidants in skin and unveiled their role in keratinocyte growth and viability. This study links severe selenoprotein deficiency to abnormalities in skin and hair and provides genetic evidence for the role of these proteins in keratinocyte function and cutaneous development.

  9. Altered hippocampus synaptic function in selenoprotein P deficient mice

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    Peters Melinda M

    2006-09-01

    Full Text Available Abstract Selenium is an essential micronutrient that function through selenoproteins. Selenium deficiency results in lower concentrations of selenium and selenoproteins. The brain maintains it's selenium better than other tissues under low-selenium conditions. Recently, the selenium-containing protein selenoprotein P (Sepp has been identified as a possible transporter of selenium. The targeted disruption of the selenoprotein P gene (Sepp1 results in decreased brain selenium concentration and neurological dysfunction, unless selenium intake is excessive However, the effect of selenoprotein P deficiency on the processes of memory formation and synaptic plasticity is unknown. In the present studies Sepp1(-/- mice and wild type littermate controls (Sepp1(+/+ fed a high-selenium diet (1 mg Se/kg were used to characterize activity, motor coordination, and anxiety as well as hippocampus-dependent learning and memory. Normal associative learning, but disrupted spatial learning was observed in Sepp1(-/- mice. In addition, severe alterations were observed in synaptic transmission, short-term plasticity and long-term potentiation in hippocampus area CA1 synapses of Sepp1(-/- mice on a 1 mg Se/kg diet and Sepp1(+/+ mice fed a selenium-deficient (0 mg Se/kg diet. Taken together, these data suggest that selenoprotein P is required for normal synaptic function, either through presence of the protein or delivery of required selenium to the CNS.

  10. Compatibilidad química por calorimetría diferencial de barrido y termogravimetría del auranofin tabletas 3 mg Chemical compatibility of 3 mg Auranofin tablets demonstrated by differential scanning calorimetry and thermogravimetry

    Directory of Open Access Journals (Sweden)

    Luis Octavio Martínez Álvarez

    2011-03-01

    Full Text Available Como parte de la pre-estabilidad de la preformulación de auranofin tabletas, se realizó un estudio de compatibilidad química, para lo cual se emplearon técnicas de análisis térmico como la calorimetría diferencial de barrido y la termogravimetría. Previo a dichos estudios se caracterizó térmicamente por calorimetría diferencial de barrido el principio activo y cada uno de los excipientes. Posteriormente se procedió a la realización del estudio de compatibilidad química, mediante la preparación de mezclas físicas binarias entre el principio activo y cada uno de los excipientes. Se detectó por ambos métodos que el principio activo tuvo una transición física de fusión, no reportada en la literatura, lo que permitió poder calcular su pureza por calorimetría diferencial de barrido. Mediante la técnica calorimétrica fue posible inferir la ausencia de incompatibilidad química entre el principio activo y los excipientes estudiados. Además, mediante el cálculo de la energía de activación se estableció el siguiente orden de estabilidad térmica: auranofin:PVP> auranofin:lactosa> auranofin:explotab> auranofin:estearato> auranofin:aerosil> auranofin:celulosa, por lo que se recomienda el uso de estos excipientes en la elaboración de la formulación farmacéutica.As part of the pre-stability study of the Auranofin tablet pre-formulation, a chemical compatibility study was conducted using thermal analysis techniques such as the differential scanning calorimetry and the thermogravimetry. Prior to these studies, the active principle and each of the excipients were thermally characterized with the aid of the differential scanning calorimetry. Then, there proceeded to carry out the chemical compatibility study by preparing binary physical mixtures between the active principle and each of the excipients. Both methods showed that the active principle had a melting physical transition, not reported in the literature, which allowed

  11. Structure- and cell-specific effects of imidoselenocarbamates on selenoprotein expression and activity in liver cells in culture.

    Science.gov (United States)

    Ibáñez, Elena; Stoedter, Mette; Hofmann, Peter Josef; Plano, Daniel; Calvo, Alfonso; Nguewa, Paul A; Palop, Juan Antonio; Sanmartín, Carmen; Schomburg, Lutz

    2012-12-01

    The essential micronutrient selenium (Se) exerts its biological effects mainly through selenoproteins thereby affecting a number of physiological pathways including intracellular redox control, stress response and cancer cell proliferation. Besides affecting selenoprotein expression, some selenocompounds have been synthesized and analyzed in order to serve as chemotherapeutic substances preferentially targeting cancer cells. This promising chemotherapeutic potential has recently been verified for a particular imidoselenocarbamate in a mouse tumor model. In the present study we tested the effects of this and a number of related Se-methyl- and Se-benzyl-imidoselenocarbamates on selenoprotein expression in nontransformed and hepatic carcinoma cells in culture. Most of the Se-benzyl-imidoselenocarbamates strongly stimulated selenoprotein P (SePP) secretion while the Se-methyl-imidoselenocarbamates elicited less pronounced effects in hepatocarcinoma HepG2 cells. However, most of the Se-methyl-imidoselenocarbamates increased glutathione peroxidase (GPx) activity and decreased thioredoxin reductase (TXNRD) activity in parallel, while the majority of the Se-benzyl-imidoselenocarbamates were without a respective effect in HepG2 cells. Performing inhibitor assays in vitro, GPx activity was unaffected by the imidoselenocarbamates. In contrast, most of the Se-methyl-imidoselenocarbamates inhibited TXNRD activity in vitro in line with the results in HepG2 cells. Both classes of imidoselenocarbamates strongly induced selenoprotein S (SELS) expression without a respective increase in ER stress or unfolded protein response which are known inducers of SELS biosynthesis. Notably, many of these effects were cancer cell-specific, and not observed in nontransformed AML12 hepatocytes. Our results indicate that these novel selenocompounds affect expression and activity of crucial selenoenzymes in a compound- and cell-specific way in hepatocytes. Especially the Se

  12. Thyroid hormones regulate selenoprotein expression and selenium status in mice.

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    Jens Mittag

    Full Text Available Impaired expression of selenium-containing proteins leads to perturbed thyroid hormone (TH levels, indicating the central importance of selenium for TH homeostasis. Moreover, critically ill patients with declining serum selenium develop a syndrome of low circulating TH and a central downregulation of the hypothalamus-pituitary-thyroid axis. This prompted us to test the reciprocal effect, i.e., if TH status would also regulate selenoprotein expression and selenium levels. To investigate the TH dependency of selenium metabolism, we analyzed mice expressing a mutant TH receptor α1 (TRα1+m that confers a receptor-mediated hypothyroidism. Serum selenium was reduced in these animals, which was a direct consequence of the mutant TRα1 and not related to their metabolic alterations. Accordingly, hyperthyroidism, genetically caused by the inactivation of TRβ or by oral TH treatment of adult mice, increased serum selenium levels in TRα1+m and controls, thus demonstrating a novel and specific role for TRα1 in selenium metabolism. Furthermore, TH affected the mRNA levels for several enzymes involved in selenoprotein biosynthesis as well as serum selenoprotein P concentrations and the expression of other antioxidative selenoproteins. Taken together, our results show that TH positively affects the serum selenium status and regulates the expression of several selenoproteins. This demonstrates that selenium and TH metabolism are interconnected through a feed-forward regulation, which can in part explain the rapid parallel downregulation of both systems in critical illness.

  13. Selenoprotein P controls oxidative stress in cornea.

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    Akihiro Higuchi

    Full Text Available The ocular surface is always attacked by oxidative stress, and cornea epithelial cells are supposed to have their own recovery system against oxidative stress. Therefore we hypothesized that tears supply key molecules for preventing oxidative stress in cornea. The potential target key molecule we focused is selenoprotein P (SeP. SeP is a carrier of selenium, which is an essential trace element for many animals, for oxidative stress metabolism in the organism, and was extremely expressed in lacrimal gland. An experiment was performed with SeP eye drops in a rat dry eye model, prepared by removing the lacrimal glands. The anticipated improvement in corneal dry eye index and the suppression of oxidative stress markers were observed in SeP eye drop group. Furthermore, the concentration of SeP was significantly higher in dry eye patients compared with normal volunteers. Collectively, we concluded that tear SeP is a key molecule to protect the ocular surface cells against environmental oxidative stress.

  14. The Yin and Yang of Nrf2-Regulated Selenoproteins in Carcinogenesis

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    Regina Brigelius-Flohé

    2012-01-01

    Full Text Available The NF-E2-related factor-2 (Nrf2 is a transcription factor which regulates the major cellular defense systems and thereby contributes to the prevention of many diseases including cancer. Selenium deficiency is associated with a higher cancer risk making also this essential trace element a promising candidate for cancer prevention. Two selenoproteins, thioredoxin reductase-1 (TrxR1 and glutathione peroxidase-2 (GPx2, are targets for Nrf2. Selenium deficiency activates Nrf2 as does a TrxR1 knockout making a synergism between both systems plausible. Although this might hold true for healthy cells, the interplay may turn into the opposite in cancer cells. The induction of the detoxifying and antioxidant enzymes by Nrf2 will make cancer cells chemoresistant and will protect them against oxidative damage. The essential role of TrxR1 in maintaining proliferation makes its upregulation in cancer cells detrimental. The anti-inflammatory potential of GPx2 will help to inhibit cancer initiation and inflammation-triggered promotion, but its growth supporting potential will also support tumor growth. This paper considers beneficial and adverse consequences of the activation of Nrf2 and the selenoproteins which appear to depend on the cancer stage.

  15. Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms

    Science.gov (United States)

    Li, Xiaofen; Lan, Xiaoying; Liu, Shouting; Huang, Hongbiao; Liu, Ningning; Liao, Siyan; Zang, Dan; Song, Wenbin; Liu, Quentin; Carter, Bing Z.; Dou, Q. Ping; Wang, Xuejun; Liu, Jinbao

    2014-01-01

    Resistance to Imatinib mesylate (IM) is an emerging problem for patients with chronic myelogenous leukemia (CML). T315I mutation in the Bcr-Abl is the predominant mechanism of the acquired resistance to IM and second generation tyrosine kinase inhibitors (TKI). Therefore it is urgent to search for new measures to overcome TKI-resistance. Auranofin (AF), clinically used to treat rheumatic arthritis, was recently approved by US Food and Drug Administration for Phase II clinical trial to treat cancer. In contrast to the reports that AF induces apoptosis by increasing intracellular reactive oxygen species (ROS) levels via inhibiting thioredoxin reductase, our recent study revealed that AF-induced apoptosis depends on inhibition of proteasomal deubiquitinases (UCHL5 and USP14). Here we report that (i) AF induces apoptosis in both Bcr-Abl wild-type cells and Bcr-Abl-T315I mutation cells and inhibits the growth of IM-resistant Bcr-Abl-T315I xenografts in vivo; (ii) AF inhibits Bcr-Abl through both downregulation of Bcr-Abl gene expression and Bcr-Abl cleavage mediated by proteasome inhibition-induced caspase activation; (iii) proteasome inhibition but not ROS is required for AF-induced caspase activation and apoptosis. These findings support that AF overcomes IM resistance through both Bcr/Abl-dependent and -independent mechanisms, providing great clinical significance for cancer treatment. PMID:25193854

  16. Expression of Selenoprotein Genes Is Affected by Obesity of Pigs Fed a High-Fat Diet.

    Science.gov (United States)

    Zhao, Hua; Li, Ke; Tang, Jia-Yong; Zhou, Ji-Chang; Wang, Kang-Ning; Xia, Xin-Jie; Lei, Xin Gen

    2015-07-01

    Relations of the 25 mammalian selenoprotein genes with obesity and the associated inflammation remain unclear. This study explored impacts of high-fat diet-induced obesity on inflammation and expressions of selenoprotein and obesity-related genes in 10 tissues of pigs. Plasma and 10 tissues were collected from pigs (n = 10) fed a corn-soy-based control diet or that diet containing 3-7% lard from weanling to finishing (180 d). Plasma concentrations (n = 8) of cytokines and thyroid hormones and tissue mRNA abundance (n = 4) of 25 selenoprotein genes and 16 obesity-related genes were compared between the pigs fed the control and high-fat diets. Stepwise regression was applied to analyze correlations among all these measures, including the previously reported body physical and plasma biochemical variables. The high-fat diet elevated (P high-fat diet up-regulated 12 selenoprotein genes in 6 tissues, down-regulated 13 selenoprotein genes in 7 tissues, and exerted no effect on 5 genes in any tissue. Body weights and plasma triglyceride concentrations of pigs showed the strongest regressions to tissue mRNA abundances of selenoprotein and obesity-related genes. Among the selenoprotein genes, selenoprotein V and I were ranked as the strongest independent variables for the regression of phenotypic and plasma measures. Meanwhile, agouti signaling protein, adiponectin, and resistin genes represented the strongest independent variables of the obesity-related genes for the regression of tissue selenoprotein mRNA. The high-fat diet induced inflammation in pigs and affected their gene expression of selenoproteins associated with thioredoxin and oxidoreductase systems, local tissue thyroid hormone activity, endoplasmic reticulum protein degradation, and phosphorylation of lipids. This porcine model may be used to study interactive mechanisms between excess fat intake and selenoprotein function. © 2015 American Society for Nutrition.

  17. Selenium Regulation of the Selenoprotein and Nonselenoprotein Transcriptomes in Rodents12

    Science.gov (United States)

    Sunde, Roger A.; Raines, Anna M.

    2011-01-01

    This review discusses progress in understanding the hierarchy of selenoprotein expression at the transcriptome level from selenium (Se) deficiency to Se toxicity. Microarray studies of the full selenoproteome have found that 5 of 24 rodent selenoprotein mRNA decrease to nutrition. PMID:22332043

  18. Selenoprotein N: an endoplasmic reticulum glycoprotein with an early developmental expression pattern

    DEFF Research Database (Denmark)

    Petit, Nathalie; Lescure, Alain; Rederstorff, Mathieu

    2003-01-01

    Rigid spine muscular dystrophy and the classical form of multiminicore disease are caused by mutations in SEPN1 gene, leading to a new clinical entity referred to as SEPN1-related myopathy. SEPN1 codes for selenoprotein N, a new member of the selenoprotein family, the function of which is still...

  19. Selenoproteins regulate macrophage invasiveness and extracellular matrix-related gene expression

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    Gladyshev Vadim N

    2009-10-01

    Full Text Available Abstract Background Selenium, a micronutrient whose deficiency in diet causes immune dysfunction and inflammatory disorders, is thought to exert its physiological effects mostly in the form of selenium-containing proteins (selenoproteins. Incorporation of selenium into the amino acid selenocysteine (Sec, and subsequently into selenoproteins is mediated by Sec tRNA[Ser]Sec. Results To define macrophage-specific selenoprotein functions, we generated mice with the Sec tRNA[Ser]Sec gene specifically deleted in myeloid cells. These mutant mice were devoid of the "selenoproteome" in macrophages, yet exhibited largely normal inflammatory responses. However, selenoprotein deficiency led to aberrant expression of extracellular matrix-related genes, and diminished migration of macrophages in a protein gel matrix. Conclusion Selenium status may affect immune defense and tissue homeostasis through its effect on selenoprotein expression and the trafficking of tissue macrophages.

  20. Compatibilidad química por calorimetría diferencial de barrido y termogravimetría del auranofin tabletas 3 mg

    Directory of Open Access Journals (Sweden)

    Luis Octavio Martínez Álvarez

    2011-03-01

    Full Text Available Como parte de la pre-estabilidad de la preformulación de auranofin tabletas, se realizó un estudio de compatibilidad química, para lo cual se emplearon técnicas de análisis térmico como la calorimetría diferencial de barrido y la termogravimetría. Previo a dichos estudios se caracterizó térmicamente por calorimetría diferencial de barrido el principio activo y cada uno de los excipientes. Posteriormente se procedió a la realización del estudio de compatibilidad química, mediante la preparación de mezclas físicas binarias entre el principio activo y cada uno de los excipientes. Se detectó por ambos métodos que el principio activo tuvo una transición física de fusión, no reportada en la literatura, lo que permitió poder calcular su pureza por calorimetría diferencial de barrido. Mediante la técnica calorimétrica fue posible inferir la ausencia de incompatibilidad química entre el principio activo y los excipientes estudiados. Además, mediante el cálculo de la energía de activación se estableció el siguiente orden de estabilidad térmica: auranofin:PVP> auranofin:lactosa> auranofin:explotab> auranofin:estearato> auranofin:aerosil> auranofin:celulosa, por lo que se recomienda el uso de estos excipientes en la elaboración de la formulación farmacéutica.

  1. Attenuation of MUC4 potentiates the anticancer activity of auranofin via regulation of the Her2/Akt/FOXO3 pathway in ovarian cancer cells.

    Science.gov (United States)

    Bae, Jun Sang; Lee, Jongsung; Park, Yoonkook; Park, Kyungmoon; Kim, Jung Ryul; Cho, Dong Hyu; Jang, Kyu Yun; Park, See-Hyoung

    2017-10-01

    Previously, we reported that auranofin induces apoptosis in SKOV3 cells via regulation of the IKKβ/FOXO3 pathway. In the present study, we reveal that the anticancer activity of auranofin in SKOV3 cells could be enhanced by the attenuation of MUC4 through the regulation of the Her2/Akt/FOXO3 pathway. Compared to the control-siRNA, siRNA transfection against MUC4 into SKOV3 cells accelerated the protein degradation of Her2. Under the same conditions, the expression level of phosphorylated Akt was also downregulated leading to an increase of FOXO3 in the nucleus. Notably, auranofin treatment in SKOV3 cells also resulted in the downregulation of the expression levels of both Her2 and phosphorylated Akt. Thus, Her2 was identified as the common molecular target protein by siRNA transfection against MUC4. Western blot analysis of total and nuclear fraction lysates from SKOV3 cells revealed that attenuation of MUC4 combined with auranofin treatment in SKOV3 cells synergistically activated FOXO3 translocation from the cytoplasm to the nucleus through the regulation of the Her2/Akt/FOXO3 pathway. Attenuation of MUC4 by siRNA transfection potentiated the antitumor effect of auranofin which was examined by performing in vitro assays such as WST-1, cell counting, colony formation, TUNEL and Annexin V staining. In addition, western blot analysis of the apoptosis‑related proteins such as PARP1, caspase-3, Bim extra large (EL), Bax and Bcl2 revealed that the attenuation of MUC4 by siRNA transfection potentiates the pro-apoptotic activity of auranofin in SKOV3 cells. Collectively, auranofin could regulate the Her2/Akt/FOXO3 signaling pathway in SKOV3 cells and be used as a potential antitumor agent considering the expression of MUC4 in ovarian cancer patients.

  2. Auranofin, an anti-rheumatic gold compound, modulates apoptosis by elevating the intracellular calcium concentration ([ca2+]I) in mcf-7 breast cancer cells.

    Science.gov (United States)

    Varghese, Elizabeth; Büsselberg, Dietrich

    2014-11-06

    Auranofin, a transition metal complex is used for the treatment of rheumatoid arthritis but is also an effective anti-cancer drug. We investigate the effects of Auranofin in inducing cell death by apoptosis and whether these changes are correlated to changes of intracellular calcium concentration ([Ca2+]i) in breast cancer cells (MCF-7). Cytotoxicity of Auranofin was evaluated using MTS assay and the Trypan blue dye exclusion method. With fluorescent dyes SR-FLICA and 7-AAD apoptotic death and necrotic death were differentiated by Flow cytometry. A concentration dependent decrease in the viability occurred and cells were shifted to the apoptotic phase. Intracellular calcium ([Ca2+]i) was recorded using florescence microscopy and a calcium sensitive dye (Fluo-4 AM) with a strong negative correlation (r = -0.713) to viability. Pharmacological modulators 2-APB (50 μM), Nimodipine (10 μM), Caffeine (10 mM), SKF 96365(20 μM) were used to modify calcium entry and release. Auranofin induced a sustained increase of [Ca2+]i in a concentration and time dependent manner. The use of different blockers of calcium channels did not reveal the source for the rise of [Ca2+]i. Overall, elevation of [Ca2+]i by Auranofin might be crucial for triggering Ca2+-dependent apoptotic pathways. Therefore, in anti-cancer therapy, modulating [Ca2+]i should be considered as a crucial factor for the induction of cell death in cancer cells.

  3. Auranofin, an Anti-Rheumatic Gold Compound, Modulates Apoptosis by Elevating the Intracellular Calcium Concentration ([Ca2+]i in MCF-7 Breast Cancer Cells

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    Elizabeth Varghese

    2014-11-01

    Full Text Available Auranofin, a transition metal complex is used for the treatment of rheumatoid arthritis but is also an effective anti-cancer drug. We investigate the effects of Auranofin in inducing cell death by apoptosis and whether these changes are correlated to changes of intracellular calcium concentration ([Ca2+]i in breast cancer cells (MCF-7. Cytotoxicity of Auranofin was evaluated using MTS assay and the Trypan blue dye exclusion method. With fluorescent dyes SR-FLICA and 7-AAD apoptotic death and necrotic death were differentiated by Flow cytometry. A concentration dependent decrease in the viability occurred and cells were shifted to the apoptotic phase. Intracellular calcium ([Ca2+]i was recorded using florescence microscopy and a calcium sensitive dye (Fluo-4 AM with a strong negative correlation (r = −0.713 to viability. Pharmacological modulators 2-APB (50 μM, Nimodipine (10 μM, Caffeine (10 mM, SKF 96365(20 μM were used to modify calcium entry and release. Auranofin induced a sustained increase of [Ca2+]i in a concentration and time dependent manner. The use of different blockers of calcium channels did not reveal the source for the rise of [Ca2+]i. Overall, elevation of [Ca2+]i by Auranofin might be crucial for triggering Ca2+-dependent apoptotic pathways. Therefore, in anti-cancer therapy, modulating [Ca2+]i should be considered as a crucial factor for the induction of cell death in cancer cells.

  4. Selenotranscriptomic Analyses Identify Signature Selenoproteins in Brain Regions in a Mouse Model of Parkinson's Disease.

    Directory of Open Access Journals (Sweden)

    Xiong Zhang

    Full Text Available Genes of selenoproteome have been increasingly implicated in various aspects of neurobiology and neurological disorders, but remain largely elusive in Parkinson's disease (PD. In this study, we investigated the selenotranscriptome (24 selenoproteins in total in five brain regions (cerebellum, substantia nigra, cortex, pons and hippocampus by real time qPCR in a two-phase manner using a mouse model of chronic PD. A wide range of changes in selenotranscriptome was observed in a manner depending on selenoproteins and brain regions. While Selv mRNA was not detectable and Dio1& 3 mRNA levels were not affected, 1, 11 and 9 selenoproteins displayed patterns of increase only, decrease only, and mixed response, respectively, in these brain regions of PD mice. In particular, the mRNA expression of Gpx1-4 showed only a decreased trend in the PD mouse brains. In substantia nigra, levels of 17 selenoprotein mRNAs were significantly decreased whereas no selenoprotein was up-regulated in the PD mice. In contrast, the majority of selenotranscriptome did not change and a few selenoprotein mRNAs that respond displayed a mixed pattern of up- and down-regulation in cerebellum, cortex, hippocampus, and/or pons of the PD mice. Gpx4, Sep15, Selm, Sepw1, and Sepp1 mRNAs were most abundant across all these five brain regions. Our results showed differential responses of selenoproteins in various brain regions of the PD mouse model, providing critical selenotranscriptomic profiling for future functional investigation of individual selenoprotein in PD etiology.

  5. Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency.

    LENUS (Irish Health Repository)

    Kelly, Emer

    2009-06-19

    Z alpha(1)-antitrypsin (ZAAT) deficiency is a disease associated with emphysematous lung disease and also with liver disease. The liver disease of AAT deficiency is associated with endoplasmic reticulum (ER) stress. SEPS1 is a selenoprotein that, through a chaperone activity, decreases ER stress. To determine the effect of SEPS1 on ER stress in ZAAT deficiency, we measured activity of the grp78 promoter and levels of active ATF6 as markers of the unfolded protein response in HepG2 cells transfected with the mutant form of AAT, a ZAAT transgene. We evaluated levels of NFkappaB activity as a marker of the ER overload response. To determine the effect of selenium supplementation on the function of SEPS1, we investigated glutathione peroxidase activity, grp78 promoter activity, and NFkappaB activity in the presence or absence of selenium. SEPS1 reduced levels of active ATF6. Overexpression of SEPS1 also inhibited grp78 promoter and NFkappaB activity, and this effect was enhanced in the presence of selenium supplementation. This finding demonstrates a role for SEPS1 in ZAAT deficiency and suggests a possible therapeutic potential for selenium supplementation.

  6. Drug susceptibility testing in microaerophilic parasites: Cysteine strongly affects the effectivities of metronidazole and auranofin, a novel and promising antimicrobial

    Directory of Open Access Journals (Sweden)

    David Leitsch

    2017-12-01

    Full Text Available The microaerophilic parasites Entamoeba histolytica, Trichomonas vaginalis, and Giardia lamblia annually cause hundreds of millions of human infections which are treated with antiparasitic drugs. Metronidazole is the most often prescribed drug but also other drugs are in use, and novel drugs with improved characteristics are constantly being developed. One of these novel drugs is auranofin, originally an antirheumatic which has been relabelled for the treatment of parasitic infections. Drug effectivity is arguably the most important criterion for its applicability and is commonly assessed in susceptibility assays using in vitro cultures of a given pathogen. However, drug susceptibility assays can be strongly affected by certain compounds in the growth media. In the case of microaerophilic parasites, cysteine which is added in large amounts as an antioxidant is an obvious candidate because it is highly reactive and known to modulate the toxicity of metronidazole in several microaerophilic parasites.In this study, it was attempted to reduce cysteine concentrations as far as possible without affecting parasite viability by performing drug susceptibility assays under strictly anaerobic conditions in an anaerobic cabinet. Indeed, T. vaginalis and E. histolytica could be grown without any cysteine added and the cysteine concentration necessary to maintain G. lamblia could be reduced to 20%. Susceptibilities to metronidazole were found to be clearly reduced in the presence of cysteine. With auranofin the protective effect of cysteine was extreme, providing protection to concentrations up to 100-fold higher as observed in the absence of cysteine. With three other drugs tested, albendazole, furazolidone and nitazoxanide, all in use against G. lamblia, the effect of cysteine was less pronounced. Oxygen was found to have a less marked impact on metronidazole and auranofin than cysteine but bovine bile which is standardly used in growth media for G

  7. Role of microRNA-7 and selenoprotein P in hepatocellular carcinoma.

    Science.gov (United States)

    Tarek, Marwa; Louka, Manal Louis; Khairy, Eman; Ali-Labib, Randa; Zakaria Zaky, Doaa; Montasser, Iman F

    2017-05-01

    There is an obvious need to diagnose hepatocellular carcinoma using novel non-invasive and sensitive biomarkers. In this regard, the aim of this study was to evaluate and correlate both relative quantification of microRNA-7 using quantitative real time polymerase chain reaction and quantitative analysis of selenoprotein P using enzyme-linked immunosorbent assay in sera of hepatocellular carcinoma patients, chronic liver disease patients, as well as normal healthy subjects in order to establish a new diagnostic biomarker with a valid non-invasive technique. In addition, this study aimed to investigate whether changes in selenium supply affect microRNA-7 expression and selenoprotein P levels in human hepatocarcinoma cell line (HepG2). The results showed a highly significant decrease in serum microRNA-7 relative quantification values and selenoprotein P levels in malignant group in comparison with benign and control groups. The best cutoff for serum microRNA-7 and selenoprotein P to discriminate hepatocellular carcinoma group from benign and control groups was 0.06 and 4.30 mg/L, respectively. Furthermore, this study showed that changes in selenium supply to HepG2 cell line can alter the microRNA-7 profile and are paralleled by changes in the concentration of its target protein (selenoprotein P). Hence, serum microRNA-7 and selenoprotein P appear to be potential non-invasive diagnostic markers for hepatocellular carcinoma. Moreover, the results suggest that selenium could be used as an anticancer therapy for hepatocellular carcinoma by affecting both microRNA-7 and selenoprotein P.

  8. Characterization of mammalian selenoprotein o: a redox-active mitochondrial protein.

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    Seong-Jeong Han

    Full Text Available Selenoproteins exhibit diverse biological functions, most of which are associated with redox control. However, the functions of approximately half of mammalian selenoproteins are not known. One such protein is Selenoprotein O (SelO, the largest mammalian selenoprotein with orthologs found in a wide range of organisms, including bacteria and yeast. Here, we report characterization of mammalian SelO. Expression of this protein could be verified in HEK 293T cells by metabolic labeling of cells with 75Se, and it was abolished when selenocysteine was replaced with serine. A CxxU motif was identified in the C-terminal region of SelO. This protein was reversibly oxidized in a time- and concentration-dependent manner in HEK 293T cells when cells were treated with hydrogen peroxide. This treatment led to the formation of a transient 88 kDa SelO-containing complex. The formation of this complex was enhanced by replacing the CxxU motif with SxxC, but abolished when it was replaced with SxxS, suggesting a redox interaction of SelO with another protein through its Sec residue. SelO was localized to mitochondria and expressed across mouse tissues. Its expression was little affected by selenium deficiency, suggesting it has a high priority for selenium supply. Taken together, these results show that SelO is a redox-active mitochondrial selenoprotein.

  9. Serum selenium and selenoprotein P status in adult Danes-8-year followup

    DEFF Research Database (Denmark)

    Rasmussen, Lone Banke; Hollenbach, B.; Laurberg, P.

    2009-01-01

    Selenium is an essential micronutrient important to human health. The main objective of this study is to describe serum selenium and selenoprotein P status in two samples of the Danish population. In addition, the influence of various factors potentially associated with selenium status was invest......Selenium is an essential micronutrient important to human health. The main objective of this study is to describe serum selenium and selenoprotein P status in two samples of the Danish population. In addition, the influence of various factors potentially associated with selenium status...... subjects had filled in a food frequency questionnaire (FFQ) and a questionnaire with information about smoking habits, alcohol consumption and exercise habits. Mean serum selenium level was 98.7+/-19.8microg/L and median selenoprotein P level was 2.72 (2.18-3.49)mg/L. Serum selenium and selenoprotein P...... increased with age, and selenoprotein P was higher in men than in women. Serum selenium levels decreased by 5% on average from 1997-98 to 2004-05 (Pselenoprotein P level increased (P

  10. Determination of selenoprotein P in human plasma by solid phase extraction and inductively coupled plasma mass spectrometry

    DEFF Research Database (Denmark)

    Bendahl, L.; Sidenius, U.; Gammelgaard, Bente

    2000-01-01

    A method based on solid phase extraction was developed for the determination of selenoprotein P as selenium in human plasma. Separation of selenoprotein P from other selenium-containing proteins was accomplished by immobilized metal-ion affinity chromatography. The selenium content was subsequently...

  11. Kissing loops hide premature termination codons in pre-mRNAof selenoprotein genes and in genes containing programmedribosomal frameshifts

    DEFF Research Database (Denmark)

    Knudsen, Steen; Brunak, Søren

    1997-01-01

    A novel RNA secondary structure that places the selenocysteine codon UGA in one hairpin and a donor splice site in another, has been discovered in selenoprotein genes. The presence of the structure resolves the discrepancy that the selenocysteine triplet, UGA, should block splicing. Without...... a specific signal such as the novel RNA secondary structure, selenoproteins could not be produced from genes containing intervening sequences....

  12. Auranofin, an Anti-Rheumatic Gold Compound, Modulates Apoptosis by Elevating the Intracellular Calcium Concentration ([Ca{sup 2+}]{sub i}) in MCF-7 Breast Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Varghese, Elizabeth; Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weil Cornell Medical College in Qatar, Qatar Foundation-Education City, P.O. Box 24144 Doha (Qatar)

    2014-11-06

    Auranofin, a transition metal complex is used for the treatment of rheumatoid arthritis but is also an effective anti-cancer drug. We investigate the effects of Auranofin in inducing cell death by apoptosis and whether these changes are correlated to changes of intracellular calcium concentration ([Ca{sup 2+}]{sub i}) in breast cancer cells (MCF-7). Cytotoxicity of Auranofin was evaluated using MTS assay and the Trypan blue dye exclusion method. With fluorescent dyes SR-FLICA and 7-AAD apoptotic death and necrotic death were differentiated by Flow cytometry. A concentration dependent decrease in the viability occurred and cells were shifted to the apoptotic phase. Intracellular calcium ([Ca{sup 2+}]{sub i}) was recorded using florescence microscopy and a calcium sensitive dye (Fluo-4 AM) with a strong negative correlation (r = −0.713) to viability. Pharmacological modulators 2-APB (50 μM), Nimodipine (10 μM), Caffeine (10 mM), SKF 96365(20 μM) were used to modify calcium entry and release. Auranofin induced a sustained increase of [Ca{sup 2+}]{sub i} in a concentration and time dependent manner. The use of different blockers of calcium channels did not reveal the source for the rise of [Ca{sup 2+}]{sub i}. Overall, elevation of [Ca{sup 2+}]{sub i} by Auranofin might be crucial for triggering Ca{sup 2+}-dependent apoptotic pathways. Therefore, in anti-cancer therapy, modulating [Ca{sup 2+}]{sub i} should be considered as a crucial factor for the induction of cell death in cancer cells.

  13. Cloning, Sequencing, and Expression of Selenoprotein Transcripts in the Turkey (Meleagris gallopavo.

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    Roger A Sunde

    Full Text Available The minimum Se requirement for male turkey poults is 0.3 μg Se/g--three times higher than requirements found in rodents--based on liver and gizzard glutathione peroxidase-4 (GPX4 and GPX1 activities. In addition, turkey liver GPX4 activity is 10-fold higher and GPX1 activity is 10-fold lower than in rats, and both GPX1 and GPX4 mRNA levels are dramatically down-regulated by Se deficiency. Currently, the sequences of all annotated turkey selenoprotein transcripts and proteins in the NCBI database are only "predicted." Thus we initiated cloning and sequencing of the full turkey selenoprotein transcriptome to demonstrate expression of selenoprotein transcripts in the turkey, and to develop tools to investigate Se regulation of the full selenoproteome. Total RNA was isolated from six tissues of Se-adequate adult tom turkeys, and used to prepare reverse-transcription cDNA libraries. PCR primers were designed, based initially on chicken, rodent, porcine, bovine and human sequences and later on turkey shotgun cloning sequences. We report here the cloning of full transcript sequences for 9 selenoproteins, and 3'UTR portions for 15 additional selenoproteins, which include SECIS elements in 22 3'UTRs, and in-frame Sec (UGA codons within coding regions of 19 selenoproteins, including 12 Sec codons in SEPP1. In addition, we sequenced the gap between two contigs from the shotgun cloning of the turkey genome, and found the missing sequence for the turkey Sec-tRNA. RTPCR was used to determine the relative transcript expression in 6 tissues. GPX3 expression was high in all tissues except kidney, GPX1 expression was high in kidney, SEPW1 expression was high in heart, gizzard and muscle, and SELU expression was high in liver. SEPP2, a selenoprotein not found in mammals, was highly expressed in liver but not in other tissues. In summary, transcripts for 24 selenoproteins are expressed in the turkey, not just predicted.

  14. The possible repositioning of an oral anti-arthritic drug, auranofin, for Nrf2-activating therapy: The demonstration of Nrf2-dependent anti-oxidative action using a zebrafish model.

    Science.gov (United States)

    Fuse, Yuji; Endo, Yuka; Araoi, Sho; Daitoku, Hiroaki; Suzuki, Hiroyuki; Kato, Mitsuyasu; Kobayashi, Makoto

    2018-02-01

    The Nrf2 pathway is a biological defense system against oxidative stress. The pharmacological activation of the Nrf2 pathway is a promising therapy for oxidative stress-related diseases, but it has been challenging to find an Nrf2 activator with acceptable toxicity. To circumvent this problem, we focused on an already approved oral anti-arthritic drug, auranofin that has been reported to have the potential to activate Nrf2. We used a zebrafish model to investigate whether auranofin has protective action against oxidative stress in vivo. Auranofin pre-treatment considerably improved the survival of zebrafish larvae that were challenged with a lethal dose of hydrogen peroxide. This protective effect was not observed in an Nrf2 mutant zebrafish strain, suggesting that the activation of the biological defense against oxidative stress was Nrf2-dependent. Auranofin-induced protection was further tested by challenges with redox-active heavy metals. A clear protective effect was observed against arsenite, a highly redox-reactive toxicant. In addition, this effect was also demonstrated to be Nrf2-dependent based on the analysis of an Nrf2 mutant strain. These results clearly demonstrate the anti-oxidative action of auranofin and encourage the repositioning of auranofin as a drug that improves oxidative stress-related pathology. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Heart selenoproteins status of metabolic syndrome-exposed pups: A potential target for attenuating cardiac damage.

    Science.gov (United States)

    Serrano, Alejandra; Nogales, Fátima; Sobrino, Paula; Murillo, María Luisa; Carreras, Olimpia; Ojeda, María Luisa

    2016-12-01

    Cardiac hypertrophy is the greatest complication in metabolic syndrome (MS), in dams and in offspring. The most effective therapies to avoid the evolution of MS are anti-oxidants, anti-inflammatories, and insulin sensitizers. Among anti-oxidant elements, Selenium (Se) exerts its functions through selenoproteins, which are essential for the correct functioning of the cardiovascular system. The aim of the study is analyze selenoproteins' implication in the transmission of future cardiovascular problems to MS progeny. Heart Se deposits, antioxidant enzymes' activities, biomolecular oxidation, and the expression of selenoproteins, AMPK, and NF-kB were measured in the offspring of dams exposed to a fructose-rich diet (65%) during gestation and lactation, with a normal Se content (0.1 ppm). Thyroid hormones and MCP-1 serum levels, as well as blood pressure and heart rate were also measured. Fructose-exposed pups have cardiomegaly, oxidation, and depletion in Se heart deposits, a decrease in selenoproteins' expression and in the p-AMPK/AMPKt energy ratio; an increase in NF-kB p65 expression, and a decrease of thyroid hormones and MCP-1. Heart rate and blood pressure were altered. These data indicate that dietary Se supplementation could be an inexpensive therapy for avoiding future cardiovascular complication in the progeny of MS dams. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Selenoprotein expression in macrophages is critical for optimal clearance of parasitic helminth Helminth Nippostrongylus brasiliensis

    Science.gov (United States)

    The plasticity of macrophages is evident in helminthic parasite infections where they play a role in both inflammation and protection. Previously, we demonstrated that selenium (Se), in the form of selenoproteins, induced a phenotypic switch in macrophage activation from a pro-inflammatory (M1) towa...

  17. Four selenoproteins, protein biosynthesis, and Wnt signalling are particularly sensitive to selenium intake in mice colon

    NARCIS (Netherlands)

    Kipp, A.; Banning, A.; Schothorst, van E.M.; Meplan, C.; Schomburg, L.; Evelo, C.; Coort, S.L.; Gaj, S.; Keijer, J.; Hesketh, J.; Brigelius, R.

    2009-01-01

    Selenium is an essential micronutrient. Its recommended daily allowance is not attained by a significant proportion of the population in many countries and its intake has been suggested to affect colorectal carcinogenesis. Therefore, microarrays were used to determine how both selenoprotein and

  18. Mammalian Trit1 is a tRNA([Ser]Sec)-isopentenyl transferase required for full selenoprotein expression.

    Science.gov (United States)

    Fradejas, Noelia; Carlson, Bradley A; Rijntjes, Eddy; Becker, Niels-Peter; Tobe, Ryuta; Schweizer, Ulrich

    2013-03-01

    Selenoproteins are proteins carrying the rare amino acid Sec (selenocysteine). Full expression of selenoproteins requires modification of tRNA([Ser]Sec), including N(6)-isopentenylation of base A(37). We show that Trit1 is a dimethylallyl:tRNA([Ser]Sec) transferase. Knockdown of Trit1 reduces expression of selenoproteins. Incubation of in vitro transcribed tRNA[Ser]Sec with recombinant Trit1 transfers [(14)C]dimethylallyl pyrophosphate to tRNA([Ser]Sec). 37A>G tRNA([Ser]Sec) is resistant to isopentenylation by Trit1.

  19. Selenoprotein N deficiency in mice is associated with abnormal lung development

    Science.gov (United States)

    Moghadaszadeh, Behzad; Rider, Branden E.; Lawlor, Michael W.; Childers, Martin K.; Grange, Robert W.; Gupta, Kushagra; Boukedes, Steve S.; Owen, Caroline A.; Beggs, Alan H.

    2013-01-01

    Mutations in the human SEPN1 gene, encoding selenoprotein N (SepN), cause SEPN1-related myopathy (SEPN1-RM) characterized by muscle weakness, spinal rigidity, and respiratory insufficiency. As with other members of the selenoprotein family, selenoprotein N incorporates selenium in the form of selenocysteine (Sec). Most selenoproteins that have been functionally characterized are involved in oxidation-reduction (redox) reactions, with the Sec residue located at their catalytic site. To model SEPN1-RM, we generated a Sepn1-knockout (Sepn1−/−) mouse line. Homozygous Sepn1−/− mice are fertile, and their weight and lifespan are comparable to wild-type (WT) animals. Under baseline conditions, the muscle histology of Sepn1−/− mice remains normal, but subtle core lesions could be detected in skeletal muscle after inducing oxidative stress. Ryanodine receptor (RyR) calcium release channels showed lower sensitivity to caffeine in SepN deficient myofibers, suggesting a possible role of SepN in RyR regulation. SepN deficiency also leads to abnormal lung development characterized by enlarged alveoli, which is associated with decreased tissue elastance and increased quasi-static compliance of Sepn1−/− lungs. This finding raises the possibility that the respiratory syndrome observed in patients with SEPN1 mutations may have a primary pulmonary component in addition to the weakness of respiratory muscles.—Moghadaszadeh, B., Rider B. E., Lawlor, M. W., Childers, M. K., Grange, R. W., Gupta, K., Boukedes, S. S., Owen, C. A., Beggs, A. H. Selenoprotein N deficiency in mice is associated with abnormal lung development. PMID:23325319

  20. Different Forms of Selenoprotein M Differentially Affect Aβ Aggregation and ROS Generation

    Directory of Open Access Journals (Sweden)

    Ping Chen

    2013-02-01

    Full Text Available Selenoprotein M (SelM, one of the executants of selenium in vivo, is highly expressed in human brain and most probably involved in antioxidation, neuroprotection, and intracellular calcium regulation, which are the key factors for preventing the onset and progression of Alzheimer’s disease (AD. In this paper, human SelM was successfully overexpressed in human embryonic kidney cells HEK293T. Sodium selenite (Na2SeO3 0.5 μmol/L increased the expression of full-length SelM and inhibited the expression of truncated SelM. The full-length SelM exhibited higher antioxidant activity than its selenocysteine-to-cysteine mutation form SelM', whereas the truncated SelM had an adverse effect that increased the oxidative stress level of cells. When β-amyloid (Aβ42, an AD relevant peptide was cotransfected with the empty expression vector, SelM, or SelM' under the induction of 0.5 μmol/L Na2SeO3, the intracellular Aβ42 aggregation rates were detected to be 57.9% ± 5.5%, or 22.3% ± 2.6%, or 26.3% ± 2.1%, respectively, showing the inhibitory effects on Aβ aggregation by the full-length SelM and SelM'. Meanwhile, the intumescentia of mitochondria caused by Aβ42 transfection was significantly mitigated by the cotransfection of SelM or SelM′ with Aβ42 under the induction of 0.5 μmol/L Na2SeO3. On the contrary, cotransfection of SelM and Aβ42 without the induction of Na2SeO3 increased Aβ42 aggregation rate to 65.1% ± 3.2%, and it could not inhibit the Aβ-induced intumescent mitochondria. In conclusion, full-length SelM and SelM¢ might prevent Aβ aggregation by resisting oxidative stress generated during the formation of Aβ oligomers in cells.

  1. Association between Polymorphisms in Glutathione Peroxidase and Selenoprotein P Genes, Glutathione Peroxidase Activity, HRT Use and Breast Cancer Risk

    DEFF Research Database (Denmark)

    Méplan, Catherine; Dragsted, Lars Ove; Ravn-Haren, Gitte

    2013-01-01

    Breast cancer (BC) is one of the most common cancers in women. Evidence suggests that genetic variation in antioxidant enzymes could influence BC risk, but to date the relationship between selenoproteins and BC risk remains unclear. In this report, a study population including 975 Danish cases......GPx activity is modified by SNPs in SEPP1, GPX4 and GPX1 and by estrogens. Our data thus suggest a role of selenoproteins in BC development....

  2. Alternative transcripts and 3'UTR elements govern the incorporation of selenocysteine into selenoprotein S.

    Directory of Open Access Journals (Sweden)

    Jodi L Bubenik

    Full Text Available Selenoprotein S (SelS is a 189 amino acid trans-membrane protein that plays an important yet undefined role in the unfolded protein response. It has been proposed that SelS may function as a reductase, with the penultimate selenocysteine (Sec(188 residue participating in a selenosulfide bond with cysteine (Cys(174. Cotranslational incorporation of Sec into SelS depends on the recoding of the UGA codon, which requires a Selenocysteine Insertion Sequence (SECIS element in the 3'UTR of the transcript. Here we identify multiple mechanisms that regulate the expression of SelS. The human SelS gene encodes two transcripts (variants 1 and 2, which differ in their 3'UTR sequences due to an alternative splicing event that removes the SECIS element from the variant 1 transcript. Both transcripts are widely expressed in human cell lines, with the SECIS-containing variant 2 mRNA being more abundant. In vitro experiments demonstrate that the variant 1 3'UTR does not allow readthrough of the UGA/Sec codon. Thus, this transcript would produce a truncated protein that does not contain Sec and cannot make the selenosulfide bond. While the variant 2 3'UTR does support Sec insertion, its activity is weak. Bioinformatic analysis revealed two highly conserved stem-loop structures, one in the proximal part of the variant 2 3'UTR and the other immediately downstream of the SECIS element. The proximal stem-loop promotes Sec insertion in the native context but not when positioned far from the UGA/Sec codon in a heterologous mRNA. In contrast, the 140 nucleotides downstream of the SECIS element inhibit Sec insertion. We also show that endogenous SelS is enriched at perinuclear speckles, in addition to its known localization in the endoplasmic reticulum. Our results suggest the expression of endogenous SelS is more complex than previously appreciated, which has implications for past and future studies on the function of this protein.

  3. Polymorphisms in thioredoxin reductase and selenoprotein K genes and selenium status modulate risk of prostate cancer.

    Directory of Open Access Journals (Sweden)

    Catherine Méplan

    Full Text Available Increased dietary intake of Selenium (Se has been suggested to lower prostate cancer mortality, but supplementation trials have produced conflicting results. Se is incorporated into 25 selenoproteins. The aim of this work was to assess whether risk of prostate cancer is affected by genetic variants in genes coding for selenoproteins, either alone or in combination with Se status. 248 cases and 492 controls from an EPIC-Heidelberg nested case-control study were subjected to two-stage genotyping with an initial screening phase in which 384 tagging-SNPs covering 72 Se-related genes were determined in 94 cases and 94 controls using the Illumina Goldengate methodology. This analysis was followed by a second phase in which genotyping for candidate SNPs identified in the first phase was carried out in the full study using Sequenom. Risk of high-grade or advanced stage prostate cancer was modified by interactions between serum markers of Se status and genotypes for rs9880056 in SELK, rs9605030 and rs9605031 in TXNRD2, and rs7310505 in TXNRD1. No significant effects of SNPs on prostate cancer risk were observed when grade or Se status was not taken into account. In conclusion, the risk of high-grade or advanced-stage prostate cancer is significantly altered by a combination of genotype for SNPs in selenoprotein genes and Se status. The findings contribute to explaining the biological effects of selenium intake and genetic factors in prostate cancer development and highlight potential roles of thioredoxin reductases and selenoprotein K in tumour progression.

  4. Selenophosphate synthetase in the male accessory glands of an insect without selenoproteins.

    Science.gov (United States)

    Fuessl, Marion; Reinders, Jörg; Oefner, Peter J; Heinze, Jürgen; Schrempf, Alexandra

    2014-12-01

    Selenoproteins (containing the 21st proteinogenic amino acid selenocysteine) play important roles throughout all domains of life. Surprisingly, a number of taxa have small selenoproteomes, and Hymenopteran insects appear to have fully lost selenoproteins. Nevertheless, their genomes contain genes for several proteins of the selenocysteine insertion machinery, including selenophosphate synthetase 1 (SELD/SPS1). At present, it is unknown whether this enzyme has a selenoprotein-independent function, and whether the gene is actually translated into a protein in Hymenoptera. Here, we report that SELD/SPS1 is present as a protein in the accessory glands of males of the ant Cardiocondyla obscurior. It appears to be more abundant in the glands of winged disperser males than in those of wingless, local fighter males. Mating increases the lifespan and fecundity of queens in C. obscurior, and mating with winged males has a stronger effect on queen fitness than mating with a wingless male. SELD/SPS 1 has been suggested to play an important role in oxidative stress defense, and might therefore be involved in the life-prolonging effect of mating. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Galectin-1 Is an Interactive Protein of Selenoprotein M in the Brain

    Directory of Open Access Journals (Sweden)

    Qiong Liu

    2013-11-01

    Full Text Available Selenium, an essential trace element for human health, mainly exerts its biological function through selenoproteins. Selenoprotein M (SelM is one of the highly expressed selenoproteins in the brain, but its biological effect and molecular mechanism remain unclear. Thus, the interactive protein of SelM was investigated in this paper to guide further study. In order to avoid protein translational stop, the selenocysteine-encoding UGA inside the open reading frame of SelM was site-directly changed to the cysteine-encoding UGC to generate the SelM' mutant. Meanwhile, its N terminal transmembrane signal peptide was also cut off. This truncated SelM' was used to screen a human fetal brain cDNA library by the yeast two-hybrid system. A new interactive protein of SelM' was found to be galectin-1 (Gal-1. This protein-protein interaction was further verified by the results of fluorescence resonance energy transfer techniques, glutathione S-transferase pull-down and co-immunoprecipitation assays. As Gal-1 plays important roles in preventing neurodegeneration and promoting neuroprotection in the brain, the interaction between SelM' and Gal-1 displays a new direction for studying the biological function of SelM in the human brain.

  6. Assessment of production conditions for efficient use of Escherichia coli in high-yield heterologous recombinant selenoprotein synthesis.

    Science.gov (United States)

    Rengby, Olle; Johansson, Linda; Carlson, Lars A; Serini, Elena; Vlamis-Gardikas, Alexios; Kårsnäs, Per; Arnér, Elias S J

    2004-09-01

    The production of heterologous selenoproteins in Escherichia coli necessitates the design of a secondary structure in the mRNA forming a selenocysteine insertion sequence (SECIS) element compatible with SelB, the elongation factor for selenocysteine insertion at a predefined UGA codon. SelB competes with release factor 2 (RF2) catalyzing translational termination at UGA. Stoichiometry between mRNA, the SelB elongation factor, and RF2 is thereby important, whereas other expression conditions affecting the yield of recombinant selenoproteins have been poorly assessed. Here we expressed the rat selenoprotein thioredoxin reductase, with titrated levels of the selenoprotein mRNA under diverse growth conditions, with or without cotransformation of the accessory bacterial selA, selB, and selC genes. Titration of the selenoprotein mRNA with a pBAD promoter was performed in both TOP10 and BW27783 cells, which unexpectedly could not improve yield or specific activity compared to that achieved in our prior studies. Guided by principal component analysis, we instead discovered that the most efficient bacterial selenoprotein production conditions were obtained with the high-transcription T7lac-driven pET vector system in presence of the selA, selB, and selC genes, with induction of production at late exponential phase. About 40 mg of rat thioredoxin reductase with 50% selenocysteine content could thereby be produced per liter bacterial culture. These findings clearly illustrate the ability of E. coli to upregulate the selenocysteine incorporation machinery on demand and that this is furthermore strongly augmented in late exponential phase. This study also demonstrates that E. coli can indeed be utilized as cell factories for highly efficient production of heterologous selenoproteins such as rat thioredoxin reductase.

  7. Influence of Genetic Variations in Selenoprotein Genes on the Pattern of Gene Expression after Supplementation with Brazil Nuts

    Directory of Open Access Journals (Sweden)

    Janaina L. S. Donadio

    2017-07-01

    Full Text Available Selenium (Se is an essential micronutrient for human health. Its beneficial effects are exerted by selenoproteins, which can be quantified in blood and used as molecular biomarkers of Se status. We hypothesize that the presence of genetic polymorphisms in selenoprotein genes may: (1 influence the gene expression of specific selenoproteins and (2 influence the pattern of global gene expression after Brazil nut supplementation. The study was conducted with 130 healthy volunteers in Sao Paulo, Brazil, who consumed one Brazil nut (300 μg/Se a day for eight weeks. Gene expression of GPX1 and SELENOP and genotyping were measured by real-time PCR using TaqMan Assays. Global gene expression was assessed by microarray using Illumina HumanHT-12 v4 BeadChips. Brazil nut supplementation significantly increased GPX1 mRNA expression only in subjects with CC genotype at rs1050450 (p < 0.05. SELENOP mRNA expression was significantly higher in A-carriers at rs7579 either before or after supplementation (p < 0.05. Genotype for rs713041 in GPX4 affected the pattern of blood cell global gene expression. Genetic variations in selenoprotein genes modulated both GPX1 and SELENOP selenoprotein gene expression and global gene expression in response to Brazil nut supplementation.

  8. The human selenoprotein VCP-interacting membrane protein (VIMP) is non-globular and harbors a reductase function in an intrinsically disordered region

    DEFF Research Database (Denmark)

    Christensen, Lea Cecilie; Jensen, Njal Winther; Lages Lino Vala, Andrea

    2012-01-01

    The human selenoprotein VIMP (VCP-interacting membrane protein)/SelS (selenoprotein S) localizes to the endoplasmic reticulum (ER) membrane and is involved in the process of ER-associated degradation (ERAD). To date, little is known about the presumed redox activity of VIMP, its structure and how...

  9. Mouse Models Targeting Selenocysteine tRNA Expression for Elucidating the Role of Selenoproteins in Health and Development

    Directory of Open Access Journals (Sweden)

    Dolph L. Hatfield

    2009-09-01

    Full Text Available Selenium (Se deficiency has been known for many years to be associated with disease, impaired growth and a variety of other metabolic disorders in mammals. Only recently has the major role that Se-containing proteins, designated selenoproteins, play in many aspects of health and development begun to emerge. Se is incorporated into protein by way of the Se-containing amino acid, selenocysteine (Sec. The synthesis of selenoproteins is dependent on Sec tRNA for insertion of Sec, the 21st amino acid in the genetic code, into protein. We have taken advantage of this dependency to modulate the expression of Sec tRNA that in turn modulates the expression of selenoproteins by generating transgenic, conditional knockout, transgenic/standard knockout and transgenic/conditional knockout mouse models, all of which involve the Sec tRNA gene, to elucidate the intracellular roles of this protein class.

  10. A novel protein kinase-like domain in a selenoprotein, widespread in the tree of life.

    Directory of Open Access Journals (Sweden)

    Małgorzata Dudkiewicz

    Full Text Available Selenoproteins serve important functions in many organisms, usually providing essential oxidoreductase enzymatic activity, often for defense against toxic xenobiotic substances. Most eukaryotic genomes possess a small number of these proteins, usually not more than 20. Selenoproteins belong to various structural classes, often related to oxidoreductase function, yet a few of them are completely uncharacterised.Here, the structural and functional prediction for the uncharacterised selenoprotein O (SELO is presented. Using bioinformatics tools, we predict that SELO protein adopts a three-dimensional fold similar to protein kinases. Furthermore, we argue that despite the lack of conservation of the "classic" catalytic aspartate residue of the archetypical His-Arg-Asp motif, SELO kinases might have retained catalytic phosphotransferase activity, albeit with an atypical active site. Lastly, the role of the selenocysteine residue is considered and the possibility of an oxidoreductase-regulated kinase function for SELO is discussed.The novel kinase prediction is discussed in the context of functional data on SELO orthologues in model organisms, FMP40 a.k.a.YPL222W (yeast, and ydiU (bacteria. Expression data from bacteria and yeast suggest a role in oxidative stress response. Analysis of genomic neighbourhoods of SELO homologues in the three domains of life points toward a role in regulation of ABC transport, in oxidative stress response, or in basic metabolism regulation. Among bacteria possessing SELO homologues, there is a significant over-representation of aquatic organisms, also of aerobic ones. The selenocysteine residue in SELO proteins occurs only in few members of this protein family, including proteins from Metazoa, and few small eukaryotes (Ostreococcus, stramenopiles. It is also demonstrated that enterobacterial mchC proteins involved in maturation of bactericidal antibiotics, microcins, form a distant subfamily of the SELO proteins.The new

  11. Selenium status affects selenoprotein expression, reproduction, and F₁ generation locomotor activity in zebrafish (Danio rerio).

    Science.gov (United States)

    Penglase, Sam; Hamre, Kristin; Rasinger, Josef D; Ellingsen, Staale

    2014-06-14

    Se is an essential trace element, and is incorporated into selenoproteins which play important roles in human health. Mammalian selenoprotein-coding genes are often present as paralogues in teleost fish, and it is unclear whether the expression patterns or functions of these fish paralogues reflect their mammalian orthologues. Using the model species zebrafish (Danio rerio; ZF), we aimed to assess how dietary Se affects key parameters in Se metabolism and utilisation including glutathione peroxidase (GPX) activity, the mRNA expression of key Se-dependent proteins (gpx1a, gpx1b, sepp1a and sepp1b), oxidative status, reproductive success and F1 generation locomotor activity. From 27 d until 254 d post-fertilisation, ZF were fed diets with graded levels of Se ranging from deficient ( < 0·10 mg/kg) to toxic (30 mg/kg). The mRNA expression of gpx1a and gpx1b and GPX activity responded in a similar manner to changes in Se status. GPX activity and mRNA levels were lowest when dietary Se levels (0·3 mg/kg) resulted in the maximum growth of ZF, and a proposed bimodal mechanism in response to Se status below and above this dietary Se level was identified. The expression of the sepp1 paralogues differed, with only sepp1a responding to Se status. High dietary Se supplementation (30 mg/kg) decreased reproductive success, while the offspring of ZF fed above 0·3 mg Se/kg diet had lower locomotor activity than the other groups. Overall, the novel finding of low selenoprotein expression and activity coinciding with maximum body growth suggests that even small Se-induced variations in redox status may influence cellular growth rates.

  12. Increased Selenoprotein P in Choroid Plexus and Cerebrospinal Fluid in Alzheimer’s Disease Brain

    OpenAIRE

    Rueli, Rachel H.L.H.; Parubrub, Arlene C.; Dewing, Andrea S.T.; Hashimoto, Ann C.; Bellinger, Miyoko T.; Weeber, Edwin J.; Uyehara-Lock, Jane H.; White, Lon R.; Berry, Marla J.; Bellinger, Frederick P.

    2015-01-01

    Subjects with Alzheimer’s disease (AD) have elevated brain levels of the selenium transporter selenoprotein P (Sepp1). We investigated if this elevation results from increased release of Sepp1 from the choroid plexus (CP). Sepp1 is significantly increased in CP from AD brains in comparison to non-AD brains. Sepp1 localizes to the trans-Golgi network within CP epithelia, where it is processed for secretion. The cerebrospinal fluid from AD subjects also contains increased levels Sepp1 in compar...

  13. Direct determination of selenoproteins in polyvinylidene difluoride membranes by electrothermal atomic absorption spectrometry

    DEFF Research Database (Denmark)

    Sidenius, U; Gammelgaard, Bente

    2000-01-01

    A method for the direct determination of selenoproteins in plastic membranes after protein separation by gel electrophoresis was developed. Quantification was based on the determination of the selenium content of the proteins by electrothermal atomic absorption spectrometry (ET-AAS) after manual...... were excised and chemical modifier was added on top of the excised membrane prior to atomic absorption measurement. Acceptable linearity was achieved in the range 2-10 ng Se, corresponding to selenium concentrations close to 1 mg/L, when aqueous solutions of selenomethionine standard as well...

  14. Protective Action of Se-Supplement Against Acute Alcoholism Is Regulated by Selenoprotein P (SelP) in the Liver.

    Science.gov (United States)

    Zhang, Zhenbiao; Guo, Yingfang; Qiu, Changwei; Deng, Ganzhen; Guo, Mengyao

    2017-02-01

    Acute alcoholism is a major cause of cirrhosis and liver failure around the world. Selenium (Se) is an essential micronutrient promoting liver health in humans and animals. Selenoprotein P (SelP) is a glycoprotein secreted within the liver, which interacts with cytokines and the growth factor pathway to provide protection for hepatic cells. The present study was conducted to confirm the effect and mechanism of Se and SelP action in livers affected by acute alcoholism. In this study, a mouse model of acute alcoholism, as well as a hepatocyte model, was successfully established. The Se content of the liver was detected by atomic fluorescence spectrophotometry. The expression of messenger RNA (mRNA) was analyzed by quantitative polymerase chain reaction (qPCR). The protein expression of inflammatory factors was detected by ELISA. The other proteins were analyzed by western blotting. The results showed that pathological damage to the liver was gradually weakened by Se-supplementation, which was evaluated by hematoxylin and eosin (H&E) and TUNEL staining. Se-supplementation inhibited expression of pro-inflammatory factors TNF-α and IL-1β and promoted production of anti-inflammatory cytokine IL-10 in the liver with acute alcoholism. Se-supplementation also prevented the apoptosis of hepatocytes by suppressing the cleavage of caspases-9, 3, 6, 7, and poly(ADP-ribose) polymerase (PARP). Through correlational analysis, it was determined that the effects of Se-supplement were closely related to SelP expression, inflammatory cytokines, and apoptosis molecule production. The sienna of SelP further confirmed the protective action of Se-supplementation on the liver and that the mechanism of SelP involves the regulation of inflammatory cytokines and apoptosis molecules in acute alcoholism. These findings provide information regarding a new potential target for the treatment of acute alcoholism.

  15. Selenoprotein P is the major selenium transport protein in mouse milk.

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    Kristina E Hill

    Full Text Available Selenium is transferred from the mouse dam to its neonate via milk. Milk contains selenium in selenoprotein form as selenoprotein P (Sepp1 and glutathione peroxidase-3 (Gpx3 as well as in non-specific protein form as selenomethionine. Selenium is also present in milk in uncharacterized small-molecule form. We eliminated selenomethionine from the mice in these experiments by feeding a diet that contained sodium selenite as the source of selenium. Selenium-replete dams with deletion of Sepp1 or Gpx3 were studied to assess the effects of these genes on selenium transfer to the neonate. Sepp1 knockout caused a drop in milk selenium to 27% of the value in wild-type milk and a drop in selenium acquisition by the neonates to 35%. In addition to decreasing milk selenium by eliminating Sepp1, deletion of Sepp1 causes a decline in whole-body selenium, which likely also contributes to the decreased transfer of selenium to the neonate. Deletion of Gpx3 did not decrease milk selenium content or neonate selenium acquisition by measurable amounts. Thus, when the dam is fed selenium-adequate diet (0.25 mg selenium/kg diet, milk Sepp1 transfers a large amount of selenium to neonates but the transfer of selenium by Gpx3 is below detection by our methods.

  16. Assessment of the Selenoprotein M (SELM over-expression on human hepatocellular carcinoma tissues by immunohistochemistry

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    E. Guerriero

    2014-10-01

    Full Text Available Selenium is an essential trace mineral of fundamental importance to human healthy and exerts its biological function through selenoproteins. In particular, Selenoprotein M (SELM is located in the endoplasmic reticulum and contains the common redox motif of cysteine-X-X-selenocysteine type. It attracts great attention due to its high expression in brain and its potential roles as antioxidant, neuroprotective, and cytosolic calcium regulator. Recently, our group found SELM over-expression  in human hepatocellular carcinoma (HCC cell lines. In this report some paraffin-embedded tissues from liver biopsy of patients with hepatitis C virus (HCV-related cirrhosis and HCC were immunohistochemically stained and SELM expression scoring was evaluated. Our results evidence for the first time an increase of SELM expression in HCC liver tissues, and its gradual expression raise associated with an increased malignancy grade. Therefore, we propose to use i SELM as putative marker for HCC as well as ii simple immunohistochemistry technique to distinguish between the different grades of malignancy. 

  17. Association between Polymorphisms in Glutathione Peroxidase and Selenoprotein P Genes, Glutathione Peroxidase Activity, HRT Use and Breast Cancer Risk

    DEFF Research Database (Denmark)

    Méplan, Catherine; Dragsted, Lars Ove; Ravn-Haren, Gitte

    2013-01-01

    Breast cancer (BC) is one of the most common cancers in women. Evidence suggests that genetic variation in antioxidant enzymes could influence BC risk, but to date the relationship between selenoproteins and BC risk remains unclear. In this report, a study population including 975 Danish cases an...

  18. Regulation of Selenocysteine Content of Human Selenoprotein P by Dietary Selenium and Insertion of Cysteine in Place of Selenocysteine.

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    Anton A Turanov

    Full Text Available Selenoproteins are a unique group of proteins that contain selenium in the form of selenocysteine (Sec co-translationally inserted in response to a UGA codon with the help of cis- and trans-acting factors. Mammalian selenoproteins contain single Sec residues, with the exception of selenoprotein P (SelP that has 7-15 Sec residues depending on species. Assessing an individual's selenium status is important under various pathological conditions, which requires a reliable selenium biomarker. Due to a key role in organismal selenium homeostasis, high Sec content, regulation by dietary selenium, and availability of robust assays in human plasma, SelP has emerged as a major biomarker of selenium status. Here, we found that Cys is present in various Sec positions in human SelP. Treatment of cells expressing SelP with thiophosphate, an analog of the selenium donor for Sec synthesis, led to a nearly complete replacement of Sec with Cys, whereas supplementation of cells with selenium supported Sec insertion. SelP isolated directly from human plasma had up to 8% Cys inserted in place of Sec, depending on the Sec position. These findings suggest that a change in selenium status may be reflected in both SelP concentration and its Sec content, and that availability of the SelP-derived selenium for selenoprotein synthesis may be overestimated under conditions of low selenium status due to replacement of Sec with Cys.

  19. Compatibilidad química por calorimetría diferencial de barrido y termogravimetría del auranofin tabletas 3 mg

    OpenAIRE

    Luis Octavio Martínez Álvarez; Marlene Montes Pérez

    2011-01-01

    Como parte de la pre-estabilidad de la preformulación de auranofin tabletas, se realizó un estudio de compatibilidad química, para lo cual se emplearon técnicas de análisis térmico como la calorimetría diferencial de barrido y la termogravimetría. Previo a dichos estudios se caracterizó térmicamente por calorimetría diferencial de barrido el principio activo y cada uno de los excipientes. Posteriormente se procedió a la realización del estudio de compatibilidad química, mediante la preparació...

  20. Expression of Selenoproteins Is Maintained in Mice Carrying Mutations in SECp43, the tRNA Selenocysteine 1 Associated Protein (Trnau1ap.

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    Yassin Mahdi

    Full Text Available Selenocysteine tRNA 1 associated protein (Trnau1ap has been characterized as a tRNA[Ser]Sec-binding protein of 43 kDa, hence initially named SECp43. Previous studies reported its presence in complexes containing tRNA[Ser]Sec implying a role of SECp43 as a co-factor in selenoprotein expression. We generated two conditionally mutant mouse models targeting exons 3+4 and exons 7+8 eliminating parts of the first RNA recognition motif or of the tyrosine-rich domain, respectively. Constitutive inactivation of exons 3+4 of SECp43 apparently did not affect the mice or selenoprotein expression in several organs. Constitutive deletion of exons 7+8 was embryonic lethal. We therefore generated hepatocyte-specific Secp43 knockout mice and characterized selenoprotein expression in livers of mutant mice. We found no significant changes in the levels of 75Se-labelled hepatic proteins, selenoprotein levels as determined by Western blot analysis, enzymatic activity or selenoprotein mRNA abundance. The methylation pattern of tRNA[Ser]Sec remained unchanged. Truncated Secp43 Δ7,8mRNA increased in Secp43-mutant livers suggesting auto-regulation of Secp43 mRNA abundance. We found no signs of liver damage in Secp433-mutant mice, but neuron-specific deletion of exons 7+8 impaired motor performance, while not affecting cerebral selenoprotein expression or cerebellar development. These findings suggest that the targeted domains in the SECp43 protein are not essential for selenoprotein biosynthesis in hepatocytes and neurons. Whether the remaining second RNA recognition motif plays a role in selenoprotein biosynthesis and which other cellular process depends on SECp43 remains to be determined.

  1. Increased Selenoprotein P in Choroid Plexus and Cerebrospinal Fluid in Alzheimer’s Disease Brain

    Science.gov (United States)

    Rueli, Rachel H.L.H.; Parubrub, Arlene C.; Dewing, Andrea S.T.; Hashimoto, Ann C.; Bellinger, Miyoko T.; Weeber, Edwin J.; Uyehara-Lock, Jane H.; White, Lon R.; Berry, Marla J.; Bellinger, Frederick P.

    2015-01-01

    Subjects with Alzheimer’s disease (AD) have elevated brain levels of the selenium transporter selenoprotein P (Sepp1). We investigated if this elevation results from increased release of Sepp1 from the choroid plexus (CP). Sepp1 is significantly increased in CP from AD brains in comparison to non-AD brains. Sepp1 localizes to the trans-Golgi network within CP epithelia, where it is processed for secretion. The cerebrospinal fluid from AD subjects also contains increased levels Sepp1 in comparison to non-AD subjects. These findings suggest that AD pathology induces increased levels of Sepp1 within CP epithelia for release into the cerebrospinal fluid to ultimately increase brain selenium. PMID:25298198

  2. Lower Selenoprotein T Expression and Immune Response in the Immune Organs of Broilers with Exudative Diathesis Due to Selenium Deficiency.

    Science.gov (United States)

    Pan, Tingru; Liu, Tianqi; Tan, Siran; Wan, Na; Zhang, Yiming; Li, Shu

    2017-08-05

    The objective of the present study was to investigate whether dietary selenium (Se) deficiency would affect the expression of selenoprotein T (SelT) and immune response in the immune organs of broilers. Changes in expression of inflammatory cytokines and oxidative stress response caused by Se deficiency can lead to organism damage, which in turn leads to immune response. Sixty (1-day-old) broilers were divided into the control group and Se-deficiency group. Animal models with exudative diathesis were duplicated in the broilers by feeding them Se-deficient diet for 20 days. After the Se-deficient group exhibited symptoms of exudative diathesis, all the broilers were euthanized, and their immune organs were taken for analysis. The tissues including spleen, bursa of Fabricius, and thymus were treated to determine the pathological changes (including microscopic and ultramicroscopic), the messenger RNA (mRNA) expression levels of SelT and its synthetase (SecS and SPS1), cytokine mRNA expression levels, and antioxidant status. The microscopic and ultramicroscopic analyses showed that immune tissues were obviously injured in the Se-deficient group. The mRNA expression of SelT was decreased compared with that in the control group. Meanwhile, the mRNA expression levels of SecS and SPS1 were downregulated. In the Se-deficient group, the mRNA expression levels of IL-1R and IL-1β were higher than those of three control organs. Additionally, the IL-2 and INF-γ mRNA expression levels were lower than those of the control group. The activity of CAT was decreased, and the contents of H2O2 and •OH were increased due to Se deficiency. Pearson method analysis showed that the expression of SelT had a positive correlation with IL-2, INF-γ, SecS, and SPS1 and a negative correlation with IL-1R and IL-1β. In summary, these data indicated that Se-deficient diet decreased the SelT expression and its regulation of oxidative stress, and it inhibited a pleiotropic mechanism of the immune

  3. Comparison of different transition metal ions for immobilized metal affinity chromatography of selenoprotein P from human plasma

    DEFF Research Database (Denmark)

    Sidenius, U; Farver, O; Jøns, O

    1999-01-01

    Cu2+, Ni2+, Zn2+, Co2+ and Cd2+ were evaluated in metal ion affinity chromatography for enrichment of selenoprotein P, and immobilized Co2+ affinity chromatography was found to be the most selective chromatographic method. The chromatography was performed by fast protein liquid chromatography...... and the fractionation was followed by analysis of the collected fractions for selenium by inductively coupled plasma mass spectrometry. By the combination of immobilized Co2+ affinity chromatography and heparin affinity chromatography a simple method was developed yielding a 14,800-fold enrichment of selenoprotein P....... The purity of the protein was determined by SDS-PAGE and by sequencing from polyvinylidene difluoride blots of SDS-PAGE gels....

  4. Comparison of different transition metal ions for immobilized metal affinity chromatography of selenoprotein P from human plasma

    DEFF Research Database (Denmark)

    Sidenius, U; Farver, O; Jøns, O

    1999-01-01

    Cu2+, Ni2+, Zn2+, Co2+ and Cd2+ were evaluated in metal ion affinity chromatography for enrichment of selenoprotein P, and immobilized Co2+ affinity chromatography was found to be the most selective chromatographic method. The chromatography was performed by fast protein liquid chromatography and....... The purity of the protein was determined by SDS-PAGE and by sequencing from polyvinylidene difluoride blots of SDS-PAGE gels....

  5. Exposure to monomethylarsonous acid (MMA(III)) leads to altered selenoprotein synthesis in a primary human lung cell model.

    Science.gov (United States)

    Meno, Sarah R; Nelson, Rebecca; Hintze, Korry J; Self, William T

    2009-09-01

    Monomethylarsonous acid (MMA(III)), a trivalent metabolite of arsenic, is highly cytotoxic and recent cell culture studies suggest that it might act as a carcinogen. The general consensus of studies indicates that the cytotoxicity of MMA(III) is a result of increased levels of reactive oxygen species (ROS). A longstanding relationship between arsenic and selenium metabolism has led to the use of selenium as a supplement in arsenic exposed populations, however the impact of organic arsenicals (methylated metabolites) on selenium metabolism is still poorly understood. In this study we determined the impact of exposure to MMA(III) on the regulation of expression of TrxR1 and its activity using a primary lung fibroblast line, WI-38. The promoter region of the gene encoding the selenoprotein thioredoxin reductase 1 (TrxR1) contains an antioxidant responsive element (ARE) that has been shown to be activated in the presence of electrophilic compounds. Results from radiolabeled selenoproteins indicate that exposure to low concentrations of MMA(III) resulted in increased synthesis of TrxR1 in WI-38 cells, and lower incorporation of selenium into other selenoproteins. MMA(III) treatment led to increased mRNA encoding TrxR1 in WI-38 cells, while lower levels of mRNA coding for cellular glutathione peroxidase (cGpx) were detected in exposed cells. Luciferase activity of TrxR1 promoter fusions increased with addition of MMA(III), as did expression of a rat quinone reductase (QR) promoter fusion construct. However, MMA(III) induction of the TRX1 promoter fusion was abrogated when the ARE was mutated, suggesting that this regulation is mediated via the ARE. These results indicate that MMA(III) alters the expression of selenoproteins based on a selective induction of TrxR1, and this response to exposure to organic arsenicals that requires the ARE element.

  6. Selenium dietary supplementation as a mechanism to restore hepatic selenoprotein regulation in rat pups exposed to alcohol.

    Science.gov (United States)

    Jotty, Karick; Ojeda, M Luisa; Nogales, Fátima; Murillo, M Luisa; Carreras, Olimpia

    2013-11-01

    Ethanol exposure during gestation and lactation decreases selenium (Se) intake, disrupting body Se balance and inducing oxidative stress in rat offspring. Selenium-supplemented diet (0.5 ppm) was administered to ethanol-exposed (20% v/v) dams during gestation and lactation. When the dams' pups were 21 days old, the pups' levels of the main hepatic selenoproteins glutathione peroxidase (GPx1 and GPx4) and selenoprotein P (SelP) were measured. The pups were divided into control (C), alcohol (A), control-selenium (CS), and alcohol-selenium (AS) groups. The purpose was to evaluate the effect of the selenium-supplemented diet on the levels of Se deposits present in the livers of their pups. Alcohol decreases hepatic Se deposits, GPx activity, and GPx1 expression; alcohol increases GPx4 and SelP expression. Se was measured by furnace graphite atomic absorption spectrometry, the antioxidant activity of GPx and concentration of hepatic phospholipids (PL) were determined by spectrophotometry, and the selenoprotein expressions were detected by Western blotting. Selenite treatment prevented alcohol's effects of diminishing the Se deposits, GPx activity, and GPx1 expression, while maintaining the high levels of the expression of GPx4 and SelP. These results suggest that depletion of hepatic Se levels in rat pups, caused by ethanol exposure to their dams, affects the synthesis of the 3 main hepatic selenoproteins in different ways, which is related to a decrease in GPx activity and PL concentration, and an increase in serum Se levels. Selenium supplementation to the dams increased the expression of GPx1, GPx4, and SelP in their pups. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Selenocysteine insertion sequence binding protein 2L is implicated as a novel post-transcriptional regulator of selenoprotein expression.

    Directory of Open Access Journals (Sweden)

    Jesse Donovan

    Full Text Available The amino acid selenocysteine (Sec is encoded by UGA codons. Recoding of UGA from stop to Sec requires a Sec insertion sequence (SECIS element in the 3' UTR of selenoprotein mRNAs. SECIS binding protein 2 (SBP2 binds the SECIS element and is essential for Sec incorporation into the nascent peptide. SBP2-like (SBP2L is a paralogue of SBP2 in vertebrates and is the only SECIS binding protein in some invertebrates where it likely directs Sec incorporation. However, vertebrate SBP2L does not promote Sec incorporation in in vitro assays. Here we present a comparative analysis of SBP2 and SBP2L SECIS binding properties and demonstrate that its inability to promote Sec incorporation is not due to lower SECIS affinity but likely due to lack of a SECIS dependent domain association that is found in SBP2. Interestingly, however, we find that an invertebrate version of SBP2L is fully competent for Sec incorporation in vitro. Additionally, we present the first evidence that SBP2L interacts with selenoprotein mRNAs in mammalian cells, thereby implying a role in selenoprotein expression.

  8. Selenium-enriched milk proteins and selenium yeast affect selenoprotein activity and expression differently in mouse colon.

    Science.gov (United States)

    Hu, Ying; McIntosh, Graeme H; Le Leu, Richard K; Young, Graeme P

    2010-07-01

    Certain forms of dietary Se may have an advantage in improving Se status and reducing cancer risk. The present study compared the effects of an Se-enriched milk protein product (dairy-Se) with an Se yeast (yeast-Se) on selenoprotein activity and expression in the mouse colon. Mice were fed four diets for 4 weeks: a control milk protein diet (Se at 0.068 parts per million (ppm)), dairy-Se diets with Se at 0.5 and 1 ppm, and a yeast-Se diet with Se at 1 ppm. Cytosolic glutathione peroxidase-1 (GPx-1) activity, mRNA of selenoprotein P (SeP), GPx-1, gastrointestinal glutathione peroxidase-2 (GPx-2) and thioredoxin reductase-1 (TrxR-1) were examined in the mouse colon. Dairy-Se diets did not significantly affect GPx-1 mRNA and GPx-1 activity but produced a dose-dependent increase in SeP and GPx-2 mRNA, with a significantly higher level achieved at 1 ppm Se (P supplement had any effect on TrxR-1. The present study indicates that selenoprotein levels in the mouse colon are regulated differently depending on the Se supplement. As we have previously shown that dairy-Se at 1 ppm was protective against colorectal cancer (CRC) in an azoxymethane-induced CRC mouse model, this up-regulation of colonic GPx-2 and SeP with Se supplementation may be crucial to its chemopreventive action.

  9. Selenium requirements based on muscle and kidney selenoprotein enzyme activity and transcript expression in the turkey poult (Meleagris gallopavo.

    Directory of Open Access Journals (Sweden)

    Rachel M Taylor

    Full Text Available The current NRC selenium (Se requirement for turkeys is 0.2 μg Se/g diet. We previously fed turkey poults a Se-deficient diet (0.005 μg Se/g supplemented with 10 graded levels of Se (0, 0.025, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 1.0 μg Se/g as Na2SeO3, 5/treatment for 4 wk, and found that the minimum dietary Se requirement was 0.3 μg Se/g based on selenoprotein enzyme activity in blood, liver, gizzard and pancreas. Because the turkey is primarily a production animal, we expanded this analysis to kidney, heart, breast and thigh. Se concentrations in Se-deficient poults were 5.0, 9.8, 33, and 15% of levels in poults fed 0.4 μg Se/g in liver, kidney, thigh and breast, respectively. Increasing Se supplementation resulted in hyperbolic response curves for all tissues; breakpoint analysis indicated minimum Se requirements of 0.34-0.36 μg Se/g based on tissue Se levels in liver, kidney and thigh. Similarly, GPX1 activity in muscle tissues and kidney responded hyperbolically to increasing dietary Se, reaching well-defined plateaus with breakpoints at 0.30-0.36 μg Se/g. Minimum Se requirements based on GPX4 activity were 0.30-0.32 μg Se/g for breast and thigh. Selenoprotein transcript expression decreased significantly in Se deficiency for only 2, 3, 5, and 6 mRNA in breast, thigh, heart, and kidney, respectively, out of 24 known avian selenoproteins. Se response curves for regulated selenoprotein transcripts were hyperbolic, and reached well-defined plateaus with breakpoints in a narrow range of 0.08-0.19 μg Se/g. No selenoprotein transcript was altered by supernutritional Se. In summary, these results clearly indicate that the NRC dietary Se requirement should be raised to 0.4 μg Se/g, at least for poults, to meet the nutritional needs of the young turkey. The Se response curve plateaus further show that limits for turkey supplementation with selenite could safely be raised to 0.5 μg Se/g diet.

  10. Genetic variation in selenoprotein genes, lifestyle, and risk of colon and rectal cancer.

    Directory of Open Access Journals (Sweden)

    Martha L Slattery

    Full Text Available BACKGROUND: Associations between selenium and cancer have directed attention to role of selenoproteins in the carcinogenic process. METHODS: We used data from two population-based case-control studies of colon (n = 1555 cases, 1956 controls and rectal (n = 754 cases, 959 controls cancer. We evaluated the association between genetic variation in TXNRD1, TXNRD2, TXNRD3, C11orf31 (SelH, SelW, SelN1, SelS, SepX, and SeP15 with colorectal cancer risk. RESULTS: After adjustment for multiple comparisons, several associations were observed. Two SNPs in TXNRD3 were associated with rectal cancer (rs11718498 dominant OR 1.42 95% CI 1.16,1.74 pACT 0.0036 and rs9637365 recessive 0.70 95% CI 0.55,0.90 pACT 0.0208. Four SNPs in SepN1 were associated with rectal cancer (rs11247735 recessive OR 1.30 95% CI 1.04,1.63 pACT 0.0410; rs2072749 GGvsAA OR 0.53 95% CI 0.36,0.80 pACT 0.0159; rs4659382 recessive OR 0.58 95% CI 0.39,0.86 pACT 0.0247; rs718391 dominant OR 0.76 95% CI 0.62,0.94 pACT 0.0300. Interaction between these genes and exposures that could influence these genes showed numerous significant associations after adjustment for multiple comparisons. Two SNPs in TXNRD1 and four SNPs in TXNRD2 interacted with aspirin/NSAID to influence colon cancer; one SNP in TXNRD1, two SNPs in TXNRD2, and one SNP in TXNRD3 interacted with aspirin/NSAIDs to influence rectal cancer. Five SNPs in TXNRD2 and one in SelS, SeP15, and SelW1 interacted with estrogen to modify colon cancer risk; one SNP in SelW1 interacted with estrogen to alter rectal cancer risk. Several SNPs in this candidate pathway influenced survival after diagnosis with colon cancer (SeP15 and SepX1 increased HRR and rectal cancer (SepX1 increased HRR. CONCLUSIONS: Findings support an association between selenoprotein genes and colon and rectal cancer development and survival after diagnosis. Given the interactions observed, it is likely that the impact of cancer susceptibility from genotype is

  11. The Relationship between Selenoprotein P and Glucose Metabolism in Experimental Studies

    Directory of Open Access Journals (Sweden)

    Jinyuan Mao

    2013-05-01

    Full Text Available Selenium is an essential trace element in the diet of mammals which is important for many physiological functions. However, a number of epidemiological studies have suggested that high selenium status is a possible risk factor for the development of type 2 diabetes, although they cannot distinguish between cause and effect. Selenoprotein P (Sepp1 is central to selenium homeostasis and widely expressed in the organism. Here we review the interaction between Sepp1 and glucose metabolism with an emphasis on experimental evidence. In models with or without gene modification, glucose and insulin can regulate Sepp1 expression in the pancreas and liver, and vice versa. Especially in the liver, Sepp1 is regulated virtually like a gluconeogenic enzyme. Combining these data suggests that there could be a feedback regulation between hepatic Sepp1 and pancreatic insulin and that increasing circulating Sepp1 might be the result rather than the cause of abnormal glucose metabolism. Future studies specifically designed to overexpress Sepp1 are needed in order to provide a more robust link between Sepp1 and type 2 diabetes.

  12. Polymorphisms in the selenoprotein S gene: lack of association with autoimmune inflammatory diseases

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    Díaz-Rubio Manuel

    2008-07-01

    Full Text Available Abstract Background Selenoprotein S (SelS protects the functional integrity of the endoplasmic reticulum against the deleterious effects of metabolic stress. SEPS1/SelS polymorphisms have been involved in the increased release of pro-inflammatory cytokines interleukin (IL-1β, tumor necrosis factor (TNF-α and IL-6 in macrophages. We aimed at investigating the role of the SEPS1 variants previously associated with higher plasma levels of these cytokines and of the SEPS1 haplotypes in the susceptibility to develop immune-mediated diseases characterized by an inflammatory component. Results Six polymorphisms distributed through the SEPS1 gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171 were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study. Conclusion Lack of association of SEPS1 polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.

  13. The Subcellular Location of Selenoproteins and the Impact on Their Function

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    Alan M. Diamond

    2015-05-01

    Full Text Available Most human selenium containing proteins contain selenium in the form of the amino acid selenocysteine, which is encoded in the corresponding mRNA as a UGA codon. Only a few non-selenocysteine containing selenoproteins are present and the nature of the association with selenium is not well understood. This review focuses on two selenocysteine-containing proteins that are members of the glutathione peroxidase family, GPx-1 and GPx-4, and the selenium-associated protein referred to as Selenium Binding Protein 1. Each of these proteins have been described to reside in two or more cellular compartments, and in the case of GPx-1 and SBP1, interact with each other. The enzymatic activity of GPx-1 and GPx-4 have been well described, but it is less clear how their cellular location impacts the health related phenotypes associated with activities, while no catalytic function is assigned to SBP1. The distribution of these proteins is presented as is the possible consequences of that compartmentalization.

  14. Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer.

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    Zou, Peng; Chen, Minxiao; Ji, Jiansong; Chen, Weiqian; Chen, Xi; Ying, Shilong; Zhang, Junru; Zhang, Ziheng; Liu, Zhiguo; Yang, Shulin; Liang, Guang

    2015-11-03

    Gastric cancer (GC) is one of the leading causes of cancer mortality in the world. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for GC treatment. Auranofin (AF), clinically used to treat rheumatic arthritis, but it exhibited preclinical efficacy in GC cells. By increasing intracellular reactive oxygen species (ROS) levels, AF induces a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in cultured GC cells. Blockage of ROS production reversed AF-induced ER stress and mitochondrial pathways activation as well as apoptosis. In addition, AF displays synergistic lethality with an ROS-generating agent piperlongumine, which is a natural product isolated from the long pepper Piper longum L. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer. More importantly, it reveals that increased ROS generation might be an effective strategy in treating human gastric cancer.

  15. Effects of selenium supplementation on selenoprotein gene expression and response to influenza vaccine challenge: a randomised controlled trial.

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    Andrew J Goldson

    2011-03-01

    Full Text Available The uncertainty surrounding dietary requirements for selenium (Se is partly due to limitations in biomarkers of Se status that are related to health outcomes. In this study we determined the effect of different doses and forms of Se on gene expression of selenoprotein S (SEPS1, selenoprotein W (SEPW1 and selenoprotein R (SEPR, and responses to an immune function challenge, influenza vaccine, were measured in order to identify functional markers of Se status.A 12 week human dietary intervention study was undertaken in 119 volunteers who received placebo, 50, 100 or 200 µg/day Se-enriched yeast (Se-yeast or meals containing unenriched or Se-enriched onions (50 µg/day. Gene expression was quantified in RNA samples extracted from human peripheral blood mononuclear cells (PBMC's using quantitative RT-PCR. There was a significant increase in SEPW1 mRNA in the Se-enriched onion group (50 µg/day compared with the unenriched onion group. SEPR and SEPW1 did not change significantly over the duration of the supplementation period in the control or Se-yeast groups, except at week 10 when SEPW1 mRNA levels were significantly lower in the 200 µg/day Se-yeast group compared to the placebo group. Levels of SEPS1 mRNA increased significantly 7 days after the influenza vaccine challenge, the magnitude of the increase in SEPS1 gene expression was dose-dependent, with a significantly greater response with higher Se supplementation.This novel finding provides preliminary evidence for a role of SEPS1 in the immune response, and further supports the relationship between Se status and immune function.ClinicalTrials.gov [NCT00279812].

  16. Increased Selenoprotein P Levels in Subjects with Visceral Obesity and Nonalcoholic Fatty Liver Disease

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    Hae Yoon Choi

    2013-02-01

    Full Text Available BackgroundSelenoprotein P (SeP has recently been reported as a novel hepatokine that regulates insulin resistance and systemic energy metabolism in rodents and humans. We explored the associations among SeP, visceral obesity, and nonalcoholic fatty liver disease (NAFLD.MethodsWe examined serum SeP concentrations in subjects with increased visceral fat area (VFA or liver fat accumulation measured with computed tomography. Our study subjects included 120 nondiabetic individuals selected from participants of the Korean Sarcopenic Obesity Study. In addition, we evaluated the relationship between SeP and cardiometabolic risk factors, including homeostasis model of insulin resistance (HOMA-IR, high sensitivity C-reactive protein (hsCRP, adiponectin values, and brachial-ankle pulse wave velocity (baPWV.ResultsSubjects with NAFLD showed increased levels of HOMA-IR, hsCRP, VFA, and several components of metabolic syndrome and decreased levels of adiponectin and high density lipoprotein cholesterol than those of controls. Serum SeP levels were positively correlated with VFA, hsCRP, and baPWV and negatively correlated with the liver attenuation index. Not only subjects with visceral obesity but also those with NAFLD exhibited significantly increased SeP levels (P<0.001. In multiple logistic regression analysis, the subjects in the highest SeP tertile showed a higher risk for NAFLD than those in the lowest SeP tertile, even after adjusting for potential confounding factors (odds ratio, 7.48; 95% confidence interval, 1.72 to 32.60; P=0.007.ConclusionCirculating SeP levels were increased in subjects with NAFLD as well as in those with visceral obesity and may be a novel biomarker for NAFLD.

  17. [Altered hepatic expression of selenoprotein S1 in septic mouse induced by LPS attack].

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    Su, Mao-sheng; He, Lei; Yao, Yong-ming; Yu, Yan; Wu, Yao; Dong, Jia-hong

    2010-07-13

    To investigate the change of selenoprotein S1 (SEPS1) hepatic expression in septic mouse induced by LPS attack. The septic murine model induced by LPS attack was established. Ten mice were randomly selected as control group from 84 BALB/c mice and others as septic group. The mice were sacrificed after anesthesia in control group and 10 mg/kg LPS was injected intraperitoneally into septic group mice. Liver and blood samples were taken at 6, 12, 24, 48, 72 and 96 h after LPS injection. Ten mice were randomly selected at each time point. The levels of blood ALT, AST, LDH and liver IL-6, TNF-α were detected. And the SEPS1 expression was simultaneously detected by Western blot. There was liver damage in septic group compared with normal control group. The levels of ALT, AST and LDH markedly increased. And all peaked at 24 h. The levels were (99 ± 11), (299 ± 48) and (1523 ± 131) U/L respectively (versus level at zero hour, P 8239) ng/L, P < 0.05]. Western blot showed that SEPS1 protein expression markedly increased simultaneously in liver of septic mouse. And the peak value was reached at 24 h post-injury. Then there was a gradual decrease and normal level returned at 72 h. Immunohistochemical results showed that SEPS1 protein expression in liver of septic mouse also markedly increased. And the peak value was reached at 24 h post-injury. Pathologic results showed that liver lesion was apparent in septic mouse and it was the worst during 6-12 h. Liver damage to different extents may be induced by LPS attack in septic mouse. The levels of IL-6 and TNF-α markedly increase. The SEPS1 protein expression in liver of septic mouse is also markedly elevated. And it peaks at 24 h post-injury and returns to normal at 72 h.

  18. Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes.

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    Takayama, Hiroaki; Misu, Hirofumi; Iwama, Hisakazu; Chikamoto, Keita; Saito, Yoshiro; Murao, Koji; Teraguchi, Atsushi; Lan, Fei; Kikuchi, Akihiro; Saito, Reina; Tajima, Natsumi; Shirasaki, Takayoshi; Matsugo, Seiichi; Miyamoto, Ken-ichi; Kaneko, Shuichi; Takamura, Toshinari

    2014-01-03

    Selenoprotein P (SeP; encoded by SEPP1 in humans) is a liver-derived secretory protein that induces insulin resistance in type 2 diabetes. Suppression of SeP might provide a novel therapeutic approach to treating type 2 diabetes, but few drugs that inhibit SEPP1 expression in hepatocytes have been identified to date. The present findings demonstrate that metformin suppresses SEPP1 expression by activating AMP-activated kinase (AMPK) and subsequently inactivating FoxO3a in H4IIEC3 hepatocytes. Treatment with metformin reduced SEPP1 promoter activity in a concentration- and time-dependent manner; this effect was cancelled by co-administration of an AMPK inhibitor. Metformin also suppressed Sepp1 gene expression in the liver of mice. Computational analysis of transcription factor binding sites conserved among the species resulted in identification of the FoxO-binding site in the metformin-response element of the SEPP1 promoter. A luciferase reporter assay showed that metformin suppresses Forkhead-response element activity, and a ChIP assay revealed that metformin decreases binding of FoxO3a, a direct target of AMPK, to the SEPP1 promoter. Transfection with siRNAs for Foxo3a, but not for Foxo1, cancelled metformin-induced luciferase activity suppression of the metformin-response element of the SEPP1 promoter. The overexpression of FoxO3a stimulated SEPP1 promoter activity and rescued the suppressive effect of metformin. Metformin did not affect FoxO3a expression, but it increased its phosphorylation and decreased its nuclear localization. These data provide a novel mechanism of action for metformin involving improvement of systemic insulin sensitivity through the regulation of SeP production and suggest an additional approach to the development of anti-diabetic drugs.

  19. Metformin Suppresses Expression of the Selenoprotein P Gene via an AMP-activated Kinase (AMPK)/FoxO3a Pathway in H4IIEC3 Hepatocytes*

    Science.gov (United States)

    Takayama, Hiroaki; Misu, Hirofumi; Iwama, Hisakazu; Chikamoto, Keita; Saito, Yoshiro; Murao, Koji; Teraguchi, Atsushi; Lan, Fei; Kikuchi, Akihiro; Saito, Reina; Tajima, Natsumi; Shirasaki, Takayoshi; Matsugo, Seiichi; Miyamoto, Ken-ichi; Kaneko, Shuichi; Takamura, Toshinari

    2014-01-01

    Selenoprotein P (SeP; encoded by SEPP1 in humans) is a liver-derived secretory protein that induces insulin resistance in type 2 diabetes. Suppression of SeP might provide a novel therapeutic approach to treating type 2 diabetes, but few drugs that inhibit SEPP1 expression in hepatocytes have been identified to date. The present findings demonstrate that metformin suppresses SEPP1 expression by activating AMP-activated kinase (AMPK) and subsequently inactivating FoxO3a in H4IIEC3 hepatocytes. Treatment with metformin reduced SEPP1 promoter activity in a concentration- and time-dependent manner; this effect was cancelled by co-administration of an AMPK inhibitor. Metformin also suppressed Sepp1 gene expression in the liver of mice. Computational analysis of transcription factor binding sites conserved among the species resulted in identification of the FoxO-binding site in the metformin-response element of the SEPP1 promoter. A luciferase reporter assay showed that metformin suppresses Forkhead-response element activity, and a ChIP assay revealed that metformin decreases binding of FoxO3a, a direct target of AMPK, to the SEPP1 promoter. Transfection with siRNAs for Foxo3a, but not for Foxo1, cancelled metformin-induced luciferase activity suppression of the metformin-response element of the SEPP1 promoter. The overexpression of FoxO3a stimulated SEPP1 promoter activity and rescued the suppressive effect of metformin. Metformin did not affect FoxO3a expression, but it increased its phosphorylation and decreased its nuclear localization. These data provide a novel mechanism of action for metformin involving improvement of systemic insulin sensitivity through the regulation of SeP production and suggest an additional approach to the development of anti-diabetic drugs. PMID:24257750

  20. Selenocysteine tRNA[Ser]Sec, the Central Component of Selenoprotein Biosynthesis: Isolation, Identification, Modification, and Sequencing.

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    Carlson, Bradley A; Lee, Byeong Jae; Tsuji, Petra A; Copeland, Paul R; Schweizer, Ulrich; Gladyshev, Vadim N; Hatfield, Dolph L

    2018-01-01

    The selenocysteine (Sec) tRNA[Ser]Sec population consists of two isoforms that differ from each other by a single 2'-O-methylribosyl moiety at position 34 (Um34). These two isoforms, which are encoded in a single gene, Trsp, and modified posttranscriptionally, are involved individually in the synthesis of two subclasses of selenoproteins, designated housekeeping and stress-related selenoproteins. Techniques used in obtaining these isoforms for their characterization include extraction of RNA from mammalian cells and tissues, purifying the tRNA[Ser]Sec population by one or more procedures, and finally resolving the two isoforms from each other. Since some of the older techniques for isolating tRNA[Ser]Sec and resolving the isoforms are used in only a few laboratories, these procedures will be discussed briefly and references provided for more detailed information, while the more recently developed procedures are discussed in detail. In addition, a novel technique that was developed in sequencing tRNA[Ser]Sec for identifying their occurrence in other organisms is also presented.

  1. Biological interactions between mercury and selenium in distribution and detoxification processes in mice under controlled exposure. Effects on selenoprotein.

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    García-Sevillano, M A; Rodríguez-Moro, G; García-Barrera, T; Navarro, F; Gómez-Ariza, J L

    2015-03-05

    Antagonistic interactions between mercury (Hg) and selenium (Se), were evaluated in mouse (Mus musculus), as a mammalian model, in a series of controlled exposure experiments. The beneficial effect of Se against Hg toxicity involves a variety of biochemical and toxicological processes that have not been clarified yet. For this purpose, a metallomic workflow based on the use of size-exclusion chromatography (SEC) with inductively coupled plasma mass spectrometry (ICP-MS) detection was complemented with the speciation of selenoproteins and low molecular mass selenium species in serum and liver cytosolic extracts using a multidimensional approach based on SEC-AF-HPLC-ICPMS, using species-unspecific isotope dilution (SUID)-ICP-MS for selenium quantification. The results showed potential interactions between Hg/Se in organs and serum related to accumulation and detoxification processes, in addition to the effects of mercury on selenoproteins in hepatic cytosolic extracts and bloodstream when both elements are administrated at the same time. These results provide information about elements distribution, interactions and homeostasis and reveal the potential of metallomic approaches in exposure experiments. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Dietary Selenium Levels Affect Selenoprotein Expression and Support the Interferon-γ and IL-6 Immune Response Pathways in Mice.

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    Tsuji, Petra A; Carlson, Bradley A; Anderson, Christine B; Seifried, Harold E; Hatfield, Dolph L; Howard, Michael T

    2015-08-06

    Selenium is an essential element that is required to support a number of cellular functions and biochemical pathways. The objective of this study was to examine the effects of reduced dietary selenium levels on gene expression to assess changes in expression of non-selenoprotein genes that may contribute to the physiological consequences of selenium deficiency. Mice were fed diets that were either deficient in selenium or supplemented with selenium in the form of sodium selenite for six weeks. Differences in liver mRNA expression and translation were measured using a combination of ribosome profiling, RNA-Seq, microarrays, and qPCR. Expression levels and translation of mRNAs encoding stress-related selenoproteins were shown to be up-regulated by increased selenium status, as were genes involved in inflammation and response to interferon-γ. Changes in serum cytokine levels were measured which confirmed that interferon-γ, as well as IL-6, were increased in selenium adequate mice. Finally, microarray and qPCR analysis of lung tissue demonstrated that the selenium effects on immune function are not limited to liver. These data are consistent with previous reports indicating that adequate selenium levels can support beneficial immune responses, and further identify the IL-6 and interferon-γ pathways as being responsive to dietary selenium intake.

  3. Dietary Selenium Levels Affect Selenoprotein Expression and Support the Interferon-γ and IL-6 Immune Response Pathways in Mice

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    Petra A. Tsuji

    2015-08-01

    Full Text Available Selenium is an essential element that is required to support a number of cellular functions and biochemical pathways. The objective of this study was to examine the effects of reduced dietary selenium levels on gene expression to assess changes in expression of non-selenoprotein genes that may contribute to the physiological consequences of selenium deficiency. Mice were fed diets that were either deficient in selenium or supplemented with selenium in the form of sodium selenite for six weeks. Differences in liver mRNA expression and translation were measured using a combination of ribosome profiling, RNA-Seq, microarrays, and qPCR. Expression levels and translation of mRNAs encoding stress-related selenoproteins were shown to be up-regulated by increased selenium status, as were genes involved in inflammation and response to interferon-γ. Changes in serum cytokine levels were measured which confirmed that interferon-γ, as well as IL-6, were increased in selenium adequate mice. Finally, microarray and qPCR analysis of lung tissue demonstrated that the selenium effects on immune function are not limited to liver. These data are consistent with previous reports indicating that adequate selenium levels can support beneficial immune responses, and further identify the IL-6 and interferon-γ pathways as being responsive to dietary selenium intake.

  4. Selenoprotein W depletion induces a p53- and p21-dependent delay in cell cycle progression in RWPE-1 prostate epithelial cells

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    The anticancer activity of selenium (Se) has been demonstrated in myriad animal and in vitro studies, yet the mechanisms remain obscure. The relative importance of small selenium compounds versus selenoproteins in the cancer-protective activity of Se is unresolved, but the main form of Se in animal ...

  5. Selenoprotein expression in Hürthle cell carcinomas and in the human Hürthle cell carcinoma line XTC.UC1.

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    Menth, Marianne; Schmutzler, Cornelia; Mentrup, Birgit; Hoang-Vu, Cuong; Takahashi, Kazuhiko; Honjoh, Tsutomu; Köhrle, Josef

    2005-05-01

    Hürthle cell carcinomas (HTC) are characterized by mitochondrial amplification and enhanced oxygen metabolism. To clarify if defects in enzymes scavenging reactive oxygen species are involved in the pathogenesis of HTC, we analyzed selenium (Se)-dependent expression of various detoxifying selenoproteins in the HTC cell line XTC.UC1. Glutathione peroxidase and thioredoxin reductase activity was found both in cell lysates and conditioned media of XTC.UC1 cells and was increased by Na(2)SeO(3). Western blot analysis demonstrated the presence of thioredoxin reductase both in cell lysates and conditioned media and of glutathione peroxidase 3 in conditioned media. Type I 5'-deiodinase, another selenoprotein that catalyzes thyroid hormone metabolism, was detectable only in cell lysates by enzyme assay and Western blot, and responded to stimulation by both Na(2)SeO(3) and retinoic acid. A selenoprotein P signal was detected in conditioned media by Western blot, but was not enhanced by Na(2)SeO(3) treatment. In situ hybridization revealed glutathione peroxidase mRNAs in HTC specimen; glutathione peroxidase 3 mRNA levels were reduced. These data suggest adequate expression and Se-dependent regulation of a couple of selenoproteins involved in antioxidant defense and thyroid hormone metabolism in XTC.UC1 cells, so far giving no evidence of a role of these proteins in the pathogenesis of HTCs.

  6. The respiratory molybdo-selenoprotein formate dehydrogenases of Escherichia coli have hydrogen: benzyl viologen oxidoreductase activity

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    Trchounian Armen

    2011-08-01

    Full Text Available Abstract Background Escherichia coli synthesizes three membrane-bound molybdenum- and selenocysteine-containing formate dehydrogenases, as well as up to four membrane-bound [NiFe]-hydrogenases. Two of the formate dehydrogenases (Fdh-N and Fdh-O and two of the hydrogenases (Hyd-1 and Hyd-2 have their respective catalytic subunits located in the periplasm and these enzymes have been shown previously to oxidize formate and hydrogen, respectively, and thus function in energy metabolism. Mutants unable to synthesize the [NiFe]-hydrogenases retain a H2: benzyl viologen oxidoreductase activity. The aim of this study was to identify the enzyme or enzymes responsible for this activity. Results Here we report the identification of a new H2: benzyl viologen oxidoreductase enzyme activity in E. coli that is independent of the [NiFe]-hydrogenases. This enzyme activity was originally identified after non-denaturing polyacrylamide gel electrophoresis and visualization of hydrogen-oxidizing activity by specific staining. Analysis of a crude extract derived from a variety of E. coli mutants unable to synthesize any [NiFe]-hydrogenase-associated enzyme activity revealed that the mutants retained this specific hydrogen-oxidizing activity. Enrichment of this enzyme activity from solubilised membrane fractions of the hydrogenase-negative mutant FTD147 by ion-exchange, hydrophobic interaction and size-exclusion chromatographies followed by mass spectrometric analysis identified the enzymes Fdh-N and Fdh-O. Analysis of defined mutants devoid of selenocysteine biosynthetic capacity or carrying deletions in the genes encoding the catalytic subunits of Fdh-N and Fdh-O demonstrated that both enzymes catalyze hydrogen activation. Fdh-N and Fdh-O can also transfer the electrons derived from oxidation of hydrogen to other redox dyes. Conclusions The related respiratory molybdo-selenoproteins Fdh-N and Fdh-O of Escherichia coli have hydrogen-oxidizing activity. These findings

  7. Polymorphism analysis of six selenoprotein genes: support for a selective sweep at the glutathione peroxidase 1 locus (3p21 in Asian populations

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    Chanock Stephen J

    2006-12-01

    Full Text Available Abstract Background There are at least 25 human selenoproteins, each characterized by the incorporation of selenium into the primary sequence as the amino acid selenocysteine. Since many selenoproteins have antioxidant properties, it is plausible that inter-individual differences in selenoprotein expression or activity could influence risk for a range of complex diseases, such as cancer, infectious diseases as well as deleterious responses to oxidative stressors like cigarette smoke. To capture the common genetic variants for 6 important selenoprotein genes (GPX1, GPX2, GPX3, GPX4, TXNRD1, and SEPP1 known to contribute to antioxidant host defenses, a re-sequence analysis was conducted across these genes with particular interest directed at the coding regions, intron-exon borders and flanking untranslated regions (UTR for each gene in an 102 individual population representative of 4 major ethnic groups found within the United States. Results For 5 of the genes there was no strong evidence for selection according to the expectations of the neutral equilibrium model of evolution; however, at the GPX1 locus (3p21 there was evidence for positive selection. Strong confirmatory evidence for recent positive selection at the genomic region 3p21 in Asian populations is provided by data from the International HapMap project. Conclusion The SNPs and fine haplotype maps described in this report will be valuable resources for future functional studies, for population specific genetic studies designed to comprehensively explore the role of selenoprotein genetic variants in the etiology of various human diseases, and to define the forces responsible for a recent selective sweep in the vicinity of the GPX1 locus.

  8. Selenoprotein Transcript Level and Enzyme Activity as Biomarkers for Selenium Status and Selenium Requirements in the Turkey (Meleagris gallopavo)

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    Taylor, Rachel M.; Sunde, Roger A.

    2016-01-01

    The current National Research Council (NRC) selenium (Se) requirement for the turkey is 0.2 μg Se/g diet. The sequencing of the turkey selenoproteome offers additional molecular biomarkers for assessment of Se status. To determine dietary Se requirements using selenoprotein transcript levels and enzyme activities, day-old male turkey poults were fed a Se-deficient diet supplemented with graded levels of Se (0, 0.025, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 1.0 μg Se/g diet) as selenite, and 12.5X the vitamin E requirement. Poults fed less than 0.05 μg Se/g diet had a significantly reduced rate of growth, indicating the Se requirement for growth in young male poults is 0.05 μg Se/g diet. Se deficiency decreased plasma GPX3 (glutathione peroxidase), liver GPX1, and liver GPX4 activities to 2, 3, and 7%, respectively, of Se-adequate levels. Increasing Se supplementation resulted in well-defined plateaus for all blood, liver and gizzard enzyme activities and mRNA levels, showing that these selenoprotein biomarkers could not be used as biomarkers for supernutritional-Se status. Using selenoenzyme activity, minimum Se requirements based on red blood cell GPX1, plasma GPX3, and pancreas and liver GPX1 activities were 0.29–0.33 μg Se/g diet. qPCR analyses using all 10 dietary Se treatments for all 24 selenoprotein transcripts (plus SEPHS1) in liver, gizzard, and pancreas found that only 4, 4, and 3 transcripts, respectively, were significantly down-regulated by Se deficiency and could be used as Se biomarkers. Only GPX3 and SELH mRNA were down regulated in all 3 tissues. For these transcripts, minimum Se requirements were 0.07–0.09 μg Se/g for liver, 0.06–0.15 μg Se/g for gizzard, and 0.13–0.18 μg Se/g for pancreas, all less than enzyme-based requirements. Panels based on multiple Se-regulated transcripts were effective in identifying Se deficiency. These results show that the NRC turkey dietary Se requirement should be raised to 0.3 μg Se/g diet. PMID

  9. Selenoprotein Transcript Level and Enzyme Activity as Biomarkers for Selenium Status and Selenium Requirements in the Turkey (Meleagris gallopavo.

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    Rachel M Taylor

    Full Text Available The current National Research Council (NRC selenium (Se requirement for the turkey is 0.2 μg Se/g diet. The sequencing of the turkey selenoproteome offers additional molecular biomarkers for assessment of Se status. To determine dietary Se requirements using selenoprotein transcript levels and enzyme activities, day-old male turkey poults were fed a Se-deficient diet supplemented with graded levels of Se (0, 0.025, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 1.0 μg Se/g diet as selenite, and 12.5X the vitamin E requirement. Poults fed less than 0.05 μg Se/g diet had a significantly reduced rate of growth, indicating the Se requirement for growth in young male poults is 0.05 μg Se/g diet. Se deficiency decreased plasma GPX3 (glutathione peroxidase, liver GPX1, and liver GPX4 activities to 2, 3, and 7%, respectively, of Se-adequate levels. Increasing Se supplementation resulted in well-defined plateaus for all blood, liver and gizzard enzyme activities and mRNA levels, showing that these selenoprotein biomarkers could not be used as biomarkers for supernutritional-Se status. Using selenoenzyme activity, minimum Se requirements based on red blood cell GPX1, plasma GPX3, and pancreas and liver GPX1 activities were 0.29-0.33 μg Se/g diet. qPCR analyses using all 10 dietary Se treatments for all 24 selenoprotein transcripts (plus SEPHS1 in liver, gizzard, and pancreas found that only 4, 4, and 3 transcripts, respectively, were significantly down-regulated by Se deficiency and could be used as Se biomarkers. Only GPX3 and SELH mRNA were down regulated in all 3 tissues. For these transcripts, minimum Se requirements were 0.07-0.09 μg Se/g for liver, 0.06-0.15 μg Se/g for gizzard, and 0.13-0.18 μg Se/g for pancreas, all less than enzyme-based requirements. Panels based on multiple Se-regulated transcripts were effective in identifying Se deficiency. These results show that the NRC turkey dietary Se requirement should be raised to 0.3 μg Se/g diet.

  10. Optimization of selenoprotein P and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement: a placebo-controlled, double-blind study of selenomethionine supplementation in selenium-deficient Chinese subjects1234

    OpenAIRE

    Xia, YiMing; Hill, Kristina E.; Li, Ping; Xu, Jiayuan; Zhou, Dingyou; Motley, Amy K.; WANG, LI; Byrne, Daniel W.; Burk, Raymond F.

    2010-01-01

    Background: The intake of selenium needed for optimal health has not been established. Selenoproteins perform the functions of selenium, and the selenium intake needed for their full expression is not known.

  11. Selenium Deficiency-Induced Apoptosis of Chick Embryonic Vascular Smooth Muscle Cells and Correlations with 25 Selenoproteins.

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    Wang, Qingyu; Huang, Jiaqiang; Zhang, Hao; Lei, Xingen; Du, Zhongyao; Xiao, Chen; Chen, Silu; Ren, Fazheng

    2017-04-01

    Selenium deficiency is the major cause of exudative diathesis in chicks. Subcutaneous hemorrhage is one of the typical symptoms of the disease. However, the reason for the occurrence of blood exudation remains unknown. In the present study, the vascular smooth muscle cells (VSMCs) were isolated from 17-day-old broiler chick embryos. Cell viability, cell apoptosis, and intracellular reactive oxygen species level under different concentrations of selenium (0-0.9 μM) were investigated. The mRNA expression levels of 25 selenoproteins and apoptosis-related genes (p53, CytC, Caspase-3, Caspase-8, Bcl-2, and Bax) were also measured. Selenium deficiency significantly decreased cell viability and increased cell apoptosis (p selenium could alleviate these changes. In general, at all levels of selenium addition, Gpx1, Gpx3, Gpx4, SepW1, and Sep15 mRNAs were all highly expressed in VSMCs, whereas Gpx2, Dio1, SepN1, SelO, and SelPb were at lower levels. There was a high correlation between Gpx2, Gpx3, Gpx4, Dio1, Txnrd1, Txnrd2, and Txnrd3 gene expression. Additionally, Gpx3, Gpx4, Dio1, Txnrd1, Txnrd2, Txnrd3, SelS, and SelPb showed a strong negative correlation with pro-apoptotic gene Caspase-3 as well as a strong positive correlation with anti-apoptotic gene Bcl-2, especially SelI (r = 0.913 and r = 0.929, p selenium deficiency could induce VSMC apoptosis, and several selenoproteins may be involved in the development of apoptosis. Our findings provide information on the molecular mechanism of vascular injury by selenium deficiency.

  12. Knockout of the 15 kDa selenoprotein protects against chemically-induced aberrant crypt formation in mice.

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    Petra A Tsuji

    Full Text Available Evidence suggests that selenium has cancer preventive properties that are largely mediated through selenoproteins. Our previous observations demonstrated that targeted down-regulation of the 15 kDa selenoprotein (Sep15 in murine colon cancer cells resulted in the reversal of the cancer phenotype. The present study investigated the effect of Sep15 knockout in mice using a chemically-induced colon cancer model. Homozygous Sep15 knockout mice, and wild type littermate controls were given four weekly subcutaneous injections of azoxymethane (10 mg/kg. Sep15 knockout mice developed significantly (p<0.001 fewer aberrant crypt foci than controls demonstrating that loss of Sep15 protects against aberrant crypt foci formation. Dietary selenium above adequate levels did not significantly affect aberrant crypt foci formation in Sep15 knockout mice. To investigate molecular targets affected by loss of Sep15, gene expression patterns in colonic mucosal cells of knockout and wild type mice were examined using microarray analysis. Subsequent analyses verified that guanylate binding protein-1 (GBP-1 mRNA and protein expression were strongly upregulated in Sep15 knockout mice. GBP-1, which is expressed in response to interferon-γ, is considered to be an activation marker during inflammatory diseases, and up-regulation of GBP-1 in humans has been associated with a highly significant, increased five-year survival rate in colorectal cancer patients. In agreement with these studies, we observed a higher level of interferon-γ in plasma of Sep15 knockout mice. Overall, our results demonstrate for the first time, that Sep15 knockout mice are protected against chemically-induced aberrant crypt foci formation and that Sep15 appears to have oncogenic properties in colon carcinogenesis in vivo.

  13. Association between polymorphisms in glutathione peroxidase and selenoprotein P genes, glutathione peroxidase activity, HRT use and breast cancer risk.

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    Catherine Méplan

    Full Text Available Breast cancer (BC is one of the most common cancers in women. Evidence suggests that genetic variation in antioxidant enzymes could influence BC risk, but to date the relationship between selenoproteins and BC risk remains unclear. In this report, a study population including 975 Danish cases and 975 controls matched for age and hormone replacement therapy (HRT use was genotyped for five functional single nucleotide polymorphisms (SNPs in SEPP1, GPX1, GPX4 and the antioxidant enzyme SOD2 genes. The influence of genetic polymorphisms on breast cancer risk was assessed using conditional logistic regression. Additionally pre-diagnosis erythrocyte GPx (eGPx activity was measured in a sub-group of the population. A 60% reduction in risk of developing overall BC and ductal BC was observed in women who were homozygous Thr carriers for SEPP1 rs3877899. Additionally, Leu carriers for GPX1 Pro198Leu polymorphism (rs1050450 were at ∼2 fold increased risk of developing a non-ductal BC. Pre-diagnosis eGPx activity was found to depend on genotype for rs713041 (GPX4, rs3877899 (SEPP1, and rs1050450 (GPX1 and on HRT use. Moreover, depending on genotype and HRT use, eGPx activity was significantly lower in women who developed BC later in life compared with controls. Furthermore, GPx1 protein levels increased in human breast adenocarcinoma MCF7 cells exposed to β-estradiol and sodium selenite.In conclusion, our data provide evidence that SNPs in SEPP1 and GPX1 modulate risk of BC and that eGPx activity is modified by SNPs in SEPP1, GPX4 and GPX1 and by estrogens. Our data thus suggest a role of selenoproteins in BC development.

  14. Effect of Inorganic Dietary Selenium Supplementation on Selenoprotein and Lipid Metabolism Gene Expression Patterns in Liver and Loin Muscle of Growing Lambs.

    Science.gov (United States)

    Juszczuk-Kubiak, Edyta; Bujko, Kamila; Cymer, Monika; Wicińska, Krystyna; Gabryszuk, Mirosław; Pierzchała, Mariusz

    2016-08-01

    Effect of selenium (Se) supplementation on the selenoprotein and lipid metabolism gene expression patterns in ruminants, especially in lambs is not yet fully understood. The aim of study was to evaluate the effect of Se supplementation on the messenger RNA (mRNA) expression patterns of selected selenoproteins and genes related to lipid metabolism in growing lambs. The experiment was conducted on 48 Polish Merino lambs divided into two groups (n = 24): control (C)-lambs fed with a basal diet (BD) with no Se supplementation, and supplemented (S)-lambs fed with a BD, supplemented with 0.5 mg Se/kg as sodium selenate for 8 weeks. Expression of 12 selenoproteins and six genes related to lipid metabolism was analyzed in the liver and longissimus dorsi (LD) muscle of growing lambs by qPCR. Significant differences were found in the expression of GPX1, GPX2, SEPM, SEPW1, SEP15, SEPGS2, and TXNRD1 in the liver, and GPX1, SEPP1, SEPN1, SEPW1, SEP15, and MSRB1 in the LD muscle between S and C lambs. Se supplementation mainly upregulated SEPW1, SEP15 (P supplementation did not affect PON1, LXRα, and PPARα mRNA expression levels, but a significant increase in mRNA levels of APOE and LPL in the LD muscle (P supplemented lambs. Our study confirmed that, in lambs, similarly to other species, mRNA expression patterns of several selenoproteins highly depend on dietary Se levels, and their expression is ruled by hierarchical principles and tissue-specific mechanisms. Moreover, the study showed that changes Se intake leads to different levels of genes expression related with lipid metabolism.

  15. The effect of dietary bacterial organic selenium on growth performance, antioxidant capacity, and Selenoproteins gene expression in broiler chickens.

    Science.gov (United States)

    Dalia, A M; Loh, T C; Sazili, A Q; Jahromi, M F; Samsudin, A A

    2017-08-18

    Selenium (Se) is an essential trace mineral in broilers, which has several important roles in biological processes. Organic forms of Se are more efficient than inorganic forms and can be produced biologically via Se microbial reduction. Hence, the possibility of using Se-enriched bacteria as feed supplement may provide an interesting source of organic Se, and benefit broiler antioxidant system and other biological processes. The objective of this study was to examine the impacts of inorganic Se and different bacterial organic Se sources on the performance, serum and tissues Se status, antioxidant capacity, and liver mRNA expression of selenoproteins in broilers. Results indicated that different Se sources did not significantly (P ≤ 0.05) affect broiler growth performance. However, bacterial organic Se of T5 (basal diet +0.3 mg /kg feed ADS18 Se), T4 (basal diet +0.3 mg /kg feed ADS2 Se), and T3 (basal diet +0.3 mg /kg feed ADS1 Se) exhibited significantly (P ≤ 0.05) highest Se concentration in serum, liver, and kidney respectively. Dietary inorganic Se and bacterial organic Se were observed to significantly affect broiler serum ALT, AST, LDH activities and serum creatinine level. ADS18 supplemented Se of (Stenotrophomonas maltophilia) bacterial strain showed the highest GSH-Px activity with the lowest MDA content in serum, and the highest GSH-Px and catalase activity in the kidney, while bacterial Se of ADS2 (Klebsiella pneumoniae) resulted in a higher level of GSH-Px1 and catalase in liver. Moreover, our study showed that in comparison with sodium selenite, only ADS18 bacterial Se showed a significantly higher mRNA level in GSH-Px1, GSH-Px4, DIO1, and TXNDR1, while both ADS18 and ADS2 showed high level of mRNA of DIO2 compared to sodium selenite. The supplementation of bacterial organic Se in broiler chicken, improved tissue Se deposition, antioxidant status, and selenoproteins gene expression, and can be considered as an effective alternative source of

  16. Ubiquitous expression of selenoprotein N transcripts in chicken tissues and early developmental expression pattern in skeletal muscles.

    Science.gov (United States)

    Zhang, Jiuli; Li, Jinlong; Zhang, Ziwei; Sun, Bo; Wang, Rihua; Jiang, Zhihui; Li, Shu; Xu, Shiwen

    2012-05-01

    Previous results revealed a ubiquitous expression pattern of selenoprotein N (SelN, SEPN1) in humans, zebrafish, and mouse, suggesting that it plays a potential role during the embryogenesis of these species. However, no information is known about the tissue distribution of SelN and mRNA expression analysis in the muscle tissues during development in birds. We analyzed the mRNA expression of SelN in 26 different tissues of 90-day-old chickens and the expression of SelN in the muscle tissues of 12-day-old chicken embryos and 15-month-old adult chickens by quantitative real-time PCR. The results showed that SelN transcripts were expressed widely in the chicken tissues. Moreover, the expression of SelN mRNA in skeletal muscles was present at a high level in whole embryos and at a lower level in postnatal stages. However, the expression of SelN mRNA in cardiac muscle showed a different expression pattern compared with skeletal muscles. Our data indicate that the expression of the SelN gene in chicken is ubiquitous, suggesting a role of SelN in the development of chick embryo skeletal muscles.

  17. A Novel Organic Selenium Compound Exerts Unique Regulation of Selenium Speciation, Selenogenome, and Selenoproteins in Broiler Chicks.

    Science.gov (United States)

    Zhao, Ling; Sun, Lv-Hui; Huang, Jia-Qiang; Briens, Mickael; Qi, De-Sheng; Xu, Shi-Wen; Lei, Xin Gen

    2017-05-01

    Background: A new organic selenium compound, 2-hydroxy-4-methylselenobutanoic acid (SeO), displayed a greater bioavailability than sodium selenite (SeNa) or seleno-yeast (SeY) in several species.Objective: This study sought to determine the regulation of the speciation of selenium, expression of selenogenome and selenocysteine biosynthesis and degradation-related genes, and production of selenoproteins by the 3 forms of selenium in the tissues of broiler chicks.Methods: Day-old male chicks (n = 6 cages/diet, 6 chicks/cage) were fed a selenium-deficient, corn and soy-based diet [base diet (BD), 0.05 mg Se/kg] or the BD + SeNa, SeY, or SeO at 0.2 mg Se/kg for 6 wk. Plasma, livers, and pectoral and thigh muscles were collected at weeks 3 and 6 to assay for total selenium, selenomethionine, selenocysteine, redox status, and selected genes, proteins, and enzymes.Results: Although both SeY and SeO produced greater concentrations (P selenium (20-172%) and of selenomethionine (≤15-fold) in the liver, pectoral muscle, and thigh than those of SeNa, SeO further raised (P selenium depositions, to induce the early expression of Selenos and Mrsb1 mRNA and TXRND activity, and to enhance the protein production of GPX4, SELENOP, and SELENOU in the tissues of chicks. © 2017 American Society for Nutrition.

  18. A Reduction in Selenoprotein S Amplifies the Inflammatory Profile of Fast-Twitch Skeletal Muscle in the mdx Dystrophic Mouse

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    Craig Robert Wright

    2017-01-01

    Full Text Available Excessive inflammation is a hallmark of muscle myopathies, including Duchenne muscular dystrophy (DMD. There is interest in characterising novel genes that regulate inflammation due to their potential to modify disease progression. Gene polymorphisms in Selenoprotein S (Seps1 are associated with elevated proinflammatory cytokines, and in vitro SEPS1 is protective against inflammatory stress. Given that SEPS1 is highly expressed in skeletal muscle, we investigated whether the genetic reduction of Seps1 exacerbated inflammation in the mdx mouse. F1 male mdx mice with a heterozygous Seps1 deletion (mdx:Seps1−/+ were generated. The mdx:Seps1−/+ mice had a 50% reduction in SEPS1 protein expression in hindlimb muscles. In the extensor digitorum longus (EDL muscles, mRNA expression of monocyte chemoattractant protein 1 (Mcp-1 (P=0.034, macrophage marker F4/80 (P=0.030, and transforming growth factor-β1 (Tgf-β1 (P=0.056 were increased in mdx:Seps1−/+ mice. This was associated with a reduction in muscle fibre size; however, ex vivo EDL muscle strength and endurance were unaltered. In dystrophic slow twitch soleus muscles, SEPS1 reduction had no effect on the inflammatory profile nor function. In conclusion, the genetic reduction of Seps1 appears to specifically exacerbate the inflammatory profile of fast-twitch muscle fibres, which are typically more vulnerable to degeneration in dystrophy.

  19. Selenoprotein K Increases Efficiency of DHHC6 Catalyzed Protein Palmitoylation by Stabilizing the Acyl-DHHC6 Intermediate

    Directory of Open Access Journals (Sweden)

    Gregory J. Fredericks

    2017-12-01

    Full Text Available Selenoprotein K (SELENOK is a selenocysteine (Sec-containing protein localized in the endoplasmic reticulum (ER membrane where it interacts with the DHHC6 (where single letter symbols represent Asp-His-His-Cys amino acids enzyme to promote protein acyl transferase (PAT reactions. PAT reactions involve the DHHC enzymatic capture of palmitate via a thioester bond to cysteine (Cys residues that form an unstable palmitoyl-DHHC intermediate, followed by transfer of palmitate to Cys residues of target proteins. How SELENOK facilitates this reaction has not been determined. Splenocyte microsomal preparations from wild-type mice versus SELENOK knockout mice were used to establish PAT assays and showed decreased PAT activity (~50% under conditions of SELENOK deficiency. Using recombinant, soluble versions of DHHC6 along with SELENOK containing Sec92, Cys92, or alanine (Ala92, we evaluated the stability of the acyl-DHHC6 intermediate and its capacity to transfer the palmitate residue to Cys residues on target peptides. Versions of SELENOK containing either Ala or Cys residues in place of Sec were equivalently less effective than Sec at stabilizing the acyl-DHHC6 intermediate or promoting PAT activity. These data suggest that Sec92 in SELENOK serves to stabilize the palmitoyl-DHHC6 intermediate by reducing hydrolyzation of the thioester bond until transfer of the palmitoyl group to the Cys residue on the target protein can occur.

  20. Roles of the 15-kDa Selenoprotein (Sep15) in Redox Homeostasis and Cataract Development Revealed by the Analysis of Sep 15 Knockout Mice*

    OpenAIRE

    Kasaikina, Marina V.; Fomenko, Dmitri E.; Labunskyy, Vyacheslav M.; Lachke, Salil A.; Qiu, Wenya; Juliet A Moncaster; Zhang, Jie; Wojnarowicz, Mark W.; Natarajan, Sathish Kumar; Malinouski, Mikalai; SCHWEIZER, Ulrich; Tsuji, Petra A.; Carlson, Bradley A.; Maas, Richard L.; Lou, Marjorie F.

    2011-01-01

    The 15-kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase. Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In this study, we developed and characterized Sep15 KO mice by targeted removal of exon 2 of the Sep15 gene coding for the cysteine-rich UDP-gl...

  1. Pancreatic atrophy caused by dietary selenium deficiency induces hypoinsulinemic hyperglycemia via global down-regulation of selenoprotein encoding genes in broilers.

    Directory of Open Access Journals (Sweden)

    Jingyang Xu

    Full Text Available This study was envisaged to comprehensively profile genes in selected tissues along with a few biochemical indicators and integrate resulting information with dietary selenium (Se deficiency symptoms in broilers. A total of 120 one-day-old Cobb male broilers were equally divided into two groups and fed a Se deficient corn-soybean-based basal diet supplemented with 0.3 mg/kg sodium selenite (Control, Se adequate or without selenite (Se deficiency for five weeks. Effects of Se deficiency on mRNA abundance of twenty-three selenoprotein encoding genes and seventeen insulin signaling related genes were studied at day 35 in pancreas, liver and muscle along with plasma biochemical constituents and enzyme activities. Compared to healthy birds in control diet, Se deficient diet induced deficiency symptoms in 90% birds and classic nutritional pancreatic atrophy, depressed growth performance of broilers, and decreased (P < 0.01 to P < 0.05 total antioxidant capacity and activities of superoxide dismutase and glutathione peroxidase in plasma and three other tissues. Se deficiency resulted in 58% higher mortality than control birds. Dietary Se deficiency down-regulated (P < 0.01-0.05 eighteen selenoprotein encoding genes in pancreas, fourteen genes in muscle and nine genes in liver, and up-regulated (P < 0.05 Txnrd1 and Selx in liver. Meanwhile, six, thirteen and five insulin signaling related genes were down-regulated (P < 0.01-0.05 in pancreas, muscle and liver, respectively, and three genes were up-regulated (P < 0.01 in liver. The decrease (P < 0.05 in levels of plasma insulin, total triglyceride and total cholesterol, and concurrent elevated (P < 0.05 levels of plasma glucose and inflammatory cytokines accompanied the global down-regulation of selenoprotein encoding- and insulin signaling related- genes in Se deficient birds. It was concluded that dietary Se deficiency induces nutritional pancreatic atrophy and metabolic disorder of glucose and lipid in

  2. Dietary pattern associated with selenoprotein P and MRI-derived body fat volumes, liver signal intensity, and metabolic disorders.

    Science.gov (United States)

    di Giuseppe, Romina; Plachta-Danielzik, Sandra; Koch, Manja; Nöthlings, Ute; Schlesinger, Sabrina; Borggrefe, Jan; Both, Marcus; Müller, Hans-Peter; Kassubek, Jan; Jacobs, Gunnar; Lieb, Wolfgang

    2018-02-14

    The association of complex dietary patterns with circulating selenoprotein P (SELENOP) levels in humans is unknown. In a general population sample, we aimed to identify a dietary pattern explaining inter-individual variation in circulating SELENOP concentrations and to study this pattern in relation to prevalent diabetes, metabolic syndrome (MetS), MRI-determined total volumes of visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue, and liver signal intensity/fatty liver disease. In this cross-sectional study, serum SELENOP levels were measured in 853 individuals. In a subsample of 553 participants, whole-body MRI was performed to assess body fat distribution and liver fat. Dietary intake was assessed by a self-administered food frequency questionnaire and the dietary pattern identified using reduced-rank regression (RRR). Multivariable linear and logistic regressions were used to investigate associations between dietary pattern score and metabolic traits. Characterized by high intake of fruit, vegetables and antioxidant beverages, the RRR-derived dietary pattern displayed inverse associations with VAT, SAT, MetS, and prevalent diabetes in multivariable-adjusted restricted cubic splines. Each unit increase in dietary pattern score was associated with 31% higher SELENOP levels, 12% lower VAT (95% CI: - 19%; - 5%), 13% (95% CI: - 20%; - 6%) lower SAT values and 46% (95% CI: 27%; 60%) and 53% (95% CI: 22%; 72%) lower odds of having MetS or diabetes, respectively. No meaningful relations were observed between the dietary pattern and liver traits. Our observations propose diet-related regulation in SELENOP levels and that the identified dietary pattern is inversely related to VAT, SAT, MetS, and prevalent diabetes.

  3. Selenoprotein R Protects Human Lens Epithelial Cells against D-Galactose-Induced Apoptosis by Regulating Oxidative Stress and Endoplasmic Reticulum Stress

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    Jie Dai

    2016-02-01

    Full Text Available Selenium is an essential micronutrient for humans. Much of selenium’s beneficial influence on health is attributed to its presence within 25 selenoproteins. Selenoprotein R (SelR, known as methionine sulfoxide reductase B1 (MsrB1, is a selenium-dependent enzyme that, like other Msrs, is required for lens cell viability. In order to investigate the roles of SelR in protecting human lens epithelial (hLE cells against damage, the influences of SelR gene knockdown on d-galactose-induced apoptosis in hLE cells were studied. The results showed that both D-galactose and SelR gene knockdown by siRNA independently induced oxidative stress. When SelR-gene-silenced hLE cells were exposed to D-galactose, glucose-regulated protein 78 (GRP78 protein level was further increased, mitochondrial membrane potential was significantly decreased and accompanied by a release of mitochondrial cytochrome c. At the same time, the apoptosis cells percentage and the caspase-3 activity were visibly elevated in hLE cells. These results suggested that SelR might protect hLE cell mitochondria and mitigating apoptosis in hLE cells against oxidative stress and endoplasmic reticulum (ER stress induced by d-galactose, implying that selenium as a micronutrient may play important roles in hLE cells.

  4. Selenoprotein R Protects Human Lens Epithelial Cells against D-Galactose-Induced Apoptosis by Regulating Oxidative Stress and Endoplasmic Reticulum Stress.

    Science.gov (United States)

    Dai, Jie; Liu, Hongmei; Zhou, Jun; Huang, Kaixun

    2016-02-10

    Selenium is an essential micronutrient for humans. Much of selenium's beneficial influence on health is attributed to its presence within 25 selenoproteins. Selenoprotein R (SelR), known as methionine sulfoxide reductase B1 (MsrB1), is a selenium-dependent enzyme that, like other Msrs, is required for lens cell viability. In order to investigate the roles of SelR in protecting human lens epithelial (hLE) cells against damage, the influences of SelR gene knockdown on d-galactose-induced apoptosis in hLE cells were studied. The results showed that both d-galactose and SelR gene knockdown by siRNA independently induced oxidative stress. When SelR-gene-silenced hLE cells were exposed to d-galactose, glucose-regulated protein 78 (GRP78) protein level was further increased, mitochondrial membrane potential was significantly decreased and accompanied by a release of mitochondrial cytochrome c. At the same time, the apoptosis cells percentage and the caspase-3 activity were visibly elevated in hLE cells. These results suggested that SelR might protect hLE cell mitochondria and mitigating apoptosis in hLE cells against oxidative stress and endoplasmic reticulum (ER) stress induced by d-galactose, implying that selenium as a micronutrient may play important roles in hLE cells.

  5. Delayed cell cycle progression in selenoprotein W depleted cells is regulated by a mitogen-activated protein kinase kinase 4–p38–p53 pathway

    Science.gov (United States)

    Selenoprotein W (SEPW1) is a ubiquitous, highly conserved thioredoxin-like protein whose depletion causes a p53- and p21Cip1-dependent G1-phase cell cycle arrest in breast and prostate epithelial cells. SEPW1 depletion increases phosphorylation of Ser33 in p53, which is associated with decreased p53...

  6. Maternal reproductive health: Expression patterns of antioxidant enzyme selenoproteins of post-implantation embryos conceived by ethanol-treated murine mothers supplemented with α-tocopherol

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    Gliceria B Ramos

    2017-01-01

    Full Text Available Objective: To investigate if the protective effect of α-tocopherol against the impact of ethanol on brain morphogenesis involved the activity of the selenoproteins phospholipid hydroperoxide glutathione peroxidase (PHGPx; GPx4 and selenoprotein P (SelPP that have roles against oxidative stress. Methods: Forty female mice were randomly assigned into natural control (CON, positive control (ETOH, low-, medium-, and high-α-tocopherolsupplemented- ethanol groups (LTOC, MTOC, HTOC, respectively. CON received drinking water without ethanol while ETOH, LTOC, MTOC and HTOC groups received 20% ethanol in drinking water. The supplemented groups were given respective dosages of α-tocopherol, 0.410, 0.819, and 1.640 mg/g body weight, at day 14 before mating onwards to the day 9 of gestation. At 10.5 ED of gestation (1 100 h, the pregnant females were sacrificed by cervical dislocation and the embryos were harvested. Total RNA were extracted, cDNA synthesis and qRT- PCR analyses were carried out. Results: The level of expression of PHGPx in the positive control was significantly lower than that of the natural control. Among the three α- tocopherol-supplemented groups, only the medium dose- group was significantly higher than the positive control. The level of expression of SelPP in the positive control was significantly lower than those of the natural control, the low- and medium- dose α-tocopherol supplemented groups. In the high dose-α-tocopherol supplemented group, the level of expression was not significantly different from the positive control but significantly lower than the natural control. Conclusions: The activity of the selenoproteins PHGPx and SelPP are involved in the internetwork of antioxidative enzymes with vitamin E when given up to a medium dose only and is one of the possible pathways of shielding embryonic development against the impact of ethanol on brain morphogenesis. This study strengthens the impact of dietaryα-tocopherol and

  7. Characterization of the aerosol produced by infrared femtosecond laser ablation of polyacrylamide gels for the sensitive inductively coupled plasma mass spectrometry detection of selenoproteins

    Energy Technology Data Exchange (ETDEWEB)

    Claverie, Fanny [Laboratoire de Chimie Analytique Bio-Inorganique et Environnement, Institut Pluridisciplinaire de Recherche sur l' Environnement et les Materiaux, UMR 5254 CNRS- Universite de Pau et des Pays de l' Adour, Helioparc Pau-Pyrenees, 2 Avenue du President Angot, 64053 Pau Cedex 9 (France); Novalase SA, Z.I de la Briqueterie, 6 Impasse du bois de la Grange, 33610 Canejan (France); Pecheyran, Christophe [Laboratoire de Chimie Analytique Bio-Inorganique et Environnement, Institut Pluridisciplinaire de Recherche sur l' Environnement et les Materiaux, UMR 5254 CNRS- Universite de Pau et des Pays de l' Adour, Helioparc Pau-Pyrenees, 2 Avenue du President Angot, 64053 Pau Cedex 9 (France)], E-mail: Christophe.pecheyran@univ-pau.fr; Mounicou, Sandra [Laboratoire de Chimie Analytique Bio-Inorganique et Environnement, Institut Pluridisciplinaire de Recherche sur l' Environnement et les Materiaux, UMR 5254 CNRS- Universite de Pau et des Pays de l' Adour, Helioparc Pau-Pyrenees, 2 Avenue du President Angot, 64053 Pau Cedex 9 (France); Ballihaut, Guillaume [Laboratoire de Chimie Analytique Bio-Inorganique et Environnement, Institut Pluridisciplinaire de Recherche sur l' Environnement et les Materiaux, UMR 5254 CNRS- Universite de Pau et des Pays de l' Adour, Helioparc Pau-Pyrenees, 2 Avenue du President Angot, 64053 Pau Cedex 9 (France); Laboratoire d' Ecologie Moleculaire (Microbiologie), UMR 5254 CNRS- Universite de Pau et des Pays de l' Adour, avenue de l' Universite, B.P. 1155, F-64013 Pau (France); Fernandez, Beatriz [Laboratoire de Chimie Analytique Bio-Inorganique et Environnement, Institut Pluridisciplinaire de Recherche sur l' Environnement et les Materiaux, UMR 5254 CNRS- Universite de Pau et des Pays de l' Adour, Helioparc Pau-Pyrenees, 2 Avenue du President Angot, 64053 Pau Cedex 9 (France); Alexis, Joel [Laboratoire Genie de Production, Ecole Nationale d' Ingenieurs de Tarbes, 47 avenue d' Azereix BP 1629, 65016 Tarbes (France)] (and others)

    2009-07-15

    A 2D high repetition rate femtosecond laser ablation strategy (2-mm wide lane) previously developed for the detection of selenoproteins in gel electrophoresis by inductively coupled plasma mass spectrometry was found to increase signal sensitivity by a factor of 40 compared to conventional nanosecond ablation (0.12-mm wide lane) [G. Ballihaut, F. Claverie, C. Pecheyran, S. Mounicou, R. Grimaud and R. Lobinski, Sensitive Detection of Selenoproteins in Gel Electrophoresis by High Repetition Rate Femtosecond Laser Ablation-Inductively Coupled Plasma Mass Spectrometry, Anal. Chem. 79 (2007) 6874-6880]. Such improvement couldn't be explained solely by the difference of amount of material ablated, and then, was attributed to the aerosol properties. In order to validate this hypothesis, the characterization of the aerosol produced by nanosecond and high repetition rate femtosecond laser ablation of polyacrylamide gels was investigated. Our 2D high repetition rate femtosecond laser ablation strategy of 2-mm wide lane was found to produce aerosols of similar particle size distribution compared to nanosecond laser ablation of 0.12-mm wide lane, with 38% mass of particles < 1 {mu}m. However, at high repetition rate, when the ablated surface was reduced, the particle size distribution was shifted toward thinner particle diameter (up to 77% for a 0.12-mm wide lane at 285 {mu}m depth). Meanwhile, scanning electron microscopy was employed to visualize the morphology of the aerosol. In the case of larger ablation, the fine particles ejected from the sample were found to form agglomerates due to higher ablation rate and then higher collision probability. Additionally, investigations of the plasma temperature changes during the ablation demonstrated that the introduction of such amount of polyacrylamide gel particles had very limited impact on the ICP source ({delta}T{approx} 25 {+-} 5 K). This suggests that the cohesion forces between the thin particles composing these large

  8. Sex-specific and inter-individual differences in biomarkers of selenium status identified by a calibrated ELISA for selenoprotein P

    Directory of Open Access Journals (Sweden)

    Sandra Hybsier

    2017-04-01

    Full Text Available Selenoprotein P (SELENOP is a liver-derived transporter of selenium (Se in blood, and a meaningful biomarker of Se status. Se is an essential trace element for the biosynthesis of enzymatically-active selenoproteins, protecting the organism from oxidative damage. The usage of uncalibrated assays hinders the comparability of SELENOP concentrations and their pathophysiological interpretation across different clinical studies. On this account, we established a new sandwich SELENOP-ELISA and calibrated against a standard reference material (SRM1950. The ELISA displays a wide working range (11.6–538.4 µg/L, high accuracy (2.9% and good precision (9.3%. To verify whether SELENOP correlates to total Se and to SELENOP-bound Se, serum samples from healthy subjects and age-selected participants from the Berlin Aging Study II were analyzed by SELENOP-ELISA and Se quantification. SELENOP was affinity-purified and its Se content was determined from a subset of samples. There was a high correlation of total Se and SELENOP concentrations in young and elderly men, and in elderly women, but not in young women, indicating a specific sexual dimorphism in these biomarkers of Se status in young subjects. The Se content of isolated SELENOP was independent of sex and age (mean±SD: 5.4±0.5. By using this calibrated SELENOP-ELISA, prior reports on pathological SELENOP concentrations in diabetes and obesity are challenged as the reported values are outside reasonable limits. Biomarkers of Se status in clinical research need to be measured by validated assays in order to avoid erroneous data and incorrect interpretations, especially when analyzing young women. The Se content of circulating SELENOP differs between individuals and may provide some important diagnostic information on Se metabolism and status.

  9. Optimization of selenoprotein P and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement: a placebo-controlled, double-blind study of selenomethionine supplementation in selenium-deficient Chinese subjects1234

    Science.gov (United States)

    Xia, Yiming; Hill, Kristina E; Li, Ping; Xu, Jiayuan; Zhou, Dingyou; Motley, Amy K; Wang, Li; Byrne, Daniel W; Burk, Raymond F

    2010-01-01

    Background: The intake of selenium needed for optimal health has not been established. Selenoproteins perform the functions of selenium, and the selenium intake needed for their full expression is not known. Objective: This study sought to determine the intake of selenium required to optimize plasma selenoprotein P (SEPP1) and to compare SEPP1 with other plasma selenium biomarkers. Design: A 40-wk placebo-controlled, double-blind study of selenium repletion was carried out in 98 healthy Chinese subjects who had a daily dietary selenium intake of 14 mu g. Fourteen subjects each were assigned randomly to daily dose groups of 0, 21, 35, 55, 79, 102, and 125 mu g Se as l-selenomethionine. Plasma glutathione peroxidase (GPX) activity, SEPP1, and selenium were measured. A biomarker was considered to be optimized when its value was not different from the mean value of the subjects receiving larger supplements. Results: The SEPP1 concentration was optimized at 40 wk by the 35- mu g supplement, which indicated that 49 mu g/d could optimize it. GPX activity was optimized by 21 mu g (total ingestion: 35 mu g/d). The selenium concentration showed no tendency to become optimized. Conclusions: The present results indicate that SEPP1 concentration is the best plasma biomarker studied for assessing optimal expression of all selenoproteins, because its optimization required a larger intake of selenium than did GPX activity. On the basis of the selenium intake needed for SEPP1 optimization with adjustments for body weight and individual variation, ap 75 mu g Se/d as selenomethionine is postulated to allow full expression of selenoproteins in US residents. This trial was registered at clinicaltrials.gov as NCT00428649. PMID:20573787

  10. Monomethylarsonous acid inhibited endogenous cholesterol biosynthesis in human skin fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Lei [Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521-0403 (United States); Xiao, Yongsheng [Department of Chemistry, University of California, Riverside, CA 92521-0403 (United States); Wang, Yinsheng, E-mail: yinsheng.wang@ucr.edu [Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521-0403 (United States); Department of Chemistry, University of California, Riverside, CA 92521-0403 (United States)

    2014-05-15

    Human exposure to arsenic in drinking water is a widespread public health concern, and such exposure is known to be associated with many human diseases. The detailed molecular mechanisms about how arsenic species contribute to the adverse human health effects, however, remain incompletely understood. Monomethylarsonous acid [MMA(III)] is a highly toxic and stable metabolite of inorganic arsenic. To exploit the mechanisms through which MMA(III) exerts its cytotoxic effect, we adopted a quantitative proteomic approach, by coupling stable isotope labeling by amino acids in cell culture (SILAC) with LC-MS/MS analysis, to examine the variation in the entire proteome of GM00637 human skin fibroblasts following acute MMA(III) exposure. Among the ∼ 6500 unique proteins quantified, ∼ 300 displayed significant changes in expression after exposure with 2 μM MMA(III) for 24 h. Subsequent analysis revealed the perturbation of de novo cholesterol biosynthesis, selenoprotein synthesis and Nrf2 pathways evoked by MMA(III) exposure. Particularly, MMA(III) treatment resulted in considerable down-regulation of several enzymes involved in cholesterol biosynthesis. In addition, real-time PCR analysis showed reduced mRNA levels of select genes in this pathway. Furthermore, MMA(III) exposure contributed to a distinct decline in cellular cholesterol content and significant growth inhibition of multiple cell lines, both of which could be restored by supplementation of cholesterol to the culture media. Collectively, the present study demonstrated that the cytotoxicity of MMA(III) may arise, at least in part, from the down-regulation of cholesterol biosynthesis enzymes and the resultant decrease of cellular cholesterol content. - Highlights: • MMA(III)-induced perturbation of the entire proteome of GM00637 cells is studied. • Quantitative proteomic approach revealed alterations of multiple cellular pathways. • MMA(III) inhibits de novo cholesterol biosynthesis. • MMA

  11. Targeting thioredoxin reductase 1 reduction in cancer cells inhibits self-sufficient growth and DNA replication.

    Directory of Open Access Journals (Sweden)

    Min-Hyuk Yoo

    2007-10-01

    Full Text Available Thioredoxin reductase 1 (TR1 is a major redox regulator in mammalian cells. As an important antioxidant selenoprotein, TR1 is thought to participate in cancer prevention, but is also known to be over-expressed in many cancer cells. Numerous cancer drugs inhibit TR1, and this protein has been proposed as a target for cancer therapy. We previously reported that reduction of TR1 levels in cancer cells reversed many malignant characteristics suggesting that deficiency in TR1 function is antitumorigenic. The molecular basis for TR1's role in cancer development, however, is not understood. Herein, we found that, among selenoproteins, TR1 is uniquely overexpressed in cancer cells and its knockdown in a mouse cancer cell line driven by oncogenic k-ras resulted in morphological changes characteristic of parental (normal cells, without significant effect on cell growth under normal growth conditions. When grown in serum-deficient medium, TR1 deficient cancer cells lose self-sufficiency of growth, manifest a defective progression in their S phase and a decreased expression of DNA polymerase alpha, an enzyme important in DNA replication. These observations provide evidence that TR1 is critical for self-sufficiency in growth signals of malignant cells, that TR1 acts largely as a pro-cancer protein and it is indeed a primary target in cancer therapy.

  12. Roles of the 15-kDa Selenoprotein (Sep15) in Redox Homeostasis and Cataract Development Revealed by the Analysis of Sep 15 Knockout Mice*

    Science.gov (United States)

    Kasaikina, Marina V.; Fomenko, Dmitri E.; Labunskyy, Vyacheslav M.; Lachke, Salil A.; Qiu, Wenya; Moncaster, Juliet A.; Zhang, Jie; Wojnarowicz, Mark W.; Natarajan, Sathish Kumar; Malinouski, Mikalai; Schweizer, Ulrich; Tsuji, Petra A.; Carlson, Bradley A.; Maas, Richard L.; Lou, Marjorie F.; Goldstein, Lee E.; Hatfield, Dolph L.; Gladyshev, Vadim N.

    2011-01-01

    The 15-kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase. Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In this study, we developed and characterized Sep15 KO mice by targeted removal of exon 2 of the Sep15 gene coding for the cysteine-rich UDP-glucose:glycoprotein glucosyltransferase-binding domain. These KO mice synthesized a mutant mRNA, but the shortened protein product could be detected neither in tissues nor in Sep15 KO embryonic fibroblasts. Sep15 KO mice were viable and fertile, showed normal brain morphology, and did not activate endoplasmic reticulum stress pathways. However, parameters of oxidative stress were elevated in the livers of these mice. We found that Sep15 mRNA was enriched during lens development. Further phenotypic characterization of Sep15 KO mice revealed a prominent nuclear cataract that developed at an early age. These cataracts did not appear to be associated with severe oxidative stress or glucose dysregulation. We suggest that the cataracts resulted from an improper folding status of lens proteins caused by Sep15 deficiency. PMID:21768092

  13. Roles of the 15-kDa selenoprotein (Sep15) in redox homeostasis and cataract development revealed by the analysis of Sep 15 knockout mice.

    Science.gov (United States)

    Kasaikina, Marina V; Fomenko, Dmitri E; Labunskyy, Vyacheslav M; Lachke, Salil A; Qiu, Wenya; Moncaster, Juliet A; Zhang, Jie; Wojnarowicz, Mark W; Natarajan, Sathish Kumar; Malinouski, Mikalai; Schweizer, Ulrich; Tsuji, Petra A; Carlson, Bradley A; Maas, Richard L; Lou, Marjorie F; Goldstein, Lee E; Hatfield, Dolph L; Gladyshev, Vadim N

    2011-09-23

    The 15-kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase. Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In this study, we developed and characterized Sep15 KO mice by targeted removal of exon 2 of the Sep15 gene coding for the cysteine-rich UDP-glucose:glycoprotein glucosyltransferase-binding domain. These KO mice synthesized a mutant mRNA, but the shortened protein product could be detected neither in tissues nor in Sep15 KO embryonic fibroblasts. Sep15 KO mice were viable and fertile, showed normal brain morphology, and did not activate endoplasmic reticulum stress pathways. However, parameters of oxidative stress were elevated in the livers of these mice. We found that Sep15 mRNA was enriched during lens development. Further phenotypic characterization of Sep15 KO mice revealed a prominent nuclear cataract that developed at an early age. These cataracts did not appear to be associated with severe oxidative stress or glucose dysregulation. We suggest that the cataracts resulted from an improper folding status of lens proteins caused by Sep15 deficiency.

  14. Effects of Selenium-Enriched Probiotics on Heart Lesions by Influencing the mRNA Expressions of Selenoproteins and Heat Shock Proteins in Heat Stressed Broiler Chickens

    Directory of Open Access Journals (Sweden)

    Alam Zeb Khan1,2, Shahnawaz Kumbhar1, Muhammad Hamid1, Samreen Afzal3, Fahmida Parveen1, Yunhuan Liu1, Hao Shu1, Berhe Mekonnen Mengistu1 and Kehe Huang1*

    2016-11-01

    Full Text Available Selenium is one of the most vital trace elements regulating various body functions. Herein, we observe the effects of selenium-enriched probiotics on heart lesion in broiler chickens under high ambient temperature and explore the underlying mechanisms. Four different groups of broiler chickens were fed a corn-soybean basal diet having no Se supplementation (Con group, basal diet with the addition of probiotics (P group, a basal diet with Se supplementation in the form of sodium selenite (SS group, 0.30mg Se/kg and basal diet with the addition of selenium enriched probiotics (SP group, 0.30mg Se/kg. The results showed that P, SS, or SP supplementation significantly (P<0.05 up-regulated mRNA expression of selenoproteins (GPx1, GPx4 and down-regulated heat shock proteins (Hsp60, Hsp70 and Hsp90 in heart as compared to Con, P and SS diets. Herein, we suggest that SP product can serve as a feasible nutritive supplement, capable of protecting the heart from toxic effect of oxidative stress in summer season.

  15. Up-regulation of selenoprotein P and HIP/PAP mRNAs in hepatocytes by intermittent hypoxia via down-regulation of miR-203

    Directory of Open Access Journals (Sweden)

    Tomoko Uchiyama

    2017-09-01

    Full Text Available Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH] and is a risk factor for insulin resistance/type 2 diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human hepatocytes (JHH5, JHH7, and HepG2 to experimental IH or normoxia for 24 h, measured mRNA levels by real-time reverse transcription polymerase chain reaction (RT-PCR, and found that IH significantly increased the mRNA levels of selenoprotein P (SELENOP — a hepatokine — and hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP — one of REG (Regenerating gene family. We next investigated promoter activities of both genes and discovered that they were not increased by IH. On the other hand, a target mRNA search of micro RNA (miRNA revealed that both mRNAs have a potential target sequence for miR-203. The miR-203 level of IH-treated cells was significantly lower than that of normoxia-treated cells. Thus, we introduced miR-203 inhibitor and a non-specific control RNA (miR-203 inhibitor NC into HepG2 cells and measured the mRNA levels of SELENOP and HIP/PAP. The IH-induced expression of SELENOP and HIP/PAP was abolished by the introduction of miR-203 inhibitor but not by miR-203 inhibitor NC. These results demonstrate that IH stress up-regulates the levels of SELENOP in human hepatocytes to accelerate insulin resistance and up-regulates the levels of HIP/PAP mRNAs to proliferate such hepatocytes, via the miR-203 mediated mechanism.

  16. Evaluation of endothelial dysfunction in patients with nonalcoholic fatty liver disease: Association of selenoprotein P with carotid intima-media thickness and endothelium-dependent vasodilation.

    Science.gov (United States)

    Cetindağlı, Ibrahim; Kara, Muammer; Tanoglu, Alpaslan; Ozalper, Veysel; Aribal, Serkan; Hancerli, Yusuf; Unal, Mehmet; Ozarı, Onur; Hira, Serdar; Kaplan, Mustafa; Yazgan, Yusuf

    2017-10-01

    In patients with NAFLD, there is an increased risk of cardiovascular disease (CVD). Selenoprotein P (SelP), a hepatokine, is associated with insulin resistance (IR) and serum SelP was found to be elevated in patients with NAFLD. This study aimed to determine the risk of CVD in NAFLD patients and the association of serum SelP levels with this NAFLD related CVD risk. Ninety-three patients with NAFLD and 37 healthy controls were included in the study. Complete blood count, C-reactive protein (CRP), fasting glucose, serum lipid levels, and SelP levels were tested from fasting blood samples. Moreover, body mass index (BMI), HOMA-IR, carotid intima-media thickness (cIMT) and flow-mediated dilatation (FMD) were measured. In patients with NAFLD, the FMD ratio was significantly lower than in controls (P=0.027). cIMT measurements were similar in both groups (P=0.996). Serum SelP levels were significantly higher than controls (P<0.001). SelP levels were significantly correlated with BMI, fasting glucose, LDL-cholesterol and HOMA-IR (r=0.395, P<0.001; r=0.322, P=0.002; r=0.353, P<0.001; r=0.521, P<0.001, respectively). Also, SelP levels were significantly lower and correlated with FMD (r=-0.674, P<0.001). SelP, ESR and CRP were significantly higher (P<0.05) and FMD ratios were significantly lower (P<0.05) in patients with nonalcoholic steatohepatitis (NASH) when compared to patients with simple steatosis. These results suggest that in young NAFLD patients without additional comorbidities, there is an increased risk of CVD. FMD may be a better predictor for assessment of CVD risk when compared with cIMT. We assume that there could also be an important role of SelP in the pathogenesis of NASH. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. Association study of polymorphisms in selenoprotein genes and Kashin-Beck disease and serum selenium/iodine concentration in a Tibetan population.

    Directory of Open Access Journals (Sweden)

    Lulin Huang

    Full Text Available BACKGROUND: Kashin-Beck disease is a kind of degenerative osteoarthropathy. Genetic factors may play an important role in the pathogenesis of KBD. OBJECTIVE: To investigate the association of the selenoprotein genes GPX1 (rs1050450, rs1800668, and rs3811699, TrxR2 (rs5748469, and DIO2 (rs225014 with Kashin-Beck disease (KBD in a Tibetan population and to investigate the association of these SNPs with the serum iodine/selenium concentration in the Tibetan population. DESIGN: Five SNPs including rs1050450, rs1800668, and rs3811699 in the GPX1 gene, rs5748469 in the TrxR2 gene, and rs225014 in the DIO2 gene were analyzed in Tibetan KBD patients and controls using the SNaPshot method. P trend values of the SNPs were calculated using an additive model. RESULTS: None of the five SNPs in the three genes showed a significant association with KBD. Haplotypes TCC, TTC and TTT of rs1050450, rs1800668 and rs3811699 in GPX1 showed a significant association with KBD and controls with P value of 0.0421, 5.0E-4 and 0.0066, respectively. The GPX1 gene (rs1050450 showed a potential significant association with the iodine concentration in the Tibetan study population (P = 0.02726. However, no such association was detected with the selenium concentration (P = 0.2849. CONCLUSIONS: In this study, we showed that single SNPs in the genes GPX1 (rs1050450, rs1800668 and rs3811699, TrxR2 (rs5748469, and DIO2 (rs225014 may not be significantly associated with KBD in a Tibetan population. However, haplotype analysis of SNPs rs1050450, rs1800668 and rs3811699 in GPX1 gene showed a significant association with KBD. The results suggested that GPX1 gene play a protective role in the susceptivity of KBD in Tibetans. Furthermore, the GPX1 gene (rs1050450 may be significantly associated with the serum iodine concentration in Tibetans.

  18. Selenoprotein S (SEPS1 gene -105G>A promoter polymorphism influences the susceptibility to gastric cancer in the Japanese population

    Directory of Open Access Journals (Sweden)

    Nagasaka Mitsuo

    2009-01-01

    Full Text Available Abstract Background Inflammation is a key factor in the process of carcinogenesis from chronic gastritis induced by Helicobacter pylori. Selenoprotein S (SEPS1 is involved in the control of the inflammatory response in the endoplasmic reticulum (ER. Recently the -105G>A polymorphism in the promoter of SEPS1 was shown to increase pro-inflammatory cytokine expression. We examined the association between this polymorphism and the risk of gastric cancer. Methods We took stomach biopsies during endoscopies of 268 Japanese gastric cancer patients (193 males and 75 females, average age 65.3, and 306 control patients (184 males and 122 females, average age 62.7 and extracted the DNA from the biopsy specimens. All subjects provided written informed consent. For the genotyping of the SEPS1 promoter polymorphism at position -105G>A, PCR-RFLP methods were used and the PCR products were digested with PspGI. Logistic-regression analysis was used to estimate odds ratios (OR and 95% confidence intervals (CI, adjusting for age, sex, and H. pylori infection status. Results Among cases, the distribution of genotypes was as follows: 88.4% were GG, 11.2% were GA, and 0.4% were AA. Among controls, the distribution was as follows: 92.5% were GG, 7.2% were GA, and 0.3% were AA. Among males, carrying the A allele was associated with an increased odds of gastric cancer, compared with the GG genotype (OR: 2.0, 95% CI 1.0–4.1, p = 0.07. Compared with the GG genotype, carrying the A allele was significantly associated with increased risks of intestinal type gastric cancer (OR: 2.0, 95%CI 1.0–3.9, p Conclusion The -105G>A promoter polymorphism of SEPS1 was associated with the intestinal type of gastric cancer. This polymorphism may influence the inflammatory conditions of gastric mucosa. Larger population-based studies are needed for clarifying the relation between inflammatory responses and SEPS1 polymorphism.

  19. Selenoprotein function and muscle disease

    National Research Council Canada - National Science Library

    Lescure, Alain; Rederstorff, Mathieu; Krol, Alain; Guicheney, Pascale; Allamand, Valérie

    2009-01-01

    The crucial role of the trace element selenium in livestock and human health, in particular in striated muscle function, has been well established but the underlying molecular mechanisms remain poorly understood...

  20. Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor β-activated kinase 1 (TAK1 inhibition in KRAS-mutated colon cancer cells

    Directory of Open Access Journals (Sweden)

    Jennifer E. Hrabe

    2015-08-01

    Full Text Available Transforming growth factor β-activated kinase 1 (TAK1 is critical for survival of many KRAS mutated colorectal cancer cells, and TAK1 inhibition with 5Z-7-oxozeaenol has been associated with oxidative stress leading to tumor cell killing. When SW 620 and HCT 116 human colon cancer cells were treated with 5 µM 5Z-7-oxozeaenol, cell viability, growth, and clonogenic survival were significantly decreased. Consistent with TAK1 inhibition being causally related to thiol-mediated oxidative stress, 10 mM N-acetylcysteine (NAC partially reversed the growth inhibitory effects of 5Z-7-oxozeaenol. In addition, 5Z-7-oxozeaenol also increased steady-state levels of H2DCFDA oxidation as well as increased levels of total glutathione (GSH and glutathione disulfide (GSSG. Interestingly, depletion of GSH using buthionine sulfoximine did not significantly potentiate 5Z-7-oxozeaenol toxicity in either cell line. In contrast, pre-treatment of cells with auranofin (Au to inhibit thioredoxin reductase activity significantly increased levels of oxidized thioredoxin as well as sensitized cells to 5Z-7-oxozeaenol-induced growth inhibition and clonogenic cell killing. These results were confirmed in SW 620 murine xenografts, where treatment with 5Z-7-oxozeaenol or with Au plus 5Z-7-oxozeaenol significantly inhibited growth, with Au plus 5Z-7-oxozeaenol trending toward greater growth inhibition compared to 5Z-7-oxozeaenol alone. These results support the hypothesis that thiol-mediated oxidative stress is causally related to TAK1-induced colon cancer cell killing. In addition, these results support the hypothesis that thioredoxin metabolism is a critical target for enhancing colon cancer cell killing via TAK1 inhibition and could represent an effective therapeutic strategy in patients with these highly resistant tumors.

  1. Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer

    Directory of Open Access Journals (Sweden)

    Ling Li

    2015-04-01

    Full Text Available Inhibition of glycolysis using 2-deoxy-d-glucose (2DG, 20 mM, 24–48 h combined with inhibition of the pentose cycle using dehydroepiandrosterone (DHEA, 300 µM, 24–48 h increased clonogenic cell killing in both human prostate (PC-3 and DU145 and human breast (MDA-MB231 cancer cells via a mechanism involving thiol-mediated oxidative stress. Surprisingly, when 2DG+DHEA treatment was combined with an inhibitor of glutathione (GSH synthesis (l-buthionine sulfoximine; BSO, 1 mM that depleted GSH>90% of control, no further increase in cell killing was observed during 48 h exposures. In contrast, when an inhibitor of thioredoxin reductase (TrxR activity (Auranofin; Au, 1 µM, was combined with 2DG+DHEA or DHEA-alone for 24 h, clonogenic cell killing was significantly increased in all three human cancer cell lines. Furthermore, enhanced clonogenic cell killing seen with the combination of DHEA+Au was nearly completely inhibited using the thiol antioxidant, N-acetylcysteine (NAC, 20 mM. Redox Western blot analysis of PC-3 cells also supported the conclusion that thioredoxin-1 (Trx-1 oxidation was enhanced by treatment DHEA+Au and inhibited by NAC. Importantly, normal human mammary epithelial cells (HMEC were not as sensitive to 2DG, DHEA, and Au combinations as their cancer cell counterparts (MDA-MB-231. Overall, these results support the hypothesis that inhibition of glycolysis and pentose cycle activity, combined with inhibition of Trx metabolism, may provide a promising strategy for selectively sensitizing human cancer cells to oxidative stress-induced cell killing.

  2. Inhibitory effect of auranofin (I) and chloroquine (II) on bone degradation induced by the interleukin 1-like (IL-1-like) factor released from rheumatoid synovial tissue (RAST) in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Hodges, Y.; Maser, M.R.; Britton, M.C.; Multz, C.V.; Butler, E.; Chin, R.C.

    1986-03-01

    RAST, maintained in organ culture, releases two distinct types of bone resorptive factors and one co-resorptive factor. The first is prostaglandin E/sub 2/ (PGE/sub 2/), while the second is a protein with properties of IL-1. The co-resorptive factor collagenase, cannot induce bone resorption by itself, but augments the bone resorptive activity initiated by either PGE/sub 2/ or the IL-l-like factor. Bone resorptive activity was assessed by measuring the release of /sup 45/Ca from prelabelled rat fetal bones. We investigated the effects of five non-steroidal anti-inflammatory drugs (NSAIDs) and two disease-modifying anti-rheumatic drugs (DMARDs), (I) and (II), on bone degradation mediated by the IL-l-like factor. None of the NSAIDs tested inhibited bone degradation at 5 x 10/sup -5/ M. On the other hand, both (I) and (II) inhibited bone degradation 60 to 100% at 1 x 10/sup -6/ M and 8 x 10/sup -6/ M respectively. They can inhibit the action of IL-l-like factor on bone at therapeutically attainable concentrations. Additionally, both (I) and (II) block the release of collagenase from the organ culture of RAST with IC/sub 50/s of 5 x 10/sup -6/ M. This unique ability to inhibit collagenase release may contribute to their effectiveness is preventing bone loss in this test model.

  3. Corrosion inhibition..

    African Journals Online (AJOL)

    ABSTRACT. The corrosion inhibition of carbon steel in 3% de-aerated NaCl acidic solution with amine—fatty acid corrosion inhibitor, KI384, .... reduction reaction causing no decrease in the limiting current density of that process. On the .... value when compared to the base solution. This provides a support to the physical ...

  4. Induction of Thioredoxin Reductase 1 by Korean Red Ginseng Water Extract Regulates Cytoprotective Effects on Human Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Hye Rim Park

    2015-01-01

    Full Text Available Korean Red Ginseng is a popular herbal medicine and is widely used in many food products. KRG has biological benefits related to vascular diseases including diabetes, hypertension, atherosclerosis, and other cardiac diseases and KRG has antioxidant and anti-hyperlipidemic actions. KRG decreases the level of oxidative stress and suppresses proinflammatory cytokines and cell adhesion molecules, thus protecting endothelial dysfunction. Mammalian Thioredoxin reductase 1 is an NADPH-dependent selenoprotein, essential for antioxidant defense and DNA synthesis and repair, that regulates the redox system by modulating redox-sensitive transcription factors and thiol-containing proteins. Here, we show that KRG water extract increases the expression of TrxR1 in human umbilical vein endothelial cells via the p38 and PKC-δ signaling pathways. The induction of TrxR1 expression by KRG was confirmed by Western blot analysis and reverse transcription polymerase chain reaction. However, the increase in TrxR1 expression was abolished by specific silencing of the p38 and PKC-δ genes. In addition, we demonstrated that auranofin, a TrxR1 inhibitor, weakens the protective effect of KRG against H2O2-induced cell death as measured by the terminal transferase dUTP nick end labeling assay. These results suggest that KRG may have protective effects in vascular diseases by upregulating TrxR1 in endothelial cells, thereby inhibiting the generation of reactive oxygen species and cell death.

  5. Corrosion inhibiting organic coatings

    Energy Technology Data Exchange (ETDEWEB)

    Sasson, E.

    1984-10-16

    A corrosion inhibiting coating comprises a mixture of waxes, petroleum jelly, a hardener and a solvent. In particular, a corrosion inhibiting coating comprises candelilla wax, carnauba wax, microcrystalline waxes, white petrolatum, an oleoresin, lanolin and a solvent.

  6. Inhibition of selectin binding

    Energy Technology Data Exchange (ETDEWEB)

    Nagy, Jon O. (Rodeo, CA); Spevak, Wayne R. (Albany, CA); Dasgupta, Falguni (New Delhi, IN); Bertozzi, Carolyn (Albany, CA)

    1999-10-05

    This invention provides a system for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, this system can be used to palliate certain inflammatory and immunological conditions.

  7. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  8. Plastics for corrosion inhibition

    CERN Document Server

    Goldade, Victor A; Makarevich, Anna V; Kestelman, Vladimir N

    2005-01-01

    The development of polymer composites containing inhibitors of metal corrosion is an important endeavour in modern materials science and technology. Corrosion inhibitors can be located in a polymer matrix in the solid, liquid or gaseous phase. This book details the thermodynamic principles for selecting these components, their compatibility and their effectiveness. The various mechanisms of metal protection – barrier, inhibiting and electromechanical – are considered, as are the conflicting requirements placed on the structure of the combined material. Two main classes of inhibited materials (structural and films/coatings) are described in detail. Examples are given of structural plastics used in friction units subjected to mechano-chemical wear and of polymer films/coatings for protecting metal objects against corrosion.

  9. A Selenium-Dependent Xanthine Dehydrogenase Triggers Biofilm Proliferation in Enterococcus faecalis through Oxidant Production▿ ‡

    Science.gov (United States)

    Srivastava, Milan; Mallard, Chris; Barke, Theresa; Hancock, Lynn E.; Self, William T.

    2011-01-01

    Selenium has been shown to be present as a labile cofactor in a small class of molybdenum hydroxylase enzymes in several species of clostridia that specialize in the fermentation of purines and pyrimidines. This labile cofactor is poorly understood, yet recent bioinformatic studies have suggested that Enterococcus faecalis could serve as a model system to better understand the way in which this enzyme cofactor is built and the role of these metalloenzymes in the physiology of the organism. An mRNA that encodes a predicted selenium-dependent molybdenum hydroxylase (SDMH) has also been shown to be specifically increased during the transition from planktonic growth to biofilm growth. Based on these studies, we examined whether this organism produces an SDMH and probed whether selenoproteins may play a role in biofilm physiology. We observed a substantial increase in biofilm density upon the addition of uric acid to cells grown in a defined culture medium, but only when molybdate (Mo) and selenite (Se) were also added. We also observed a significant increase in biofilm density in cells cultured in tryptic soy broth with 1% glucose (TSBG) when selenite was added. In-frame deletion of selD, which encodes selenophosphate synthetase, also blocked biofilm formation that occurred upon addition of selenium. Moreover, mutation in the gene encoding the molybdoenzyme (xdh) prevented the induction of biofilm proliferation upon supplementation with selenium. Tungstate or auranofin addition also blocked this enhanced biofilm density, likely through inhibition of molybdenum or selenium cofactor synthesis. A large protein complex labeled with 75Se is present in higher concentrations in biofilms than in planktonic cells, and the same complex is formed in TSBG. Xanthine dehydrogenase activity correlates with the presence of this labile selenoprotein complex and is absent in a selD or an xdh mutant. Enhanced biofilm density correlates strongly with higher levels of extracellular

  10. Selective inhibition of enzyme synthesis under conditions of respiratory inhibition.

    Science.gov (United States)

    Flavell, R B; Woodward, D O

    1971-09-01

    When Neurospora mycelium is transferred from a medium containing sucrose to one containing acetate as sole source of carbon, a preferential synthesis of many Krebs cycle, glyoxylate cycle, and associated enzymes occurs. Respiration was inhibited during preferential enzyme synthesis in the following ways. (i) The amount of aeration (shaking) was reduced, (ii) cyanide was added to the culture, (iii) the carbon source, acetate, was removed, (iv) a mutant strain was starved of its Krebs cycle intermediates, and (v) respiration was inhibited by mutation. The effect of this respiratory inhibition on the synthesis of a number of enzymes was measured. It was found that the synthesis of nicotinamide adenine dinucleotide (NAD)-linked glutamate dehydrogenase and phosphoenolpyruvate carboxykinase was significantly less inhibited under conditions of respiratory inhibition than was the synthesis of Krebs cycle, glyoxylate cycle, and most other cell proteins synthesized during the adaptation period. This differential inhibition of enzyme synthesis was almost certainly not due to differential repression by regulatory metabolic end product effectors. Inhibition of mitochondrial respiration under these conditions most likely results in a limitation of the energy supply of the cell. Thus, it is suggested that the inhibition of synthesis of most proteins after inhibition of mitochondrial respiration results from a lack of energy in a utilizable form. Possible reasons to account for the relative insensitivity of NAD-linked glutamate dehydrogenase and phosphoenolpyruvate carboxykinase to inhibition under these conditions are discussed.

  11. Pharmacological inhibition of FTO.

    Directory of Open Access Journals (Sweden)

    Fiona McMurray

    Full Text Available In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO's demethylase activity could be therapeutically useful for the treatment of obesity.

  12. Beneficial bacteria inhibit cachexia

    Science.gov (United States)

    Varian, Bernard J.; Goureshetti, Sravya; Poutahidis, Theofilos; Lakritz, Jessica R.; Levkovich, Tatiana; Kwok, Caitlin; Teliousis, Konstantinos; Ibrahim, Yassin M.; Mirabal, Sheyla; Erdman, Susan E.

    2016-01-01

    Muscle wasting, known as cachexia, is a debilitating condition associated with chronic inflammation such as during cancer. Beneficial microbes have been shown to optimize systemic inflammatory tone during good health; however, interactions between microbes and host immunity in the context of cachexia are incompletely understood. Here we use mouse models to test roles for bacteria in muscle wasting syndromes. We find that feeding of a human commensal microbe, Lactobacillus reuteri, to mice is sufficient to lower systemic indices of inflammation and inhibit cachexia. Further, the microbial muscle-building phenomenon extends to normal aging as wild type animals exhibited increased growth hormone levels and up-regulation of transcription factor Forkhead Box N1 [FoxN1] associated with thymus gland retention and longevity. Interestingly, mice with a defective FoxN1 gene (athymic nude) fail to inhibit sarcopenia after L. reuteri therapy, indicating a FoxN1-mediated mechanism. In conclusion, symbiotic bacteria may serve to stimulate FoxN1 and thymic functions that regulate inflammation, offering possible alternatives for cachexia prevention and novel insights into roles for microbiota in mammalian ontogeny and phylogeny. PMID:26933816

  13. Beneficial bacteria inhibit cachexia.

    Science.gov (United States)

    Varian, Bernard J; Goureshetti, Sravya; Poutahidis, Theofilos; Lakritz, Jessica R; Levkovich, Tatiana; Kwok, Caitlin; Teliousis, Konstantinos; Ibrahim, Yassin M; Mirabal, Sheyla; Erdman, Susan E

    2016-03-15

    Muscle wasting, known as cachexia, is a debilitating condition associated with chronic inflammation such as during cancer. Beneficial microbes have been shown to optimize systemic inflammatory tone during good health; however, interactions between microbes and host immunity in the context of cachexia are incompletely understood. Here we use mouse models to test roles for bacteria in muscle wasting syndromes. We find that feeding of a human commensal microbe, Lactobacillus reuteri, to mice is sufficient to lower systemic indices of inflammation and inhibit cachexia. Further, the microbial muscle-building phenomenon extends to normal aging as wild type animals exhibited increased growth hormone levels and up-regulation of transcription factor Forkhead Box N1 [FoxN1] associated with thymus gland retention and longevity. Interestingly, mice with a defective FoxN1 gene (athymic nude) fail to inhibit sarcopenia after L. reuteri therapy, indicating a FoxN1-mediated mechanism. In conclusion, symbiotic bacteria may serve to stimulate FoxN1 and thymic functions that regulate inflammation, offering possible alternatives for cachexia prevention and novel insights into roles for microbiota in mammalian ontogeny and phylogeny.

  14. [Penicillium-inhibiting yeasts].

    Science.gov (United States)

    Benítez Ahrendts, M R; Carrillo, L

    2004-01-01

    The objective of this work was to establish the in vitro and in vivo inhibition of post-harvest pathogenic moulds by yeasts in order to make a biocontrol product. Post-harvest pathogenic moulds Penicillium digitatum, P. italicum, P. ulaiense, Phyllosticta sp., Galactomyces geotrichum and yeasts belonging to genera Brettanomyces, Candida, Cryptococcus, Kloeckera, Pichia, Rhodotorula were isolated from citrus fruits. Some yeasts strains were also isolated from other sources. The yeasts were identified by their macro and micro-morphology and physiological tests. The in vitro and in vivo activities against P. digitatum or P. ulaiense were different. Candida cantarellii and one strain of Pichia subpelliculosa produced a significant reduction of the lesion area caused by the pathogenic moulds P. digitatum and P. ulaiense, and could be used in a biocontrol product formulation.

  15. Propolis inhibits osteoclast maturation.

    Science.gov (United States)

    Pileggi, Roberta; Antony, Kathryn; Johnson, Kristie; Zuo, Jian; Shannon Holliday, L

    2009-12-01

    Propolis, a natural product produced by the honey bee, has been successfully used in medicine as an anti-inflammatory and antimicrobial agent. Traumatic injuries to the teeth, especially avulsion injuries, present a challenging situation for the clinician because of post-treatment complications, such as inflammatory and/or replacement resorption. Agents that reduce osteoclast numbers and activity may be useful in the treatment of traumatic injuries to the teeth. In this study, we evaluated propolis as an anti-resorptive agent. Calcitriol-stimulated mouse marrow cultures, which contain both osteoclasts and osteoblasts, were exposed to the ethanol extracts of propolis or vehicle control and stained for tartrate-resistant acid phosphatase (TRAP)-activity to identify osteoclasts. A significant, dose-dependent reduction in multinuclear TRAP+ cells was demonstrated, although the propolis treatment accommodated cell growth and survival (P Propolis also reduced the formation of actin rings in pure cultures of RAW 264.7 osteoclast-like cells, suggesting that it exerts direct actions on osteoclast maturation. In summary, our data suggest that propolis inhibits late stages of osteoclast maturation including fusion of osteoclasts precursors to form giant cells and formation of actin rings. This supports the hypothesis that it may prove useful as a medicament to reduce resorption associated with traumatic injuries to the teeth.

  16. Can Arousal Modulate Response Inhibition?

    Science.gov (United States)

    Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

    2015-01-01

    The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

  17. [Cabergoline for inhibition of lactation].

    Science.gov (United States)

    Bravo-Topete, Enrique Gómez; Mendoza-Hernández, Freddy; Cejudo-Alvarez, José; Briones-Garduño, Carlos

    2004-01-01

    Despite advances in prevention inhibition of lactation, only administration of estrogens or these combined with androgens show variable effectiveness and are indirectly associated with high percentage for lactation rebound, thrombosis, or pulmonary embolism or both of the later during puerperium; in addition, bromocriptine, also used indirectly for inhibition of lactation, is associated with lactation, rebound in 18-40%. Cabergolin is a new ergoline with efficient and durable prolactin reducer effect with fewer adverse effects. Which will the smallest cabergolin dosage be to inhibit lactation? To demonstrate clinical effectiveness with smallest cabergolina dosage in lactation inhibition. We carried on a the Service Clinical test on patients hospitalization with an indication to inhibit lactation as the Hospital of Gynecology and Obstetrics, Infantil Maternal Institute of the State of Mexico (IMIEM). The study was done 80 patients to who we administered oral 0.5 mg cabergoline to 40 patients and another group of 40 whom we administered 1.0 mg of cabergoline orally at random and blinded by means of out-patient consultation. We studied correlation between dose and inhibition of lactation as well as presence of adverse effects. In the group of patients to whom administered 0.5 mg, we found 65% (n = 26) with lactation inhibition; adverse effects in this group appeared in 32.5% (n = 13) the second group with a dose of 1.0 mg; 95% with adverse effects in 25% P < 0.001. Inhibition of lactation with unique dose of 1.0 has satisfactory clinical effectiveness, this being the smaller dose to inhibit lactation at a suitable percentage.

  18. Memory inhibition across the lifespan

    OpenAIRE

    Teale, Julia C.

    2015-01-01

    Age can affect memory performance. This statement is so often heard that it has become almost a truism. When research surrounding memory inhibition – the ability to ignore irrelevant material to aid in the retrieval of a target memory – is examined specifically, a more mixed picture of findings emerges. Whilst some previous work has found evidence of an age-related deficit, other research has rather found intact memory inhibition in older adults. Less often discussed, too, are the effects of ...

  19. Inhibition of MMPs by alcohols

    Science.gov (United States)

    Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Hoshika, Tomohiro; Uchiyama, Toshikazu; Tjäderhane, Leo; Breschi, Lorenzo; Mazzoni, Annalisa; Thompson, Jeremy M.; McCracken, Courtney E.; Looney, Stephen W.; Tay, Franklin R.; Pashley, David H.

    2011-01-01

    Objectives While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. Methods The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 moles/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC50). Results Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose-dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3-heptanol and 1-octanol gave the strongest inhibition. Significance The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID:21676453

  20. Dihydroxyoctadecamonoenoate esters inhibit the neutrophil ...

    Indian Academy of Sciences (India)

    PRAKASH

    inhibited by methyl 9,10-/12,13-DiHOME. Neutrophil activation is characterized by a wide variety of signal transduction events. Assembly of the multiprotein. NADPH oxidase complex is required for superoxide production and is preceded by the phosphorylation of p47phox and translocation of p47phox to the membrane.

  1. Testing of Biologically Inhibiting Surface

    DEFF Research Database (Denmark)

    Bill Madsen, Thomas; Larsen, Erup

    2003-01-01

    The main purpose of this course is to examine a newly developed biologically inhibiting material with regards to galvanic corrosion and electrochemical properties. More in detail, the concern was how the material would react when exposed to cleaning agents, here under CIP cleaning (Cleaning...

  2. DETECTION OF HAEMAGGLUTINATION—INHIBITION ...

    African Journals Online (AJOL)

    A survey of haemagglutination inhibition lHl) antibodies against influenza A virus was carried out on pigs sera collected at Bodija abattoir, Ibadan between December, 2001 and August 2002. Out of the 107 sera tested, 101. 94.39%) had ill antibodies to influenza A (IhNi) human strain while the remaining 6 (5.61%) were ...

  3. Threat interferes with response inhibition.

    Science.gov (United States)

    Hartikainen, Kaisa M; Siiskonen, Anna R; Ogawa, Keith H

    2012-05-09

    A potential threat, such as a spider, captures attention and engages executive functions to adjust ongoing behavior and avoid danger. We and many others have reported slowed responses to neutral targets in the context of emotional distractors. This behavioral slowing has been explained in the framework of attentional competition for limited resources with emotional stimuli prioritized. Alternatively, slowed performance could reflect the activation of avoidance/freezing-type motor behaviors associated with threat. Although the interaction of attention and emotion has been widely studied, little is known on the interaction between emotion and executive functions. We studied how threat-related stimuli (spiders) interact with executive performance and whether the interaction profile fits with a resource competition model or avoidance/freezing-type motor behaviors. Twenty-one young healthy individuals performed a Go-NoGo visual discrimination reaction time (RT) task engaging several executive functions with threat-related and emotionally neutral distractors. The threat-related distractors had no effect on the RT or the error rate in the Go trials. The NoGo error rate, reflecting failure in response inhibition, increased significantly because of threat-related distractors in contrast to neutral distractors, P less than 0.05. Thus, threat-related distractors temporarily impaired response inhibition. Threat-related distractors associated with increased commission errors and no effect on RT does not suggest engagement of avoidance/freezing-type motor behaviors. The results fit in the framework of the resource competition model. A potential threat calls for evaluation of affective significance as well as inhibition of undue emotional reactivity. We suggest that these functions tax executive resources and may render other executive functions, such as response inhibition, temporarily compromised when the demands for resources exceed availability.

  4. Th2 cytokines inhibit lymphangiogenesis.

    Directory of Open Access Journals (Sweden)

    Ira L Savetsky

    Full Text Available Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2 cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4 and interleukin-13 (IL-13 have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis.

  5. Combined autophagy and proteasome inhibition

    Science.gov (United States)

    Vogl, Dan T; Stadtmauer, Edward A; Tan, Kay-See; Heitjan, Daniel F; Davis, Lisa E; Pontiggia, Laura; Rangwala, Reshma; Piao, Shengfu; Chang, Yunyoung C; Scott, Emma C; Paul, Thomas M; Nichols, Charles W; Porter, David L; Kaplan, Janeen; Mallon, Gayle; Bradner, James E; Amaravadi, Ravi K

    2014-01-01

    The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy. PMID:24991834

  6. RAAS inhibition and cardiorenal syndrome.

    Science.gov (United States)

    Onuigbo, Macaulay Amechi C

    2014-01-01

    The consensus conference on cardio-renal syndromes (2008) defined 'cardio-renal syndromes' as 'disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other' and identified five subtypes of the syndromes. Various pathophysiologic mechanisms underlie cardiorenal syndrome including hemodynamic derangements, reduced cardiac output leading to impaired renal perfusion, reduced stroke volume, raised atrial filling pressures, elevated atrial pressures, sodium and water retention, venous congestion, right ventricular dysfunction and venous hypertension causing increased renal venous pressure, intra-abdominal hypertension, various neurohormonal adaptations including activation of the renin-angiotensin-aldosterone system, adaptive activation of the sympathetic nervous system, cytokine release and oxidative stress. Although there are standardized clinical guidelines for the management of heart failure, and chronic kidney disease, respectively, there are no similar consensus clinical guidelines for the management of the cardiorenal syndromes. RAAS inhibition is advocated in treating systolic heart failure. There is evidence that RAAS inhibition is also useful in cardiorenal syndrome. However, RAAS inhibition, while potentially useful in the management of cardiorenal syndrome, is not the 'magic bullet', is sometimes limited by adverse renal events, is not applicable to all patients, and must be applied by physicians with due diligence and caution. Nevertheless, a more comprehensive multidisciplinary multipronged approach to managing patients with cardiorenal syndrome is even more pragmatic and commonsense given the multiple mechanisms and pathogenetic pathways implicated in the causation and perpetuation of cardiorenal syndrome.

  7. Self-regulation, ego depletion, and inhibition.

    Science.gov (United States)

    Baumeister, Roy F

    2014-12-01

    Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Action inhibition in Tourette syndrome.

    Science.gov (United States)

    Ganos, Christos; Kühn, Simone; Kahl, Ursula; Schunke, Odette; Feldheim, Jan; Gerloff, Christian; Roessner, Veit; Bäumer, Tobias; Thomalla, Götz; Haggard, Patrick; Münchau, Alexander

    2014-10-01

    Tourette syndrome is a neuropsychiatric disorder characterized by tics. Tic generation is often linked to dysfunction of inhibitory brain networks. Some previous behavioral studies found deficiencies in inhibitory motor control in Tourette syndrome, but others suggested normal or even better-than-normal performance. Furthermore, neural correlates of action inhibition in these patients are poorly understood. We performed event-related functional magnetic resonance imaging during a stop-signal reaction-time task in 14 uncomplicated adult Tourette patients and 15 healthy controls. In patients, we correlated activations in stop-signal reaction-time task with their individual motor tic frequency. Task performance was similar in both groups. Activation of dorsal premotor cortex was stronger in the StopSuccess than in the Go condition in healthy controls. This pattern was reversed in Tourette patients. A significant positive correlation was present between motor tic frequency and activations in the supplementary motor area during StopSuccess versus Go in patients. Inhibitory brain networks differ between healthy controls and Tourette patients. In the latter the supplementary motor area is probably a key relay of inhibitory processes mediating both suppression of tics and inhibition of voluntary action. © 2014 International Parkinson and Movement Disorder Society.

  9. Graphene: corrosion-inhibiting coating.

    Science.gov (United States)

    Prasai, Dhiraj; Tuberquia, Juan Carlos; Harl, Robert R; Jennings, G Kane; Rogers, Bridget R; Bolotin, Kirill I

    2012-02-28

    We report the use of atomically thin layers of graphene as a protective coating that inhibits corrosion of underlying metals. Here, we employ electrochemical methods to study the corrosion inhibition of copper and nickel by either growing graphene on these metals, or by mechanically transferring multilayer graphene onto them. Cyclic voltammetry measurements reveal that the graphene coating effectively suppresses metal oxidation and oxygen reduction. Electrochemical impedance spectroscopy measurements suggest that while graphene itself is not damaged, the metal under it is corroded at cracks in the graphene film. Finally, we use Tafel analysis to quantify the corrosion rates of samples with and without graphene coatings. These results indicate that copper films coated with graphene grown via chemical vapor deposition are corroded 7 times slower in an aerated Na(2)SO(4) solution as compared to the corrosion rate of bare copper. Tafel analysis reveals that nickel with a multilayer graphene film grown on it corrodes 20 times slower while nickel surfaces coated with four layers of mechanically transferred graphene corrode 4 times slower than bare nickel. These findings establish graphene as the thinnest known corrosion-protecting coating.

  10. Greener Approach towards Corrosion Inhibition

    Directory of Open Access Journals (Sweden)

    Neha Patni

    2013-01-01

    Full Text Available Corrosion control of metals is technically, economically, environmentally, and aesthetically important. The best option is to use inhibitors for protecting metals and alloys against corrosion. As organic corrosion inhibitors are toxic in nature, so green inhibitors which are biodegradable, without any heavy metals and other toxic compounds, are promoted. Also plant products are inexpensive, renewable, and readily available. Tannins, organic amino acids, alkaloids, and organic dyes of plant origin have good corrosion-inhibiting abilities. Plant extracts contain many organic compounds, having polar atoms such as O, P, S, and N. These are adsorbed on the metal surface by these polar atoms, and protective films are formed, and various adsorption isotherms are obeyed. Various types of green inhibitors and their effect on different metals are mentioned in the paper.

  11. Survival Processing Eliminates Collaborative Inhibition.

    Science.gov (United States)

    Reysen, Matthew B; Bliss, Heather; Baker, Melissa A

    2017-04-11

    The present experiments examined the effect of processing words for their survival value, relevance to moving, and pleasantness on participants' free recall scores in both nominal groups (non-redundant pooled individual scores) and collaborative dyads. Overall, participants recalled more words in the survival processing conditions than in the moving and pleasantness processing conditions. Furthermore, nominal groups in both the pleasantness condition (Experiment 1) and the moving and pleasantness conditions (Experiment 2) recalled more words than collaborative groups, thereby replicating the oft-observed effect of collaborative inhibition. However, processing words for their survival value appeared to eliminate the deleterious effects of collaborative remembering in both Experiments 1 and 2. These results are discussed in the context of the retrieval strategy disruption hypothesis and the effects of both expertise and collaborative skill on group remembering.

  12. Mood stabilizers inhibit cytomegalovirus infection.

    Science.gov (United States)

    Ornaghi, Sara; Davis, John N; Gorres, Kelly L; Miller, George; Paidas, Michael J; van den Pol, Anthony N

    2016-12-01

    Cytomegalovirus (CMV) infection can generate debilitating disease in immunocompromised individuals and neonates. It is also the most common infectious cause of congenital birth defects in infected fetuses. Available anti-CMV drugs are partially effective but are limited by some toxicity, potential viral resistance, and are not recommended for fetal exposure. Valproate, valpromide, and valnoctamide have been used for many years to treat epilepsy and mood disorders. We report for the first time that, in contrast to the virus-enhancing actions of valproate, structurally related valpromide and valnoctamide evoke a substantial and specific inhibition of mouse and human CMV in vitro. In vivo, both drugs safely attenuate mouse CMV, improving survival, body weight, and developmental maturation of infected newborns. The compounds appear to act by a novel mechanism that interferes with CMV attachment to the cell. Our work provides a novel potential direction for CMV therapeutics through repositioning of agents already approved for use in psychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Reduced surround inhibition in musicians.

    Science.gov (United States)

    Shin, Hae-Won; Kang, Suk Y; Hallett, Mark; Sohn, Young H

    2012-06-01

    To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1,000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia.

  14. The pharmacology of visuospatial attention and inhibition

    NARCIS (Netherlands)

    Logemann, H.N.A.

    2013-01-01

    Attention and inhibition are of vital importance in everyday functioning. Problems of attention and inhibition are central to disorders such as Attention Deficit/Hyperactivity Disorder (ADHD). Both bias and disengagement key components of visuospatial attention. Bias refers to neuronal signals that

  15. Optimal Decision Making in Neural Inhibition Models

    Science.gov (United States)

    van Ravenzwaaij, Don; van der Maas, Han L. J.; Wagenmakers, Eric-Jan

    2012-01-01

    In their influential "Psychological Review" article, Bogacz, Brown, Moehlis, Holmes, and Cohen (2006) discussed optimal decision making as accomplished by the drift diffusion model (DDM). The authors showed that neural inhibition models, such as the leaky competing accumulator model (LCA) and the feedforward inhibition model (FFI), can mimic the…

  16. Methanol Extract of Myelophycus caespitosus Inhibits the ...

    African Journals Online (AJOL)

    Methanol Extract of Myelophycus caespitosus Inhibits the Inflammatory Response in Lipopolysaccharidestimulated BV2 Microglial Cells by Downregulating NF-kB via Inhibition of the Akt Signaling Pathway. ... The level of NO production was analyzed using Griess reaction. The release of PGE2 was determined using ...

  17. Factors Impacting the Child with Behavioral Inhibition

    Science.gov (United States)

    Hornbuckle, Suzanne R.

    2010-01-01

    Various factors influence the developmental course of the behaviorally inhibited child. These factors include reciprocating, contextual factors, such as the child's own traits, the environment, the maternal characteristics, and the environment. Behaviorally inhibited children show physiological and behavioral signs of fear and anxiety when…

  18. CORROSION INHIBITION BY CASHEW NUT SHELL LIQUID

    African Journals Online (AJOL)

    MECHANISTIC STUDIES OF CARBON STEEL. CORROSION INHIBITION BY CASHEW NUT SHELL. LIQUID. JYN Philip, J Buchweishaija and LL Mkayula. Department of Chemistry, University of Dar es Salaam,. P. O. Box 35061, Dar es Salaam, Tanzania. ABSTRACT. The inhibition mechanism of the Cashew Nut Shell ...

  19. Adsorptive, Kinetic, Thermodynamic and Inhibitive Properties of ...

    African Journals Online (AJOL)

    The adsorption of Cissus populnea stem extract and its subsequent corrosion inhibition properties on aluminum in 0.5 M HCl solutions have been investigated using weight loss measurements. Inhibition efficiency of the plant extract increased with concentration but decreased with rise in temperature. The adsorption of the ...

  20. Cortisol involvement in mechanisms of behavioral inhibition

    NARCIS (Netherlands)

    Tops, Mattie; Boksem, Maarten A. S.

    We studied whether baseline cortisol is associated with post-error slowing, a measure that depends upon brain areas involved in behavioral inhibition. Moreover, we studied whether this association holds after controlling for positive associations with behavioral inhibition scores and error-related

  1. Inhibition: Mental Control Process or Mental Resource?

    Science.gov (United States)

    Im-Bolter, Nancie; Johnson, Janice; Ling, Daphne; Pascual-Leone, Juan

    2015-01-01

    The current study tested 2 models of inhibition in 45 children with language impairment and 45 children with normally developing language; children were aged 7 to 12 years. Of interest was whether a model of inhibition as a mental-control process (i.e., executive function) or as a mental resource would more accurately reflect the relations among…

  2. A Qualitative Approach to Enzyme Inhibition

    Science.gov (United States)

    Waldrop, Grover L.

    2009-01-01

    Most general biochemistry textbooks present enzyme inhibition by showing how the basic Michaelis-Menten parameters K[subscript m] and V[subscript max] are affected mathematically by a particular type of inhibitor. This approach, while mathematically rigorous, does not lend itself to understanding how inhibition patterns are used to determine the…

  3. Amiodarone Inhibits Apamin-Sensitive Potassium Currents

    Science.gov (United States)

    Turker, Isik; Yu, Chih-Chieh; Chang, Po-Cheng; Chen, Zhenhui; Sohma, Yoshiro; Lin, Shien-Fong; Chen, Peng-Sheng; Ai, Tomohiko

    2013-01-01

    Background Apamin sensitive potassium current (IKAS), carried by the type 2 small conductance Ca2+-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles. Objective To test the hypothesis that amiodarone inhibits IKAS in human embryonic kidney 293 (HEK-293) cells. Methods We used the patch-clamp technique to study IKAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration. Results Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67±0.25 µM with 1 µM intrapipette Ca2+). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6±3.1% of IKAS induced with 1 µM intrapipette Ca2+ (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca2+-dependent: 30 µM amiodarone inhibited 81.5±1.9% of IKAS induced with 1 µM Ca2+ (n = 4), and 16.4±4.9% with 250 nM Ca2+ (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca2+ dependent inhibition of IKAS. Conclusion Both amiodarone and desethylamiodarone inhibit IKAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca2+ concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles. PMID:23922993

  4. Amiodarone inhibits apamin-sensitive potassium currents.

    Directory of Open Access Journals (Sweden)

    Isik Turker

    Full Text Available Apamin sensitive potassium current (I KAS, carried by the type 2 small conductance Ca(2+-activated potassium (SK2 channels, plays an important role in post-shock action potential duration (APD shortening and recurrent spontaneous ventricular fibrillation (VF in failing ventricles.To test the hypothesis that amiodarone inhibits I KAS in human embryonic kidney 293 (HEK-293 cells.We used the patch-clamp technique to study I KAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration.Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67 ± 0.25 µM with 1 µM intrapipette Ca(2+. Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6 ± 3.1% of IKAS induced with 1 µM intrapipette Ca(2+ (n = 3. IKAS inhibition by amiodarone was not voltage-dependent, but was Ca(2+-dependent: 30 µM amiodarone inhibited 81.5±1.9% of I KAS induced with 1 µM Ca(2+ (n = 4, and 16.4±4.9% with 250 nM Ca(2+ (n = 5. Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca(2+ dependent inhibition of I KAS.Both amiodarone and desethylamiodarone inhibit I KAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca(2+ concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles.

  5. BST2/Tetherin Inhibition of Alphavirus Exit

    Directory of Open Access Journals (Sweden)

    Yaw Shin Ooi

    2015-04-01

    Full Text Available Alphaviruses such as chikungunya virus (CHIKV and Semliki Forest virus (SFV are small enveloped RNA viruses that bud from the plasma membrane. Tetherin/BST2 is an interferon-induced host membrane protein that inhibits the release of many enveloped viruses via direct tethering of budded particles to the cell surface. Alphaviruses have highly organized structures and exclude host membrane proteins from the site of budding, suggesting that their release might be insensitive to tetherin inhibition. Here, we demonstrated that exogenously-expressed tetherin efficiently inhibited the release of SFV and CHIKV particles from host cells without affecting virus entry and infection. Alphavirus release was also inhibited by the endogenous levels of tetherin in HeLa cells. While rubella virus (RuV and dengue virus (DENV have structural similarities to alphaviruses, tetherin inhibited the release of RuV but not DENV. We found that two recently identified tetherin isoforms differing in length at the N-terminus exhibited distinct capabilities in restricting alphavirus release. SFV exit was efficiently inhibited by the long isoform but not the short isoform of tetherin, while both isoforms inhibited vesicular stomatitis virus exit. Thus, in spite of the organized structure of the virus particle, tetherin specifically blocks alphavirus release and shows an interesting isoform requirement.

  6. Angiotensin inhibition in heart failure

    Directory of Open Access Journals (Sweden)

    John JV Mcmurray

    2004-03-01

    Full Text Available Survival in patients with heart failure remains very poor, and is worse than that for most common cancers, including bowel cancer in men and breast cancer in women. The renin-angiotensin-aldosterone system (RAAS is not completely blocked by angiotensin-converting enzyme (ACE inhibition. Blockade of the RAAS at the AT1-receptor has the theoretical benefit of more effective blockade of the actions of angiotensin II. ACE inhibitors (ACE-Is prevent the breakdown of bradykinin: this has been blamed for some of the unwanted effects of ACE-Is although bradykinin may have advantageous effects in heart failure. Consequently, ACE-Is and ARBs might be complementary or even additive treatments; recent trials have tested these hypotheses. The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM programme compared the angiotensin receptor blocker (ARB candesartan (target dose 32 mg once daily to placebo in three distinct but complementary populations of patients with symptomatic heart failure. These were: patients with reduced left ventricular ejection fraction (LVEF who were ACE-I-intolerant (CHARM-Alternative; patients with reduced LVEF who were being treated with ACE-Is (CHARM-Added; and patients with preserved left ventricular systolic function (CHARM-Preserved. There were substantial and statistically significant reductions in the primary composite end point (risk of cardiovascular death or hospital admission for heart failure in CHARM-Alternative. This was also the case in CHARM-Added, supporting and extending the findings of Val-HeFT. In CHARM-Preserved, the effect of candesartan on the primary end point did not reach conventional statistical significance though hospital admission for heart failure was reduced significantly with candesartan. In the CHARM-Overall programme there was a statistically borderline reduction in all-cause mortality with a clear reduction in cardiovascular mortality. All-cause mortality was

  7. Angiotensin inhibition in heart failure

    Directory of Open Access Journals (Sweden)

    John JV McMurray

    2004-03-01

    Full Text Available Survival in patients with heart failure remains very poor, and is worse than that for most common cancers, including bowel cancer in men and breast cancer in women. The renin-angiotensin-aldosterone system (RAAS is not completely blocked by angiotensin-converting enzyme (ACE inhibition. Blockade of the RAAS at the AT1-receptor has the theoretical benefit of more effective blockade of the actions of angiotensin II. ACE inhibitors (ACE-Is prevent the breakdown of bradykinin: this has been blamed for some of the unwanted effects of ACE-Is although bradykinin may have advantageous effects in heart failure. Consequently, ACE-Is and ARBs might be complementary or even additive treatments; recent trials have tested these hypotheses.The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM programme compared the angiotensin receptor blocker (ARB candesartan (target dose 32 mg once daily to placebo in three distinct but complementary populations of patients with symptomatic heart failure. These were: patients with reduced left ventricular ejection fraction (LVEF who were ACE-I-intolerant (CHARM-Alternative; patients with reduced LVEF who were being treated with ACE-Is (CHARM-Added; and patients with preserved left ventricular systolic function (CHARM-Preserved.There were substantial and statistically significant reductions in the primary composite end point (risk of cardiovascular death or hospital admission for heart failure in CHARM-Alternative. This was also the case in CHARM-Added, supporting and extending the findings of Val-HeFT. In CHARM-Preserved, the effect of candesartan on the primary end point did not reach conventional statistical significance though hospital admission for heart failure was reduced significantly with candesartan. In the CHARM-Overall programme there was a statistically borderline reduction in all-cause mortality with a clear reduction in cardiovascular mortality. All-cause mortality was

  8. Cellulase Inhibition by High Concentrations of Monosaccharides

    DEFF Research Database (Denmark)

    Hsieh, Chia-Wen; Cannella, David; Jørgensen, Henning

    2014-01-01

    that low free water availability contributes to cellulase inhibition. Of the hydrolytic enzymes involved, those acting on the cellulose substrate, that is, exo- and endoglucanases, were the most inhibited. The β -glucosidases were shown to be less sensitive to high monosaccharide concentrations except......Biological degradation of biomass on an industrial scale culminates in high concentrations of end products. It is known that the accumulation of glucose and cellobiose, end products of hydrolysis, inhibit cellulases and decrease glucose yields. Aside from these end products, however, other...

  9. Studies of Ca2+ ATPase (SERCA) inhibition.

    Science.gov (United States)

    Inesi, Giuseppe; Hua, Suming; Xu, Cheng; Ma, Hailun; Seth, Malini; Prasad, Anand M; Sumbilla, Carlota

    2005-12-01

    The Ca(2+) transport ATPase of intracellular membranes (SERCA) can be inhibited by a series of chemical compounds such as Thapsigargin (TG), 2,5-di(tert-butyl)hydroquinone (DBHQ) and 1,3-dibromo-2,4,6-tris (methyl-isothio-uronium) benzene (Br(2)-TITU). These compounds have specific binding sites in the ATPase protein, and different mechanisms of inhibition. On the other hand, SERCA gene silencing offers a convenient and specific method for suppression of SERCA activity in cells. The physiological and pharmacological implications of SERCA inhibition are discussed.

  10. The IFITMs Inhibit Zika Virus Replication

    Directory of Open Access Journals (Sweden)

    George Savidis

    2016-06-01

    Full Text Available Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses.

  11. Should We Stop Thinking About Inhibition? Searching for Individual and Age Differences in Inhibition Ability.

    Science.gov (United States)

    Rey-Mermet, Alodie; Gade, Miriam; Oberauer, Klaus

    2017-09-28

    Inhibition is often conceptualized as a unitary construct reflecting the ability to ignore and suppress irrelevant information. At the same time, it has been subdivided into inhibition of prepotent responses (i.e., the ability to stop dominant responses) and resistance to distracter interference (i.e., the ability to ignore distracting information). The present study investigated the unity and diversity of inhibition as a psychometric construct, and tested the hypothesis of an inhibition deficit in older age. We measured inhibition in young and old adults with 11 established laboratory tasks: antisaccade, stop-signal, color Stroop, number Stroop, arrow flanker, letter flanker, Simon, global-local, positive and negative compatibility tasks, and n-2 repetition costs in task switching. In both age groups, the inhibition measures from individual tasks had good reliabilities, but correlated only weakly among each other. Structural equation modeling identified a 2-factor model with factors for inhibition of prepotent responses and resistance to distracter interference. Older adults scored worse in the inhibition of prepotent response, but better in the resistance to distracter interference. However, the model had low explanatory power. Together, these findings call into question inhibition as a psychometric construct and the hypothesis of an inhibition deficit in older age. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  12. Nitric oxide synthases: structure, function and inhibition

    National Research Council Canada - National Science Library

    Alderton, W K; Cooper, C E; Knowles, R G

    2001-01-01

    This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family...

  13. Glycerol inhibition of ruminal lipolysis in vitro

    Science.gov (United States)

    Supplemental glycerol inhibits rumen lipolysis, a prerequisite for rumen biohydrogenation, which is responsible for the saturation of dietary fatty acids consumed by ruminant animals. Feeding excess glycerol, however, adversely affects dry matter digestibility. To more clearly define the effect of...

  14. Piperine, a dietary phytochemical, inhibits angiogenesis

    OpenAIRE

    Doucette, Carolyn D.; Hilchie, Ashley L.; Liwski, Robert; Hoskin, David W.

    2012-01-01

    Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G1/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induce...

  15. Aurantiogliocladin inhibits biofilm formation at subtoxic concentrations

    Directory of Open Access Journals (Sweden)

    Kamila Tomoko Yuyama

    2017-01-01

    Full Text Available Infections where pathogens are organized in biofilms are difficult to treat due to increased antibiotic resistances in biofilms. To overcome this limitation new approaches are needed to control biofilms. One way is to screen natural products from organisms living in a wet environment. The rational is that these organisms are preferentially threatened by biofilm formation and may have developed strategies to control pathogens in these biofilms. In a screen of fungal isolates obtained from the Harz mountains in Germany several strains have been found producing compounds for the inhibition of biofilms. One of these strains has been identified as Clonostachys candelabrumproducing aurantiogliocladin. Biological tests showed aurantiogliocladin as a weak antibiotic which was active against Staphylococcus epidermidisbut not S. aureus. Aurantiogliocladin could also inhibit biofilm formation of several of the tested bacterial strains. This inhibition, however, was never complete but biofilm inhibition activity was also found at concentrations below the minimal inhibitory concentrations, e. g. Bacillus cereuswith a MIC of 128 μg mL–1showed at 32 μg mL–1still 37% biofilm inhibition. In agreement with this finding was the observation that aurantiogliocladin was bacteriostatic for the tested bacteria but not bactericidal. Because several closely related toluquinones with different antibiotic activities have been reported from various fungi screening of a chemical library of toluquinones is suggested for the improvement of biofilm inhibition activities.

  16. Inhibition of COX isoforms by nutraceuticals.

    Science.gov (United States)

    Seaver, Ben; Smith, Jerry Robert

    2004-01-01

    Humans have two isoforms of Prostaglandin H Synthase or cyclooxygenase: COX-1 and COX-2. COX-1 is cytoprotective. COX-2 inhibitors reduce inflammation without the risk of ulceration and kidney damage. The ideal nutraceutical would inhibit COX-2 synthesis while preserving COX-1 synthesis. The hypothesis for this research was that COX inhibitors would fall primarily into three categories: COX-2 specific inhibition, non-specific inhibition (COX-1 and COX-2), and minimal inhibition. The human Cayman COX inhibitor screening assay was used to determine the inhibitory concentration 50 (IC50) of COX-1/ COX-2 activity of each nutraceutical. The assay was run, in duplicate, with three concentrations of a suspected inhibitor, a standard curve of eight concentrations, a non-specific binding sample, and a maximum binding sample. The inhibition and concentration of each sample was then put on a multiple regression best-fit line and the IC50 determined. For comparison, ibuprofen, rofecoxib, naproxen, and indomethacin were used. Positive results were seen for ipriflavone, resveratrol, MSV-60, amentoflavone, ruscus extract and notoginseng. Glucosamine, nexrutine, and berberine did not inhibit either isoform.

  17. Inhibition of Heme Peroxidases by Melamine

    Directory of Open Access Journals (Sweden)

    Pattaraporn Vanachayangkul

    2012-01-01

    Full Text Available In 2008 melamine-contaminated infant formula and dairy products in China led to over 50,000 hospitalizations of children due to renal injuries. In North America during 2007 and in Asia during 2004, melamine-contaminated pet food products resulted in numerous pet deaths due to renal failure. Animal studies have confirmed the potent renal toxicity of melamine combined with cyanuric acid. We showed previously that the solubility of melamine cyanurate is low at physiologic pH and ionic strength, provoking us to speculate how toxic levels of these compounds could be transported through the circulation without crystallizing until passing into the renal filtrate. We hypothesized that melamine might be sequestered by heme proteins, which could interfere with heme enzyme activity. Four heme peroxidase enzymes were selected for study: horseradish peroxidase (HRP, lactoperoxidase (LPO, and cyclooxygenase-1 and -2 (COX-1 and -2. Melamine exhibited noncompetitive inhibition of HRP (9.5±0.7mM, and LPO showed a mixed model of inhibition (14.5±4.7mM. The inhibition of HRP and LPO was confirmed using a chemiluminescent peroxidase assay. Melamine also exhibited COX-1 inhibition, but inhibition of COX-2 was not detected. Thus, our results demonstrate that melamine inhibits the activity of three heme peroxidases.

  18. Inhibition of 2-methoxyestradiol glucuronidation by probenecid.

    Science.gov (United States)

    Qian, Yuli; Sherbini, Ahmad; Matin, Bahar; Zhao, Yanli; Castellot, John; Greenblatt, David J

    2015-11-01

    2-Methoxyestradiol (2ME2), a metabolite of estradiol, has antitumour activity in vitro. However, potential clinical applicability has been limited by low oral bioavailability. Probenecid was evaluated in vitro as an inhibitor of 2ME2 glucuronidation for purposes of enhancing 2ME2 oral bioavailability. Human liver microsomes were used to determine kinetic parameters for transformation of 2ME2 to its glucuronide metabolites (M1, M2) and inhibition of the reactions by probenecid. M1 and M2 formation from 2ME2 proceeded with features of substrate inhibition. Probenecid inhibited metabolite formation, with mean inhibition constant (Ki ) values of 0.9 and 2.6 mM, respectively. Inhibition was reversible, with mixed competitive-non-competitive characteristics. The Ki values for probenecid inhibition of 2ME2 glucuronide formation, when compared to maximum probenecid plasma concentrations anticipated clinically, indicate that probenecid co-administration has the potential to augment systemic plasma levels of 2ME2 after oral dosage in humans. © 2015 Royal Pharmaceutical Society.

  19. Piperine, a dietary phytochemical, inhibits angiogenesis

    Science.gov (United States)

    Doucette, Carolyn D.; Hilchie, Ashley L.; Liwski, Robert; Hoskin, David W.

    2012-01-01

    Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G1/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induced angiogenic activity by rat aorta explants and breast cancer cell-induced angiogenesis in chick embryos. Although piperine binds to and activates the cation channel transient receptor potential vanilloid 1 (TRPV1), its effects on endothelial cells did not involve TRPV1 since the antiproliferative effect of piperine was not affected by TRPV1-selective antagonists, nor did HUVECs express detectable TRPV1 mRNA. Importantly, piperine inhibited phosphorylation of Ser 473 and Thr 308 residues of Akt (protein kinase B), which is a key regulator of endothelial cell function and angiogenesis. Consistent with Akt inhibition as the basis of piperine’s action on HUVECs, inhibition of the phosphoinositide-3 kinase/Akt signaling pathway with LY-294002 also inhibited HUVEC proliferation and collagen-induced angiogenesis. Taken together, these data support the further investigation of piperine as an angiogenesis inhibitor for use in cancer treatment. PMID:22902327

  20. Inhibition in the Human Auditory Cortex.

    Directory of Open Access Journals (Sweden)

    Koji Inui

    Full Text Available Despite their indispensable roles in sensory processing, little is known about inhibitory interneurons in humans. Inhibitory postsynaptic potentials cannot be recorded non-invasively, at least in a pure form, in humans. We herein sought to clarify whether prepulse inhibition (PPI in the auditory cortex reflected inhibition via interneurons using magnetoencephalography. An abrupt increase in sound pressure by 10 dB in a continuous sound was used to evoke the test response, and PPI was observed by inserting a weak (5 dB increase for 1 ms prepulse. The time course of the inhibition evaluated by prepulses presented at 10-800 ms before the test stimulus showed at least two temporally distinct inhibitions peaking at approximately 20-60 and 600 ms that presumably reflected IPSPs by fast spiking, parvalbumin-positive cells and somatostatin-positive, Martinotti cells, respectively. In another experiment, we confirmed that the degree of the inhibition depended on the strength of the prepulse, but not on the amplitude of the prepulse-evoked cortical response, indicating that the prepulse-evoked excitatory response and prepulse-evoked inhibition reflected activation in two different pathways. Although many diseases such as schizophrenia may involve deficits in the inhibitory system, we do not have appropriate methods to evaluate them; therefore, the easy and non-invasive method described herein may be clinically useful.

  1. CMP substitutions preferentially inhibit polysialic acid synthesis.

    Science.gov (United States)

    Miyazaki, Tatsuo; Angata, Kiyohiko; Seeberger, Peter H; Hindsgaul, Ole; Fukuda, Minoru

    2008-02-01

    It is widely reported that derivatives of sugar moieties can be used to metabolically label cell surface carbohydrates or inhibit a particular glycosylation. However, few studies address the effect of substitution of the cytidylmonophosphate (CMP) portion on sialyltransferase activities. Here we first synthesized 2'-O-methyl CMP and 5-methyl CMP and then asked if these CMP derivatives are recognized by alpha2,3-sialyltransferases (ST3Gal-III and ST3Gal-IV), alpha2,6-sialyltransferase (ST6Gal-I), and alpha2,8-sialyltransferase (ST8Sia-II, ST8Sia-III, and ST8Sia-IV). We found that ST3Gal-III and ST3Gal-IV but not ST6Gal-I was inhibited by 2'-O-methyl CMP as potently as by CMP, while ST3Gal-III, ST3Gal-IV, and ST6Gal-I were moderately inhibited by 5-methyl CMP. Previously, it was reported that polysialyltransferase ST8Sia-II but not ST8Sia-IV was inhibited by CMP N-butylneuraminic acid. We found that ST8Sia-IV as well as ST8Sia-II and ST8Sia-III are inhibited by 2'-O-methyl CMP as robustly as by CMP and moderately by 5-methyl CMP. Moreover, the addition of CMP, 2'-O-methyl CMP, and 5-methyl CMP to the culture medium resulted in the decrease of polysialic acid expression on the cell surface and NCAM of Chinese hamster ovary cells. These results suggest that 2'-O-methyl CMP and 5-methyl CMP can be used to preferentially inhibit sialyltransferases, in particular, polysialyltransferases in vitro and in vivo. Such inhibition may be useful to determine the function of a carbohydrate synthesized by a specific sialyltransferase such as polysialyltransferase.

  2. Characterization of acetylcholinesterase-inhibition by itopride.

    Science.gov (United States)

    Iwanaga, Y; Kimura, T; Miyashita, N; Morikawa, K; Nagata, O; Itoh, Z; Kondo, Y

    1994-11-01

    Itopride is a gastroprokinetic benzamide derivative. This agent inhibited both electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE). The IC50 of itopride with AChE (2.04 +/- 0.27 microM) was, however, 100-fold less than that with BuChE, whereas in the case of neostigmine with AChE (11.3 +/- 3.4 nM), it was 10-fold less. The recovery of AChE activity inhibited by 10(-7) M neostigmine was partial, but that inhibited by up to 3 x 10(-5) M itopride was complete when the reaction mixture was subjected to ultrafiltration. Double reciprocal plots of the experimental data showed that both Km and Vmax were affected by itopride, suggesting that the inhibition is a "mixed" type, although primarily being an uncompetitive one. The inhibitory effect of itopride on cholinesterase (ChE) activity in guinea pig gastrointestine was much weaker than that on pure AChE. However, in the presence of a low dose of diisopropyl fluorophosphate, just enough to inhibit BuChE but not AChE, the IC50s of itopride against ChE activities were found to be about 0.5 microM. In conclusion, itopride exerts reversible and a "mixed" type of inhibition preferably against AChE. The IC50 of itopride for electric eel and guinea pig gastrointestinal AChE inhibition was 200 times and 50 times as large as that of neostigmine, respectively.

  3. Chunking in task sequences modulates task inhibition.

    Science.gov (United States)

    Koch, Iring; Philipp, Andrea M; Gade, Miriam

    2006-04-01

    In a study of the formation of representations of task sequences and its influence on task inhibition, participants first performed tasks in a predictable sequence (e.g., ABACBC) and then performed the tasks in a random sequence. Half of the participants were explicitly instructed about the predictable sequence, whereas the other participants did not receive these instructions. Task-sequence learning was inferred from shorter reaction times (RTs) in predictable relative to random sequences. Persisting inhibition of competing tasks was indicated by increased RTs in n- 2 task repetitions (e.g., ABA) compared with n- 2 nonrepetitions (e.g., CBA). The results show task-sequence learning for both groups. However, task inhibition was reduced in predictable relative to random sequences among instructed-learning participants who formed an explicit representation of the task sequence, whereas sequence learning and task inhibition were independent in the noninstructed group. We hypothesize that the explicit instructions led to chunking of the task sequence, and that n- 2 repetitions served as chunk points (ABA-CBC), so that within-chunk facilitation modulated the inhibition effect.

  4. Collaborative inhibition in spatial memory retrieval.

    Science.gov (United States)

    Sjolund, Lori A; Erdman, Matthew; Kelly, Jonathan W

    2014-08-01

    Collaborative inhibition refers to the finding that pairs of people working together to retrieve information from memory-a collaborative group-often retrieve fewer unique items than do nominal pairs, who retrieve individually but whose performance is pooled. Two experiments were designed to explore whether collaborative inhibition, which has heretofore been studied using traditional memory stimuli such as word lists, also characterizes spatial memory retrieval. In the present study, participants learned a layout of objects and then reconstructed the layout from memory, either individually or in pairs. The layouts created by collaborative pairs were more accurate than those created by individuals, but less accurate than those of nominal pairs, providing evidence for collaborative inhibition in spatial memory retrieval. Collaborative inhibition occurred when participants were allowed to dictate the order of object placement during reconstruction (Exp. 1), and also when object order was imposed by the experimenter (Exp. 2), which was intended to disrupt the retrieval processes of pairs as well as of individuals. Individual tests of perspective taking indicated that the underlying representations of pair members were no different than those of individuals; in all cases, spatial memories were organized around a reference frame aligned with the studied perspective. These results suggest that inhibition is caused by the product of group recall (i.e., seeing a partner's object placement), not by the process of group recall (i.e., taking turns choosing an object to place). The present study has implications for how group performance on a collaborative spatial memory task may be optimized.

  5. ROCK inhibition activates MCF-7 cells.

    Directory of Open Access Journals (Sweden)

    Seungwon Yang

    Full Text Available Dormant carcinoma cancer cells showing epithelial characteristics can be activated to dissipate into the surrounding tissue or organs through epithelial-mesenchymal transition (EMT. However, the molecular details underlying the activation of dormant cancer cells have been less explored. In this study, we examined the molecular pathway to activate dormant breast cancer cells. Rho-associated kinase (ROCK inhibition disrupted cell junction, promoted cell proliferation and migration / invasion in both two-dimensional and three-dimensional substrates. The disintegration of cell junction upon ROCK inhibition, coupled with the loss of E-cadherin and b-catenin from the cell membrane, was associated with the activation of Rac1 upon ROCK inhibition. Migration / invasion also increased upon ROCK inhibition. However, the activation of MCF-7 cells upon ROCK inhibition was not associated with the up-regulation of typical EMT markers, such as snail and slug. Based on these results, we suggest the potential risk for dormant cancer cells to dissipate through non-typical EMT when ROCK activity is down-regulated.

  6. Inhibition of arylesterase by aliphatic alcohols.

    Science.gov (United States)

    Debord, J; Dantoine, T; Bollinger, J C; Abraham, M H; Verneuil, B; Merle, L

    1998-05-15

    The inhibition of arylesterase (EC 3.1.8.1) by 11 aliphatic alcohols (one to seven carbon atoms) was studied in blood serum from healthy donors. Inhibition curves were described by the Hill equation, with a Hill coefficient (n) close to unity, except for some alcohols, mainly the lowest. The inhibiting activity of the alcohols was highly dependent on their structure, since the C50 values covered about three orders of magnitude. The least active compound was methanol (C50 approximately 1 M) and the most active was heptanol (C50 approximately 7.4 x 10(-4) M). The A and B isozymes (differing by the amino acid at position 191) had similar inhibition parameters with the alcohols tested. Quantitative structure-activity relationships were computed with either the experimental solvation parameters of Abraham [6] or the theoretical parameters of Wilson and Famini [11]. Both methods gave similar results, with a slight advantage to the empirical parameters in terms of simplicity and statistical significance. The two main determinants of inhibition were identified as molecular volume and lack of polarity. The effect of volume was non-linear, tending to a maximum when the length of the alcohol increased. For a given number of carbon atoms, the best inhibitor was the least polar compound. These results point to a binding site consisting mainly of nonpolar aliphatic amino acids, and located in the depth of the protein molecule.

  7. The role of (dis)inhibition in creativity: decreased inhibition improves idea generation.

    Science.gov (United States)

    Radel, Rémi; Davranche, Karen; Fournier, Marion; Dietrich, Arne

    2015-01-01

    There is now a large body of evidence showing that many different conditions related to impaired fronto-executive functioning are associated with the enhancement of some types of creativity. In this paper, we pursue the possibility that the central mechanism associated with this effect might be a reduced capacity to exert inhibition. We tested this hypothesis by exhausting the inhibition efficiency through prolonged and intensive practice of either the Simon or the Eriksen Flanker task. Performance on another inhibition task indicated that only the cognitive resources for inhibition of participants facing high inhibition demands were impaired. Subsequent creativity tests revealed that exposure to high inhibition demands led to enhanced fluency in a divergent thinking task (Alternate Uses Task), but no such changes occurred in a convergent task (Remote Associate Task; studies 1a and 1b). The same manipulation also led to a hyper-priming effect for weakly related primes in a Lexical Decision Task (Study 2). Together, these findings suggest that inhibition selectively affects some types of creative processes and that, when resources for inhibition are lacking, the frequency and the originality of ideas was facilitated. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants.

    Science.gov (United States)

    Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

    2016-01-08

    Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity.

  9. Checkpoint kinase 1 inhibition sensitises transformed cells to dihydroorotate dehydrogenase inhibition

    OpenAIRE

    Arnould, Stéphanie; Rodier, Geneviève; Matar, Gisèle; Vincent, Charles; Pirot, Nelly; Delorme, Yoann; Berthet, Charlène; Buscail, Yoan; Noël, Jean Yohan; Lachambre, Simon; Jarlier, Marta; Bernex, Florence; Delpech, Hélène; Vidalain, Pierre Olivier; Janin, Yves L.

    2017-01-01

    Reduction in nucleotide pools through the inhibition of mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) has been demonstrated to effectively reduce cancer cell proliferation and tumour growth. The current study sought to investigate whether this antiproliferative effect could be enhanced by combining Chk1 kinase inhibition. The pharmacological activity of DHODH inhibitor teriflunomide was more selective towards transformed mouse embryonic fibroblasts than their primary or immortalis...

  10. Anticancer Alkaloid Lamellarins Inhibit Protein Kinases

    Directory of Open Access Journals (Sweden)

    Laurent Meijer

    2008-10-01

    Full Text Available Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, display promising anti-tumor activity. They induce apoptotic cell death through multi-target mechanisms, including inhibition of topoisomerase I, interaction with DNA and direct effects on mitochondria. We here report that lamellarins inhibit several protein kinases relevant to cancer such as cyclin-dependent kinases, dualspecificity tyrosine phosphorylation activated kinase 1A, casein kinase 1, glycogen synthase kinase-3 and PIM-1. A good correlation is observed between the effects of lamellarins on protein kinases and their action on cell death, suggesting that inhibition of specific kinases may contribute to the cytotoxicity of lamellarins. Structure/activity relationship suggests several paths for the optimization of lamellarins as kinase inhibitors.

  11. Mesoporous silica nanoparticles inhibit cellular respiration.

    Science.gov (United States)

    Tao, Zhimin; Morrow, Matthew P; Asefa, Tewodros; Sharma, Krishna K; Duncan, Cole; Anan, Abhishek; Penefsky, Harvey S; Goodisman, Jerry; Souid, Abdul-Kader

    2008-05-01

    We studied the effect of two types of mesoporous silica nanoparticles, MCM-41 and SBA-15, on mitochondrial O 2 consumption (respiration) in HL-60 (myeloid) cells, Jurkat (lymphoid) cells, and isolated mitochondria. SBA-15 inhibited cellular respiration at 25-500 microg/mL; the inhibition was concentration-dependent and time-dependent. The cellular ATP profile paralleled that of respiration. MCM-41 had no noticeable effect on respiration rate. In cells depleted of metabolic fuels, 50 microg/mL SBA-15 delayed the onset of glucose-supported respiration by 12 min and 200 microg/mL SBA-15 by 34 min; MCM-41 also delayed the onset of glucose-supported respiration. Neither SBA-15 nor MCM-41 affected cellular glutathione. Both nanoparticles inhibited respiration of isolated mitochondria and submitochondrial particles.

  12. Silver-Palladium Surfaces Inhibit Biofilm Formation

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Schroll, Casper; Hilbert, Lisbeth Rischel

    2009-01-01

    Undesired biofilm formation is a major concern in many areas. In the present study, we investigated biofilm-inhibiting properties of a silver-palladium surface that kills bacteria by generating microelectric fields and electrochemical redox processes. For evaluation of the biofilm inhibition...... efficacy and study of the biofilm inhibition mechanism, the silver-sensitive Escherichia coli J53 and the silver-resistant E. coli J53[pMG101] strains were used as model organisms, and batch and flow chamber setups were used as model systems. In the case of the silver-sensitive strain, the silver......-palladium surfaces killed the bacteria and prevented biofilm formation under conditions of low or high bacterial load. In the case of the silver-resistant strain, the silver-palladium surfaces killed surface-associated bacteria and prevented biofilm formation under conditions of low bacterial load, whereas under...

  13. The inhibition of monoamine oxidase by esomeprazole.

    Science.gov (United States)

    Petzer, A; Pienaar, A; Petzer, J P

    2013-09-01

    Virtual screening of a library of drugs has suggested that esomeprazole, the S-enantiomer of omeprazole, may possess binding affinities for the active sites of the monoamine oxidase (MAO) A and B enzymes. Based on this finding, the current study examines the MAO inhibitory properties of esomeprazole. Using recombinant human MAO-A and MAO-B, IC50 values for the inhibition of these enzymes by esomeprazole were experimentally determined. To examine the reversibility of MAO inhibition by esomeprazole, the recoveries of the enzymatic activities after dilution of the enzyme-inhibitor complexes were evaluated. In addition, reversibility of inhibition was also examined by measuring the recoveries of enzyme activities after dialysis of enzyme-inhibitor mixtures. Lineweaver-Burk plots were constructed to evaluate the mode of MAO inhibition and to measure Ki values. The results document that esomeprazole inhibits both MAO-A and MAO-B with IC50 values of 23 µM and 48 µM, respectively. The interactions of esomeprazole with MAO-A and MAO-B are reversible and most likely competitive with Ki values for the inhibition of the respective enzymes of 8.99 µM and 31.7 µM. Considering the available pharmacokinetic data and typical therapeutic doses of esomeprazole, these inhibitory potencies are unlikely to be of pharmacological relevance in humans. The MAO inhibitory effects of esomeprazole should however be taken into consideration when using this drug in animal experiments where higher doses are often administered. © Georg Thieme Verlag KG Stuttgart · New York.

  14. Nanostructured Block Copolymer Coatings for Biofouling Inhibition

    Science.gov (United States)

    2015-06-30

    Office of Naval Research 875 North Randolph St. Arlington, VA, 22203-1995 10. SPONSOR/MONITOR’S ACRONYM(S) ONR 11. SPONSOR/MONITOR’S REPORT NUMBER...we hoped. Inhibition, but not highly tunable by change of MW ratio The inhibition of diatoms by the diblocks was not significant (See figure 13). M...OH O a. £ o EC o a. in £ 0 Cu Figure 13 - The initial attachment density of the diatom Navicula on PS-b-PMMA coatings after gentle

  15. Inhibition of spinach bolting by growth regulators

    Directory of Open Access Journals (Sweden)

    Jan Borkowski

    2015-06-01

    Full Text Available Spinach (Spinacia oleracea L. plants must be harvested during a short period of time because they bolt just after producing some edible leaves. Maleic hydrazide (MH and its commercial preparation "Antyrost" were found to inhibit bolting very strongly. The preparation Off-shoot-O showed very weak activity in suppressing bolting but diminished markedly the resistance of spinach plants to fungus diseases. Triiodobenzoic acid stimulated bolting, and the retardant succinic acid-2-2-dimethylhydrazide (SADH did not affect bolting. Application of MH to inhibit spinach bolting cannot be recommended in practice before investigating the residues of this compound in leaves.

  16. Halenaquinone inhibits RANKL-induced osteoclastogenesis.

    Science.gov (United States)

    Tsukamoto, Sachiko; Takeuchi, Tomoharu; Kawabata, Tetsuro; Kato, Hikaru; Yamakuma, Michiko; Matsuo, Kanae; El-Desoky, Ahmed H; Losung, Fitje; Mangindaan, Remy E P; de Voogd, Nicole J; Arata, Yoichiro; Yokosawa, Hideyoshi

    2014-11-15

    Halenaquinone was isolated from the marine sponge Petrosia alfiani as an inhibitor of osteoclastogenic differentiation of murine RAW264 cells. It inhibited the RANKL (receptor activator of nuclear factor-κB ligand)-induced upregulation of TRAP (tartrate-resistant acid phosphatase) activity as well as the formation of multinuclear osteoclasts. In addition, halenaquinone substantially suppressed RANKL-induced IκB degradation and Akt phosphorylation. Thus, these results suggest that halenaquinone inhibits RANKL-induced osteoclastogenesis at least by suppressing the NF-κB and Akt signaling pathways. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

    DEFF Research Database (Denmark)

    Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine Marie Laure

    2011-01-01

    Background: Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine disrupting compounds (EDCs) share a high...... of endocrine disruption. Results: We found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis and it was correlated with a reduced testosterone production. The inhibition of PG synthesis occurs...

  18. Proton pump inhibitors inhibit pancreatic secretion

    DEFF Research Database (Denmark)

    Wang, Jing; Barbuskaite, Dagne; Tozzi, Marco

    2015-01-01

    +/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar...... localizations in duct cell monolayers (Capan-1) and human pancreas, and notably the gastric pumps are localized on the luminal membranes. In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis. Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations...

  19. Peptide inhibition of human cytomegalovirus infection

    Directory of Open Access Journals (Sweden)

    Morris Cindy A

    2011-02-01

    Full Text Available Abstract Background Human cytomegalovirus (HCMV is the most prevalent congenital viral infection in the United States and Europe causing significant morbidity and mortality to both mother and child. HCMV is also an opportunistic pathogen in immunocompromised individuals, including human immunodeficiency virus (HIV- infected patients with AIDS, and solid organ and allogeneic stem cell transplantation recipients. Current treatments for HCMV-associated diseases are insufficient due to the emergence of drug-induced resistance and cytotoxicity, necessitating novel approaches to limit HCMV infection. The aim of this study was to develop therapeutic peptides targeting glycoprotein B (gB, a major glycoprotein of HCMV that is highly conserved across the Herpesviridae family, that specifically inhibit fusion of the viral envelope with the host cell membrane preventing HCMV entry and infection. Results Using the Wimley-White Interfacial Hydrophobicity Scale (WWIHS, several regions within gB were identified that display a high potential to interact with lipid bilayers of cell membranes and hydrophobic surfaces within proteins. The ability of synthetic peptides analogous to WWIHS-positive sequences of HCMV gB to inhibit viral infectivity was evaluated. Human foreskin fibroblasts (HFF were infected with the Towne-GFP strain of HCMV (0.5 MOI, preincubated with peptides at a range of concentrations (78 nm to 100 μM, and GFP-positive cells were visualized 48 hours post-infection by fluorescence microscopy and analyzed quantitatively by flow cytometry. Peptides that inhibited HCMV infection demonstrated different inhibitory concentration curves indicating that each peptide possesses distinct biophysical properties. Peptide 174-200 showed 80% inhibition of viral infection at a concentration of 100 μM, and 51% and 62% inhibition at concentrations of 5 μM and 2.5 μM, respectively. Peptide 233-263 inhibited infection by 97% and 92% at concentrations of 100

  20. Investigation of antihemolytic, xanthine oxidase inhibition ...

    African Journals Online (AJOL)

    Material and methods: To investigate SVEs antihemolytic activity, the 2,2,-azobis (2-amidinopropane) dihydrochloride (AAPH) was used to induce erythrocyte oxidative hemolysis. In XO inhibition test, xanthine was used as substrate and cytochrome c for generating superoxide anions. The antioxidant activity of SVEs was ...

  1. Detection Of Haemagglutination–Inhibition Antibodies Against ...

    African Journals Online (AJOL)

    A survey of haemagglutination inhibition (HI) antibodies against influenza A virus was carried out on pigs sera collected at Bodija abattoir, Ibadan between December, 2001 and August 2002. Out of the 107 sera tested, 101 (94.39%) had HI antibodies to influenza A (H1N1) human strain while the remaining 6 (5.61%) were ...

  2. Nobiletin Inhibits Expression of Inflammatory Mediators and ...

    African Journals Online (AJOL)

    Multi-fold increases in the level of NO were seen. Moreover, increased levels of inflammatory cytokine,. Figure 2: Nobiletin inhibited IL-1β- induced apoptosis of ..... TNF-alpha stimulate. VEGF production by dedifferentiated chondrocytes. Osteoarthritis and. Cartilage 2004; 12: 683-691. 6. Sinkov V, Cymet T. Osteoarthritis: ...

  3. Challenges Inhibiting the Transformation of Subsistence Farming ...

    African Journals Online (AJOL)

    Challenges Inhibiting the Transformation of Subsistence Farming into Thriving Agri-business in Rural Uganda. ... Ghana Journal of Development Studies ... The aim of the study was to find out why there is a difficult transition from subsistence farming to a properly functioning agri-business in rural communities even when ...

  4. Inhibiting Translation One Protein at a Time.

    Science.gov (United States)

    Disney, Matthew D

    2017-06-01

    Historically, translational inhibitors have been confined to anti-bacterials that globally affect translation. Lintner et al. demonstrate that small molecules can specifically inhibit translation of a single disease-associated protein by stalling the ribosome's nascent chain [1], opening up a new therapeutic strategy for 'undruggable' proteins. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Inhibition of lipid peroxidation mediated by indolizines

    NARCIS (Netherlands)

    Nasir, AI; Gundersen, LL; Rise, F; Antonsen, O; Kristensen, T; Langhelle, B; Bast, A; Custers, [No Value; Haenen, GRMM; Wikstrom, H

    1998-01-01

    Esters, ethers, carbonates and carbamates of 1-indolizinols and azaindolizinols exhibit a profound inhibition of lipid peroxidation in vitro. The antioxidants were prepared by cyclization of pyridines and diazines with diphenylcyclopropenone followed by introduction of the O-substituent. (C) 1998

  6. An historic perspective of proteasome inhibition.

    Science.gov (United States)

    Esseltine, Dixie-Lee; Mulligan, George

    2012-07-01

    The ubiquitin-proteasome system (UPS) and associated signaling pathways are regarded today as an exciting area of development for novel therapeutics. However, two decades ago, following the discovery and elucidation of ubiquitin and the 26S proteasome as key mediators of protein turnover, the concept of inhibiting the UPS was not even considered a feasible therapeutic approach due to the assumption that inhibition of this pathway would have widespread deleterious effects. Subsequent clinical developments with the first-in-class proteasome inhibitor bortezomib have radically overturned that view, with the proteasome now recognized as a validated target and proteasome inhibition demonstrated to be a highly successful treatment for a number of hematologic malignancies. Here we provide a historic perspective on the emergence of proteasome inhibition, sharing some of the lessons learned along the way. We describe the development of bortezomib and the elucidation of the effects of its novel mechanism of action, and place the cutting-edge work described elsewhere in this issue in the context of these historic developments. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Probenazole treatment inhibits anthocyanins biosynthesis via ...

    African Journals Online (AJOL)

    It has been found that anthocyanins were accumulated in Arabidopsis under drought or salt stress. In this study, such accumulation was found to be inhibited by external applied probenazole (3-allyloxy-1, 2-benzisothiazole-1,1-dioxide, PBZ), which is the active ingredient in oryzemate used for the protection of rice from ...

  8. Product inhibition of five Hypocrea jecorina cellulases

    DEFF Research Database (Denmark)

    Murphy, Leigh; Westh, Peter; Bohlin, Christina

    2013-01-01

    Product inhibition of cellulolytic enzymes has been deemed a critical factor in the industrial saccharification of cellulosic biomass. Several investigations have addressed this problem using crude enzyme preparations or commercial (mixed) cellulase products, but quantitative information on indiv......Product inhibition of cellulolytic enzymes has been deemed a critical factor in the industrial saccharification of cellulosic biomass. Several investigations have addressed this problem using crude enzyme preparations or commercial (mixed) cellulase products, but quantitative information...... cellulose may be monitored by calorimetry. The key advantage of this approach is that it directly measures the rate of hydrolysis while being essentially blind to the background of added product. We investigated the five major cellulases from Hypocrea jecorina (anamorph: Tricoderma reesei), Cel7A (formerly...... CBH1), Cel6A (CBH2), Cel7B (EG1), Cel5A (EG2) and Cel12A (EG3), for their sensitivity to the products glucose and cellobiose. The strongest inhibition was found for Cel7A, which showed a 50% activity-loss in 19 mM cellobiose (IC50 = 19 mM). The other exoglucanase, Cel6A, was much less inhibited...

  9. Inhibiting Intuitive Thinking in Mathematics Education

    Science.gov (United States)

    Thomas, Michael O. J.

    2015-01-01

    The papers in this issue describe recent collaborative research into the role of inhibition of intuitive thinking in mathematics education. This commentary reflects on this research from a mathematics education perspective and draws attention to some of the challenges that arise in collaboration between research fields with different cultures,…

  10. Targeted inhibition of cancer-inflammation

    NARCIS (Netherlands)

    Gomes Coimbra, M.J.

    2012-01-01

    The new paradigm in cancer treatment that aims to inhibit the smoldering inflammatory response in tumors is explored to develop new anticancer treatments. It appears that targeted drug delivery is essential in this concept as high local levels of anti-inflammatory agents are needed to observe the

  11. Osthole inhibits bone metastasis of breast cancer.

    Science.gov (United States)

    Wu, Chunyu; Sun, Zhenping; Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

    2017-08-29

    Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potential mechanism of this inhibition. In the murine model of breast cancer osseous metastasis, mice that received osthole developed significantly less bone metastases and displayed decreased tumor burden when compared with mice in the control group. Osthole inhibited breast cancer cell growth, migration, and invasion, and induced apoptosis of breast cancer cells. Additionally, it also regulated OPG/RANKL signals in the interactions between bone cells (osteoblasts and osteoclasts) and cancer cells. Besides, it also inhibited TGF-β/Smads signaling in breast cancer metastasis to bone in MDA-231BO cells. The results of this study suggest that osthole has real potential as a therapeutic candidate in the treatment of breast cancer patients with bone metastases.

  12. Linking algal growth inhibition to chemical activity

    DEFF Research Database (Denmark)

    Schmidt, Stine N.; Mayer, Philipp

    2015-01-01

    Recently, high-quality data were published on the algal growth inhibition caused by 50 non-polar narcotic compounds, of which 39 were liquid compounds with defined water solubility. In the present study, the toxicity data for these liquids were applied to challenge the chemical activity range...

  13. Cortisol inhibits apoptosis in carp neutrophilic granulocytes.

    NARCIS (Netherlands)

    Weyts, F.A.A.; Flik, G.; Verburg-van Kemenade, B.M.L.

    1998-01-01

    The direct effect of cortisol treatment on carp neutrophil viability was examined in vitro. Cortisol treatment caused an inhibition of neutrophil apoptosis. The effect was blocked by glucocorticoid receptor blocker RU486, showing that rescue from apoptosis was receptor mediated. Using binding

  14. Temporal Preparation, Response Inhibition and Impulsivity

    Science.gov (United States)

    Correa, Angel; Trivino, Monica; Perez-Duenas, Carolina; Acosta, Alberto; Lupianez, Juan

    2010-01-01

    Temporal preparation and impulsivity involve overlapping neural structures (prefrontal cortex) and cognitive functions (response inhibition and time perception), however, their interrelations had not been investigated. We studied such interrelations by comparing the performance of groups with low vs. high non-clinical trait impulsivity during a…

  15. Hemagglutinin inhibition assay with swine sera

    Science.gov (United States)

    Hemagglutination is based on the ability of certain viruses to agglutinate red blood cells (RBC) of certain animal species by formation of cross-linking lattices between RBC. Antibodies that have the ability to inhibit the hemagglutination property of influenza A viruses are generally thought to pro...

  16. Inhibition of Corneal Neovascularization by Hydrazinocurcumin

    African Journals Online (AJOL)

    This article previously published in Volume 15 Issue 2 of this journal in February 2016 has been retracted in line with the guidelines from the Committee on Publication Ethics (COPE, http://publicationethics.org/resources/guidelines). Retracted: Zhan W, Zhu J, Zhang Y. Inhibition of corneal neovascularization by ...

  17. Retracted: Inhibition of Corneal Neovascularization by ...

    African Journals Online (AJOL)

    This article previously published in Volume 15 Issue 2 of this journal in February 2016 has been retracted in line with the guidelines from the Committee on Publication Ethics (COPE, http://publicationethics.org/resources/guidelines). Retracted: Zhan W, Zhu J, Zhang Y. Inhibition of corneal neovascularization by ...

  18. The Mechanism Underlying Inhibition of Saccadic Return

    Science.gov (United States)

    Ludwig, Casimir J. H.; Farrell, Simon; Ellis, Lucy A.; Gilchrist, Iain D.

    2009-01-01

    Human observers take longer to re-direct gaze to a previously fixated location. Although there has been some exploration of the characteristics of inhibition of saccadic return (ISR), the exact mechanisms by which ISR operates are currently unknown. In the framework of accumulation models of response times, in which evidence is integrated over…

  19. Product inhibition in native-state proteolysis.

    Directory of Open Access Journals (Sweden)

    Joseph R Kasper

    Full Text Available The proteolysis kinetics of intact proteins by nonspecific proteases provides valuable information on transient partial unfolding of proteins under native conditions. Native-state proteolysis is an approach to utilize the proteolysis kinetics to assess the energetics of partial unfolding in a quantitative manner. In native-state proteolysis, folded proteins are incubated with nonspecific proteases, and the rate of proteolysis is determined from the disappearance of the intact protein. We report here that proteolysis of intact proteins by nonspecific proteases, thermolysin and subtilisin deviates from first-order kinetics. First-order kinetics has been assumed for the analysis of native-state proteolysis. By analyzing the kinetics of proteolysis with varying concentrations of substrate proteins and also with cleavage products, we found that the deviation from first-order kinetics results from product inhibition. A kinetic model including competitive product inhibition agrees well with the proteolysis time course and allows us to determine the uninhibited rate constant for proteolysis as well as the apparent inhibition constant. Our finding suggests that the likelihood of product inhibition must be considered for quantitative assessment of proteolysis kinetics.

  20. Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation.

    Science.gov (United States)

    Capozzi, Megan E; Hammer, Sandra S; McCollum, Gary W; Penn, John S

    2016-12-14

    The objective of the present study was to assess the effect of elevating epoxygenated fatty acids on retinal vascular inflammation. To stimulate inflammation we utilized TNFα, a potent pro-inflammatory mediator that is elevated in the serum and vitreous of diabetic patients. In TNFα-stimulated primary human retinal microvascular endothelial cells, total levels of epoxyeicosatrienoic acids (EETs), but not epoxydocosapentaenoic acids (EDPs), were significantly decreased. Exogenous addition of 11,12-EET or 19,20-EDP when combined with 12-(3-adamantane-1-yl-ureido)-dodecanoic acid (AUDA), an inhibitor of epoxide hydrolysis, inhibited VCAM-1 and ICAM-1 expression and protein levels; conversely the diol product of 19,20-EDP hydrolysis, 19,20-DHDP, induced VCAM1 and ICAM1 expression. 11,12-EET and 19,20-EDP also inhibited leukocyte adherence to human retinal microvascular endothelial cell monolayers and leukostasis in an acute mouse model of retinal inflammation. Our results indicate that this inhibition may be mediated through an indirect effect on NFκB activation. This is the first study demonstrating a direct comparison of EET and EDP on vascular inflammatory endpoints, and we have confirmed a comparable efficacy from each isomer, suggesting a similar mechanism of action. Taken together, these data establish that epoxygenated fatty acid elevation will inhibit early pathology related to TNFα-induced inflammation in retinal vascular diseases.

  1. Illustrating Enzyme Inhibition Using Gibbs Energy Profiles

    Science.gov (United States)

    Bearne, Stephen L.

    2012-01-01

    Gibbs energy profiles have great utility as teaching and learning tools because they present students with a visual representation of the energy changes that occur during enzyme catalysis. Unfortunately, most textbooks divorce discussions of traditional kinetic topics, such as enzyme inhibition, from discussions of these same topics in terms of…

  2. Sultam Thiourea Inhibition of West Nile Virus▿

    Science.gov (United States)

    Barklis, Eric; Still, Amelia; Sabri, Mohammad I.; Hirsch, Alec J.; Nikolich-Zugich, Janko; Brien, James; Dhenub, Tenzin Choesang; Scholz, Isabel; Alfadhli, Ayna

    2007-01-01

    We have identified sultam thioureas as novel inhibitors of West Nile virus (WNV) replication. One such compound inhibited WNV, with a 50% effective concentration of 0.7 μM, and reduced reporter expression from cells that harbored a WNV-based replicon. Our results demonstrate that sultam thioureas can block a postentry, preassembly step of WNV replication. PMID:17452483

  3. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A. [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States); Yap, Sook Fan [Faculty of Medicine and Health Sciences, Department of Pre-Clinical Sciences, University of Tunku Abdul Rahman (Malaysia); Ngeow, Yun Fong [Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603 (Malaysia); Chin, Khew-Voon, E-mail: khew-voon.chin@utoledo.edu [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States)

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer Salinomycin inhibits preadipocyte differentiation into adipocytes. Black-Right-Pointing-Pointer Salinomycin inhibits transcriptional regulation of adipogenesis. Black-Right-Pointing-Pointer Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor {gamma}. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  4. Gold Nanoparticles Inhibit Matrix Metalloproteases without Cytotoxicity.

    Science.gov (United States)

    Hashimoto, M; Sasaki, J I; Yamaguchi, S; Kawai, K; Kawakami, H; Iwasaki, Y; Imazato, S

    2015-08-01

    Nanoparticles (NPs) are currently the focus of considerable attention for dental applications; however, their biological effects have not been fully elucidated. The long-term, slow release of matrix metalloproteases (MMPs) digests collagen fibrils within resin-dentin bonds. Therefore, MMP inhibitors can prolong the durability of resin-dentin bonds. However, there have been few reports evaluating the combined effect of MMP inhibition and the cytotoxic effects of NPs for dentin bonding. The aim of this study was to evaluate MMP inhibition and cytotoxic responses to gold (AuNPs) and platinum nanoparticles (PtNPs) stabilized by polyvinylpyrrolidone (PVP) in cultured murine macrophages (RAW264) by using MMP inhibition assays, measuring cell viability and inflammatory responses (quantitative reverse transcription polymerase chain reaction [RT-qPCR]), and conducting a micromorphological analysis by fluorescence and transmission electron microscopy. Cultured RAW264 cells were exposed to metal NPs at various concentrations (1, 10, 100, and 400 µg/mL). AuNPs and PtNPs markedly inhibited MMP-8 and MMP-9 activity. Although PtNPs were cytotoxic at high concentrations (100 and 400 µg/mL), no cytotoxic effects were observed for AuNPs at any concentration. Transmission electron microscopy images showed a significant nonrandom intercellular distribution for AuNPs and PtNPs, which were mostly observed to be localized in lysosomes but not in the nucleus. RT-qPCR analysis demonstrated inflammatory responses were not induced in RAW264 cells by AuNPs or PtNPs. The cytotoxicity of nanoparticles might depend on the core metal composition and arise from a "Trojan horse" effect; thus, MMP inhibition could be attributed to the surface charge of PVP, which forms the outer coating of NPs. The negative charge of the surface coating of PVP binds to Zn(2+) from the active center of MMPs by chelate binding and results in MMP inhibition. In summary, AuNPs are attractive NPs that effectively

  5. Polysulfonate suramin inhibits Zika virus infection.

    Science.gov (United States)

    Tan, Chee Wah; Sam, I-Ching; Chong, Wei Lim; Lee, Vannajan Sanghiran; Chan, Yoke Fun

    2017-07-01

    Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition. Suramin, an FDA-approved anti-parasitic drug, inhibits ZIKV infection with 3-5 log 10  PFU viral reduction with IC 50 value of ∼2.5-5 μg/ml (1.93 μM-3.85 μM). A time-of-drug-addition study revealed that suramin remains potent even when administrated at 1-24 hpi. Suramin inhibits ZIKV infection by preventing viral adsorption, entry and replication. Molecular dynamics simulation revealed stronger interaction of suramin with ZIKV NS3 helicase than with the envelope protein. Suramin warrants further investigation as a potential antiviral candidate for ZIKV infection. Heparan sulfate (HS) is a cellular attachment receptor for multiple flaviviruses. However, no direct ZIKV-heparin interaction was observed in heparin-binding analysis, and downregulate or removal of cellular HS with sodium chlorate or heparinase I/III did not inhibit ZIKV infection. This indicates that cell surface HS is not utilized by ZIKV as an attachment receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Neural synchrony during response production and inhibition.

    Directory of Open Access Journals (Sweden)

    Viktor Müller

    Full Text Available Inhibition of irrelevant information (conflict monitoring and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300-600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations.

  7. Mullerian Inhibiting Substances (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

    National Research Council Canada - National Science Library

    Gupta, Vandana

    2006-01-01

    MIS is a member of the TGF family. The purpose of this study is to test the hypothesis that MIS and IFN-gamma might be more effective in the inhibition of breast cancer cell growth than either agent alone...

  8. Structural requirements of alloxan and ninhydrin for glucokinase inhibition and of glucose for protection against inhibition.

    Science.gov (United States)

    Lenzen, S.; Brand, F. H.; Panten, U.

    1988-01-01

    1. In order to elucidate the mechanism underlying the interactions between glucose and alloxan when competing for the sugar binding site of glucokinase from pancreatic B-cells or liver, the structural requirements of the enzyme for inhibition by alloxan and for protection by glucose were determined. 2. With a half-maximal inhibitory concentration of 5 microM, alloxan was the most potent pyrimidine derivative inhibitor of glucokinase. Uramil was a less potent enzyme inhibitor. A variety of other pyrimidine derivatives and related substances were ineffective. 3. Ninhydrin also inhibited glucokinase with a half-maximal inhibitory concentration of 5 microM. Isatin was a slightly less potent enzyme inhibitor. Several other indoline derivatives were ineffective. 4. Only glucose derivatives with a sufficiently bulky substituent in position C-2, such as the glucokinase substrates glucose and mannose and the inhibitors mannoheptulose, glucosamine, and N-acetylglucosamine, protected glucokinase against inhibition by alloxan by binding to the active site of the enzyme. Glucose epimers which differed in other positions did not protect the enzyme against alloxan inhibition. 5. DTT (dithiothreitol) protected glucokinase against inhibition by alloxan and reversed the inhibition of the enzyme induced by alloxan. Thus the mechanism of glucokinase inhibition by alloxan and other inhibitors, such as uramil and ninhydrin, is an oxidation of functionally essential SH groups of the enzyme, where the most reactive keto group of the inhibitor acts as the hydrogen acceptor. The protective action of glucose and several C-2 epimers demonstrates that these functionally essential SH groups are situated in the sugar binding site of the glucokinase. 6. The present results support our contention, that the pancreatic B-cell glucokinase is the major target mediating the inhibition of insulin secretion by alloxan. PMID:3207996

  9. Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells.

    Science.gov (United States)

    Rangarajan, Parthasarathy; Subramaniam, Dharmalingam; Paul, Santanu; Kwatra, Deep; Palaniyandi, Kanagaraj; Islam, Shamima; Harihar, Sitaram; Ramalingam, Satish; Gutheil, William; Putty, Sandeep; Pradhan, Rohan; Padhye, Subhash; Welch, Danny R; Anant, Shrikant; Dhar, Animesh

    2015-09-29

    Pancreatic cancer is the fourth leading cause of cancer deaths in the US and no significant treatment is currently available. Here, we describe the effect of crocetinic acid, which we purified from commercial saffron compound crocetin using high performance liquid chromatography. Crocetinic acid inhibits proliferation of pancreatic cancer cell lines in a dose- and time-dependent manner. In addition, it induced apoptosis. Moreover, the compound significantly inhibited epidermal growth factor receptor and Akt phosphorylation. Furthermore, crocetinic acid decreased the number and size of the pancospheres in a dose-dependent manner, and suppressed the expression of the marker protein DCLK-1 (Doublecortin Calcium/Calmodulin-Dependent Kinase-1) suggesting that crocetinic acid targets cancer stem cells (CSC). To understand the mechanism of CSC inhibition, the signaling pathways affected by purified crocetinic acid were dissected. Sonic hedgehog (Shh) upon binding to its cognate receptor patched, allows smoothened to accumulate and activate Gli transcription factor. Crocetinic acid inhibited the expression of both Shh and smoothened. Finally, these data were confirmed in vivo where the compound at a dose of 0.5 mg/Kg bw suppressed growth of tumor xenografts. Collectively, these data suggest that purified crocetinic acid inhibits pancreatic CSC, thereby inhibiting pancreatic tumorigenesis.

  10. Measurement and Reliability of Response Inhibition

    Directory of Open Access Journals (Sweden)

    Eliza eCongdon

    2012-02-01

    Full Text Available Response inhibition plays a critical role in adaptive functioning and can be assessed with the Stop-signal task, which requires participants to suppress prepotent motor responses. Evidence suggests that this ability to inhibit a motor response that has already been initiated (reflected as Stop-signal reaction time (SSRT is a quantitative and heritable measure of interindividual variation in brain function. In order to examine the reliability of this measure, we pooled data across three separate studies and examined the influence of multiple SSRT calculation methods and outlier calling on reliability (using Intra-class correlation. Our results suggest that an approach which uses the average of all available sessions, all trials of each session, and excludes outliers based on predetermined lenient criteria yields reliable SSRT estimates, while not excluding too many participants. Our findings support the reliability of SSRT as an index of inhibitory control, and provide support for its continued use as a neurocognitive phenotype.

  11. Direct renin inhibition in chronic kidney disease

    DEFF Research Database (Denmark)

    Persson, Frederik; Rossing, Peter; Parving, Hans-Henrik

    2013-01-01

    that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need...... early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic...... kidney disease by reporting of the studies published so far as well as perspective on the future possibilites....

  12. Transcriptional inhibition by the retinoblastoma protein

    DEFF Research Database (Denmark)

    Fattaey, A; Helin, K; Harlow, E

    1993-01-01

    The retinoblastoma protein, pRB, appears to play a key role in coordinating the regulation of cell cycle position and transcriptional events. pRB undergoes specific cell-cycle-dependent phosphorylation, being underphosphorylated in G1 and heavily phosphorylated in S, G2, and M....... The underphosphorylated form is able to interact with the E2F transcription factor. Recently, we have cloned a cDNA for E2F-1. By using this clone and a series of non-pRB binding mutants, we have been able to show that the binding of pRB to E2F-1 causes inhibition of E2F-mediated transactivation. pRB's inhibition of E2F......-mediated transcription would be lost by mutation in the retinoblastoma gene in human tumours, by pRB's interaction with DNA tumour virus oncoproteins, or by phosphorylation during the cell cycle....

  13. The Kinetics of Carrier Transport Inhibition

    DEFF Research Database (Denmark)

    Rosenberg, T.; Wilbrandt, Robert Walter

    1962-01-01

    The kinetical treatment of enzymatic carrier transports as given in previous communications has been extended to conditions of inhibition. Various possible types of inhibitors have been considered differing in the site of attack (enzyme or carrier), in the mode of action (competing...... and polyphloretinephosphate. The results of the analysis for these inhibitors indicate a substrate competitive mode of action. The effect of reversing the transport direction by interchanging the substrate concentration has been treated for the case of a non-penetrating substrate competitive inhibitor in the external medium...... with the substrate for the enzyme or the carrier or for both, competing with the carrier for the enzyme, or non-competitive) and in the ability of penetrating the membrane. Experiments are reported on the inhibition of glucose and fructose transport across the human red cell membrane by phlorizine, phloretine...

  14. Progressive inhibition of neuromuscular structures (PINS) technique.

    Science.gov (United States)

    Dowling, D J

    2000-05-01

    Progressive inhibition of neuromuscular structures (PINS) is a technique that can be included in the osteopathic manipulative treatment repertoire. It relies on knowledge of anatomy and neuromuscular physiologic features as well as on standard forms of osteopathic palpatory diagnosis and treatment. It is a variant of the inhibition technique that has been taught as an osteopathic manipulative technique for many years, and it bears some resemblance to other manual medicine techniques. The emphasis of the approach is the determination of the alteration of the tissues due to dysfunction, delivering treatment based on palpatory evaluation and patient feedback. Two related points are initially chosen, followed by a progression from one to the other. Relationships to similar techniques are also discussed. Theoretical as well as selected practical applications are presented.

  15. Structural analysis of kasugamycin inhibition of translation.

    Science.gov (United States)

    Schuwirth, Barbara S; Day, J Michael; Hau, Cathy W; Janssen, Gary R; Dahlberg, Albert E; Cate, Jamie H Doudna; Vila-Sanjurjo, Antón

    2006-10-01

    The prokaryotic ribosome is an important target of antibiotic action. We determined the X-ray structure of the aminoglycoside kasugamycin (Ksg) in complex with the Escherichia coli 70S ribosome at 3.5-A resolution. The structure reveals that the drug binds within the messenger RNA channel of the 30S subunit between the universally conserved G926 and A794 nucleotides in 16S ribosomal RNA, which are sites of Ksg resistance. To our surprise, Ksg resistance mutations do not inhibit binding of the drug to the ribosome. The present structural and biochemical results indicate that inhibition by Ksg and Ksg resistance are closely linked to the structure of the mRNA at the junction of the peptidyl-tRNA and exit-tRNA sites (P and E sites).

  16. Theobromine inhibits sensory nerve activation and cough.

    Science.gov (United States)

    Usmani, Omar S; Belvisi, Maria G; Patel, Hema J; Crispino, Natascia; Birrell, Mark A; Korbonits, Márta; Korbonits, Dezso; Barnes, Peter J

    2005-02-01

    Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

  17. Inhibition of Plasmodium Liver Infection by Ivermectin.

    Science.gov (United States)

    Mendes, António M; Albuquerque, Inês S; Machado, Marta; Pissarra, Joana; Meireles, Patrícia; Prudêncio, Miguel

    2017-02-01

    Avermectins are powerful endectocides with an established potential to reduce the incidence of vector-borne diseases. Here, we show that several avermectins inhibit the hepatic stage of Plasmodium infection in vitro Notably, ivermectin potently inhibits liver infection in vivo by impairing parasite development inside hepatocytes. This impairment has a clear impact on the ensuing blood stage parasitemia, reducing disease severity and enhancing host survival. Ivermectin has been proposed as a tool to control malaria transmission because of its effects on the mosquito vector. Our study extends the effect of ivermectin to the early stages of mammalian host infection and supports the inclusion of this multipurpose drug in malaria control strategies. Copyright © 2017 Mendes et al.

  18. [Inhibition of cytochrome b2 by acrylamide].

    Science.gov (United States)

    Kulis, Iu Iu; Shvirmitskas, G Iu; Antanavichius, V S; Vaitkiavichius, R K

    1982-04-01

    Acrylamide (0.4--0.9 M) irreversibly inhibits reduced (Ered) cytochrome b2 (L (+) -lactate: cytochrome c oxidoreductase) from the yeast Hansenula anomala (ki = 1,67 min-1 at 35 degrees in 0.73 M solution of acrylamide). Changes in fluorescence of FMN, which reflect the changes in protein structure occur symbatically to the inactivation. The rate of inactivation depends on concentration of acrylamide in a degree of 6.4. The inactivation of the oxidized enzyme occurs faster than that of th reduced one at concentrations less than 0.5 M. The inactivation of Ered by acrylonitrile and acrylic acid occurs 10 times slower and does not correlate with the rate of mercaptoethanol binding to the monomers. The inhibition of Ered is caused by specific effects of carylamide and modification of the enzyme active center.

  19. Caffeine Inhibits Acetylcholinesterase, But Not Butyrylcholinesterase

    Directory of Open Access Journals (Sweden)

    Petr Dobes

    2013-05-01

    Full Text Available Caffeine is an alkaloid with a stimulant effect in the body. It can interfere in transmissions based on acetylcholine, epinephrine, norepinephrine, serotonin, dopamine and glutamate. Clinical studies indicate that it can be involved in the slowing of Alzheimer disease pathology and some other effects. The effects are not well understood. In the present work, we focused on the question whether caffeine can inhibit acetylcholinesterase (AChE and/or, butyrylcholinesterase (BChE, the two enzymes participating in cholinergic neurotransmission. A standard Ellman test with human AChE and BChE was done for altering concentrations of caffeine. The test was supported by an in silico examination as well. Donepezil and tacrine were used as standards. In compliance with Dixon’s plot, caffeine was proved to be a non-competitive inhibitor of AChE and BChE. However, inhibition of BChE was quite weak, as the inhibition constant, Ki, was 13.9 ± 7.4 mol/L. Inhibition of AChE was more relevant, as Ki was found to be 175 ± 9 µmol/L. The predicted free energy of binding was −6.7 kcal/mol. The proposed binding orientation of caffeine can interact with Trp86, and it can be stabilize by Tyr337 in comparison to the smaller Ala328 in the case of human BChE; thus, it can explain the lower binding affinity of caffeine for BChE with reference to AChE. The biological relevance of the findings is discussed.

  20. Osthole inhibits bone metastasis of breast cancer

    OpenAIRE

    Wu, Chunyu; Sun, Zhenping; Guo, Baofeng; Ye, Yiyi; Han, Xianghui; Qin, Yuenong; Liu, Sheng

    2017-01-01

    Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potent...

  1. Voriconazole Inhibits Melanization in Cryptococcus neoformans▿

    OpenAIRE

    Martinez, Luis R.; Ntiamoah, Patricia; Gácser, Attila; Casadevall, Arturo; Nosanchuk, Joshua D.

    2007-01-01

    Voriconazole is a triazole antifungal drug that inhibits ergosterol synthesis and has broad activity against yeast and molds. While studying the interaction of voriconazole and Cryptococcus neoformans, we noted that cells grown in the presence of subinhibitory concentrations of voriconazole reduced melanin pigmentation. We investigated this effect systematically by assessing melanin production in the presence of voriconazole, amphotericin B, caspofungin, itraconazole, and fluconazole. Only vo...

  2. Fermentation of lignocellulosic hydrolysates: Inhibition and detoxification

    Energy Technology Data Exchange (ETDEWEB)

    Palmqvist, E.

    1998-02-01

    The ethanol yield and productivity obtained during fermentation of lignocellulosic hydrolysates is decreased due to the presence of inhibiting compounds, such as weak acids, furans and phenolic compounds produced during hydrolysis. Evaluation of the effect of various biological, physical and chemical detoxification treatments by fermentation assays using Saccharomyces cerevisiae was used to characterise inhibitors. Inhibition of fermentation was decreased after removal of the non-volatile compounds, pre-fermentation by the filamentous fungus Trichoderma reesei, treatment with the lignolytic enzyme laccase, extraction with ether, and treatment with alkali. Yeast growth in lignocellulosic hydrolysates was inhibited below a certain fermentation pH, most likely due to high concentrations of undissociated weak acids. The effect of individual compounds were studied in model fermentations. Furfural is reduced to furfuryl alcohol by yeast dehydrogenases, thereby affecting the intracellular redox balance. As a result, acetaldehyde accumulated during furfural reduction, which most likely contributed to inhibition of growth. Acetic acid (10 g 1{sup -1}) and furfural (3 g 1{sup -1}) interacted antagonistically causing decreased specific growth rate, whereas no significant individual or interaction effects were detected by the lignin-derived compound 4-hydroxybenzoic acid (2 g 1{sup -1}). By maintaining a high cell mass density in the fermentor, the process was less sensitive to inhibitors affecting growth and to fluctuations in fermentation pH, and in addition the depletion rate of bioconvertible inhibitors was increased. A theoretical ethanol yield and high productivity was obtained in continuous fermentation of spruce hydrolysate when the cell mass concentration was maintained at a high level by applying cell recirculation 164 refs, 16 figs, 5 tabs

  3. Evidence of dopaminergic processing of executive inhibition.

    Directory of Open Access Journals (Sweden)

    Rajendra D Badgaiyan

    Full Text Available Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand ((11C-raclopride after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging.

  4. Physiological functions of glucose-inhibited neurones.

    Science.gov (United States)

    Burdakov, D; González, J A

    2009-01-01

    Glucose-inhibited neurones are an integral part of neurocircuits regulating cognitive arousal, body weight and vital adaptive behaviours. Their firing is directly suppressed by extracellular glucose through poorly understood signalling cascades culminating in opening of post-synaptic K(+) or possibly Cl(-) channels. In mammalian brains, two groups of glucose-inhibited neurones are best understood at present: neurones of the hypothalamic arcuate nucleus (ARC) that express peptide transmitters NPY and agouti-related peptide (AgRP) and neurones of the lateral hypothalamus (LH) that express peptide transmitters orexins/hypocretins. The activity of ARC NPY/AgRP neurones promotes food intake and suppresses energy expenditure, and their destruction causes a severe reduction in food intake and body weight. The physiological actions of ARC NPY/AgRP cells are mediated by projections to numerous hypothalamic areas, as well as extrahypothalamic sites such as the thalamus and ventral tegmental area. Orexin/hypocretin neurones of the LH are critical for normal wakefulness, energy expenditure and reward-seeking, and their destruction causes narcolepsy. Orexin actions are mediated by highly widespread central projections to virtually all brain areas except the cerebellum, including monosynaptic innervation of the cerebral cortex and autonomic pre-ganglionic neurones. There, orexins act on two specific G-protein-coupled receptors generally linked to neuronal excitation. In addition to sensing physiological changes in sugar levels, the firing of both NPY/AgRP and orexin neurones is inhibited by the 'satiety' hormone leptin and stimulated by the 'hunger' hormone ghrelin. Glucose-inhibited neurones are thus well placed to coordinate diverse brain states and behaviours based on energy levels.

  5. VAGUS NERVE STIMULATION INHIBITS CORTICAL SPREADING DEPRESSION

    OpenAIRE

    Chen, Shih-Pin; Ay, Ilknur; de Morais, Andreia Lopes; Qin, Tao; Zheng,Yi; Sadhegian, Homa; Oka, Fumiaki; Simon, Bruce; Eikermann-Haerter, Katharina; Ayata, Cenk

    2016-01-01

    Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura, and a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its anti-migraine effect. Vagus nerve stimulation was delivered either non-invasively through the skin or directly by electrodes placed around the vagus nerve unilaterally. Systemic physiology was monito...

  6. The system neurophysiological basis of backward inhibition.

    Science.gov (United States)

    Zhang, Rui; Stock, Ann-Kathrin; Fischer, Rico; Beste, Christian

    2016-12-01

    Task switching is regularly required in our everyday life. To succeed in switching, it is important to inhibit the most recently performed task and instead activate the currently relevant task. The process that inhibits a recently performed task when a new task is to be performed is referred to as 'backward inhibition' (BI). While the BI effect has been subject to intense research in cognitive psychology, little is known about the neuronal mechanisms that are related to the BI effect and those that relate to differences in the magnitude of the BI effect. In the current study, we examined the system neurophysiological basis of BI processes using event-related potentials (ERPs) and sLORETA by also taking inter-individual differences in the magnitude of the BI into account. The results suggest that BI processes and inter-individual differences in them strongly depend upon attentional selection mechanisms (reflected by N1-ERP modulations in the current task/trial) mediated via networks consisting of extrastriate occipital areas, the temporo-parietal junction and the inferior frontal gyrus. Other processes and mechanisms related to conflict monitoring, response selection, or the updating, organization and implementation of a new task-set (i.e. N2 and P3 processes) were not shown to be modulated by BI processes and differences in their magnitude, as evoked with a common BI paradigm.

  7. Inhibition of cathelicidin activity by bacterial exopolysaccharides.

    Science.gov (United States)

    Foschiatti, Michela; Cescutti, Paola; Tossi, Alessandro; Rizzo, Roberto

    2009-06-01

    The interaction of bacterial exopolysaccharides, produced by opportunistic lung pathogens, with antimicrobial peptides of the innate primate immune system was investigated. The exopolysaccharides were produced by Pseudomonas aeruginosa, Inquilinus limosus and clinical isolates of the Burkholderia cepacia complex, bacteria that are all involved in lung infections of cystic fibrosis patients. The effects of the biological activities of three orthologous cathelicidins from Homo sapiens sapiens, Pongo pygmaeus (orangutan) and Presbitys obscurus (dusky leaf monkey) were examined. Inhibition of the antimicrobial activity of peptides was assessed using minimum inhibitory concentration assays on a reference Escherichia coli strain in the presence and absence of exopolysaccharides, whereas complex formation between peptides and exopolysaccharides was investigated by means of circular dichroism, fluorescence spectroscopy and atomic force microscopy. Biological assays revealed that the higher the negative charge of exopolysaccharides the stronger was their inhibiting effect. Spectroscopic studies indicated the formation of molecular complexes of varying stability between peptides and exopolysaccharides, explaining the inhibition. Atomic force microscopy provided a direct visualization of the molecular complexes. A model is proposed where peptides with an alpha-helical conformation interact with exopolysaccharides through electrostatic and other non-covalent interactions.

  8. Ormeloxifene efficiently inhibits ovarian cancer growth.

    Science.gov (United States)

    Maher, Diane M; Khan, Sheema; Nordquist, Jordan L; Ebeling, Mara C; Bauer, Nichole A; Kopel, Lucas; Singh, Man Mohan; Halaweish, Fathi; Bell, Maria C; Jaggi, Meena; Chauhan, Subhash C

    2015-01-28

    Ovarian cancer continues to be a leading cause of cancer related deaths for women. Anticancer agents effective against chemo-resistant cells are greatly needed for ovarian cancer treatment. Repurposing drugs currently in human use is an attractive strategy for developing novel cancer treatments with expedited translation into clinical trials. Therefore, we examined whether ormeloxifene (ORM), a non-steroidal Selective Estrogen Receptor Modulator (SERM) currently used for contraception, is therapeutically effective at inhibiting ovarian cancer growth. We report that ORM treatment inhibits cell growth and induces apoptosis in ovarian cancer cell lines, including cell lines resistant to cisplatin. Furthermore, ORM treatment decreases Akt phosphorylation, increases p53 phosphorylation, and modulates the expression and localization patterns of p27, cyclin E, cyclin D1, and CDK2. In a pre-clinical xenograft mouse ORM treatment significantly reduces tumorigenesis and metastasis. These results indicate that ORM effectively inhibits the growth of cisplatin resistant ovarian cancer cells. ORM is currently in human use and has an established record of patient safety. Our encouraging in vitro and pre-clinical in vivo findings indicate that ORM is a promising candidate for the treatment of ovarian cancer. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Tiotropium bromide inhibits human monocyte chemotaxis

    Directory of Open Access Journals (Sweden)

    Kurai M

    2012-08-01

    Full Text Available Tiotropium bromide (Spiriva® is used as a bronchodilator in chronic obstructive pulmonary disease (COPD. However, clinical evidence suggests that tiotropium bromide may improve COPD by mechanisms beyond bronchodilation. We hypothesized that tiotropium bromide may act as an anti-inflammatory agent by inhibiting monocyte chemotaxis, a process that plays an important role in the lung inflammation of COPD. To test this hypothesis monocytes were pretreated with tiotropium bromide prior to exposure to chemotactic agents and monocyte chemotactic activity (MCA was evaluated with a blind chamber technique. Tiotropium bromide inhibited MCA in a dose- and time- dependent manner (respectively, p< 0.01 by directly acting on the monocyte. Acetylcholine (ACh challenge increased MCA (p< 0.01, and tiotropium bromide effectively reduced (p< 0.01 the increase in MCA by ACh. The inhibition of MCA by tiotropium bromide was reversed by a muscarinic type 3 (M3-muscarinic receptor antagonist (p< 0.01, and was not effected by an M2 receptor antagonist. Furthermore, a selective M3 receptor agonist, cevimeline, and Gq protein stimulator, Pasteurella multocida toxin, significantly increased MCA (P < 0.01, and tiotropium bromide pretreatment reduced (p< 0.01 the increase in MCA induced by these agents. These results suggest that tiotropium might regulate monocyte chemotaxis, in part, by interfering with M3-muscarinic receptor coupled Gq protein signal transduction. These results provide new insight that an anti-cholinergic therapeutic may provide anti-inflammatory action in the pulmonary system.

  10. Imitation inhibition in children with Tourette syndrome.

    Science.gov (United States)

    Brandt, Valerie Cathérine; Moczydlowski, Agnes; Jonas, Melanie; Boelmans, Kai; Bäumer, Tobias; Brass, Marcel; Münchau, Alexander

    2017-08-12

    Echopraxia, that is, the open and automatic imitation of other peoples' actions, is common in patients with Gilles de la Tourette syndrome, autism spectrum disorder, and also those with frontal lobe lesions. While systematic reaction time tasks have confirmed increased automatic imitation in the latter two groups, adult patients with Tourette syndrome appear to compensate for automatic imitation tendencies by an overall slowing in response times. However, whether children with Tourette syndrome are already able to inhibit automatic imitation tendencies has not been investigated. Fifteen children with Tourette syndrome and 15 healthy children (aged 7-12 years) performed an imitation inhibition paradigm. Participants were asked to respond to an auditory cue by lifting their index finger or their little finger. Participants were simultaneously presented with either compatible or incompatible visual stimuli. Overall responses in children with Tourette syndrome were slower than in healthy children. Although responses were faster in compatible than in incompatible trials in both groups, this 'interference effect' was smaller in children with Tourette syndrome. Children with Tourette syndrome have a smaller interference effect than healthy children, indicating an enhanced ability to behaviourally control automatic imitation tendencies at the cost of reacting slower. The results suggest that children with Tourette syndrome already employ different or additional inhibition strategies compared to healthy children. © 2017 The British Psychological Society.

  11. Inhibition of enveloped viruses infectivity by curcumin.

    Directory of Open Access Journals (Sweden)

    Tzu-Yen Chen

    Full Text Available Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter than for the pseudorabies virus (approximately 180 nm and the vaccinia virus (roughly 335 × 200 × 200 nm. These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses.

  12. Lead inhibition of enzyme synthesis in soil.

    Science.gov (United States)

    Cole, M A

    1977-02-01

    Addition of 2 mg of Pb2+/g of soil concident with or after amendment with starch or maltose resulted in 75 and 50% decreases in net synthesis of amylase and alpha-glucosidase, respectively. Invertase synthesis in sucrose-amended soil was transiently reduced after Pb2+ addition. Amylase activity was several times less sensitive to Pb2+ inhibition than was enzyme synthesis. In most cases, the rate of enzyme synthesis returned to control (Pb2+) values 24 to 48 h after the addition of Pb. The decrease in amylase synthesis was paralleled by a decrease in the number of Pb-sensitive, amylase-producing bacteria, whereas recovery of synthesis was associated with an increase in the number of amylase-producing bacteria. The degree of inhibition of enzyme synthesis was related to the quantity of Pb added and to the specific form of lead. PbSO4 decreased amylase synthesis at concentrations of 10.2 mg of Pb2+/g of soil or more, whereas PbO did not inhibit amylase synthesis at 13 mg of Pb2+/g of soil. Lead acetate, PbCl2, and PbS reduced amylase synthesis at total Pb2+ concentrations of 0.45 mg of Pb2+/g of soil or higher. The results indicated that lead is a potent but somewhat selective inhibitor of enzyme synthesis in soil, and that highly insoluble lead compounds, such as PbS, may be potent modifiers of soil biological activity.

  13. In Vivo Pharmacodynamic Imaging of Proteasome Inhibition

    Directory of Open Access Journals (Sweden)

    Erin A. Kimbrel

    2009-05-01

    Full Text Available Inhibiting the proteolytic activity of the 26S proteasome has been shown to have selective apoptotic effects on cancer cells and to be clinically efficacious in certain malignancies. There is an unmet medical need for additional proteasome inhibitors, and their development will be facilitated by surrogate markers of proteasome function. Toward this end, ectopic fusion of the destruction domain from ornithine decarboxylase (ODC to reporter proteins is often used for assessing proteasome function. For luciferase-based reporters, we hypothesized that the oxygen-dependent destruction domain (ODD from hypoxia-inducible factor 1α (HIF-1α may provide improved sensitivity over luciferase-ODC, owing to its extremely rapid turnover by the proteasome (HIF-1α has a half-life of less than 5 minutes. In the current study, we show that ODD-luciferase affords a greater dynamic range and faster kinetics than luciferase-ODC in sensing proteasome inhibition in vitro. Importantly, ODD-luciferase also serves as an effective in vivo marker of proteasome function in xenograft tumor models, with inhibition being detected by noninvasive imaging within 3 hours of bortezomib administration. These data establish ODD-luciferase as a surrogate marker of proteasome function that can be used both in vitro and in vivo for the development of novel proteasome inhibitors.

  14. Gas hydrate inhibition of drilling fluid additives

    Energy Technology Data Exchange (ETDEWEB)

    Xiaolan, L.; Baojiang, S.; Shaoran, R. [China Univ. of Petroleum, Dongying (China). Inst. of Petroleum Engineering

    2008-07-01

    Gas hydrates that form during offshore well drilling can have adverse impacts on well operational safety. The hydrates typically form in the risers and the annulus between the casing and the drillstring, and can stop the circulation of drilling fluids. In this study, experiments were conducted to measure the effect of drilling fluid additives on hydrate inhibition. Polyalcohols, well-stability control agents, lubricating agents, and polymeric materials were investigated in a stirred tank reactor at temperatures ranging from -10 degree C to 60 degrees C. Pressure, temperature, and torque were used to detect onset points of hydrate formation and dissociation. The inhibitive effect of the additives on hydrate formation was quantified. Phase boundary shifts were measured in terms of temperature difference or sub-cooling gained when chemicals were added to pure water. Results showed that the multiple hydroxyl groups in polyalcohol chemicals significantly inhibited hydrate formation. Polymeric and polyacrylamide materials had only a small impact on hydrate formation, while sulfonated methyl tannins were found to increase hydrate formation. 6 refs., 1 tab., 4 figs.

  15. Inhibition of Enterococcus faecalis by Calcium Peroxide.

    Science.gov (United States)

    Su, Yong Liang; Wang, Xiao Yan

    2016-06-01

    To investigate the inhibition of Enterococcus faecalis by calcium peroxide (CaO₂). The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Enterococcus faecalis by CaO₂ and calcium hydroxide (Ca(OH)₂) were determined by direct exposure tests (n = 10). The inhibition zone of E. faecalis mycoderm treated with CaO₂ and Ca(OH)₂ paste (53% w/w) was observed using agar diffusion tests (n = 20). The inhibition of E. faecalis biofilms by CaO₂/phosphate-buffered saline (PBS) and Ca(OH)₂/PBS suspensions were observed using confocal laser scanning microscopy and the percentages of live bacteria in the biofilms calculated. The MIC of Ca(OH)₂ (4.5 to 5.5 mg/ml) was higher than the MIC of CaO₂ (2.0 to 2.5 mg/ml) (P faecalis biofilms after treatment (P faecalis by CaO₂ was greater than that by Ca(OH)₂.

  16. Bioassays for the determination of nitrification inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Grunditz, Camilla

    1999-07-01

    Requirements for nitrogen reduction in wastewater treatment plants were introduced in Sweden in the early 1990's. This was a governmental move to reduce the nitrogen discharges to the Baltic and Kattegat in order to prevent eutrophication. The nitrification process in wastewater treatment plants is performed by nitrifying bacteria. These are susceptible to inhibition and it is of great importance that the influent water does not contain toxic compounds. Therefore, there is a need for assays for the determination of nitrification inhibition. This thesis describes the development and applications of such bioassays. Pure cultures of Nitrosomonas sp. and Nitrobacter sp. were isolated from activated sludge of a wastewater treatment plant. These cultures were used as test organisms in the development of bioassays for nitrification inhibition measurements. The assays are based on two different principles; cell suspensions of the bacteria, performed in test tubes, and mediated amperometric biosensors with the bacteria immobilised. Ammonia oxidation and nitrite oxidation are studied separately without interference from other organisms, which makes it easier to interpret the results. The cell suspension assays were applied to samples of industrial and municipal wastewater. The Nitrosomonas and Nitrobacter assays showed to have different inhibition patterns. A large percentage of the Swedish municipal wastewater treatment plants were found to receive inhibitory influent water, but the inhibition level was generally low. Compared to an assay based on activated sludge, the screening method, the pure culture assays found more samples of influent water strongly inhibitory or stimulating. The highest correlation was found between the screening method and the Nitrosomonas assay. The Nitrobacter assay was found to be the most sensitive method. Assessment of toxicity of a number of chemical substances was studied using the biosensors, together with the cell suspension assays

  17. Assessment of the inhibition risk of shikonin on cytochrome P450 via cocktail inhibition assay.

    Science.gov (United States)

    Tang, Shuowen; Chen, Ang; Zhou, Xiaojing; Zeng, Li; Liu, Mingyao; Wang, Xin

    2017-11-05

    Shikonin is a naphthoquinone pigment extracted from roots of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae), and possesses various pharmaceutical activities, such as anti-inflammation and anti-cancer effects. In addition, shikonin as a natural red colorant for food garnishment and cosmetics ingredient is widely used in the world. However, the inhibition risk of shikonin on cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the potential inhibition of shikonin against CYP1A2, CYP2B1/6, CYP2C9/11, CYP2D1/6, CYP2E1 and CYP3A2/4 activities in human and rat liver microsomes through cocktail approach in vitro. The results demonstrated that shikonin exhibited no time-dependent inhibition of CYP activities. In human liver microsomes, shikonin was not only a mixed inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2D6 and CYP3A4, but also a competitive inhibitor of CYP2E1, with Ki values no more than 7.72μM. In rat liver microsomes, shikonin also exhibited the mixed inhibition on CYP1A2, CYP2B1, CYP2C11, CYP2D1, and the competitive inhibition on CYP2E1. Interestingly, shikonin presented an atypical kinetic inhibition of CYP3A2-mediated midazolam 1-hydroxylation in rats. In conclusion, the relatively low Ki values of shikonin would have a high risk potential to cause the possible toxicity, especially drug-drug or food-drug interactions based on the potent inhibition of CYP enzymes. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Methanol Extract of Hydroclathrus clathratus Inhibits Production of ...

    African Journals Online (AJOL)

    Methanol Extract of Hydroclathrus clathratus Inhibits Production of Nitric Oxide, Prostaglandin E 2 and Tumor Necrosis Factor-α in Lipopolysaccharidestimulated BV2 Microglial Cells via Inhibition of NF-κB Activity.

  19. The development of children’s inhibition: Does parenting matter?

    OpenAIRE

    Stievenart, Marie

    2014-01-01

    Whereas a large body of research has investigated the maturation of inhibition in relation to the prefrontal cortex, far less research has been devoted to environmental factors that could contribute to inhibition improvement. The aim of the current study was to test whether and to what extent parenting matters for inhibition development from 2 to 8 years of age. Data were collected from 421 families, with 348 mother–child dyads and 342 father–child dyads participating. Children’s inhibition c...

  20. The development of children's inhibition: Does parenting matter?

    OpenAIRE

    Roskam, I.; Stievenart, Marie; Meunier, J.-C.; Noël, M.-P.

    2014-01-01

    Whereas a large body of research has investigated the maturation of inhibition in relation to the prefrontal cortex, far less research has been devoted to environmental factors that could contribute to inhibition improvement. The aim of the current study was to test whether and to what extent parenting matters for inhibition development from 2 to 8. years of age. Data were collected from 421 families, with 348 mother-child dyads and 342 father-child dyads participating. Children's inhibition ...

  1. Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin

    Science.gov (United States)

    Verespy III, Stephen; Mehta, Akul Y.; Afosah, Daniel; Al-Horani, Rami A.; Desai, Umesh R.

    2016-01-01

    Allosteric partial inhibition of soluble, monomeric proteases can offer major regulatory advantages, but remains a concept on paper to date; although it has been routinely documented for receptors and oligomeric proteins. Thrombin, a key protease of the coagulation cascade, displays significant conformational plasticity, which presents an attractive opportunity to discover small molecule probes that induce sub-maximal allosteric inhibition. We synthesized a focused library of some 36 sulfated coumarins to discover two agents that display sub-maximal efficacy (~50%), high potency (thrombin (>150-fold). Michaelis-Menten, competitive inhibition, and site-directed mutagenesis studies identified exosite 2 as the site of binding for the most potent sulfated coumarin. Stern-Volmer quenching of active site-labeled fluorophore suggested that the allosteric regulators induce intermediate structural changes in the active site as compared to those that display ~80–100% efficacy. Antithrombin inactivation of thrombin was impaired in the presence of the sulfated coumarins suggesting that allosteric partial inhibition arises from catalytic dysfunction of the active site. Overall, sulfated coumarins represent first-in-class, sub-maximal inhibitors of thrombin. The probes establish the concept of allosteric partial inhibition of soluble, monomeric proteins. This concept may lead to a new class of anticoagulants that are completely devoid of bleeding. PMID:27053426

  2. A fusion-inhibiting peptide against Rift Valley fever virus inhibits multiple, diverse viruses.

    Directory of Open Access Journals (Sweden)

    Jeffrey W Koehler

    Full Text Available For enveloped viruses, fusion of the viral envelope with a cellular membrane is critical for a productive infection to occur. This fusion process is mediated by at least three classes of fusion proteins (Class I, II, and III based on the protein sequence and structure. For Rift Valley fever virus (RVFV, the glycoprotein Gc (Class II fusion protein mediates this fusion event following entry into the endocytic pathway, allowing the viral genome access to the cell cytoplasm. Here, we show that peptides analogous to the RVFV Gc stem region inhibited RVFV infectivity in cell culture by inhibiting the fusion process. Further, we show that infectivity can be inhibited for diverse, unrelated RNA viruses that have Class I (Ebola virus, Class II (Andes virus, or Class III (vesicular stomatitis virus fusion proteins using this single peptide. Our findings are consistent with an inhibition mechanism similar to that proposed for stem peptide fusion inhibitors of dengue virus in which the RVFV inhibitory peptide first binds to both the virion and cell membranes, allowing it to traffic with the virus into the endocytic pathway. Upon acidification and rearrangement of Gc, the peptide is then able to specifically bind to Gc and prevent fusion of the viral and endocytic membranes, thus inhibiting viral infection. These results could provide novel insights into conserved features among the three classes of viral fusion proteins and offer direction for the future development of broadly active fusion inhibitors.

  3. Cellobionic acid inhibition of cellobiohydrolase I and cellobiose dehydrogenase

    Science.gov (United States)

    End-product inhibition by cellobiose and glucose is a rate-limiting factor in cellulose hydrolysis by cellulases. While cellobiose and glucose inhibition have been extensively investigated, cellobionate inhibition has been minimally studied despite the discovery that accessory proteins such as cello...

  4. Inhibition and Adsorption impact of Leave Extracts of Cnidoscolus ...

    African Journals Online (AJOL)

    Corrosion inhibition in the presence of alokaloid and non alkaloid extracts of Cnidoscolus aconitifolius in 1M HCl was studied using the weight loss and hydrogen evolution techniques at 303, 313 and 333 K. The results obtained revealed that the inhibition efficiency decreased with increase in temperature. Inhibition ...

  5. Inhibition of Fungal Aflatoxin B1 Biosynthesis by Diverse Botanically ...

    African Journals Online (AJOL)

    Results: Neither the tea-derived polyphenol mixture nor individual polyphenol compound, except quercetin, inhibited A. flavus growth. Quercetin detectably inhibited growth at 800 μg/mL; none of the remaining polyphenols inhibited fungal proliferation, even at 1,000 μg/mL. However, catechin mixture and all individual ...

  6. Inhibition of respiration of Escherichia coli by thioglycerol.

    OpenAIRE

    Javor, G T

    1983-01-01

    Anaerobic growth on glucose significantly protected Escherichia coli from growth inhibition by thioglycerol. Methionine and anaerobiosis completely overcame growth inhibition by 2 to 90 mM thioglycerol. The respiration of aerobically growing cells was partially inhibited by 20 to 90 mM thioglycerol.

  7. Inhibition of Inducible Nitric Oxide Synthase, Cycleooxygenase-2 ...

    African Journals Online (AJOL)

    Inhibition of Inducible Nitric Oxide Synthase, Cycleooxygenase-2 and Lipid Peroxidation by Methanol Extract of Pericarpium Zanthoxyli. ... Production of iNOS induced by LPS was significantly (p < 0.05) inhibited by the extract, suggesting that the extract inhibits nitric oxide (NO) production by suppressing iNOS expression.

  8. Zinc ions bind to and inhibit activated protein C

    DEFF Research Database (Denmark)

    Zhu, Tianqing; Ubhayasekera, Wimal; Nickolaus, Noëlle

    2010-01-01

    Zn2+ ions were found to efficiently inhibit activated protein C (APC), suggesting a potential regulatory function for such inhibition. APC activity assays employing a chromogenic peptide substrate demonstrated that the inhibition was reversible and the apparent K I was 13 +/- 2 microM. k cat was ...

  9. Contour detection based on nonclassical receptive field inhibition

    NARCIS (Netherlands)

    Grigorescu, Cosmin; Petkov, Nicolai; Westenberg, Michel A.

    We propose a biologically motivated computational step, called nonclassical receptive field (non-CRF) inhibition, more generally surround inhibition or suppression, to improve contour detection in machine vision. Non-CRF inhibition is exhibited by 80% of the orientation-selective neurons in the

  10. Cannabidiol inhibits angiogenesis by multiple mechanisms

    Science.gov (United States)

    Solinas, M; Massi, P; Cantelmo, AR; Cattaneo, MG; Cammarota, R; Bartolini, D; Cinquina, V; Valenti, M; Vicentini, LM; Noonan, DM; Albini, A; Parolaro, D

    2012-01-01

    BACKGROUND AND PURPOSE Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. EXPERIMENTAL APPROACH Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability – through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis – and in vitro motility – both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. KEY RESULTS CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. CONCLUSIONS AND IMPLICATIONS This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy. PMID:22624859

  11. Myeloperoxidase Inhibition Increases Neurogenesis after Ischemic Stroke.

    Science.gov (United States)

    Kim, HyeonJu; Wei, Ying; Lee, Ji Yong; Wu, Yue; Zheng, Yi; Moskowitz, Michael A; Chen, John W

    2016-11-01

    The relationship between inflammation and neurogenesis in stroke is currently not well understood. Focal ischemia enhances cell proliferation and neurogenesis in the neurogenic regions, including the subventricular zone (SVZ), dentate gyrus, as well as the non-neurogenic striatum, and cortex in the ischemic hemisphere. Myeloperoxidase (MPO) is a potent oxidizing enzyme secreted during inflammation by activated leukocytes, and its enzymatic activity is highly elevated after stroke. In this study, we investigated whether the inhibition of MPO activity by a specific irreversible inhibitor, 4-aminobenzoic acid hydrazide (ABAH) (MPO(-/-) mice) can increase neurogenesis after transient middle cerebral artery occlusion in mice. ABAH administration increased the number of proliferating bromodeoxyuridine (BrdU)-positive cells expressing markers for neural stems cells, astrocytes, neuroprogenitor cells (Nestin), and neuroblasts (doublecortin) in the ischemic SVZ, anterior SVZ, striatum, and cortex. MPO inhibition also increased levels of brain-derived neurotrophic factor, phosphorylation of cAMP response element-binding protein (Ser133), acetylated H3, and NeuN to promote neurogenesis in the ischemic SVZ. ABAH treatment also increased chemokine CXC receptor 4 expression in the ischemic SVZ. MPO-deficient mice treated with vehicle or ABAH both showed similar effects on the number of BrdU(+) cells in the ischemic hemisphere, demonstrating that ABAH is specific to MPO. Taken together, our results underscore a detrimental role of MPO activity to postischemia neurogenesis and that a strategy to inhibit MPO activity can increase cell proliferation and improve neurogenesis after ischemic stroke. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  12. Interferon-γ Inhibits Ebola Virus Infection.

    Directory of Open Access Journals (Sweden)

    Bethany A Rhein

    Full Text Available Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  13. Research on inhibition of corneal neovascularization

    Directory of Open Access Journals (Sweden)

    Zhang-Hui Yang

    2015-12-01

    Full Text Available Corneal transparency is the basis of the normal physiological functions.However, corneal neovascularization(CNVmay occur in the infection, mechanical and chemical injury or under other pathological conditions,which make the cornea lose original transparency and severe visual impairment. In recent years, along with the development of immunology, molecular biology, biochemistry and other disciplines, there is more in-depth understanding on the CNV, and clinical treatment of CNV has made new breakthroughs. This article provides an overview of the inhibition of CNV.

  14. Saw palmetto ethanol extract inhibits adipocyte differentiation.

    Science.gov (United States)

    Villaverde, Nicole; Galvis, Adriana; Marcano, Adriana; Priestap, Horacio A; Bennett, Bradley C; Barbieri, M Alejandro

    2013-07-01

    The fruits of saw palmetto have been used for the treatment of a variety of urinary and reproductive system problems. In this study we investigated whether the fruit extracts affect in vitro adipogenesis. Saw palmetto ethanol extract inhibited the lipid droplet accumulation by induction media in a dose-dependent manner, and it also attenuated the protein expressions of C-EBPα and PPARγ. Phosphorylation of Erk1/2 and Akt1 were also decreased by saw palmetto ethanol extract. This report suggests that saw palmetto extracts selectively affect the adipocyte differentiation through the modulation of several key factors that play a critical role during adipogenesis.

  15. CMP substitutions preferentially inhibit polysialic acid synthesis

    OpenAIRE

    Miyazaki, Tatsuo; Angata, Kiyohiko; Seeberger, Peter H.; Hindsgaul, Ole; Fukuda, Minoru

    2007-01-01

    It is widely reported that derivatives of sugar moieties can be used to metabolically label cell surface carbohydrates or inhibit a particular glycosylation. However, few studies address the effect of substitution of the cytidylmonophosphate (CMP) portion on sialyltransferase activities. Here we first synthesized 2′-O-methyl CMP and 5-methyl CMP and then asked if these CMP derivatives are recognized by α2,3-sialyltransferases (ST3Gal-III and ST3Gal-IV), α2,6-sialyltransferase (ST6Gal-I), and ...

  16. Linking algal growth inhibition to chemical activity

    DEFF Research Database (Denmark)

    Schmidt, Stine N.; Mayer, Philipp

    to chemical activity, as opposed to e.g. the total concentration. Baseline toxicity (narcosis) for neutral hydrophobic organic compounds has been shown to initiate in the narrow chemical activity range of 0.01 to 0.1. This presentation focuses on linking algal growth inhibition to chemical activity...... of the presentation focuses on extending the utilisation of the chemical activity concept. More specifically, the chemical activity concept is applied to a much larger range of algal toxicity data, including a wide range of solids and liquids, covering several expected modes of action and also several algal species...

  17. Aminopeptidase from Brevibacterium linens: activation and inhibition.

    Science.gov (United States)

    Foissy, H

    1978-04-18

    Activation and inhibition of a purified aminopeptidase from Brevibacterium linens was investigated using L-alpha-leucyl-4-nitroanilide and L-leucyl-L-leucine as substrates. The enzyme was activated by cobalt, provided that the enzyme was preincubated with the metal. Strong inhibitory effects were derived from heavy metals, metal-complexing compounds, reducing agents, the modification of aromatic amino acids, and the presence of hydrophobic substances or certain amino acids in the test mixtures. Supposing that this B. linens aminopeptidase plays a part during surface-ripening of cheeses, possible consequences of specific technological conditions for its activity are discussed.

  18. LOX1 inhibition with small molecules

    DEFF Research Database (Denmark)

    Gousiadou, Chryssoula; Kouskoumvekaki, Irene

    2016-01-01

    the attention as targets and great effort has been made for the discovery and design of suitable inhibitors, to which end both pharmacological and computational methods have been employed. In the present work, using pharmacophore modeling and docking, we attempt to elucidate the inhibition of LOX1 with a new...... inhibitor, albidoside, an iridoid glucoside isolated from plants of the Scutellaria genus. Through a pharmacophore approach, complementarities between the ligand and the binding site are explored and a plausible mode of binding with the protein is suggested for albidoside....

  19. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    of 1.4-49.7 mM. Carbamazepine, gabapentin, primidone, topiramate and vigabatrin showed no inhibition. Additionally, binary drug combinations were tested to investigate if combination therapy could potentiate the aromatase inhibition. Additive inhibition was seen in combination experiments...... with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered....

  20. Inhibition control and working memory capacity in children with SLI.

    Science.gov (United States)

    Marton, Klara; Kelmenson, Lyudmyla; Pinkhasova, Milana

    2007-01-01

    This study examined the "inefficient inhibition hypothesis" (IIH; Bjorklund & Harnishfeger, 1990; Wilson & Kipp, 1998) in three groups: children with specific language impairment (SLI), age-matched and language-matched controls. The IIH suggests that individuals with efficient inhibition skills perform better on working memory tasks because they are able to keep out irrelevant information from working memory. Children with SLI show processing capacity limitations. This study examined whether the working memory limitations are impacted by inhibition problems in this population. Working memory capacity was measured with a listening span task and children's inhibition errors were categorized. These errors reflected either immediate or delayed inhibition problems and they indicated either contextual distractions or perseverations. Children with SLI produced more inhibition errors than their peers in most categories. The results show an association between inhibition control and working memory capacity, but the direction of causality is not clear.

  1. Soluble Aβ aggregates can inhibit prion propagation.

    Science.gov (United States)

    Sarell, Claire J; Quarterman, Emma; Yip, Daniel C-M; Terry, Cassandra; Nicoll, Andrew J; Wadsworth, Jonathan D F; Farrow, Mark A; Walsh, Dominic M; Collinge, John

    2017-11-01

    Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrPC). Ligands that bind to PrPC can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrPC, and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP in vitro also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Aβ can compete with prions for binding to PrPC and emphasize the bidirectional nature of the interplay between Aβ and PrPC in Alzheimer's and prion diseases. Such inhibitory effects of Aβ on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Aβ deposition is common. © 2017 The Authors.

  2. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis.

    Science.gov (United States)

    Szkudlarek-Mikho, Maria; Saunders, Rudel A; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

    2012-11-30

    The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor γ. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Erythrocyte membrane skeleton inhibits nanoparticle endocytosis

    Science.gov (United States)

    Gao, Xinli; Yue, Tongtao; Tian, Falin; Liu, Zhiping; Zhang, Xianren

    2017-06-01

    Red blood cells (RBCs), also called erythrocytes, have been experimentally proposed in recent decades as the biological drug delivery systems through entrapping certain drugs by endocytosis. However, the internalization pathway of endocytosis seems to conflict with the robust mechanical properties of RBCs that is induced by the spectrin-actin network of erythrocyte membrane skeleton. In this work, we employed a minimum realistic model and the dissipative particle dynamics method to investigate the influence of the spectrin-actin membrane skeleton on the internalization of nanoparticles (NPs). Our simulations show that the existence of skeleton meshwork indeed induces an inhibiting effect that effectively prevents NPs from internalization. The inhibiting effect is found to depend on the membrane-NP attraction, skeleton tension and relative size of the NP to the membrane skeleton mesh. However, our simulations also demonstrate that there are two possibilities for successful internalization of NPs in the presence of the membrane skeleton. The first case is for NPs that has a much smaller size than the dimension of skeleton meshes, and the other is that the skeleton tension is rather weak so that the formed vesicle can still move inward for NP internalization.

  4. Targeting Sphingosine Kinase-1 To Inhibit Melanoma

    Science.gov (United States)

    Madhunapantula, SubbaRao V.; Hengst, Jeremy; Gowda, Raghavendra; Fox, Todd E.; Yun, Jong K; Robertson, Gavin P.

    2012-01-01

    SUMMARY Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient’s tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage dependent and independent growth as well as sensitized melanoma cells to apoptosis inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I, decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents. PMID:22236408

  5. Silkworm Apolipophorin Protein Inhibits Staphylococcus aureus Virulence*

    Science.gov (United States)

    Hanada, Yuichi; Sekimizu, Kazuhisa; Kaito, Chikara

    2011-01-01

    Silkworm hemolymph inhibits hemolysin production by Staphylococcus aureus. We purified a factor in the silkworm hemolymph responsible for this inhibitory activity. The final fraction with the greatest specific activity contained 220- and 74-kDa proteins. Determination of the N-terminal amino acid sequence revealed that the 220- and 74-kDa proteins were apolipophorin I and apolipophorin II, respectively, indicating that the factor was apolipophorin (ApoLp). The purified ApoLp fraction showed decreased expression of S. aureus hla encoding α-hemolysin, hlb encoding β-hemolysin, saeRS, and RNAIII, which activate the expression of these hemolysin genes. Injection of an anti-ApoLp antibody into the hemolymph increased the sensitivity of silkworms to the lethal effect of S. aureus. Hog gastric mucin, a mammalian homologue of ApoLp, decreased the expression of S. aureus hla and hlb. These findings suggest that ApoLp in the silkworm hemolymph inhibits S. aureus virulence and contributes to defense against S. aureus infection and that its activity is conserved in mammalian mucin. PMID:21937431

  6. Neuroprotective Mechanisms Mediated by CDK5 Inhibition.

    Science.gov (United States)

    Mushtaq, Gohar; Greig, Nigel H; Anwar, Firoz; Al-Abbasi, Fahad A; Zamzami, Mazin A; Al-Talhi, Hasan A; Kamal, Mohammad A

    2016-01-01

    Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase belonging to the family of cyclin-dependent kinases. In addition to maintaining the neuronal architecture, CDK5 plays an important role in the regulation of synaptic plasticity, neurotransmitter release, neuron migration and neurite outgrowth. Although various reports have shown links between neurodegeneration and deregulation of cyclin-dependent kinases, the specific role of CDK5 inhibition in causing neuroprotection in cases of neuronal insult or in neurodegenerative diseases is not wellunderstood. This article discusses current evidence for the involvement of CDK5 deregulation in neurodegenerative disorders and neurodegeneration associated with stroke through various mechanisms. These include upregulation of cyclin D1 and overactivation of CDK5 mediated neuronal cell death pathways, aberrant hyperphosphorylation of human tau proteins and/or neurofilament proteins, formation of neurofibrillary lesions, excitotoxicity, cytoskeletal disruption, motor neuron death (due to abnormally high levels of CDK5/p25) and colchicine- induced apoptosis in cerebellar granule neurons. A better understanding of the role of CDK5 inhibition in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious pharmacological inhibitors of CDK5 for therapeutic use against human neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis and neuronal loss associated with stroke.

  7. Understanding biocatalyst inhibition by carboxylic acids

    Directory of Open Access Journals (Sweden)

    Laura R Jarboe

    2013-09-01

    Full Text Available Carboxylic acids are an attractive biorenewable chemical in terms of their flexibility and usage as precursors for a variety of industrial chemicals. It has been demonstrated that such carboxylic acids can be fermentatively produced using engineered microbes, such as Escherichia coli and Saccharomyces cerevisiae. However, like many other attractive biorenewable fuels and chemicals, carboxylic acids become inhibitory to these microbes at concentrations below the desired yield and titer. In fact, their potency as microbial inhibitors is highlighted by the fact that many of these carboxylic acids are routinely used as food preservatives. This review highlights the current knowledge regarding the impact that saturated, straight-chain carboxylic acids, such as hexanoic, octanoic, decanoic and lauric acids can have on E. coli and S. cerevisiae, with the goal of identifying metabolic engineering strategies to increase robustness. Key effects of these carboxylic acids include damage to the cell membrane and a decrease of the microbial internal pH. Certain changes in cell membrane properties, such as composition, fluidity, integrity and hydrophobicity, and intracellular pH are often associated with increased tolerance. The availability of appropriate exporters, such as Pdr12, can also increase tolerance. The effect on metabolic processes, such as maintaining appropriate respiratory function, regulation of Lrp activity and inhibition of production of key metabolites such as methionine, are also considered. Understanding the mechanisms of biocatalyst inhibition by these desirable products can aid in the engineering of robust strains with improved industrial performance.

  8. Inhibition of saccades elicits attentional suppression.

    Science.gov (United States)

    Dhawan, Saurabh; Deubel, Heiner; Jonikaitis, Donatas

    2013-05-17

    Visuospatial attention has been shown to have a central role in planning and generation of saccades but what role, if any, it plays in inhibition of saccades remains unclear. In this study, we used an oculomotor delayed match- or nonmatch-to-sample task in which a cued location has to be encoded and memorized for one of two very different goals-to plan a saccade to it or to avoid making a saccade to it. We measured the spatial allocation of attention during the delay and found that while marking a location as a future saccade target resulted in an attentional benefit at that location, marking it as forbidden to saccades led to an attentional cost. Additionally, saccade trajectories were found to deviate away more from the "don't look" location than from a saccade-irrelevant distractor confirming greater inhibition of an actively forbidden location in oculomotor programming. Our finding that attention is suppressed at locations forbidden to saccades confirms and complements the claim of a selective and obligatory coupling between saccades and attention-saccades at the memorized location could neither be planned nor suppressed independent of a corresponding effect on attentional performance.

  9. Stanniocalcin-2 Inhibits Mammalian Growth by Proteolytic Inhibition of the Insulin-like Growth Factor Axis*

    Science.gov (United States)

    Jepsen, Malene R.; Kløverpris, Søren; Mikkelsen, Jakob H.; Pedersen, Josefine H.; Füchtbauer, Ernst-Martin; Laursen, Lisbeth S.; Oxvig, Claus

    2015-01-01

    Mammalian stanniocalcin-2 (STC2) is a secreted polypeptide widely expressed in developing and adult tissues. However, although transgenic expression in mice is known to cause severe dwarfism, and targeted deletion of STC2 causes increased postnatal growth, its precise biological role is still unknown. We found that STC2 potently inhibits the proteolytic activity of the growth-promoting metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). Proteolytic inhibition requires covalent binding of STC2 to PAPP-A and is mediated by a disulfide bond, which involves Cys-120 of STC2. Binding of STC2 prevents PAPP-A cleavage of insulin-like growth factor-binding protein (IGFBP)-4 and hence release within tissues of bioactive IGF, required for normal growth. Concordantly, we show that STC2 efficiently inhibits PAPP-A-mediated IGF receptor signaling in vitro and that transgenic mice expressing a mutated variant of STC2, STC2(C120A), which is unable to inhibit PAPP-A, grow like wild-type mice. Our work identifies STC2 as a novel proteinase inhibitor and a previously unrecognized extracellular component of the IGF system. PMID:25533459

  10. Stachytarpheta cayennensis extract inhibits promastigote and amastigote growth in Leishmania amazonensis via parasite arginase inhibition.

    Science.gov (United States)

    Maquiaveli, Claudia do Carmo; Oliveira E Sá, Amanda Maria; Vieira, Paulo Cezar; da Silva, Edson Roberto

    2016-11-04

    Stachytarpheta cayennensis is a plant that is traditionally used to treat tegumentary leishmaniasis and as an anti-inflammatory agent. This study aimed to evaluate the action of S. cayennensis extracts on the Leishmania (Leishmania) amazonensis arginase enzyme. S. cayennensis was collected from the Brazilian Amazon region. Aqueous extracts were fractionated with n-butanol. The leishmanicidal effects of the n-butanolic fraction (BUF) were evaluated in L. (L.) amazonensis promastigotes and amastigotes. BUF was tested against recombinant arginase from both L. (L.) amazonensis and macrophage arginase. Promastigote cultures and infected macrophage cultures were supplemented with L-ornithine to verify arginase inhibition. NMR analysis was used to identify the major components of BUF. BUF showed an EC50 of 51 and 32µg/mL against promastigotes and amastigotes of L. (L.) amazonensis, respectively. BUF contains a mixture of verbascoside and isoverbascoside (7:3 ratio) and is a potent L. (L.) amazonensis arginase inhibitor (IC50=1.2µg/mL), while macrophage arginase was weakly inhibited (IC50>1000µg/mL). The inhibition of arginase by BUF in promastigotes and amastigotes could be demonstrated by culture media supplementation with L-ornithine, a product of the hydrolysis of L-arginine by arginase. Leishmanicidal effects of the S. cayennensis BUF fraction on L. (L.) amazonensis are associated with selective parasite arginase inhibition. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Inhibition in language switching: what is inhibited when switching between languages in naming tasks?

    Science.gov (United States)

    Philipp, Andrea M; Koch, Iring

    2009-09-01

    When people switch between languages, inhibition of currently irrelevant languages is assumed to occur. The authors examined inhibition of irrelevant languages with a cued language-switching paradigm. A cue indicated in which of 3 languages (German, English, or French) a visual stimulus was to be named. In 2 experiments, the authors found that naming latencies were increased in n-2 language repetitions (e.g., German/English/German) compared with in n-2 language nonrepetitions (e.g., French/English/German). This difference (n-2 repetition costs) indicates persisting inhibition of abandoned languages. It is important to note that n-2 language-repetition costs also occurred in conditions in which the language but not the cue (Experiment 1) or the stimulus/response set (Experiment 2) repeated from trial n-2 to trial n. These data demonstrate that inhibition is not restricted to a specific cue or stimulus/response set. Rather, the data suggest more global inhibitory processes that affect the mental representation of competing languages. (c) 2009 APA, all rights reserved.

  12. Ketoconazole inhibits the cellular uptake of anandamide via inhibition of FAAH at pharmacologically relevant concentrations.

    Directory of Open Access Journals (Sweden)

    Emmelie Björklund

    Full Text Available The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA.The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 µM, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component of 34 µM.The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer.

  13. Checkpoint kinase 1 inhibition sensitises transformed cells to dihydroorotate dehydrogenase inhibition.

    Science.gov (United States)

    Arnould, Stéphanie; Rodier, Geneviève; Matar, Gisèle; Vincent, Charles; Pirot, Nelly; Delorme, Yoann; Berthet, Charlène; Buscail, Yoan; Noël, Jean Yohan; Lachambre, Simon; Jarlier, Marta; Bernex, Florence; Delpech, Hélène; Vidalain, Pierre Olivier; Janin, Yves L; Theillet, Charles; Sardet, Claude

    2017-11-10

    Reduction in nucleotide pools through the inhibition of mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) has been demonstrated to effectively reduce cancer cell proliferation and tumour growth. The current study sought to investigate whether this antiproliferative effect could be enhanced by combining Chk1 kinase inhibition. The pharmacological activity of DHODH inhibitor teriflunomide was more selective towards transformed mouse embryonic fibroblasts than their primary or immortalised counterparts, and this effect was amplified when cells were subsequently exposed to PF477736 Chk1 inhibitor. Flow cytometry analyses revealed substantial accumulations of cells in S and G2/M phases, followed by increased cytotoxicity which was characterised by caspase 3-dependent induction of cell death. Associating PF477736 with teriflunomide also significantly sensitised SUM159 and HCC1937 human triple negative breast cancer cell lines to dihydroorotate dehydrogenase inhibition. The main characteristic of this effect was the sustained accumulation of teriflunomide-induced DNA damage as cells displayed increased phospho serine 139 H2AX (γH2AX) levels and concentration-dependent phosphorylation of Chk1 on serine 345 upon exposure to the combination as compared with either inhibitor alone. Importantly a similar significant increase in cell death was observed upon dual siRNA mediated depletion of Chk1 and DHODH in both murine and human cancer cell models. Altogether these results suggest that combining DHODH and Chk1 inhibitions may be a strategy worth considering as a potential alternative to conventional chemotherapies.

  14. Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans.

    Science.gov (United States)

    Di Lazzaro, V; Oliviero, A; Saturno, E; Dileone, M; Pilato, F; Nardone, R; Ranieri, F; Musumeci, G; Fiorilla, T; Tonali, P

    2005-04-15

    Experimental studies have demonstrated that the GABAergic system modulates acetylcholine release and, through GABA(A) receptors, tonically inhibits cholinergic activity. Little is known about the effects of GABA on the cholinergic activity in the human central nervous system. In vivo evaluation of some cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with TMS of the motor cortex. Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short latency afferent inhibition, SAI). We investigated whether GABA(A) activity enhancement by lorazepam modifies SAI. We also evaluated the effects produced by lorazepam on a different TMS protocol of cortical inhibition, the short interval intracortical inhibition (SICI), which is believed to be directly related to GABA(A) activity. In 10 healthy volunteers, the effects of lorazepam were compared with those produced by quetiapine, a psychotropic drug with sedative effects with no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors, and with those of a placebo using a randomized double-blind study design. Administration of lorazepam produced a significant increase in SICI (F(3,9) = 3.19, P = 0.039). In contrast to SICI, SAI was significantly reduced by lorazepam (F(3,9) = 9.39, P = 0.0002). Our findings demonstrate that GABA(A) activity enhancement determines a suppression of SAI and an increase of SICI.

  15. Equol inhibits growth, induces atresia, and inhibits steroidogenesis of mouse antral follicles in vitro.

    Science.gov (United States)

    Mahalingam, Sharada; Gao, Liying; Gonnering, Marni; Helferich, William; Flaws, Jodi A

    2016-03-15

    Equol is a non-steroidal estrogen metabolite produced by microbial conversion of daidzein, a major soy isoflavone, in the gut of some humans and many animal species. Isoflavones and their metabolites can affect endogenous estradiol production, action, and metabolism, potentially influencing ovarian follicle function. However, no studies have examined the effects of equol on intact ovarian antral follicles, which are responsible for sex steroid synthesis and further development into ovulatory follicles. Thus, the present study tested the hypothesis that equol inhibits antral follicle growth, increases follicle atresia, and inhibits steroidogenesis in the adult mouse ovary. To test this hypothesis, antral follicles isolated from adult CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or equol (600 nM, 6 μM, 36 μM, and 100 μM) for 48 and 96 h. Every 24h, follicle diameters were measured to monitor growth. At 48 and 96 h, the culture medium was subjected to measurement of hormone levels, and the cultured follicles were subjected to gene expression analysis. Additionally, follicles were histologically evaluated for signs of atresia after 96 h of culture. The results indicate that equol (100 μM) inhibited follicle growth, altered the mRNA levels of bcl2-associated X protein and B cell leukemia/lymphoma 2, and induced follicle atresia. Further, equol decreased the levels of estradiol, testosterone, androstenedione, and progesterone, and it decreased mRNA levels of cholesterol side-chain cleavage, steroid 17-α-hydroxalase, and aromatase. Collectively, these data indicate that equol inhibits growth, increases atresia, and inhibits steroidogenesis of cultured mouse antral follicles. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Doxycycline inhibits leukemic cell migration via inhibition of matrix metalloproteinases and phosphorylation of focal adhesion kinase

    Science.gov (United States)

    WANG, CHUNHUAI; XIANG, RU; ZHANG, XIANGZHONG; CHEN, YUNXIAN

    2015-01-01

    Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel® matrix-coated Transwell® chamber assays; leukemic cell lines treated with doxycycline (1 µg/ml) or anti-β1-integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)-2 and MMP-9 expression. Furthermore, incubation with blocking anti-β1-integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia. PMID:26004127

  17. Temporal Dynamics of Proactive and Reactive Motor Inhibition

    Directory of Open Access Journals (Sweden)

    Ulrike M. Krämer

    2017-04-01

    Full Text Available Proactive motor inhibition refers to endogenous preparatory mechanisms facilitating action inhibition, whereas reactive motor inhibition is considered to be a sudden stopping process triggered by external signals. Previous studies were inconclusive about the temporal dynamics of involved neurocognitive processes during proactive and reactive motor control. Using electroencephalography (EEG, we investigated the time-course of proactive and reactive inhibition, measuring event-related oscillations and event-related potentials (ERPs. Participants performed in a cued go/nogo paradigm with cues indicating whether the motor response might or might not have to be inhibited. Based on the dual mechanisms of control (DMC framework by Braver, we investigated the role of attentional effects, motor preparation in the sensorimotor cortex and prefrontal cognitive control mechanisms, separating effects before and after target onset. In the cue-target interval, proactive motor inhibition was associated with increased attention, reflected in reduced visual alpha power and an increased contingent negative variation (CNV. At the same time, motor inhibition was modulated by reduced sensorimotor beta power. After target onset, proactive inhibition resulted in an increased N1, indicating allocation of attention towards relevant stimuli, increased prefrontal beta power and a modulation of sensorimotor mu activity. As in previous studies, reactive stopping of motor actions was associated with increased prefrontal beta power and increased sensorimotor beta activity. The results stress the relevance of attentional mechanisms for proactive inhibition and speak for different neurocognitive mechanisms being involved in the early preparation for and in later implementation of motor inhibition.

  18. Inhibition effect of food preservatives on endoproteinases.

    Science.gov (United States)

    Esimbekova, Elena N; Asanova, Anastasiya A; Deeva, Anna A; Kratasyuk, Valentina A

    2017-11-15

    The present manuscript proposes a novel approach to assess the impact of food additives on human metabolism by analysing their effect on biomarker enzyme activity. Alterations in the activity of pancreatic enzymes, such as chymotrypsin and trypsin, which are affected by the most common food preservatives, sodium benzoate (E211), potassium sorbate (E202) and sorbic acid (E200), have been evaluated. The proteinase activity was analysed with a bioluminescent method using the light intensity decay constant. Our study revealed that the preservatives reduce proteinase activity by 50% (EC50) at a much lower concentration than their acceptable daily intake (ADI). Thus, sodium benzoate and sorbic acid have an inhibition effect on chymotrypsin at concentrations 14 times lower and 70 times lower than their ADI and this increases with exposure time. Food preservative consumption impacts negatively on protein digestion, which is especially dangerous for patients with pancreatitis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. ACAT inhibition and amyloid beta reduction.

    Science.gov (United States)

    Bhattacharyya, Raja; Kovacs, Dora M

    2010-08-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disorder. Accumulation and deposition of the beta-amyloid (Abeta) peptide generated from its larger amyloid precursor protein (APP) is one of the pathophysiological hallmarks of AD. Intracellular cholesterol was shown to regulate Abeta production. Recent genetic and biochemical studies indicate that not only the amount, but also the distribution of intracellular cholesterol is critical to regulate Abeta generation. Acyl-coenzyme A: cholesterol acyl-transferase (ACAT) is a family of enzymes that regulates the cellular distribution of cholesterol by converting membrane cholesterol into hydrophobic cholesteryl esters for cholesterol storage and transport. Using pharmacological inhibitors and transgenic animal models, we and others have identified ACAT1 as a potential therapeutic target to lower Abeta generation and accumulation. Here we discuss data focusing on ACAT inhibition as an effective strategy for the prevention and treatment of AD. Copyright 2010 Elsevier B.V. All rights reserved.

  20. Ubiquitylation of terminal deoxynucleotidyltransferase inhibits its activity.

    Directory of Open Access Journals (Sweden)

    So Maezawa

    Full Text Available Terminal deoxynucleotidyltransferase (TdT, which template-independently synthesizes DNA during V(DJ recombination in lymphoid cells, is ubiquitylated by a BPOZ-2/Cul3 complex, as the ubiquitin ligase, and then degraded by the 26 S proteasome. We show here that TdT is ubiquitylated by the Cul3-based ubiquitylation system in vitro. Because TdT could also be ubiquitylated in the absence of Cul/BPOZ-2, we determined that it could also be directly ubiquitylated by the E2 proteins UbcH5a/b/c and UbcH6, E3-independently. Furthermore, the ubiquitylated TdT inhibited its nucleotidyltransferase activity.

  1. Inhibition shapes the organization of hippocampal representations.

    Science.gov (United States)

    McKenzie, Sam

    2017-09-16

    Hippocampal neurons become tuned to stimuli that predict behaviorally salient outcomes. This plasticity suggests that memory formation depends upon shifts in how different anatomical inputs can drive hippocampal activity. Here, I present evidence that inhibitory neurons can provide such a mechanism for learning-related changes in the tuning of pyramidal cells. Inhibitory currents arriving on the dendrites of pyramidal cells determine whether an excitatory input can drive action potential output. Specificity and plasticity of this dendritic modulation allows for precise, modifiable changes in how afferent inputs are integrated, a process that defines a neuron's receptive field. In addition, feedback inhibition plays a fundamental role in biasing which excitatory neurons may be co-active. By defining the rules of synchrony and the rules of input integration, interneurons likely play an important role in the organization of memory representation within the hippocampus. © 2017 Wiley Periodicals, Inc.

  2. Inhibition of gene expression by RNase P.

    Science.gov (United States)

    Lundblad, Eirik Wasmuth; Altman, Sidney

    2010-07-31

    The ability to interfere with gene expression is of crucial importance to unravel the function of genes and is also a promising therapeutic strategy. Here we discuss methodologies for inhibition of target RNAs based on the cleavage activity of the essential enzyme, Ribonuclease P (RNase P). RNase P-mediated cleavage of target RNAs can be directed by external guide sequences (EGSs) or by the use of the catalytic M1 RNA from E. coli linked to a guide sequence (M1GSs). These are not only basic tools for functional genetic studies in prokaryotic and eukaryotic cells but also promising antibacterial, anticancer and antiviral agents. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  3. Behavioral inhibition and PTSD symptoms in veterans

    Science.gov (United States)

    Myers, Catherine E.; VanMeenen, Kirsten M.; Servatius, Richard J.

    2012-01-01

    Behavioral inhibition (BI), a temperamental bias to respond to novel stimuli with avoidance behaviors, is a risk factor for posttraumatic stress disorder (PTSD). It is unclear whether BI accounts for additional variance in PTSD symptom severity beyond that accounted for by general anxiety. Here, 109 veterans (mean age 50.4 years, 9.2% female) provided self-assessment of PTSD symptoms, state and trait anxiety, combat exposure, and current (adult) and retrospective (childhood) BI. Adult BI was correlated with anxiety and PTSD symptom severity, especially cluster C (avoidance) symptoms, but not with combat exposure. A regression model including adult BI, state and trait anxiety, and combat exposure was able to correctly classify over 80% of participants according to presence or absence of severe PTSD symptoms. Because avoidance behaviors are a core component of PTSD, self-assessments of BI may be an important tool in understanding PTSD and potentially assessing vulnerability to the disorder. PMID:22397911

  4. Method of inhibiting corrosion in acidizing wells

    Energy Technology Data Exchange (ETDEWEB)

    Williams, D.A.; Holifield, P.K.; Looney, J.R.; McDougall, L.A.

    1992-02-18

    This patent describes improvement in a method of acidizing a subterranean formation penetrated by a borehole which has metal pipe positioned therein wherein an aqueous acid solution is pumped down the pipe and into the formation. The improvement comprises introducing components of a nonacetylenic corrosion inhibitor directly into the aqueous acid solution to form the corrosion inhibitor in the acid solution at a concentration to inhibit corrosion of the metal, the components consisting essentially of: an antimony compound which provides from 0.04 to 2.0 wt % of antimony ions in the aqueous acid; from 0.2 to 10 wt % of a quaternary ammonium compound capable of forming a complex with the antimony ions; and from 0.1 to 25 wt % of a surfactant capable of water wetting the pipe.

  5. Covalent inhibition of the lymphoid tyrosine phosphatase.

    Science.gov (United States)

    Ahmed, Vanessa F; Bottini, Nunzio; Barrios, Amy M

    2014-02-01

    Covalent inhibitors of lymphoid tyrosine phosphatase (LYP) were identified from a screen of the NIH Molecular Libraries Small Molecules Repository (MLSMR). Both of the two lead compounds identified have phosphotyrosine-mimetic benzoic acid moieties as well as electrophilic acrylonitrile groups. Inhibition kinetics of both compounds are consistent with covalent modification of the enzyme, with nanomolar KI and reciprocal millisecond kinact values, representing the best efficiency ratios (kinact /KI ) among currently reported covalent LYP inhibitors. Covalent inhibitors can provide longer efficacy and better selectivity than more conventional noncovalent inhibitors, and these lead compounds are an important step toward the development of protein tyrosine phosphatase (PTP)-targeted covalent therapeutic compounds. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Inhibition of Quorum Sensing in Staphylococcus spp.

    Science.gov (United States)

    Brackman, Gilles; Coenye, Tom

    2015-01-01

    The Gram-positive, facultative anaerobic coccus-shaped bacteria of the genus Staphylococcus are among the most important causative agents of acute and chronic bacterial infections in humans as well as in animals. Treatment of Staphylococcus infections has become increasingly challenging due to the growing problem of antibiotic resistance. For this reason innovative antimicrobials with novel targets and modes of action are needed. Since the discovery that QS is used by Staphylococcus spp. to coordinate the expression of several genes involved in virulence, biofilm formation and pathogenicity, QS inhibition has gained increasing attention as an alternative anti-pathogenic strategy. A major advantage compared with antibiotic therapy is that QSIs are used in concentrations that do not affect bacterial growth. For this reason, it is expected that these compounds would exert less pressure towards the development of resistance. However, some important points still need to be addressed. Although several inhibitors have proven to be active antipathogenic agents in vitro and in several in vivo models, it is still unknown whether these compounds will also be useful in humans. Furthermore, several fundamental mechanisms by which the different QS systems in Staphylococcus spp. exert their regulatory functions and how they are inhibited by QSIs are still poorly understood. In order to achieve real-life applications with QSIs, these challenges should be addressed and more research will be needed. In this article, we will discuss the different QS systems present in Staphylococcus spp., how they are used to control virulence and biofilm formation and how they can be blocked.

  7. Rhabdoid tumor growth is inhibited by flavopiridol.

    Science.gov (United States)

    Smith, Melissa E; Cimica, Velasco; Chinni, Srinivasa; Challagulla, Kavitha; Mani, Sridhar; Kalpana, Ganjam V

    2008-01-15

    Rhabdoid tumors are aggressive and incurable pediatric malignancies. INI1/hSNF5, a tumor suppressor biallelically deleted/inactivated in rhabdoid tumors, directly represses cyclin D1. Rhabdoid tumors and cells are exquisitely dependent on cyclin D1 for genesis and survival, suggesting that targeting the cyclin/cyclin-dependent kinase (cdk) axis may be an effective therapeutic strategy for these tumors. Because cdk inhibitors have not been used for preclinical or clinical testing on rhabdoid tumors, we investigated the effect of flavopiridol, a pan-cdk inhibitor with promising clinical activity, on rhabdoid tumors. The effect of flavopiridol on rhabdoid cells was tested in vitro using survival, cell cycle, and apoptosis assays. Its effect was assessed in vivo using xenografted rhabdoid tumor models. Immunoblot and immunohistochemical analysis was used to assess the effect of flavopiridol on cyclin D1 and p21 expression in vitro and in vivo, respectively. Nanomolar concentrations of flavopiridol inhibited rhabdoid cell growth (IC(50) approximately 200 nmol/L), induced G(1) and G(2) arrest, and apoptosis in vitro in a concentration-dependent manner. These effects were correlated with the down-modulation of cyclin D1, up-regulation of p21, and induction of caspase 3/7 activities. Flavopiridol (at 7.5 mg/kg) significantly inhibited the growth of xenografted rhabdoid tumors, and its effect was correlated with the induction of p21 and down-modulation of cyclin D1. Flavopiridol is effective in inducing cell cycle arrest and cytotoxicity in rhabdoid tumors. Its effects are correlated with the down-regulation of cyclin D1 and the up-regulation of p21. Flavopiridol is potentially a novel chemotherapeutic agent for rhabdoid tumors.

  8. Primary proteasome inhibition results in cardiac dysfunction

    Science.gov (United States)

    Herrmann, Joerg; Wohlert, Christine; Saguner, Ardan M.; Flores, Ana; Nesbitt, Lisa L.; Chade, Alejandro; Lerman, Lilach O.; Lerman, Amir

    2013-01-01

    Aims The proteasome prevents the intracellular accumulation of proteins and its impairment can lead to structural and functional alterations, as noted for the coronary vasculature in a previous study. Utilizing the same model, this study was designed to test the hypothesis that chronic proteasome inhibition (PSI) also leads to structural and functional changes of the heart. Methods and results Female domestic pigs were randomized to a normal diet without (N) or with twice-weekly subcutaneous injections of the proteasome inhibitor MLN-273 (0.08 mg/kg, N + PSI, n = 5 each group). In vivo data on cardiac structure and function as well as myocardial perfusion and microvascular permeability response to adenosine and dobutamine were obtained by electron beam computed tomography after 11 weeks. Subsequent ex vivo myocardial analyses included immunoblotting, immunostaining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labelling), Masson trichrome, and Congo red staining. Compared with N, an increase in LV mass was observed in N + PSI (106.5 ± 16.4 g vs. 183.1 ± 24.2 g, P < 0.05). The early to late diastolic filling ratio was increased in N + PSI vs. N (3.5 ± 0.6 vs. 1.8 ± 0.1, P < 0.05). The EF tended to be lower (46 ± 12% and 53 ± 9%, respectively) and cardiac output was significantly lower in N + PSI than in N (2.9 ± 1.1 vs. 4.7 ± 1.1 L/min, P < 0.05). Tissue analyses demonstrated an accumulation of proteasome substrates, apoptosis, and fibrosis in the PSI group. Compared with N, the myocardial perfusion response was reduced and microvascular permeability was increased in N + PSI. Conclusion The current study demonstrates that chronic proeasome inhibition affects the cardiovascular system, leading to functional and structural alteration of the heart consistent with a hypertrophic–restrictive cardiomyopathy phenotype. PMID:23616520

  9. Mechanisms of hop inhibition: hop ionophores.

    Science.gov (United States)

    Behr, Jürgen; Vogel, Rudi F

    2009-07-22

    In this work, the mechanism of hop inhibition toward (beer spoiling) bacteria is revised. The mode of action of iso-alpha-acids was investigated via bilayer lipid membrane (BLM) measurements and growth challenges of hop-sensitive and -resistant Lactobacillus brevis strains in the presence of uncouplers of class I and II or a H(+)/Mn(2+) exchanger. The antibacterial action of iso-alpha-acids as proton ionophores could be confirmed by the BLM measurements; however, the reported ionophore properties, as electroneutral H(+)/Mn(2+) exchangers, could not be verified. Potentiometric measurements indicated the manganese-dependent enhancement of transmembrane charge permeation. The origin of high membrane potentials in the presence of manganese, as well as the strongly elevated membrane conductivity with concomitant increase in effectiveness of an uncoupler, suggest a different origin of charge transfer under these conditions. The mode of antibacterial action of hop ionophores can be described as proton ionophores of class I/II, which are capable transporting protons within a wide range of pH due to their inherent complexity of chemical composition. However, growth challenges in the presence of both types of ionophore classes in combination with the measured unusual high BLM potentials in the presence of manganese and at low pH indicate an additional mechanism of inhibition by hop compounds. The latter may be due to the nature/properties of hop compounds, which are known to be highly reactive substances. As a consequence, hop resistance of bacteria can be described as multiple resistance to a heterogeneous mixture of compounds comprising different known and yet unknown charge transport mechanisms, which were dependent on several factors, for example, compound concentrations, cation composition, and pH value. Thus, only specialists such as some L. brevis strains, which can cope with unusually low intracellular manganese levels, can survive hop stress. Accordingly, cross

  10. Enoxacin directly inhibits osteoclastogenesis without inducing apoptosis.

    Science.gov (United States)

    Toro, Edgardo J; Zuo, Jian; Ostrov, David A; Catalfamo, Dana; Bradaschia-Correa, Vivian; Arana-Chavez, Victor; Caridad, Aliana R; Neubert, John K; Wronski, Thomas J; Wallet, Shannon M; Holliday, L Shannon

    2012-05-18

    Enoxacin has been identified as a small molecule inhibitor of binding between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments. It inhibits bone resorption by calcitriol-stimulated mouse marrow cultures. We hypothesized that enoxacin acts directly and specifically on osteoclasts by disrupting the interaction between plasma membrane-directed V-ATPases, which contain the osteoclast-selective a3-subunit of V-ATPase, and microfilaments. Consistent with this hypothesis, enoxacin dose-dependently reduced the number of multinuclear cells expressing tartrate-resistant acid phosphatase (TRAP) activity produced by RANK-L-stimulated osteoclast precursors. Enoxacin (50 μM) did not induce apoptosis as measured by TUNEL and caspase-3 assays. V-ATPases containing the a3-subunit, but not the "housekeeping" a1-subunit, were isolated bound to actin. Treatment with enoxacin reduced the association of V-ATPase subunits with the detergent-insoluble cytoskeleton. Quantitative PCR revealed that enoxacin triggered significant reductions in several osteoclast-selective mRNAs, but levels of various osteoclast proteins were not reduced, as determined by quantitative immunoblots, even when their mRNA levels were reduced. Immunoblots demonstrated that proteolytic processing of TRAP5b and the cytoskeletal protein L-plastin was altered in cells treated with 50 μM enoxacin. Flow cytometry revealed that enoxacin treatment favored the expression of high levels of DC-STAMP on the surface of osteoclasts. Our data show that enoxacin directly inhibits osteoclast formation without affecting cell viability by a novel mechanism that involves changes in posttranslational processing and trafficking of several proteins with known roles in osteoclast function. We propose that these effects are downstream to blocking the binding interaction between a3-containing V-ATPases and microfilaments.

  11. Enoxacin Directly Inhibits Osteoclastogenesis without Inducing Apoptosis*

    Science.gov (United States)

    Toro, Edgardo J.; Zuo, Jian; Ostrov, David A.; Catalfamo, Dana; Bradaschia-Correa, Vivian; Arana-Chavez, Victor; Caridad, Aliana R.; Neubert, John K.; Wronski, Thomas J.; Wallet, Shannon M.; Holliday, L. Shannon

    2012-01-01

    Enoxacin has been identified as a small molecule inhibitor of binding between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments. It inhibits bone resorption by calcitriol-stimulated mouse marrow cultures. We hypothesized that enoxacin acts directly and specifically on osteoclasts by disrupting the interaction between plasma membrane-directed V-ATPases, which contain the osteoclast-selective a3-subunit of V-ATPase, and microfilaments. Consistent with this hypothesis, enoxacin dose-dependently reduced the number of multinuclear cells expressing tartrate-resistant acid phosphatase (TRAP) activity produced by RANK-L-stimulated osteoclast precursors. Enoxacin (50 μm) did not induce apoptosis as measured by TUNEL and caspase-3 assays. V-ATPases containing the a3-subunit, but not the “housekeeping” a1-subunit, were isolated bound to actin. Treatment with enoxacin reduced the association of V-ATPase subunits with the detergent-insoluble cytoskeleton. Quantitative PCR revealed that enoxacin triggered significant reductions in several osteoclast-selective mRNAs, but levels of various osteoclast proteins were not reduced, as determined by quantitative immunoblots, even when their mRNA levels were reduced. Immunoblots demonstrated that proteolytic processing of TRAP5b and the cytoskeletal protein l-plastin was altered in cells treated with 50 μm enoxacin. Flow cytometry revealed that enoxacin treatment favored the expression of high levels of DC-STAMP on the surface of osteoclasts. Our data show that enoxacin directly inhibits osteoclast formation without affecting cell viability by a novel mechanism that involves changes in posttranslational processing and trafficking of several proteins with known roles in osteoclast function. We propose that these effects are downstream to blocking the binding interaction between a3-containing V-ATPases and microfilaments. PMID:22474295

  12. Evaluation of selenite effects on selenoproteins and cytokinome in human hepatoma cell lines

    National Research Council Canada - National Science Library

    Rusolo, Fabiola; Pucci, Biagio; Colonna, Giovanni; Capone, Francesca; Guerriero, Eliana; Milone, Maria Rita; Nazzaro, Melissa; Volpe, Maria Grazia; Di Bernardo, Gianni; Castello, Giuseppe; Costantini, Susan

    2013-01-01

    .... The aim of this work was to test in vitro the effect of sodium selenite on the human hepatoma cell lines, HepG2 and Huh7, to assess its effect on the expression of GPX1, SELK and SELENBP1 and also...

  13. Inhibition of acetylcholinesterase by diisocyanates and its spontaneous reactivation.

    Science.gov (United States)

    Dewair, M; Baur, X; Mauermayer, R

    1983-01-01

    The inhibition of human acetylcholinesterase (AchE) by 4,4'-diphenylmethane diisocyanate (MDI) is determined and compared with the previously described inhibition of this enzyme by two other industrially used diisocyanates: toluene diisocyanate (TDI) and hexamethylene diisocyanate (HDI). The inhibition potency of these three diisocyanates is found to be in the oder HDI greater than TDI greater than MDI. The spontaneous reactivation of inhibited AchE is reanalysed with the help of a computer program designed to fit the reactivation data to the exponential rate equation Vt = Vinf (1 - e-Kobs X (t - to) ). The enzyme inhibited by HDI and MDI undergoes very slow and limited spontaneous reactivation. The rate of delivery of diisocyanates into the respiratory tract of an exposed worker may be faster than the rate of spontaneous reactivation of the inhibited enzyme. These results are discussed in connection with the obstructive lung disease observed in approximately 5% of the workers employed in the isocyanate industry.

  14. Is There a Therapeutic Role for Selenium in Alpha-1 Antitrypsin Deficiency?

    Directory of Open Access Journals (Sweden)

    Noel G. McElvaney

    2013-03-01

    Full Text Available Selenium is an essential trace mineral of fundamental importance to human health. Much of its beneficial influence is attributed to its presence within selenoproteins, a group of proteins containing the rare amino acid selenocysteine. There are 25 known human selenoproteins including glutathione peroxidases, thioredoxin reductases and selenoproteins. Selenoprotein S (SEPS1 is an endoplasmic reticulum (ER resident selenoprotein involved in the removal of misfolded proteins from the ER. SEPS1 expression can be induced by ER stress, an event that is associated with conformational disorders and occurs due to accumulation of misfolded proteins within the ER. Alpha-1 antitrypsin (AAT deficiency, also known as genetic emphysema, is a conformational disorder in which the roles of ER stress, SEPS1 and selenium have been investigated. SEPS1 can relieve ER stress in an in vitro model of AAT deficiency by reducing levels of active ATF6 and inhibiting grp78 promoter- and NFκB activity; some of these effects are enhanced in the presence of selenium supplementation. Other studies examining the molecular mechanisms by which selenium mediates its anti-inflammatory effects have identified a role for prostaglandin 15d-PGJ2 in targeting NFκB and PPARγ. Together these ER stress-relieving and anti-inflammatory properties suggest a therapeutic potential for selenium supplementation in genetic emphysema.

  15. Non Parametric Estimation of Inhibition for Point Process Data

    OpenAIRE

    Beyor, Alexa Lake

    2015-01-01

    For a single geyser one eruption may inhibit another eruption. The objective is to estimate the inhibition function of geyser eruptions using a non parametric algorithm by extending the non parametric estimation method of Marsan and Lenglin?(2008) for clustered Hawkes processes to the case where there may be inhibition. The proposed method is tested using simulated geyser eruption data from known densities: Exponential, Pareto, Normal, and Uniform. The method is then applied ot the actual dat...

  16. High molecular weight polysaccharide that binds and inhibits virus

    Science.gov (United States)

    Konowalchuk, Thomas W

    2014-01-14

    This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods on inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

  17. High molecular weight polysaccharide that binds and inhibits virus

    Energy Technology Data Exchange (ETDEWEB)

    Konowalchuk, Thomas W.; Konowalchuk, Jack

    2017-07-18

    This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods of inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further includes methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

  18. Inhibition of Human Vascular NADPH Oxidase by Apocynin Derived Oligophenols

    OpenAIRE

    Mora-Pale, Mauricio; Weïwer, Michel; Yu, Jingjing; Linhardt, Robert J.; Dordick, Jonathan S.

    2009-01-01

    Enzymatic oxidation of apocynin, which may mimic in vivo metabolism, affords a large number of oligomers (apocynin oxidation products, AOP) that inhibit vascular NADPH oxidase. In vitro studies of NADPH oxidase activity were performed to identify active inhibitors, resulting in a trimer hydroxylated quinone (IIIHyQ) that inhibited NADPH oxidase with an IC50 = 31 nM. Apocynin itself possessed minimal inhibitory activity. NADPH oxidase is believed to be inhibited through prevention of the inter...

  19. New drug target in protozoan parasites: the role of thioredoxin reductase

    Directory of Open Access Journals (Sweden)

    Rosa M. Andrade

    2015-09-01

    Full Text Available Amebiasis causes approximately 70,000 deaths annually and is the third cause of death due to parasites worldwide. It is treated primarily with metronidazole, which has adverse side effects, is mutagenic and carcinogenic, and emergence of resistance is an increasing concern. Unfortunately, better therapeutic alternatives are lacking. Re-purposing of older FDA approved drugs is advantageous to drug discovery since safety and pharmacokinetic effects in humans are already known. In high throughput screening studies, we recently demonstrated that auranofin, a gold containing compound originally approved to treat rheumatoid arthritis, has activity against trophozoites of E. histolytica, the causative agent of amebiasis. Auranofin’s anti-parasitic activity is attributed to its monovalent gold molecule that readily inhibits E.histolytica thioredoxin reductase. This anti-oxidant enzyme is the only thiol-dependent flavo-reductase present in E.histolytica. Auranofin has also shown promising activity against other protozoans of significant public health importance. Altogether, this evidence suggests that auranofin has the potential to become a broad spectrum alternative therapeutic agent for diseases with a large global burden.

  20. Timing of growth inhibition following shoot inversion in Pharbitis nil

    Science.gov (United States)

    Abdel-Rahman, A. M.; Cline, M. G.

    1989-01-01

    Shoot inversion in Pharbitis nil results in the enhancement of ethylene production and in the inhibition of elongation in the growth zone of the inverted shoot. The initial increase in ethylene production previously was detected within 2 to 2.75 hours after inversion. In the present study, the initial inhibition of shoot elongation was detected within 1.5 to 4 hours with a weighted mean of 2.4 hours. Ethylene treatment of upright shoots inhibited elongation in 1.5 hours. A cause and effect relationship between shoot inversion-enhanced ethylene production and inhibition of elongation cannot be excluded.

  1. Selective and nonselective inhibition of competitors in picture naming.

    Science.gov (United States)

    Shao, Zeshu; Meyer, Antje S; Roelofs, Ardi

    2013-11-01

    The present study examined the relation between nonselective inhibition and selective inhibition in picture naming performance. Nonselective inhibition refers to the ability to suppress any unwanted response, whereas selective inhibition refers to the ability to suppress specific competing responses. The degree of competition in picture naming was manipulated by presenting targets along with distractor words that could be semantically related (e.g., a picture of a dog combined with the word cat) or unrelated (tree) to the picture name. The mean naming response time (RT) was longer in the related than in the unrelated condition, reflecting semantic interference. Delta plot analyses showed that participants with small mean semantic interference effects employed selective inhibition more effectively than did participants with larger semantic interference effects. The participants were also tested on the stop-signal task, which taps nonselective inhibition. Their performance on this task was correlated with their mean naming RT but, importantly, not with the selective inhibition indexed by the delta plot analyses and the magnitude of the semantic interference effect. These results indicate that nonselective inhibition ability and selective inhibition of competitors in picture naming are separable to some extent.

  2. Obesity, Cardiovascular Fitness, and Inhibition Function: An Electrophysiological Study

    National Research Council Canada - National Science Library

    Song, Tai-Fen; Chi, Lin; Chu, Chien-Heng; Chen, Feng-Tzu; Zhou, Chenglin; Chang, Yu-Kai

    2016-01-01

    The purpose of the present study was to examine how obesity and cardiovascular fitness are associated with the inhibition aspect of executive function from behavioral and electrophysiological perspectives...

  3. Cognitive inhibition in students with and without dyslexia and dyscalculia.

    Science.gov (United States)

    Wang, Li-Chih; Tasi, Hung-Ju; Yang, Hsien-Ming

    2012-01-01

    The present study presents a comparison of the cognitive inhibition abilities of dyslexic, dyscalculic, and control students. The participants were 45 dyslexic students, 45 dyscalculic students, and 45 age-, gender-, and IQ-matched control students. The major evaluation tools included six cognitive inhibition tasks which were restructured during principal component analysis into three categories: graph inhibition, number inhibition, and word inhibition. Comparisons of the 3 groups of students revealed that in graph inhibition, dyscalculic students performed worst of the 3 groups, with dyslexic students also performing worse than control students in this category. For number inhibition, the control students' performances were equal to those of dyslexic students, with both groups performing better than dyscalculic students. For word inhibition, control students' performances were equal to those of dyscalculic students; both groups had shorter response times and lower incorrect rates than dyslexic students. These results suggest the complexity of the different cognitive inhibition abilities displayed by dyslexic, dyscalculic, and control students. However, some regular patterns occurred. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ying-Nan P.; LaMarche, Matthew J.; Chan, Ho Man; Fekkes, Peter; Garcia-Fortanet, Jorge; Acker, Michael G.; Antonakos, Brandon; Chen, Christine Hiu-Tung; Chen, Zhouliang; Cooke, Vesselina G.; Dobson, Jason R.; Deng, Zhan; Fei, Feng; Firestone, Brant; Fodor, Michelle; Fridrich, Cary; Gao, Hui; Grunenfelder, Denise; Hao, Huai-Xiang; Jacob, Jaison; Ho, Samuel; Hsiao, Kathy; Kang, Zhao B.; Karki, Rajesh; Kato, Mitsunori; Larrow, Jay; La Bonte, Laura R.; Lenoir, Francois; Liu, Gang; Liu, Shumei; Majumdar, Dyuti; Meyer, Matthew J.; Palermo, Mark; Perez, Lawrence; Pu, Minying; Price, Edmund; Quinn, Christopher; Shakya, Subarna; Shultz, Michael D.; Slisz, Joanna; Venkatesan, Kavitha; Wang, Ping; Warmuth, Markus; Williams, Sarah; Yang, Guizhi; Yuan, Jing; Zhang, Ji-Hu; Zhu, Ping; Ramsey, Timothy; Keen, Nicholas J.; Sellers, William R.; Stams, Travis; Fortin, Pascal D.

    2016-06-29

    The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase1. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma1, 2, 3, 4, 5. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway2, 3. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways6, 7. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy8, 9. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

  5. Picrorhiza kurroa Inhibits Experimental Arthritis Through Inhibition of Pro-inflammatory Cytokines, Angiogenesis and MMPs.

    Science.gov (United States)

    Kumar, Rohit; Gupta, Yogendra Kumar; Singh, Surender; Arunraja, S

    2016-01-01

    The present study investigates the anti-arthritic activity of Picrorhiza kurroa (PK), on formaldehyde and adjuvant-induced arthritis (AIA) in rat. Administration of Picrorhiza kurroa rhizome extract (PKRE) significantly inhibited joint inflammation in both animal models. In AIA-induced arthritic rat, treatment with PKRE considerably decreased synovial expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor receptor-1 (TNF-R1) and vascular endothelial growth factor as compared with control. The anti-arthritic activity was found to be well substantiated with significant suppression of oxidative and inflammatory markers as there was decreased malonaldehyde, Nitric oxide, tumor necrosis factor alpha levels accompanied with increased glutathione and superoxide dismutase, catalase activities. Additionally, PKRE significantly inhibited the expression of degrading enzymes, matrix metalloproteinases-3 and matrix metalloproteinases-9 in AIA-induced arthritic rat. Histopathology of paw tissue displayed decreased inflammatory cell infiltration as compared with control. Taken together, these results demonstrated the anti-arthritic activity of PKRE against experimental arthritis, and the underlying mechanism behind this efficacy might be mediated by inhibition of inflammatory mediators and angiogenesis, improvement of the synovium redox status and decreased expression of matrix metalloproteinases. Copyright © 2015 John Wiley & Sons, Ltd.

  6. Downregulation of SIRT2 Inhibits Invasion of Hepatocellular Carcinoma by Inhibiting Energy Metabolism

    Directory of Open Access Journals (Sweden)

    Shan Huang

    2017-12-01

    Full Text Available Hepatocellular carcinoma (HCC is one of the most common neoplasms, and metastasis is the most important feature for HCC-related deaths. Mounting evidence implies the dynamic regulatory role of SIRT2, a histone deacetylase, in cancer cells. Unfortunately, the role of SIRT2 and the antitumor activity of its inhibition are not known in HCC. The present study aims to evaluate the biological function of SIRT2 in HCC and identify the target of SIRT2 as well as evaluate its therapeutic efficacy. We found that SIRT2 was upregulated in HCC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. Although CCK8 and colony-formation assays showed that SIRT2 inhibiton marginally promotes proliferation in HCC cell lines, SIRT2 knockdown decreased the invasion of HCC cells. We demonstrated that downregulation of SIRT2 could inhibit its downstream target phosphoenolpyruvate carboxykinase 1 and glutaminase, which is related to mitochondrial metabolism and the E-Cadherin pathway. These results demonstrate, for the first time that downregulation of SIRT2 decreases migration as well as invasion in human HCC cells, indicating that inhibiting SIRT2 may be an effective therapeutic strategy for treating HCC.

  7. PAC-1 and its derivative WF-210 Inhibit Angiogenesis by inhibiting VEGF/VEGFR pathway.

    Science.gov (United States)

    Wang, Fangyang; Wang, Lihui; Li, Yi; Wang, Nannan; Wang, Yating; Cao, Qi; Gong, Ping; Yang, Jingyu; Wu, Chunfu

    2017-12-19

    Procaspase Activating Compound-1 (PAC-1) and its derivative WF-210 induce apoptosis in cancer cells by activating procaspase-3 to caspase-3. The aim of this study was to extend current knowledge about the mechanisms of PAC-1 and WF-210, particularly about their effects on tumor angiogenesis. PAC-1 and WF-210 restrained VEGF-induced human umbilical vascular endothelial cells (HUVECs) proliferation, invasion, and tube formation. PAC-1 and WF-210 abrogated VEGF-induced vessel sprouting from rat aortic rings and inhibited vascular formation in the Matrigel plug assay. PAC-1 and WF-210 suppressed phosphorylation of VEGFR2 and its downstream protein kinases c-Src, FAK, and AKT in both HUVECs and U-87 cells. When given to mice bearing subcutaneous or orthotopic xenograft, PAC-1 and WF-210 inhibited the tumor growth and tumor angiogenesis. Further tests showed that PAC-1 and WF-210 inhibited stemness and induced autophagy flux of U-87 cells. This study revealed mechanisms of PAC-1 and WF-210 other than inducing apoptosis, which provides additional support for their using in the clinic. Copyright © 2017. Published by Elsevier B.V.

  8. Desflurane inhibits endothelium-dependent vasodilation more than sevoflurane with inhibition of endothelial nitric oxide synthase by different mechanisms.

    Science.gov (United States)

    Kazuma, Satoshi; Tokinaga, Yasuyuki; Takada, Yukimasa; Azumaguchi, Ryu; Kimizuka, Motonobu; Hayashi, Shunsuke; Yamakage, Michiaki

    2018-01-01

    The effects of desflurane on endothelium-dependent vasodilation remain uncertain, whereas sevoflurane is known to inhibit it. Endothelium-dependent vasodilation is mainly mediated by endothelial nitric oxide synthase. The effects of desflurane on endothelium-dependent vasodilation were compared with those of sevoflurane, and inhibition mechanisms, including phosphorylation of endothelial nitric oxide synthase and the calcium pathway, were evaluated for the two anesthetics. We hypothesized that desflurane would inhibit endothelium-dependent vasodilation in a concentration-dependent manner more than sevoflurane, with inhibition of a calcium pathway. Isolated rat aortic rings were randomly assigned to treatment with desflurane or sevoflurane for measurements of the vasodilation ratio. To determine NO production with desflurane and sevoflurane, an in vitro assay was performed with cultured bovine aortic endothelial cells. These cells were also used for measurement of intracellular calcium or Western blotting. For endothelium-dependent vasodilation, the ratio of vasodilation was more significantly inhibited by 11.4% desflurane than by 4.8% sevoflurane. Inhibition did not between 5.7% desflurane and 2.4% sevoflurane. No inhibitory effect of desflurane or sevoflurane was observed in endothelium-denuded aorta. Desflurane inhibited nitric oxide production caused by stimulation of bradykinin significantly more than sevoflurane. Desflurane had a greater suppressive effect on the bradykinin-induced increase in intracellular calcium concentration than did sevoflurane. Sevoflurane, but not desflurane, inhibited phosphorylation of the serine 1177 residue by bradykinin stimulation. Desflurane inhibited endothelium-dependent vasodilation more than sevoflurane through inhibition of a calcium pathway. Sevoflurane inhibited endothelium-dependent vasodilation by inhibition of phosphorylation of the serine 1177 residue of endothelial nitric oxide synthase. Copyright © 2017 Elsevier

  9. An alternative inhibition method for determining cross-reactive allergens.

    Science.gov (United States)

    Schmidt-Hieltjes, Yvonne; Teodorowicz, Malgorzata; Jansen, Ad; den Hartog, Gerco; Elfvering-Berendsen, Lisette; de Jong, Nicolette W; Savelkoul, Huub F J; Ruinemans-Koerts, Janneke

    2017-02-01

    Inhibition assays are an useful tool to identify the allergen of primary sensitization of cross-reactive allergens. Classical ELISA-based inhibition assays are limited by both the availability of commercial standardized allergen extracts and the experience and knowledge needed for making home-made extracts. Moreover the direct comparison of the inhibition ELISAs outcomes between different laboratories is difficult because of different sources of used allergen extracts and a number of methodological variations. Therefore, we propose a novel ImmunoCap (Phadia, Thermofisher Scientific) based immunoinhibition method with the use of commercially available Caps as the allergen source. The novel ImmunoCap based immunoinhibition method was developed and tested with sera from patients with a well-known cross-reactive sensitization for fig (Ficus carica) and ficus (Ficus benjamina). Results were compared with a classically applied inhibition method, i.e. addition of homemade allergen extract to patient serum. The amount of allergens (fig and ficus extracts) needed to reach a similar degree of inhibition was comparable for both inhibition methods. The ImmunoCap based inhibition assay, in addition to classical inhibition methods, is a valuable tool as the ImmunoCap analyzer and commercial allergens (Caps) are more widely available which makes the outcomes of inhibition tests comparable between different laboratories. Furthermore, in the ImmunoCap inhibition method the same protein source is used for both the inhibition of sIgE and sIgE measurement, which might be even more relevant when multiple cross-reactive allergens are tested.

  10. Paraquat inhibits progesterone synthesis in human placental mitochondria.

    Science.gov (United States)

    Milczarek, Ryszard; Sokołowska, Ewa; Rybakowska, Iwona; Kaletha, Krystian; Klimek, Jerzy

    2016-07-01

    Human placenta mitochondria produces huge amounts of progesterone necessary for maintaining the pregnancy. Lipid peroxidation in human placental mitochondria inhibits progesterone synthesis and that inhibition can be reversed by superoxide dismutase and other antioxidants. Paraquat (PQ) a highly toxic herbicide generates superoxide radical inside cells and induces lipid peroxidation. Hence, it is supposed to stimulate lipid peroxidation in human placental mitochondria and in consequence to inhibit a placental mitochondrial steroidogenesis. Placentas were obtained from normal pregnancies. All experiments were done using isolated human placental mitochondria. Mitochondrial lipid peroxidation was determined as tiobarbituric acid reactive substances (TBARS). A conversion of cholesterol to pregnenolone or pregnenolone to progesterone was measured using radiolabeled steroids and thin layer chromatography. PQ enhanced the iron-dependent lipid peroxidation as also PQ heightened the inhibitory action of this process on progesterone synthesis in isolated human placental mitochondria. Paradoxically, a superoxide dismutase (SOD) reversed the inhibition of progesterone synthesis only minimally although it strongly inhibited PQ stimulated iron-dependent lipid peroxidation. When iron was absent, PQ stimulated only negligible lipid peroxidation but strongly inhibited progesterone synthesis. SOD had no effect on inhibition of progesterone synthesis by PQ. PQ strongly inhibited of the conversion of cholesterol to pregnenolone but had not got any influence on the enzymatic activity of mitochondrial 3β-hydroxysteroid dehydrogenase. PQ strongly decreased the efficiency of NADPH-dependent cytochrome P450 reduction as well as it promoted the rapid oxidation of the pre-reduced mitochondrial cytochrome P450. However PQ has not inhibited combined activity of adrenodoxin reductase and adrenodoxin. We conclude that the most important reason of the inhibition of progesterone synthesis by PQ

  11. Stathmin potentiates vinflunine and inhibits Paclitaxel activity.

    Directory of Open Access Journals (Sweden)

    Soazig Malesinski

    Full Text Available Cell biology and crystallographic studies have suggested a functional link between stathmin and microtubule targeting agents (MTAs. In a previous study we showed that stathmin increases vinblastine (VLB binding to tubulin, and that conversely VLB increases stathmin binding to tubulin. This constituted the first biochemical evidence of the direct relationship between stathmin and an antimitotic drug, and revealed a new mechanism of action for VLB. The question remained if the observed interaction was specific for this drug or represented a general phenomenon for all MTAs. In the present study we investigated the binding of recombinant stathmin to purified tubulin in the presence of paclitaxel or another Vinca alkaloid, vinflunine, using Isothermal Titration Calorimetry (ITC. These experiments revealed that stathmin binding to tubulin is increased in the presence of vinflunine, whereas no signal is observed in the presence of paclitaxel. Further investigation using turbidity and co-sedimentation showed that stathmin inhibited paclitaxel microtubule-stabilizing activity. Taken together with the previous study using vinblastine, our results suggest that stathmin can be seen as a modulator of MTA activity and binding to tubulin, providing molecular explanation for multiple previous cellular and in vivo studies showing that stathmin expression level affects MTAs efficiency.

  12. IL-18-producing Salmonella inhibit tumor growth

    Science.gov (United States)

    Loeffler, Markus; Le'Negrate, Gaelle; Krajewska, Maryla; Reed, John C.

    2009-01-01

    Previous studies have shown that intravenously applied bacteria can accumulate in tumors and lead to sporadic tumor regression. Recently, systemic administration of attenuated Salmonella typhimurium was demonstrated to generate no significant side effects in humans, but also no anti-tumor responses. We report the enhanced antitumor activity in preclinical mouse cancer models of non-virulent S. typhimurium engineered to synthesize the cytokine, Interleukin-18 (IL-18). IL-18-producing bacteria (but not control bacteria) inhibit the growth of primary subcutaneous tumors as well as pulmonary metastases in immunocompetent mice challenged with syngeneic multi-drug resistant clones of murine carcinoma cell lines, without overt toxicity to normal tissues. Anti-tumor activity was associated with increased accumulation of T-lymphocytes and NK cells in tumors, and massive infiltration of granulocytes, as well as increased intra-tumoral production of several cytokines. In summary, these findings provide evidence of promising preclinical anti-tumor activity of IL-18-expressing, attenuated S. typhimurium, suggesting a novel strategy for cancer immunotherapy. PMID:18654612

  13. [Inhibition of lactation with lisuride. CLinical evaluation].

    Science.gov (United States)

    Sereno Coló, J A; Navarrete Horta, M T

    1994-01-01

    Lactation in humans requires the collaboration of neural and endocrine systems. During pregnancy and after parturition prolactin and also sex steroids, corticoids, growth hormone and human placental lactogen are necessary for lactogenesis. In an open, simple and prospective study, 50 women with normal delivery or cesarean section, between 34 and 41 weeks of gestation, were treated with lisuride, 0.2 mg t.i.d. for 14 days in order to inhibit lactation. The arrest of lactation was mandatory for medical reasons and the results were evaluated by changes in breast related with shape, volume, symmetry, coloring, temperature, turgescence, venous appearance, nipple condition, colostrum and lymph nodes increase. Lactation that was already present in 87% of patients in the first exploration 24 hours after delivery was satisfactorily suppressed and also breast pain, engorgement and discomfort caused by milk leakage. None had rebound lactation. 5 patients had light nausea. The dopamine agonist lisuride can be used for primary arrest of lactation with clinical effectiveness and without potential dangerous side effects of hormonal compounds.

  14. Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity.

    Science.gov (United States)

    Zheng, Shunsheng; Koh, Xin Yu; Goh, Hui Chin; Rahmat, Siti Aishah B; Hwang, Le-Ann; Lane, David P

    2017-08-15

    Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a first-line chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed. Cancer Res; 77(16); 4342-54. ©2017 AACR. ©2017 American Association for Cancer Research.

  15. [Mutual inhibition between positive and negative emotions].

    Science.gov (United States)

    Shimokawa, A

    1994-02-01

    The purpose of this study is to examine the relationship between positive and negative emotions. In study 1, 62 emotional items were selected in order to measure subjective emotional experiences. In study 2, comics, photos and poems were randomly presented to 1,220 college students to induce emotion. Subjects were asked to rate their momentary emotional intensity on two set of 5-point scales (general emotional intensity scale and 62 specific emotional intensity scale). In analysis 1, positive correlations were suggested between general emotional intensity scale and some of the specific emotional intensity scales which were activated by stimuli. In analysis 2, 10 positive and 10 negative emotional items were extracted from 62 items by factor analysis. In analysis 3, 4 and 5, it became clear that the distribution of frequency of correlations of 10 positive x 10 negative items changed according to the general emotional intensity scale. That is, from low to moderate levels of GEIS, the two kinds of emotion had no or slightly positive correlation, but at high level they became to be negatively correlated. From the facts described above, it is concluded that positive and negative emotions is not always independent, but show mutual inhibition in case of high intensity level of one of each emotions.

  16. Inhibition of glioblastoma malignancy by Lgl1.

    Science.gov (United States)

    Gont, Alexander; Hanson, Jennifer E L; Lavictoire, Sylvie J; Daneshmand, Manijeh; Nicholas, Garth; Woulfe, John; Kassam, Amin; Da Silva, Vasco F; Lorimer, Ian A J

    2014-11-30

    lethal giant larvae (lgl) was first identified as a tumor suppressor in Drosophila, where its loss repressed the differentiation and promoted the invasion of neuroblasts, the Drosophila equivalent of the neural stem cell. Recently we have shown that a human homolog of Lgl, Lgl1 (LLGL1), is constitutively phosphorylated and inactivated in glioblastoma cells; this occurs as a downstream consequence of PTEN loss, one of the most frequent genetic events in glioblastoma. Here we have investigated the consequences of this loss of functional Lgl1 in glioblastoma in vivo. We used a doxycycline-inducible system to express a non-phosphorylatable, constitutively active version of Lgl1 (Lgl3SA) in either a glioblastoma cell line or primary glioblastoma cells isolated under neural stem cell culture conditions from patients. In both types of cells, expression of Lgl3SA, but not wild type Lgl1, inhibited cell motility in vitro. Induction of Lgl3SA in intracerebral xenografts markedly reduced the in vivo invasion of primary glioblastoma cells. Lgl3SA expression also induced the differentiation of glioblastoma cells in vitro and in vivo along the neuronal lineage. Thus the central features of Lgl function as a tumor suppressor in Drosophila are conserved in human glioblastoma.

  17. Inhibition of RAS in diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Yacoub R

    2015-04-01

    Full Text Available Rabi Yacoub, Kirk N Campbell Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Abstract: Diabetic kidney disease (DKD is a progressive proteinuric renal disorder in patients with type 1 or type 2 diabetes mellitus. It is a common cause of end-stage kidney disease worldwide, particularly in developed countries. Therapeutic targeting of the renin–angiotensin system (RAS is the most validated clinical strategy for slowing disease progression. DKD is paradoxically a low systematic renin state with an increased intrarenal RAS activity implicated in its pathogenesis. Angiotensin II (AngII, the main peptide of RAS, is not only a vasoactive peptide but functions as a growth factor, activating interstitial fibroblasts and mesangial and tubular cells, while promoting the synthesis of extracellular matrix proteins. AngII also promotes podocyte injury through increased calcium influx and the generation of reactive oxygen species. Blockade of the RAS using either angiotensin converting enzyme inhibitors, or angiotensin receptor blockers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in humans with DKD. In this review, we summarize the role of intrarenal RAS activation in the pathogenesis and progression of DKD and the rationale for RAS inhibition in this population. Keywords: renin–angiotensin system, diabetic kidney disease, angiotensin II, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers

  18. Motor inhibition in hysterical conversion paralysis.

    Science.gov (United States)

    Cojan, Yann; Waber, Lakshmi; Carruzzo, Alain; Vuilleumier, Patrik

    2009-09-01

    Brain mechanisms underlying hysterical conversion symptoms are still poorly known. Recent hypotheses suggested that activation of motor pathways might be suppressed by inhibitory signals based on particular emotional situations. To assess motor and inhibitory brain circuits during conversion paralysis, we designed a go-nogo task while a patient underwent functional magnetic resonance imaging (fMRI). Preparatory activation arose in right motor cortex despite left paralysis, indicating preserved motor intentions, but with concomitant increases in vmPFC regions that normally mediate motivational and affective processing. Failure to execute movement on go trials with the affected left hand was associated with activations in precuneus and ventrolateral frontal gyrus. However, right frontal areas normally subserving inhibition were activated by nogo trials for the right (normal) hand, but not during go trials for the left hand (affected by conversion paralysis). By contrast, a group of healthy controls who were asked to feign paralysis showed similar activation on nogo trials and left-go trials with simulated weakness, suggesting that distinct inhibitory mechanisms are implicated in simulation and conversion paralysis. In the patient, right motor cortex also showed enhanced functional connectivity with the posterior cingulate cortex, precuneus, and vmPFC. These results suggest that conversion symptoms do not act through cognitive inhibitory circuits, but involve selective activations in midline brain regions associated with self-related representations and emotion regulation.

  19. Merlin inhibits neurite outgrowth in the CNS.

    Science.gov (United States)

    Schulz, Alexander; Geissler, Katja J; Kumar, Sujeet; Leichsenring, Gregor; Morrison, Helen; Baader, Stephan L

    2010-07-28

    The neurofibromatosis type 2 gene product merlin is known to provoke gliogenic tumors as a result of its mutagenic loss. Merlin's physiological anti-mitogenic function makes it unique among its ezrin-radixin-moesin (ERM) family members. Although ERM proteins and merlin are known to be expressed in glial cells of the peripheral nervous system and CNS, the neuronal expression pattern and function of merlin have been less well investigated. We report here expression of merlin in developing and mature neurons of the murine CNS. Within cerebellar Purkinje cells (PCs), merlin was localized in the soma, sprouting dendrites and axons. Merlin expression in PCs was high during the period of initial dendrite regression and declined during later phases of dendrite elongation. Consistently, merlin expression in vivo was increased in Engrailed-2-overexpressing PCs, which are characterized by a reduced dendritic extension. Furthermore, overexpression of merlin in dissociated cerebellar cultures and in neurogenic P19 cells caused a significant decline in neurite outgrowth, while, conversely, inhibition of merlin expression increased process formation. This effect was dependent on phosphorylation of serine 518 and involved the inactivation of the growth-promoting GTPase Rac. We thus provide evidence that merlin plays a pivotal role in controlling the neuronal wiring in the developing CNS.

  20. Inhibition of Midkine Augments Osteoporotic Fracture Healing.

    Directory of Open Access Journals (Sweden)

    Melanie Haffner-Luntzer

    Full Text Available The heparin-binding growth and differentiation factor midkine (Mdk is proposed to negatively regulate osteoblast activity and bone formation in the adult skeleton. As Mdk-deficient mice were protected from ovariectomy (OVX-induced bone loss, this factor may also play a role in the pathogenesis of postmenopausal osteoporosis. We have previously demonstrated that Mdk negatively influences bone regeneration during fracture healing. Here, we investigated whether the inhibition of Mdk using an Mdk-antibody (Mdk-Ab improves compromised bone healing in osteoporotic OVX-mice. Using a standardized femur osteotomy model, we demonstrated that Mdk serum levels were significantly enhanced after fracture in both non-OVX and OVX-mice, however, the increase was considerably greater in osteoporotic mice. Systemic treatment with the Mdk-Ab significantly improved bone healing in osteoporotic mice by increasing bone formation in the fracture callus. On the molecular level, we demonstrated that the OVX-induced reduction of the osteoanabolic beta-catenin signaling in the bony callus was abolished by Mdk-Ab treatment. Furthermore, the injection of the Mdk-Ab increased trabecular bone mass in the skeleton of the osteoporotic mice. These results implicate that antagonizing Mdk may be useful for the therapy of osteoporosis and osteoporotic fracture-healing complications.

  1. Polyspermy inhibition in the oyster, Crassostrea virginica.

    Science.gov (United States)

    Alliegro, M C; Wright, D A

    1983-07-01

    Inhibition of polyspermy is a critical response during fertilization which ensures that only one sperm nucleus will fuse with the female pronucleus to restore the diploid state. Oyster (Crassostrea virginica) eggs prevent polyspermy by a process occurring at the cell surface. However, 5 min after fertilization, there are still functional sperm receptor sites available for penetration by supernumerary sperm. Reinsemination experiments indicate that there is no decrease in the number of penetration sites during this interval. Yet, the number of sperm entering eggs is restricted to one per fertilized egg at a sperm:egg ratio of 1000:1. At a sperm:egg ratio of 10(5):1, an average of only six sperm were able to penetrate each egg. Gamete binding experiments indicate that there is a gradual decrease in the number of sperm bound to eggs starting at approximately 75 sec and continuing until all sperm are detached. Since eggs are fertilized within seconds of insemination and this process takes at least 12 min, it is considered an unlikely mechanism for the polyspermy block. There are no ultrastructural correlates to the polyspermy block nor to the unbinding of sperm, such as secretion of cortical granules or fertilization envelope formation. Based on reinsemination experiments, kinetic data, and ultrastructural observations, we suggest a physiological block to polyspermy which prevents fusion of gamete plasma membranes, and is mediated by an inhibitory effect directly upon the sperm.

  2. Arthropod venom citrate inhibits phospholipase A2.

    Science.gov (United States)

    Fenton, A W; West, P R; Odell, G V; Hudiburg, S M; Ownby, C L; Mills, J N; Scroggins, B T; Shannon, S B

    1995-06-01

    Citrate has been identified as a major component of honey bee (Apis mellifera) venom by gas liquid chromatography-mass spectrometry. A citrate concentration of 9% was found for dried bee venom by a coupled enzyme assay, aconitase-isocitric dehydrogenase. A liquid honey bee venom would contain 140 mM citrate concentration (if the solids content were 30%). Bee venom phospholipase was inhibited at a 43% level with a citrate concentration of 20 mM and calcium ion at 3 mM with the enzyme assay. Citrate was also found in the venoms of bumble bee, Bombus fervidus, 7%; yellow jacket, Vespula maculifrons, 4%; scorpion, Centruroides sculpturatus, 8%; tarantula, Grammastola cala, 8% and brown recluse spider venom gland extract, Loxoceles reclusa, 1.5% based on dried venom solids. Citrate may serve as an endogenous inhibitor of divalent metal ion-dependent enzymes in arthropod venoms as described by Francis et al. (1992, Toxicon 30, 1239-1246). Many arthropod venoms contain calcium-dependent phospholipases. A direct effect of citrate as a venom component may be possible. The presence of citrate in venoms must be considered in research on receptors, ion channels and divalent ion-dependent toxins.

  3. Inhibition of osteoblast activity by zoledronic acid

    Directory of Open Access Journals (Sweden)

    Fernanda Gonçalves Basso

    2013-10-01

    Full Text Available INTRODUCTION: Patients treated with nitrogen-containing bisphosphonates, such as zoledronic acid (ZA, have frequently shown oral bone exposure areas, termed osteonecrosis. In addition, these patients may also present low repair and regeneration potential, mainly after tooth extractions. These side-effects caused by bisphosphonates may be due to their inhibitory effects on oral mucosa and local bone cells. OBJECTIVE: To evaluate the effects of ZA on the mineralization capacity of cultured osteoblasts. MATERIALS AND METHODS: Human immortalized osteoblasts (SaOs-2 were grown in plain culture medium (Dulbecco's Modified Eagle Medium [DMEM] + 10% fetal bovine serum [FBS] in wells of 24-well plates. After 48-hour incubation, the plain DMEM was replaced by a solution with ZA at 5 µM which was maintained in contact with cells for seven, 14 or 21 days. After these periods, cells were evaluated regarding alkaline phosphatase (ALP activity and mineral nodule formation (alizarin red. Data were statistically analyzed by Mann-Whitney test, at 5% of significance level. RESULTS: ZA caused significant reduction on ALP activity and mineral nodules formation by cultured osteoblasts in all evaluated periods (p < 0.05. CONCLUSION: These data indicate that ZA causes inhibition on the osteogenic phenotype of cultured human osteoblasts, which, in turn, may reduce bone repair in patients subjected to ZA therapy.

  4. ODAM Expression Inhibits Human Breast Cancer Tumorigenesis

    Science.gov (United States)

    Kestler, Daniel P.; Foster, James S.; Bruker, Charles T.; Prenshaw, John W.; Kennel, Stephen J.; Wall, Jonathan S.; Weiss, Deborah T.; Solomon, Alan

    2011-01-01

    We have posited that Odontogenic Ameloblast Associated Protein (ODAM) serves as a novel prognostic biomarker in breast cancer and now have investigated its potential role in regulating tumor growth and metastasis. Human breast cancer MDA-MB-231 cells were transfected with a recombinant ODAM plasmid construct (or, as a control, the plasmid vector alone). ODAM expression increased adhesion and apoptosis of the transfected MDA-MB-231 cells and suppressed their growth rate, migratory activity, and capability to invade extracellular matrix-coated membranes. Implantation of such cells into mouse mammary fat pads resulted in significantly smaller tumors than occurred in animals that received control cells; furthermore, ODAM-expressing cells, when injected intravenously into mice, failed to metastasize, whereas the control-transfected counterparts produced extensive lung lesions. Our finding that induction of ODAM expression in human breast cancer cells markedly inhibited their neoplastic properties provides further evidence for the regulatory role of this molecule in tumorigenesis and, consequently, is of potential clinical import. PMID:21603257

  5. Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis.

    Science.gov (United States)

    Lee, Ji-Min; Seo, Woo-Young; Han, Hye-Sook; Oh, Kyoung-Jin; Lee, Yong-Soo; Kim, Don-Kyu; Choi, Seri; Choi, Byeong Hun; Harris, Robert A; Lee, Chul-Ho; Koo, Seung-Hoi; Choi, Hueng-Sik

    2016-01-01

    The role of a glucagon/cAMP-dependent protein kinase-inducible coactivator PGC-1α signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner-interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB β-deficient (PKBβ(-/-)) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4-mediated transcriptional activity via direct competition with PGC-1α. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  6. Inhibition of Oxidation in Nuclear Graphite

    Energy Technology Data Exchange (ETDEWEB)

    Phil Winston; James W. Sterbentz; William E. Windes

    2013-10-01

    Graphite is a fundamental material of high temperature gas cooled nuclear reactors, providing both structure and neutron moderation. Its high thermal conductivity, chemical inertness, thermal heat capacity, and high thermal structural stability under normal and off normal conditions contribute to the inherent safety of these reactor designs. One of the primary safety issues for a high temperature graphite reactor core is the possibility of rapid oxidation of the carbon structure during an off normal design basis event where an oxidizing atmosphere (air ingress) can be introduced to the hot core. Although the current Generation IV high temperature reactor designs attempt to mitigate any damage caused by a postualed air ingress event, the use of graphite components that inhibit oxidation is a logical step to increase the safety of these reactors. Recent experimental studies of graphite containing between 5.5 and 7 wt% boron carbide (B4C) indicate that oxidation is dramatically reduced even at prolonged exposures at temperatures up to 900°C. The proposed addition of B4C to graphite components in the nuclear core would necessarily be enriched in B-11 isotope in order to minimize B-10 neutron absorption and graphite swelling. The enriched boron can be added to the graphite during billet fabrication. Experimental oxidation rate results and potential applications for borated graphite in nuclear reactor components will be discussed.

  7. Inhibition of carcinogenesis by retinoids. [Review

    Energy Technology Data Exchange (ETDEWEB)

    Nettesheim, P.

    1979-01-01

    Progress made in recent years in the search for retinoids with anticarcinogenic activity is reviewed. There are many studies to be found in the literature which show no substantial effect of retinoids on carcinogenesis or tumor growth. Some of these negative findings may be related to the carcinogen dose used, the type of retinoid used, the dose, dose schedule or mode of administration of the retinoid. Others may indicate that the particular type of tumor or tumor system is, indeed, refractory to retinoids in general or to those retinoids that were tested. A great gap still exists in our knowledge concerning the pharmake-kinetics of most retinoids their availability to various normal and cancerous tissues, and the role and existence of transport and binding proteins. There are studies which indicate that under certain conditions, particularly conditions of topical application, some retinoids may even enhance carcinogenesis. It seems, however, indisputable by now that some retinoids are effective inhibitors of carcinogenesis in some organ systems and can even inhibit the growth of some established tumors. While the mechanisms of these inhibitory effects are presently not understood, it does seem clear that they are not mediated via the cytotoxic mechanisms typical of chemotherapeutic agents. The hope that retinoids might become an effective tool to halt the progression of some neoplastic diseases, seems to be justified.

  8. Vagus nerve stimulation inhibits cortical spreading depression.

    Science.gov (United States)

    Chen, Shih-Pin; Ay, Ilknur; de Morais, Andreia Lopes; Qin, Tao; Zheng, Yi; Sadeghian, Homa; Oka, Fumiaki; Simon, Bruce; Eikermann-Haerter, Katharina; Ayata, Cenk

    2016-04-01

    Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura and is a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its antimigraine effect. Unilateral vagus nerve stimulation was delivered either noninvasively through the skin or directly by electrodes placed around the nerve. Systemic physiology was monitored throughout the study. Both noninvasive transcutaneous and invasive direct vagus nerve stimulations significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke a spreading depression was elevated by more than 2-fold, the frequency of spreading depressions during continuous topical 1 M KCl was reduced by ∼40%, and propagation speed of spreading depression was reduced by ∼15%. This effect developed within 30 minutes after vagus nerve stimulation and persisted for more than 3 hours. Noninvasive transcutaneous vagus nerve stimulation was as efficacious as direct invasive vagus nerve stimulation, and the efficacy did not differ between the ipsilateral and contralateral hemispheres. Our findings provide a potential mechanism by which vagus nerve stimulation may be efficacious in migraine and suggest that susceptibility to spreading depression is a suitable platform to optimize its efficacy.

  9. In vitro screening of soil bacteria for inhibiting phytopathogenic fungi ...

    African Journals Online (AJOL)

    Bradyrhizobium japonicum could highly inhibit the mycelial growth of five moulds (Botrytis cinerea, Phoma medicaginis, Fusarium verticilloides, Rhizoctonia solani and Phytophtora infestans) with a growth inhibition varying between 12.38 and 37.61%. 12 Bacillus strains and five Pseudomonas strains were antagonistic to ...

  10. DNA damage protection and 5-lipoxygenase inhibiting activity of areca

    African Journals Online (AJOL)

    Administrator

    2011-09-21

    Sep 21, 2011 ... inhibiting activity on 5-lipoxygenase of areca inflorescence extracts were studied in vitro. The results show that the boiling ... degradation, inhibit the activity of tyrosinase and has protective effect on human serum .... inhibitory activity towards soybean lipoxygenase, 10 µl of different phenolic compounds at ...

  11. Inhibition of Fungal Aflatoxin B1 Biosynthesis by Diverse Botanically ...

    African Journals Online (AJOL)

    Tropical Journal of Pharmaceutical Research April 2015; 14 (4): 605-609. ISSN: 1596-5996 (print); 1596-9827 ... Results: Neither the tea-derived polyphenol mixture nor individual polyphenol compound, except quercetin, inhibited A. flavus ... compound that also inhibits fungal proliferation. Botanically-derived polyphenols ...

  12. Probe substrate and enzyme source-dependent inhibition of UDP ...

    African Journals Online (AJOL)

    Background: Drug-metabolizing enzymes (DMEs) inhibition based drug-drug interaction and herb-drug interaction severely challenge the R&D process of drugs or herbal ingredients. Objective: To evaluate the inhibition potential of wogonin (an important flavonoid isolated from the root of Scutellaria baicalensis) towards ...

  13. An alternative inhibition method for determining cross-reactive allergens

    NARCIS (Netherlands)

    Schmidt-Hieltjes, Yvonne; Teodorowicz, Gosia; Jansen, Ad; Hartog, Den Gerco; Elfvering-Berendsen, Lisette; Jong, De Nicolette W.; Savelkoul, Huub F.J.; Ruinemans-Koerts, Janneke

    2017-01-01

    Inhibition assays are an useful tool to identify the allergen of primary sensitization of cross-reactive allergens. Classical ELISA-based inhibition assays are limited by both the availability of commercial standardized allergen extracts and the experience and knowledge needed for making home-made

  14. Attention Inhibition Training Can Reduce Betel-Nut Chewing Time

    Directory of Open Access Journals (Sweden)

    Ming-Chou Ho

    2011-05-01

    Full Text Available Betel nut (or areca is the fourth most commonly used drug worldwide after tobacco, alcohol, and caffeine. Many chemical ingredients of betel nut are carcinogenic. We examined whether the manipulation of attentional inhibition toward the areca-related stimuli could affect betel-nut chewing time. Three matched groups of habitual chewers were recruited: inhibit-areca, inhibit-non-areca, and control. This study consisted of a Go/No-Go task for inhibition training, followed by a taste test for observing chewing behavior. The Go/No-Go task constituted three phases (pretest, training and posttest. In the taste test, the habitual chewers were asked to rate the flavors of one betel nut and one gum. The purpose (blind to the chewers of this taste test was to observe whether their picking order and chewing time were affected by experimental manipulation. Results from the Go/No-Go task showed successful training. Further, the training groups (the inhibit-areca and inhibit-non-areca groups showed a significant reduction in betel nut chewing time, in comparison to the control group. Since both training groups showed reduced chewing time, the inhibition training may affect general control ability, in regardless of the stimulus (areca or not to be inhibited. Reduced chewing time is important for reducing areca-related diseases.

  15. Effect of lisuride on inhibition of lactation and serum prolactin.

    Science.gov (United States)

    De Cecco, L; Venturini, P L; Ragni, N; Rossato, P; Maganza, C; Gaggero, G; Horowski, R

    1979-11-01

    Lisuride, a new semisynthetic ergot derivative, was given to 53 women to inhibit lactation; 26 women had 300 micrograms daily and 27 had 600 micrograms daily for seven days. Eight lactating women acted as controls. Lisuride effectively inhibited lactation and also suppressed the serum prolactin levels; the latter effect was dose related. Lisuride produced no untoward side effects.

  16. Social inhibition sense of belonging and vulnerability to internalizing problems

    NARCIS (Netherlands)

    de Moor, E.L.; Denollet, J.; Laceulle, O.M.

    2018-01-01

    Background The aim of this study was to provide a conceptual test of how social inhibition, sense of belonging and internalizing problems are related, and whether sense of belonging moderates or mediates the relation between social inhibition and internalizing problems. Methods Data were used from

  17. On the dependence of response inhibition processes on sensory modality.

    Science.gov (United States)

    Bodmer, Benjamin; Beste, Christian

    2017-04-01

    The ability to inhibit responses is a central sensorimotor function but only recently the importance of sensory processes for motor inhibition mechanisms went more into the research focus. In this regard it is elusive, whether there are differences between sensory modalities to trigger response inhibition processes. Due to functional neuroanatomical considerations strong differences may exist, for example, between the visual and the tactile modality. In the current study we examine what neurophysiological mechanisms as well as functional neuroanatomical networks are modulated during response inhibition. Therefore, a Go/NoGo-paradigm employing a novel combination of visual, tactile, and visuotactile stimuli was used. The data show that the tactile modality is more powerful than the visual modality to trigger response inhibition processes. However, the tactile modality loses its efficacy to trigger response inhibition processes when being combined with the visual modality. This may be due to competitive mechanisms leading to a suppression of certain sensory stimuli and the response selection level. Variations in sensory modalities specifically affected conflict monitoring processes during response inhibition by modulating activity in a frontal parietal network including the right inferior frontal gyrus, anterior cingulate cortex and the temporoparietal junction. Attentional selection processes are not modulated. The results suggest that the functional neuroanatomical networks involved in response inhibition critically depends on the nature of the sensory input. Hum Brain Mapp 38:1941-1951, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  18. Inhibition of nitrification and carbon dioxide evolution as rapid tools ...

    African Journals Online (AJOL)

    Inhibition of nitrite formation and CO2 evolution displayed similar levels of sensitivities at 95% confidence levels. These results indicate that monitoring inhibition of metabolic processes rather than mortality was a more rapid and sensitive tool for ecotoxicological evaluation of chemicals employed in the petroleum industry in ...

  19. A Subinhibitory Concentration of Clarithromycin Inhibits Mycobacterium avium Biofilm Formation

    OpenAIRE

    Carter, George; Young, Lowell S.; Bermudez, Luiz E.

    2004-01-01

    Mycobacterium avium causes disseminated infection in immunosuppressed individuals and lung infection in patients with chronic lung diseases. M. avium forms biofilm in the environment and possibly in human airways. Antibiotics with activity against the bacterium could inhibit biofilm formation. Clarithromycin inhibits biofilm formation but has no activity against established biofilm.

  20. Social Anxiety and Dating Inhibitions: Assessment and Treatment.

    Science.gov (United States)

    Arkowitz, Hal

    Recent research on the behavioral assessment and treatment of social anxiety and inhibition is reviewed. Subjects for the studies were college men and women selected on the basis of heterosexual anxiety and inhibition. The first part of the paper is concerned with assessment. The behavioral assessment procedures developed include: (1) direct…

  1. Experimental and quantum chemical studies on corrosion inhibition ...

    Indian Academy of Sciences (India)

    Abstract. The corrosion inhibition effect of fluconazole (FLU) was investigated on steel in 1 M hydrochloric acid solution. Weight loss measurements and atomic force microscope analysis were utilized to investigate the corrosion inhibition properties and film formation behaviour of FLU. Quantum chemical approach was also ...

  2. Experimental and quantum chemical studies on corrosion inhibition ...

    Indian Academy of Sciences (India)

    The corrosion inhibition effect of fluconazole (FLU) was investigated on steel in 1 M hydrochloric acid solution. Weight loss measurements and atomic force microscope analysis were utilized to investigate the corrosion inhibition properties and film formation behaviour of FLU. Quantum chemical approach was also used to ...

  3. INHIBITION OF THE CORROSION OF MILD STEEL IN ...

    African Journals Online (AJOL)

    ABSTRACT. The inhibition of corrosion of mild steel in hydrochloric acid by isatin glycine (ING) and isatin (IN) at 30-60 oC and concentrations of 0.0001 M to 0.0005 M was studied via weight loss method. At the highest inhibitor concentration studied ING exhibited inhibition efficiency of 87% while IN exhibited 84% at 60 oC.

  4. INHIBITION OF CORROSION OF ZINC IN (HNO3 + HCl) ACID ...

    African Journals Online (AJOL)

    2015-05-01

    May 1, 2015 ... ABSTRACT. Corrosion of Zinc metal in (HNO3 + HCl) binary acid mixture and inhibition efficiency of aniline has been studied by weight loss method and polarization technique. Corrosion rate increases with the concentration of acid mixture and the temperature. Inhibition efficiency. (I.E.) of aniline increases ...

  5. Comparative study of the inhibition effects of alkaloid and non ...

    African Journals Online (AJOL)

    The Alkaloid and Non- alkaloid fractions of the ethanolic extracts from Costus afer (AECA and NAECA) were comparatively studied for their inhibitive properties on the corrosion of mild steel in 5 M HCl solution using Gravimetric and Gasometric techniques. The results revealed that both extracts inhibited the corrosion of ...

  6. Inhibitive and Synergistic Properties of Ethanolic Extract of ...

    African Journals Online (AJOL)

    The higher the corrodent (HCl) concentration the higher the corrosion rate, while lower inhibition efficiency was observed in the absence and presence of the inhibitor and halides. The decrease in inhibition efficiency (and increase in reaction number values) was found to be in the order I− > Br− > Cl− which clearly indicates ...

  7. Inhibition of eye blinking reveals subjective perceptions of stimulus salience.

    Science.gov (United States)

    Shultz, Sarah; Klin, Ami; Jones, Warren

    2011-12-27

    Spontaneous eye blinking serves a critical physiological function, but it also interrupts incoming visual information. This tradeoff suggests that the inhibition of eye blinks might constitute an adaptive reaction to minimize the loss of visual information, particularly information that a viewer perceives to be important. To test this hypothesis, we examined whether the timing of blink inhibition, during natural viewing, is modulated between as well as within tasks, and also whether the timing of blink inhibition varies as a function of viewer engagement and stimulus event type. While viewing video scenes, we measured the timing of blinks and blink inhibition, as well as visual scanning, in a group of typical two-year-olds, and in a group of two-year-olds known for attenuated reactivity to affective stimuli: toddlers with Autism Spectrum Disorders (ASD). Although both groups dynamically adjusted the timing of their blink inhibition at levels greater than expected by chance, they inhibited their blinking and shifted visual fixation differentially with respect to salient onscreen events. Moreover, typical toddlers inhibited their blinking earlier than toddlers with ASD, indicating active anticipation of the unfolding of those events. These findings indicate that measures of blink inhibition can serve as temporally precise markers of perceived stimulus salience and are useful quantifiers of atypical processing of social affective signals in toddlers with ASD.

  8. Inhibiting Aspergillus flavus growth and degrading aflatoxin B1 by ...

    African Journals Online (AJOL)

    ajl2

    2012-08-14

    Aug 14, 2012 ... of this study was to select the most effective method and products for inhibiting A. flavus growth and ... The supernatants were filtered to remove microbes with 0.20 μm Minisart High-flow filter (Sartorius Stedim .... pseudoplanturum 371 could inhibit mold growth and aflatoxin production, and the inhibitory ...

  9. Inhibition of growth of some phytopathogenic and mycotoxigenic ...

    African Journals Online (AJOL)

    The aqueous extract of C. imberbe wood ash exhibited significant capacity to inhibit growth of all the test fungi, with the exception of A. alternata. Arrest of fungal growth by the extract involved inhibition of glucomamylase. Investigation of the chemistry of the ash using Fourier-Transform Infrared (FT-IR) spectroscopy and Xray ...

  10. Forgetting the Literal: The Role of Inhibition in Metaphor Comprehension

    Science.gov (United States)

    George, Tim; Wiley, Jennifer

    2016-01-01

    In order for a person to comprehend metaphoric expressions, do metaphor-irrelevant aspects of literal information need to be inhibited? Previous research using sentence-verification paradigms has found that literal associates take longer to process after reading metaphorical sentences; however, it is problematic to infer inhibition from this…

  11. Sticky Plans: Inhibition and Binding during Serial-Task Control

    Science.gov (United States)

    Mayr, Ulrich

    2009-01-01

    Recent evidence suggests substantial response-time costs associated with lag-2 repetitions of tasks within explicitly controlled task sequences [Koch, I., Philipp, A. M., Gade, M. (2006). Chunking in task sequences modulates task inhibition. "Psychological Science," 17, 346-350; Schneider, D. W. (2007). Task-set inhibition in chunked task…

  12. Emodin inhibits proliferation and invasion, and induces apoptosis in ...

    African Journals Online (AJOL)

    Emodin inhibits proliferation and invasion, and induces apoptosis in human esophageal cancer cell line ECA109. ... Tropical Journal of Pharmaceutical Research ... Conclusion: These results suggest that emodin inhibits cell proliferation and cell invasion, but induces cell apoptosis in human esophageal cancer cell line ...

  13. Inhibition effects of acetyl coumarines and thiazole derivatives on ...

    Indian Academy of Sciences (India)

    The corrosion inhibition characteristics of acetyl coumarine (AC), bromo acetyl coumarine (BAC) and thiazole derivatives (BTMQ and BTCQ) on the corrosion of zinc in 0.1 M HCl solution were investigated by weight loss, potentiodynamic polarization and impedance techniques. The inhibition efficiency increased with ...

  14. Comparison of the inhibition capability of oleanolic acid and ...

    African Journals Online (AJOL)

    acid towards drug-metabolizing enzymes. Wei Xiao ... Results: The inhibition of capability of oleanolic acid towards UGT1A6 and UGT1A8 were higher than betulinic acid. However, no significant ... Furthermore, concentration-dependent behaviour was determined for the inhibition of oleanolic acid and betulinic acid towards ...

  15. In vitro inhibition of the paraoxonase from human serum with ...

    African Journals Online (AJOL)

    SERVER

    2008-03-04

    Mar 4, 2008 ... The purified PON1 enzyme was stored at 4oCin the presence of 2. mM calcium chloride in order to maintain activity. In vitro inhibition kinetic studies. For the inhibition studies, different concentrations of sulfonamide were added to the each enzyme activity. Paraoxonase and aryle- sterase activities with ...

  16. Belief Inhibition in Children's Reasoning: Memory-Based Evidence

    Science.gov (United States)

    Steegen, Sara; Neys, Wim De

    2012-01-01

    Adult reasoning has been shown as mediated by the inhibition of intuitive beliefs that are in conflict with logic. The current study introduces a classic procedure from the memory field to investigate belief inhibition in 12- to 17-year-old reasoners. A lexical decision task was used to probe the memory accessibility of beliefs that were cued…

  17. Improved contour detection by non-classical receptive field inhibition

    NARCIS (Netherlands)

    Grigorescu, C; Petkov, N; Westenberg, MA; Bulthoff, HH; Lee, SW; Poggio, TA; Wallraven, C

    2002-01-01

    We propose a biologically motivated computational step, called non-classical receptive field (non-CRF) inhibition, to improve the performance of contour detectors. We introduce a Gabor energy operator augmented with non-CRF inhibition, which we call the bar cell operator. We use natural images with

  18. Study of electroplated silver-palladium biofouling inhibiting coating

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Hilbert, Lisbeth Rischel; Schroll, Casper

    2008-01-01

    Biofouling can cause many undesirable effects in industrial and medical settings. In this study, a new biofouling inhibiting Ag-Pd surface was designed to form an inhibiting effect by itself. This design was based on silver combined with nobler palladium, both with catalytic properties. Owing to ...

  19. Cognitive Inhibition in Students with and without Dyslexia and Dyscalculia

    Science.gov (United States)

    Wang, Li-Chih; Tasi, Hung-Ju; Yang, Hsien-Ming

    2012-01-01

    The present study presents a comparison of the cognitive inhibition abilities of dyslexic, dyscalculic, and control students. The participants were 45 dyslexic students, 45 dyscalculic students, and 45 age-, gender-, and IQ-matched control students. The major evaluation tools included six cognitive inhibition tasks which were restructured during…

  20. Stuttering Inhibition via Altered Auditory Feedback during Scripted Telephone Conversations

    Science.gov (United States)

    Hudock, Daniel; Kalinowski, Joseph

    2014-01-01

    Background: Overt stuttering is inhibited by approximately 80% when people who stutter read aloud as they hear an altered form of their speech feedback to them. However, levels of stuttering inhibition vary from 60% to 100% depending on speaking situation and signal presentation. For example, binaural presentations of delayed auditory feedback…

  1. Leukotriene inhibition in hamster periodontitis. A histochemical and morphometric study

    Directory of Open Access Journals (Sweden)

    B. Baroukh

    1992-01-01

    Full Text Available The effects of leukotriene (LT inhibition on gingival and adjacent bone compartments were assessed by using phenidone (100 mg/kg/d and ketoconazole (50 mg/kg/d given for 4 weeks to periodontitis-affected hamsters. In the gingiva the two agents significantly decreased PMNL recruitment and migration and increased the vascular lumen. At the bone level, they reduced significantly preosteoclast and osteoclast numbers but did not affect osteoclast activity. Phenidone had no action on periodontitis induced inhibition of bone formation; in contrast ketoconazole enhanced formation. As both phenidone and ketoconazole are unspecific LT inhibitors it cannot be ascertained that the effects observed were actually due to LT inhibition. However, phenidone and ketoconazole induced changes different from indomethacin used in previous studies to inhibit the cyclooxygenase pathway. These discrepancies suggest that LT inhibition occurred in the present study and that they participate in gingival inflammation and osteoclastic destruction during hamster periodontitis.

  2. Associative learning phenomena in the snail (Helix aspersa): conditioned inhibition.

    Science.gov (United States)

    Acebes, Félix; Solar, Patricia; Moris, Joaquín; Loy, Ignacio

    2012-03-01

    Two experiments using garden snails (Helix aspersa) showed conditioned inhibition using both retardation and summation tests. Conditioned inhibition is a procedure by which a stimulus becomes a predictor of the absence of a relevant event--the unconditioned stimulus (US). Typically, conditioned inhibition consists of pairings between an initially neutral conditioned stimulus, CS(2), and an effective excitatory conditioned stimulus, CS(1), in the absence of the US. Retardation and summation tests are required in order to confirm that CS(2) has acquired inhibitory properties. Conditioned inhibition has previously been found in invertebrates; however, these demonstrations did not use the retardation and summation tests required for an unambiguous demonstration of inhibition, allowing for alternative explanations. The implications of our results for the fields of comparative cognition and invertebrate physiological models of learning are discussed.

  3. . Psychological predictors of inhibition development in educational environments

    Directory of Open Access Journals (Sweden)

    Symanyuk, Elvira E.

    2016-09-01

    Full Text Available This article examines psychological predictors of inhibition in educational environments as well as various aspects of pedagogical communication, including facilitation, which is aimed at enhancing educational effectiveness and developing students by means of using a particular communication style and the teacher’s personality. The need to study inhibition (the deterioration of teacher-children interactions; the negation of a student’s individuality; the inability to understand and accept students’ viewpoints; teacher-provoked conflicts; and emotional callousness is substantiated. The essence of psychological predictors as independent variables, changes in which lead to changes in other dependent variables, allowing the prediction of inhibition development, is explained. The research objective was to identify psychological predictors of the development of inhibition in pedagogical communication. An empirical study was conducted using standardized techniques for diagnosing communicative attitudes (V. Boyko, developing general communicative tolerance (V. Boyko, identifying aggressiveness (A. Asinger, identifying the level of empathy (V. Boyko, and identifying the degree of pedagogical inhibition (L. Polosova. The sample contained 375 teachers from Yekaterinburg educational institutions, with participant selection made using stratified sampling. The teacher’s personality features (a negative communicative attitude, low communicative tolerance and empathy, and higher levels of aggression were shown to be key predictors of inhibition, which itself was found to depend on the length of teaching experience. At the beginning of one’s professional teaching career, the level of inhibition is minimal. However, the level of inhibition reaches its maximum level after 5-10 years of teaching, and after 20 years, there is a sharp decrease in the level of inhibition. The conclusion of this study stresses the importance of developing strategies to

  4. Inhibition of inflammatory arthritis using fullerene nanomaterials.

    Science.gov (United States)

    Dellinger, Anthony L; Cunin, Pierre; Lee, David; Kung, Andrew L; Brooks, D Bradford; Zhou, Zhiguo; Nigrovic, Peter A; Kepley, Christopher L

    2015-01-01

    Inflammatory arthritis (e.g. rheumatoid arthritis; RA) is a complex disease driven by the interplay of multiple cellular lineages. Fullerene derivatives have previously been shown to have anti-inflammatory capabilities mediated, in part, by their ability to prevent inflammatory mediator release by mast cells (MC). Recognizing that MC can serve as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis, it was hypothesized that fullerene derivatives might be used to target this inflammatory disease. A panel of fullerene derivatives was tested for their ability to affect the function of human skin-derived MC as well as other lineages implicated in arthritis, synovial fibroblasts and osteoclasts. It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts. MC inhibition by fullerene derivatives was mediated through the reduction of mitochondrial membrane potential and FcγR-mediated increases in cellular reactive oxygen species and NF-κB activation. Based on these in vitro data, two fullerene derivatives (ALM and TGA) were selected for in vivo studies using K/BxN serum transfer arthritis in C57BL/6 mice and collagen-induced arthritis (CIA) in DBA/1 mice. Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls. In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α. Fullerenes remained capable of attenuating K/BxN arthritis in mast cell-deficient mice Cre-Master mice, suggesting that lineages beyond the MC represent relevant targets in this system. These studies suggest that fullerene derivatives may hold promise both as an assessment tool and as anti-inflammatory therapy of arthritis.

  5. Inhibition of Suicidal Erythrocyte Death by Reversine

    Directory of Open Access Journals (Sweden)

    Mohamed Jemaà

    2017-04-01

    Full Text Available Background/Aims: The A3 adenosine receptor antagonist reversine (2-(4-morpholinoanilino-6-cyclohexylaminopurine influences cellular differentiation, inhibits cell proliferation, induces cell-cycle arrest, triggers apoptosis, causes cell swelling with polyploidy and stimulates autophagy. The effect on apoptosis involves mitochondria and caspases. Erythrocytes are lacking mitochondria but express caspases and are, similar to apoptosis of nucleated cells, able to enter suicidal erythrocyte death or eryptosis. Stimulators of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i, energy depletion and oxidative stress. The present study explored, whether reversine influences eryptosis. Methods: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding and cell volume from forward scatter. Measurements were made without or with energy depletion (glucose deprivation for 48 hours, Ca2+ loading (30 minutes treatment with 1 µM Ca2+ ionophore ionomycin, or oxidative stress (15 min exposure to 0.3 mM tert-butylhydroperoxide. Results: A 48 hours exposure of human erythrocytes to reversine (1-10 µM did not significantly modify the percentage of annexin-V-binding cells and forward scatter. Energy depletion, Ca2+ loading, and oxidative stress were each followed by profound and significant increase of the percentage annexin-V-binding erythrocytes and a significant decrease of forward scatter. The effects of each, Ca2+ loading, energy depletion and oxidative stress on annexin-V-binding were significantly blunted in the presence of reversine (1-10 µM. The effect of ionomycin, but not the effects of energy depletion and oxidative stress on forward scatter were again significantly blunted in the presence of reversine (≥1 µM]. Conclusions: Reversine is a powerful inhibitor of cell membrane scrambling following energy depletion, Ca2+ loading and oxidative stress.

  6. Dopamine inhibits mitochondrial motility in hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    Sigeng Chen

    2008-07-01

    Full Text Available The trafficking of mitochondria within neurons is a highly regulated process. In an earlier study, we found that serotonin (5-HT, acting through the 5-HT1A receptor subtype, promotes axonal transport of mitochondria in cultured hippocampal neurons by increasing Akt activity, and consequently decreasing glycogen synthase kinase (GSK3beta activity. This finding suggests a critical role for neuromodulators in the regulation of mitochondrial trafficking in neurons. In the present study, we investigate the effects of a second important neuromodulator, dopamine, on mitochondrial transport in hippocampal neurons.Here, we show that dopamine, like 5-HT, regulates mitochondrial motility in cultured hippocampal neurons through the Akt-GSK3beta signaling cascade. But, in contrast to the stimulatory effect of 5-HT, administration of exogenous dopamine or bromocriptine, a dopamine 2 receptor (D2R agonist, caused an inhibition of mitochondrial movement. Moreover, pretreatment with bromocriptine blocked the stimulatory effect of 5-HT on mitochondrial movement. Conversely, in cells pretreated with 5-HT, no further increases in movement were observed after administration of haloperidol, a D2R antagonist. In contrast to the effect of the D2R agonist, addition of SKF38393, a dopamine 1 receptor (D1R agonist, promoted mitochondrial transport, indicating that the inhibitory effect of dopamine was actually the net summation of opposing influences of the two receptor subtypes. The most pronounced effect of dopamine signals was on mitochondria that were already moving directionally. Western blot analysis revealed that treatment with either a D2R agonist or a D1R antagonist decreased Akt activity, and conversely, treatment with either a D2R antagonist or a D1R agonist increased Akt activity.Our observations strongly suggest a role for both dopamine and 5-HT in regulating mitochondrial movement, and indicate that the integrated effects of these two neuromodulators may be

  7. Volatile hydrocarbons inhibit methanogenic crude oil degradation

    Directory of Open Access Journals (Sweden)

    Angela eSherry

    2014-04-01

    Full Text Available Methanogenic degradation of crude oil in subsurface sediments occurs slowly, but without the need for exogenous electron acceptors, is sustained for long periods and has enormous economic and environmental consequences. Here we show that volatile hydrocarbons are inhibitory to methanogenic oil biodegradation by comparing degradation of an artificially weathered crude oil with volatile hydrocarbons removed, with the same oil that was not weathered. Volatile hydrocarbons (nC5-nC10, methylcyclohexane, benzene, toluene and xylenes were quantified in the headspace of microcosms. Aliphatic (n-alkanes nC12-nC34 and aromatic hydrocarbons (4-methylbiphenyl, 3-methylbiphenyl, 2-methylnaphthalene, 1-methylnaphthalene were quantified in the total hydrocarbon fraction extracted from the microcosms. 16S rRNA genes from key microorganisms known to play an important role in methanogenic alkane degradation (Smithella and Methanomicrobiales were quantified by quantitative PCR. Methane production from degradation of weathered oil in microcosms was rapid (1.1 ± 0.1 µmol CH4/g sediment/day with stoichiometric yields consistent with degradation of heavier n-alkanes (nC12-nC34. For non-weathered oil, degradation rates in microcosms were significantly lower (0.4 ± 0.3 µmol CH4/g sediment/day. This indicated that volatile hydrocarbons present in the non-weathered oil inhibit, but do not completely halt, methanogenic alkane biodegradation. These findings are significant with respect to rates of biodegradation of crude oils with abundant volatile hydrocarbons in anoxic, sulphate-depleted subsurface environments, such as contaminated marine sediments which have been entrained below the sulfate-reduction zone, as well as crude oil biodegradation in petroleum reservoirs and contaminated aquifers.

  8. Inhibition of inflammatory arthritis using fullerene nanomaterials.

    Directory of Open Access Journals (Sweden)

    Anthony L Dellinger

    Full Text Available Inflammatory arthritis (e.g. rheumatoid arthritis; RA is a complex disease driven by the interplay of multiple cellular lineages. Fullerene derivatives have previously been shown to have anti-inflammatory capabilities mediated, in part, by their ability to prevent inflammatory mediator release by mast cells (MC. Recognizing that MC can serve as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis, it was hypothesized that fullerene derivatives might be used to target this inflammatory disease. A panel of fullerene derivatives was tested for their ability to affect the function of human skin-derived MC as well as other lineages implicated in arthritis, synovial fibroblasts and osteoclasts. It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts. MC inhibition by fullerene derivatives was mediated through the reduction of mitochondrial membrane potential and FcγR-mediated increases in cellular reactive oxygen species and NF-κB activation. Based on these in vitro data, two fullerene derivatives (ALM and TGA were selected for in vivo studies using K/BxN serum transfer arthritis in C57BL/6 mice and collagen-induced arthritis (CIA in DBA/1 mice. Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls. In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α. Fullerenes remained capable of attenuating K/BxN arthritis in mast cell-deficient mice Cre-Master mice, suggesting that lineages beyond the MC represent relevant targets in this system. These studies suggest that fullerene derivatives may hold promise both as an assessment tool and as anti-inflammatory therapy of arthritis.

  9. Contingent Involuntary Motoric Inhibition: The Involuntary Inhibition of a Motor Response Contingent on Top-Down Goals

    Science.gov (United States)

    Anderson, Brian A.; Folk, Charles L.

    2012-01-01

    Effective motor control involves both the execution of appropriate responses and the inhibition of inappropriate responses that are evoked by response-associated stimuli. The inhibition of a motor response has traditionally been characterized as either a voluntary act of cognitive control or a low-level perceptual bias arising from processes such…

  10. Flavonoids from Citrus unshiu Marc. inhibit cancer cell adhesion to endothelial cells by selective inhibition of VCAM-1.

    Science.gov (United States)

    Jin, Hana; Lee, Won Sup; Yun, Jeong Won; Jung, Ji Hyun; Yi, Sang Mi; Kim, Hye Jung; Choi, Yung Hyun; Kim, Gonsup; Jung, Jin-Myung; Ryu, Chung Ho; Shin, Sung Chul; Hong, Soon Chan

    2013-11-01

    Citrus fruits have been used as edible fruit and a component of traditional medicine for various diseases including cancer since ancient times. Herein, we investigated the anticancer activity of flavonoids of Citrus unshiu Marc. (FCM) focusing on anti-metastatic effects. We prepared FCM and performed experiments using MDA-MB-231 human breast cancer cells. FCM inhibited TNF-induced cancer cell adhesion to human umbilical vein endothelial cells (HUVECs) without showing any toxicity. FCM inhibited the expression of VCAM-1, but not of ICAM-1, on MDA-MB-231 cells as well as HUVECs. FCM inhibited protein kinase C (PKC) phosphorylation, but not Akt phosphorylation. FCM also inhibited cancer cell invasion in a dose-dependent manner, but not MMP-9 expression. In conclusion, this study suggested that FCM inhibits TNF-induced cancer cell adhesion to HUVECs by inhibiting VCAM-1 through inhibition of PKC, providing evidence that FCM have anti-metastatic activity by inhibiting adhesion molecules and invasion on human breast cancer cells.

  11. Corrosion Inhibition of Aluminum Alloy 3SR in HCl by Polyvinylpyrrolidone and Polyacrylamide:. Effect of Molecular Structure on Inhibition Efficiency

    Science.gov (United States)

    Umoren, S. A.

    The inhibitive performance of two water soluble polymers-polyacrylamide (PA) and polyvinylpyrrolidone (PVP) on the corrosion behavior of aluminum alloy 3SR in HCl solution was investigated using weight loss, hydrogen evolution, and thermometric methods at 30-60°C. Results obtained indicate that both polymers inhibited acid-induced corrosion of aluminum at the temperatures studied. PVP was found to be a better corrosion inhibitor than PA. All measurements from the three techniques show that inhibition efficiencies increase with increase in inhibitor concentration and decrease with increase in temperature. This indicates that the inhibitive actions of the polymers were mainly due to adsorption. Adsorption of these inhibitors follows Temkin and El-Awady adsorption isotherm models. Kinetic/thermodynamic parameters (Ea, Kads, Δ G{ o}{ ads}) of adsorption of the studied inhibitors reveal that the adsorption was physical in nature and spontaneous. Differences in inhibition efficiency of the two polymers could be linked to their differences in molecular structure.

  12. Thioredoxin glutathione reductase as a novel drug target: evidence from Schistosoma japonicum.

    Directory of Open Access Journals (Sweden)

    LiJun Song

    Full Text Available BACKGROUND: Schistosomiasis remains a major public health concern affecting billions of people around the world. Currently, praziquantel is the only drug of choice for treatment of human schistosomiasis. The emergence of drug resistance to praziquantel in schistosomes makes the development of novel drugs an urgent task. Thioredoxin glutathione reductase (TGR enzymes in Schistosoma mansoni and some other platyhelminths have been identified as alternative targets. The present study was designed to confirm the existense and the potential value of TGR as a target for development of novel antischistosomal agents in Schistosoma japonicum, a platyhelminth endemic in Asia. METHODS AND FINDINGS: After cloning the S. japonicum TGR (SjTGR gene, the recombinant SjTGR selenoprotein was purified and characterized in enzymatic assays as a multifunctional enzyme with thioredoxin reductase (TrxR, glutathione reductase (GR and glutaredoxin (Grx activities. Immunological and bioinformatic analyses confirmed that instead of having separate TrxR and GR proteins in mammalian, S. japonicum only encodes TGR, which performs the functions of both enzymes and plays a critical role in maintaining the redox balance in this parasite. These results were in good agreement with previous findings in Schistosoma mansoni and some other platyhelminths. Auranofin, a known inhibitor against TGR, caused fatal toxicity in S. japonicum adult worms in vitro and reduced worm and egg burdens in S. japonicum infected mice. CONCLUSIONS: Collectively, our study confirms that a multifunctional enzyme SjTGR selenoprotein, instead of separate TrxR and GR enzymes, exists in S. japonicum. Furthermore, TGR may be a potential target for development of novel agents against schistosomes. This assumption is strengthened by our demonstration that the SjTGR is an essential enzyme for maintaining the thiol-disulfide redox homeostasis of S. japonicum.

  13. The mechanism of chondrogenesis inhibition by X-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Jong Yeol; Lim, Young Bin; Lee, Yoon Ae; Sonn, Jong Kyung [Kyungpook National University, Daegu (Korea, Republic of); Lee, Joon Il [Taegu Health College, Daegu (Korea, Republic of)

    2003-06-15

    The purpose of this study is to investigate the mechanism of inhibition of chondrogenic differentiation by X-irradiation. Cultures of chick limb bud mesenchymal cells were exposed to various dose of X-ray and chondrogenesis was examined. X-irradiation inhibited accumulation of proteoglycan based on the observation of alcian blue staining and expression of chondorcyte specific-type II collagen. X-irradiation also inhibited expression of protein kinase Ca while expression of PKC{lambda}({iota}, {epsilon} was not altered. Expression of Erk-1 was not changed by X-irradiation but phosphorylation of Erk-1 was increased. In addition, inhibition of Erk-1 phosphorylation by PD98059 overcame inhibitory effect of X-irradiation on the chondrogenic differentiation. PNA staining data showed that X-irradiation inhibited cellular aggregation. Taken together, these results suggest that X-irradiation inhibits chondrogenic differentiation by inhibiting cellular aggregation and suppressing expression of PKCa and promoting phosphorylation of Erk-1. In addition to above pathway, our results also suggest that X-irradiation may exerts its inhibitory effect by another signaling pathways.

  14. Cadmium ion inhibition of quorum signalling in Chromobacterium violaceum.

    Science.gov (United States)

    Thornhill, Starla G; Kumar, Manish; Vega, Leticia M; McLean, Robert J C

    2017-10-01

    Single-celled bacteria are capable of acting as a community by sensing and responding to population density via quorum signalling. Quorum signalling in Chromobacterium violaceum, mediated by the luxI/R homologue, cviI/R, regulates a variety of phenotypes including violacein pigmentation, virulence and biofilm formation. A number of biological and organic molecules have been described as quorum signalling inhibitors but, to date, metal-based inhibitors have not been widely tested. In this study, we show that quorum sensing is inhibited in C. violaceum in the presence of sub-lethal concentrations of cadmium salts. Notable Cd2+-inhibition was seen against pigmentation, motility, chitinase production and biofilm formation. Cd-inhibition of quorum-signalling genes occurred at the level of transcription. There was no direct inhibition of chitinase activity by Cd2+ at the concentrations tested. Addition of the cognate quorum signals, N-hexanoyl homoserine lactone or N-decanoyl homoserine lactone, even at concentrations in excess of physiological levels, did not reverse the inhibition, suggesting that Cd-inhibition of quorum signaling is irreversible. This study represents the first description of heavy metal-based quorum inhibition in C. violaceum.

  15. Neural correlates of central inhibition during physical fatigue.

    Directory of Open Access Journals (Sweden)

    Masaaki Tanaka

    Full Text Available Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG. Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs in the posterior cingulated cortex (PCC, with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue.

  16. Methylene Blue Inhibits Caspases by Oxidation of the Catalytic Cysteine.

    Science.gov (United States)

    Pakavathkumar, Prateep; Sharma, Gyanesh; Kaushal, Vikas; Foveau, Bénédicte; LeBlanc, Andrea C

    2015-09-24

    Methylene blue, currently in phase 3 clinical trials against Alzheimer Disease, disaggregates the Tau protein of neurofibrillary tangles by oxidizing specific cysteine residues. Here, we investigated if methylene blue can inhibit caspases via the oxidation of their active site cysteine. Methylene blue, and derivatives, azure A and azure B competitively inhibited recombinant Caspase-6 (Casp6), and inhibited Casp6 activity in transfected human colon carcinoma cells and in serum-deprived primary human neuron cultures. Methylene blue also inhibited recombinant Casp1 and Casp3. Furthermore, methylene blue inhibited Casp3 activity in an acute mouse model of liver toxicity. Mass spectrometry confirmed methylene blue and azure B oxidation of the catalytic Cys163 cysteine of Casp6. Together, these results show a novel inhibitory mechanism of caspases via sulfenation of the active site cysteine. These results indicate that methylene blue or its derivatives could (1) have an additional effect against Alzheimer Disease by inhibiting brain caspase activity, (2) be used as a drug to prevent caspase activation in other conditions, and (3) predispose chronically treated individuals to cancer via the inhibition of caspases.

  17. The development of children's inhibition: does parenting matter?

    Science.gov (United States)

    Roskam, Isabelle; Stievenart, Marie; Meunier, Jean-Christophe; Noël, Marie-Pascale

    2014-06-01

    Whereas a large body of research has investigated the maturation of inhibition in relation to the prefrontal cortex, far less research has been devoted to environmental factors that could contribute to inhibition improvement. The aim of the current study was to test whether and to what extent parenting matters for inhibition development from 2 to 8years of age. Data were collected from 421 families, with 348 mother-child dyads and 342 father-child dyads participating. Children's inhibition capacities and parenting behaviors were assessed in a three-wave longitudinal data collection. The main analyses examined the impact of parenting on the development of children's inhibition capacities. They were conducted using a multilevel modeling (MLM) framework. The results lead to the conclusion that both mothers and fathers contribute through their child-rearing behavior to their children's executive functioning, even when controlling for age-related improvement (maturation) and important covariates such as gender, verbal IQ, and place of enrollment. More significant relations between children's inhibition development and parenting were displayed for mothers than for fathers. More precisely, parenting behaviors that involve higher monitoring, lower discipline, inconsistency and negative controlling, and a positive parenting style are associated with good development of inhibition capacities in children. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Caries inhibition around gallium alloy by fluoride releasing resin cement

    Directory of Open Access Journals (Sweden)

    Nasman Nur'alim

    2009-03-01

    Full Text Available Fluoride-releasing materials inhibit secondary caries. Gallium alloy has been developed to replace mercury-based amalgam. The purpose of this study was to test a new F releasing resin-ionomer cement for inhibition of 24 extracted human premolars. The experimental cavity (ARG were filled using etching, priming, and F releasing resin-ionomer cement (All-bond 2 & Presinomer, Bisco followed by condensation of gallium alloy (G Tokuriki Honten, Japan. Three different controls were used: gallium alloy only (G, no etching, Presinomer, gallium alloy (RG, etching, priming, non-F cement (All-bond C&B, Bisco and gallium alloy (ACG The teeth were thermocycled 500x, stored in humidor 28 days, then exposed to artificial caries for 21 days using a strep. mutans culture. Next, they were sectioned and examined by microradiography. The microradiographs were examined for the presence of a caries inhibition zone near the restoration and classified as strongly inhibited (SI, moderately inhibited (MI or not inhibited (N at the enamel and dentin wall. A Chi-square analysis showed that G is different from ARG, ACG is different from ARG, and RG is different from ACG (p<0.05. The results show that the fluoride-releasing resin-ionomer cement provided caries inhibition with or without etching and bonding and that etching and bonding alone is not as effective as fluoride release.

  19. BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells

    Directory of Open Access Journals (Sweden)

    Jingjun Li

    2016-09-01

    Full Text Available Neural stem cells and progenitor cells (NPCs are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers. Through screening small molecule libraries with annotated targets, we identified BET bromodomain inhibition as a novel mechanism for enhancing neurogenesis. BET bromodomain proteins, Brd2, Brd3, and Brd4 were found to be downregulated in NPCs upon differentiation, while their levels remain unaltered in proliferating NPCs. Consistent with the pharmacological study using bromodomain selective inhibitor (+-JQ-1, knockdown of each BET protein resulted in an increase in the number of neurons with simultaneous reduction in both astrocytes and oligodendrocytes. Gene expression profiling analysis demonstrated that BET bromodomain inhibition induced a broad but specific transcription program enhancing directed differentiation of NPCs into neurons while suppressing cell cycle progression and gliogenesis. Together, these results highlight a crucial role of BET proteins as epigenetic regulators in NPC development and suggest a therapeutic potential of BET inhibitors in treating brain injuries and neurodegenerative diseases.

  20. Resveratrol Inhibited Non-small Cell Lung Cancer Through Inhibiting STAT-3 Signaling.

    Science.gov (United States)

    Li, Xin; Wang, Dan; Zhao, Qing Chun; Shi, Tao; Chen, Jun

    2016-11-01

    Resveratrol has demonstrated many beneficial effects against cancers; however, the mechanism remains unclear. Non-small cell lung cancer accounts for 80% of lung cancers. The present study was designed to observe the effects and related mechanisms of resveratrol on non-small cell lung cancer in in vitro A549 cells. The anticancer effects of resveratrol were analyzed on cell viability, migration and invasion, proliferation and apoptosis. Cell viability was determined by sulphorhodamine B assays. Cell proliferation and apoptosis were determined by flow cytometry and migration and invasion by transwell chamber analysis. Expression of STAT-3 was examined by real-time polymerase chain reaction and western blot. Overexpressing vector of STAT-3 was also constructed and transfected into A549 cells to observe the effects of resveratrol on STAT-3 signaling. The results showed that resveratrol displayed a dose-dependent and time-dependent cytotoxicity action on A549 cell viability. Resveratrol also inhibited proliferation, migration and invasion and promoted apoptosis in a time-dependent manner from 0-72 hours. Further study showed that resveratrol inhibited the messenger RNA and protein expression of STAT-3, and overexpressed STAT-3 abolished the effects of resveratrol on proliferation, apoptosis, migration and invasion totally or in part. These results suggest that the anticancer effects of resveratrol are mediated by STAT-3 signaling. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  1. Inhibition factors and Kinetic model for ammonium inhibition on the anammox process of the SNAD biofilm.

    Science.gov (United States)

    Zheng, Zhaoming; Li, Jun; Ma, Jing; Du, Jia; Wang, Fan; Bian, Wei; Zhang, Yanzhuo; Zhao, Baihang

    2017-03-01

    The aim of the present work was to evaluate the anaerobic ammonium oxidation (anammox) activity of simultaneous partial nitrification, anammox and denitrification (SNAD) biofilm with different substrate concentrations and pH values. Kaldnes rings taken from the SNAD biofilm reactor were incubated in batch tests to determine the anammox activity. Haldane model was applied to investigate the ammonium inhibition on anammox process. As for nitrite inhibition, the NH 4 + -N removal rate of anammox process remained 87.4% of the maximum rate with the NO 2 - -N concentration of 100mg/L. Based on the results of Haldane model, no obvious difference in kinetic coefficients was observed under high or low free ammonia (FA) conditions, indicating that ammonium rather than FA was the true inhibitor for anammox process of SNAD biofilm. With the pH value of 7.0, the r max , Ks and K I of ammonium were 0.209kg NO 2 - -N/kg VSS/day, 9.5mg/L and 422mg/L, respectively. The suitable pH ranges for anammox process were 5.0 to 9.0. These results indicate that the SNAD biofilm performs excellent tolerance to adverse conditions. Copyright © 2016. Published by Elsevier B.V.

  2. Synthesis of novel benzimidazole acrylonitriles for inhibition of Plasmodium falciparum growth by dual target inhibition.

    Science.gov (United States)

    Sharma, Kalicharan; Shrivastava, Apeksha; Mehra, Ram N; Deora, Girdhar S; Alam, Mohammad M; Zaman, Mohammad S; Akhter, Mymoona

    2017-12-11

    Antimalarial drug resistance has emerged as a threat for treating malaria, generating a need to design and develop newer, more efficient antimalarial agents. This research aimed to identify novel leads as antimalarials. Dual receptor mechanism could be a good strategy to combat developing drug resistance. A series of benzimidazole acrylonitriles containing 18 compounds were designed, synthesized and evaluated for cytotoxicity, heme binding, ferriprotoporphyrin IX biomineralisation inhibition, and falcipain-2 enzyme assay. Furthermore, in silico docking and MD simulation studies were also performed.The tests revealed quite encouraging results. Three compounds, viz. R-01 (0.69 μM), R-04 (1.60 μM), and R-08 (1.61 μM), were found to have high antimalarial activity. These compounds were found to be in bearable cytotoxicity limits and their biological assay suggested that they had inhibitory activity against falcipain-2 and hemozoin formation. The docking revealed the binding mode of benzimidazole acrylonitrile derivatives and MD simulation studies revealed that the protein-ligand complex was stable. The agents exhibit good hemozoin formation inhibition activity and, hence, may be utilized as leads to design a newer drug class to overcome the drug resistance of hemozoin formation inhibitors such as chloroquine. © 2017 Deutsche Pharmazeutische Gesellschaft.

  3. Inhibition of auxin movement from the shoot into the root inhibits lateral root development in Arabidopsis

    Science.gov (United States)

    Reed, R. C.; Brady, S. R.; Muday, G. K.

    1998-01-01

    In roots two distinct polar movements of auxin have been reported that may control different developmental and growth events. To test the hypothesis that auxin derived from the shoot and transported toward the root controls lateral root development, the two polarities of auxin transport were uncoupled in Arabidopsis. Local application of the auxin-transport inhibitor naphthylphthalamic acid (NPA) at the root-shoot junction decreased the number and density of lateral roots and reduced the free indoleacetic acid (IAA) levels in the root and [3H]IAA transport into the root. Application of NPA to the basal half of or at several positions along the root only reduced lateral root density in regions that were in contact with NPA or in regions apical to the site of application. Lateral root development was restored by application of IAA apical to NPA application. Lateral root development in Arabidopsis roots was also inhibited by excision of the shoot or dark growth and this inhibition was reversible by IAA. Together, these results are consistent with auxin transport from the shoot into the root controlling lateral root development.

  4. Sex differences in emotional contexts modulation on response inhibition.

    Science.gov (United States)

    Ramos-Loyo, Julieta; Angulo-Chavira, Armando; Llamas-Alonso, Luis A; González-Garrido, Andrés A

    2016-10-01

    The aim of the present study was to explore sex differences in the effects that emotional contexts exert on the temporal course of response inhibition using event-related potentials (ERP). Participants performed a Go-NoGo response inhibition task under 3 context conditions: with 1) neutral background stimuli, and 2) pleasant, and 3) unpleasant emotional contexts. No sex differences were found in relation to accuracy. Women showed higher N2NoGo amplitudes than men in both emotional contexts; whereas during inhibition men tended to show higher P3NoGo amplitudes than women in the unpleasant context. Both groups experienced a relevant effect of the presence of the unpleasant context during inhibition processing, as shown by the enhancement of the N2NoGo amplitudes in frontal regions compared to results from the neutral and pleasant conditions. In addition, women showed differences between the pleasant and unpleasant contexts, with the latter inducing higher amplitude values. Only in men did inhibition accuracy correlate with higher N2NoGo and lower P3NoGo amplitudes in the emotional context conditions. These findings suggest that when an inhibition task is performed in an emotionally-neutral background context no sex differences are observed in either accuracy or ERP components. However, when the emotional context was introduced -especially the unpleasant one- some gender differences did become evident. The higher N2NoGo amplitude at the presence of the unpleasant context may reflect an effect on attention and conflict monitoring. In addition, results suggest that during earlier processing stages, women invested more resources to process inhibition than men. Furthermore, men who invested more neural resources during earlier stages showed better response inhibition than those who did it during later processing stages, more closely-related to cognitive and motor inhibition processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Mechanism of Inhibition of Estrogen Biosynthesis by Azole Fungicides

    Science.gov (United States)

    Egbuta, Chinaza; Lo, Jessica

    2014-01-01

    Biosynthesis of estrogens from androgens is catalyzed by cytochrome P450 aromatase. Aromatase inhibition by the triazole compounds letrozole (LTZ) and anastrozole is a prevalent therapy for estrogen-dependent postmenopausal breast cancer. Azoles are widely used as agricultural fungicides and antimycotic drugs that target 14α-demethylase. Some were previously shown to inhibit aromatase, thereby raising the possibility of endocrine disruptive effects. However, mechanistic analysis of their inhibition has never been undertaken. We have evaluated the inhibitory effects of 3 common fungicides, bifonazole, imazalil, and flusilazole, in human aromatase purified from placenta and compared them with LTZ, the most potent inhibitor of aromatase. Bifonazole exhibits strong inhibitory effects with an IC50 of 270nM and Ki (Michaeles-Menten inhibition constant) of 68nM, compared with 10nM and 13nM, respectively, for LTZ. The IC50 and Ki are 1100nM and 278nM for imazilil and 3200nM and 547nM for flusilazole, respectively. Analyses of inhibition kinetics suggest that the modes of inhibition by azole fungicides are mixed or competitive, whereas LTZ inhibition could be noncompetitive or mixed. We interpret the inhibition mechanism in the context of the x-ray structure of aromatase-androstenedione complex. Structural data show that aromatase has 3 binding pockets in relation to the heme. The substrate-binding cavity at the heme-distal site closely compliments the structures of the natural substrate, androstenedione, and steroidal aromatase inhibitors. Because the structures of LTZ and the azole fungicides are entirely dissimilar to the androstenedione backbone, the azoles possibly inhibit by binding to a structurally rearranged active site, the 2 other catalytically important sites, or both, in agreement with the kinetics data. PMID:25243857

  6. Inhibition of the cooperative adhesion of Streptococcus sanguis to hydroxylapatite.

    Science.gov (United States)

    Zhang, X H; Rosenberg, M; Doyle, R J

    1990-09-15

    The adhesion of Streptococcus sanguis to hydroxylapatite is a process involving several adhesins and receptors. Binding isotherms and Scatchard plots of the adhesion suggest that cooperative interactions occur at low cell densities. It was found that sulfolane, a hydrophobic-bond diluent, was capable of inhibiting the cooperative adhesion of S. sanguis to saliva-coated hydroxylapatite beads. Sodium thiocyanate, a chaotropic agent, inhibited not only cooperative adhesion, but also the adhesion thought to result from noncooperative interactions. It is suggested that strong chaotropic agents may not only inhibit adhesin-receptor complexes, but also may influence the secondary/tertiary structures of interacting species.

  7. AMP-activated protein kinase inhibits TREK channels.

    Science.gov (United States)

    Kréneisz, Orsolya; Benoit, Justin P; Bayliss, Douglas A; Mulkey, Daniel K

    2009-12-15

    AMP-activated protein kinase (AMPK) is a serine/threonine kinase activated by conditions that increase the AMP : ATP ratio. In carotid body glomus cells, AMPK is thought to link changes in arterial O(2) with activation of glomus cells by inhibition of unidentified background K(+) channels. Modulation by AMPK of individual background K(+) channels has not been described. Here, we characterize effects of activated AMPK on recombinant TASK-1, TASK-3, TREK-1 and TREK-2 background K(+) channels expressed in HEK293 cells. We found that TREK-1 and TREK-2 channels but not TASK-1 or TASK-3 channels are inhibited by AMPK. AMPK-mediated inhibition of TREK involves key serine residues in the C-terminus that are also known to be important for PKA and PKC channel modulation; inhibition of TREK-1 requires Ser-300 and Ser-333 and inhibition of TREK-2 requires Ser-326 and Ser-359. Metabolic inhibition by sodium azide can also inhibit both TREK and TASK channels. The effects of azide on TREK occlude subsequent channel inhibition by AMPK and are attenuated by expression of a dominant negative catalytic subunit of AMPK (dnAMPK), suggesting that metabolic stress modulates TREK channels by an AMPK mechanism. By contrast, inhibition of TASK channels by azide was unaffected by expression of dnAMPK, suggesting an AMPK-independent mechanism. In addition, prolonged exposure (6-7 min) to hypoxia ( = 11 +/- 1 mmHg) inhibits TREK channels and this response was blocked by expression of dnAMPK. Our results identify a novel modulation of TREK channels by AMPK and indicate that select residues in the C-terminus of TREK are points of convergence for multiple signalling cascades including AMPK, PKA and PKC. To the extent that carotid body O(2) sensitivity is dependent on AMPK, our finding that TREK-1 and TREK-2 channels are inhibited by AMPK suggests that TREK channels may represent the AMPK-inhibited background K(+) channels that mediate activation of glomus cells by hypoxia.

  8. Complement inhibiting properties of dragon's blood from Croton draco.

    Science.gov (United States)

    Tsacheva, Ivanka; Rostan, Joerg; Iossifova, Tania; Vogler, Bernhard; Odjakova, Mariela; Navas, Hernan; Kostova, Ivanka; Kojouharova, Michaela; Kraus, Wolfgang

    2004-01-01

    The latex of Croton draco, its extracts and several latex components have been investigated for their influence on both classical (CP) and alternative (AP) activation pathways of the complement system using a hemolytic assay. The best inhibition was found for the classical pathway. The latex, ethyl acetate and ethyl ether extracts exhibited extremely high inhibition on the CP (94, 90 and 77%, respectively) at a concentration of 1 mg/ml. The flavonoid myricitrin, the alkaloid taspine and the cyclopeptides P1 and P2 showed high inhibition on CP (83, 91, 78 and 63%, respectively) at a concentration of 0.9 mM.

  9. Quercetin inhibits hexose transport in a human diploid fibroblast

    Energy Technology Data Exchange (ETDEWEB)

    Salter, D.W.; Custead-Jones, S.; Cook, J.S.

    1978-01-01

    The flavonol quercetin, a phloretin analog, inhibits transport of 2-deoxyglucose and 3-O-methylglucose in a cultured human diploid fibroblast. This inhibition is related to transport itself and not to the reported effects of flavonoids on membrane-bound ATPases. From concentration-inhibition curves at several pH's we conclude that uncharged (acid) quercetin (pH = 7.65) is the inhibitory form of the molecule (K/sub I/ = 10 ..mu..m). Quercetin, unlike phloretin, is rapidly degraded in 0.1 N NaOH; the degradation products are weakly inhibitory to hexose transport.

  10. Cytochalasins inhibit arachidonic acid metabolism in thrombin-stimulated platelets.

    OpenAIRE

    Siess, W; Lapetina, E G; Cuatrecasas, P

    1982-01-01

    Low concentrations (0.5-1 microM) of cytochalasins inhibit the thrombin-stimulated polymerization of monomeric actin to filamentous actin in platelets. Similar concentrations of cytochalasin B inhibit the formation and metabolism of arachidonic acid in horse platelets stimulated by low concentrations of thrombin (0.1-0.5 unit/ml). However, the release of serotonin is not inhibited by cytochalasin B. Cytochalasins B and D (0.5-1 microM) markedly reduce, in thrombin-stimulated human or horse pl...

  11. Antibody inhibition of protein activity in starfish oocytes.

    Science.gov (United States)

    Okumura, Eiichi; Hara, Masatoshi; Kishimoto, Takeo

    2014-01-01

    Antibodies are widely utilized in cell and molecule biology for immunoblots, immunostaining, immunoprecipitation, immunoaffinity purification, and immunoassay. Some antibodies can be used for in vivo inhibition experiments. These antibodies bind to their target molecules and neutralize their functions, providing functional information in the study of their biological role. Here, we describe our methods for obtaining inhibitory antibodies against desired proteins. We then describe in the starfish oocyte system how to inhibit a target protein, even in the nucleus, by injection of antibody into the cytoplasm, and how to evaluate antibody inhibition of cell cycle regulators in small numbers of oocytes.

  12. Boric acid and boronic acids inhibition of pigeonpea urease.

    Science.gov (United States)

    Reddy, K Ravi Charan; Kayastha, Arvind M

    2006-08-01

    Urease from the seeds of pigeonpea was competitively inhibited by boric acid, butylboronic acid, phenylboronic acid, and 4-bromophenylboronic acid; 4-bromophenylboronic acid being the strongest inhibitor, followed by boric acid > butylboronic acid > phenylboronic acid, respectively. Urease inhibition by boric acid is maximal at acidic pH (5.0) and minimal at alkaline pH (10.0), i.e., the trigonal planar B(OH)3 form is a more effective inhibitor than the tetrahedral B(OH)4 -anionic form. Similarly, the anionic form of phenylboronic acid was least inhibiting in nature.

  13. Deletion of glutathione peroxidase-2 inhibits azoxymethane-induced colon cancer development.

    Directory of Open Access Journals (Sweden)

    Mike F Müller

    Full Text Available The selenoprotein glutathione peroxidase-2 (GPx2 appears to have a dual role in carcinogenesis. While it protected mice from colon cancer in a model of inflammation-triggered carcinogenesis (azoxymethane and dextran sodium sulfate treatment, it promoted growth of xenografted tumor cells. Therefore, we analyzed the effect of GPx2 in a mouse model mimicking sporadic colorectal cancer (azoxymethane-treatment only. GPx2-knockout (KO and wild-type (WT mice were adjusted to an either marginally deficient (-Se, adequate (+Se, or supranutritional (++Se selenium status and were treated six times with azoxymethane (AOM to induce tumor development. In the -Se and ++Se groups, the number of tumors was significantly lower in GPx2-KO than in respective WT mice. On the +Se diet, the number of dysplastic crypts was reduced in GPx2-KO mice. This may be explained by more basal and AOM-induced apoptotic cell death in GPx2-KO mice that eliminates damaged or pre-malignant epithelial cells. In WT dysplastic crypts GPx2 was up-regulated in comparison to normal crypts which might be an attempt to suppress apoptosis. In contrast, in the +Se groups tumor numbers were similar in both genotypes but tumor size was larger in GPx2-KO mice. The latter was associated with an inflammatory and tumor-promoting environment as obvious from infiltrated inflammatory cells in the intestinal mucosa of GPx2-KO mice even without any treatment and characterized as low-grade inflammation. In WT mice the number of tumors tended to be lowest in +Se compared to -Se and ++Se feeding indicating that selenium might delay tumorigenesis only in the adequate status. In conclusion, the role of GPx2 and presumably also of selenium depends on the cancer stage and obviously on the involvement of inflammation.

  14. Inhibiting prenylation augments chemotherapy efficacy in renal cell carcinoma through dual inhibition on mitochondrial respiration and glycolysis.

    Science.gov (United States)

    Huang, Jiangrong; Yang, Xiaoyu; Peng, Xiaochun; Huang, Wei

    2017-11-18

    Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines. Combination of pitavastatin and paclitaxel is significantly more effective than pitavastatin or paclitaxel alone as shown by both in vitro cell culture system and in vivo RCC xenograft model. Importantly, pitavastatin treatment inhibits mitochondrial respiration via suppressing mitochondrial complex I and II enzyme activities. Interestingly, different from mitochondrial inhibitor phenformin that inhibits mitochondrial respiration but activates glycolytic rate in RCC cells, pitavastatin significantly decreases glycolytic rate. The dual inhibitory action of pitavastatin on mitochondrial respiration and glycolysis results in remarkable energy depletion and oxidative stress in RCC cells. In addition, inhibition of prenylation by depleting Isoprenylcysteine carboxylmethyltransferase (Icmt) also mimics the inhibitory effects of pitavastatin in RCC cells. Our work demonstrates the previously unappreciated association between prenylation inhibition and energy metabolism in RCC, which can be therapeutically exploited, likely in tumors that largely rely on energy metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Irreversible inhibition of RANK expression as a possible mechanism for IL-3 inhibition of RANKL-induced osteoclastogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Khapli, Shruti M.; Tomar, Geetanjali B.; Barhanpurkar, Amruta P.; Gupta, Navita; Yogesha, S.D.; Pote, Satish T. [National Center for Cell Science, University of Pune Campus, Pune 411 007 (India); Wani, Mohan R., E-mail: mohanwani@nccs.res.in [National Center for Cell Science, University of Pune Campus, Pune 411 007 (India)

    2010-09-03

    Research highlights: {yields} IL-3 inhibits receptor activator of NF-{kappa}B ligand (RANKL)-induced osteoclastogenesis. {yields} IL-3 inhibits RANKL-induced JNK activation. {yields} IL-3 down-regulates expression of c-Fos and NFATc1 transcription factors. {yields} IL-3 down-regulates RANK expression posttranscriptionally and irreversibly. {yields} IL-3 inhibits in vivo RANK expression. -- Abstract: IL-3, a cytokine secreted by activated T lymphocytes, stimulates the proliferation, differentiation and survival of pluripotent hematopoietic stem cells. In this study, we investigated the mechanism of inhibitory action of IL-3 on osteoclast differentiation. We show here that IL-3 significantly inhibits receptor activator of NF-{kappa}B (RANK) ligand (RANKL)-induced activation of c-Jun N-terminal kinase (JNK). IL-3 down-regulates expression of c-Fos and nuclear factor of activated T cells (NFATc1) transcription factors. In addition, IL-3 down-regulates RANK expression posttranscriptionally in both purified osteoclast precursors and whole bone marrow cells. Furthermore, the inhibitory effect of IL-3 on RANK expression was irreversible. Interestingly, IL-3 inhibits in vivo RANK expression in mice. Thus, we provide the first evidence that IL-3 irreversibly inhibits RANK expression that results in inhibition of important signaling molecules induced by RANKL.

  16. Inhibiting multiple mode vibration in controlled flexible systems

    Science.gov (United States)

    Hyde, James M.; Chang, Kenneth W.; Seering, Warren P.

    1991-01-01

    Viewgraphs on inhibiting multiple mode vibration in controlled flexible systems are presented. Topics covered include: input pre-shaping background; developing multiple-mode shapers; Middeck Active Control Experiment (MACE) test article; and tests and results.

  17. Inhibition of cholera toxin by human milk fractions and sialyllactose.

    Science.gov (United States)

    Idota, T; Kawakami, H; Murakami, Y; Sugawara, M

    1995-03-01

    The effects of human milk fractions on clolera toxin B subunit binding to monosialoganglioside 1 (GM1) were investigated. Human milk, human defatted milk, whey, and a low-molecular-weight fraction of human milk inhibited the binding, but casein did not inhibit it. The inhibitory activity of whey from bovine-milk-based infant formula was less than that of whey from human milk. Differences in composition between human and bovine whey seemed to influence the extent of the inhibitory activity. Sialylated oligosaccharides were considered to be the possible components that inhibited cholera toxin. The effects of sialyllactose, a predominant sialylated component of human milk, on cholera toxin-induced diarrhea were investigated by the rabbit intestinal loop method. Sialyllactose inhibited the cholera toxin inducing fluid accumulation, although neither sialic acid nor lactose had an effect on it. The results suggest that sialyllactose is responsible for the inhibitory activity of milk on cholera toxin.

  18. Rofecoxib inhibits heterotopic ossification after total hip arthroplasty.

    NARCIS (Netherlands)

    Heide, H.J. van der; Koorevaar, R.C.; Lemmens, J.A.M.; Kampen, A. van; Schreurs, B.W.

    2007-01-01

    INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent heterotopic ossification but gastrointestinal complaints are frequently. Selective cyclooxygenase-2 (COX-2) inhibiting NSAID produce less gastrointestinal side effects. PATIENTS AND METHODS: A prospective two-stage study design for

  19. In vitro inhibition of pathogenic Verticillium dahliae , causal agent of ...

    African Journals Online (AJOL)

    In vitro inhibition of pathogenic Verticillium dahliae, causal agent of potato wilt disease in China by Trichoderma isolates. C Xiaojun, S Wongkaew, Y Jie, Y Xuehui, H Haiyong, W Shiping, T Qigqun, W Lishuang, D Athinuwat, N Buensanteai ...

  20. Melanogenesis inhibition activity of floralginsenoside A from Panax ginseng berry

    Directory of Open Access Journals (Sweden)

    Dae Young Lee

    2017-10-01

    Conclusion: FGA showed the most potent inhibition of melanogenesis in both in vitro and in vivo studies. This study suggests that FGA purified from P. ginseng may be an effective melanogenesis inhibitor.

  1. Overcoming heat shock protein inhibition at critical temperature vital ...

    African Journals Online (AJOL)

    Overcoming heat shock protein inhibition at critical temperature vital for survival in Solanum tuberosum L. in vivo condition. Bengyella Louis, Pranab Roy, Tamgue Ousman, Sayanika Waikhom Devi, Narayan Chandra Talukdar ...

  2. Functional mechanisms involved in the internal inhibition of taboo words.

    Science.gov (United States)

    Severens, Els; Kühn, Simone; Hartsuiker, Robert J; Brass, Marcel

    2012-04-01

    The present study used functional magnetic resonance imaging to investigate brain processes associated with the inhibition of socially undesirable speech. It is tested whether the inhibition of undesirable speech is solely related to brain areas associated with classical stop signal tasks or rather also involves brain areas involved in endogenous self-control. During the experiment, subjects had to do a SLIP task, which was designed to elicit taboo or neutral spoonerisms. Here we show that the internal inhibition of taboo words activates the right inferior frontal gyrus, an area that has previously been associated with externally triggered inhibition. This finding strongly suggests that external social rules become internalized and act as a stop-signal.

  3. Somatosensory Integration Controlled by Dynamic Thalamocortical Feed-Forward Inhibition

    National Research Council Canada - National Science Library

    Gabernet, Laetitia; Jadhav, Shantanu P; Feldman, Daniel E; Carandini, Matteo; Scanziani, Massimo

    2005-01-01

    .... Here, we show that in the rodent barrel cortex, the temporal window for integration of thalamic inputs is under the control of thalamocortical feed-forward inhibition and can vary from 1 to 10 ms...

  4. synthesis, DNA interaction and comparison of lipase inhibition propert

    Indian Academy of Sciences (India)

    GÜNAY KAYA KANTAR

    obesity agent acting locally in the gastrointestinal tract by reversibly inhibiting pancreatic and gastric lipases. Pancreatic and gastric lipases are involved in the disruption of long chain triglycerides. Controlling obesity with orlistat is limited because.

  5. Growth Inhibition of Grain Spoilage Fungi by Selected Herbs and ...

    African Journals Online (AJOL)

    ) and Thymus schimperi (thymus) were found to be the most effective. However piper nigrum (black pepper) had no effect on the test organisms. In MIC, spore germination inhibition and grain protection assay, cinnamon essential oil was found ...

  6. Inhibiting DNA Polymerases as a Therapeutic Intervention against Cancer

    Directory of Open Access Journals (Sweden)

    Anthony J. Berdis

    2017-11-01

    Full Text Available Inhibiting DNA synthesis is an important therapeutic strategy that is widely used to treat a number of hyperproliferative diseases including viral infections, autoimmune disorders, and cancer. This chapter describes two major categories of therapeutic agents used to inhibit DNA synthesis. The first category includes purine and pyrmidine nucleoside analogs that directly inhibit DNA polymerase activity. The second category includes DNA damaging agents including cisplatin and chlorambucil that modify the composition and structure of the nucleic acid substrate to indirectly inhibit DNA synthesis. Special emphasis is placed on describing the molecular mechanisms of these inhibitory effects against chromosomal and mitochondrial DNA polymerases. Discussions are also provided on the mechanisms associated with resistance to these therapeutic agents. A primary focus is toward understanding the roles of specialized DNA polymerases that by-pass DNA lesions produced by DNA damaging agents. Finally, a section is provided that describes emerging areas in developing new therapeutic strategies targeting specialized DNA polymerases.

  7. Inhibition of Nitric Oxide and Prostaglandin E 2 Expression by ...

    African Journals Online (AJOL)

    Inhibition of Nitric Oxide and Prostaglandin E 2 Expression by Methanol Extract of Polyopes affinis in Lipopolysaccharide-stimulated BV2 Microglial Cells through Suppression of Akt-dependent NF-kB Activity and MAPK Pathway.

  8. Acute Simvastatin Inhibits KATP Channels of Porcine Coronary Artery Myocytes

    National Research Council Canada - National Science Library

    Seto, Sai Wang; Au, Alice Lai Shan; Poon, Christina Chui Wa; Zhang, Qian; Li, Rachel Wai Sum; Yeung, John Hok Keung; Kong, Siu Kai; Ngai, Sai Ming; Wan, Song; Ho, Ho Pui; Lee, Simon Ming Yuen; Hoi, Maggie Pui Man; Chan, Shun Wan; Leung, George Pak Heng; Kwan, Yiu Wa

    2013-01-01

    ...]o uptake measurements. Results The cromakalim (10 nM to 10 µM)- and pinacidil (10 nM to 10 µM)-induced concentration-dependent relaxation of porcine coronary artery was inhibited by simvastatin...

  9. Nitric oxide inhibits glycogen synthesis in isolated rat hepatocytes

    NARCIS (Netherlands)

    Sprangers, F.; Sauerwein, H. P.; Romijn, J. A.; van Woerkom, G. M.; Meijer, A. J.

    1998-01-01

    There is increasing evidence for the existence of intrahepatic regulation of glucose metabolism by Kupffer cell products. Nitric oxide (NO) is known to inhibit gluconeogenic flux through pyruvate carboxylase and phosphoenolpyruvate carboxykinase. However, NO may also influence glucose metabolism at

  10. Behavioural inhibition: is it a risk factor for anxiety?

    Science.gov (United States)

    Lahat, Ayelet; Hong, Melanie; Fox, Nathan A

    2011-06-01

    Behavioural inhibition is a stable temperamental trait that is identifiable during infancy and toddlerhood and is characterized by fearful reactivity to novelty. Children identified as behaviourally inhibited have been shown to be at increased risk for developing anxiety disorders such as social phobia. The current review addresses the link between behavioural inhibition and the risk for developing anxiety disorders. Research suggests that this risk may be modulated by a number of extrinsic and intrinsic factors. Extrinsic factors include particular parental beliefs, parenting styles, and childrearing contexts. Intrinsic factors include executive function capacities such as attention bias, attention shifting, inhibitory control, and self-monitoring. In the present paper we review the contribution of these factors to the development of anxiety in behaviourally inhibited children.

  11. Serum factors affecting the cell migration inhibition response to lepromin.

    Science.gov (United States)

    Fliess, E L; Ruibal-Ares, B; Braun, M

    1975-01-01

    Cell migration inhibition of white blood cells in the presence of total protein lepromin (TPL) was studied in ten lepromatous patients, six tuberculoid patients, and ten normal controls; adding normal, tuberculoid, lepromatous, or no serum to the culture medium. Using normal or no serum, lepromatous patients and skin negative controls gave negative reactions, while tuberculoid patients and skin positive controls gave positive cell migration inhibitions. The addition of lepromatous serum gave a very significant overall increase of migration indices in all groups of subjects, turning to negative the positive reactions of lepromatous patients and positive controls. On the contrary, the addition of tuberculoid serum gave a decrease of migration index in all groups of subjects, turning to positive the reactions in lepromatous patients. The significance of these circulating factors, able to enhance or inhibit cell migration inhibition responses in patients and controls, is discussed.

  12. Emotional content modulates response inhibition and perceptual processing.

    Science.gov (United States)

    Yang, Suyong; Luo, Wenbo; Zhu, Xiangru; Broster, Lucas S; Chen, Taolin; Li, Jinzhen; Luo, Yuejia

    2014-11-01

    In this study, event-related potentials were used to investigate the effect of emotion on response inhibition. Participants performed an emotional go/no-go task that required responses to human faces associated with a "go" valence (i.e., emotional, neutral) and response inhibition to human faces associated with a "no-go" valence. Emotional content impaired response inhibition, as evidenced by decreased response accuracy and N2 amplitudes in no-go trials. More importantly, emotional expressions elicited larger N170 amplitudes than neutral expressions, and this effect was larger in no-go than in go trials, indicating that the perceptual processing of emotional expression had priority in inhibitory trials. In no-go trials, correlation analysis showed that increased N170 amplitudes were associated with decreased N2 amplitudes. Taken together, our findings suggest that emotional content impairs response inhibition due to the prioritization of emotional content processing. Copyright © 2014 Society for Psychophysiological Research.

  13. MECHANISMS IN THE INHIBITION OF MICROORGANISMS BY SORBIC ACID

    Science.gov (United States)

    York, George K.; Vaughn, Reese H.

    1964-01-01

    York, George K. (University of California, Davis), and Reese H. Vaughn. Mechanisms in the inhibition of microorganisms by sorbic acid. J. Bacteriol. 88:411–417. 1964.—Oxidative assimilation of glucose, acetate, succinate, and fumarate by washed cells of Escherichia coli, Pseudomonas aeruginosa, and Saccharomyces cerevisiae was inhibited by concentrations of sorbic acid ranging from 15 to 105 mg per 100 ml. At higher concentrations, the oxidation of these substrates was inhibited. Oxidative phosphorylation by submicroscopic particles of E. coli was reduced by about 30% by 37 mg per 100 ml of sorbic acid. The sulfhydryl enzymes fumarase, aspartase, and succinic dehydrogenase were inhibited by sorbic acid. The loss of activity of sorbic acid after reacting with cysteine suggested that a thiol addition occurred, which is believed to be the mechanism of action against sulfhydryl enzymes or cofactors. PMID:14203358

  14. Noninvasive optical inhibition with a red-shifted microbial rhodopsin

    Science.gov (United States)

    Chuong, Amy S; Miri, Mitra L; Busskamp, Volker; Matthews, Gillian A C; Acker, Leah C; Sørensen, Andreas T; Young, Andrew; Klapoetke, Nathan C; Henninger, Mike A; Kodandaramaiah, Suhasa B; Ogawa, Masaaki; Ramanlal, Shreshtha B; Bandler, Rachel C; Allen, Brian D; Forest, Craig R; Chow, Brian Y; Han, Xue; Lin, Yingxi; Tye, Kay M; Roska, Botond; Cardin, Jessica A; Boyden, Edward S

    2014-01-01

    Optogenetic inhibition of the electrical activity of neurons enables the causal assessment of their contributions to brain functions. Red light penetrates deeper into tissue than other visible wavelengths. We present a red-shifted cruxhalorhodopsin, Jaws, derived from Haloarcula (Halobacterium) salinarum (strain Shark) and engineered to result in red light–induced photocurrents three times those of earlier silencers. Jaws exhibits robust inhibition of sensory-evoked neural activity in the cortex and results in strong light responses when used in retinas of retinitis pigmentosa model mice. We also demonstrate that Jaws can noninvasively mediate transcranial optical inhibition of neurons deep in the brains of awake mice. The noninvasive optogenetic inhibition opened up by Jaws enables a variety of important neuroscience experiments and offers a powerful general-use chloride pump for basic and applied neuroscience. PMID:24997763

  15. Mildiomycin: a nucleoside antibiotic that inhibits protein synthesis.

    Science.gov (United States)

    Feduchi, E; Cosín, M; Carrasco, L

    1985-03-01

    Mildiomycin, a new nucleoside antibiotic, selectively inhibits protein synthesis in HeLa cells, and is less active in the inhibition of RNA or DNA synthesis. An increased inhibition of translation by mildiomycin is observed in cultured HeLa cells when they are permeabilized by encephalomyocarditis virus. This observation suggests that this antibiotic does not easily pass through the cell membrane, as occurs with other nucleoside and aminoglycoside antibiotics. The inhibition of translation is also observed in cell-free systems, such as endogenous protein synthesis in a rabbit reticulocyte lysate or the synthesis of polyphenylalanine directed by poly (U). Finally the mode of action of mildiomycin was investigated and the results suggest that the compound blocks the peptidyl-transferase center.

  16. Hyperoxia Inhibits T Cell Activation in Mice

    Science.gov (United States)

    Hughes-Fulford, M.; Meissler, J.; Aguayo, E. T.; Globus, R.; Aguado, J.; Candelario, T.

    2013-02-01

    , spleens were removed and the splenocytes were isolated and kept as individual biological samples. We have also examined transcription factors (JASPAR) and pathways of the immune system to help us understand the mechanism of regulation. Results: Our recent mouse immunology experiment aboard STS-131 suggests that the early T cell immune response was inhibited in animals that have been exposed to spaceflight, even 24 hours after return to earth. Moreover, recent experiments in hyperoxic mice show that many of the same genes involved in early T cell activation were altered. Specifically, expression of IL-2Rα, Cxcl2, TNFα, FGF2, LTA and BCL2 genes are dysregulated in mice exposed to hyperoxia. Conclusions: If these hyperoxia-induced changes of gene expression in early T cell activation are additive to the changes seen in the microgravity of spaceflight, there could be an increased infection risk to EVA astronauts, which should be addressed prior to conducting a Mars or other long-term mission.

  17. Silymarin inhibits cisplatin-mediated apoptosis via inhibition of hydrogen peroxide and hydroxyl radical generation

    Directory of Open Access Journals (Sweden)

    Angkana Tantituvanont

    2015-04-01

    Full Text Available Cisplatin mediated nephrotoxicity has been continuously reported and recognized as a major obstacle for cisplatinbased chemotherapy. The present study aimed to demonstrate the potential use of silymarin, an extract from the seed of Silybum marianum L., as a combination therapy with cisplatin. Previous studies indicated that cisplatin-mediated toxicity was primarily caused by cellular oxidative stress. This study found that pretreatment with silymarin significantly attenuated oxidative stress induced by cisplatin in human renal epithelial cells (HK2-cells and protected against cisplatin-mediated apoptosis. Moreover, the present study demonstrated that silymarin could attenuate hydrogen peroxide and hydroxyl radical generated by cisplatin while having minimal effect on superoxide anion level. In summary, these observation showed significant impact of silymarin in the inhibition of cisplatin-mediated renal cell death in vitro and could be beneficial for the development of this compound as a combination therapy in patients before receiving cisplatin.

  18. Comparison of the inhibition capability of oleanolic acid and ...

    African Journals Online (AJOL)

    At various concentrations of oleanolic acid and betulinic acid, the inhibition of oleanolic acid towards UGT1A6 and UGT1A8 was higher than betulinic acid. Conslusion: Given that UGT1A6 and UGT1A8 play key role in the the inhibition of oleanolic acid towards UGT1A6 and UGT1A8 will induce drug-drug interaction and the ...

  19. Inhibition of noradrenaline release by lysergic acid diethylamide

    Science.gov (United States)

    Hughes, J.

    1973-01-01

    Lysergic acid diethylamide (LSD) inhibits the release of labelled noradrenaline from the guinea-pig vas deferens during intramural nerve stimulation and causes a corresponding reduction in the contractions of the smooth muscle. These effects of LSD are most prominent at low stimulus frequencies and they are prevented by treatment with phentolamine. It is concluded that LSD inhibits noradrenaline release by interacting with presynaptic α-adrenoceptors. PMID:4788042

  20. Inhibition of eye blinking reveals subjective perceptions of stimulus salience

    OpenAIRE

    Shultz, Sarah; Klin, Ami; Jones, Warren

    2011-01-01

    Spontaneous eye blinking serves a critical physiological function, but it also interrupts incoming visual information. This tradeoff suggests that the inhibition of eye blinks might constitute an adaptive reaction to minimize the loss of visual information, particularly information that a viewer perceives to be important. To test this hypothesis, we examined whether the timing of blink inhibition, during natural viewing, is modulated between as well as within tasks, and also whether the timin...

  1. Protons inhibit anoctamin 1 by competing with calcium.

    Science.gov (United States)

    Chun, Hyeyeon; Cho, Hawon; Choi, Jimi; Lee, Jesun; Kim, Sung Min; Kim, Hyungsup; Oh, Uhtaek

    2015-11-01

    Cl(-) efflux through Ca(2+)-activated Cl(-) channels (CaCCs) in secretory epithelial cells plays a key role in the regulation of fluid secretion. The fluid and electrolyte secretion is closely related to intracellular pH. CaCCs have been known to be inhibited by intracellular acid. However, the molecular mechanism for the inhibition remains unknown. Anoctamin 1 (ANO1) is a Ca(2+)-activated Cl(-) channel that mediates numerous physiological functions including fluid secretion in secretory epithelia. However, little is known about whether ANO1 can be modulated by change of intracellular pH. Here, we demonstrate that Ca(2+)-induced activation of ANO1 and its homolog ANO2 are strongly inhibited by intracellular acid. Intracellular acid caused a rightward shift of the concentration-response curve of Ca(2+) in activating ANO1 and ANO2. To identify the location of the acid-induced inhibition, mutations were made on each of all histidine residues in cytoplasmic part of ANO1. However, none of the His-mutant showed the reduction in the acid-induced inhibition. Furthermore, mutation on Glu- or Asp-residues in the multiple acidic-amino acid regions was ineffective in blocking the acid-induced inhibition. Because the Ca(2+)-binding site of a fungal anoctamin (nhTMEM16) was uncovered by crystallography, mutagenesis was performed in this region. Surprisingly, mutations at Glu, Asp or Asn residues in the hydrophobic core that are known to be essential for Ca(2+)-induced activation of ANO1 blocked the acid-induced inhibition. These results suggest that protons interfere with Ca(2+) at the Ca(2+) binding site of ANO1. These findings provide a molecular mechanism underlying the acid-induced inhibition of ANO1, which may contribute to control fluid and electrolyte secretion in the secretory epithelia. Copyright © 2015. Published by Elsevier Ltd.

  2. Inhibition and impulsivity: behavioral and neural basis of response control.

    Science.gov (United States)

    Bari, Andrea; Robbins, Trevor W

    2013-09-01

    In many circumstances alternative courses of action and thoughts have to be inhibited to allow the emergence of goal-directed behavior. However, this has not been the accepted view in the past and only recently has inhibition earned its own place in the neurosciences as a fundamental cognitive function. In this review we first introduce the concept of inhibition from early psychological speculations based on philosophical theories of the human mind. The broad construct of inhibition is then reduced to its most readily observable component which necessarily is its behavioral manifestation. The study of 'response inhibition' has the advantage of dealing with a relatively simple and straightforward process, the overriding of a planned or already initiated action. Deficient inhibitory processes profoundly affect everyday life, causing impulsive conduct which is generally detrimental for the individual. Impulsivity has been consistently linked to several types of addiction, attention deficit/hyperactivity disorder, mania and other psychiatric conditions. Our discussion of the behavioral assessment of impulsivity will focus on objective laboratory tasks of response inhibition that have been implemented in parallel for humans and other species with relatively few qualitative differences. The translational potential of these measures has greatly improved our knowledge of the neurobiological basis of behavioral inhibition and impulsivity. We will then review the current models of behavioral inhibition along with their expression via underlying brain regions, including those involved in the activation of the brain's emergency 'brake' operation, those engaged in more controlled and sustained inhibitory processes and other ancillary executive functions. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Inhibition control and working memory capacity in children with SLI

    OpenAIRE

    Marton, Klara; Kelmenson, Lyudmyla; Pinkhasova, Milana

    2007-01-01

    This study examined the “inefficient inhibition hypothesis” (IIH; Bjorklund & Harnishfeger, 1990; Wilson & Kipp, 1998) in three groups: children with specific language impairment (SLI), age-matched and language-matched controls. The IIH suggests that individuals with efficient inhibition skills perform better on working memory tasks because they are able to keep out irrelevant information from working memory. Children with SLI show processing capacity limitations. This study examined whether ...

  4. Novel Antimicrobial Peptides That Inhibit Gram Positive Bacterial Exotoxin Synthesis

    Science.gov (United States)

    Merriman, Joseph A.; Nemeth, Kimberly A.; Schlievert, Patrick M.

    2014-01-01

    Gram-positive bacteria, such as Staphylococcus aureus, cause serious human illnesses through combinations of surface virulence factors and secretion of exotoxins. Our prior studies using the protein synthesis inhibitor clindamycin and signal transduction inhibitors glycerol monolaurate and α-globin and β-globin chains of hemoglobin indicate that their abilities to inhibit exotoxin production by S. aureus are separable from abilities to inhibit growth of the organism. Additionally, our previous studies suggest that inhibition of exotoxin production, in absence of ability to kill S. aureus and normal flora lactobacilli, will prevent colonization by pathogenic S. aureus, while not interfering with lactobacilli colonization. These disparate activities may be important in development of novel anti-infective agents that do not alter normal flora. We initiated studies to explore the exotoxin-synthesis-inhibition activity of hemoglobin peptides further to develop potential agents to prevent S. aureus infections. We tested synthesized α-globin chain peptides, synthetic variants of α-globin chain peptides, and two human defensins for ability to inhibit exotoxin production without significantly inhibiting S. aureus growth. All of these peptides were weakly or not inhibitory to bacterial growth. However, the peptides were inhibitory to exotoxin production with increasing activity dependent on increasing numbers of positively-charged amino acids. Additionally, the peptides could be immobilized on agarose beads or have amino acid sequences scrambled and still retain exotoxin-synthesis-inhibition. The peptides are not toxic to human vaginal epithelial cells and do not inhibit growth of normal flora L. crispatus. These peptides may interfere with plasma membrane signal transduction in S. aureus due to their positive charges. PMID:24748386

  5. Beyond Behavioral Inhibition: A Computer Avatar Task Designed to Assess Behavioral Inhibition Extends to Harm Avoidance

    Directory of Open Access Journals (Sweden)

    Michael Todd Allen

    2017-09-01

    Full Text Available Personality factors such as behavioral inhibition (BI, a temperamental tendency for avoidance in the face of unfamiliar situations, have been identified as risk factors for anxiety disorders. Personality factors are generally identified through self-report inventories. However, this tendency to avoid may affect the accuracy of these self-report inventories. Previously, a computer based task was developed in which the participant guides an on-screen “avatar” through a series of onscreen events; performance on the task could accurately predict participants’ BI, measured by a standard paper and pencil questionnaire (Adult Measure of Behavioral Inhibition, or AMBI. Here, we sought to replicate this finding as well as compare performance on the avatar task to another measure related to BI, the harm avoidance (HA scale of the Tridimensional Personality Questionnaire (TPQ. The TPQ includes HA scales as well as scales assessing reward dependence (RD, novelty seeking (NS and persistence. One hundred and one undergraduates voluntarily completed the avatar task and the paper and pencil inventories in a counter-balanced order. Scores on the avatar task were strongly correlated with BI assessed via the AMBI questionnaire, which replicates prior findings. Females exhibited higher HA scores than males, but did not differ on scores on the avatar task. There was a strong positive relationship between scores on the avatar task and HA scores. One aspect of HA, fear of uncertainty was found to moderately mediate the relationship between AMBI scores and avatar scores. NS had a strong negative relationship with scores on the avatar task, but there was no significant relationship between RD and scores on the avatar task. These findings indicate the effectiveness of the avatar task as a behavioral alternative to self-report measures to assess avoidance. In addition, the use of computer based behavioral tasks are a viable alternative to paper and pencil self

  6. Lipocortin inhibition of extracellular and intracellular phospholipases A2 is substrate concentration dependent

    NARCIS (Netherlands)

    Aarsman, A.J.; Mynbeek, G.; Bosch, H. van den; Rothhut, B.; Prieur, B.; Comera, C.; Jordan, J.; Russo-Marie, F.

    1987-01-01

    Hydrolysis of Escherichia coli membrane phospholipids by pancreatic phospholipase A2 was inhibited by lipocortin from human monocytes in a substrate dependent manner. Inhibition was completely overcome at substrate concentrations above 250 μM. Lipocortin also inhibited partially purified

  7. Palmitoylethanolamide Inhibits Glutamate Release in Rat Cerebrocortical Nerve Terminals

    Directory of Open Access Journals (Sweden)

    Tzu-Yu Lin

    2015-03-01

    Full Text Available The effect of palmitoylethanolamide (PEA, an endogenous fatty acid amide displaying neuroprotective actions, on glutamate release from rat cerebrocortical nerve terminals (synaptosomes was investigated. PEA inhibited the Ca2+-dependent release of glutamate, which was triggered by exposing synaptosomes to the potassium channel blocker 4-aminopyridine. This release inhibition was concentration dependent, associated with a reduction in cytosolic Ca2+ concentration, and not due to a change in synaptosomal membrane potential. The glutamate release-inhibiting effect of PEA was prevented by the Cav2.1 (P/Q-type channel blocker ω-agatoxin IVA or the protein kinase A inhibitor H89, not affected by the intracellular Ca2+ release inhibitors dantrolene and CGP37157, and partially antagonized by the cannabinoid CB1 receptor antagonist AM281. Based on these results, we suggest that PEA exerts its presynaptic inhibition, likely through a reduction in the Ca2+ influx mediated by Cav2.1 (P/Q-type channels, thereby inhibiting the release of glutamate from rat cortical nerve terminals. This release inhibition might be linked to the activation of presynaptic cannabinoid CB1 receptors and the suppression of the protein kinase A pathway.

  8. Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons

    Science.gov (United States)

    Hawryluk, J. M.; Ferrari, L. L.; Keating, S. A.

    2012-01-01

    Adenosine has been proposed as an endogenous homeostatic sleep factor that accumulates during waking and inhibits wake-active neurons to promote sleep. It has been specifically hypothesized that adenosine decreases wakefulness and promotes sleep recovery by directly inhibiting wake-active neurons of the basal forebrain (BF), particularly BF cholinergic neurons. We previously showed that adenosine directly inhibits BF cholinergic neurons. Here, we investigated 1) how adenosine modulates glutamatergic input to BF cholinergic neurons and 2) how adenosine uptake and adenosine metabolism are involved in regulating extracellular levels of adenosine. Our experiments were conducted using whole cell patch-clamp recordings in mouse brain slices. We found that in BF cholinergic neurons, adenosine reduced the amplitude of AMPA-mediated evoked glutamatergic excitatory postsynaptic currents (EPSCs) and decreased the frequency of spontaneous and miniature EPSCs through presynaptic A1 receptors. Thus we have demonstrated that in addition to directly inhibiting BF cholinergic neurons, adenosine depresses excitatory inputs to these neurons. It is therefore possible that both direct and indirect inhibition may synergistically contribute to the sleep-promoting effects of adenosine in the BF. We also found that blocking the influx of adenosine through the equilibrative nucleoside transporters or inhibiting adenosine kinase and adenosine deaminase increased endogenous adenosine inhibitory tone, suggesting a possible mechanism through which adenosine extracellular levels in the basal forebrain are regulated. PMID:22357797

  9. Common neural substrates for inhibition of spoken and manual responses.

    Science.gov (United States)

    Xue, Gui; Aron, Adam R; Poldrack, Russell A

    2008-08-01

    The inhibition of speech acts is a critical aspect of human executive control over thought and action, but its neural underpinnings are poorly understood. Using functional magnetic resonance imaging and the stop-signal paradigm, we examined the neural correlates of speech control in comparison to manual motor control. Initiation of a verbal response activated left inferior frontal cortex (IFC: Broca's area). Successful inhibition of speech (naming of letters or pseudowords) engaged a region of right IFC (including pars opercularis and anterior insular cortex) as well as presupplementary motor area (pre-SMA); these regions were also activated by successful inhibition of a hand response (i.e., a button press). Moreover, the speed with which subjects inhibited their responses, stop-signal reaction time, was significantly correlated between speech and manual inhibition tasks. These findings suggest a functional dissociation of left and right IFC in initiating versus inhibiting vocal responses, and that manual responses and speech acts share a common inhibitory mechanism localized in the right IFC and pre-SMA.

  10. Rosiglitazone Regulates Anti-Inflammation and Growth Inhibition via PTEN

    Directory of Open Access Journals (Sweden)

    Chiou-Feng Lin

    2014-01-01

    Full Text Available Peroxisome proliferator-activated receptor gamma (PPARγ agonist has anti-inflammatory and anticancer properties. However, the mechanisms by which PPARγ agonist rosiglitazone interferes with inflammation and cancer via phosphatase and tensin homolog-(PTEN-dependent pathway remain unclear. We found that lower doses (<25 μM of rosiglitazone significantly inhibited lipopolysaccharide-(LPS-induced nitric oxide (NO release (via inducible nitric oxide synthase, iNOS, prostaglandin E2 (PGE2 production (via cyclooxygenase-2, COX-2, and activation of Akt in RAW 264.7 murine macrophages. However, rosiglitazone did not inhibit the production of reactive oxygen species (ROS. In PTEN knockdown (shPTEN cells exposed to LPS, rosiglitazone did not inhibit NO release, PGE2 production, and activation of Akt. These cells had elevated basal levels of iNOS, COX-2, and ROS. However, higher doses (25–100 μM of rosiglitazone, without LPS stimulation, did not block NO release and PGE2 productions, but they inhibited p38 MAPK phosphorylation and blocked ROS generation in shPTEN cells. In addition, rosiglitazone caused G1 arrest and reduced the number of cells in S + G2/M phase, leading to growth inhibition. These results indicate that the anti-inflammatory property of rosiglitazone is related to regulation of PTEN independent of inhibition on ROS production. However, rosiglitazone affected the dependence of PTEN-deficient cell growth on ROS.

  11. The effect of vagus nerve stimulation on response inhibition.

    Science.gov (United States)

    Schevernels, Hanne; van Bochove, Marlies E; De Taeye, Leen; Bombeke, Klaas; Vonck, Kristl; Van Roost, Dirk; De Herdt, Veerle; Santens, Patrick; Raedt, Robrecht; Boehler, C Nico

    2016-11-01

    In the current study, we explored whether vagus nerve stimulation (VNS) in patients with epilepsy, which is believed to increase norepinephrine (NE) levels via activation of the locus coeruleus, would positively affect response inhibition. Moreover, we tried to identify the dynamics of the underlying neural processes by investigating event-related potentials (ERPs) and pupil size. Patients performed a stop-signal task once when stimulation was switched on and once when it was switched off. We found a correlational pattern suggesting that patients who clinically benefit more from VNS treatment also show a larger behavioral advantage, in terms of faster response inhibition, when the vagus nerve is being stimulated. Event-related potential (ERP) results suggested more pronounced reactive inhibition when stimulation was switched on, independent of the individual amount of seizure reduction. Transient go-locked pupil size was increased from go trials to successful stop trials to unsuccessful stop trials but without displaying a clear VNS effect, which however, might relate to limited sensitivity. We conclude that VNS likely has a positive effect on response inhibition, at least in patients with epilepsy that benefit clinically from the treatment, presumably relating to enhancements of response-inhibition mechanisms and, therefore, identify enhanced response inhibition as a possible cognitive benefit of VNS. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Comparing the context specificity of extinction and latent inhibition.

    Science.gov (United States)

    Miller, Ralph R; Laborda, Mario A; Polack, Cody W; Miguez, Gonzalo

    2015-12-01

    Exposure to a cue alone either before (i.e., latent inhibition treatment) or after (i.e., extinction) the cue is paired with an unconditioned stimulus results in attenuated conditioned responding to the cue. Here we report two experiments in which potential parallels between the context specificity of the effects of extinction and latent inhibition treatments were directly compared in a lick suppression preparation with rats. The reversed ordering of conditioning and nonreinforcement in extinction and latent inhibition designs allowed us to examine the effect of training order on the context specificity of what is learned given phasic reinforcement and nonreinforcement of a target cue. Experiment 1 revealed that when conditioned-stimulus (CS) conditioning and CS nonreinforcement were administered in the same context, both extinction and latent inhibition treatments had reduced impacts on test performance, relative to excitatory conditioning when testing occurred outside the treatment context. Similarly, Experiment 2 showed that when conditioning was administered in one context and nonreinforcement was administered in a second context, the effects of both extinction and latent inhibition treatments were attenuated when testing occurred in a neutral context, relative to the context in which the CS was nonreinforced. The observed context specificity of extinction and latent inhibition treatments has been previously reported in both cases, but not in a single experiment under otherwise identical conditions. The results of the two experiments convergently suggest that memory of nonreinforcement becomes context dependent after a cue is both reinforced and nonreinforced, independent of the order of training.

  13. Alpha2 subunit specificity of cyclothiazide inhibition on glycine receptors.

    Science.gov (United States)

    Zhang, Xiao-Bing; Sun, Guang-Chun; Liu, Lu-Ying; Yu, Fang; Xu, Tian-Le

    2008-04-01

    In the mammalian cortex, alpha2 subunit-containing glycine receptors (GlyRs) mediate tonic inhibition, but the precise functional role of this type of GlyRs is difficult to establish because of the lack of subtype-selective antagonist. In this study, we found that cyclothiazide (CTZ), an epileptogenic agent, potently inhibited GlyR-mediated current (I(Gly)) in cultured rat hippocampal neurons. The inhibition was glycine concentration-dependent, suggesting a competitive mechanism. Note that GlyRs containing the alpha2 but not alpha1 or alpha3 subunits, when being heterologously expressed in human embryonic kidney 293T cells, were inhibited by CTZ, indicating subunit specificity of CTZ action. In addition, the degree of CTZ inhibition on I(Gly) in rat spinal neurons declined with time in culture, in parallel with a decline of alpha2 subunit expression, which is known to occur during spinal cord development. Furthermore, site-directed mutagenesis indicates that a single-amino acid threonine at position 59 near the N terminus of the alpha2 subunit confers the specificity of CTZ action. Thus, CTZ is a potent and selective inhibitor of alpha2-GlyRs, and threonine at position 59 plays a critical role in the susceptibility of GlyR to CTZ inhibition.

  14. Magnetoencephalographic signatures of right prefrontal cortex involvement in response inhibition.

    Science.gov (United States)

    Hege, Maike A; Preissl, Hubert; Stingl, Krunoslav T

    2014-10-01

    The prefrontal cortex has a pivotal role in top-down control of cognitive and sensory functions. In complex go-nogo tasks, the right dorsolateral prefrontal cortex is considered to be important for guiding the response inhibition. However, little is known about the temporal dynamics and neurophysiological nature of this activity. To address this issue, we recorded magnetoencephalographic brain activity in 20 women during a visual go-nogo task. The right dorsolateral prefrontal cortex showed an increase for the amplitude of the event-related fields and an increase in induced alpha frequency band activity for nogo in comparison to go trials. The peak of this prefrontal activity preceded the mean reaction time of around 360 ms for go trials, and thus supports the proposed role of right dorsolateral prefrontal cortex in gating the response inhibition and further suggests that right prefrontal alpha band activity might be involved in this gating. However, the results in right dorsolateral prefrontal cortex were similar for both successful and unsuccessful response inhibition. In these conditions, we instead observed pre- and poststimulus differences in alpha band activity in occipital and central areas. Thus, successful response inhibition seemed to additionally depend on prestimulus anticipatory alpha desynchronization in sensory areas as it was reduced prior to unsuccessful response inhibition. In conclusion, we suggest a role for functional inhibition by alpha synchronization not only in sensory, but also in prefrontal areas. Copyright © 2014 Wiley Periodicals, Inc.

  15. Inhibition of influenza virus replication by adlay tea.

    Science.gov (United States)

    Nagai, Emiko; Iwai, Miwa; Koketsu, Ritsuko; Sogabe, Riho; Morimoto, Ryosuke; Suzuki, Yuri; Ohta, Yoichiro; Okuno, Yoshinobu; Ohshima, Atsushi; Enomoto, Toshiki; Isegawa, Yuji

    2017-09-13

    The present study was conducted aiming to examine the antiviral activity of adlay tea and its components against influenza viruses. We further aimed to clarify the mechanism by which these components regulate virus replication. Adlay tea at a concentration suitable for drinking inhibited the multiplication of influenza viruses. Moreover, our results suggest that individual components of the tea had antiviral activities against the influenza A/PR/8/34 virus. Adlay tea inhibited multiplication of the H1N1, H3N2 and B types of influenza virus, including oseltamivir-resistant viruses. In addition, adlay tea inhibited influenza infection during the periods of virus adsorption to the cell and virus replication. Adlay tea did not suppress hemagglutination inhibition or cell fusion, although it slightly inhibited virus binding to Malin Darby canine kidney cells. Furthermore, our findings suggest that the antiviral compounds included in adlay tea were ingredients other than polyphenols and that there were several types of effective compounds in adlay tea inhibiting several steps of viral replication. The results of the present study demonstrate that adlay tea had antiviral effects against influenza viruses. Our findings with respect to adlay tea suggest that the polyphenols might have a small influence on its antiviral activity and that other ingredients might have more influence. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  16. Alpha oscillatory correlates of motor inhibition in the aged brain

    Directory of Open Access Journals (Sweden)

    Marlene eBoenstrup

    2015-10-01

    Full Text Available Exerting inhibitory control is a cognitive ability mediated by functions known to decline with age. The goal of this study is to add to the mechanistic understanding of cortical inhibition during motor control in aged brains. Based on behavioral findings of impaired inhibitory control with age we hypothesized that elderly will show a reduced or a lack of EEG alpha-power increase during tasks that require motor inhibition. Since inhibitory control over movements has been shown to rely on prior motor memory formation, we investigated cortical inhibitory processes at two points in time - early after learning and after an overnight consolidation phase and hypothesized an overnight increase of inhibitory capacities. Young and elderly participants acquired a complex finger movement sequence and in each experimental session brain activity during execution and inhibition of the sequence was recorded with multi-channel EEG. We assessed cortical processes of sustained inhibition by means of task-induced changes of alpha oscillatory power. During inhibition of the learned movement, young participants showed a significant alpha power increase at the sensorimotor cortices whereas elderly did not. Interestingly, for both groups, the overnight consolidation phase improved up-regulation of alpha power during sustained inhibition. This points to deficits in the generation and enhancement of local inhibitory mechanisms at the sensorimotor cortices in aged brains. However, the alpha power increase in both groups implies neuroplastic changes that strengthen the network of alpha power generation over time in young as well as elderly brains.

  17. Inhibition properties of propolis extracts to some clinically important enzymes.

    Science.gov (United States)

    Baltas, Nimet; Yildiz, Oktay; Kolayli, Sevgi

    2016-01-01

    The present study was conducted to envisage inhibition effects of propolis on the crucial enzymes, urease, xanthine oxidase (XO) and acetylcholinesterase (AChE). Some of the antioxidant properties of the propolis samples were determined using the total phenolic content (TPE) and total flavonoids in the eight different ethanolic propolis extracts (EPE) samples. Inhibition values of the enzymes were expressed as inhibition concentration (IC50; mg/mL or μg/mL) causing 50% inhibition of the enzymes with donepezil, acetohydroxamic acid and allopurinol as reference inhibitors. All the propolis extracts exhibited variable inhibition effects on these enzymes, but the higher the phenolic contents the lower the inhibitions values (IC50 = 0.074 to 1.560 mg/mL). IC50 values of the P5 propolis sample having the highest TPE, obtained from Zonguldak, for AChE, urease and XO were 0.081 ± 0.009, 0.080 ± 0.006 and 0.074 ± 0.011 μg/mL, respectively. The EPE proved to be a good source of inhibitor agents that can be used as natural inhibitors to serve human health.

  18. CD47 promotes ovarian cancer progression by inhibiting macrophage phagocytosis

    Science.gov (United States)

    Gao, Peng; Yu, Hu; Wang, Ke; Fu, Zheng; Ju, Baohui; Zhao, Meng; Dong, Shangwen; Li, Zhijun; He, Yifeng; Huang, Yuting; Yao, Zhi

    2017-01-01

    Targeting CD47 efficiently enhances macrophage phagocytosis in both physiological and pathological conditions. Anti-CD47 antibodies have been shown to inhibit the progression of several types of cancer. However, the mechanism of anti-CD47 monoclonal antibody (mAb) treatment remains controversial. In this study, we confirmed that CD47 protein is highly expressed in ovarian cancer, and is correlated with poor clinical characteristics and prognosis. CD47 knockdown in the ovarian cancer cell line, SK-OV-3, promoted phagocytosis by macrophages in vitro and inhibited tumor growth in vivo. These data combined suggest that CD47 inhibition is a potential strategy for cancer treatment. Using an anti-CD47 mAb, we found that CD47 inhibition in both SK-OV-3 cells and primary cancer cells was able to recapitulate our knockdown results and led to an increase in the number of infiltrating macrophages. In addition, the CD133+ tumor initiating cells expressed a high level of CD47, and anti-CD47 mAb treatment was able to trigger the phagocytosis of this cell population. In conclusion, our results indicate that CD47 inhibits macrophage phagocytosis of ovarian cancer cells, and down-regulation of CD47 or inhibiting CD47 by mAb was able to reverse the negative effect. Thus, CD47 antibody therapy may be a promising strategy to treat ovarian cancer. PMID:28380460

  19. Inhibition of multiplication of herpes simplex virus by caffeic acid.

    Science.gov (United States)

    Ikeda, Keiko; Tsujimoto, Kazuko; Uozaki, Misao; Nishide, Mitsunori; Suzuki, Yukiko; Koyama, A Hajime; Yamasaki, Hisashi

    2011-10-01

    Hot water extracts of coffee grinds and commercial instant coffee solutions have been shown to exhibit marked antiviral and virucidal activities against herpes simplex virus type 1 (HSV-1). Specifically, it has been shown that caffeine and N-methyl-pyridinium formate inhibit the multiplication of HSV-1 in HEp-2 cells. The present study examined the virological properties and the antiviral activity of caffeic acid against HSV-1. Caffeic acid inhibited the multiplication of HSV-1 in vitro, while chlorogenic acid, a caffeic acid ester with quinic acid, did not. These reagents did not have a direct virucidal effect. The one-step growth curve of HSV-1 showed that the addition of caffeic acid at 8 h post infection (h p.i.) did not significantly affect the formation of progeny viruses. An analysis of the influence of the time of caffeic acid addition, revealed that addition at an early time post infection remarkably inhibited the formation of progeny infectious virus in the infected cells, but its addition after 6 h p.i. (i.e., the time of the completion of viral genome replication) did not efficiently inhibit this process. These results indicate that caffeic acid inhibits HSV-1 multiplication mainly before the completion of viral DNA replication, but not thereafter. Although caffeic acid showed some cytotoxicity by prolonged incubation, the observed antiviral activity is likely not the secondary result of the cytotoxic effect of the reagent, because the inhibition of the virus multiplication was observed before appearance of the notable cytotoxicity.

  20. A role of electrical inhibition in sensorimotor integration.

    Science.gov (United States)

    Weiss, Shennan A; Preuss, Thomas; Faber, Donald S

    2008-11-18

    Although it is accepted that extracellular fields generated by neuronal activity can influence the excitability of neighboring cells, whether this form of neurotransmission has a functional role remains open. In vivo field effects occur in the teleost Mauthner (M)-cell system, where a combination of structural features support the concept of inhibitory electrical synapses. A single spike in one M-cell evoked within as little as 2.2 ms of the onset of an abrupt sound, simulating a predatory strike, initiates a startle-escape behavior [Zottoli SJ (1977) J Exp Biol 66:243-254]. We show that such sounds produce synchronized action potentials in as many as 20 or more interneurons that mediate feed-forward electrical inhibition of the M-cell. The resulting action currents produce an electrical inhibition that coincides with the electrotonic excitatory drive to the M-cell; the amplitude of the peak of the inhibition is approximately 40% of that of the excitation. When electrical inhibition is neutralized with an extracellular cathodal current pulse, subthreshold auditory stimuli are converted into ones that produce an M-spike. Because the timing of electrical inhibition is often the same as the latency of M-cell firing in freely swimming fish, we conclude that electrical inhibition participates in regulating the threshold of the acoustic startle-escape behavior. Therefore, a field effect is likely to be essential to the normal functioning of the neural network.

  1. Synaptic Inhibition in Avian Interaural Level Difference Sound Localizing Neurons.

    Science.gov (United States)

    Curry, Rebecca J; Lu, Yong

    2016-01-01

    Synaptic inhibition plays a fundamental role in the neural computation of the interaural level difference (ILD), an important cue for the localization of high-frequency sound. Here, we studied the inhibitory synaptic currents in the chicken posterior portion of the dorsal nucleus of the lateral lemniscus (LLDp), the first binaural level difference encoder of the avian auditory pathway. Using whole-cell recordings in brain slices, we provide the first evidence confirming a monosynaptic inhibition driven by direct electrical and chemical stimulation of the contralateral LLDp, establishing the reciprocal inhibitory connection between the two LLDps, a long-standing assumption in the field. This inhibition was largely mediated by GABA A receptors; however, functional glycine receptors were also identified. The reversal potential for the Cl - channels measured with gramicidin-perforated patch recordings was hyperpolarizing (-88 mV), corresponding to a low intracellular Cl - concentration (5.2 mm). Pharmacological manipulations of KCC2 (outwardly Cl - transporter) activity demonstrate that LLDp neurons can maintain a low intracellular Cl - concentration under a high Cl - load, allowing for the maintenance of hyperpolarizing inhibition. We further demonstrate that hyperpolarizing inhibition was more effective at regulating cellular excitability than depolarizing inhibition in LLDp neurons.

  2. Gingival tissue-produced inhibition of platelet aggregation and the loss of inhibition in streptozotocin-induced diabetic rats

    Energy Technology Data Exchange (ETDEWEB)

    Kawamura, Keiichiroh; Tamai, Kazuharu; Shirakawa, Masaharu; Okamoto, Hiroshi; Dohi, Toshihiro; Tsujimoto, Akira

    1988-01-01

    Addition of medium incubated with normal rat gingival tissue to platelet-rich plasma inhibited ADP-induced platelet aggregation. The ability of rat gingiva to produce activity inhibiting platelet aggregation was enhanced by the addition of arachidonic acid. Diabetic rat gingiva failed to inhibit platelet aggregation but did produce the anti-platelet aggregating activity in the presence of arachidonic acid. Indomethacin blocked the production of anti-platelet aggregating activity. There was no difference in conversion of (1-/sup 14/C)arachidonic acid to prostaglandins by normal and diabetic rat gingiva. These results suggest that an arachidonic acid metabolite released from gingiva during incubation inhibits platelet aggregation, and the synthesis of the metabolite is impaired in diabetic rat gingiva. A decrease in availability of arachidonic acid may be a causal factor of the defect in diabetic rat gingiva.

  3. Inhibition of Nitric Oxide Synthase (NOS) Underlies Aluminum-Induced Inhibition of Root Elongation in Hibiscus moscheutos

    National Research Council Canada - National Science Library

    Qiu-Ying Tian; Dong-Hua Sun; Min-Gui Zhao; Wen-Hao Zhang

    2007-01-01

    .... Here, we investigated the role of NO in Al toxicity to Hibiscus moscheutos. Exposure of H. moscheutos to led to a rapid inhibition of root elongation, and the inhibitory effect was alleviated by NO donor sodium nitroprusside...

  4. Allosteric Inhibition of Factor XIIIa. Non-Saccharide Glycosaminoglycan Mimetics, but Not Glycosaminoglycans, Exhibit Promising Inhibition Profile.

    Directory of Open Access Journals (Sweden)

    Rami A Al-Horani

    Full Text Available Factor XIIIa (FXIIIa is a transglutaminase that catalyzes the last step in the coagulation process. Orthostery is the only approach that has been exploited to design FXIIIa inhibitors. Yet, allosteric inhibition of FXIIIa is a paradigm that may offer a key advantage of controlled inhibition over orthosteric inhibition. Such an approach is likely to lead to novel FXIIIa inhibitors that do not carry bleeding risks. We reasoned that targeting a collection of basic amino acid residues distant from FXIIIa's active site by using sulfated glycosaminoglycans (GAGs or non-saccharide GAG mimetics (NSGMs would lead to the discovery of the first allosteric FXIIIa inhibitors. We tested a library of 22 variably sulfated GAGs and NSGMs against human FXIIIa to discover promising hits. Interestingly, although some GAGs bound to FXIIIa better than NSGMs, no GAG displayed any inhibition. An undecasulfated quercetin analog was found to inhibit FXIIIa with reasonable potency (efficacy of 98%. Michaelis-Menten kinetic studies revealed an allosteric mechanism of inhibition. Fluorescence studies confirmed close correspondence between binding affinity and inhibition potency, as expected for an allosteric process. The inhibitor was reversible and at least 9-fold- and 26-fold selective over two GAG-binding proteins factor Xa (efficacy of 71% and thrombin, respectively, and at least 27-fold selective over a cysteine protease papain. The inhibitor also inhibited the FXIIIa-mediated polymerization of fibrin in vitro. Overall, our work presents the proof-of-principle that FXIIIa can be allosterically modulated by sulfated non-saccharide agents much smaller than GAGs, which should enable the design of selective and safe anticoagulants.

  5. CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function.

    Science.gov (United States)

    Tiyerili, Vedat; Zimmer, Sebastian; Jung, Suzin; Wassmann, Kerstin; Naehle, Claas P; Lütjohann, Dieter; Zimmer, Andreas; Nickenig, Georg; Wassmann, Sven

    2010-07-01

    Inhibition of the cannabinoid receptor CB(1) (CB(1)-R) exerts numerous positive cardiovascular effects such as modulation of blood pressure, insulin sensitivity and serum lipid concentrations. However, direct vascular effects of CB(1)-R inhibition remain unclear. CB(1)-R expression was validated in vascular smooth muscle cells (VSMCs) and aortic tissue of mice. Apolipoprotein E-deficient (ApoE-/-) mice were treated with cholesterol-rich diet and the selective CB(1)-R antagonist rimonabant or vehicle for 7 weeks. CB(1)-R inhibition had no effect on atherosclerotic plaque development, collagen content and macrophage infiltration but led to improved aortic endothelium-dependent vasodilation and decreased aortic reactive oxygen species (ROS) production and NADPH oxidase activity. Treatment of cultured VSMC with rimonabant resulted in reduced angiotensin II-mediated but not basal ROS production and NADPH oxidase activity. CB(1)-R inhibition with rimonabant and AM251 led to down-regulation of angiotensin II type 1 receptor (AT1-R) expression, whereas stimulation with the CB(1)-R agonist CP 55,940 resulted in AT1-R up-regulation, indicating that AT1-R expression is directly regulated by the CB(1)-R. CB(2)-R inhibition had no impact on AT1-R expression in VSMC. Consistently, CB(1)-R inhibition decreased aortic AT1-R expression in vivo. CB(1)-R inhibition leads to decreased vascular AT1-R expression, NADPH oxidase activity and ROS production in vitro and in vivo. This antioxidative effect is associated with improved endothelial function in ApoE-/- mice, indicating beneficial direct vascular effects of CB(1)-R inhibition.

  6. Neural inhibition during maximal eccentric and concentric quadriceps contraction: effects of resistance training

    DEFF Research Database (Denmark)

    Aagaard, Per; Simonsen, E.B.; Andersen, J.L.

    2000-01-01

    neuromuscular activation, muscle strength, neural efferent drive, eccentric activation deficiency, force inhibition......neuromuscular activation, muscle strength, neural efferent drive, eccentric activation deficiency, force inhibition...

  7. Minimal RNA aptamer sequences that can inhibit or alleviate noncompetitive inhibition of the muscle-type nicotinic acetylcholine receptor.

    Science.gov (United States)

    Sivaprakasam, Kannan; Pagán, Oné R; Hess, George P

    2010-02-01

    Combinatorially synthesized nucleotide polymers have been used during the last decade to find ligands that bind to specific sites on biological molecules, including membrane-bound proteins such as the nicotinic acetylcholine receptors (nAChRs). The neurotransmitter receptors belong to a group of four structurally related proteins that regulate signal transmission between ~10(11) neurons of the mammalian nervous system. The nAChRs are inhibited by compounds such as the anticonvulsant MK-801 [(+)-dizocilpine] and abused drugs such as cocaine. Based on predictions arising from the mechanism of receptor inhibition by MK-801 and cocaine, we developed two classes of RNA aptamers: class I members, which inhibit the nAChR, and class II members, which alleviate inhibition of the receptor by MK-801 and cocaine. The systematic evolution of ligands by the exponential enrichment (SELEX) method was used to obtain these compounds. Here, we report that we have truncated RNA aptamers in each class to determine the minimal nucleic acid sequence that retains the characteristic function for which the aptamer was originally selected. We demonstrate that a truncated class I aptamer containing a sequence of seven nucleotides inhibits the nAChR and that a truncated class II aptamer containing a sequence of only four nucleotides can alleviate MK-801 inhibition.

  8. Neuronal nitric oxide inhibits intestinal smooth muscle growth.

    Science.gov (United States)

    Pelletier, Anne-Marie; Venkataramana, Shriram; Miller, Kurtis G; Bennett, Brian M; Nair, Dileep G; Lourenssen, Sandra; Blennerhassett, Michael G

    2010-06-01

    Hyperplasia of smooth muscle contributes to the thickening of the intestinal wall that is characteristic of inflammation, but the mechanisms of growth control are unknown. Nitric oxide (NO) from enteric neurons expressing neuronal NO synthase (nNOS) might normally inhibit intestinal smooth muscle cell (ISMC) growth, and this was tested in vitro. In ISMC from the circular smooth muscle of the adult rat colon, chemical NO donors inhibited [(3)H]thymidine uptake in response to FCS, reducing this to baseline without toxicity. This effect was inhibited by the guanylyl cyclase inhibitor ODQ and potentiated by the phosphodiesterase-5 inhibitor zaprinast. Inhibition was mimicked by 8-bromo (8-Br)-cGMP, and ELISA measurements showed increased levels of cGMP but not cAMP in response to sodium nitroprusside. However, 8-Br-cAMP and cilostamide also showed inhibitory actions, suggesting an additional role for cAMP. Via a coculture model of ISMC and myenteric neurons, immunocytochemistry and image analysis showed that innervation reduced bromodeoxyuridine uptake by ISMC. Specific blockers of nNOS (7-NI, NAAN) significantly increased [(3)H]thymidine uptake in response to a standard stimulus, showing that nNOS activity normally inhibits ISMC growth. In vivo, nNOS axon number was reduced threefold by day 1 of trinitrobenzene sulfonic acid-induced rat colitis, preceding the hyperplasia of ISMC described earlier in this model. We conclude that NO can inhibit ISMC growth primarily via a cGMP-dependent mechanism. Functional evidence that NO derived from nNOS causes inhibition of ISMC growth in vitro predicts that the loss of nNOS expression in colitis contributes to ISMC hyperplasia in vivo.

  9. Inhibition of xanthine oxidase by Puerto Rican plant extracts.

    Science.gov (United States)

    Guerrero, R O; Guzman, A L

    1998-12-01

    This study was conducted to search for xanthine oxidase inhibitors in natural products obtained from plants collected in Puerto Rico and to assess the influence of these extracts in the prevention of cataractogenesis. Allopurinol is currently a xanthine oxidase inhibitor used in the treatment of gout. New alternatives with increased therapeutic activity and less side effects should be investigated. Preclusion of cataractogenesis in diabetic rats is also the focus of this investigation. Natural products in the form of plant extracts from Puerto Rico offer a rich and relatively untapped source for the discovery of new drugs that may address these kind of problems. Nineteen collections of Myrtaceae plant extracts were screened for xanthine oxidase inhibition. A spectrophotometrical method was used employing allopurinol as positive control and a blank as negative control. A protocol of the assay with slight modifications was followed from the literature. Two extracts with the highest percentages of xanthine oxidase inhibition were evaluated for possible prevention of cataractogenesis in streptozotocin diabetic rats. The animals were given to drink these plant extracts ad libitum for three months while controls received water. The appearance of cataracts was assessed physically. Two of the nineteen plant extracts showed high inhibition percentages of xanthine oxidase. Eucalyptus deglupta and Syzygium malaccense displayed 51% and 64% inhibitions (IC50 44.5 micrograms/ml and IC50 51 micrograms/ml), respectively. As for the cataractogenesis inhibition, laboratory animals that drank E. deglupta for three months did not develop cataracts. Two plant extracts provided positive results with varying degrees of inhibition of xanthine oxidase. S. malaccense demonstrated the greatest xanthine oxidase inhibitory activity whereas E. deglupta presented the best finding for cataractogenesis prevention. The procedures used in this investigation are useful for the in vitro screening of

  10. Aspergillus ficuum phytase activity is inhibited by cereal grain components.

    Science.gov (United States)

    Bekalu, Zelalem Eshetu; Madsen, Claus Krogh; Dionisio, Giuseppe; Brinch-Pedersen, Henrik

    2017-01-01

    In the current study, we report for the first time that grain components of barley, rice, wheat and maize can inhibit the activity of Aspergillus ficuum phytase. The phytase inhibition is dose dependent and varies significantly between cereal species, between cultivars of barley and cultivars of wheat and between Fusarium graminearum infected and non-infected wheat grains. The highest endpoint level of phytase activity inhibition was 90%, observed with grain protein extracts (GPE) from F. graminearum infected wheat. Wheat GPE from grains infected with F. graminearum inhibits phytase activity significantly more than GPE from non-infected grains. For four barley cultivars studied, the IC50 value ranged from 0.978 ± 0.271 to 3.616 ± 0.087 mg×ml-1. For two non-infected wheat cultivars investigated, the IC50 values were varying from 2.478 ± 0.114 to 3.038 ± 0.097 mg×ml-1. The maize and rice cultivars tested gaveIC50 values on 0.983 ± 0.205 and 1.972 ± 0.019 mg×ml-1, respectively. After purifying the inhibitor from barley grains via Superdex G200, an approximately 30-35 kDa protein was identified. No clear trend for the mechanism of inhibition could be identified via Michaelis-Menten kinetics and Lineweaver-Burk plots. However, testing of the purified phytase inhibitor together with the A. ficuum phytase and the specific protease inhibitors pepstatin A, E64, EDTA and PMSF revealed that pepstatin A repealed the phytase inhibition. This indicates that the observed inhibition of A. ficuum phytase by cereal grain extracts is caused by protease activity of the aspartic proteinase type.

  11. Task Dominance Determines Backward Inhibition in Task Switching

    Directory of Open Access Journals (Sweden)

    Kerstin Jost

    2017-05-01

    Full Text Available Switching between tasks is assumed to be accompanied by inhibiting currently irrelevant, but competing tasks. A dominant task that strongly interferes with performing a weaker task may receive especially strong inhibition. We tested this prediction by letting participants switch among three tasks that differ in dominance: a location discrimination task with strong stimulus–response bindings (responding with left-hand and right-hand button presses to stimuli presented left or right to the fixation cross was combined with a color/pattern and a shape discrimination task, for which stimulus–response mappings were arbitrary (e.g., left-hand button press mapped to a red stimulus. Across three experiments, the dominance of the location task was documented by faster and more accurate responses than in the other tasks. This even held for incompatible stimulus–response mappings (i.e., right-hand response to a left-presented stimulus and vice versa, indicating that set-level compatibility (i.e., “dimension overlap” was sufficient for making this location task dominant. As a behavioral marker for backward inhibition, we utilized n-2 repetition costs that are defined by higher reaction times for a switch back to a just abandoned and thus just inhibited task (ABA sequence than for a switch to a less recently inhibited task (CBA, n-2 non-repetition. Reliable n-2 task repetition costs were obtained for all three tasks. Importantly, these costs were largest for the location task, suggesting that inhibition indeed was stronger for the dominant task. This finding adds to other evidence that the amount of inhibition is adjusted in a context-sensitive way.

  12. Global Precipitation Measurement (GPM) Safety Inhibit Timeline Tool

    Science.gov (United States)

    Dion, Shirley

    2012-01-01

    The Global Precipitation Measurement (GPM) Observatory is a joint mission under the partnership by National Aeronautics and Space Administration (NASA) and the Japan Aerospace Exploration Agency (JAXA), Japan. The NASA Goddard Space Flight Center (GSFC) has the lead management responsibility for NASA on GPM. The GPM program will measure precipitation on a global basis with sufficient quality, Earth coverage, and sampling to improve prediction of the Earth's climate, weather, and specific components of the global water cycle. As part of the development process, NASA built the spacecraft (built in-house at GSFC) and provided one instrument (GPM Microwave Imager (GMI) developed by Ball Aerospace) JAXA provided the launch vehicle (H2-A by MHI) and provided one instrument (Dual-Frequency Precipitation Radar (DPR) developed by NTSpace). Each instrument developer provided a safety assessment which was incorporated into the NASA GPM Safety Hazard Assessment. Inhibit design was reviewed for hazardous subsystems which included the High Gain Antenna System (HGAS) deployment, solar array deployment, transmitter turn on, propulsion system release, GMI deployment, and DPR radar turn on. The safety inhibits for these listed hazards are controlled by software. GPM developed a "pathfinder" approach for reviewing software that controls the electrical inhibits. This is one of the first GSFC in-house programs that extensively used software controls. The GPM safety team developed a methodology to document software safety as part of the standard hazard report. As part of this process a new tool "safety inhibit time line" was created for management of inhibits and their controls during spacecraft buildup and testing during 1& Tat GSFC and at the Range in Japan. In addition to understanding inhibits and controls during 1& T the tool allows the safety analyst to better communicate with others the changes in inhibit states with each phase of hardware and software testing. The tool was very

  13. Lithium preferentially inhibits adenylyl cyclase V and VII isoforms.

    Science.gov (United States)

    Mann, Liad; Heldman, Eliahu; Shaltiel, Galit; Belmaker, R H; Agam, Galila

    2008-06-01

    Lithium ions' inhibition of adenylyl cyclase (AC) has not been previously studied for the newly discovered AC isoforms. COS7 cells were transfected with each of the nine membrane-bound AC isoforms cDNAs with or without D1- or D2-dopamine receptor cDNA. AC activity was measured as [3H]cAMP accumulation in cells pre-incubated with [3H]adenine followed by incubation with phosphodiesterase inhibitors together with either the D1 agonist SKF-82958 alone, or forskolin, in the presence or absence of the D2 agonist quinpirole. At 1 mm or 2 mm lithium inhibited only AC-V activity when the enzyme was stimulated by forskolin, a direct activator of AC. Lithium inhibited AC-V (by 50%), AC-VII (by 40%) and AC-II (by 25%) when stimulated via the D1 receptors, but did not affect the Ca2+-activated isoforms when stimulated by the Ca2+ ionophore A23187. Quinpirole inhibits AC via the Gi protein. Lithium did not affect quinpirole-inhibited FSK-activated AC-V activity nor did it affect superactivated AC-V or AC-I following the removal of quinpirole. The data suggest interference of lithium with transduction pathways mediated via AC-V or AC-VII; only the active conformation of these AC isoforms is inhibited by lithium; the inhibitory effect of lithium is abolished when the enzyme is superactivated. The marked inhibition of AC-V and AC-VII by lithium suggests that these two isoforms may be involved in mediating the mood-stabilizing effect of lithium.

  14. Chlorpromazine inhibits tumour necrosis factor synthesis and cytotoxicity in vitro.

    Science.gov (United States)

    Zinetti, M; Galli, G; Demitri, M T; Fantuzzi, G; Minto, M; Ghezzi, P; Alzani, R; Cozzi, E; Fratelli, M

    1995-01-01

    Chlorpromazine (CPZ) has been previously shown to protect against endotoxin [lipopolysaccharide (LPS)] lethality and inhibit the release of tumour necrosis factor in vivo. We investigated at the cellular level whether this was due to direct inhibition of tumour necrosis factor-alpha (TNF-alpha) synthesis, using LPS-stimulated THP-1 human monocytic leukemia cells. We also studied the effect of CPZ on human TNF-alpha action by assessing TNF-alpha cytotoxicity on mouse fibrosarcoma L929 cells. CPZ (1-100 microM) inhibited TNF-alpha production in THP-1 cells in a dose dependent manner by a maximum of 80%. This effect was comparable to that of two well-known inhibitory drugs, dexamethasone and cyclicAMP. Inhibition was also evident at the mRNA level. On the other hand CPZ (10-25 microM) also inhibited TNF-alpha activity: in fact it reduced the cytotoxicity of TNF-alpha on L929 cells (EC50 was increased four times) and could provide protection even as a post-treatment. CPZ inhibited TNF-induced apoptosis in L929 cells, as detected by analysis of nuclear morphology. However, since we showed that apoptosis was very limited, and was not the main mode of cell death in our conditions, this could not explain the overall protection. Since CPZ did not interfere with either the oligomerization state of TNF-alpha or its receptor binding, our data suggest that it reduced cytotoxicity by inhibiting some steps in the TNF-alpha signalling pathways. Images Figure 1 Figure 4 PMID:8550079

  15. Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

    Science.gov (United States)

    Sikora, Joanna; Mateusiak, Łukasz; Mikiciuk-Olasik, Elżbieta; Huttunen, Kristiina M.

    2017-01-01

    The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer's disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC50 = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future. PMID:28770024

  16. Amiodarone inhibits tissue factor expression in monocytic THP-1 cells.

    Science.gov (United States)

    Yamamoto, Yumiko; Morita, Toshihiro; Tanaka, Tomofumi; Ikeda, Kenichi; Kikuchi, Hironobu; Oguri, Gaku; Nakamura, Fumitaka; Nakajima, Toshiaki; Nagai, Ryozo

    2013-02-15

    There is a possibility thrombus formation is closely involved in sudden cardiac death. Amiodarone, a potassium channel inhibitor, is known to reduce mortality in patients with coronary artery disease or low ejection fraction, having antithrombotic actions. Using human monocytic THP-1 cells, we investigated the effects of amiodarone on tissue factor mRNA and protein expression. The involvement of the two main potassium channels existing in THP-1 cells was also investigated. Amiodarone (10μM) significantly and almost completely inhibited the increase of tissue factor mRNA and protein expression induced by tumor necrosis factor-α (100ng/ml). The inhibitory effects of amiodarone on tissue factor mRNA expression showed dose-dependency. Margatoxin (1nM), a selective blocker of voltage-dependent potassium channel Kv1.3, also inhibited tissue factor protein expression, but didn't significantly inhibit mRNA expression. Ba(2+), a blocker of inwardly rectifying potassium channel Kir2.1, partly inhibited the increase of tissue factor mRNA and protein expression. This is the first study that shows amiodarone inhibits tissue factor expression in monocytic cells, by inhibiting mRNA transcription. The result may correlate with the facts amiodarone has antithrombotic actions in patients under extraordinary conditions where thrombus formation is enhanced. The inhibitory effects of amiodarone on tissue factor expression are drastic, different from those of margatoxin and Ba(2+). The result suggests amiodarone has an underlying mechanism to intensely inhibit tissue factor expression other than blocking Kv1.3 and Kir2.1. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease.

    Science.gov (United States)

    Peng, Min; Ostrovsky, Julian; Kwon, Young Joon; Polyak, Erzsebet; Licata, Joseph; Tsukikawa, Mai; Marty, Eric; Thomas, Jeffrey; Felix, Carolyn A; Xiao, Rui; Zhang, Zhe; Gasser, David L; Argon, Yair; Falk, Marni J

    2015-09-01

    Mitochondrial respiratory chain (RC) disease therapies directed at intra-mitochondrial pathology are largely ineffective. Recognizing that RC dysfunction invokes pronounced extra-mitochondrial transcriptional adaptations, particularly involving dysregulated translation, we hypothesized that translational dysregulation is itself contributing to the pathophysiology of RC disease. Here, we investigated the activities, and effects from direct inhibition, of a central translational regulator (mTORC1) and its downstream biological processes in diverse genetic and pharmacological models of RC disease. Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells. Even more effective was probucol, a PPAR-activating anti-lipid drug that we show also inhibits mTORC1. However, directly inhibiting mTORC1-regulated downstream activities yielded the most pronounced and sustained benefit. Partial inhibition of translation by cycloheximide, or of autophagy by lithium chloride, rescued viability, preserved cellular respiratory capacity and induced mitochondrial translation and biogenesis. Cycloheximide also ameliorated proteotoxic stress via a uniquely selective reduction of cytosolic protein translation. RNAseq-based transcriptome profiling of treatment effects in gas-1(fc21) mutants provide further evidence that these therapies effectively restored altered translation and autophagy pathways toward that of wild-type animals. Overall, partially inhibiting cytosolic translation and autophagy offer novel treatment strategies to improve health across the diverse array

  18. Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

    Directory of Open Access Journals (Sweden)

    Magdalena Markowicz-Piasecka

    2017-01-01

    Full Text Available The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM may predispose to Alzheimer’s disease (AD. The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition and BuChE (IC50 = 28 nmol/mL, mixed type inhibition, while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL. Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

  19. Menthol Binding and Inhibition of α7-Nicotinic Acetylcholine Receptors

    Science.gov (United States)

    Ashoor, Abrar; Nordman, Jacob C.; Veltri, Daniel; Yang, Keun-Hang Susan; Al Kury, Lina; Shuba, Yaroslav; Mahgoub, Mohamed; Howarth, Frank C.; Sadek, Bassem; Shehu, Amarda; Kabbani, Nadine; Oz, Murat

    2013-01-01

    Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the α7 subunit of the nicotinic acetylcholine (nACh) receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit α7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca2+-dependent Cl− channels, since menthol inhibition remained unchanged by intracellular injection of the Ca2+ chelator BAPTA and perfusion with Ca2+-free bathing solution containing Ba2+. Furthermore, increasing ACh concentrations did not reverse menthol inhibition and the specific binding of [125I] α-bungarotoxin was not attenuated by menthol. Studies of α7- nACh receptors endogenously expressed in neural cells demonstrate that menthol attenuates α7 mediated Ca2+ transients in the cell body and neurite. In conclusion, our results suggest that menthol inhibits α7-nACh receptors in a noncompetitive manner. PMID:23935840

  20. Menthol binding and inhibition of α7-nicotinic acetylcholine receptors.

    Directory of Open Access Journals (Sweden)

    Abrar Ashoor

    Full Text Available Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the α7 subunit of the nicotinic acetylcholine (nACh receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit α7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca(2+-dependent Cl(- channels, since menthol inhibition remained unchanged by intracellular injection of the Ca(2+ chelator BAPTA and perfusion with Ca(2+-free bathing solution containing Ba(2+. Furthermore, increasing ACh concentrations did not reverse menthol inhibition and the specific binding of [(125I] α-bungarotoxin was not attenuated by menthol. Studies of α7- nACh receptors endogenously expressed in neural cells demonstrate that menthol attenuates α7 mediated Ca(2+ transients in the cell body and neurite. In conclusion, our results suggest that menthol inhibits α7-nACh receptors in a noncompetitive manner.