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Sample records for auranofin inhibit selenoprotein

  1. 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.

  2. Selenoprotein P Inhibits Radiation-Induced Late Reactive Oxygen Species Accumulation and Normal Cell Injury

    Energy Technology Data Exchange (ETDEWEB)

    Eckers, Jaimee C.; Kalen, Amanda L.; Xiao, Wusheng; Sarsour, Ehab H.; Goswami, Prabhat C., E-mail: prabhat-goswami@uiowa.edu

    2013-11-01

    Purpose: Radiation is a common mode of cancer therapy whose outcome is often limited because of normal tissue toxicity. We have shown previously that the accumulation of radiation-induced late reactive oxygen species (ROS) precedes cell death, suggesting that metabolic oxidative stress could regulate cellular radiation response. The purpose of this study was to investigate whether selenoprotein P (SEPP1), a major supplier of selenium to tissues and an antioxidant, regulates late ROS accumulation and toxicity in irradiated normal human fibroblasts (NHFs). Methods and Materials: Flow cytometry analysis of cell viability, cell cycle phase distribution, and dihydroethidium oxidation, along with clonogenic assays, were used to measure oxidative stress and toxicity. Human antioxidant mechanisms array and quantitative real-time polymerase chain reaction assays were used to measure gene expression during late ROS accumulation in irradiated NHFs. Sodium selenite addition and SEPP1 overexpression were used to determine the causality of SEPP1 regulating late ROS accumulation and toxicity in irradiated NHFs. Results: Irradiated NHFs showed late ROS accumulation (4.5-fold increase from control; P<.05) that occurs after activation of the cell cycle checkpoint pathways and precedes cell death. The mRNA levels of CuZn- and Mn-superoxide dismutase, catalase, peroxiredoxin 3, and thioredoxin reductase 1 increased approximately 2- to 3-fold, whereas mRNA levels of cold shock domain containing E1 and SEPP1 increased more than 6-fold (P<.05). The addition of sodium selenite before the radiation treatment suppressed toxicity (45%; P<.05). SEPP1 overexpression suppressed radiation-induced late ROS accumulation (35%; P<.05) and protected NHFs from radiation-induced toxicity (58%; P<.05). Conclusion: SEPP1 mitigates radiation-induced late ROS accumulation and normal cell injury.

  3. Auranofin

    Science.gov (United States)

    ... painful or tender and swollen joints and morning stiffness.This medication is sometimes prescribed for other uses; ... case of overdose, call your local poison control center at 1-800-222-1222. If the victim ...

  4. Selenoprotein-Transgenic Chlamydomonas reinhardtii

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Bulman, Christina A; Bidlow, Chelsea M; Lustigman, Sara; Cho-Ngwa, Fidelis; Williams, David; Rascón, Alberto A; Tricoche, Nancy; Samje, Moses; Bell, Aaron; Suzuki, Brian; Lim, K C; Supakorndej, Nonglak; Supakorndej, Prasit; Wolfe, Alan R; Knudsen, Giselle M; Chen, Steven; Wilson, Chris; Ang, Kean-Hooi; Arkin, Michelle; Gut, Jiri; Franklin, Chris; Marcellino, Chris; McKerrow, James H; Debnath, Anjan; Sakanari, Judy A

    2015-02-01

    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. PMID:25700363

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Selenoprotein-Transgenic Chlamydomonas reinhardtii

    OpenAIRE

    Jiazuan Ni; Zhangli Hu; Jing Tian; Qintang Hou; Qiong Liu; Shi Qiu

    2013-01-01

    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 ...

  8. Repurposing auranofin for the treatment of cutaneous staphylococcal infections.

    Science.gov (United States)

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F N; Sobreira, Tiago J P; Seleem, Mohamed N

    2016-03-01

    The scourge of multidrug-resistant bacterial infections necessitates the urgent development of novel antimicrobials to address this public health challenge. Drug repurposing is a proven strategy to discover new antimicrobial agents; given that these agents have undergone extensive toxicological and pharmacological analysis, repurposing is an effective method to reduce the time, cost and risk associated with traditional antibiotic innovation. In this study, the in vitro and in vivo antibacterial activities of an antirheumatic drug, auranofin, was investigated against multidrug-resistant Staphylococcus aureus. The results indicated that auranofin possesses potent antibacterial activity against all tested strains of S. aureus, including meticillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), with minimum inhibitory concentrations (MICs) ranging from 0.0625μg/mL to 0.125μg/mL. In vivo, topical auranofin proved superior to conventional antimicrobials, including fusidic acid and mupirocin, in reducing the mean bacterial load in infected wounds in a murine model of MRSA skin infection. In addition to reducing the bacterial load, topical treatment of auranofin greatly reduced the production of inflammatory cytokines, including tumour necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and monocyte chemoattractant protein-1 (MCP-1), in infected skin lesions. Moreover, auranofin significantly disrupted established in vitro biofilms of S. aureus and Staphylococcus epidermidis, more so than the traditional antimicrobials linezolid and vancomycin. Taken together, these results support that auranofin has potential to be repurposed as a topical antimicrobial agent for the treatment of staphylococcal skin and wound infections. PMID:26895605

  9. 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.

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

    Science.gov (United States)

    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. PMID:26876147

  11. Aqueous extracts of selenium-fertilized broccoli increase selenoprotein activity and inhibit DNA single-strand breaks, but decrease the activity of quinone reductase in Hepa 1c1c7 cells.

    Science.gov (United States)

    Keck, Anna-Sigrid; Finley, John W

    2006-05-01

    Depending on growth conditions, broccoli may be enriched in the isothiocyanate sulforaphane and/or the mineral selenium (Se); both compounds may play an important role in the reduction of intracellular oxidative stress and chronic disease prevention. Sulforaphane up-regulates transcription of Phase II detoxification proteins (e.g. quinone reductase [QR]), whereas Se is needed for the production of thioredoxin reductase (TR) and glutathione peroxidase-1 (GPx1), both of which exhibit antioxidant activity. The objective of the present study was to determine whether the fertilization of broccoli with Se increases the antioxidant ability of broccoli. Hydrogen peroxide-induced DNA single-strand breaks (measured by single cell electrophoresis, Comet assay) and activity of antioxidant enzymes (GPx, TR and QR) were measured in mouse hepatoma cells (Hepa 1c1c7 cells) treated with purified sulforaphane, sodium selenite or extracts of selenized broccoli. When supplied separately as chemically pure substances, sodium selenite was more effective than sulforaphane for reduction of single-strand breaks. Se-fertilized broccoli extracts were the most effective for reduction of DNA single-strand breaks, and extracts that contained 0.71 microM Se and 0.08 microM sulforaphane inhibited 94% of DNA single-strand breaks. A significant positive association (r = 0.81, p = 0.009) between GPx1 activity and inhibition of DNA single-strand breaks as well as a 24h lag time between addition of Se, sulforaphane or broccoli extract and inhibition of single-strand breaks suggests that some of the antioxidant protection is mediated through selenoproteins. Conversely, fertilization of broccoli with Se decreased the ability of broccoli extract to induce QR activity. These results demonstrate that Se and sulforaphane, alone or as a component of broccoli, may help decrease oxidative stress. They further suggest that Se is the most important for decreasing oxidative stress, but maximizing the Se content

  12. A Method for Identification of Selenoprotein Genes in Archaeal Genomes

    Institute of Scientific and Technical Information of China (English)

    Mingfeng Li; Yanzhao Huang; Yi Xiao

    2009-01-01

    The genetic codon UGA has a dual function: serving as a terminator and encoding selenocysteine. However, most popular gene annotation programs only take it as a stop signal, resulting in misannotation or completely missing selenoprotein genes. We developed a computational method named Asec-Prediction that is specific for the prediction of archaeal selenoprotein genes. To evaluate its effectiveness, we first applied it to 14 archaeal genomes with previously known selenoprotein genes, and Asec-Prediction identified all reported selenoprotein genes without redundant results. When we applied it to 12 archaeal genomes that had not been researched for selenoprotein genes, Asec-Prediction detected a novel selenoprotein gene in Methanosarcina acetivorans. Further evidence was also collected to support that the predicted gene should be a real selenoprotein gene. The result shows that Asec-Prediction is effective for the prediction of archaeal selenoprotein genes.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Time course of selenium labelling of selenoproteins in Se adequate and Se deficient rats

    International Nuclear Information System (INIS)

    Column chromatography has identified a number of new selenoproteins. To discriminate between selenoproteins and Se-binding proteins, the authors used SDS-PAGE to remove loosely-bound 75Se and thus quantitate 75Se-labelled selenoproteins. +Se (Wayne Lab Blox) and -Se rats (75Se]selenite (0.5 ug Se) and sacrificed 1, 3, 24 or 72 hr later. 75Se-proteins in various tissues were separated according to subunit molecular weight by SDS-PAGE, and gel slices were counted to determine 75Se labelling. In +Se plasma, a 55kDa protein was the major 75Se-protein at 1 and 3 hr; gluathione peroxidase (GSH-Px, 20kDa subunit) was labelled at 24 and 72 hr. In -Se plasma the 55kDa 75Se-protein was 4-fold higher and GSH-Px 75Se was reduced. In +Se liver cytosol GSH-Px was the major 75Se- species at all times; GSH-Px 75Se was greater in +Se than -Se liver. In +Se and -Se testes, a 17kDa protein was labelled increasingly over 72 hr. Notably, a number of additional 75Se-proteins were observed, but cycloheximide pretreatment completely blocked 75Se-labelling of all selenoproteins in both +Se and -Se rats. This study shows that SDS-PAGE can be used to resolve and quantify a number of selenoproteins in addition to GSH-Px. The cycloheximide inhibition of labelling further suggests that these species are true selenoproteins that are labelled only during or immediately after protein synthesis

  15. A double blind multicentre study of OM-8980 and auranofin in rheumatoid arthritis.

    OpenAIRE

    Vischer, T L

    1988-01-01

    The therapeutic efficacy of the immunomodulator OM-8980 in rheumatoid arthritis was compared with that of auranofin, an oral gold salt, in a double blind, randomised multicentre study lasting six months. Seventy patients were treated with auranofin and 75 with OM-8980. The patients of both groups improved significantly at three and six months for all the clinical parameters observed: Ritchie index, number of swollen joints, morning stiffness, pain, grip strength, intake of non-steroidal anti-...

  16. Selenoprotein P in colitis-associated carcinoma

    Science.gov (United States)

    Short, Sarah P.; Whitten-Barrett, Caitlyn; Williams, Christopher S.

    2016-01-01

    ABSTRACT Patients with inflammatory bowel disease are often deficient in micronutrients such as selenium and have an increased risk of colon cancer. We tested whether the selenium transport protein, selenoprotein P, could modify colitis-associated cancer. Our results indicate that global SEPP1 haploinsufficiency augments tumorigenesis and mediates oxidative damage in the intestine. PMID:27314080

  17. Ebola viral selenoproteins:a metallomics analysis

    Institute of Scientific and Technical Information of China (English)

    Somsri; Wiwanitkit; Viroj; Wiwanitkit

    2015-01-01

    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 palhophysiology.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.

  18. Selenoprotein P in der kolorektalen Karzinogenese

    OpenAIRE

    Eußner, Ursula

    2003-01-01

    DNA-Schädigungen durch Sauerstoff-Radikale werden als bedeutende pathogene Faktoren der kolorektalen Karzinogenese angesehen. Als ein antioxidativer Schutzmechanismus im Gastrointestinaltrakt wird u. a. das Selenoprotein P vermutet, dessen mRNA-Expression in Kolonadenomen im Vergleich zu angrenzender gesunder Darmmukosa stark vermindert nachgewiesen wurde. Interessant ist zudem die Lokalisation des SePP-Gens auf Chromosom 5q31 in der Nähe des APC-Gens, eines schon in frühen Stadien der kolore...

  19. Selenoprotein P. A selenium-rich extracellular glycoprotein.

    Science.gov (United States)

    Burk, R F; Hill, K E

    1994-10-01

    Selenoprotein P is a glycoprotein that has been purified from rat and human plasma. In selenium-replete rats it contains 65% of the plasma selenium and its concentration is 25-30 mg protein/L. In selenium-deficient rats its concentration is life of 75Se in selenoprotein P is 3 to 4 h, indicating a rapid turnover. Purified rat selenoprotein P contains 7.5 +/- 1 selenium atoms per molecule as selenocysteine. The sequence of the cloned cDNA predicts 10 selenocysteine residues, which suggests that the protein in plasma is a modification of the predicted one. Deduced amino acid sequence identity between rats and humans is 72%. The 3' untranslated region of selenoprotein P cDNA contains two predicted stem loops of the type essential for selenocysteine incorporation. Northern analysis indicates that selenoprotein P is expressed by many tissues. Hepatic selenoprotein P mRNA level, but not its transcription, decreases during selenium deficiency. The decrease is less than the decrease of glutathione peroxidase mRNA, however. Selenoprotein P is postulated to serve as an extracellular oxidant defense because its presence correlates with selenium protection of selenium-deficient rats against diquat-induced lipid peroxidation and liver necrosis. More research will be required to test this hypothesis and to establish the biochemical function of selenoprotein P. PMID:7931697

  20. 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

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

    Directory of Open Access Journals (Sweden)

    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

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

    OpenAIRE

    Elizabeth Varghese; Dietrich Büsselberg

    2014-01-01

    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 a...

  3. Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial.

    Science.gov (United States)

    Ward, J R; Williams, H J; Egger, M J; Reading, J C; Boyce, E; Altz-Smith, M; Samuelson, C O; Willkens, R F; Solsky, M A; Hayes, S P

    1983-11-01

    A prospective controlled, double-blind multicenter trial compared placebo, auranofin (an orally administered gold complex), and parenteral gold sodium thiomalate (GST) in patients with active rheumatoid arthritis (RA). Of 193 patients who received any treatment, the only important improvement identified for either auranofin or GST was for pain/tenderness scores. When 161 patients who completed 20 weeks of treatment were examined, both auranofin and GST treatments were superior to placebo as measured by improvement in number of painful and/or tender joints, joint pain/tenderness scores, physician's assessment of disease activity, and decrease in erythrocyte sedimentation rate when elevated at entry. GST was superior to placebo in improvement of joint swelling scores, anemia, thrombocytosis, and rheumatoid factor. No drug-related remissions were observed. The only statistically significant advantages of GST over auranofin for efficacy were an increase in hemoglobin concentration and decrease of thrombocytosis with GST. Withdrawals for adverse effects were 5 times more frequent with GST treatment. Thrombocytopenia, proteinuria, elevated liver enzymes, "nitritoid" reactions, and "gold pneumonitis" were observed only in the GST treatment group. These results confirm that both parenteral and oral gold may be effective for the treatment of RA, that GST tends to show greater efficacy than auranofin, and that auranofin has fewer significant adverse effects than GST. However, long-term benefits, tolerability, and safety cannot be inferred from this study. PMID:6416259

  4. Dexamethasone-induced selenoprotein S degradation is required for adipogenesis

    OpenAIRE

    Kim, Choon Young; Kim, Kee-Hong

    2013-01-01

    Although adipogenesis is associated with induction of endoplasmic reticulum (ER) stress, the role of selenoprotein S (SEPS1), an ER resident selenoprotein known to regulate ER stress and ER-associated protein degradation, is unknown. We found an inverse relationship between SEPS1 level in adipose tissue and adiposity in mice. While SEPS1 expression was increased during adipogenesis, a markedly reduced SEPS1 protein level was found in the early phase of adipogenesis due to dexamethasone (DEX)-...

  5. Einfluss von Selenoprotein P auf die intestinale Tumorigenese im Mausmodell

    OpenAIRE

    Michaelis, Marten

    2009-01-01

    Das essentielle Spurenelement Selen (Se) wird als einziges Spurenelement über den genetischen Code als Bestandteil der 21. proteinogene Aminosäure Selenocystein (SeCys) in eine kleine Gruppe von Proteinen eingebaut. Als Bestandteil des aktiven Zentrums dieser Selenoproteine ist Se bzw. SeCys essentiell für deren Funktion. Die Biosynthese der Selenoproteine ist durch eine Reihe von Besonderheiten gekennzeichnet, so z.B. durch eine hierarchisch abgestimmte Versorgung der unterschiedlichen Organ...

  6. Altered hippocampus synaptic function in selenoprotein P deficient mice

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    Aniruddha Sengupta

    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.

  8. Selenoprotein P is the essential selenium transporter for bones.

    Science.gov (United States)

    Pietschmann, Nicole; Rijntjes, Eddy; Hoeg, Antonia; Stoedter, Mette; Schweizer, Ulrich; Seemann, Petra; Schomburg, Lutz

    2014-05-01

    Selenium (Se) plays an important role in bone physiology as best reflected by Kashin-Beck disease, an endemic Se-dependent osteoarthritis. Bone development is delayed in children with mutations in SECIS binding protein 2 (SBP2), a central factor for selenoprotein biosynthesis. Circulating selenoprotein P (SePP) is positively associated with bone turnover in humans, yet its function for bone homeostasis is not known. We have analysed murine models of altered Se metabolism. Most of the known selenoprotein genes and factors needed for selenoprotein biosynthesis are expressed in bones. Bone Se is not associated with the mineral but exclusively with the organic matrix. Genetic ablation of Sepp-expression causes a drastic decline in serum (25-fold) but only a mild reduction in bone (2.5-fold) Se concentrations. Cell-specific expression of a SePP transgene in hepatocytes efficiently restores bone Se levels in Sepp-knockout mice. Of the two known SePP receptors, Lrp8 was detected in bones while Lrp2 was absent. Interestingly, Lrp8 mRNA concentrations were strongly increased in bones of Sepp-knockout mice likely in order to counteract the developing Se deficiency. Our data highlight SePP as the essential Se transporter to bones, and suggest a novel feedback mechanism for preferential uptake of Se in Se-deprived bones, thereby contributing to our understanding of hepatic osteodystrophy and the consistent bone phenotype observed in subjects with inherited selenoprotein biosynthesis mutations. PMID:24626785

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

    OpenAIRE

    Charles E Chapple; Roderic Guigó

    2008-01-01

    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 investiga...

  10. Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. Subsets of responses.

    Science.gov (United States)

    Ward, J R; Williams, H J; Boyce, E; Egger, M J; Reading, J C; Samuelson, C O

    1983-12-30

    A comparison of placebo, auranofin, and parenteral gold sodium thiomalate therapy in 209 patients with active rheumatoid arthritis was performed in a 21-week prospective, controlled, double-blind multicenter trial. When the 161 patients who completed at least 20 weeks of treatment were analyzed for different degrees of response, no remissions were identified. When 50 percent or greater improvement of pain/tenderness scores were compared for end of trial versus entry values, 9 percent of placebo-treated patients, 34 percent of auranofin-treated patients, and 48 percent of gold sodium thiomalate-treated patients showed important improvement that was statistically significant for both gold treatments. When 50 percent improvement for joint swelling was analyzed, 12 percent of the placebo-treated group, 28 percent in the auranofin-treated group, and 37 percent in the gold sodium thiomalate-treated group showed this degree of improvement. Auranofin almost achieved statistical significance for improvement in joint swelling when compared with placebo (p = 0.07), but gold sodium thiomalate was much better than placebo (p = 0.009). There was no statistically significant difference between the two gold treatments. Thus it appears that a subset of patients had an important response to gold therapy that would not be evident by the usual analyses of mean or median changes. Analysis for predictors of response did not discriminate between responders and nonresponders. Because the trial was limited to 21 weeks of therapy, no prediction of the longer-term-effects, especially for auranofin, should be inferred. PMID:6419595

  11. Selenoproteins are Essential for Proper Keratinocyte Function and Skin Development

    OpenAIRE

    Sengupta, Aniruddha; Lichti, Ulrike F.; Carlson, Bradley A.; Andrew O Ryscavage; Yuspa, Stuart H.; Hatfield, Dolph L.; Gladyshev, Vadim

    2010-01-01

    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 ...

  12. Selenoproteins Are Essential for Proper Keratinocyte Function and Skin Development

    OpenAIRE

    Aniruddha Sengupta; Lichti, Ulrike F.; Carlson, Bradley A.; Ryscavage, Andrew O.; Gladyshev, Vadim N.; Yuspa, Stuart H; Hatfield, Dolph L.

    2010-01-01

    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 ...

  13. Selenoproteins reduce susceptibility to DMBA-induced mammary carcinogenesis

    OpenAIRE

    Hudson, Tamaro S.; Carlson, Bradley A.; Hoeneroff, Mark J.; Young, Heather A.; Sordillo, Lorraine; Muller, William J.; Hatfield, Dolph L.; Green, Jeffrey E.

    2012-01-01

    Selenium is an essential micronutrient in the diet of humans and other mammals. Based largely on animal studies and epidemiological evidence, selenium is purported to be a promising cancer chemopreventive agent. However, the biological mechanisms by which chemopreventive activity takes place are poorly understood. It remains unclear whether selenium acts in its elemental form, through incorporation into organic compounds, through selenoproteins or any combination of these. The purpose of this...

  14. Molekulare Regulation der Selenoprotein-Biosynthese und des Selentransports

    OpenAIRE

    Schomburg, Lutz

    2010-01-01

    The essential trace element selenium (Se) has aquired an unparalleled status for biochemistry and physiology since the identification of the 21st proteinogenic amino acid selenocysteine (Sec). The unique physical and chemical properties of Sec are exploited by a small number of selenoproteins which catalyse reactions that are of prime importance for general metabolism, intracellular redox-balance and antioxidative defense. Some of these reactions and some of the responsible selenoenzymes are ...

  15. Reduced serum selenoprotein P concentrations in German prostate cancer patients.

    Science.gov (United States)

    Meyer, Hellmuth-Alexander; Hollenbach, Birgit; Stephan, Carsten; Endermann, Tobias; Morgenthaler, Nils G; Cammann, Henning; Köhrle, Josef; Jung, Klaus; Schomburg, Lutz

    2009-09-01

    Selenium (Se) is essentially needed for the biosynthesis of selenoproteins. Low Se intake causes reduced selenoprotein biosynthesis and constitutes a risk factor for tumorigenesis. Accordingly, some Se supplementation trials have proven effective to reduce prostate cancer risk, especially in poorly supplied individuals. Because Se metabolism is controlled by selenoprotein P (SEPP), we have tested whether circulating SEPP concentrations correlate to prostate cancer stage and grade. A total of 190 men with prostate cancer (n = 90) and "no evidence of malignancy" (NEM; n = 100) histologically confirmed by prostate biopsy were retrospectively analyzed for established tumor markers and for their Se and SEPP status. Prostate specific antigen (PSA), free PSA, total Se, and SEPP concentrations were determined from serum samples and compared with clinicopathologic parameters. The diagnostic performance was analyzed with receiver operating characteristic curves. Median Se and SEPP concentrations differed significantly (P curve (AUC) of a marker combination with age, PSA, and percent free PSA (%fPSA) in combination with the SEPP concentration, yielded the highest diagnostic value (AUC 0.80) compared with the marker combination without SEPP (AUC 0.77) or %fPSA (AUC 0.76). We conclude that decreased SEPP concentration in serum might represent an additional valuable marker for prostate cancer diagnostics. PMID:19690186

  16. New selenoproteins identified in silico from the genome of Anopheles gambiae

    Institute of Scientific and Technical Information of China (English)

    JIANG Liang; LIU Qiong; CHEN Ping; GAO ZhongHong; XU HuiBi

    2007-01-01

    Selenoprotein is biosynthesized by the incorporation of selenocysteine into proteins, where the TGA codon in the open reading frame does not act as a stop signal but is translated into selenocysteine. The dual functions of TGA result in mis-annotation or lack of selenoproteins in the sequenced genomes of many species. Available computational tools fail to correctly predict selenoproteins. Thus, we developed a new method to identify selenoproteins from the genome of Anopheles gambiae computationally.Based on released genomic information, several programs were edited with PERL language to identify selenocysteine insertion sequence (SECIS) element, the coding potential of TGA codons, and cysteine-containing homologs of selenoprotein genes. Our results showed that 11365 genes were terminated with TGA codons, 918 of which contained SECIS elements. Similarity search revealed that 58genes contained Sec/Cys pairs and similar flanking regions around in-frame TGA codons. Finally, 7genes were found to fully meet requirements for selenoproteins, although they have not been annotated as selenoproteins in NCBI databases. Deduced from their basic properties, the newly found selenoproteins in the genome of Anopheles gambiae are possibly related to in vivo oxidation tolerance and protein regulation in order to interfere with anopheles' vectorial capacity of Plasmodium. This study may also provide theoretical bases for the prevention of malaria from anopheles transmission.

  17. 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...

  18. Cloning of human 15ku selenoprotein gene from H9 T cells

    Institute of Scientific and Technical Information of China (English)

    Ke-Jun Nan; Chun-Li Li; Yong-Chang Wei; Chen-Guang Sui; Zhao Jing; Hai-Xia Qin; Li-Jun Zhao; Bo-Rong Pan

    2003-01-01

    AIM: To clone human 15ku selenoprotein gene.METHODS: H9 human T cells were cultured in RPMI1640medium supplemented with 100 mL/L fetal calf serum. mRNA was isolated from the cells. cDNA library was constructed by RT-PCR. The human 15ku selenoprotein gene was obtained by PCR and cloned into T vector and sequenced.RESULTS: A unique cDNA fragment about 1 244 bp was obtained. Sequence analysis identified an open reading frame within the cDNA. The gene had an in-frame TGA, which encoded selenocysteine (Sec), and a 3′-UTR SECIS element,which was required for synthesis of selenoprotein. The predicted protein molecular mass was about 15ku (162residues). The result was identical with human liver 15ku selenoprotein gene published in Genbank.CONCLUSION: Human 15ku selenoprotein gene can be successfully obtained from T cell line.

  19. Secisbp2 Is Essential for Embryonic Development and Enhances Selenoprotein Expression

    Science.gov (United States)

    Seeher, Sandra; Atassi, Tarik; Mahdi, Yassin; Carlson, Bradley A.; Braun, Doreen; Wirth, Eva K.; Klein, Marc O.; Reix, Nathalie; Miniard, Angela C.; Schomburg, Lutz; Hatfield, Dolph L.; Driscoll, Donna M.

    2014-01-01

    Abstract Aims: The selenocysteine insertion sequence (SECIS)-binding protein 2 (Secisbp2) binds to SECIS elements located in the 3′-untranslated region of eukaryotic selenoprotein mRNAs. Selenoproteins contain the rare amino acid selenocysteine (Sec). Mutations in SECISBP2 in humans lead to reduced selenoprotein expression thereby affecting thyroid hormone-dependent growth and differentiation processes. The most severe cases also display myopathy, hearing impairment, male infertility, increased photosensitivity, mental retardation, and ataxia. Mouse models are needed to understand selenoprotein-dependent processes underlying the patients' pleiotropic phenotypes. Results: Unlike tRNA[Ser]Sec-deficient embryos, homozygous Secisbp2-deleted embryos implant, but fail before gastrulation. Heterozygous inactivation of Secisbp2 reduced the amount of selenoprotein expressed, but did not affect the thyroid hormone axis or growth. Conditional deletion of Secisbp2 in hepatocytes significantly decreased selenoprotein expression. Unexpectedly, the loss of Secisbp2 reduced the abundance of many, but not all, selenoprotein mRNAs. Transcript-specific and gender-selective effects on selenoprotein mRNA abundance were greater in Secisbp2-deficient hepatocytes than in tRNA[Ser]Sec-deficient cells. Despite the massive reduction of Dio1 and Sepp1 mRNAs, significantly more corresponding protein was detected in primary hepatocytes lacking Secisbp2 than in cells lacking tRNA[Ser]Sec. Regarding selenoprotein expression, compensatory nuclear factor, erythroid-derived, like 2 (Nrf2)-dependent gene expression, or embryonic development, phenotypes were always milder in Secisbp2-deficient than in tRNA[Ser]Sec-deficient mice. Innovation: We report the first Secisbp2 mutant mouse models. The conditional mutants provide a model for analyzing Secisbp2 function in organs not accessible in patients. Conclusion: In hepatocyte-specific conditional mouse models, Secisbp2 gene inactivation is less

  20. A new target for gold(I) compounds : Glutathione-S-transferase inhibition by auranofin

    NARCIS (Netherlands)

    De Luca, Anastasia; Hartinger, Christian G.; Dyson, Paul J.; Lo Bello, Mario; Casini, Angela

    2013-01-01

    Nowadays, gold compounds occupy a relevant position constituting a promising class of experimental anticancer metallodrugs. Several research efforts have been devoted to the investigations of the pharmacological properties of gold(I) complexes bearing phosphine ligands, such as the antiarthritic dru

  1. Selenoprotein P – Expression, Functions, and Roles in Mammals

    OpenAIRE

    Raymond F Burk; Hill, Kristina E.

    2009-01-01

    Selenoprotein P (Sepp1) is a secreted protein that is made up of 2 domains. The larger N-terminal domain contains 1 selenocysteine residue in a redox motif and the smaller C-terminal domain contains the other 9 selenocysteines. Sepp1 isoforms of varying length occur but quantitation of them has not been achieved. Hepatic synthesis of Sepp1 affects whole-body selenium content and the liver is the source of most plasma Sepp1. ApoER2, a member of the lipoprotein receptor family, binds Sepp1 and ...

  2. Untersuchungen zur Expression und Verteilung von Selenoprotein P

    OpenAIRE

    Scharpf, Marcus

    2012-01-01

    We studied the distribution of Selenoprotein P (SePP) on mRNA and protein level. Using in-situ hybridisation on selected murine tissues, we showed tissue- and cell specific SePP-mRNA distribution. These results were confirmed and correlated using a commercially available human mRNA expression array. In an effort to study SePP protein localization, we established immunohistochemical stainings using three different antibodies directed against human SePP. Distribution of SePP in the Human brain ...

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

    International Nuclear Information System (INIS)

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Selenium Deficiency Mainly Influences Antioxidant Selenoproteins Expression in Broiler Immune Organs.

    Science.gov (United States)

    Yang, Zijiang; Liu, Ci; Liu, Chunpeng; Teng, Xiaohua; Li, Shu

    2016-07-01

    Selenoprotein has many functions in chicken, and the expression of selenoproteins is closely associated with the selenium (Se) level. However, little is known about the expression patterns of selenoproteins in chicken immune organs. Here, we investigated the effect of dietary Se deficiency on the expressions of 23 selenoproteins in broiler immune organs. In this study, 150 broilers were randomly divided into two groups (75 chickens per group). The chickens were maintained either on a diet supplemented with Se through the addition of 0.2 mg/kg of Se (C group) via sodium selenite or on a Se-deficient granulated diet (L group) until the broilers exhibited an onset of exudative diathesis (ED). Following euthanasia, the samples from the immune tissues (including the spleen, thymus, and bursa of Fabricius) were quickly collected, and the messenger RNA (mRNA) expression levels of 23 selenoproteins were examined by real-time quantitative PCR and analyzed using principal component analysis. The results showed that Se deficiency decreased the mRNA levels of 23 selenoproteins in the thymus, spleen, and bursa of the Fabricius tissues of broiler chickens. Furthermore, we found that among 23 selenoproteins, the mRNA levels of Dio1 in the thymus, Txnrd2 in the spleen, and Txnrd3 in the bursa of Fabricius decreased significantly (90.9 %, 83.3 %, and 96.8 %, respectively). In addition, the principal component analysis (PCA) results suggested that Se deficiency mainly influenced the expression of antioxidative selenoproteins, especially glutathione peroxidases (Gpxs), thioredoxin reductases (Txnrds), and iodothyronine deiodinases (Dios) in chicken immune organs. The results of this study are valuable for understanding the relevance of selenoprotein activity in vivo. PMID:26631053

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

    DEFF Research Database (Denmark)

    Rasmussen, Lone Banke; Hollenbach, B.; Laurberg, P.; Carlé, A.; Hög, A.; Jørgensen, T.; Vejbjerg, P.; Ovesen, L.; Schomburg, L.

    2009-01-01

    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...... selenoprotein P level. Smoking status, alcohol intake, exercise habits, BMI and medicine use did not influence selenium status. It is concluded that selenium status in this Danish population is at an acceptable level. No major groups with regard to age, sex or lifestyle factors could be identified as being in...

  7. The protozoa dinoflagellate Oxyrrhis marina contains selenoproteins and the relevant translation apparatus

    International Nuclear Information System (INIS)

    In the phylogenetic tree, selenoproteins and the corresponding translation machinery are found in Archaea, Eubacteria, and animals, but not in fungi and higher plants. As very little is known about Protozoa, we searched for the presence of selenoproteins in the primitive dinoflagellate Oxyrrhis marina, belonging to the Protoctista kingdom. Four selenoproteins could be obtained from O. marina cells cultured in the presence of 75Se. Using O. marina or bovine liver cytosolic extracts, we could serylate and selenylate in vitro total O. marina tRNAs. Moreover, the existence of a tRNASec could be deduced from in vivo experiments. Lastly, an anti-serum against the specialized mammalian translation elongation factor mSelB reacted with a protein of 48-kDa molecular mass. Altogether, our data showed that O. marina contains selenoproteins and suggests that the corresponding translation machinery is related to that found in animals

  8. Identification of selenocyst- eine insertion sequence (SECIS) element in eukaryotic selenoproteins by RNA Draw program

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The computer program RNA Draw was used to identify the secondary structures in the 3′ untranslated re- gions (3′UTRs) of the mRNAs from 46 eukaryotic seleno- proteins among 7 species. The program found one or two possible SECIS elements in these selenoproteins. The SECIS element consists of a stem-loop or hairpin structure with three conserved sequences of AUGA-(A)AA-GA. SECIS element was not found by the RNA Draw program in randomly selected non-selenoproteins. The results showed that SECIS element is the unique character of the genes of eukaryotic selenoproteins. Thus it is possible to use RNA Draw to search the SECIS elements in gene bank for poten- tial new selenoproteins.

  9. Selenoproteins-What unique properties can arise with selenocysteine in place of cysteine?

    Energy Technology Data Exchange (ETDEWEB)

    Arner, Elias S.J., E-mail: Elias.Arner@ki.se [Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm (Sweden)

    2010-05-01

    The defining entity of a selenoprotein is the inclusion of at least one selenocysteine (Sec) residue in its sequence. Sec, the 21st naturally occurring genetically encoded amino acid, differs from its significantly more common structural analog cysteine (Cys) by the identity of a single atom: Sec contains selenium instead of the sulfur found in Cys. Selenium clearly has unique chemical properties that differ from sulfur, but more striking are perhaps the similarities between the two elements. Selenium was discovered by Joens Jacob Berzelius, a renowned Swedish scientist instrumental in establishing the institution that would become Karolinska Institutet. Written at the occasion of the bicentennial anniversary of Karolinska Institutet, this mini review focuses on the unique selenium-derived properties that may potentially arise in a protein upon the inclusion of Sec in place of Cys. With 25 human genes encoding selenoproteins and in total several thousand selenoproteins yet described in nature, it seems likely that the presence of that single selenium atom of Sec should convey some specific feature, thereby explaining the existence of selenoproteins in spite of demanding and energetically costly Sec-specific synthesis machineries. Nonetheless, most, if not all, of the currently known selenoproteins are also found as Cys-containing non-selenoprotein orthologues in other organisms, wherefore any potentially unique properties of selenoproteins are yet a matter of debate. The pK{sub a} of free Sec (approximately 5.2) being significantly lower than that of free Cys (approximately 8.5) has often been proposed as one of the unique features of Sec. However, as discussed herein, this pK{sub a} difference between Sec and Cys can hardly provide an evolutionary pressure for maintenance of selenoproteins. Moreover, the typically 10- to 100-fold lower enzymatic efficiencies of Sec-to-Cys mutants of selenoprotein oxidoreductases, are also weak arguments for the overall existence

  10. Selenoproteins-What unique properties can arise with selenocysteine in place of cysteine?

    Science.gov (United States)

    Arnér, Elias S J

    2010-05-01

    The defining entity of a selenoprotein is the inclusion of at least one selenocysteine (Sec) residue in its sequence. Sec, the 21st naturally occurring genetically encoded amino acid, differs from its significantly more common structural analog cysteine (Cys) by the identity of a single atom: Sec contains selenium instead of the sulfur found in Cys. Selenium clearly has unique chemical properties that differ from sulfur, but more striking are perhaps the similarities between the two elements. Selenium was discovered by Jöns Jacob Berzelius, a renowned Swedish scientist instrumental in establishing the institution that would become Karolinska Institutet. Written at the occasion of the bicentennial anniversary of Karolinska Institutet, this mini review focuses on the unique selenium-derived properties that may potentially arise in a protein upon the inclusion of Sec in place of Cys. With 25 human genes encoding selenoproteins and in total several thousand selenoproteins yet described in nature, it seems likely that the presence of that single selenium atom of Sec should convey some specific feature, thereby explaining the existence of selenoproteins in spite of demanding and energetically costly Sec-specific synthesis machineries. Nonetheless, most, if not all, of the currently known selenoproteins are also found as Cys-containing non-selenoprotein orthologues in other organisms, wherefore any potentially unique properties of selenoproteins are yet a matter of debate. The pK(a) of free Sec (approximately 5.2) being significantly lower than that of free Cys (approximately 8.5) has often been proposed as one of the unique features of Sec. However, as discussed herein, this pK(a) difference between Sec and Cys can hardly provide an evolutionary pressure for maintenance of selenoproteins. Moreover, the typically 10- to 100-fold lower enzymatic efficiencies of Sec-to-Cys mutants of selenoprotein oxidoreductases, are also weak arguments for the overall existence of

  11. Selenoproteins-What unique properties can arise with selenocysteine in place of cysteine?

    International Nuclear Information System (INIS)

    The defining entity of a selenoprotein is the inclusion of at least one selenocysteine (Sec) residue in its sequence. Sec, the 21st naturally occurring genetically encoded amino acid, differs from its significantly more common structural analog cysteine (Cys) by the identity of a single atom: Sec contains selenium instead of the sulfur found in Cys. Selenium clearly has unique chemical properties that differ from sulfur, but more striking are perhaps the similarities between the two elements. Selenium was discovered by Joens Jacob Berzelius, a renowned Swedish scientist instrumental in establishing the institution that would become Karolinska Institutet. Written at the occasion of the bicentennial anniversary of Karolinska Institutet, this mini review focuses on the unique selenium-derived properties that may potentially arise in a protein upon the inclusion of Sec in place of Cys. With 25 human genes encoding selenoproteins and in total several thousand selenoproteins yet described in nature, it seems likely that the presence of that single selenium atom of Sec should convey some specific feature, thereby explaining the existence of selenoproteins in spite of demanding and energetically costly Sec-specific synthesis machineries. Nonetheless, most, if not all, of the currently known selenoproteins are also found as Cys-containing non-selenoprotein orthologues in other organisms, wherefore any potentially unique properties of selenoproteins are yet a matter of debate. The pKa of free Sec (approximately 5.2) being significantly lower than that of free Cys (approximately 8.5) has often been proposed as one of the unique features of Sec. However, as discussed herein, this pKa difference between Sec and Cys can hardly provide an evolutionary pressure for maintenance of selenoproteins. Moreover, the typically 10- to 100-fold lower enzymatic efficiencies of Sec-to-Cys mutants of selenoprotein oxidoreductases, are also weak arguments for the overall existence of

  12. Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage

    OpenAIRE

    Caitlyn W Barrett; Reddy, Vishruth K.; Short, Sarah P.; Motley, Amy K.; Lintel, Mary K.; Bradley, Amber M.; Freeman, Tanner; Vallance, Jefferson; Ning, Wei; Parang, Bobak; Poindexter, Shenika V.; Fingleton, Barbara; Chen, Xi; Washington, Mary K.; Wilson, Keith T.

    2015-01-01

    Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice wi...

  13. Effects of Selenium Supplementation on Selenoprotein Gene Expression and Response to Influenza Vaccine Challenge: A Randomised Controlled Trial

    OpenAIRE

    Goldson, Andrew J.; Fairweather-Tait, Susan J; Armah, Charlotte N.; Bao, Yongping; Broadley, Martin R.; Dainty, Jack R.; Furniss, Caroline; Hart, David J.; Teucher, Birgit; Hurst, Rachel

    2011-01-01

    Background 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. Methods and Finding...

  14. Deletion of Selenoprotein P Results in Impaired Function of Parvalbumin Interneurons and Alterations in Fear Learning and Sensorimotor Gating

    OpenAIRE

    Pitts, Matthew W.; Raman, Arjun V; Hashimoto, Ann C; Todorovic, Cedomir; Nichols, Robert A.; Berry, Marla J.

    2012-01-01

    One of the primary lines of defense against oxidative stress is the selenoprotein family, a class of proteins that contain selenium in the form of the 21st amino acid, selenocysteine. Within this class of proteins, Selenoprotein P (Sepp1) is unique, as it contains multiple selenocysteine residues and is postulated to act in selenium transport. Recent findings have demonstrated that neuronal selenoprotein synthesis is required for the development of parvalbumin (PV)-interneurons, a class of GA...

  15. Thioredoxin reductase inhibitor auranofin prevents membrane transport of diphtheria toxin into the cytosol and protects human cells from intoxication.

    Science.gov (United States)

    Schnell, Leonie; Dmochewitz-Kück, Lydia; Feigl, Peter; Montecucco, Cesare; Barth, Holger

    2016-06-15

    During cellular uptake, diphtheria toxin delivers its catalytic domain DTA from acidified endosomes into the cytosol, which requires reduction of the disulfide linking DTA to the transport domain. In vitro, thioredoxin reduces this disulfide and thioredoxin reductase (TrxR) is part of a cytosolic complex facilitating DTA-translocation. We found that the TrxR-specific inhibitor auranofin prevented DTA delivery into the cytosol and intoxication of HeLa cells with diphtheria toxin, offering perspectives for novel pharmacological strategies against diphtheria. PMID:25911959

  16. 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.

  17. Selenium Deficiency Influences the mRNA Expression of Selenoproteins and Cytokines in Chicken Erythrocytes.

    Science.gov (United States)

    Luan, Yilin; Zhao, Jinxin; Yao, Haidong; Zhao, Xia; Fan, Ruifeng; Zhao, Wenchao; Zhang, Ziwei; Xu, Shiwen

    2016-06-01

    Selenium (Se) deficiency induces hemolysis in chickens, but the molecular mechanism for this effect remains unclear. Se primarily elicits its function through the activity of selenoproteins, which contain the unique amino acid selenocysteine (Sec). In this study, we aimed to investigate the effect of Se deficiency on the expression of 24 selenoproteins and 10 cytokines. One hundred eighty chickens were randomly divided into 2 groups (90 chickens per group). During the entire experimental period, chickens were allowed ad libitum consumption of feed and water. The chickens were fed either a Se-deficient diet (0.008 mg Se/kg; produced in the Se-deficient area of Heilongjiang, China) or a Se-supplemented diet (as sodium selenite) at 0.2 mg/kg for 35 days. At the 35th day, the messenger RNA (mRNA) levels of 24 selenoproteins and 10 cytokines were examined in erythrocytes of 5 chickens per group, and the correlation was analyzed. The results showed that the expression of 24 selenoproteins and 7 cytokines (IL-2, IL-4, IL-8, IL-10, IL-12β, TGF-β4, and IFN-γ) decreased (P < 0.05), and the expression of 3 cytokines (IL-1γ, IL-6 and IL-7) was higher in the Se-deficient group. In both groups, glutathione peroxidase (GPX), thioredoxin 1 (Txnrd1), selenoprotein P1 (SELP), and selenoprotein synthetase (SPS2) were highly expressed compared to the other selenoproteins in chicken erythrocytes (P < 0.05). These data suggest that GPXs, Txnrd1, SELP, and SPS2 possibly play a more important role than the other selenoproteins. The increase of pro-inflammatory cytokines (IL-1γ, IL-6, and IL-7) suggested that the immune system of chickens was damaged by the Se deficiency. Correlation analysis suggested that although the expression of 24 selenoproteins and 7 cytokines decreased and that of 3 cytokines increased, there was a close correlation between their expression levels and a Se diet. These results suggested that Se deficiency influenced the expressions of 24 selenoproteins

  18. Factors impacting the aminoglycoside-induced UGA stop codon readthrough in selenoprotein translation.

    Science.gov (United States)

    Martitz, Janine; Hofmann, Peter Josef; Johannes, Jörg; Köhrle, Josef; Schomburg, Lutz; Renko, Kostja

    2016-09-01

    Aminoglycosides (AG) are oligosaccharide antibiotics that interfere with the small ribosomal subunit in aerobic, Gram-negative bacteria, causing pathogen-destructing error rates in their protein biosynthesis. Aminoglycosides also induce mRNA misinterpretation in eukaryotic cells, especially of the UGA (Opal)-stop codon, albeit to a lower extent. UGA recoding is essentially required for the incorporation of selenocysteine (Sec) into growing selenoproteins during translation. Selenocysteine incorporation requires the presence of a selenoprotein-specific stem-loop structure within the 3'-untranslated region of the mRNA, the so-called Sec-insertion sequence (SECIS) element. Interestingly, selenoprotein genes differ in their SECIS-element sequence and in their UGA base context. We hypothesized that the SECIS-element and the specific codon context synergize in controlling the effects of AG on stop codon readthrough. To this end, the SECIS-elements of glutathione peroxidase 1, glutathione peroxidase 4 and selenoprotein P transcripts were cloned into a reporter system and analyzed in combination with different UGA codon contexts. Our results indicate that a cytosine in position 4 (directly downstream of UGA) confers strongest effects on both the Se- and AG-dependent readthrough. Overall selenoprotein biosynthesis rate depends on the Se-status, AG concentration and the specific SECIS-element present in the transcript. These findings help to get a better understanding for the susceptibility of different transcripts towards AG-mediated interference with the biosynthesis of functional Se-containing selenoproteins, and highlight the importance of the Se-status for successful selenoprotein biosynthesis under antibiotic therapy. PMID:27157664

  19. 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.

  20. Identification of a redox-modulatory interaction between selenoprotein W and 14-3-3 protein.

    Science.gov (United States)

    Jeon, Yeong Ha; Ko, Kwan Young; Lee, Jea Hwang; Park, Ki Jun; Jang, Jun Ki; Kim, Ick Young

    2016-01-01

    Selenoprotein W (SelW) contains a selenocysteine (Sec, U) in a conserved CXXU motif corresponding to the CXXC redox motif of thioredoxin, suggesting a putative redox function of SelW. We have previously reported that the binding of 14-3-3 protein to its target proteins, including CDC25B, Rictor and TAZ, is inhibited by the interaction of 14-3-3 protein with SelW. However, the binding mechanism is unclear. In this study, we sought to determine the binding site of SelW to understand the regulatory mechanism of the interaction between SelW and 14-3-3 and its biological effects. Phosphorylated Ser(pS) or Thr(pT) residues in RSXpSXP or RXXXp(S/T)XP motifs are well-known common 14-3-3-binding sites, but Thr41, Ser59, and T69 of SelW, which are computationally predicted to serve are phosphorylation sites, were neither phosphorylation sites nor sites involved in the interaction. A mutant SelW in which Sec13 is changed to Ser (U13S) was unable to interact with 14-3-3 protein and thus did not inhibit the interaction of 14-3-3 to other target proteins. However, other Cys mutants of SelW(C10S, C33S and C37S) normally interacted with 14-3-3 protein. The interaction of SelW to 14-3-3 protein was enhanced by diamide or H2O2 and decreased by dithiothreitol (DTT). Taken together, these findings demonstrate that the Sec of SelW is involved in its interaction with 14-3-3 protein and that this interaction is increased under oxidative stress conditions. Thus, SelW may have a regulatory function in redox cell signaling by interacting with 14-3-3 protein. PMID:26474786

  1. Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to coordination defects in mice

    Science.gov (United States)

    Seeher, Sandra; Carlson, Bradley A.; Miniard, Angela C.; Wirth, Eva K.; Mahdi, Yassin; Hatfield, Dolph L.; Driscoll, Donna M.; Schweizer, Ulrich

    2014-01-01

    Selenocysteine Insertion Sequence (SECIS)-Binding Protein 2 (Secisbp2) binds to SECIS elements located in the 3′-untranslated region of eukaryotic selenoprotein mRNAs. It facilitates incorporation of the rare amino acid selenocysteine in response to UGA codons. Inactivation of Secisbp2 in hepatocytes greatly reduced selenoprotein levels. Neuron-specific inactivation of Secisbp2 (CamK-Cre; Secisbp2fl/fl) reduced cerebral expression of selenoproteins to a lesser extent than inactivation of tRNA[Ser]Sec. This allowed us to study the development of cortical parvalbumin-positive (PV+) interneurons, which are completely lost in tRNA[Ser]Sec mutants. PV+ interneuron density was reduced in the somatosensory cortex, hippocampus, and striatum. In situ-hybridization for Gad67 confirmed the reduction of GABAergic interneurons. Because of the obvious movement phenotype involving a broad, dystonic gait, we suspected basal ganglia dysfunction. Tyrosine hydroxylase expression was normal in substantia nigra neurons and their striatal terminals. However the densities of striatal PV+ and Gad67+ neurons were decreased by 65% and 49%, respectively. Likewise, the density of striatal cholinergic neurons was reduced by 68%. Our observations demonstrate that several classes of striatal interneurons depend on selenoprotein expression. These findings may offer an explanation for the movement phenotype of selenoprotein P-deficient mice and the movement disorder and mental retardation described in a patient carrying SECISBP2 mutations. PMID:24844465

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Deletion of Selenoprotein P Upregulates Urinary Selenium Excretion and Depresses Whole-body Selenium Content

    OpenAIRE

    Raymond F Burk; Hill, Kristina E.; Motley, Amy K.; Austin, Lori M.; Norsworthy, Brooke K.

    2006-01-01

    Deletion of the mouse selenoprotein P gene (Sepp1) lowers selenium concentrations in many tissues. We examined selenium homeostasis in Sepp1−/− and Sepp1+/+ mice to assess the mechanism of this. The liver produces and exports selenoprotein P, which transports selenium to peripheral tissues, and urinary selenium metabolites, which regulate whole-body selenium. At intakes of selenium near the nutritional requirement, Sepp1−/− mice had whole-body selenium concentrations 72 to 75% of Sepp1+/+ mic...

  4. Immunomodulatory effects of therapeutic gold compounds. Gold sodium thiomalate inhibits the activity of T cell protein kinase C.

    OpenAIRE

    Hashimoto, K; Whitehurst, C. E.; Matsubara, T.; Hirohata, K; Lipsky, P E

    1992-01-01

    Previous studies have shown that the gold compounds, gold sodium thiomalate (GST) and auranofin (AUR), which are effective in the treatment of rheumatoid arthritis, inhibit functional activities of a variety of cells, but the biochemical basis of their effect is unknown. In the current studies, human T cell proliferation and interleukin 2 production by Jurkat cells were inhibited by GST or AUR at pharmacologically relevant concentrations. Because it has been documented that protein kinase C (...

  5. Selenoprotein S expression in reactive astrocytes following brain injury.

    Science.gov (United States)

    Fradejas, Noelia; Serrano-Pérez, Maria Del Carmen; Tranque, Pedro; Calvo, Soledad

    2011-06-01

    Selenoprotein S (SelS) is an endoplasmic reticulum (ER)-resident protein involved in the unfolded protein response. Besides reducing ER-stress, SelS attenuates inflammation by decreasing pro-inflammatory cytokines. We have recently shown that SelS is responsive to ischemia in cultured astrocytes. To check the possible association of SelS with astrocyte activation, here we investigate the expression of SelS in two models of brain injury: kainic acid (KA) induced excitotoxicity and cortical mechanical lesion. The regulation of SelS and its functional consequences for neuroinflammation, ER-stress, and cell survival were further analyzed using cultured astrocytes from mouse and human. According to our immunofluorescence analysis, SelS expression is prominent in neurons and hardly detectable in astrocytes from control mice. However, brain injury intensely upregulates SelS, specifically in reactive astrocytes. SelS induction by KA was evident at 12 h and faded out after reaching maximum levels at 3-4 days. Analysis of mRNA and protein expression in cultured astrocytes showed SelS upregulation by inflammatory stimuli as well as ER-stress inducers. In turn, siRNA-mediated SelS silencing combined with adenoviral overexpression assays demonstrated that SelS reduces ER-stress markers CHOP and spliced XBP-1, as well as inflammatory cytokines IL-1β and IL-6 in stimulated astrocytes. SelS overexpression increased astrocyte resistance to ER-stress and inflammatory stimuli. Conversely, SelS suppression compromised astrocyte viability. In summary, our results reveal the upregulation of SelS expression in reactive astrocytes, as well as a new protective role for SelS against inflammation and ER-stress that can be relevant to astrocyte function in the context of inflammatory neuropathologies. PMID:21456042

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

    OpenAIRE

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

    2015-01-01

    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 reticu...

  7. Selenoprotein W controls epidermal growth factor receptor surface expression, activation and degradation via receptor ubiquitination

    Science.gov (United States)

    Epidermal growth factor (EGF) receptor (EGFR) is the founding member of the ErbB family of growth factor receptors that modulate a complex network of intracellular signaling pathways controlling growth, proliferation and differentiation. Selenoprotein W (SEPW1) is a diet-regulated, highly conserved...

  8. 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

    2013-04-01

    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. PMID:23325319

  9. In vivo and in vitro auranofin activity against Trypanosoma cruzi: Possible new uses for an old drug.

    Science.gov (United States)

    da Silva, Marco Túlio Alves; Silva-Jardim, Izaltina; Portapilla, Gisele Bulhões; de Lima, Gustavo Machado Alvares; Costa, Fernanda Cristina; Anibal, Fernanda de Freitas; Thiemann, Otavio Henrique

    2016-07-01

    Chagas disease, Sleeping Sickness, Nagana and Leishmaniasis are serious infections caused by protozoa of the order Kinetoplastidae. They were described over a century ago by seminal work of different physician-researchers and, despite the initial discoveries, few drugs have been made available for the treatment of these infections. The drugs available present serious efficacy and toxicity problems. Moreover, the emergence of resistant strains has rendered the development of novel chemotherapeutic strategies a priority. Auranofin is currently in use to treat rheumatoid arthritis in humans. Previous reports showed that this compound presents activity against Trypanosoma brucei and Leishmania cells. In Trypanosoma cruzi cells, auranofin resulted in a more potent compound than benznidazole in vitro when tested in different DTUs. In vivo experiments, although not decreasing T. cruzi parasitemia, decreases host mortality. Therefore, we propose auranofin as a potential alternative for a new chemotherapy in Chagas disease with the added advantage of already being approved for use in humans. PMID:26183422

  10. 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.

  11. Selenium controls sex-specific immune response and selenoprotein expression during the acute phase response in mice

    OpenAIRE

    Stoedter, Mette; Renko, Kostja; Hoeg, Antonia; Schomburg, Lutz

    2010-01-01

    Abstract Selenium modifies inflammatory reactions in rodents and humans. The liver controls metabolism and transport of selenium via hepatically-derived selenoprotein P (SEPP). Intracellular selenoprotein S (SEPS) modifies endoplasmic reticulum function and immune cell activity. Polymorphisms in SEPS were associated with cytokine levels and inflammatory diseases in a subset of clinical studies. We hypothesized that sex and selenium represent decisive parameters controlling immune r...

  12. 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; Gammelgaard, Bente

    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...... selenoprotein P. The purity of the protein was determined by SDS-PAGE and by sequencing from polyvinylidene difluoride blots of SDS-PAGE gels....

  13. Hepatic selenoprotein P (Sepp) expression restores selenium transport and prevents infertility and motor-incoordination in Sepp-knockout mice

    OpenAIRE

    Renko, Kostja; Werner, Margarethe; Renner-Müller, Ingrid; Trevor G Cooper; Yeung, Ching Hei; Hollenbach, Birgit; Scharpf, Marcus; Köhrle, Josef; Schomburg, Lutz; Schweizer, Ulrich

    2007-01-01

    Abstract Selenoprotein P (SePP) is central for selenium (Se) transport and distribution. Targeted inactivation of the Sepp gene in mice leads to reduced Se content in plasma, kidney, testis, and brain. Accordingly, activities of selenoenzymes are reduced in Sepp -/-} organs. Male Sepp -/-} mice are infertile. Unlike Se deficiency, Sepp-deficiency leads to neurological impairment with ataxia and seizures. Hepatocyte-specific inactivation of selenoprotein biosynthesis reduces plasma ...

  14. Mutations in the selenocysteine insertion sequence–binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans

    OpenAIRE

    Schoenmakers, Erik; Agostini, Maura; Mitchell, Catherine; Schoenmakers, Nadia; Papp, Laura; Rajanayagam, Odelia; Padidela, Raja; Ceron-Gutierrez, Lourdes; Doffinger, Rainer; Prevosto, Claudia; Luan, Jian’an; Montano, Sergio; Lu, Jun; Castanet, Mireille; Clemons, Nick

    2010-01-01

    Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence–binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a comple...

  15. Selenoprotein Genes Exhibit Differential Expression Patterns Between Hepatoma HepG2 and Normal Hepatocytes LO2 Cell Lines.

    Science.gov (United States)

    Zhao, Hua; Tang, Jiayong; Xu, Jingyang; Cao, Lei; Jia, Gang; Long, Dingbiao; Liu, Guangmang; Chen, Xiaoling; Wang, Kangning

    2015-10-01

    The purpose of this study was to compare messenger RNA (mRNA) expression of selenoprotein genes between hepatoma HepG2 and normal hepatocytes LO2 cell lines. Liver HepG2 and LO2 cells were cultured in 12-well plates under the same condition until cells grew to complete confluence, and then cells were harvested for total RNA and protein extraction. The qPCRs were performed to compare gene expression of 14 selenoprotein genes and 5 cancer signaling-related genes. Enzyme activities were also assayed. The results showed that human hepatoma HepG2 cells grew faster than normal hepatocytes LO2 cells. Among the genes investigated, 10 selenoprotein genes (Gpx1, Gpx3, Gpx4, Selx, Sepp, Sepw1, Sepn1, Selt, Seli, Selh) and 3 cancer signaling-related genes (Bcl-2A, caspase-3, and P38) were upregulated (P < 0.05), while Selo and Bcl-2B were downregulated (P < 0.05) in hepatoma HepG2 cells compared to LO2 cells. Significant correlations were found between selenoprotein genes and the cancer signaling-related genes Caspase3, P53, Bc1-2A, and Bc1-2B. Our results revealed that selenoprotein genes were aberrantly expressed in hepatoma HepG2 cells compared to normal liver LO2 cells, which indicated that those selenoprotein genes may play important roles in the occurrence and development of liver carcinogenesis. PMID:25846212

  16. Mutations in the selenocysteine insertion sequence–binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans

    Science.gov (United States)

    Schoenmakers, Erik; Agostini, Maura; Mitchell, Catherine; Schoenmakers, Nadia; Papp, Laura; Rajanayagam, Odelia; Padidela, Raja; Ceron-Gutierrez, Lourdes; Doffinger, Rainer; Prevosto, Claudia; Luan, Jian’an; Montano, Sergio; Lu, Jun; Castanet, Mireille; Clemons, Nick; Groeneveld, Matthijs; Castets, Perrine; Karbaschi, Mahsa; Aitken, Sri; Dixon, Adrian; Williams, Jane; Campi, Irene; Blount, Margaret; Burton, Hannah; Muntoni, Francesco; O’Donovan, Dominic; Dean, Andrew; Warren, Anne; Brierley, Charlotte; Baguley, David; Guicheney, Pascale; Fitzgerald, Rebecca; Coles, Alasdair; Gaston, Hill; Todd, Pamela; Holmgren, Arne; Khanna, Kum Kum; Cooke, Marcus; Semple, Robert; Halsall, David; Wareham, Nicholas; Schwabe, John; Grasso, Lucia; Beck-Peccoz, Paolo; Ogunko, Arthur; Dattani, Mehul; Gurnell, Mark; Chatterjee, Krishna

    2010-01-01

    Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence–binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation–induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes. PMID:21084748

  17. 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.

  18. Gene-specific regulation of hepatic selenoprotein expression by interleukin-6.

    Science.gov (United States)

    Martitz, J; Becker, N-P; Renko, K; Stoedter, M; Hybsier, S; Schomburg, L

    2015-11-01

    Sepsis is a severe inflammatory disease resulting in excessive production of pro-inflammatory cytokines including interleukin-6 (IL-6), causing oxidative stress, tissue damage and organ dysfunction. Health benefits have been observed upon selenium (Se) supplementation in severe sepsis. Selenium is incorporated into selenoproteins implicated in anti-oxidative defence, thyroid hormone metabolism and immunoregulation. Selenium metabolism is controlled by hepatocytes synthesizing and secreting the Se transporter selenoprotein P (SePP). The circulating SePP declines in sepsis causing low serum Se levels. Dysregulation of the hepatic selenoenzyme deiodinase type 1 (DIO1) potentially contributes to the low T3 (thyroid hormone) syndrome observed in severe diseases. We hypothesized that IL-6 affects hepatic selenoprotein biosynthesis directly. Testing human hepatocytes in culture, IL-6 reduced the concentrations of SePP mRNA and secreted SePP in a dose-dependent manner. In parallel, expression of DIO1 declined at the mRNA, protein and enzyme activity level. The effects of IL-6 on glutathione peroxidase (GPX) expression were isozyme-specific; GPX1 remained unaffected, while transcript concentrations of GPX2 increased and those of GPX4 decreased. This pattern of IL-6-dependent effects was mirrored in reporter gene experiments with SePP, DIO1, GPX1, and GPX2 promoter constructs pointing to direct transcriptional effects of IL-6. The redirection of hepatic selenoprotein biosynthesis by IL-6 may represent a central regulatory circuit responsible for the decline of serum Se and low T3 concentrations in sepsis. Accordingly, therapeutic IL-6 targeting may be effective for improving the Se and thyroid hormone status, adjuvant Se supplementation success and survival in sepsis. PMID:26399395

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

    OpenAIRE

    Jinyuan Mao; Weiping Teng

    2013-01-01

    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 a...

  20. Selenoprotein P status correlates to cancer-specific mortality in renal cancer patients.

    Directory of Open Access Journals (Sweden)

    Hellmuth A Meyer

    Full Text Available Selenium (Se is an essential trace element for selenoprotein biosynthesis. Selenoproteins have been implicated in cancer risk and tumor development. Selenoprotein P (SePP serves as the major Se transport protein in blood and as reliable biomarker of Se status in marginally supplied individuals. Among the different malignancies, renal cancer is characterized by a high mortality rate. In this study, we aimed to analyze the Se status in renal cell cancer (RCC patients and whether it correlates to cancer-specific mortality. To this end, serum samples of RCC patients (n = 41 and controls (n = 21 were retrospectively analyzed. Serum Se and SePP concentrations were measured by X-ray fluorescence and an immunoassay, respectively. Clinical and survival data were compared to serum Se and SePP concentrations as markers of Se status by receiver operating characteristic (ROC curve and Kaplan-Meier and Cox regression analyses. In our patients, higher tumor grade and tumor stage at diagnosis correlated to lower SePP and Se concentrations. Kaplan-Meier analyses indicated that low Se status at diagnosis (SePP<2.4 mg/l, bottom tertile of patient group was associated with a poor 5-year survival rate of 20% only. We conclude that SePP and Se concentrations are of prognostic value in RCC and may serve as additional diagnostic biomarkers identifying a Se deficit in kidney cancer patients potentially affecting therapy regimen. As poor Se status was indicative of high mortality odds, we speculate that an adjuvant Se supplementation of Se-deficient RCC patients might be beneficial in order to stabilize their selenoprotein expression hopefully prolonging their survival. However, this assumption needs to be rigorously tested in prospective clinical trials.

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

    OpenAIRE

    Hae Yoon Choi; Soon Young Hwang; Chang Hee Lee; Ho Cheol Hong; Sae Jeong Yang; Hye Jin Yoo; Ji A Seo; Sin Gon Kim; Nan Hee Kim; Sei Hyun Baik; Dong Seop Choi; Kyung Mook Choi

    2013-01-01

    Background Selenoprotein 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). Methods We 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 f...

  2. Selenoprotein P status correlates to cancer-specific mortality in renal cancer patients.

    Science.gov (United States)

    Meyer, Hellmuth A; Endermann, Tobias; Stephan, Carsten; Stoedter, Mette; Behrends, Thomas; Wolff, Ingmar; Jung, Klaus; Schomburg, Lutz

    2012-01-01

    Selenium (Se) is an essential trace element for selenoprotein biosynthesis. Selenoproteins have been implicated in cancer risk and tumor development. Selenoprotein P (SePP) serves as the major Se transport protein in blood and as reliable biomarker of Se status in marginally supplied individuals. Among the different malignancies, renal cancer is characterized by a high mortality rate. In this study, we aimed to analyze the Se status in renal cell cancer (RCC) patients and whether it correlates to cancer-specific mortality. To this end, serum samples of RCC patients (n = 41) and controls (n = 21) were retrospectively analyzed. Serum Se and SePP concentrations were measured by X-ray fluorescence and an immunoassay, respectively. Clinical and survival data were compared to serum Se and SePP concentrations as markers of Se status by receiver operating characteristic (ROC) curve and Kaplan-Meier and Cox regression analyses. In our patients, higher tumor grade and tumor stage at diagnosis correlated to lower SePP and Se concentrations. Kaplan-Meier analyses indicated that low Se status at diagnosis (SePP<2.4 mg/l, bottom tertile of patient group) was associated with a poor 5-year survival rate of 20% only. We conclude that SePP and Se concentrations are of prognostic value in RCC and may serve as additional diagnostic biomarkers identifying a Se deficit in kidney cancer patients potentially affecting therapy regimen. As poor Se status was indicative of high mortality odds, we speculate that an adjuvant Se supplementation of Se-deficient RCC patients might be beneficial in order to stabilize their selenoprotein expression hopefully prolonging their survival. However, this assumption needs to be rigorously tested in prospective clinical trials. PMID:23056383

  3. 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.

  4. 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. PMID:24666596

  5. Genetic Variation in Selenoprotein Genes, Lifestyle, and Risk of Colon and Rectal Cancer

    OpenAIRE

    Martha L Slattery; Lundgreen, Abbie; Welbourn, Bill; Corcoran, Christopher; Wolff, Roger K.

    2012-01-01

    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 compari...

  6. Selenoprotein S/SEPS1 Modifies Endoplasmic Reticulum Stress in Z Variant α1-Antitrypsin Deficiency*

    OpenAIRE

    Kelly, Emer; Catherine M. Greene; Carroll, Tomás P; Noel G. McElvaney; O'Neill, Shane J

    2009-01-01

    Z α1-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...

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

    OpenAIRE

    Díaz-Rubio Manuel; de la Calle Hermenegildo; Mendoza Juan; Lamas José; Márquez Ana; Varadé Jezabel; Santiago Jose; Martínez Alfonso; de la Concha Emilio G; Fernández-Gutiérrez Benjamín; Urcelay Elena

    2008-01-01

    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 susc...

  8. Progression of neurodegeneration and morphologic changes in the brains of juvenile mice with selenoprotein P deleted

    OpenAIRE

    Samuel W Caito; Milatovic, Dejan; Hill, Kristina E.; Aschner, Michael; Raymond F Burk; Valentine, William M.

    2011-01-01

    Selenoprotein P (Sepp1) is an important protein involved in selenium (Se) transport and homeostasis. Severe neurologic dysfunction develops in Sepp1 null mice (Sepp1−/−) fed a selenium-deficient diet. Sepp1−/− mice fed a selenium-deficient diet have extensive degeneration of the brainstem and thalamus, and even when supplemented with selenium exhibit subtle learning deficits and altered basal synaptic transmission and short-term plasticity in the CA1 region of the hippocampus. The goal of thi...

  9. 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 as...

  10. Direct Interaction of Selenoprotein R with Clusterin and Its Possible Role in Alzheimer’s Disease

    OpenAIRE

    Chen, Ping; Wang, Chao; Ma, Xiaojie; Zhang, Yizhe; Liu, Qing; Qiu, Shi; Liu, Qiong; Tian, Jing; Ni, Jiazuan

    2013-01-01

    Selenoprotein R (SelR) plays an important role in maintaining intracellular redox balance by reducing the R-form of methionine sulfoxide to methionine. As SelR is highly expressed in brain and closely related to Alzheimer′s disease (AD), its biological functions in human brain become a research focus. In this paper, the selenocysteine-coding TGA of SelR gene was mutated to cysteine-coding TGC and used to screen the human fetal brain cDNA library with a yeast two-hybrid system. Our results dem...

  11. Impaired Homocysteine Transmethylation and Protein-Methyltransferase Activity Reduce Expression of Selenoprotein P: Implications for Obesity and Metabolic Syndrome

    Science.gov (United States)

    Obesity causes Metabolic Syndrome and Type-II Diabetes, disrupting hepatic function, methionine (Met)/homocysteine (Hcy) transmethylation and methyltransferase (PRMT) activities. Selenoprotein P (SEPP1), exported from the liver, is the predominate form of plasma selenium (Se) and the physiological S...

  12. 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 spe...

  13. 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...

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

    Directory of Open Access Journals (Sweden)

    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. 

  15. Regulation of Selenocysteine Incorporation into the Selenium Transport Protein, Selenoprotein P*

    Science.gov (United States)

    Shetty, Sumangala P.; Shah, Ravi; Copeland, Paul R.

    2014-01-01

    Selenoproteins are unique as they contain selenium in their active site in the form of the 21st amino acid selenocysteine (Sec), which is encoded by an in-frame UGA stop codon. Sec incorporation requires both cis- and trans-acting factors, which are known to be sufficient for Sec incorporation in vitro, albeit with low efficiency. However, the abundance of the naturally occurring selenoprotein that contains 10 Sec residues (SEPP1) suggests that processive and efficient Sec incorporation occurs in vivo. Here, we set out to study native SEPP1 synthesis in vitro to identify factors that regulate processivity and efficiency. Deletion analysis of the long and conserved 3′-UTR has revealed that the incorporation of multiple Sec residues is inherently processive requiring only the SECIS elements but surprisingly responsive to the selenium concentration. We provide evidence that processive Sec incorporation is linked to selenium utilization and that reconstitution of known Sec incorporation factors in a wheat germ lysate does not permit multiple Sec incorporation events, thus suggesting a role for yet unidentified mammalian-specific processes or factors. The relationship between our findings and the channeling theory of translational efficiency is discussed. PMID:25063811

  16. Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage

    Science.gov (United States)

    Barrett, Caitlyn W.; Reddy, Vishruth K.; Short, Sarah P.; Motley, Amy K.; Lintel, Mary K.; Bradley, Amber M.; Freeman, Tanner; Vallance, Jefferson; Ning, Wei; Parang, Bobak; Poindexter, Shenika V.; Fingleton, Barbara; Chen, Xi; Washington, Mary K.; Wilson, Keith T.; Shroyer, Noah F.; Hill, Kristina E.; Burk, Raymond F.; Williams, Christopher S.

    2015-01-01

    Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions. PMID:26053663

  17. 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...... reductase, and we speculate that the plasticity of the intrinsically disordered C-terminal region allows the protein to access many different and structurally diverse substrates....

  18. Selenoprotein W was Correlated with the Protective Effect of Selenium on Chicken Myocardial Cells from Oxidative Damage.

    Science.gov (United States)

    Liu, Wei; Yao, Haidong; Zhao, Wenchao; Shi, Yuguang; Zhang, Ziwei; Xu, Shiwen

    2016-06-01

    Selenium (Se) mainly performs its function through Se-containing proteins. Selenoprotein W (SelW), one member of the selenoprotein family, plays important roles in the normal function of the heart. To investigate the possible relationship between Se and SelW for the regulation of oxidative damage in chicken embryo myocardial cells, we treated myocardial cells with Se and H2O2. Then, the levels of lactate dehydrogenase (LDH) and 3,4-methylenedioxyamphetamine in the culture media, levels of SelW, inflammatory genes NF-κB, tumor necrosis factor (TNF)-α, p53, and the cell cycle were analyzed. Furthermore, the correlation between SelW and the levels of these factors was determined. The results indicated that Se treatment increased the expression of SelW (P chicken myocardial cells. PMID:26463750

  19. 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

  20. Glutathione enzyme and selenoprotein polymorphisms associate with mercury biomarker levels in Michigan dental professionals

    International Nuclear Information System (INIS)

    Mercury is a potent toxicant of concern to both the general public and occupationally exposed workers (e.g., dentists). Recent studies suggest that several genes mediating the toxicokinetics of mercury are polymorphic in humans and may influence inter-individual variability in mercury accumulation. This work hypothesizes that polymorphisms in key glutathione synthesizing enzyme, glutathione s-transferase, and selenoprotein genes underlie inter-individual differences in mercury body burden as assessed by analytical mercury measurement in urine and hair, biomarkers of elemental mercury and methylmercury, respectively. Urine and hair samples were collected from a population of dental professionals (n = 515), and total mercury content was measured. Average urine (1.06 ± 1.24 ug/L) and hair mercury levels (0.49 ± 0.63 ug/g) were similar to national U.S. population averages. Taqman assays were used to genotype DNA from buccal swab samples at 15 polymorphic sites in genes implicated in mercury metabolism. Linear regression modeling assessed the ability of polymorphisms to modify the relationship between mercury biomarker levels and exposure sources (e.g., amalgams, fish consumption). Five polymorphisms were significantly associated with urine mercury levels (GSTT1 deletion), hair mercury levels (GSTP1-105, GSTP1-114, GSS 5′), or both (SEPP1 3′UTR). Overall, this study suggests that polymorphisms in selenoproteins and glutathione-related genes may influence elimination of mercury in the urine and hair or mercury retention following exposures to elemental mercury (via dental amalgams) and methylmercury (via fish consumption). -- Highlights: ► We explore the influence of 15 polymorphisms on urine and hair Hg levels. ► Urine and hair Hg levels in dental professionals were similar to the US population. ► GSTT1 and SEPP1 polymorphisms associated with urine Hg levels. ► Accumulation of Hg in hair following exposure from fish was modified by genotype. ► GSTP1, GSS

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

    Science.gov (United States)

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

    2015-11-01

    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. PMID:26431378

  2. Evaluation of Selenite Effects on Selenoproteins and Cytokinome in Human Hepatoma Cell Lines

    Directory of Open Access Journals (Sweden)

    Susan Costantini

    2013-02-01

    Full Text Available The need to explore new alternative therapeutic strategies and chemoprevention methods for hepatocellular carcinoma is growing significantly. Selenium is a trace element that plays a critical role in physiological processes, and is used in cancer chemoprevention. 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 to evaluate its action on inflammation determinants such as cytokines. Our results show that: (i the increase observed for the GPX1 and SELK expression is correlated with an increase in the sodium selenite concentration, also evidencing an inverse association between the levels of these two proteins and SELENBP1; (ii the selenium concentrations evaluated in protein extracts increase in proportional way with the selenite concentrations used in the treatment, suggesting that other selenoproteins can also be modulated and should be evaluated in further studies, and (iii some cytokines, VEGF and three pro-inflammatory cytokines, i.e., IL-6, IL-8, and IL-17, decreased with an increasing selenite concentration. Finally, interactomic studies show that GPX1 and SELK, and the four pro-inflammatory cytokines are functionally correlated evidencing a putative anti-inflammatory role for the selenite.

  3. Association of selenoprotein S gene polymorphism with ischemic stroke in a Chinese case-control study.

    Science.gov (United States)

    Li, Xiao-Xia; Guan, Hong-Jun; Liu, Jian-Ping; Guo, Yu-Peng; Yang, Yong; Niu, Ying-Ying; Yao, Li-Yan; Yang, Yin-Dong; Yue, Hong-Yu; Meng, Li-Li; Cui, Xin-Yu; Yang, Xiao-Wei; Gao, Jin-Xiao

    2015-03-01

    Previous studies showed that selenoprotein S (SELS) was associated with a range of inflammatory markers, and its gene expression was influenced by a polymorphism in the promoter region. The genetic basis of the ischemic stroke has now been largely determined, so the aim of the study was to examine the role of SELS genetic variants in the ischemic stroke risk in a Chinese population. We conducted a case-control study with 239 ischemic stroke patients and 240 controls. Two single-nucleotide polymorphisms (SNPs) in SELS genes were analyzed for association with the risk of ischemic stroke in the Chinese Han population. No evidence of ischemic stroke association was observed with the SNP rs34713741. Interestingly, the strongest evidence showed that SELS SNP rs4965814 was associated with ischemic stroke (P hazard ratio: 2.43(1.03-5.75)]; a similar trend was also found in men carrying the TC genotype of rs4965814 [hazard ratio: 1.81(1.06-3.08)]. SNP rs4965814 of SELS may affect the susceptibility to ischemic stroke. Understanding the inflammatory mechanisms of ischemic stroke may give new therapeutic targets to pharmacologists. PMID:25390504

  4. Characterization of Selenoprotein M and Its Response to Selenium Deficiency in Chicken Brain.

    Science.gov (United States)

    Huang, Jia-Qiang; Ren, Fa-Zheng; Jiang, Yun-Yun; Lei, XinGen

    2016-04-01

    Selenoprotein M (SelM) may function as thiol disulfide oxidoreductase that participates in the formation of disulfide bonds and can be implicated in calcium responses. SelM may have a functional role in catalyzing free radicals and has been associated with Alzheimer's disease (AD). However, studies of SelM in chicken remain very limited. In this study, two groups of day-old broiler chicks (n = 40/group) were fed a corn-soy basal diet (BD, 13 μg Se/kg) and BD supplemented with Se (as sodium selenite) at 0.3 mg/kg. The brain was collected at 14, 21, 28, and 42 days of age. We performed a sequence analysis and predicted the structure and function of SelM. We also investigated the effects of Se deficiency on the expression of Selt, Selw, and Selm and the Se status in the chicken brain. The results show that Se deficiency induced the lower (P chicken, which might shed light on the role of SelM in human neurodegenerative disease. More studies are needed to confirm our conclusion. PMID:26315306

  5. Identification and comparisons of selenoproteins in rat brain and mouse neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Zinn, K.; Chaudhuri, T.; Trokey, D.; Sunde, R.; O' Dell, B. (Univ. of Missouri, Columbia (United States))

    1991-03-11

    Male weanling rats, fed a Se-deficient torula-yeast diet or Se-adequate diet for 5 weeks, were injected with 400 {mu}Ci of {sup 75}Se as selenite, and sacrificed 2 and 4 wk after injection. Selenoproteins identified by SDS-PAGE included 6 major {sup 75}Se-peaks in cortex and cerebellum. While Se deficiency increased {sup 75}Se labeling of brain proteins, the percentages in each of the 6 peaks were unaffected by Se status. The total Se content of deficient cortex was only 5-10% less than adequate cortex, while deficient liver Se was 25-fold lower than adequate liver. The same 6 {sup 75}Se-peaks were identified in liver, with the 23-kDa peak greatly increased in Se adequate liver. When the 23-kDa peak was excluded, the relative distribution of {sup 75}Se in the remaining peaks was similar for liver, cortex, and cerebellum. Mouse neuroblastoma cells grown with {sup 75}Se-selenite showed labeling of 6 proteins of similar molecular weight as rat cortex, but {sup 75}Se distribution was different. Overall, the liver 23-kDa protein appeared to be the only {sup 75}Se-peak greatly changed as a result of Se status.

  6. Selenium and its relationship with selenoprotein P and glutathione peroxidase in children and adolescents with Hashimoto's thyroiditis and hypothyroidism.

    Science.gov (United States)

    Nourbakhsh, Mitra; Ahmadpour, Fatemeh; Chahardoli, Behnam; Malekpour-Dehkordi, Zahra; Nourbakhsh, Mona; Hosseini-Fard, Seyed Reza; Doustimotlagh, Amirhossein; Golestani, Abolfazl; Razzaghy-Azar, Maryam

    2016-03-01

    The essential trace element selenium (Se) is required for thyroid hormone synthesis and metabolism. Selenoproteins contain selenocysteine and are responsible for biological functions of selenium. Glutathione peroxidase (GPx) is one of the major selenoproteins which protects the thyroid cells from oxidative damage. Selenoprotein P (SePP) is considered as the plasma selenium transporter to tissues. The aim of this study was to evaluate serum Se and SePP levels, and GPx activity in erythrocytes of children and adolescents with treated Hashimoto's thyroiditis, hypothyroidism, and normal subjects. Blood samples were collected from 32 patients with Hashimoto's thyroiditis, 20 with hypothyroidism, and 25 matched normal subjects. All the patients were under treatment with levothyroxine and at the time of analysis all of the thyroid function tests were normal. GPx enzyme activity was measured by spectrophotometry at 340 nm. Serum selenium levels were measured by high-resolution continuum source graphite furnace atomic absorption. SePP, TPOAb (anti-thyroid peroxidase antibody), and TgAb (anti-thyroglobulin antibody) were determined by ELISA kits. T4, T3, T3 uptake and TSH were also measured. Neither GPx activity nor SePP levels were significantly different in patients with Hashimoto's thyroiditis or hypothyroidism compared to normal subjects. Although GPx and SePP were both lower in patients with hypothyroidism compared to those with Hashimoto's thyroiditis and normal subjects but the difference was not significant. Serum Se levels also did not differ significantly in patients and normal subjects. We did not find any correlation between GPx or SePP with TPOAb or TgAb but SePP was significantly correlated with Se. Results show that in patients with Hashimoto's thyroiditis or hypothyroidism who have been under treatment with levothyroxine and have normal thyroid function tests, the GPx, SePP and Se levels are not significantly different. PMID:26854239

  7. 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

    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......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...

  8. 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

    measured by inductively coupled plasma mass spectrometry (ICP-MS) monitoring the Se-82 isotope. Linear response was observed in the concentration range 0.3-70.8 mu g/l selenium as selenoprotein P with a correlation coefficient of 0.9994. The precision expressed as relative standard deviation was better...... than 2% in this range. The estimated limit of detection was 2 mu g/l and the experimentally verified quantification limit was 5 mu g/l, giving a relative standard deviation less than 2%. (C) 2000 Elsevier Science B.V. All rights reserved...

  9. Selenoprotein P in seminal fluid is a novel biomarker of sperm quality.

    Science.gov (United States)

    Michaelis, Marten; Gralla, Oliver; Behrends, Thomas; Scharpf, Marcus; Endermann, Tobias; Rijntjes, Eddy; Pietschmann, Nicole; Hollenbach, Birgit; Schomburg, Lutz

    2014-01-17

    Hepatically-derived selenoprotein P (SePP) transports selenium (Se) via blood to other tissues including the testes. Male Sepp-knockout mice are infertile. SePP-mediated Se transport to Sertoli cells is needed for supporting biosynthesis of the selenoenzyme glutathione peroxidase-4 (GPX4) in spermatozoa. GPX4 becomes a structural component of sperm midpiece during sperm maturation, and its expression correlates to semen quality. We tested whether SePP is also present in seminal plasma, potentially correlating to fertility parameters. Semen quality was assessed by sperm density, morphology and motility. SePP was measured by an immunoluminometric assay, and trace elements were determined by X-ray fluorescence spectroscopy. SePP levels were considerably lower in seminal plasma as compared to serum (0.4±0.1 mg/l vs. 3.5±1.0 mg/l); Se concentrations showed a similar but less pronounced difference (48.9±20.7 μg/l vs. 106.7±17.3 μg/l). Se and Zn correlated positively in seminal fluid but not in serum. Seminal plasma SePP concentrations were independent of serum SePP concentrations, but correlated positively to sperm density and fraction of vital sperm. SePP concentrations in seminal plasma of vasectomized men were similar to controls indicating that accessory sex glands are a testes-independent source of SePP. This notion was corroborated by histochemical analyses localizing SePP in epithelial cells of seminal vesicles. We conclude that SePP is not only involved in Se transport to testes supporting GPX4 biosynthesis but it also becomes secreted into seminal plasma, likely important to protect sperm during storage, genital tract passage and final journey. PMID:24361887

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Direct Interaction of Selenoprotein R with Clusterin and Its Possible Role in Alzheimer's Disease.

    Science.gov (United States)

    Chen, Ping; Wang, Chao; Ma, Xiaojie; Zhang, Yizhe; Liu, Qing; Qiu, Shi; Liu, Qiong; Tian, Jing; Ni, Jiazuan

    2013-01-01

    Selenoprotein R (SelR) plays an important role in maintaining intracellular redox balance by reducing the R-form of methionine sulfoxide to methionine. As SelR is highly expressed in brain and closely related to Alzheimer's disease (AD), its biological functions in human brain become a research focus. In this paper, the selenocysteine-coding TGA of SelR gene was mutated to cysteine-coding TGC and used to screen the human fetal brain cDNA library with a yeast two-hybrid system. Our results demonstrated that SelR interacts with clusterin (Clu), a chaperone protein. This protein interaction was further verified by fluorescence resonance energy transfer (FRET), coimmunoprecipitation (co-IP), and pull-down assays. The interacting domain of Clu was determined by co-IP to be a dynamic, molten globule structure spanning amino acids 315 to 381 with an amphipathic-helix. The interacting domain of SelR was investigated by gene manipulation, ligand replacement, protein over-expression, and enzyme activity measurement to be a tetrahedral complex consisting of a zinc ion binding with four Cys residues. Study on the mutual effect of SelR and Clu showed synergic property between the two proteins. Cell transfection with SelR gene increased the expression of Clu, while cell transfection with Clu promoted the enzyme activity of SelR. Co-overexpression of SelR and Clu in N2aSW cells, an AD model cell line, significantly decreased the level of intracellular reactive oxygen species. Furthermore, FRET and co-IP assays demonstrated that Clu interacted with β-amyloid peptide, a pathological protein of AD, which suggested a potential effect of SelR and Aβ with the aid of Clu. The interaction between SelR and Clu provides a novel avenue for further study on the mechanism of SelR in AD prevention. PMID:23805218

  12. Direct Interaction of Selenoprotein R with Clusterin and Its Possible Role in Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Ping Chen

    Full Text Available Selenoprotein R (SelR plays an important role in maintaining intracellular redox balance by reducing the R-form of methionine sulfoxide to methionine. As SelR is highly expressed in brain and closely related to Alzheimer's disease (AD, its biological functions in human brain become a research focus. In this paper, the selenocysteine-coding TGA of SelR gene was mutated to cysteine-coding TGC and used to screen the human fetal brain cDNA library with a yeast two-hybrid system. Our results demonstrated that SelR interacts with clusterin (Clu, a chaperone protein. This protein interaction was further verified by fluorescence resonance energy transfer (FRET, coimmunoprecipitation (co-IP, and pull-down assays. The interacting domain of Clu was determined by co-IP to be a dynamic, molten globule structure spanning amino acids 315 to 381 with an amphipathic-helix. The interacting domain of SelR was investigated by gene manipulation, ligand replacement, protein over-expression, and enzyme activity measurement to be a tetrahedral complex consisting of a zinc ion binding with four Cys residues. Study on the mutual effect of SelR and Clu showed synergic property between the two proteins. Cell transfection with SelR gene increased the expression of Clu, while cell transfection with Clu promoted the enzyme activity of SelR. Co-overexpression of SelR and Clu in N2aSW cells, an AD model cell line, significantly decreased the level of intracellular reactive oxygen species. Furthermore, FRET and co-IP assays demonstrated that Clu interacted with β-amyloid peptide, a pathological protein of AD, which suggested a potential effect of SelR and Aβ with the aid of Clu. The interaction between SelR and Clu provides a novel avenue for further study on the mechanism of SelR in AD prevention.

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

    Science.gov (United States)

    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 ...

  14. S-Adenosylmethionine-dependent protein methylation Is required for expression of selenoprotein P and gluconeogenic enzymes in HepG2 human hepatocytes

    Science.gov (United States)

    Cellular methylation processes enable expression of gluconeogenic enzymes and metabolism of the nutrient selenium (Se). Se status may relate to type-II diabetes and plasma levels of selenoprotein P (SEPP1) are positively correlated with insulin resistance. Increased expression of gluconeogenic enzym...

  15. Selenoprotein Transcript Level and Enzyme Activity as Biomarkers for Selenium Status and Selenium Requirements of Chickens (Gallus gallus)

    Science.gov (United States)

    Li, Jin-Long; Sunde, Roger A.

    2016-01-01

    The NRC selenium (Se) requirement for broiler chicks is 0.15 μg Se/g diet, based primarily on weight gain and feed intake studies reported in 1986. To determine Se requirements in today’s rapidly growing broiler chick, day-old male chicks were fed Se-deficient basal diets supplemented with graded levels of Se (0, 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, 0.5, 0.75, and 1.0 μg Se/g) as Na2SeO3 (5/treatment). Diets contained 15X the vitamin E requirement, and there were no gross signs of Se-deficiency. At 29 d, Se-deficient chicks weighed 62% of Se-supplemented chicks; 0.025 μg Se/g reversed this effect, indicating a minimum Se requirement of 0.025 μg Se/g diet for growth for male broiler chicks. Enzyme activities in Se-deficient chicks for plasma GPX3, liver and gizzard GPX1, and liver and gizzard GPX4 decreased dramatically to 3, 2, 5, 10 and 5%, respectively, of Se-adequate levels, with minimum Se requirements of 0.10–0.13 μg Se/g, and with defined plateaus above these levels. Pancreas GPX1 and GPX4 activities, however, lacked defined plateaus, with breakpoints at 0.3 μg Se/g. qPCR measurement of all 24 chicken selenoprotein transcripts, plus SEPHS1, found that SEPP1 in liver, GPX3 in gizzard, and SEPP1, GPX3 and SELK in pancreas were expressed at levels comparable to housekeeping transcripts. Only 33%, 25% and 50% of selenoprotein transcripts were down-regulated significantly by Se deficiency in liver, gizzard and pancreas, respectively. No transcripts could be used as biomarkers for supernutritional Se status. For export selenoproteins SEPP1 and GPX3, tissue distribution, high expression and Se-regulation clearly indicate unique Se metabolism, which may underlie tissues targeted by Se deficiency. Based on enzyme activities in liver, gizzard, and plasma, the minimum Se requirement in today’s broiler chick is 0.15 μg Se/g diet; pancreas data indicate that the Se requirement should be raised to 0.2 μg Se/g diet to provide a margin of safety. PMID:27045754

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

    Science.gov (United States)

    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

  17. Selenoprotein Transcript Level and Enzyme Activity as Biomarkers for Selenium Status and Selenium Requirements of Chickens (Gallus gallus).

    Science.gov (United States)

    Li, Jin-Long; Sunde, Roger A

    2016-01-01

    The NRC selenium (Se) requirement for broiler chicks is 0.15 μg Se/g diet, based primarily on weight gain and feed intake studies reported in 1986. To determine Se requirements in today's rapidly growing broiler chick, day-old male chicks were fed Se-deficient basal diets supplemented with graded levels of Se (0, 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, 0.5, 0.75, and 1.0 μg Se/g) as Na2SeO3 (5/treatment). Diets contained 15X the vitamin E requirement, and there were no gross signs of Se-deficiency. At 29 d, Se-deficient chicks weighed 62% of Se-supplemented chicks; 0.025 μg Se/g reversed this effect, indicating a minimum Se requirement of 0.025 μg Se/g diet for growth for male broiler chicks. Enzyme activities in Se-deficient chicks for plasma GPX3, liver and gizzard GPX1, and liver and gizzard GPX4 decreased dramatically to 3, 2, 5, 10 and 5%, respectively, of Se-adequate levels, with minimum Se requirements of 0.10-0.13 μg Se/g, and with defined plateaus above these levels. Pancreas GPX1 and GPX4 activities, however, lacked defined plateaus, with breakpoints at 0.3 μg Se/g. qPCR measurement of all 24 chicken selenoprotein transcripts, plus SEPHS1, found that SEPP1 in liver, GPX3 in gizzard, and SEPP1, GPX3 and SELK in pancreas were expressed at levels comparable to housekeeping transcripts. Only 33%, 25% and 50% of selenoprotein transcripts were down-regulated significantly by Se deficiency in liver, gizzard and pancreas, respectively. No transcripts could be used as biomarkers for supernutritional Se status. For export selenoproteins SEPP1 and GPX3, tissue distribution, high expression and Se-regulation clearly indicate unique Se metabolism, which may underlie tissues targeted by Se deficiency. Based on enzyme activities in liver, gizzard, and plasma, the minimum Se requirement in today's broiler chick is 0.15 μg Se/g diet; pancreas data indicate that the Se requirement should be raised to 0.2 μg Se/g diet to provide a margin of safety. PMID:27045754

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

    OpenAIRE

    Nagasaka Mitsuo; Nakamura Masakatsu; Kamiya Yoshio; Fujita Hiroshi; Maruyama Naoko; Yoshioka Daisuke; Ohkubo Masaaki; Tahara Tomomitsu; Arisawa Tomiyasu; Shibata Tomoyuki; Iwata Masami; Takahama Kazuya; Watanabe Makoto; Hirata Ichiro

    2009-01-01

    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 ...

  19. Cellular Selenoprotein mRNA Tethering via Antisense Interactions with Ebola and HIV-1 mRNAs May Impact Host Selenium Biochemistry.

    Science.gov (United States)

    Taylor, Ethan Will; Ruzicka, Jan A; Premadasa, Lakmini; Zhao, Lijun

    2016-01-01

    Regulation of protein expression by non-coding RNAs typically involves effects on mRNA degradation and/or ribosomal translation. The possibility of virus-host mRNA-mRNA antisense tethering interactions (ATI) as a gain-of-function strategy, via the capture of functional RNA motifs, has not been hitherto considered. We present evidence that ATIs may be exploited by certain RNA viruses in order to tether the mRNAs of host selenoproteins, potentially exploiting the proximity of a captured host selenocysteine insertion sequence (SECIS) element to enable the expression of virally-encoded selenoprotein modules, via translation of in-frame UGA stop codons as selenocysteine. Computational analysis predicts thermodynamically stable ATIs between several widely expressed mammalian selenoprotein mRNAs (e.g., isoforms of thioredoxin reductase) and specific Ebola virus mRNAs, and HIV-1 mRNA, which we demonstrate via DNA gel shift assays. The probable functional significance of these ATIs is further supported by the observation that, in both viruses, they are located in close proximity to highly conserved in-frame UGA stop codons at the 3' end of open reading frames that encode essential viral proteins (the HIV-1 nef protein and the Ebola nucleoprotein). Significantly, in HIV/AIDS patients, an inverse correlation between serum selenium and mortality has been repeatedly documented, and clinical benefits of selenium in the context of multi-micronutrient supplementation have been demonstrated in several well-controlled clinical trials. Hence, in the light of our findings, the possibility of a similar role for selenium in Ebola pathogenesis and treatment merits serious investigation. PMID:26369818

  20. Cellular Selenoprotein mRNA Tethering via Antisense Interactions with Ebola and HIV-1 mRNAs May Impact Host Selenium Biochemistry

    Science.gov (United States)

    Taylor, Ethan Will; Ruzicka, Jan A.; Premadasa, Lakmini; Zhao, Lijun

    2016-01-01

    Regulation of protein expression by non-coding RNAs typically involves effects on mRNA degradation and/or ribosomal translation. The possibility of virus-host mRNA-mRNA antisense tethering interactions (ATI) as a gain-of-function strategy, via the capture of functional RNA motifs, has not been hitherto considered. We present evidence that ATIs may be exploited by certain RNA viruses in order to tether the mRNAs of host selenoproteins, potentially exploiting the proximity of a captured host selenocysteine insertion sequence (SECIS) element to enable the expression of virally-encoded selenoprotein modules, via translation of in-frame UGA stop codons as selenocysteine. Computational analysis predicts thermodynamically stable ATIs between several widely expressed mammalian selenoprotein mRNAs (e.g., isoforms of thioredoxin reductase) and specific Ebola virus mRNAs, and HIV-1 mRNA, which we demonstrate via DNA gel shift assays. The probable functional significance of these ATIs is further supported by the observation that, in both viruses, they are located in close proximity to highly conserved in-frame UGA stop codons at the 3′ end of open reading frames that encode essential viral proteins (the HIV-1 nef protein and the Ebola nucleoprotein). Significantly, in HIV/AIDS patients, an inverse correlation between serum selenium and mortality has been repeatedly documented, and clinical benefits of selenium in the context of multi-micronutrient supplementation have been demonstrated in several well-controlled clinical trials. Hence, in the light of our findings, the possibility of a similar role for selenium in Ebola pathogenesis and treatment merits serious investigation. PMID:26369818

  1. Sepp1UF forms are N-terminal selenoprotein P truncations that have peroxidase activity when coupled with thioredoxin reductase-1

    OpenAIRE

    Kurokawa, Suguru; Eriksson, Sofi; Rose, Kristie L.; Wu, Sen; Motley, Amy K.; Hill, Salisha; Winfrey, Virginia P.; McDonald, W. Hayes; Capecchi, Mario R.; Atkins, John F; Arnér, Elias S. J.; Hill, Kristina E.; Raymond F Burk

    2014-01-01

    Mouse selenoprotein P (Sepp1) consists of an N-terminal domain (residues 1-239) that contains 1 selenocysteine (U) as residue 40 in a proposed redox-active motif (-UYLC-) and a C-terminal domain (residues 240-361) that contains 9 selenocysteines. Sepp1 transports selenium from the liver to other tissues by receptor-mediated endocytosis. It also reduces oxidative stress in vivo by an unknown mechanism. A previously uncharacterized plasma form of Sepp1 is filtered in the glomerulus and taken up...

  2. 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...

  3. 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

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

    International Nuclear Information System (INIS)

    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

  5. Progress of the study on genetic polymorphisms of Selenoprotein P%硒蛋白P基因多态性的研究进展

    Institute of Scientific and Technical Information of China (English)

    孙文艳; 陈群; 熊咏民

    2009-01-01

    硒蛋白是人和动物必需微量元素硒的主要功能表现形式,硒蛋白P(Selenoprotein P,SEPP)是其中比较特殊的一种,近年来对硒蛋白P的研究越来越多,尤其是硒蛋白P基因多态性与疾病的关系也日益受到关注.鉴于硒蛋白P基因多态性对疾病易感性的意义,本文从硒蛋白P的分子生物学特点、生物功能以及基因多态性与疾病关系的研究进展进行综述,以期为缺硒性地方病的研究开拓新的思路.

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

    International Nuclear Information System (INIS)

    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 μm. 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 μm 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 (ΔT∼ 25 ± 5 K). This suggests that the cohesion forces between the thin particles composing these large aggregates were weak

  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. Molecular characterization and expression analyses of cDNAs encoding the thioredoxin-interacting protein and selenoprotein P genes and histological changes in Nile tilapia (Oreochromis niloticus) in response to silver nanoparticle exposure.

    Science.gov (United States)

    Thummabancha, Kubpaphas; Onparn, Nuttaphon; Srisapoome, Prapansak

    2016-02-15

    Herein, Nile tilapia thioredoxin-interacting protein (On-TXNIP) and selenoprotein P (On-SEPP) cDNAs were cloned and characterized. The full-length On-TXNIP cDNA contained 2 arrestin domains, 2 conserved cysteine residues that bind to thioredoxin to inhibit thioredoxin function, and 2 PPXY motifs, which negatively regulate the protein by stimulating binding to E3 ubiquitin ligase. The On-SEPP cDNA contained 17 selenocysteines (Sec) encoded by the TGA codon, which can be recognized as either a stop codon or a Sec codon. The On-SEPP cDNA also carried 2 typical SECIS elements located in the 3'UTR that are important for selenocysteine translation. Evolutionary analyses of both the On-TXNIP and On-SEPP genes revealed that these genes are closely related to the TXNIP and SEPP genes in zebrafish (Danio rerio), with amino acid similarities of 91.8% and 61.9%, respectively. A normal tissue distribution analysis indicated that the On-TXNIP and On-SEPP genes were ubiquitously expressed in all tissues examined, and the highest expression levels of these genes were observed in peripheral blood leukocytes (PBLs) and the trunk kidney, respectively. The expression levels of On-TXNIP and On-SEPP transcripts were acutely and chronically analyzed following the injection of fish with 1, 10 or 100mg/kg silver nanoparticles (Ag NPs). Significant up-regulation of On-TXNIP and On-SEPP transcripts was observed in the liver, spleen, and head kidney at the early phase of Ag NP exposure (hours 6 through 48). Down-regulation of On-SEPP transcripts was clearly observed in the liver at weeks 1 to 4. Histopathology analysis demonstrated that the fish livers exhibited a dramatic infiltration of Kupffer cells, elevated bi-nucleated cells, expanded sinusoidal blood congestion and severe necrosis in a dose-dependent manner. Based on these findings, coupling of the expression analysis of these two cellular stress response genes and histopathological observation of fish exposed to Ag NPs should be

  9. Research Progress in Selenoproteins and Their Modulatory Effects on Macrophage Functions%硒蛋白及其对巨噬细胞功能调节作用的研究进展

    Institute of Scientific and Technical Information of China (English)

    孙纳新; 王成华

    2012-01-01

    Selenium can exert its physiological tractions in the form of selenoproteins in immune system. Macrophages play a pivotal role in immune regulation and bacterial defense. Recently, it has been found by using mice fed on selenium-rich diets, gene knockout mice and monoclonal antibody technology that selenoproteins have significant impact on redox status, migration and inflammatory responses of macrophages. In this article, we review recent research advances in the effects of selenoproteins on redox level, walk characteristics and inflammation in macrophages at the molecular level. This review suggests that selenoproteins may have complicated molecular modulation mechanisms and prospect medicinal benefits.%硒蛋白作为体内硒的主要存在形式,在免疫反应等许多方面发挥重要的生理功能,而巨噬细胞则在免疫调节与抗微生物感染等方面具有关键作用。近年来,通过硒饲喂实验、基因敲除、单克隆抗体等多种实验手段,发现硒蛋白对巨噬细胞功能具有重要的调节作用。本文总结近年来硒蛋白在分子水平上,对巨噬细胞胞内的氧化还原水平、游走特征以及炎症反应影响,显示出硒蛋白在免疫反应中的复杂分子调节机制及未来的药用前景。

  10. 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.

  11. 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.

  12. 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.

  13. Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration

    Science.gov (United States)

    Burk, Raymond F.; Hill, Kristina E.; Motley, Amy K.; Winfrey, Virginia P.; Kurokawa, Suguru; Mitchell, Stuart L.; Zhang, Wanqi

    2014-01-01

    Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from ∼120 to ∼50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1−/− or apoER2−/− mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was ∼35 ng/g. In extreme selenium deficiency, however, brain selenium of ∼12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them.—Burk, R. F., Hill, K. E., Motley, A. K., Winfrey, V. P., Kurokawa, S., Mitchell, S. L., Zhang, W. Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration. PMID:24760755

  14. 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.

  15. 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

    International Nuclear Information System (INIS)

    RAST, maintained in organ culture, releases two distinct types of bone resorptive factors and one co-resorptive factor. The first is prostaglandin E2 (PGE2), 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 PGE2 or the IL-l-like factor. Bone resorptive activity was assessed by measuring the release of 45Ca 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 10-5 M. On the other hand, both (I) and (II) inhibited bone degradation 60 to 100% at 1 x 10-6 M and 8 x 10-6 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 IC50s of 5 x 10-6 M. This unique ability to inhibit collagenase release may contribute to their effectiveness is preventing bone loss in this test model

  16. PROTECTIVE EFFECT OF SOYBEAN SELENOPROTEIN ON MYOCARDIAL INJURIES IN DIABETIC RATS%大豆硒蛋白对糖尿病大鼠心肌损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    刘红; 阳辉; 艾民仙

    2012-01-01

    目的 探讨大豆硒蛋白对糖尿病大鼠心肌损伤的保护作用.方法 Wistar大鼠50只,,随机分为正常对照组(NC)、糖尿病对照组(DM)、低剂量Se治疗组(L-Se)、中剂量Se治疗组(M-Se)、高剂量Se治疗组(H-Se).后4组腹腔注射链脲佐菌素55 mg/kg制备DM模型.第7w起,NC、DM组于0.5% CMC-Na 10ml/(kg.d),L-Se、M-Se、H-Se组分别予大豆硒蛋白2,4,8g/(kg.d)灌胃.第12w末处死大鼠,检测血糖、血清及心肌组织中SOD、GSH-Px、NOS活性和MDA、NO含量以及心肌组织中Na+-K+-ATPase、Ca2+-ATPase活性.结果 与模型组比较,补充外源性大豆硒蛋白后,M-Se、H-Se组可明显降低糖尿病大鼠血糖及MDA含量(均P<0.001),显著增加血清GSH-Px、NOS活性(P<0.001),同时使心肌线粒GSH-Px活性、NO含量明显增加(均P<0.001),并且使心肌组织Na+-K+-ATPase、Ca2+-ATPase活性显著增加(P<0.01,P<0.001).结论 大豆硒蛋白对糖尿病大鼠心肌损伤具有保护作用.%Objective To investigate the effect of soybean selenoprotein on myocardial injuries in diabetic rats. Method Fifty Wistar rats were randomly divided into five groups: normal control group (NC), diabetic model group (DM), three Se treatment groups (L-Se, M-Se, H-Se). The rats were given ip streptozotocin (STZ) 55 mg/kg except NC group. After 6 w, 2, 4, 8 g/(kg · d) soybean selenoprotein containing 9.48, 18 96, 37.92 μg/(kg·d) Se respecfively were given ig in L-Se, M-Se, H-Se groups. Carboxymethylcellulose-sodium (CMC-Na) was similarly given in NC and DM groups. At the 12th weekend, the rats were killed, and the blood sugar, serum SOD, GSH-Px, NOS activites, MDA, NO contents, and myocardial Na+-K.+-ATPase, Ca2+- ATPase activities were determined. Results Compared to the model group, soybean Se-containing protein could obviously reduce the blood sugar and MDA content of diabetic rats (P <0.001), significantly increase GSH -Px, and NOS activities (P<0.001) in serum, as well as myocardial

  17. Accurate Quantification of Selenoprotein P (SEPP1) in Plasma Using Isotopically Enriched Seleno-peptides and Species-Specific Isotope Dilution with HPLC Coupled to ICP-MS/MS.

    Science.gov (United States)

    Deitrich, Christian L; Cuello-Nuñez, Susana; Kmiotek, Diana; Torma, Frank Attila; Del Castillo Busto, Maria Estela; Fisicaro, Paola; Goenaga-Infante, Heidi

    2016-06-21

    A novel strategy for the absolute quantification of selenium (Se) included in selenoprotein P (SEPP1), an important biomarker for human nutrition and disease, including diabetes and cancer, is presented here for the first time. It is based on the use of species-specific double isotope dilution mass spectrometry (SSIDA) in combination with HPLC-ICP-MS/MS for the determination of protein bound Se down to the peptide level in a complex plasma matrix with a total content of Se of 105.5 μg kg(-1). The method enabled the selective Se speciation analysis of human plasma samples without the need of extensive cleanup or preconcentration steps as required for traditional protein mass spectrometric approaches. To assess the method accuracy, two plasma reference materials, namely, BCR-637 and SRM1950, for which literature data and a reference value for SEPP1 have been reported, were analyzed using complementary hyphenated methods and the species-specific approach developed in this work. The Se mass fractions obtained via the isotopic ratios (78)Se/(76)Se and (82)Se/(76)Se for each of the Se-peptides, namely, ENLPSLCSUQGLR (ENL) and AEENITESCQUR (AEE) (where U is SeCys), were found to agree within 2.4%. A relative expanded combined uncertainty (k = 2) of 5.4% was achieved for a Se (as SEPP1) mass fraction of approximately 60 μg kg(-1). This work represents a systematic approach to the accurate quantitation of plasma SEPP1 at clinical levels using SSIDA quantification. Such methodology will be invaluable for the certification of reference materials and the provision of reference values to clinical measurements and clinical trials. PMID:27108743

  18. 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.

  19. 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.

  20. 鸡硒蛋白T的硒代半胱氨酸插入序列元件、蛋白结构与功能及组织表达差异%Analysis of selenocysteine insertion sequence element, structures and functions and expression profiles of selenoprotein T in chicken

    Institute of Scientific and Technical Information of China (English)

    葛延松; 曹嫦妤; 王丽丽; 李楠; 江秀清; 李金龙

    2014-01-01

    应用生物软件分析鸡和其他11种脊椎动物硒蛋白 T ( selenoprotein T ,SelT )的硒代半胱氨酸插入序列( selenocysteine insertion sequence , SECIS)元件、SelT核苷酸和氨基酸序列的同源性,并分析鸡SelT 的结构及功能;采用实时荧光定量PCR( fluorescent quantitative real-time PCR , fqRT-PCR)方法检测SelT基因在35日龄鸡体内30种组织中的表达谱.结果显示:脊椎动物 SelT的SECIS元件均属于Ⅱ型结构;鸡 SelT核苷酸序列与其他11种脊椎动物的同源性在48.0%~85.1%之间,而氨基酸序列与非洲爪蟾、斑马鱼的同源性低于90.0%,与其他9种动物的同源性在90.6%~94.9%之间;鸡 SelT 属于跨膜蛋白,存在信号肽,属于 RDx 家族,酶活性分类为EC 2.5.1.18,具有氧化还原功能,且存在Ca2+结合位点.SelT在鸡各组织中广泛表达,在睾丸中含量极其丰富,提示鸡SelT在雄性生殖系统中可能发挥功能.%Selenium ( Se) was an important , biologically necessary trace element , which played an important biological roles in avian growth , reproduction , immune function and disease resistance . The biological significance of Se was attributed to its occurrence in selenoproteins in the form of selenocysteine ( Sec) with a 21 amino acid genetic code . Se uses the stop codon UGA as the coding codon encoding Sec . Selenoproteins involved in many life processes such as antioxidant defense , cell signal transduction , metabolic pathway , development , immune function , and hormone regulates , and it was related to the occurrence and mechanism of many diseases . Selenoprotein T (SelT) was originally identified through silico studies ,cloned and expressed in a mammalian cell line ,confirmed as a selenoprotein . Previous studies have proved that SelT mainly occurred in Golgi apparatus and endoplasmic reticulum , with important biological function . SelT can act on the Ca2+ homeostasis , involved in neuroendocrine secretion . SelT has

  1. Inhibition in multiclass classification

    OpenAIRE

    Huerta, Ramón; Vembu, Shankar; Amigó, José M.; Nowotny, Thomas; Elkan, Charles

    2012-01-01

    The role of inhibition is investigated in a multiclass support vector machine formalism inspired by the brain structure of insects. The so-called mushroom bodies have a set of output neurons, or classification functions, that compete with each other to encode a particular input. Strongly active output neurons depress or inhibit the remaining outputs without knowing which is correct or incorrect. Accordingly, we propose to use a classification function that embodies unselective inhibition and ...

  2. 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, Caroline (Albany, CA)

    2001-10-09

    This invention provides compositions 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, these composition scan be used to palliate certain inflammatory and immunological conditions.

  3. Inhibition of selectin binding

    Energy Technology Data Exchange (ETDEWEB)

    Nagy, J.O.; Spevak, W.R.; Dasgupta, F.; Bertozzi, C.

    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.

  4. 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, Caroline (Albany, CA)

    1999-01-01

    This invention provides compositions 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, these composition scan be used to palliate certain inflammatory and immunological conditions.

  5. Inhibition of selectin binding

    Energy Technology Data Exchange (ETDEWEB)

    Nagy, J.O.; Spevak, W.R.; Dasgupta, F.; Bertozzi, C.

    1999-11-16

    This invention provides compositions 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, these composition scan be used to palliate certain inflammatory and immunological conditions.

  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. Methods of Telomerase Inhibition

    OpenAIRE

    Andrews, Lucy G.; Tollefsbol, Trygve O.

    2008-01-01

    Telomerase is central to cellular immortality and is a key component of most cancer cells although this enzyme is rarely expressed to significant levels in normal cells. Therefore, the inhibition of telomerase has garnered considerable attention as a possible anticancer approach. Many of the methods applied to telomerase inhibition focus on either of the two major components of the ribonucleoprotein holoenzyme, that is, the telomerase reverse transcriptase (TERT) catalytic subunit or the telo...

  8. 2型糖尿病患者硒蛋白P和胰岛素抵抗的相关性%Selenoprotein P in type 2 diabetes mellitus and its association with insulin resistance

    Institute of Scientific and Technical Information of China (English)

    潘洁敏; 于浩泳; 张磊; 韩峻峰; 包玉倩; 贾伟平

    2014-01-01

    Objective To explore the relationship between selenoprotein P ( SEPP ) and insulin resistance in subjects with normal glucose tolerance and type 2 diabetes mellitus .Methods A total of 156 subjects with newly onset diabetes and 64 subjects with normal glucose tolerance were enrolled .Fasting plasma glucose ( FPG ) , fasting insulin ( FIN ) , lipid profile and SEPP level were measured and height , weight and blood pressure were recorded.Insulin resistance index was calculated by homeostatic model assessment ( HOMA-IR).Results The SEPP level was significantly higher in obese and non-obese diabetic groups than control group ((4.43 ±1.95), (3.01 ±1.20) vs (2.34 ±2.30)mmol/L, both P<0.01).The SEPP level was significantly higher in obese subgroup of diabetic group than non -obese subgroup ( P<0.05).The SEPP level was positively correlated with FIN , FPG, body mass index (BMI), triglycerides (TG) and HOMA-IR (r=0.401, 0.202, 0.420, 0.239, 0.445, P<0.05) and negatively with ISI (r=-0.414, P <0.01 ).Multivariate regression analysis demonstrated that SEPP level was independently correlated with insulin resistance (β=0.293, P<0.01).And the independent factors for ISI were systolic pressure, HbA1c and SEPP level (β=-0.195, -0.185 and -0.246, P<0.05).Conclusion Serum SEPP level may be an independent risk factor for insulin resistance regardless of age , blood pressure or lipid profile.%目的:研究健康人和2型糖尿病患者中硒蛋白P ( SEPP )和胰岛素抵抗的相关性。方法入组门诊初发2型糖尿病患者156例和64名健康人作为对照,测定空腹血糖( FPG)、空腹胰岛素( FIN)、血脂谱、SEPP 水平,记录身高、体重和血压,采用稳态模型评估胰岛素抵抗指数(HOMA-IR)和计算胰岛素敏感性指数(ISI)。结果(1)肥胖和非肥胖糖尿病组的SEPP水平均显著高于对照组[(4.43±1.95)、(3.01±1.20)比(2.34±2.30)mmol/L,均P<0.01],肥胖糖尿病组的SEPP水平

  9. Quorum sensing inhibition

    DEFF Research Database (Denmark)

    Persson, T.; Givskov, Michael Christian; Nielsen, J.

    2005-01-01

    /receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural...

  10. 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 with...

  11. 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.

  12. Drug repurposing for gastrointestinal stromal tumor.

    Science.gov (United States)

    Pessetto, Ziyan Y; Weir, Scott J; Sethi, Geetika; Broward, Melinda A; Godwin, Andrew K

    2013-07-01

    Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25 to 30 million people in the United States alone. Given the costs associated with the discovery, development, and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, "drug repurposing" or "repositioning," has emerged as an alternative to the traditional drug development process. In this study, we screened 796 U.S. Food and Drug Administration (FDA)-approved drugs and found that two of these compounds, auranofin (Ridaura) and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs, including imatinib-resistant cells. One of the most notable drug hits, auranofin, an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis, was found to inhibit thioredoxin reductase activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anticancer activity associated with auranofin was independent of imatinib-resistant status, but was closely related to the endogenous and inducible levels of ROS. Coupled with the fact that auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for patients with GIST, particularly in those suffering from imatinib-resistant and recurrent forms of this disease. PMID:23657945

  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. PMID:26933816

  14. Checkpoint inhibition in meningiomas.

    Science.gov (United States)

    Bi, Wenya Linda; Wu, Winona W; Santagata, Sandro; Reardon, David A; Dunn, Ian F

    2016-06-01

    Meningiomas are increasingly appreciated to share similar features with other intra-axial central nervous system neoplasms as well as systemic cancers. Immune checkpoint inhibition has emerged as a promising therapy in a number of cancers, with durable responses of years in a subset of patients. Several lines of evidence support a role for immune-based therapeutic strategies in the management of meningiomas, especially high-grade subtypes. Meningiomas frequently originate juxtaposed to venous sinuses, where an anatomic conduit for lymphatic drainage resides. Multiple populations of immune cells have been observed in meningiomas. PD-1/PD-L1 mediated immunosuppression has been implicated in high-grade meningiomas, with association between PD-L1 expression with negative prognostic outcome. These data point to the promise of future combinatorial therapeutic strategies in meningioma. PMID:27197540

  15. Backward semantic inhibition in toddlers

    OpenAIRE

    Chow, J.; Aimola Davies, AM; Fuentes, LJ; Plunkett, KR

    2016-01-01

    Attention-switching is a crucial ability required in our everyday life, from toddlerhood to adulthood. In adults, shifting attention from one word (e.g., dog) to another (e.g., sea) results in backward semantic inhibition, i.e., the inhibition of the initial word (dog). This study examines whether attention-switching is accompanied by backward semantic inhibition in toddlers using the preferential looking paradigm. The findings demonstrate that a backward inhibitory mechanism operates during ...

  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. Forcing contact inhibition of locomotion

    OpenAIRE

    Roycroft, A.; Mayor, R.

    2015-01-01

    Contact inhibition of locomotion drives a variety of biological phenomenon, from cell dispersion to collective cell migration and cancer invasion. New imaging techniques have allowed contact inhibition of locomotion to be visualised in vivo for the first time, helping to elucidate some of the molecules and forces involved in this phenomenon.

  18. Balanced feedforward inhibition and dominant recurrent inhibition in olfactory cortex.

    Science.gov (United States)

    Large, Adam M; Vogler, Nathan W; Mielo, Samantha; Oswald, Anne-Marie M

    2016-02-23

    Throughout the brain, the recruitment of feedforward and recurrent inhibition shapes neural responses. However, disentangling the relative contributions of these often-overlapping cortical circuits is challenging. The piriform cortex provides an ideal system to address this issue because the interneurons responsible for feedforward and recurrent inhibition are anatomically segregated in layer (L) 1 and L2/3 respectively. Here we use a combination of optical and electrical activation of interneurons to profile the inhibitory input received by three classes of principal excitatory neuron in the anterior piriform cortex. In all classes, we find that L1 interneurons provide weaker inhibition than L2/3 interneurons. Nonetheless, feedforward inhibitory strength covaries with the amount of afferent excitation received by each class of principal neuron. In contrast, intracortical stimulation of L2/3 evokes strong inhibition that dominates recurrent excitation in all classes. Finally, we find that the relative contributions of feedforward and recurrent pathways differ between principal neuron classes. Specifically, L2 neurons receive more reliable afferent drive and less overall inhibition than L3 neurons. Alternatively, L3 neurons receive substantially more intracortical inhibition. These three features--balanced afferent drive, dominant recurrent inhibition, and differential recruitment by afferent vs. intracortical circuits, dependent on cell class--suggest mechanisms for olfactory processing that may extend to other sensory cortices. PMID:26858458

  19. 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 ...

  20. Homo Economicus Belief Inhibits Trust

    OpenAIRE

    Ziqiang Xin; Guofang Liu

    2013-01-01

    As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit t...

  1. Valpromide inhibits human epoxide hydrolase.

    OpenAIRE

    Pacifici, G. M.; Franchi, M; Bencini, C; Rane, A

    1986-01-01

    The effect of antipileptic drug valpromide (VPM) on the activity of epoxide hydrolase was studied in human adult and foetal liver, kidneys, lungs, intestine and in placenta. The activity of the epoxide hydrolase was measured with both styrene oxide and benzo(a)pyrene-4,5-oxide as substrates. VPM inhibited the epoxide hydrolase obtained from all organs studied. The degree of inhibition was independent of the substrate used. A lowering of the epoxide hydrolase activity by 50% was observed when ...

  2. Tunneling inhibition for subwavelength light

    CERN Document Server

    Huang, Changming; Ye, Fangwei; Kartashov, Yaroslav V; Chen, Xianfeng; Torner, Lluis

    2013-01-01

    We show that light tunneling inhibition may take place in suitable dynamically modulated waveguide arrays for light spots whose features are remarkably smaller than the wavelength of light. We found that tunneling between neighboring waveguides can be suppressed for specific frequencies of the out-of-phase refractive index modulation, affording undistorted propagation of the input subwavelength light spots over hundreds of Rayleigh lengths. Tunneling inhibition turns out to be effective only when the waveguide separation in the array is above a critical threshold. Inclusion of a weak focusing nonlinearity is shown to improve localization. We analyze the phenomenon in purely dielectric structures and also in arrays containing periodically spaced metallic layers.

  3. Homo economicus belief inhibits trust.

    Science.gov (United States)

    Xin, Ziqiang; Liu, Guofang

    2013-01-01

    As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust. PMID:24146907

  4. Homo economicus belief inhibits trust.

    Directory of Open Access Journals (Sweden)

    Ziqiang Xin

    Full Text Available As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  5. 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 In...

  6. Behavioral Inhibition: Type or Continuum?

    Science.gov (United States)

    Scholmerich, Axel; And Others

    This study investigated whether behavioral inhibition is best conceptualized as a continuous variable or as a distinct typology with two or more subcategories. The following data were gathered on 58 infants at 5, 7, 10, and 13 months of age; physiological functioning (cardiovascular activity and salivary cortisol); emotional expressivity in…

  7. Repurposing Auranofin as a Lead Candidate for Treatment of Lymphatic Filariasis and Onchocerciasis

    OpenAIRE

    Bulman, Christina A.; Bidlow, Chelsea M.; Sara Lustigman; Fidelis Cho-Ngwa; David Williams; Rascón, Alberto A; Nancy Tricoche; Moses Samje; Aaron Bell; Brian Suzuki; K C Lim; Nonglak Supakorndej; Prasit Supakorndej; Wolfe, Alan R.; Knudsen, Giselle M.

    2015-01-01

    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 infe...

  8. Osteogenic Inhibition in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Nasim Kalantari

    2013-01-01

    Full Text Available Objective: Multiple myeloma (MM is a plasma cell malignancy where plasma cells are increased in the bone marrow (BM and usually do not enter peripheral blood, but produce harmful factors creating problems in these patients (e.g. malignant plasma cells over activate osteoclasts and inhibit osteoblasts with factors like RANKL and DKK. These factors are a main cause of bone lesion in MM patients. Recently SOST gene which responsible to encodes the sclerostin protein was identify. This protein specifically inhibits Wnt signaling in osteoblasts (inhibition of osteoblast differentiation and proliferation and decrease bone formation and can also cause bone lesion in MM patients.Materials and Methods: In this experimental study, human myeloma cell lines (U266 b1 were purchased from Pasteur Institute of Iran. Samples consisted of BM aspirates from the iliac crest of MM patients. BM with more than 70% plasma cell were selected for our study (6 patients and one healthy donor. RNA extraction was done with Qiagen kit. was undertaken on mRNA of samples and cell lines. Also we purchased unrestricted somatic stem cells from Bonyakhte Company to evaluate the effect of soluble factors from myeloma cell lines on osteogenic differentiation medium.Results: Our results showed that SOST is expressed significantly in primary myeloma cells derived from MM patients and myeloma cell lines. In other words, patients with more bone problems, express SOST in their plasma cells at a higher level. In addition, myeloma cells inhibit osteoblast differentiation in progenitor cells from umbilical cord blood stem cell (UCSC in osteogenic inducing medium.Conclusion: There are many osteoblast maturation inhibitory factors such as DKK, Sfrp and Sclerostin that inhibit maturation of osteoblast in bone. Among osteoblast inhibitory agents (DKK, Sfrp, Sclerostin sclerostin has the highest specificity and therefore will have less side effect versus non-specific inhibitory agents. Our

  9. 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.

  10. Inhibition Performance in Children with Math Disabilities

    OpenAIRE

    Winegar, Kathryn Lileth

    2013-01-01

    This study examined the inhibition deficit hypothesis in children with math disabilities (MD). Children with and without MD were compared on two inhibition tasks that included the random generation of numbers and letters. The results addressed three hypotheses. Weak support was found for the first hypothesis which stated difficulties related to inhibition are significantly related to math performance. I found partial support for this hypothesis in that inhibition was related to math problem s...

  11. Intentional inhibition of actions in humans

    OpenAIRE

    Misirlisoy, E.

    2015-01-01

    A crucial component of human behavioural flexibility is the capacity to inhibit actions at the last moment before action execution. This behavioural inhibition is often not an immediate reaction to external stimuli, but rather an endogenous ‘free’ decision. Knowledge about such ‘intentional inhibition’ is currently limited, with most research focused on stimulus-driven inhibition. This thesis will examine intentional inhibition, using several different experimental approaches. The behavioural...

  12. MMP inhibition in prostate cancer.

    Science.gov (United States)

    Lokeshwar, B L

    1999-06-30

    Matrix metalloproteinases (MMPs) play a significant role during the development and metastasis of prostate cancer (CaP). CaP cells secrete high levels of MMPs and low levels of endogenous MMP inhibitors (TIMPs), thus creating an excess balance of MMPs. Established CaP cell lines that express high levels of MMPs frequently metastasize to the bone and the lungs. Drugs such as Taxol and alendronate that reduce cell motility and calcium metabolism reduce bony metastasis of xenografted CaP tumors. We tested several synthetic, nontoxic inhibitors of MMPs that can be administered orally, including doxycycline (DC) and chemically modified tetracyclines (CMTs) on CaP cells in vitro and on a rat CaP model in vivo. Among several anti-MMP agents tested, CMT-3 (6-deoxy, 6-demethyl,4-de-dimethylamino tetracycline) showed highest activity against CaP cell invasion and cell proliferation. Micromolar concentration of CMT-3 and DC inhibited both the secretion and activity of MMPs by CaP cells. When tested for in vivo efficacy in the Dunning rat CaP model by daily oral gavage, CMT-3 and DC both reduced the lung metastases (> 50%). CMT-3, but not DC, inhibited tumor incidence (55 +/- 9%) and also reduced the tumor growth rate (27 +/- 9.3%). More significantly, the drugs showed minimum systemic toxicity. Ongoing studies indicate that CMT-3 may inhibit the skeletal metastases of CaP cells and delay the onset of paraplegia due to lumbar metastases. These preclinical studies provide the basis for clinical trials of CMT-3 for the treatment of metastatic disease. PMID:10415736

  13. Behavioral inhibition and obsessive-compulsive disorder.

    Science.gov (United States)

    Coles, Meredith E; Schofield, Casey A; Pietrefesa, Ashley S

    2006-01-01

    Behavioral inhibition is frequently cited as a vulnerability factor for development of anxiety. However, few studies have examined the unique relationship between behavioral inhibition and obsessive-compulsive disorder (OCD). Therefore, the current study addressed the relationship between behavioral inhibition and OCD in a number of ways. In a large unselected student sample, frequency of current OC symptoms was significantly correlated with retrospective self-reports of total levels of childhood behavioral inhibition. In addition, frequency of current OC symptoms was also significantly correlated with both social and nonsocial components of behavioral inhibition. Further, there was evidence for a unique relationship between behavioral inhibition and OC symptoms beyond the relationship of behavioral inhibition and social anxiety. In addition, results showed that reports of childhood levels of behavioral inhibition significantly predicted levels of OCD symptoms in adulthood. Finally, preliminary evidence suggested that behavioral inhibition may be more strongly associated with some types of OC symptoms than others, and that overprotective parenting may moderate the impact of behavioral inhibition on OC symptoms. The current findings suggest the utility of additional research examining the role of behavioral inhibition in the etiology of OCD. PMID:16621440

  14. Magnetic Catalysis vs Magnetic Inhibition

    CERN Document Server

    Fukushima, Kenji

    2012-01-01

    We discuss the fate of chiral symmetry in an extremely strong magnetic field B. We investigate not only quark fluctuations but also neutral meson effects. The former would enhance the chiral-symmetry breaking at finite B according to the Magnetic Catalysis, while the latter would suppress the chiral condensate once B exceeds the scale of the hadron structure. Using a chiral model we demonstrate how neutral mesons are subject to the dimensional reduction and the low dimensionality favors the chiral-symmetric phase. We point out that this effect, the Magnetic Inhibition, can be a feasible explanation for recent lattice-QCD data indicating the decreasing behavior of the chiral-restoration temperature with increasing B.

  15. Regulating anxiety with extrasynaptic inhibition.

    Science.gov (United States)

    Botta, Paolo; Demmou, Lynda; Kasugai, Yu; Markovic, Milica; Xu, Chun; Fadok, Jonathan P; Lu, Tingjia; Poe, Michael M; Xu, Li; Cook, James M; Rudolph, Uwe; Sah, Pankaj; Ferraguti, Francesco; Lüthi, Andreas

    2015-10-01

    Aversive experiences can lead to complex behavioral adaptations including increased levels of anxiety and fear generalization. The neuronal mechanisms underlying such maladaptive behavioral changes, however, are poorly understood. Here, using a combination of behavioral, physiological and optogenetic approaches in mouse, we identify a specific subpopulation of central amygdala neurons expressing protein kinase C δ (PKCδ) as key elements of the neuronal circuitry controlling anxiety. Moreover, we show that aversive experiences induce anxiety and fear generalization by regulating the activity of PKCδ(+) neurons via extrasynaptic inhibition mediated by α5 subunit-containing GABAA receptors. Our findings reveal that the neuronal circuits that mediate fear and anxiety overlap at the level of defined subpopulations of central amygdala neurons and demonstrate that persistent changes in the excitability of a single cell type can orchestrate complex behavioral changes. PMID:26322928

  16. 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.

  17. Renin inhibition activity by chitooligosaccharides.

    Science.gov (United States)

    Park, Pyo-Jam; Ahn, Chang-Bum; Jeon, You-Jin; Je, Jae-Young

    2008-04-01

    Six kinds of chitooligosaccharides (COSs) with different molecular weight (MW) and degree of deacetylation (DD) were prepared using ultrafiltration membrane reactor, and their renin inhibition modes were evaluated. All the COSs showed the renin-inhibitory activities with dose-dependent manner, and 90-COSs had the potent renin-inhibitory activity than that of 50-COSs. Among them, 90-MMWCOS (1000-5000Da) exhibits the highest activity with IC(50) value of 0.51mg/mL and acts as competitive inhibitor with K(i) value of 0.28mg/mL by Lineweaver-Burk and Dixon plots. These results indicated that DD value and MW of COSs are important factors affecting renin-inhibitory activity. PMID:18313296

  18. Well having inhibited microbial growth

    Science.gov (United States)

    Lee, Brady D.; Dooley, Kirk J.

    2006-08-15

    The invention includes methods of inhibiting microbial growth in a well. A packing material containing a mixture of a first material and an antimicrobial agent is provided to at least partially fill a well bore. One or more access tubes are provided in an annular space around a casing within the well bore. The access tubes have a first terminal opening located at or above a ground surface and have a length that extends from the first terminal opening at least part of the depth of the well bore. The access tubes have a second terminal opening located within the well bore. An antimicrobial material is supplied into the well bore through the first terminal opening of the access tubes. The invention also includes well constructs.

  19. Inhibition of aflatoxin production by selected insecticides.

    OpenAIRE

    Draughon, F A; Ayres, J. C.

    1981-01-01

    The insecticide naled completed inhibition production of aflatoxins B1, B2, G1, and G2 by and growth of Aspergillus parasiticus at a 100-ppm (100 microgram/ml) concentration. The insecticides dichlorvos, Landrin, pyrethrum, Sevin, malathion, and Diazinon significantly (P = 0.05) inhibited production of aflatoxins at a 100-ppm concentration. However, at a concentration of 10 ppm, significant inhibition in production of aflatoxins was found only with naled, dichlorvos, Sevin, Landrin, and pyret...

  20. Enhanced latent inhibition in high schizotypy individuals

    OpenAIRE

    Granger, Kiri T.; Moran, Paula M.; Buckley, Matthew G.; Haselgrove, Mark

    2016-01-01

    Latent inhibition refers to a retardation in learning about a stimulus that has been rendered familiar by non-reinforced preexposure, relative to a non-preexposed stimulus. Latent inhibition has been shown to be inversely correlated with schizotypy, and abnormal in people with schizophrenia, but these findings are inconsistent. One potential contributing factor to this inconsistency is that many tasks that purport to measure latent inhibition are confounded by alternative effects that also re...

  1. Phosphate Inhibits Acetotrophic Methanogenesis on Rice Roots

    OpenAIRE

    Conrad, Ralf; Klose, Melanie; Claus, Peter

    2000-01-01

    The contribution of acetate- and H2/CO2-dependent methanogenesis to total CH4 production was determined in excised washed rice roots by radiolabeling, methyl fluoride inhibition, and stable carbon isotope fractionation. Addition of ≥20 mM phosphate inhibited methanogenesis, which then was exclusively from H2/CO2. Otherwise, acetate contributed about 50 to 60% of the total methanogenesis, demonstrating that phosphate specifically inhibited acetotrophic methanogens on rice roots.

  2. GPM Timeline Inhibits For IT Processing

    Science.gov (United States)

    Dion, Shirley K.

    2014-01-01

    The Safety Inhibit Timeline Tool was created as one approach to capturing and understanding inhibits and controls from IT through launch. Global Precipitation Measurement (GPM) Mission, which launched from Japan in March 2014, was a joint mission under a partnership between the National Aeronautics and Space Administration (NASA) and the Japan Aerospace Exploration Agency (JAXA). GPM was one of the first NASA Goddard in-house programs that extensively used software controls. Using this tool during the GPM buildup allowed a thorough review of inhibit and safety critical software design for hazardous subsystems such as the high gain antenna boom, solar array, and instrument deployments, transmitter turn-on, propulsion system release, and instrument radar turn-on. The GPM safety team developed a methodology to document software safety as part of the standard hazard report. As a result of this process, a new tool safety inhibit timeline was created for management of inhibits and their controls during spacecraft buildup and testing during IT at GSFC and at the launch range in Japan. The Safety Inhibit Timeline Tool was a pathfinder approach for reviewing software that controls the electrical inhibits. The Safety Inhibit Timeline Tool strengthens the Safety Analysts understanding of the removal of inhibits during the IT process with safety critical software. With this tool, the Safety Analyst can confirm proper safe configuration of a spacecraft during each IT test, track inhibit and software configuration changes, and assess software criticality. In addition to understanding inhibits and controls during IT, the tool allows the Safety Analyst to better communicate to engineers and management the changes in inhibit states with each phase of hardware and software testing and the impact of safety risks. Lessons learned from participating in the GPM campaign at NASA and JAXA will be discussed during this session.

  3. Inhibition in Autism: Children with Autism Have Difficulty Inhibiting Irrelevant Distractors but Not Prepotent Responses

    Science.gov (United States)

    Adams, Nena C.; Jarrold, Christopher

    2012-01-01

    Resistance to distractor inhibition tasks have previously revealed impairments in children with autism. However, on the classic Stroop task and other prepotent response tasks, children with autism show intact inhibition. These data may reflect a distinction between prepotent response and resistance to distractor inhibition. The current study…

  4. Formation of excitation-inhibition balance: inhibition listens and changes its tune

    OpenAIRE

    Tao, Huizhong W.; Li, Ya-tang; Zhang, Li I.

    2014-01-01

    Recently, Xue, Atallah, and Scanziani reported that excitation/inhibition ratios across cortical pyramidal neurons are equalized by activity-dependent modulations of parvalbumin-neuron mediated feedforward inhibition. Their results raise questions about the developmental formation of this excitation-inhibition balance and the potential activity-dependent synaptic plasticity rules that mediate this process.

  5. Cortisol involvement in mechanisms of behavioral inhibition

    NARCIS (Netherlands)

    Tops, Mattie; Boksem, Maarten A. S.

    2011-01-01

    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 n

  6. 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…

  7. Contour Detection Operators Based on Surround Inhibition

    NARCIS (Netherlands)

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

    2003-01-01

    We propose a biologically motivated computational step, called non-classical receptive field (non-CRF) inhibition, to improve contour detection in images of natural scenes. We augment a Gabor energy operator with non-CRF inhibition. The resulting contour operator responds strongly to isolated lines,

  8. Inhibition of Corynebacterium vaginale by metronidazole.

    Science.gov (United States)

    Smith, R F; Dunkelberg, W E

    1977-01-01

    Metronidazole [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole], previously thought to only inhibit obligately anaerobic bacteria, was found in vitro, to inhibit the growth of 15 facultatively anaerobic strains of Corynebacterium vaginale (Haemophilus vaginalis) using agar disk diffusion and broth dilution methods. PMID:867202

  9. Quorum Sensing Inhibition, Relevance to Periodontics

    OpenAIRE

    Yada, Sudheer; B Kamalesh; Sonwane, Siddharth; Guptha, Indra; Swetha, R K

    2015-01-01

    Quorum sensing helps bacteria to communicate with each other and in coordinating their behavior. Many diseases of human beings, plants, and animals are mediated by quorum sensing. Various approaches are being tried to inhibit this communication to control the diseases caused by bacteria. Periodontal pathogens also communicate through quorum sensing and new approaches to treat periodontal disease using quorum sensing inhibition need to explored.

  10. Inhibition of aflatoxin production by selected insecticides.

    Science.gov (United States)

    Draughon, F A; Ayres, J C

    1981-04-01

    The insecticide naled completed inhibition production of aflatoxins B1, B2, G1, and G2 by and growth of Aspergillus parasiticus at a 100-ppm (100 microgram/ml) concentration. The insecticides dichlorvos, Landrin, pyrethrum, Sevin, malathion, and Diazinon significantly (P = 0.05) inhibited production of aflatoxins at a 100-ppm concentration. However, at a concentration of 10 ppm, significant inhibition in production of aflatoxins was found only with naled, dichlorvos, Sevin, Landrin, and pyrethrum. Dichlorvos, Landrin, Sevin, and naled inhibited growth of A. parasiticus by 28.9 , 18.9, 15.7, and 100%, respectively, at 100 ppm. Stimulation of growth was observed when diazinon was added to cultures. Aflatoxin B1 was most resistant to inhibition by insecticides, followed by G1, G2, and B2, respectively. PMID:6786222

  11. 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 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 and......, with the result that a certain asymmetry of inhibition (stronger inhibition of exit than of entrance) is to be expected. This asymmetry was termed “first order asymmetry”. In experiments with each of the three inhibitors an asymmetry of inhibition in the expected direction was observed which however...

  12. Gold-containing drugs and the control of proteolytic enzymes.

    OpenAIRE

    Rohozková, D.; Steven, F. S.

    1983-01-01

    1 NaAuCl4 and aurothioglucose inhibited trypsin in free solution without the need of a carrier molecule. 2 NaAuCl4, aurothioglucose, aurothiomalate, auranofin and chloro-triethyl phosphine) gold all inhibited the trypsin-like neutral protease on the surfaces of Ehrlich ascites tumour cell membranes equally well. 3 Crude cathepsin preparations were activated by low concentrations of dithiothreitol and also by aurothioglucose, due to the displacement of an inhibitor. 4 Thiol-activated cathepsin...

  13. Inhibition of ethylene production by cobaltous ion

    International Nuclear Information System (INIS)

    The effect of Co2+ on ethylene production by mung bean (Phaseolus aureus Roxb.) and by apple tissues was studied. Co2+, depending on concentrations applied, effectively inhibited ethylene production by both tissues. It also strongly inhibited the ethylene production induced by IAA, kinetin, IAA plus kinetin, Ca2+, kinetin plus Ca2+, or Cu2+ treatments in mung bean hypocotyl segments. While Co2+ greatly inhibited ethylene production, it had little effect on the respiration of apple tissue, indicating that Co2+ does not exert its inhibitory effect as a general metabolic inhibitor. Ni2+, which belongs to the same group as Co2+ in the periodic table, also markedly curtailed both the basal and the induced ethylene production by apple and mung bean hypocotyl tissues. In a system in which kinetin and Ca2+ were applied together, kinetin greatly enhanced Ca2+ uptake, thus enhancing ethylene production. Co2+, however, slightly inhibited the uptake of Ca2+ but appreciably inhibited ethylene production, either in the presence or in the absence of kinetin. Tracer experiments using apple tissue indicated that Co2+ strongly inhibited the in vivo conversion of L-[U--14C]methionine to 14C-ethylene. These data suggested that Co2+ inhibited ethylene production by inhibiting the conversion of methionine to ethylene, a common step which is required for ethylene formation by higher plants. Co2+ is known to promote elongation, leaf expansion, and hook opening in excised plant parts in response to applied auxins or cytokinins.Since ethylene is known to inhibit those growth phenomena, it is suggested that Co2+ exerts its promotive effect, at least in part, by inhibiting ethylene formation

  14. Lysophospholipase inhibition by organophosphorus toxicants

    International Nuclear Information System (INIS)

    Lysophospholipases (LysoPLAs) are a large family of enzymes for removing lysophospholipids from cell membranes. Potent inhibitors are needed to define the importance of LysoPLAs as targets for toxicants and potential therapeutics. This study considers organophosphorus (OP) inhibitors with emphasis on mouse brain total LysoPLA activity relative to the mipafox-sensitive neuropathy target esterase (NTE)-LysoPLA recently established as 17% of the total activity and important in the action of OP delayed toxicants. The most potent inhibitors of total LysoPLA in mouse brain are isopropyl dodecylphosphonofluoridate (also for LysoPLA of Vibrio bacteria), ethyl octylphosphonofluoridate (EOPF), and two alkyl-benzodioxaphosphorin 2-oxides (BDPOs)[(S)-octyl and dodecyl] (IC50 2-8 nM). OP inhibitors acting in vitro and in vivo differentiate a more sensitive portion but not a distinct NTE-LysoPLA compared with total LysoPLA activity. For 10 active inhibitors, NTE-LysoPLA is 17-fold more sensitive than total LysoPLA, but structure-activity comparisons give a good correlation (r2 = 0.94) of IC50 values, suggesting active site structural similarity or identity. In mice 4 h after intraperitoneal treatment with discriminating doses, EOPF, tribufos (a plant defoliant), and dodecanesulfonyl fluoride inhibit 41-57% of the total brain LysoPLA and 85-99% of the NTE-LysoPLA activity. Total LysoPLA as well as NTE-LysoPLA is decreased in activity in Nte+/--haploinsufficient mice compared to their Nte+/+ littermates. The lysolecithin level of spinal cord but not brain is elevated significantly following EOPF treatment (3 mg/kg), thereby focusing attention on localized rather than general alterations in lysophospholipid metabolism in OP-induced hyperactivity and toxicity

  15. Cardiac remodelling and RAS inhibition.

    Science.gov (United States)

    Ferrario, Carlos M

    2016-06-01

    Risk factors such as hypertension and diabetes are known to augment the activity and tissue expression of angiotensin II (Ang II), the major effector peptide of the renin-angiotensin system (RAS). Overstimulation of the RAS has been implicated in a chain of events that contribute to the pathogenesis of cardiovascular (CV) disease, including the development of cardiac remodelling. This chain of events has been termed the CV continuum. The concept of CV disease existing as a continuum was first proposed in 1991 and it is believed that intervention at any point within the continuum can modify disease progression. Treatment with antihypertensive agents may result in regression of left ventricular hypertrophy, with different drug classes exhibiting different degrees of efficacy. The greatest decrease in left ventricular mass is observed following treatment with angiotensin converting enzyme inhibitors (ACE-Is), which inhibit Ang II formation. Although ACE-Is and angiotensin receptor blockers (ARBs) provide significant benefits in terms of CV events and stroke, mortality remains high. This is partly due to a failure to completely suppress the RAS, and, as our knowledge has increased, an escape phenomenon has been proposed whereby the human sequence of the 12 amino acid substrate angiotensin-(1-12) is converted to Ang II by the mast cell protease, chymase. Angiotensin-(1-12) is abundant in a wide range of organs and has been shown to increase blood pressure in animal models, an effect abolished by the presence of ACE-Is or ARBs. This review explores the CV continuum, in addition to examining the influence of the RAS. We also consider novel pathways within the RAS and how new therapeutic approaches that target this are required to further reduce Ang II formation, and so provide patients with additional benefits from a more complete blockade of the RAS. PMID:27105891

  16. 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.

  17. Cross-talk between two antioxidants, thioredoxin reductase and heme oxygenase-1, and therapeutic implications for multiple myeloma.

    Science.gov (United States)

    Raninga, Prahlad V; Di Trapani, Giovanna; Vuckovic, Slavica; Tonissen, Kathryn F

    2016-08-01

    Multiple myeloma (MM) is characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Despite recent advancements in anti-myeloma therapies, MM remains an incurable disease. Antioxidant molecules are upregulated in many cancers, correlating with tumor proliferation, survival, and chemoresistance and therefore, have been suggested as potential therapeutic targets. This study investigated the cross-talk between two antioxidant molecules, thioredoxin reductase (TrxR) and heme oxygenase-1 (HO-1), and their therapeutic implications in MM. We found that although auranofin, a TrxR inhibitor, significantly inhibited TrxR activity by more than 50% at lower concentrations, myeloma cell proliferation was only inhibited at higher concentrations of auranofin. Inhibition of TrxR using lower auranofin concentrations induced HO-1 protein expression in myeloma cells. Using a sub-lethal concentration of auranofin to inhibit TrxR activity in conjunction with HO-1 inhibition significantly decreased myeloma cell growth and induced apoptosis. TrxR was shown to regulate HO-1 via the Nrf2 signaling pathway in a ROS-dependent manner. Increased HO-1 mRNA levels were observed in bortezomib-resistant myeloma cells compared to parent cells and HO-1 inhibition restored the sensitivity to bortezomib in bortezomib-resistant myeloma cells. These findings indicate that concurrent inhibition of HO-1 with either a TrxR inhibitor or with bortezomib would improve therapeutic outcomes in MM patients. Hence, our findings further support the need to target multiple antioxidant systems alone or in combination with other therapeutics to improve therapeutic outcomes in MM patients. PMID:26795735

  18. Inhibition of chymotrypsin by heparin cofactor II.

    OpenAIRE

    CHURCH, F. C.; Noyes, C M; Griffith, M J

    1985-01-01

    Human heparin cofactor II is a plasma protein that is known to inhibit thrombin. The rate of thrombin inhibition by heparin cofactor II is accelerated (greater than or equal to 1000-fold) in the presence of the glycosaminoglycans, heparin and dermatan sulfate. We have found that chymotrypsin A alpha is also inhibited by heparin cofactor II with a second-order rate constant value of 1.8 X 10(6) M-1 X min-1 at pH 8.0 and 25 degrees C. However, there was no measurable effect of heparin or dermat...

  19. The IFITMs Inhibit Zika Virus Replication.

    Science.gov (United States)

    Savidis, George; Perreira, Jill M; Portmann, Jocelyn M; Meraner, Paul; Guo, Zhiru; Green, Sharone; Brass, Abraham L

    2016-06-14

    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. PMID:27268505

  20. Cellulase Inhibition by High Concentrations of Monosaccharides

    DEFF Research Database (Denmark)

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

    2014-01-01

    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...... 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...

  1. 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...

  2. 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.

  3. Disodium cromoglycate inhibits production of immunoglobulin E.

    Science.gov (United States)

    Seo, S B; Park, S J; Park, S T; Cho, C C; Park, B H; Lee, S J; Kim, H M; Kajiuchi, T; Shin, T Y

    2001-05-01

    Disodium cromoglycate (DSCG) has been shown to inhibit the release of mediators from mast cells. In the present study, the effect of DSCG on active anaphylactic reaction was studied in mice. DSCG dose-dependently inhibited the active systemic anaphylactic reaction and serum immunoglobulin (Ig)E production induced by immunization with ovalbumin, Bordetella pertussis toxin and aluminum hydroxide gel. DSCG strongly inhibited IL-4-dependent IgE production by lipopolysaccharide-stimulated murine whole spleen cells. In the case of U266 human IgE-bearing B cells, DSCG also showed an inhibitory effect on the IgE production. These results suggest that DSCG has an anti-anaphylactic activity by inhibition of IgE production from B cells. PMID:11417850

  4. 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...... individual cellulases hydrolyzing insoluble cellulose remains insufficient. Such knowledge is necessary to pinpoint and quantify inhibitory weak-links in cellulose hydrolysis, but has proven challenging to come by. Here we show that product inhibition of mono-component cellulases hydrolyzing unmodified...... 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 by...

  5. 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...

  6. Adenosine triphosphate inhibition of yeast trehalase.

    Science.gov (United States)

    Panek, A D

    1969-09-01

    Yeast trehalase has been found to be inhibited non-competitively by adenosine triphosphate. Such a biological control could explain the accumulation of trehalose during the stationary phase of the growth curve. PMID:5370287

  7. Cross-domain inhibition of TACE ectodomain

    DEFF Research Database (Denmark)

    Tape, Christopher J; Willems, Sofie H; Dombernowsky, Sarah L;

    2011-01-01

    target for the treatment of cancer and arthritis. Prior attempts to antagonize cell-surface TACE activity have focused on small-molecule inhibition of the metalloprotease active site. Given the highly conserved nature of metalloprotease active sites, this paradigm has failed to produce a truly specific...... individual antibody variable domains to desired epitopes. The resulting "cross-domain" human antibody is a previously undescribed selective TACE antagonist and provides a unique alternative to small-molecule metalloprotease inhibition....

  8. Inhibition of glycosphingolipid biosynthesis induces cytokinesis failure

    OpenAIRE

    Atilla-Gokcumen, G. E.; Bedigian, A. V.; S. Sasse; Eggert, U. S.

    2011-01-01

    Although cells undergo dramatic shape changes during cytokinesis, the role of the plasma membrane and lipids is poorly understood. We report that inactivation of glucosyl ceramide synthase (GCS), either by RNAi or with the small molecule PPMP, causes failure of cleavage furrow ingression. Using mass spectrometry-based global lipid profiling, we identify individual lipids that are enhanced or depleted due to GCS inhibition. We show that GCS inhibition results in the mis-localization of actin a...

  9. Fear Inhibition in High Trait Anxiety

    OpenAIRE

    Merel Kindt; Marieke Soeter

    2014-01-01

    Trait anxiety is recognized as an individual risk factor for the development of anxiety disorders but the neurobiological mechanisms remain unknown. Here we test whether trait anxiety is associated with impaired fear inhibition utilizing the AX+/BX- conditional discrimination procedure that allows for the independent evaluation of startle fear potentiation and inhibition of fear [1]. Sixty undergraduate students participated in the study - High Trait Anxious: n = 28 and Low Trait Anxious: n =...

  10. Inhibition in the Human Auditory Cortex

    OpenAIRE

    Koji Inui; Kei Nakagawa; Makoto Nishihara; Eishi Motomura; Ryusuke Kakigi

    2016-01-01

    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 observe...

  11. The pharmacology of visuospatial attention and inhibition

    OpenAIRE

    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 modulate the sensitivity of the sensory cortex. Disengagement refers to the decoupling of attention, in case of a (relevant) stimulus occurring at an unattended location. Inhibitory functioning is ...

  12. Adaptive regulation of sparseness by feedforward inhibition

    OpenAIRE

    Assisi, Collins; Stopfer, Mark; Laurent, Gilles; Bazhenov, Maxim

    2007-01-01

    In the mushroom body of insects, odors are represented by very few spikes in a small number of neurons, a highly efficient strategy known as sparse coding. Physiological studies of these neurons have shown that sparseness is maintained across thousand-fold changes in odor concentration. Using a realistic computational model, we propose that sparseness in the olfactory system is regulated by adaptive feedforward inhibition. When odor concentration changes, feedforward inhibition modulates the ...

  13. Activin inhibits telomerase activity in cancer

    Energy Technology Data Exchange (ETDEWEB)

    Katik, Indzi; Mackenzie-Kludas, Charley; Nicholls, Craig [Department of Immunology, Monash University, Melbourne (Australia); Jiang, Fang-Xu [Centre for Diabetes Research, Western Australian Institute for Medical Research and The University of Western Australia, Perth (Australia); Zhou, Shufeng [School of Health Sciences, RMIT University, Melbourne (Australia); Li, He [Department of Immunology, Monash University, Melbourne (Australia); Liu, Jun-Ping, E-mail: jun-ping.liu@med.monash.edu.au [Department of Immunology, Monash University, Melbourne (Australia)

    2009-11-27

    Activin is a pleiotropic cytokine with broad tissue distributions. Recent studies demonstrate that activin-A inhibits cancer cell proliferation with unknown mechanisms. In this report, we demonstrate that recombinant activin-A induces telomerase inhibition in cancer cells. In breast and cervical cancer cells, activin-A resulted in telomerase activity in a concentration-dependent manner. Significant inhibition was observed at 10 ng/ml of activin-A, with a near complete inhibition at 80 ng/ml. Consistently, activin-A induced repression of the telomerase reverse transcriptase (hTERT) gene, with the hTERT gene to be suppressed by 60-80% within 24 h. In addition, activin-A induced a concomitant increase in Smad3 signaling and decrease of the hTERT gene promoter activity in a concentration-dependent fashion. These data suggest that activin-A triggered telomerase inhibition by down-regulating hTERT gene expression is involved in activin-A-induced inhibition of cancer cell proliferation.

  14. 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.

  15. Detecting age differences in inhibition processes with a test of perceptual and motor inhibition

    OpenAIRE

    Jennings, J. Richard; Mendelson, David N.; Redfern, Mark S.; Nebes, Robert D.

    2011-01-01

    We asked whether different forms of inhibition are altered differently by aging using a Motor and Perceptual Inhibition Test (MAPIT) based on Nassauer and Halperin (Nassauer & Halperin, 2003). Ninety-eight individuals participating in studies of balance and attention were separated into younger (mean age 25 years) and older participants (mean age 73). Older participants showed less Perceptual and Motor Inhibition than younger participant with moderation of this effect by gender. The two score...

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

    OpenAIRE

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

    2016-01-01

    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 pro...

  17. Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha-Glucosidases-Not Glycolipid Processing Enzymes.

    Science.gov (United States)

    Sayce, Andrew C; Alonzi, Dominic S; Killingbeck, Sarah S; Tyrrell, Beatrice E; Hill, Michelle L; Caputo, Alessandro T; Iwaki, Ren; Kinami, Kyoko; Ide, Daisuke; Kiappes, J L; Beatty, P Robert; Kato, Atsushi; Harris, Eva; Dwek, Raymond A; Miller, Joanna L; Zitzmann, Nicole

    2016-03-01

    It has long been thought that iminosugar antiviral activity is a function of inhibition of endoplasmic reticulum-resident α-glucosidases, and on this basis, many iminosugars have been investigated as therapeutic agents for treatment of infection by a diverse spectrum of viruses, including dengue virus (DENV). However, iminosugars are glycomimetics possessing a nitrogen atom in place of the endocyclic oxygen atom, and the ubiquity of glycans in host metabolism suggests that multiple pathways can be targeted via iminosugar treatment. Successful treatment of patients with glycolipid processing defects using iminosugars highlights the clinical exploitation of iminosugar inhibition of enzymes other than ER α-glucosidases. Evidence correlating antiviral activity with successful inhibition of ER glucosidases together with the exclusion of alternative mechanisms of action of iminosugars in the context of DENV infection is limited. Celgosivir, a bicyclic iminosugar evaluated in phase Ib clinical trials as a therapeutic for the treatment of DENV infection, was confirmed to be antiviral in a lethal mouse model of antibody-enhanced DENV infection. In this study we provide the first evidence of the antiviral activity of celgosivir in primary human macrophages in vitro, in which it inhibits DENV secretion with an EC50 of 5 μM. We further demonstrate that monocyclic glucose-mimicking iminosugars inhibit isolated glycoprotein and glycolipid processing enzymes and that this inhibition also occurs in primary cells treated with these drugs. By comparison to bicyclic glucose-mimicking iminosugars which inhibit glycoprotein processing but do not inhibit glycolipid processing and galactose-mimicking iminosugars which do not inhibit glycoprotein processing but do inhibit glycolipid processing, we demonstrate that inhibition of endoplasmic reticulum-resident α-glucosidases, not glycolipid processing, is responsible for iminosugar antiviral activity against DENV. Our data suggest that

  18. Inhibition of bacterial luminescence by cerulenin

    International Nuclear Information System (INIS)

    Bacterial luminescence is very sensitive to cerulenin, a fungal inhibitor of fatty acid (FA) synthesis. Cerulenin does not inhibit luciferase itself, but rather the synthesis of its aldehyde substrate by FA reductase. The acyl-CoA reductase (58 kDa) component of the Photobacterium phosphoreum FA reductase complex was inhibited by cerulenin in vitro. Similarly, acylation of the corresponding Vibrio harveyi 57 kDa protein with [3H]myristic acid was preferentially decreased, while cerulenin had no effect on the activities of luciferase or the acyltransferase (32 kDa) responsible for FA supply to luminescence. Light emission of wild type V. harveyi was less sensitive to cerulenin at 10 μg/ml (5-fold decrease at 1h) than that of the FA-stimulatable dark mutant M17 (100-fold inhibition), which lacks the 32 kDa acyltransferase. The V. harveyi reductase subunit was also labeled by [3H]tetrahydrocerulenin in vivo in M17 but not wild type cells; this labeling could be prevented by preincubating M17 cells with cerulenin or FA. These results suggest that (a) cerulenin specifically and covalently inhibits the reductase component of aldehyde synthesis, and (b) this enzyme is partially protected from inhibition in vivo in the wild type cell

  19. Aspartate inhibits Staphylococcus aureus biofilm formation.

    Science.gov (United States)

    Yang, Hang; Wang, Mengyue; Yu, Junping; Wei, Hongping

    2015-04-01

    Biofilm formation renders Staphylococcus aureus highly resistant to conventional antibiotics and host defenses. Four D-amino acids (D-Leu, D-Met, D-Trp and D-Tyr) have been reported to be able to inhibit biofilm formation and disassemble established S. aureus biofilms. We report here for the first time that both D- and L-isoforms of aspartate (Asp) inhibited S. aureus biofilm formation on tissue culture plates. Similar biofilm inhibition effects were also observed against other staphylococcal strains, including S. saprophyticus, S. equorum, S. chromogenes and S. haemolyticus. It was found that Asp at high concentrations (>10 mM) inhibited the growth of planktonic N315 cells, but at subinhibitory concentrations decreased the cellular metabolic activity without influencing cell growth. The decreased cellular metabolic activity might be the reason for the production of less protein and DNA in the matrix of the biofilms formed in the presence of Asp. However, varied inhibition efficacies of Asp were observed for biofilms formed by clinical staphylococcal isolates. There might be mechanisms other than decreasing the metabolic activity, e.g. the biofilm phenotypes, affecting biofilm formation in the presence of Asp. PMID:25687923

  20. Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

    Directory of Open Access Journals (Sweden)

    Susan Skanderup Falkenberg

    2012-01-01

    Full Text Available 12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM and collagen- (2.0 μg/mL induced aggregations in human blood. These four species in respective extracts (in brackets were Blechnum chilense (MeOH, Luma apiculata (H2O, Amomyrtus luma (DCM : MeOH 1 : 1 and Cestrum parqui (DCM : MeOH 1 : 1. The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1, and L. apiculata (H2O were substantial and confirmed by inhibition of platelet surface activation markers.

  1. 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...... suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades....

  2. Targeted inhibition in tumors with ALK dependency

    Directory of Open Access Journals (Sweden)

    Kwak EL

    2013-01-01

    Full Text Available Eunice L Kwak, Jeffrey W Clark, Alice T ShawMassachusetts General Hospital Cancer Center, Boston, MA, USAAbstract: The oncogenic function of gene translocations involving the anaplastic lymphoma kinase (ALK was first reported in rare subtypes of non-Hodgkin's lymphoma almost two decades ago. More recently, aberrant ALK signaling was found to be an oncogenic driver in subsets of non-small cell lung cancer (NSCLC, particularly in patients with little or no tobacco smoking history. The advent of molecularly targeted therapies that inhibit ALK has allowed the pairing of ALK inhibitors such as crizotinib as treatment for ALK-positive NSCLC, yielding dramatic responses and long-term disease control. The clinicopathologic features of ALK-driven NSCLC, the clinical development of ALK inhibitors, and the genetic determinants of acquired resistance to ALK inhibition are among the topics covered in this review.Keywords: targeted inhibition, tumors, ALK dependency

  3. Inhibition of melanogenesis by Xanthium strumarium L.

    Science.gov (United States)

    Li, Hailan; Min, Young Sil; Park, Kyoung-Chan; Kim, Dong-Seok

    2012-01-01

    Xanthium strumarium L. (Asteraceae) is traditionally used in Korea to treat skin diseases. In this study, we investigated the effects of a X. strumarium stem extract on melanin synthesis. It inhibited melanin synthesis in a concentration-dependent manner, but it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme, and instead downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase expression. MITF, the master regulator of pigmentation, is a target of the Wnt signaling pathway, which includes glycogen synthase kinase 3β (GSK3β) and β-catenin. Hence, the influence of X. strumarium stem extract on GSK3β and β-catenin was further investigated. X. strumarium induced GSK3β phosphorylation (inactivation), but the level of β-catenin did not change. Moreover, a specific GSK3β inhibitor restored X. strumarium-induced melanin reduction. Hence, we suggest that X. strumarium inhibits melanin synthesis through downregulation of tyrosinase via GSK3β phosphorylation. PMID:22484949

  4. The IFITMs Inhibit Zika Virus Replication

    OpenAIRE

    George Savidis; Jill M. Perreira; Jocelyn M. Portmann; Paul Meraner; Zhiru Guo; Sharone Green; Abraham L. Brass

    2016-01-01

    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 mig...

  5. Sprout inhibition in roots, tubers and bulbs

    International Nuclear Information System (INIS)

    The treatment with ionizing radiations to low dose impedes that appear sprouts in the tubers (potatoes); bulbs (onion and garlic) and in roots like the ginger and the yucca. The purpose is to inhibit the germination during the process of manipulation and storage, and this way to avoid the lost ones post crop of these products. The radiation dose required to inhibit the germination goes to depend of: the development conditions, the differences of variety, of the storage state of the bulbs and the conditions of cured and storage. (Author)

  6. Proton pump inhibitors inhibit pancreatic secretion

    DEFF Research Database (Denmark)

    Wang, Jing; Barbuskaite, Dagne; Tozzi, Marco; Giannuzzo, Andrea; Sørensen, Christiane Elisabeth; Novak, Ivana

    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 of...

  7. A novel approach to inhibit bone resorption

    DEFF Research Database (Denmark)

    Panwar, Preety; Søe, Kent; Guido, Rafael VC;

    2016-01-01

    pathways. The present study investigates the antiresorptive effect of an exosite inhibitor that selectively inhibits only the therapeutically relevant collagenase activity of CatK. EXPERIMENTAL APPROACH: Human osteoclasts and fibroblasts were used to analyse the effect of the exosite inhibitor, ortho...... RESULTS: DHT1 selectively inhibited the collagenase activity of CatK, without affecting the viability of osteoclasts. Both inhibitors abolished the formation of resorption trenches, with DHT1 having a slightly higher IC50 value than ODN. Maximal reductions of other resorption parameters by DHT1 and ODN...

  8. 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

  9. Phytic Acid Inhibits Lipid Peroxidation In Vitro

    OpenAIRE

    Alicja Zajdel; Adam Wilczok; Ludmiła Węglarz; Zofia Dzierżewicz

    2013-01-01

    Phytic acid (PA) has been recognized as a potent antioxidant and inhibitor of iron-catalyzed hydroxyl radical formation under in vitro and in vivo conditions. Therefore, the aim of the present study was to investigate, with the use of HPLC/MS/MS, whether PA is capable of inhibiting linoleic acid autoxidation and Fe(II)/ascorbate-induced peroxidation, as well as Fe(II)/ascorbate-induced lipid peroxidation in human colonic epithelial cells. PA at 100 μM and 500 μM effectively inhibited the deca...

  10. Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

    OpenAIRE

    Susan Skanderup Falkenberg; Inge Tarnow; Alfonso Guzman; Per Mølgaard; Henrik Toft Simonsen

    2012-01-01

    12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM) and collagen- (2.0 μg/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H2O), Amomyrtus l...

  11. Reversal of 2-bromoethanesulfonate inhibition of methanogenesis in Methanosarcina sp.

    OpenAIRE

    Smith, M. R.

    1983-01-01

    2-Bromoethanesulfonate (BES) inhibition of methanogenesis from methanol by resting-cell suspensions or cell extracts of Methanosarcina was reversed by coenzyme M. BES inhibition of methylcoenzyme M methylreductase activity in cell-free extracts was reversed by methylcoenzyme M but not by coenzyme M. Methanol/coenzyme M methyltransferase activity was not inhibited by 10 microM BES. Inhibition of methylreductase by BES and 3-bromopropionate was competitive with methylcoenzyme M, but inhibition ...

  12. Serum amyloid P inhibits dermal wound healing

    Science.gov (United States)

    The repair of open wounds depends on granulation tissue formation and contraction, which is primarily mediated by myofibroblasts. A subset of myofibroblasts originates from bone-marrow-derived monocytes which differentiate into fibroblast-like cells called fibrocytes. Serum amyloid P (SAP) inhibits ...

  13. Curcumin inhibition of angiogenesis and adipogenesis

    Science.gov (United States)

    The growth of new blood vessels or angiogenesis is necessary for the growth of adipose tissue. Adipokines produced by fat cells stimulate this process. Some dietary polyphenols with antiangiogenic activity may suppress adipose tissue growth not only by inhibiting angiogenesis, but also by interferin...

  14. Cumulative Intertrial Inhibition in Repeated Visual Search

    Science.gov (United States)

    Takeda, Yuji

    2007-01-01

    In the present study the author examined visual search when the items remain visible across trials but the location of the target varies. Reaction times for inefficient search cumulatively increased with increasing numbers of repeated search trials, suggesting that inhibition for distractors carried over successive trials. This intertrial…

  15. AKT Inhibition Promotes Nonautonomous Cancer Cell Survival.

    Science.gov (United States)

    Salony; Solé, Xavier; Alves, Cleidson P; Dey-Guha, Ipsita; Ritsma, Laila; Boukhali, Myriam; Lee, Ju H; Chowdhury, Joeeta; Ross, Kenneth N; Haas, Wilhelm; Vasudevan, Shobha; Ramaswamy, Sridhar

    2016-01-01

    Small molecule inhibitors of AKT (v-akt murine thymoma viral oncogene homolog) signaling are being evaluated in patients with various cancer types, but have so far proven therapeutically disappointing for reasons that remain unclear. Here, we treat cancer cells with subtherapeutic doses of Akti-1/2, an allosteric small molecule AKT inhibitor, in order to experimentally model pharmacologic inhibition of AKT signaling in vitro. We then apply a combined RNA, protein, and metabolite profiling approach to develop an integrated, multiscale, molecular snapshot of this "AKT(low)" cancer cell state. We find that AKT-inhibited cancer cells suppress thousands of mRNA transcripts, and proteins related to the cell cycle, ribosome, and protein translation. Surprisingly, however, these AKT-inhibited cells simultaneously upregulate a host of other proteins and metabolites posttranscriptionally, reflecting activation of their endo-vesiculo-membrane system, secretion of inflammatory proteins, and elaboration of extracellular microvesicles. Importantly, these microvesicles enable rapidly proliferating cancer cells of various types to better withstand different stress conditions, including serum deprivation, hypoxia, or cytotoxic chemotherapy in vitro and xenografting in vivo. These findings suggest a model whereby cancer cells experiencing a partial inhibition of AKT signaling may actually promote the survival of neighbors through non-cell autonomous communication. PMID:26637368

  16. 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.

  17. LOX1 inhibition with small molecules

    DEFF Research Database (Denmark)

    Gousiadou, Chryssoula; Kouskoumvekaki, Irene

    2016-01-01

    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...

  18. 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 for...

  19. Linking algal growth inhibition to chemical activity

    DEFF Research Database (Denmark)

    Schmidt, Stine N.; Mayer, Philipp

    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 with the...

  20. Behavioral Inhibition in Children with Learning Disabilities

    Science.gov (United States)

    De Weerdt, Frauke; Desoete, Annemie; Roeyers, Herbert

    2013-01-01

    Children with reading disabilities (RD, n = 17), mathematical disabilities (MD, n = 22), combined reading and mathematical disabilities (RD + MD, n = 28) and control peers (n = 45) were tested on behavioral inhibition with a Go/no-go task in a picture, letter and digit-modality. In contrast to children without RD, children with RD made…

  1. Polyene antibiotic that inhibits membrane transport proteins.

    Science.gov (United States)

    te Welscher, Yvonne Maria; van Leeuwen, Martin Richard; de Kruijff, Ben; Dijksterhuis, Jan; Breukink, Eefjan

    2012-07-10

    The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol-dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains. PMID:22733749

  2. Heme oxygenase metabolites inhibit tubuloglomerular feedback (TGF).

    Science.gov (United States)

    Ren, YiLin; D'Ambrosio, Martin A; Wang, Hong; Liu, Ruisheng; Garvin, Jeffrey L; Carretero, Oscar A

    2008-10-01

    Tubuloglomerular feedback (TGF) is the mechanism by which the macula densa (MD) senses increases in luminal NaCl concentration and sends a signal to constrict the afferent arteriole (Af-Art). The kidney expresses constitutively heme oxygenase-2 (HO-2) and low levels of HO-1. HOs release carbon monoxide (CO), biliverdin, and free iron. We hypothesized that renal HOs inhibit TGF via release of CO and biliverdin. Rabbit Af-Arts and attached MD were simultaneously microperfused in vitro. The TGF response was determined by measuring Af-Art diameter before and after increasing NaCl in the MD perfusate. When HO activity was inhibited by adding stannous mesoporphyrin (SnMP) to the MD perfusate, the TGF response increased from 2.1+/-0.2 to 4.1+/-0.4 microm (P=0.003, control vs. SnMP, n=7). When a CO-releasing molecule, (CORM-3; 50 microM), was added to the MD perfusate, the TGF response decreased by 41%, from 3.6+/-0.3 to 2.1+/-0.2 microm (PSnMP and CORM-3 were not blocked by inhibition of nitric oxide synthase. We concluded that renal HO inhibits TGF probably via release of CO and biliverdin. HO regulation of TGF is a novel mechanism that could lead to a better understanding of the control of renal microcirculation and function. PMID:18715939

  3. 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,…

  4. TRIMETHYLTIN REDUCES RECURRENT INHIBITION IN RATS

    Science.gov (United States)

    Rats with electrodes chronically implanted in the perforant path for electrical stimulation, and dentate gyrus for recording were treated with a single oral administration of either saline, 5 mg/kg trimethyltin (TMT) or 6 mg/kg TMT. Recurrent inhibition was assessed by paired pul...

  5. 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…

  6. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    International Nuclear Information System (INIS)

    Highlights: ► Salinomycin inhibits preadipocyte differentiation into adipocytes. ► Salinomycin inhibits transcriptional regulation of adipogenesis. ► 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 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.

  7. Targeted inhibition of tumor growth and angiogenesis

    NARCIS (Netherlands)

    van der Meel, R.

    2013-01-01

    Two main strategies have been pursued for the development of an effective and targeted anti-cancer treatment. The first strategy comprised the generation of a targeted nanomedicine for the inhibition of tumor cell proliferation by blocking growth factor receptor pathways. The epidermal growth factor

  8. The temporal dynamic of response inhibition in early childhood: An ERP study of partial and successful inhibition

    OpenAIRE

    Chevalier, Nicolas; Kelsey, Kathleen; Wiebe, Sandra; Espy, Kimberly

    2014-01-01

    Event-related potentials were recorded while five-year-old children completed a Go/No-Go task that distinguished between partial inhibition (i.e., response is initiated but cancelled before completion) and successful inhibition (i.e., response is inhibited before it is initiated). Partial inhibition trials were characterized by faster response initiation and later latency of the lateral frontal negativity (LFN) than successful Go and successful inhibition trials. The speed of response initiat...

  9. 3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis

    OpenAIRE

    XIAN, SHU-LIN; Cao, Wei; Zhang, Xiao-Dong; Lu, Yun-Fei

    2014-01-01

    Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro. However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It wa...

  10. How many carbonic anhydrase inhibition mechanisms exist?

    Science.gov (United States)

    Supuran, Claudiu T

    2016-01-01

    Six genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described to date. Inhibition of CAs has pharmacologic applications in the field of antiglaucoma, anticonvulsant, anticancer, and anti-infective agents. New classes of CA inhibitors (CAIs) were described in the last decade with enzyme inhibition mechanisms differing considerably from the classical inhibitors of the sulfonamide or anion type. Five different CA inhibition mechanisms are known: (i) the zinc binders coordinate to the catalytically crucial Zn(II) ion from the enzyme active site, with the metal in tetrahedral or trigonal bipyramidal geometries. Sulfonamides and their isosters, most anions, dithiocarbamates and their isosters, carboxylates, and hydroxamates bind in this way; (ii) inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion (phenols, carboxylates, polyamines, 2-thioxocoumarins, sulfocoumarins); (iii) inhibitors which occlude the entrance to the active site cavity (coumarins and their isosters), this binding site coinciding with that where CA activators bind; (iv) compounds which bind out of the active site cavity (a carboxylic acid derivative was seen to inhibit CA in this manner), and (v) compounds for which the inhibition mechanism is not known, among which the secondary/tertiary sulfonamides as well as imatinib/nilotinib are the most investigated examples. As CAIs are used clinically in many pathologies, with a sulfonamide inhibitor (SLC-0111) in Phase I clinical trials for the management of metastatic solid tumors, this review updates the recent findings in the field which may be useful for a structure-based drug design approach of more selective/potent modulators of the activity of these enzymes. PMID:26619898

  11. Contrasting neural effects of aging on proactive and reactive response inhibition

    NARCIS (Netherlands)

    Bloemendaal, Mirjam; Zandbelt, Bram; Wegman, Joost; Nieuwerth-van de Rest, Ondine; Cools, Roshan; Aarts, Esther

    2016-01-01

    Two distinct forms of response inhibition may underlie observed deficits in response inhibition in aging. We assessed whether age-related neurocognitive impairments in response inhibition reflect deficient reactive inhibition (outright stopping) or also deficient proactive inhibition (anticipator

  12. Potent Glycosidase Inhibition with Heterovalent Fullerenes: Unveiling the Binding Modes Triggering Multivalent Inhibition.

    Science.gov (United States)

    Abellán Flos, Marta; García Moreno, M Isabel; Ortiz Mellet, Carmen; García Fernández, Jose Manuel; Nierengarten, Jean-Francois; Vincent, Stéphane P

    2016-08-01

    Glycosidases are key enzymes in metabolism, pathogenic/antipathogenic mechanisms and normal cellular functions. Recently, a novel approach for glycosidase inhibition that conveys multivalent glycomimetic conjugates has emerged. Many questions regarding the mechanism(s) of multivalent enzyme inhibition remain unanswered. Herein we report the synthesis of a collection of novel homo- and heterovalent glyco(mimetic)-fullerenes purposely conceived for probing the contribution of non-catalytic pockets in glysosidases to the multivalent inhibitory effect. Their affinities towards selected glycosidases were compared with data from homovalent fullerene conjugates. An original competitive glycosidase-lectin binding assay demonstrated that the multivalent derivatives and the substrate compete for low affinity non-glycone binding sites of the enzyme, leading to inhibition by a "recognition and blockage" mechanism. Most notably, this work provides evidence for enzyme inhibition by multivalent glycosystems, which will likely have a strong impact in the glycosciences given the utmost relevance of multivalency in Nature. PMID:27374430

  13. Sparse Coding and Lateral Inhibition Arising from Balanced and Unbalanced Dendrodendritic Excitation and Inhibition

    OpenAIRE

    Yu, Yuguo; Migliore, Michele; Michael L Hines; Shepherd, Gordon M.

    2014-01-01

    The precise mechanism by which synaptic excitation and inhibition interact with each other in odor coding through the unique dendrodendritic synaptic microcircuits present in olfactory bulb is unknown. Here a scaled-up model of the mitral–granule cell network in the rodent olfactory bulb is used to analyze dendrodendritic processing of experimentally determined odor patterns. We found that the interaction between excitation and inhibition is responsible for two fundamental computational mecha...

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

    OpenAIRE

    Stephen Verespy III; Mehta, Akul Y.; Daniel Afosah; 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...

  15. Perceptual and behavioral adjustments after action inhibition.

    Science.gov (United States)

    Kirsch, Wladimir; Kunde, Wilfried

    2015-10-01

    Inhibiting a motor action typically prompts a more cautious action mode, leaning toward accuracy rather than speed. In the present study, we explored whether action inhibition is also accompanied by changes of visual perception. Our participants performed goal-directed hand movements from a start to a target position and then judged the start-target distance. On a proportion of the trials, movement execution had to be stopped before the target position was reached. The results of two experiments revealed smaller start-target distance estimates after interrupted than after unrestricted movements. Moreover, movement amplitudes were decreased in movements that followed interrupted ones. In line with the predictions of action-specific accounts of perception, this outcome indicates that subjective perceptual changes might inform us how to plan future actions. PMID:25504460

  16. Photon Aided and Inhibited Tunneling of Photons

    CERN Document Server

    liu, xuele

    2013-01-01

    In the light of the interest in the transport of single photons in arrays of waveguides, fiber couplers, photonic crystals, etc., we consider the quantum mechanical process of the tunneling of photons through evanescently or otherwise coupled structures. We specifically examine the issue of tunneling between two structures when one structure already contains few photons. We demonstrate the possibility of both photon aided and inhibited tunneling of photons. The Bosonic nature of photons enhances the tunneling probability. We also show how the multiphoton tunneling probability can be either enhanced or inhibited due to the presence of photons. We find similar results for the higher order tunneling. Finally, we show that the presence of a squeezed field changes the nature of tunneling considerably.

  17. Proton pump inhibitors inhibit pancreatic secretion

    DEFF Research Database (Denmark)

    Wang, Jing; Barbuskaite, Dagne; Tozzi, Marco;

    2015-01-01

    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 of......The mechanism by which pancreas secretes high HCO3- has not been fully resolved. This alkaline secretion, formed in pancreatic ducts, can be achieved by transporting HCO3- from serosa to mucosa or by moving H+ in the opposite direction. The aim of the present study was to determine whether H......+/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...

  18. 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...... inhibition in chronic kidney disease by reporting of the studies published so far as well as perspective on the future possibilites....... was terminated 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...

  19. How x rays inhibit amphibian limb regeneration

    Energy Technology Data Exchange (ETDEWEB)

    Maden, M.; Wallace, H.

    1976-07-01

    The effects of an inhibiting dose of 2,000 rad of x-rays on the regenerating limbs of axolotl larvae have been examined in a histological and cytological study. Particular attention was paid to the mitotic indices of normal and irradiated epidermal and blastemal cells. Both the characteristic pattern of epidermal mitotic stimulation which normally follows amputation and the later increase in blastemal mitoses are suppressed by irradiation. In most cells the effects are permanent, but in a small proportion a mitotic delay is induced and upon subsequent division chromosome damage in the form of micronuclei is revealed. Thus irradiated cells which do divide almost certainly die. These results are discussed in relation to other theories of x-ray inhibition of regeneration with particular reference to the view that irradiated cells can be reactivated.

  20. Inhibition Controls Asynchronous States of Neuronal Networks

    Science.gov (United States)

    Treviño, Mario

    2016-01-01

    Computations in cortical circuits require action potentials from excitatory and inhibitory neurons. In this mini-review, I first provide a quick overview of findings that indicate that GABAergic neurons play a fundamental role in coordinating spikes and generating synchronized network activity. Next, I argue that these observations helped popularize the notion that network oscillations require a high degree of spike correlations among interneurons which, in turn, produce synchronous inhibition of the local microcircuit. The aim of this text is to discuss some recent experimental and computational findings that support a complementary view: one in which interneurons participate actively in producing asynchronous states in cortical networks. This requires a proper mixture of shared excitation and inhibition leading to asynchronous activity between neighboring cells. Such contribution from interneurons would be extremely important because it would tend to reduce the spike correlation between neighboring pyramidal cells, a drop in redundancy that could enhance the information-processing capacity of neural networks. PMID:27274721

  1. Inhibition of Return after Color Singletons

    OpenAIRE

    Priess, Heinz-Werner; Born, Sabine; Ansorge, Ulrich

    2012-01-01

    Inhibition of return (IOR) is the faster selection of hitherto unattended than previously attended positions. Some previous studies failed to find evidence for IOR after attention capture by color singletons. Others, however, did report IOR effects after color singletons. The current study examines the role of cue relevance for obtaining IOR effects. By using a potentially more sensitive method – saccadic IOR – we tested and found IOR after relevant color singleton cues that required an atten...

  2. Inhibited oxidation of polymethylsiloxane, containing cerium

    International Nuclear Information System (INIS)

    The kinetics of oxidation of oligomeric polydimethylsiloxane in the presence of cerium-containing organosilicon antioxidant at 285-310 deg was investigated. High energy of activation for initiation process (around 272 kJ/mole) was established as a feature specific for chain oxidation of polydimethylsiloxane. It was found that cerium-containing antioxidant, as well as the iron-containing one, based on iron capronate, is of the ''depleting'' inhibitors, i.e. it looses its inhibiting ability during oxidation

  3. Spongian diterpenoids inhibit androgen receptor activity

    OpenAIRE

    Yang, Yu Chi; Labros G Meimetis; Tien, Amy H; Mawji, Nasrin R.; Carr, Gavin; Wang, Jun; Andersen, Raymond J.; Sadar, Marianne D.

    2013-01-01

    Androgen receptor (AR) is a ligand-activated transcription factor and a validated drug target for all stages of prostate cancer. Antiandrogens compete with physiological ligands for AR ligand-binding domain (LBD). High-throughput screening of a marine natural product library for small molecules that inhibit AR transcriptional activity yielded the furanoditerpenoid spongia-13(16),-14-dien-19-oic acid, designated terpene 1 (T1). Characterization of T1 and the structurally related semi-synthetic...

  4. 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.

  5. 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.

  6. Behavioral inhibition and PTSD symptoms in veterans

    OpenAIRE

    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 ...

  7. 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

  8. 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...

  9. Nicotine administration enhances conditioned inhibition in rats

    OpenAIRE

    MacLeod, Jill E.; Potter, Alexandra S.; Simoni, Michael K.; Bucci, David J.

    2006-01-01

    The effect of nicotine on conditioned inhibition was examined using a serial feature negative discrimination task. Nicotine (0.35mg/kg) or vehicle was administered before each of 16 training sessions. On some trials in each session, a tone was presented and followed by food reward. On other trials, the tone was preceded by a visual stimulus and not reinforced. Nicotine-treated rats exhibited greater discrimination between the two trial types as evidenced by less frequent responding during non...

  10. Inhibited Sexual Desire and Sexual Avoidance

    OpenAIRE

    Morse, William I.

    1985-01-01

    Inhibited sexual desire (ISD) is one of the most common sexual dysfunctions, especially in women. Family physicians have an opportunity to recognize ISD before the associated problems become entrenched, and to guide couples toward satisfactory resolution. A summary is presented of current thinking on ISD and its causes. Case reports and observations about frequency of and treatment for ISD are included. Much less has been written about sexual avoidance in the presence of desire. A definition ...

  11. Fermented Broth in Tyrosinase- and Melanogenesis Inhibition

    Directory of Open Access Journals (Sweden)

    Chin-Feng Chan

    2014-08-01

    Full Text Available Fermented broth has a long history of applications in the food, pharmaceutical and cosmetic industries. Recently, the use of fermented broth in skin care products is in ascendance. This review investigates the efficacy of fermented broth in inhibiting tyrosinase and melanogenesis. Possible active ingredients and hypopigmentation mechanisms of fermented broth are discussed, and potential applications of fermented broth in the cosmetic industry are also addressed.

  12. Cathepsin Protease Inhibition Reduces Endometriosis Lesion Establishment.

    Science.gov (United States)

    Porter, Kristi M; Wieser, Friedrich A; Wilder, Catera L; Sidell, Neil; Platt, Manu O

    2016-05-01

    Endometriosis is a gynecologic disease characterized by the ectopic presence of endometrial tissue on organs within the peritoneal cavity, causing debilitating abdominal pain and infertility. Current treatments alleviate moderate pain symptoms associated with the disorder but exhibit limited ability to prevent new or recurring lesion establishment and growth. Retrograde menstruation has been implicated for introducing endometrial tissue into the peritoneal cavity, but molecular mechanisms underlying attachment and invasion are not fully understood. We hypothesize that cysteine cathepsins, a group of powerful extracellular matrix proteases, facilitate endometrial tissue invasion and endometriosis lesion establishment in the peritoneal wall and inhibiting this activity would decrease endometriosis lesion implantation. To test this, we used an immunocompetent endometriosis mouse model and found that endometriotic lesions exhibited a greater than 5-fold increase in active cathepsins compared to tissue from peritoneal wall or eutopic endometrium, with cathepsins L and K specifically implicated. Human endometriosis lesions also exhibited greater cathepsin activity than adjacent peritoneum tissue, supporting the mouse results. Finally, we tested the hypothesis that inhibiting cathepsin activity could block endometriosis lesion attachment and implantation in vivo. Intraperitoneal injection of the broad cysteine cathepsin inhibitor, E-64, significantly reduced the number of attached endometriosis lesions in our murine model compared to vehicle-treated controls demonstrating that cathepsin proteases contribute to endometriosis lesion establishment, and their inhibition may provide a novel, nonhormonal therapy for endometriosis. PMID:26482207

  13. Ormeloxifene efficiently inhibits ovarian cancer growth

    Science.gov (United States)

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

    2014-01-01

    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. PMID:25306892

  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. Gabapentin inhibits central sensitization during migraine

    Institute of Scientific and Technical Information of China (English)

    Yanbo Zhang; Guo Shao; Wei Zhang; Sijie Li; Jingzhong Niu; Dongmei Hu; Mingfeng Yang; Xunming Ji

    2013-01-01

    Peripheral and central sensitizations are phenomena that occur during migraine. The role of pentin, a migraine preventive drug, on central sensitization remains unclear. In this study, a rat model of migraine was established by electrical stimulation of the trigeminal ganglion, and the an-imals were given intragastric gabapentin. Changes in amino acid content in the cerebrospinal fluid and protein kinase C membrane translocation in the spinal trigeminal nucleus were examined to clarify the mechanisms underlying the efficacy of gabapentin in the treatment of central sensitization during migraine. Electrophysiology, liquid chromatography-mass spectrometry and western blot analysis results revealed that gabapentin reduces neuronal excitability in the spinal nucleus in the trigeminal nerve, decreases excitatory amino acid content and inhibits the activation of protein ki-nase C. This provides evidence that excitatory amino acids and protein kinase C are involved in the formation and maintenance of central sensitization during migraine. Gabapentin inhibits migraine by reducing excitatory amino acid content in the cerebrospinal fluid and inhibiting protein kinase C ac-tivation.

  16. Simvastatin inhibits protein isoprenylation in the brain.

    Science.gov (United States)

    Ostrowski, Stephen M; Johnson, Kachael; Siefert, Matthew; Shank, Sam; Sironi, Luigi; Wolozin, Benjamin; Landreth, Gary E; Ziady, Assem G

    2016-08-01

    Evidence suggests that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, may reduce the risk of Alzheimer's disease (AD). Statin action in patients with AD, as in those with heart disease, is likely to be at least partly independent of the effects of statins on cholesterol. Statins can alter cellular signaling and protein trafficking through inhibition of isoprenylation of Rho, Cdc42, and Rab family GTPases. The effects of statins on protein isoprenylation in vivo, particularly in the central nervous system, are poorly studied. We utilized two-dimensional gel electrophoresis approaches to directly monitor the levels of isoprenylated and non-isoprenylated forms of Rho and Rab family GTPases. We report that simvastatin significantly inhibits RhoA and Rab4, and Rab6 isoprenylation at doses as low as 50nM in vitro. We also provide the first in vivo evidence that statins inhibit the isoprenylation of RhoA in the brains of rats and RhoA, Cdc42, and H-Ras in the brains of mice treated with clinically relevant doses of simvastatin. PMID:27180285

  17. Alpha-amylase inhibition kinetics by caulerpenyne

    Directory of Open Access Journals (Sweden)

    S. CENGIZ

    2012-12-01

    Full Text Available Many algae have important secretions which are generally used for defensive purposes. These secretions take attentions of a lot of researchers who are wondering if these metabolites can be used for medical researches or not. Among these metabolites, caulerpenyne (CYN which is the main metabolite of Caulerpa species, have had an important place in Caulerpa researches since the results related to its determined properties such as cytotoxic, antiviral, antiproliferative and apoptotic effects have been proven by many scientific reports. In the present study, the inhibitory effect of CYN isolated from C. prolifera on alpha-amylase was investigated. The inhibition experiments were done with CYN by spectrophotometric determination method. In order to evaluate the type of inhibition Lineweaver–Burk plot was produced. The results obtained from enzyme kinetic studies exhibited an un-competitive type of inhibition, which is characterized by the difference of Vmax and KM from those of the free enzyme, of alpha-amylase in the presence of CYN. The present study showed that Caulerpa species can be a potential target for producing diabetic drugs in the light of the results obtained for CYN.

  18. Sticky steps inhibit step motions near equilibrium

    Science.gov (United States)

    Akutsu, Noriko

    2012-12-01

    Using a Monte Carlo method on a lattice model of a vicinal surface with a point-contact-type step-step attraction, we show that, at low temperature and near equilibrium, there is an inhibition of the motion of macrosteps. This inhibition leads to a pinning of steps without defects, adsorbates, or impurities (self-pinning of steps). We show that this inhibition of the macrostep motion is caused by faceted steps, which are macrosteps that have a smooth side surface. The faceted steps result from discontinuities in the anisotropic surface tension (the surface free energy per area). The discontinuities are brought into the surface tension by the point-contact-type step-step attraction. The point-contact-type step-step attraction also originates “step droplets,” which are locally merged steps, at higher temperatures. We derive an analytic equation of the surface stiffness tensor for the vicinal surface around the (001) surface. Using the surface stiffness tensor, we show that step droplets roughen the vicinal surface. Contrary to what we expected, the step droplets slow down the step velocity due to the diminishment of kinks in the merged steps (smoothing of the merged steps).

  19. Inhibition of SIRT2 suppresses hepatic fibrosis.

    Science.gov (United States)

    Arteaga, Maribel; Shang, Na; Ding, Xianzhong; Yong, Sherri; Cotler, Scott J; Denning, Mitchell F; Shimamura, Takashi; Breslin, Peter; Lüscher, Bernhard; Qiu, Wei

    2016-06-01

    Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis. PMID:27125275

  20. Hypoxia inhibits abdominal expiratory nerve activity.

    Science.gov (United States)

    Fregosi, R F; Knuth, S L; Ward, D K; Bartlett, D

    1987-07-01

    Our purpose was to examine the influence of steady-state changes in chemical stimuli, as well as discrete peripheral chemoreceptor stimulation, on abdominal expiratory motor activity. In decerebrate, paralyzed, vagotomized, and ventilated cats that had bilateral pneumothoraces, we recorded efferent activity from a phrenic nerve and from an abdominal nerve (cranial iliohypogastric nerve, L1). All cats showed phasic expiratory abdominal nerve discharge at normocapnia [end-tidal PCO2 38 +/- 2 Torr], but small doses (2-6 mg/kg) of pentobarbital sodium markedly depressed this activity. Hyperoxic hypercapnia consistently enhanced abdominal expiratory activity and shortened the burst duration. Isocapnic hypoxia caused inhibition of abdominal nerve discharge in 11 of 13 cats. Carotid sinus nerve denervation (3 cats) exacerbated the hypoxic depression of abdominal nerve activity and depressed phrenic motor output. Stimulation of peripheral chemoreceptors with NaCN increased abdominal nerve discharge in 7 of 10 cats, although 2 cats exhibited marked inhibition. Four cats with intact neuraxis, but anesthetized with ketamine, yielded qualitatively similar results. We conclude that when cats are subjected to steady-state chemical stimuli in isolation (no interference from proprioceptive inputs), hypercapnia potentiates, but hypoxia attenuates, abdominal expiratory nerve activity. Mechanisms to explain the selective inhibition of expiratory motor activity by hypoxia are proposed, and physiological implications are discussed. PMID:3624126

  1. 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.

  2. Phytic Acid Inhibits Lipid Peroxidation In Vitro

    Directory of Open Access Journals (Sweden)

    Alicja Zajdel

    2013-01-01

    Full Text Available Phytic acid (PA has been recognized as a potent antioxidant and inhibitor of iron-catalyzed hydroxyl radical formation under in vitro and in vivo conditions. Therefore, the aim of the present study was to investigate, with the use of HPLC/MS/MS, whether PA is capable of inhibiting linoleic acid autoxidation and Fe(II/ascorbate-induced peroxidation, as well as Fe(II/ascorbate-induced lipid peroxidation in human colonic epithelial cells. PA at 100 μM and 500 μM effectively inhibited the decay of linoleic acid, both in the absence and presence of Fe(II/ascorbate. The observed inhibitory effect of PA on Fe(II/ascorbate-induced lipid peroxidation was lower (10–20% compared to that of autoxidation. PA did not change linoleic acid hydroperoxides concentration levels after 24 hours of Fe(II/ascorbate-induced peroxidation. In the absence of Fe(II/ascorbate, PA at 100 μM and 500 μM significantly suppressed decomposition of linoleic acid hydroperoxides. Moreover, PA at the tested nontoxic concentrations (100 μM and 500 μM significantly decreased 4-hydroxyalkenal levels in Caco-2 cells which structurally and functionally resemble the small intestinal epithelium. It is concluded that PA inhibits linoleic acid oxidation and reduces the formation of 4-hydroxyalkenals. Acting as an antioxidant it may help to prevent intestinal diseases induced by oxygen radicals and lipid peroxidation products.

  3. Oxidation of fats and possibility of its inhibition

    International Nuclear Information System (INIS)

    Factors influencing on the inhibition of oxidation of fats are discussed. Thermal, microwave, photo-initiated and singlet oxygen oxidation of fats were studied. Additives of the rosemary or sage (0.1 mass %) inhibited oxidation of fats

  4. 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

  5. Pyocin inhibition of Neisseria gonorrhoeae: mechanism of action.

    OpenAIRE

    S. A. Morse; Jones, B V; Lysko, P G

    1980-01-01

    Purified R-type pyocins (611 131) from Pseudomonas aeruginosa PA103 exhibited bactericidal activity against Neisseria gonorrhoeae. Killing of gonococci was a single-hit process requiring as few as 1 pyocin per colony-forming unit. Deoxyriboinucleic acid, ribonucleic acid, protein, and lipid syntheses were rapidly and completely inhibited. Oxygen uptake was also inhibited, but occurred after the inhibition of macromolecular synthesis. The cell lysis which occurred after pyocin inhibition of go...

  6. Differential effects of cognitive inhibition and intelligence on creativity

    OpenAIRE

    Benedek, Mathias; Franz, Fabiola; Heene, Moritz; Aljoscha C. Neubauer

    2012-01-01

    There are different conceptions about how cognitive inhibition is related to creativity. Creativity has either been associated with effective inhibition, or with disinhibition, or with an adaptive engagement of inhibition. In this study, we examined the relationship of cognitive inhibition, assessed by means of the random motor generation task, with different measures of creativity. We also analyzed whether this relation is mediated by intelligence. We generally found a positive correlation o...

  7. Selective and nonselective inhibition of competitors in picture naming

    OpenAIRE

    Shao, Z.; Meyer, A. S; Roelofs, A.P.A.

    2013-01-01

    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 c...

  8. Phosphonoacetic Acid Inhibition of Frog Virus 3 Replication

    OpenAIRE

    Elliott, R. M.; Bateson, A.; Kelly, D C

    1980-01-01

    Phosphonoacetic acid at concentrations above 200 μg/ml inhibited the replication of frog virus 3 in BHK cells. The inhibition of viral DNA replication observed in these cells was reversible and correlated with the inhibition of the virus-induced DNA polymerase activity in an in vitro assay. The synthesis of frog virus 3-induced late or γ polypeptides was also inhibited by phosphonoacetic acid, although the early (α and β) polypeptides were unaffected.

  9. The role of behavioural inhibition in preschoolers' emotion understanding

    OpenAIRE

    Bernstein, Dagmar

    2009-01-01

    Behavioural inhibition to the unfamiliar is a temperamental style of reacting to novel situations, peers or adults with fear, wariness and avoidance. Childhood behavioural inhibition is a well-established risk factor for anxiety disorders, particularly social phobia. However, there is presently a gap in the literature with regard to possible links between behavioural inhibition and children’s social development, including their social cognition. There is evidence that behavioural inhibition p...

  10. 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...

  11. 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 ...

  12. Use of bacillus subtilis strains to inhibit postharvest pathogenic fungi

    International Nuclear Information System (INIS)

    An isolate (87) of the bacillus subtilis strains isolated from cold stored citrus fruit 13 proved to inhibit the growth in vitro of the penicillium italicum used in the experiment (from 50.6% to 92.2%) and to inhibit botrytis cinerea (from 65.3% to 95.9%). A further test, superimposing on plates containing PDA strains Nos. 13, 173, and 160, totally inhibited the fungi. Tested in vivo on artificially bruised oranges, they significantly inhibited two fungi

  13. Inhibition of acetylcholinesterase activity by essential oil from Citrus paradisi.

    Science.gov (United States)

    Miyazawa, M; Tougo, H; Ishihara, M

    2001-01-01

    Inhibition of acetylcholinesterase (AChE) activity by essential oils of Citrus paradisi (grapefruit pink in USA) was studied. Inhibition of AChE was measured by the colorimetric method. Nootkatone and auraptene were isolated from C. paradisi oil and showed 17-24% inhibition of AChE activity at the concentration of 1.62 microg/mL. PMID:11858553

  14. Contour detection based on nonclassical receptive field inhibition

    NARCIS (Netherlands)

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

    2003-01-01

    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 prim

  15. 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.

  16. 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 (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

  17. Cardamonin inhibits agonist-induced vascular contractility via Rho-kinase and MEK inhibition.

    Science.gov (United States)

    Je, Hyun Dong; Jeong, Ji Hoon

    2016-01-01

    The present study was undertaken to investigate the influence of cardamonin on vascular smooth muscle contractility and to determine the mechanism(s) involved. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Cardamonin significantly relaxed fluoride-, phenylephrine-, and phorbol ester-induced vascular contractions, suggesting that it has an anti-hypertensive effect on agonist-induced vascular contraction regardless of endothelial nitric oxide synthesis. Furthermore, cardamonin significantly inhibited the fluoride-induced increase in pMYPT1 level and phenylephrine-induced increase in pERK1/2 level, suggesting inhibition of Rho-kinase and MEK activity and subsequent phosphorylation of MYPT1 and ERK1/2. This study provides evidence that the relaxing effect of cardamonin on agonist-induced vascular contraction regardless of endothelial function involves inhibition of Rho-kinase and MEK activity. PMID:26807025

  18. 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.

  19. Metabotropic glutamate receptors inhibit microglial glutamate release

    Directory of Open Access Journals (Sweden)

    Gary Guo Li

    2012-08-01

    Full Text Available Pro-inflammatory stimuli evoke an export of glutamate from microglia that is sufficient to contribute to excitotoxicity in neighbouring neurons. Since microglia also express various glutamate receptors themselves, we were interested in the potential feedback of glutamate on this system. Several agonists of mGluRs (metabotropic glutamate receptors were applied to primary rat microglia, and the export of glutamate into their culture medium was evoked by LPS (lipopolysaccharide. Agonists of group-II and -III mGluR ACPD [(1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid] and L-AP4 [L-(+-2-amino-4-phosphonobutyric acid] were both capable of completely blocking the glutamate export without interfering with the production of NO (nitric oxide; the group-I agonist tADA (trans-azetidine-2,4-dicarboxylic acid was ineffective. Consistent with the possibility of feedback, inhibition of mGluR by MSPG [(R,S-α-2-methyl-4sulfonophenylglycine] potentiated glutamate export. As the group-II and -III mGluR are coupled to Gαi-containing G-proteins and the inhibition of adenylate cyclase, we explored the role of cAMP in this effect. Inhibition of cAMP-dependent protein kinase [also known as protein kinase A (PKA] by H89 mimicked the effect of ACPD, and the mGluR agonist had its actions reversed by artificially sustaining cAMP through the PDE (phosphodiesterase inhibitor IBMX (isobutylmethylxanthine or the cAMP mimetic dbcAMP (dibutyryl cAMP. These data indicate that mGluR activation attenuates a potentially neurotoxic export of glutamate from activated microglia and implicate cAMP as a contributor to this aspect of microglial action.

  20. Brain hyaluronan binding protein inhibits tumor growth

    Institute of Scientific and Technical Information of China (English)

    高锋; 曹曼林; 王蕾

    2004-01-01

    Background Great efforts have been made to search for the angiogenic inhibitors in avascular tissues. Several proteins isolated from cartilage have been proved to have anti-angiogenic or anti-tumour effects. Because cartilage contains a great amount of hyaluronic acid (HA) oligosaccharides and abundant HA binding proteins (HABP), therefore, we speculated that HABP might be one of the factors regulating vascularization in cartilage or anti-angiogenesis in tumours. The purpose of this research was to evaluale the effects of hyaluronan binding protein on inhibiting tumour growth both in vivo and vitro. Methods A unique protein termed human brain hyaluronan (HA) binding protein (b-HABP) was cloned from human brain cDNA library. MDA-435 human breast cancer cell line was chosen as a transfectant. The in vitro underlying mechanisms were investigated by determining the possibilities of MDA-435/b-HABP colony formation on soft agar, the effects of the transfectant on the proliferation of endothelial cells and the expression levels of caspase 3 and FasL from MDA-435/b-HABP. The in vivo study included tumour growth on the chorioallantoic membrane (CAM) of chicken embryos and nude mice. Results Colony formation assay revealed that the colonies formed by MDA-435/b-HABP were greatly reduced compared to mock transfectants. The conditioned media from MDA-435/b-HABP inhibited the growth of endothelial cells in culture. Caspase 3 and FasL expressions were induced by MDA-435/b-HABP. The size of tumours of MDA-435/b-HABP in both CAM and nude mice was much smaller than that of MDA-435 alone. Conclusions Human brain hyaluronan binding protein (b-HABP) may represent a new kind of naturally existing anti-tumour substance. This brain-derived glycoprotein may block tumour growth by inducing apoptosis of cancer cells or by decreasing angiogenesis in tumour tissue via inhibiting proliferation of endothelial cells.

  1. Novel agents inhibit human leukemic cells

    Institute of Scientific and Technical Information of China (English)

    Wei-ping YU; Juan LI

    2012-01-01

    Ouabain (OUA) and pyrithione zinc (PZ) have been proved as the potential drugs for treating acute myeloid leukemia (AML).Selected from a screening among 1040 Food and Drug Administration-approved pharmacological agents,both drugs showability to induce apoptosis of the culturing AML cells,exhibiting the poisoning effect on the cells.Studies also reveal the efficiency of the drugs in inhibiting the growth of human AML cells injected into the mice lacking of immunity and killing primary AML cells from the peripheral blood of AML patients[1].

  2. Structural basis of kynurenine 3-monooxygenase inhibition

    OpenAIRE

    Amaral, Marta; Levy, Colin; Heyes, Derren J; Lafite, Pierre; Outeiro, Tiago F.; Giorgini, Flaviano; Leys, David; Scrutton, Nigel S.

    2013-01-01

    Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (i.e. kynurenine pathway), leads to amelioration of Huntington’s disease-relevant phenotypes in yeast, fruit fly, and mouse models 1–5 , as well as a mouse model of Alzheimer’s disease 3 . KMO is a FAD-dependent monooxygenase, and is located in the outer mitochondrial membrane where it converts L-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolit...

  3. Phenols displaying tyrosinase inhibition from Humulus lupulus.

    Science.gov (United States)

    Kim, Dae Wook; Woo, Hyun Sim; Kim, Jeong Yoon; Ryuk, Jin Ah; Park, Ki Hun; Ko, Byoung Seob

    2016-10-01

    Tyrosinase is the rate-limiting enzyme for the production of melanin and other pigments via the oxidation of l-tyrosine. The methanol extract from Humulus lupulus showed potent inhibition against mushroom tyrosinase. The bioactivity-guided fractionation of this methanol extract resulted in the isolation of seven flavonoids (1-7), identified as xanthohumol (1), 4'-O-methylxanthohumol (2), xanthohumol C (3), flavokawain C (4), xanthoumol B (5), 6-prenylnaringenin (6) and isoxanthohumol (7). All isolated flavonoids (1-7) effectively inhibited the monophenolase (IC50s = 15.4-58.4 µM) and diphenolase (IC50s = 27.1-117.4 µM) activities of tyrosinase. Kinetic studies using Lineweaver-Burk and Dixon-plots revealed that chalcones (1-5) were competitive inhibitors, whereas flavanones (6 and 7) exhibited both mixed and non-competitive inhibitory characteristics. In conclusion, this study is the first to demonstrate that the phenolic phytochemicals of H. lupulus display potent inhibitory activities against tyrosinase. PMID:26162028

  4. Diacylglycerol Kinase Inhibition and Vascular Function.

    Science.gov (United States)

    Choi, Hyehun; Allahdadi, Kyan J; Tostes, Rita C A; Webb, R Clinton

    2009-01-01

    Diacylglycerol kinases (DGKs), a family of lipid kinases, convert diacylglycerol (DG) to phosphatidic acid (PA). Acting as a second messenger, DG activates protein kinase C (PKC). PA, a signaling lipid, regulates diverse functions involved in physiological responses. Since DGK modulates two lipid second messengers, DG and PA, regulation of DGK could induce related cellular responses. Currently, there are 10 mammalian isoforms of DGK that are categorized into five groups based on their structural features. These diverse isoforms of DGK are considered to activate distinct cellular functions according to extracellular stimuli. Each DGK isoform is thought to play various roles inside the cell, depending on its subcellular localization (nuclear, ER, Golgi complex or cytoplasm). In vascular smooth muscle, vasoconstrictors such as angiotensin II, endothelin-1 and norepinephrine stimulate contraction by increasing inositol trisphosphate (IP(3)), calcium, DG and PKC activity. Inhibition of DGK could increase DG availability and decrease PA levels, as well as alter intracellular responses, including calcium-mediated and PKC-mediated vascular contraction. The purpose of this review is to demonstrate a role of DGK in vascular function. Selective inhibition of DGK isoforms may represent a novel therapeutic approach in vascular dysfunction. PMID:21547002

  5. Dynamic characteristics of multisensory facilitation and inhibition.

    Science.gov (United States)

    Wang, W Y; Hu, L; Valentini, E; Xie, X B; Cui, H Y; Hu, Y

    2012-10-01

    Multimodal integration, which mainly refers to multisensory facilitation and multisensory inhibition, is the process of merging multisensory information in the human brain. However, the neural mechanisms underlying the dynamic characteristics of multimodal integration are not fully understood. The objective of this study is to investigate the basic mechanisms of multimodal integration by assessing the intermodal influences of vision, audition, and somatosensory sensations (the influence of multisensory background events to the target event). We used a timed target detection task, and measured both behavioral and electroencephalographic responses to visual target events (green solid circle), auditory target events (2 kHz pure tone) and somatosensory target events (1.5 ± 0.1 mA square wave pulse) from 20 normal participants. There were significant differences in both behavior performance and ERP components when comparing the unimodal target stimuli with multimodal (bimodal and trimodal) target stimuli for all target groups. Significant correlation among reaction time and P3 latency was observed across all target conditions. The perceptual processing of auditory target events (A) was inhibited by the background events, while the perceptual processing of somatosensory target events (S) was facilitated by the background events. In contrast, the perceptual processing of visual target events (V) remained impervious to multisensory background events. PMID:24082962

  6. Sprouting inhibition of rhizomes by gamma irradiation

    International Nuclear Information System (INIS)

    Sprouting inhibition by gamma irradiation to prolong the storage life of 4 species of rhizomes, namely curcuma domestica, kaemferia galanga, curcuma xanthoriza and curcuma aeruginosa, has been carried out. Two groups of samples were used, freshly harvested rhizomes and fresh rhizomes which have been stored for about two weeks. The samples were packed in a plastic net bag, each contained about 100 grams of rhizomes. Irradiation was carried out at room temperature at the doses of 0, 0.02, 0.04, 0.06, 0.08, 0.10, 0.15, 0.20 and 0.25 kGy. Post irradiation storage was done at room temperature with relative humidity ranging between 85 and 95%. The results showed that irradiation doses of 0.06 to 0.08 kGy was sufficient to inhibit sprouting of freshly harvested rhizomes and prolonged its storage life for 6 weeks, while in the other group sprouting still occured at the dose of 0.25 kGy. Irradiation dose up to 0.25 kGy did not cause significant effect on moisture and volatile oil contents, as well as volatile oil characteristics of the samples. About 50% of weight losses were found either in irradiated or unirradiated samples after being stored for 8 weeks. Odour and texture were evaluated organoleptically while mould growth and insect damage were observed visually. (author)

  7. Elmo1 inhibits ubiquitylation of Dock180.

    Science.gov (United States)

    Makino, Yoshinori; Tsuda, Masumi; Ichihara, Shin; Watanabe, Takuya; Sakai, Mieko; Sawa, Hirofumi; Nagashima, Kazuo; Hatakeyama, Shigetsugu; Tanaka, Shinya

    2006-03-01

    Dock180, a member of the CDM family of proteins, plays roles in biological processes such as phagocytosis and motility through its association with the signalling adaptor protein Crk. Recently, the complex formation between Dock180 and Elmo1 was reported to function as a bipartite guanine nucleotide exchange factor for Rac. In this study, we demonstrated that the amount of Dock180 increased when Elmo1 was co-expressed. Dock180 was found to be ubiquitylated and Dock180 protein levels could be augmented by treatment with proteasome inhibitor. The ubiquitylation of Dock180 was enhanced by epidermal growth factor (EGF), Crk and adhesion-dependent signals. Furthermore, Elmo1 inhibited ubiquitylation of Dock180, resulting in the increase in Dock180 levels. The Elmo1 mutant Delta531, which encompasses amino acids required for Dock180 binding, preserved the inhibitory effects on ubiquitylation of Dock180. Upon EGF stimulation, both Dock180 and ubiquitin were demonstrated to translocate to the cell periphery by immunofluorescence, and we found ubiquitylation of Dock180 and its inhibition by Elmo1 to occur in cellular membrane fractions by in vivo ubiquitylation assay. These data suggest that Dock180 is ubiquitylated on the plasma membrane, and also that Elmo1 functions as an inhibitor of ubiquitylation of Dock180. Therefore, an ubiquitin-proteasome-dependent protein degradation mechanism might contribute to the local activation of Rac on the plasma membrane. PMID:16495483

  8. TNIK inhibition abrogates colorectal cancer stemness

    Science.gov (United States)

    Masuda, Mari; Uno, Yuko; Ohbayashi, Naomi; Ohata, Hirokazu; Mimata, Ayako; Kukimoto-Niino, Mutsuko; Moriyama, Hideki; Kashimoto, Shigeki; Inoue, Tomoko; Goto, Naoko; Okamoto, Koji; Shirouzu, Mikako; Sawa, Masaaki; Yamada, Tesshi

    2016-01-01

    Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach. PMID:27562646

  9. Ribosome Inactivating Proteins from Plants Inhibiting Viruses

    Institute of Scientific and Technical Information of China (English)

    Inderdeep Kaur; R C Gupta; Munish Puri

    2011-01-01

    Many plants contain ribosome inactivating proteins (RIPs) with N-glycosidase activity,which depurinate large ribosomal RNA and arrest protein synthesis.RIPs so far tested inhibit replication of mRNA as well as DNA viruses and these proteins,isolated from plants,are found to be effective against a broad range of viruses such as human immunodeficiency virus (HIV),hepatitis B virus (HBV) and herpes simplex virus (HSV).Most of the research work related to RIPs has been focused on antiviral activity against HIV; however,the exact mechanism of antiviral activity is still not clear.The mechanism of antiviral activity was thought to follow inactivation of the host cell ribosome,leading to inhibition of viral protein translation and host cell death.Enzymatic activity of RIPs is not hmited to depurination of the large rRNA,in addition they can depurinate viral DNA as well as RNA.Recently,Phase Ⅰ/Ⅱ clinical trials have demonstrated the potential use of RIPs for treating patients with HIV disease.The aim of this review is to focus on various RIPs from plants associated with anti-HIV activity.

  10. Inhibition of dioscin on Saprolegnia in vitro.

    Science.gov (United States)

    Liu, Lei; Shen, Yu-Feng; Liu, Guang-Lu; Ling, Fei; Liu, Xin-Yang; Hu, Kun; Yang, Xian-Le; Wang, Gao-Xue

    2015-12-01

    As one of the most serious pathogens in the freshwater aquatic environment, Saprolegnia can induce a high mortality rate during the fish egg incubation period. This study investigated the anti-Saprolegnia activity of a total of 108 plants on Saprolegnia parasitica in vitro and Dioscorea collettii was selected for further studies. By loading on an open silica gel column and eluting with petroleum ether-ethyl acetate-methanol, dioscin (C45H72O16) was isolated from D. collettii. Saprolegnia parasitica growth was inhibited significantly when dioscin concentration was more than 2.0 mg L(-1). When compared with formalin and hydrogen peroxide, dioscin showed a higher inhibitory effect. As potential inhibition mechanisms, dioscin could cause the S. parasitica mycelium morphologic damage, dense folds, or disheveled protuberances observed by field emission scanning electron microscopy and the influx of Propidium iodide. The structural changes in the treated mycelium were indicative of an efficient anti-Saprolegnia activity of dioscin. The oxidative stress results showed that dioscin also accumulated reactive oxygen species excessively and increased total antioxidant and superoxide dismutase activity. These situations could render S. parasitica more vulnerable to oxidative damage. Additionally, when dioscin concentration was less than 2.0 mg L(-1), the survival rate of embryos was more than 70%. Therefore, the use of dioscin could be a viable way of preventing and controlling saprolegniasis. PMID:26472687

  11. Structural basis of kynurenine 3-monooxygenase inhibition.

    Science.gov (United States)

    Amaral, Marta; Levy, Colin; Heyes, Derren J; Lafite, Pierre; Outeiro, Tiago F; Giorgini, Flaviano; Leys, David; Scrutton, Nigel S

    2013-04-18

    Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (that is, kynurenine pathway), leads to amelioration of Huntington's-disease-relevant phenotypes in yeast, fruitfly and mouse models, as well as in a mouse model of Alzheimer's disease. KMO is a flavin adenine dinucleotide (FAD)-dependent monooxygenase and is located in the outer mitochondrial membrane where it converts l-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained unknown. Here we report the first crystal structure of Saccharomyces cerevisiae KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active-site structure, preventing productive binding of the substrate l-kynurenine. Functional assays and targeted mutagenesis reveal that the active-site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO-UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases. PMID:23575632

  12. Glycerol inhibition of ruminal lipolysis in vitro.

    Science.gov (United States)

    Edwards, H D; Anderson, R C; Miller, R K; Taylor, T M; Hardin, M D; Smith, S B; Krueger, N A; Nisbet, D J

    2012-09-01

    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 supplemental glycerol on rumen lipolysis, mixed populations of ruminal bacteria were incubated with 6 or 20% glycerol (vol/vol). After 48-h anaerobic incubation of mixed culture rumen fluid, rates of free fatty acid production (nmol/mL per h) for the 6 and 20% glycerol-supplemented samples were decreased by 80 and 86%, respectively, compared with rates from nonsupplemented control cultures (12.4±1.0; mean ± SE). Conversely, assay of the prominent ruminal lipase-producing bacteria Anaerovibrio lipolyticus 5S, Butyrivibrio fibrisolvens 49, and Propionibacterium species avidum and acnes revealed no effect of 2 or 10% (vol/vol) added glycerol on lipolytic activity by these organisms. Supplementing glycerol at 6% on a vol/vol basis, equivalent to supplementing glycerol at approximately 8 to 15% of diet dry matter, effectively reduced lipolysis. However, the mechanism of glycerol inhibition of ruminal lipolysis remains to be demonstrated. PMID:22916923

  13. Inhibition Of Washed Sludge With Sodium Nitrite

    Energy Technology Data Exchange (ETDEWEB)

    Congdon, J. W.; Lozier, J. S.

    2012-09-25

    This report describes the results of electrochemical tests used to determine the relationship between the concentration of the aggressive anions in washed sludge and the minimum effective inhibitor concentration. Sodium nitrate was added as the inhibitor because of its compatibility with the DWPF process. A minimum of 0.05M nitrite is required to inhibit the washed sludge simulant solution used in this study. When the worst case compositions and safety margins are considered, it is expected that a minimum operating limit of nearly 0.1M nitrite will be specified. The validity of this limit is dependent on the accuracy of the concentrations and solubility splits previously reported. Sodium nitrite additions to obtain 0.1M nitrite concentrations in washed sludge will necessitate the additional washing of washed precipitate in order to decrease its sodium nitrite inhibitor requirements sufficiently to remain below the sodium limits in the feed to the DWPF. Nitrite will be the controlling anion in "fresh" washed sludge unless the soluble chloride concentration is about ten times higher than predicted by the solubility splits. Inhibition of "aged" washed sludge will not be a problem unless significant chloride dissolution occurs during storage. It will be very important tomonitor the composition of washed sludge during processing and storage.

  14. Denitrification inhibition by high nitrate wastes

    International Nuclear Information System (INIS)

    The processing of radioactive metal products at nuclear weapons plants and research labs has produced wastewaters containing high concentrations of nitrate, often greater than 50,000 mg/l N. The adaptation of activated sludge and inhibition of denitrification at high nitrate concentrations was studied using pH controlled bench-scale sequencing batch reactors (SBRs), operated with 50% of the SBR volume recycled (recycle volume = influent volume). Denitrification of 1,350 and 2,700 mg/l NO3--N was completed after approximately 5 hours and 15 hours, respectively. No denitrification of 5,400 mg/l NO3--N was observed. These results suggest that there is a progressive inhibition of denitrification as nitrate concentrations increase from 1,350 to 5,400 mg/l NO3--N. In a subsequent series of experiments at an initial reactor nitrate concentration of 1,350 mg/l N, a significant accumulation of nitrate was observed, resulting once in destabilization with loss of denitrification and once in successful adaptation of the activated sludge. At a nitrate concentration of 1,350 mg/l N, the adaptation of activated sludge appears to be unstable, resulting sometimes in stable denitrification and sometimes in biomass washout

  15. Inhibition of the dorsal premotor cortex does not repair surround inhibition in writer's cramp patients

    NARCIS (Netherlands)

    Veugen, L.C.; Hoffland, B.S.; Stegeman, D.F.; Warrenburg, B.P.C. van de

    2013-01-01

    Writer's cramp is a task-specific form of focal dystonia, characterized by abnormal movements and postures of the hand and arm during writing. Two consistent abnormalities in its pathophysiology are a loss of surround inhibition and overactivity of the dorsal premotor cortex (PMd). This study aimed

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

    Science.gov (United States)

    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

    2016-07-01

    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 phosphatase. 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 neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. 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. PMID:27362227

  17. 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. PMID:26876617

  18. Expressive inhibition following interpersonal trauma: an analysis of reported function.

    Science.gov (United States)

    Clapp, Joshua D; Jones, Judiann M; Jaconis, Maryanne; Olsen, Shira A; Woodward, Matthew J; Beck, J Gayle

    2014-03-01

    Existing research indicates veterans with posttraumatic stress disorder (PTSD) may deliberately inhibit the expression of emotion. However, the degree to which inhibition generalizes to other trauma populations and the specific reasons survivors with PTSD inhibit expression remains unclear. The present study looked to evaluate expressive inhibition among survivors of intimate partner violence (N = 74), to determine reasons for inhibition in this population, and to examine whether any justifications for inhibition are unique to individuals with PTSD. The frequency and intensity of inhibition scores were similar to those noted in previous research although no differences were observed across women with and without PTSD. Self-reported justifications for inhibition indicated five general themes: Concern for others, Mistrust/fear of exploitation, Perception of others as indifferent/uncaring, Control/Experiential avoidance, and Situation-specific inhibition. Only mistrust/exploitation motives were uniquely associated with PTSD. Whereas expressive inhibition may be elevated within help-seeking samples, individuals who develop PTSD appear to hold unique reasons for restricting emotional expression. PMID:24507632

  19. Radiation inhibits proteasomes and increases ubiquitinated proteins

    International Nuclear Information System (INIS)

    Full text: Exposure of cells to ionizing radiation results in accumulation of a number of short lived proteins that mediate cell survival/death, proliferation, repair, and differentiation. Expression of most of these proteins, including p53, mdm2, p21, c-jun, IkB-a, bcl-2, bax, cyclins A, B, E, Cdc25A, DNA-PKcs, and caspase-3 is regulated at the post-transcriptional level through ubiquitin/26S proteasome pathway. Several previous studies have shown that inhibition of proteasome activity by drugs leads to accumulation of ubiquitinated proteins. In this study we show that irradiation can do the same due to its inhibitory effect on 26S, but not 20S, proteasome activity. Two prostate cancer cell lines, murine TRAMP-C1 and human PC3, were used to examine the effect of ionizing radiation on the catalytic activity of the 26S proteasome. Cells were irradiated with different doses ranging from 0.25 to 20 Gy and lysed at different time points after irradiation. Crude extracts of both cell lines showed a rapid 30-50% decrease in chymotryptic activity of the 26S proteasome, as measured by a fluorogenic assay. The same level of inhibition was observed if purified 26S proteasomes were themselves irradiated, indicating that radiation has direct effects on this multicatalytic enzyme complex. Neither direct irradiation of proteasomes or cells had effect on 20S catalytic activity, suggesting that radiation selectively acts on 26S structure. Next, we examined whether this partial inhibition had any effect on ability of 26S proteasome to efficiently remove ubiquitinated proteins. Cells were irradiated with 10Gy and lysed at different time points. Ubiquitinated proteins were precipitated and examined by Western blot. Levels of ubiquitinated conjugates slowly increased over time and peaked at 7h post-irradiation. Accumulation of ubiquitinated conjugates has been shown to lead to formation of protein aggregates which can induce cell death. It has also been shown that monoubiquitination

  20. 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.

  1. CEACAM1-Mediated Inhibition of Virus Production.

    Science.gov (United States)

    Vitenshtein, Alon; Weisblum, Yiska; Hauka, Sebastian; Halenius, Anne; Oiknine-Djian, Esther; Tsukerman, Pinchas; Bauman, Yoav; Bar-On, Yotam; Stern-Ginossar, Noam; Enk, Jonatan; Ortenberg, Rona; Tai, Julie; Markel, Gal; Blumberg, Richard S; Hengel, Hartmut; Jonjic, Stipan; Wolf, Dana G; Adler, Heiko; Kammerer, Robert; Mandelboim, Ofer

    2016-06-14

    Cells in our body can induce hundreds of antiviral genes following virus sensing, many of which remain largely uncharacterized. CEACAM1 has been previously shown to be induced by various innate systems; however, the reason for such tight integration to innate sensing systems was not apparent. Here, we show that CEACAM1 is induced following detection of HCMV and influenza viruses by their respective DNA and RNA innate sensors, IFI16 and RIG-I. This induction is mediated by IRF3, which bound to an ISRE element present in the human, but not mouse, CEACAM1 promoter. Furthermore, we demonstrate that, upon induction, CEACAM1 suppresses both HCMV and influenza viruses in an SHP2-dependent process and achieves this broad antiviral efficacy by suppressing mTOR-mediated protein biosynthesis. Finally, we show that CEACAM1 also inhibits viral spread in ex vivo human decidua organ culture. PMID:27264178

  2. CEACAM1-Mediated Inhibition of Virus Production

    Directory of Open Access Journals (Sweden)

    Alon Vitenshtein

    2016-06-01

    Full Text Available Cells in our body can induce hundreds of antiviral genes following virus sensing, many of which remain largely uncharacterized. CEACAM1 has been previously shown to be induced by various innate systems; however, the reason for such tight integration to innate sensing systems was not apparent. Here, we show that CEACAM1 is induced following detection of HCMV and influenza viruses by their respective DNA and RNA innate sensors, IFI16 and RIG-I. This induction is mediated by IRF3, which bound to an ISRE element present in the human, but not mouse, CEACAM1 promoter. Furthermore, we demonstrate that, upon induction, CEACAM1 suppresses both HCMV and influenza viruses in an SHP2-dependent process and achieves this broad antiviral efficacy by suppressing mTOR-mediated protein biosynthesis. Finally, we show that CEACAM1 also inhibits viral spread in ex vivo human decidua organ culture.

  3. Silencing FAT10 inhibits metastasis of osteosarcoma.

    Science.gov (United States)

    Ma, Chengbin; Zhang, Zhiyu; Cui, Yan; Yuan, Hongmou; Wang, Feng

    2016-08-01

    Metastasis is the main challenge of osteosarcoma treatment. Herein, we first reveal the oncogenic role of FAT10 in metastasis of osteosarcoma. FAT10 was upregulated in osteosarcoma, especially in metastatic osteosarcoma. High level of FAT10 was associated with poorer prognosis of osteosarcoma patients. Moreover, Transwell and Matrigel assays revealed that silencing FAT10 significantly inhibited the invasive and migratory abilities of osteosarcoma cells. Metastasis assay in vivo showed that silencing FAT10 decreased the number of mice with distant metastasis. We also found that FAT10 may act its oncogenic functions through regulating HOXB9. Collectively, the results suggested that FAT10 may be a novel therapeutic target for osteosarcoma patients. PMID:27279480

  4. Inhibition of strigolactones promotes adventitious root formation.

    Science.gov (United States)

    Rasmussen, Amanda; Beveridge, Christine A; Geelen, Danny

    2012-06-01

    Roots that form from non-root tissues (adventitious roots) are crucial for cutting propagation in the forestry and horticulture industries. Strigolactone has been demonstrated to be an important regulator of these roots in both Arabidopsis and pea using strigolactone deficient mutants and exogenous hormone applications. Strigolactones are produced from a carotenoid precursor which can be blocked using the widely available but broad terpenoid biosynthesis blocker, fluridone. We demonstrate here that fluridone can be used to promote adventitious rooting in the model species Pisum sativum (pea). In addition, in the garden species Plumbago auriculata and Jasminium polyanthum fluridone was equally as successful at promoting roots as a commercial rooting compound containing NAA and IBA. Our findings demonstrate that inhibition of strigolactone signaling has the potential to be used to improve adventitious rooting in commercially relevant species. PMID:22580687

  5. 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.

  6. Mechanism of allopurinol induced TPMT inhibition.

    Science.gov (United States)

    Blaker, P A; Arenas-Hernandez, M; Smith, M A; Shobowale-Bakre, E A; Fairbanks, L; Irving, P M; Sanderson, J D; Marinaki, A M

    2013-08-15

    Up to 1/5 of patients with wildtype thiopurine-S-methyltransferase (TPMT) activity prescribed azathioprine (AZA) or mercaptopurine (MP) demonstrate a skewed drug metabolism in which MP is preferentially methylated to yield methylmercaptopurine (MeMP). This is known as thiopurine hypermethylation and is associated with drug toxicity and treatment non-response. Co-prescription of allopurinol with low dose AZA/MP (25-33%) circumvents this phenotype and leads to a dramatic reduction in methylated metabolites; however, the biochemical mechanism remains unclear. Using intact and lysate red cell models we propose a novel pathway of allopurinol mediated TPMT inhibition, through the production of thioxanthine (TX, 2-hydroxymercaptopurine). In red blood cells pre-incubated with 250 μM MP for 2h prior to the addition of 250 μM TX or an equivalent volume of Earle's balanced salt solution, there was a significant reduction in the concentration of MeMP detected at 4h and 6h in cells exposed to TX (4 h, 1.68, p=0.0005, t-test). TX acts as a direct TPMT inhibitor with an apparent Ki of 0.329 mM. In addition we have confirmed that the mechanism is relevant to in vivo metabolism by demonstrating raised urinary TX levels in patients receiving combination therapy. We conclude that the formation of TX in patients receiving combination therapy with AZA/MP and allopurinol, likely explains the significant reduction of methylated metabolites due to direct TPMT inhibition. PMID:23770457

  7. Condensation on Aerosol Particles and its Inhibition.

    Science.gov (United States)

    Liu, Peter Shen King

    The atmospheric aerosol is of primary importance in the formation of precipitation. Except in the neighbourhood of large sources of pollution most of the atmospheric particles are of natural origin, but human contribution is increasing at such a rate that within a comparatively short time it may equal nature's. Such an increase in the atmospheric particulate load may have significant effects on the distribution and intensity of precipitation. There is a general perception that most of the atmospheric particulate load is soluble in water or has some soluble component and soluble particles condense water more readily than insoluble. In this work a study is made of the solubility of the atmospheric aerosol at various relative humidities. The results confirm that much of the atmospheric aerosol is indeed soluble, but that the soluble proportion is highly variable. This result has significant implications for studies of air pollution in which the respirable fraction of the atmospheric aerosol is deduced from the results of long term dichotomous sampling. Results are also presented of studies in which an attempt was made to inhibit the condensation of water on man-made and adventitious particles with a view to modifying their possible climatic effects. This work has demonstrated that certain agents, notably long chain amines, do indeed have an inhibiting effect on the condensation of water on particles which have been exposed to them, but that the effect of the agents so far tested is not sufficiently great to be of immediate practical importance. It is concluded that further advances must await more precise methods of producing small supersaturations reliably and reproducibly.

  8. Radiation sensitization by inhibition of activated ras

    International Nuclear Information System (INIS)

    Background and purpose: Ras has been identified as a significant contributor to radiation resistance. This article reviews preclinical and phase I clinical studies that reported on combining inhibition of activated Ras and downstream effectors of Ras with radiotherapy. Material and methods: transfection studies and RNA interference were used to check the role of the Ras isoforms for intrinsic radiation sensibility. Western blotting was used to control for prenylation inhibition of the respective Ras isoforms and for changes in activity of downstream proteins. Clonogenic assays with human and rodent tumor cell lines served for testing radiosensitivity. In vivo, farnesyltransferase inhibitors (FTIs) and irradiation were used to treat xenograft tumors. Ex vivo plating efficiency measurements, regrowth of tumors, and EF5 staining for detection of hypoxia were endpoints in these studies. Simultaneous treatment with L-778,123 and irradiation was performed in non-small cell lung cancer, head and neck cancer, and pancreatic cancer patients. Results: radiation sensitization was achieved in vitro and in vivo blocking the prenylation of Ras proteins in cell lines with Ras activated by mutations or receptor signaling. Among the many Ras downstream pathways the phosphoinositide 3 (PI3) kinase-Akt pathway was identified as a contributor to Ras-mediated radiation resistance. Furthermore, increased oxygenation was observed in xenograft tumors after FTI treatment. Combined treatment in a phase I study was safe and effective. Conclusion: the rational combination of FTIs with radiotherapy may improve the clinical results of patients with tumors who bear mutant or receptor-signaling activated Ras. (orig.)

  9. Indirubin derivative E804 inhibits angiogenesis

    International Nuclear Information System (INIS)

    It has previously been shown that indirubin derivative E804 (IDR-E804) blocks signal transducer and activator of transcription-3 signaling in human breast and prostate cancer cells and inhibits Src kinase activity. To further establish its role in angiogenesis, we tested its potential using human umbilical vein endothelial cells (HUVECs) and analyzed the effects of IDR-E804 on cellular and molecular events related to angiogenesis. The anti-angiogenic effects of IDR-E804 were examined by assessing the proliferation, migration and capillary tube formation of HUVECs were induced by vascular endothelial growth factor (VEGF) with or without various concentrations of IDR-E804. The inhibitory effect of IDR-E804 angiogenesis and tumor growth in vivo was also investigated in Balb/c mice subcutaneously transplanted with CT-26 colon cancer cells. IDR-E804 significantly decreased proliferation, migration and tube formation of vascular endothelial growth factor VEGF-treated HUVECs. These effects were accompanied by decreased phosphorylation of VEGF receptor (VEGFR)-2, AKT and extracellular signal regulated kinase in VEGF-treated HUVECs. Intratumor injections of IDR-E804 inhibited the growth of subcutaneously inoculated CT-26 allografts in syngenic mice. Immunohistochemistry revealed a decreased CD31 microvessel density index and Ki-67 proliferative index, but an increased apoptosis index in IDR-E804-treated tumors. These data revealed that IDR-E804 is an inhibitor of angiogenesis and also provide evidence for the efficacy of IDR-E804 for anti-tumor therapies

  10. Inhibition of corrosive processes in wet atmosphere

    International Nuclear Information System (INIS)

    Toluylalanine (TALA) is an additive in industrial cleaning baths and an effective temporary inhibitor of the corrosion of steel in neutral and weak alkaline electrolytes as well as in wet atmosphere. In dependence on the relative humidity of the atmosphere and the presence of hygroscopic salts, thin water films condense. The interaction between the metallic surface and the condensed liquid depends strongly on the surface tension. In our case we obtained a hydrophilic effect after the adsorption of the inhibitor. It can be assumed, that the water of the cleaning bath drains off the metal much better than in the case of hydrophobic layers. These effects in the range of monolayers could be studied with the quartz microbalance due to the high sensitivity of this technique. Improving our model, we obtained a lower and homogenous deposition of salt after the dipping in solution with TALA, which causes also a reduced homogenous condensation of water. Thus, corrosive attacks become less probable. The reactions in the cleaning bath and in films of condensed water were investigated by electrochemical methods in bulk electrolytes. In the presence of inhibitor the corrosion potential was shifted into the anodic direction, simultaneously the thickness of the oxide layer was increased in the presence of TALA. The characteristic data of pitting corrosion were obtained from anodic potentiodynamic sweeps. These results show, that pitting is hindered by TALA. Besides the stabilization of the passive layer, the growth of pits is also inhibited and repassivation is accelerated. From the polarization of probes precorroded at wet atmosphere we yielded in solutions with TALA an re-inhibition, too. Additionally we observed in unprotected solutions the sensitivity of this method to active corrosion centers, which cause pitting at lower overvoltages

  11. Btk inhibition treats TLR7/IFN driven murine lupus.

    Science.gov (United States)

    Bender, Andrew T; Pereira, Albertina; Fu, Kai; Samy, Eileen; Wu, Yin; Liu-Bujalski, Lesley; Caldwell, Richard; Chen, Yi-Ying; Tian, Hui; Morandi, Federica; Head, Jared; Koehler, Ursula; Genest, Melinda; Okitsu, Shinji L; Xu, Daigen; Grenningloh, Roland

    2016-03-01

    Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors. In vitro studies using primary human macrophages revealed that Btk inhibition can block activation by immune complexes and TLR7 which contributes to tissue damage in SLE. Overall, our results provide translational insight into how Btk inhibition may provide benefit to a variety of SLE patients by affecting both BCR and FcR signaling. PMID:26821304

  12. Study on the Inhibition of Fermented Soybean to Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    LU Yan; WANG Wei; SHAN Yi; E Zhiqiang; WANG Liqun

    2009-01-01

    In the experiment, the inhibition of isoflavones extracted from soybean and tempe to SP2/0 and Hela cells was studied,and the inhibition rate of each unit for cancer cells was also studied. The results showed that the inhibition rate of tempe isoflavones to SP2/0 was 96.9% and to Hela cells was 69.5% when the concentration was 20 μg·mL-1. In the same condition, the inhibition rate of soybean isoflavones was 83.16% and 60.5%. With the decline of concentration, the inhibition rate decreased. The inhibition of isoflavones to SP2/0 did not exist when the concentration was 5-1.25 μg·mL-1.

  13. Inhibition of MAO by fractions and constituents of hypericum extract.

    Science.gov (United States)

    Bladt, S; Wagner, H

    1994-10-01

    The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as pure substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition. PMID:7857511

  14. Molecular mechanisms of DNA repair inhibition by caffeine

    International Nuclear Information System (INIS)

    Caffeine potentiates the mutagenic and lethal effects of genotoxic agents. It is thought that this is due, at least in some organisms, to inhibition of DNA repair. However, direct evidence for inhibition of repair enzymes has been lacking. Using purified Escherichia coli DNA photolyase and (A)BC excinuclease, we show that the drug inhibits photoreactivation and nucleotide excision repair by two different mechanisms. Caffeine inhibits photoreactivation by interfering with the specific binding of photolyase to damaged DNA, and it inhibits nucleotide excision repair by promoting nonspecific binding of the damage-recognition subunit, UvrA, of (A)BC excinuclease. A number of other intercalators, including acriflavin and ethidium bromide, appear to inhibit the excinuclease by a similar mechanism--that is, by trapping the UvrA subunit in nonproductive complexes on undamaged DNA

  15. Cocaine inhibition of nicotinic acetylcholine receptors influences dopamine release

    OpenAIRE

    Alexandra eAcevedo-Rodriguez; Lifen eZhang; Fuwen eZhou; Suzhen eGong; Howard eGu; Mariella eDe Biasi; Fu-Ming eZhou; Dani, John A.

    2014-01-01

    Nicotinic acetylcholine receptors (nAChRs) potently regulate dopamine (DA) release in the striatum and alter cocaine’s ability to reinforce behaviors. Since cocaine is a weak nAChR inhibitor, we hypothesized that cocaine may alter DA release by inhibiting the nAChRs in DA terminals in the striatum and thus contribute to cocaine's reinforcing properties primarily associated with the inhibition of DA transporters. We found that biologically relevant concentrations of cocaine can mildly inhibit...

  16. Cross inhibition improves activity selection when switching incurs time costs

    OpenAIRE

    Favreau-Peigne, Angélique; Fromhage, Lutz; McNamara, John M.; Meah, Lianne F.S.; Houston, Alasdair I.

    2015-01-01

    We consider a behavioural model of an animal choosing between two activities, based on positive feedback, and examine the effect of introducing cross inhibition between the motivations for the two activities. While cross-inhibition has previously been included in models of decision making, the question of what benefit it may provide to an animal's activity selection behaviour has not previously been studied. In neuroscience and in collective behaviour cross-inhibition, and other equivalent me...

  17. Nonspecific Inhibition of the Motor System during Response Preparation

    OpenAIRE

    Greenhouse, Ian; Sias, Ana; Labruna, Ludovica; Ivry, Richard B

    2015-01-01

    Motor system excitability is transiently inhibited during the preparation of responses. Previous studies have attributed this inhibition to the operation of two mechanisms, one hypothesized to help resolve competition between alternative response options, and the other to prevent premature response initiation. By this view, inhibition should be restricted to task-relevant muscles. Although this prediction is supported in one previous study (Duque et al., 2010), studies of stopping ongoing act...

  18. Are individual differences in arithmetic fact retrieval related to inhibition?

    OpenAIRE

    Bellon, Elien

    2016-01-01

    Although it has been proposed that inhibition is related to individual differences in mathematical achievement, it is not clear how it is related to specific aspects of mathematical skills, such as arithmetic fact retrieval. The present study therefore investigated the association between inhibition and arithmetic fact retrieval and further examined the unique role of inhibition in individual differences in arithmetic fact retrieval, in addition to numerical magnitude processin...

  19. Ultraviolet light inhibition of oriented fibrin formation in psoriasis

    International Nuclear Information System (INIS)

    Radially-oriented fibrin crystallization was induced by incubation of blood from psoriatic patients with killed Pseudomonas aeruginosa. The phenomenon was inhibited by irradiation of the buffy coat in plasma with UB-B. It was not inhibited by UV-A unless trioxsalen had been added. Addition of UV-B-irradiated plasma to non-irradiated buffy coat also inhibits the fibrin formation. (author)

  20. INHIBITION COGNITIVE, TRAITEMENT EMOTIONNEL IMPLICITE et TROUBLE DEPRESSIF MAJEUR

    OpenAIRE

    Gendry-Gohier, Bénédicte

    2011-01-01

    Major depressive disorder is characterized by impairments in memory, attention and executive functions, particularly the cognitive inhibition and in emotional regulation. The objective of this study was to evaluate the process of emotional processing in major depressive disorder byfocusing on cognitive inhibition and the implicit treatment of emotional information. In a first experiment, we evaluated the ability of cognitive inhibition in a population of twenty patients suffering from major d...

  1. Inhibition of lymphocyte activation by gold sodium thiomalate.

    OpenAIRE

    Hopkins, S J; Jayson, M I; Zeil, P.

    1983-01-01

    Activation of lymphoid cells by both T and B cell mitogens was inhibited by gold sodium thiomalate (GST). The action of GST did not appear to be exerted at early stages of lymphocyte activation. Inhibition by GST was sustained throughout 4 days of culture. The inhibitory effect of GST was reduced at low serum concentrations. Sodium thiomalate and sodium chloroaurate were also able to inhibit lymphocyte activation.

  2. Ethanol inhibition of baroreflex bradycardia: role of brainstem GABA receptors.

    OpenAIRE

    Varga, K.; Kunos, G.

    1990-01-01

    Ethanol administered i.v. or into the nucleus tractus solitarii (NTS) of rats anaesthetized with urethane inhibits baroreflex bradycardia elicited by phenylephrine. This effect is prevented or reduced by pretreatment of rats with 3-mercaptopropionic acid, bicuculline, or RO 15-4513. Intra-NTS injection of muscimol also inhibits baroreflex bradycardia and causes a pressor response which is potentiated by intra-NTS ethanol. It is proposed that ethanol inhibits baroreflex bradycardia, at least i...

  3. 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.

  4. Inhibition of DNA gyrase by optically active ofloxacin.

    OpenAIRE

    Imamura, M.; Shibamura, S; Hayakawa, I.; Osada, Y

    1987-01-01

    Inhibition of DNA gyrase activity by optically active ofloxacins was studied and compared with the inhibition of norfloxacin and ciprofloxacin. The (-)-isomer of ofloxacin inhibited the supercoiling activity of gyrase from Micrococcus luteus more effectively than did the (+)-isomer. The 50% inhibitory concentrations of (-)-, (+/-)-, and (+)-ofloxacin; norfloxacin; and ciprofloxacin for gyrase from Escherichia coli were 0.78, 0.98, 7.24, 0.78, and 1.15 microgram/ml, respectively. These values ...

  5. Characterizing Metabolic Inhibition Using Electrochemical Enzyme-DNA Biosensors

    Science.gov (United States)

    Hull, Dominic O.; Bajrami, Besnik; Jansson, Ingela; Schenkman, John B.; Rusling, James F.

    2009-01-01

    Studies of metabolic enzyme inhibition are necessary in drug development and toxicity investigations as potential tools to limit or prevent appearance of deleterious metabolites formed, for example by cytochrome (cyt) P450 enzymes. In this paper, we evaluate the use of enzyme/DNA toxicity biosensors as tools to investigate enzyme inhibition. We have examined DNA damage due to cyt P450cam metabolism of styrene using DNA/enzyme films on pyrolytic graphite (PG) electro*des monitored via Ru(bpy)32+–mediated DNA oxidation. Styrene metabolism initiated by hydrogen peroxide was evaluated with and without the inhibitors, imidazole, imidazole-4-acetic acid and sulconazole (in micromolar range) to monitor DNA damage inhibition. The initial rates of DNA damage decreased with increased inhibitor concentrations. Linear and nonlinear fits of Michaelis-Menten inhibition models were used to determine apparent inhibition constants (KI*) for the inhibitors. Elucidation of the best fitting inhibition model was achieved by comparing correlation coefficients and the sum of the square of the errors (SSE) from each inhibition model. Results confirmed the utility of the enzyme/DNA biosensor for metabolic inhibition studies. A simple competitive inhibition model best approximated the data for imidazole, imidazole-4-acetic acid and sulconazole with KI* of 268.2, 142.3 and 204.2 µM, respectively. PMID:19099359

  6. [Inhibition of adenovirus reproduction in cell culture by specific antibodies].

    Science.gov (United States)

    Povnytsia, O Iu; Nosach, L M; Zhovnovata, V L; Zahorodnia, S D; Vantsak, N P; Tokarchuk, L V; Polishchuk, O M; Diachenko, N S

    2009-01-01

    The capacity of specific antibodies to inhibit the reproduction of homo- and heterologous adenoviruses in Hela cell added to culture medium after virus adsorption was studied. The inhibiting effect of polyclonal antivirus and monospecific antihexone antibodies to homo- and heterologous adenoviruses was shown. The effect was more expressed when using antibodies to homologous antibodies. The intensity of inhibition depended on antibodies concentration in the medium and infecting dose of the virus. Essential reduction of the quantity of infected cells and a decrease of the titer of adenovirus synthesized in the presence of homo- and heterologous antibodies was shown but adenovirus reproduction was not inhibited completely. PMID:19663330

  7. A small yeast RNA inhibits HCV IRES mediated translation and inhibits replication of poliovirus in vivo

    Institute of Scientific and Technical Information of China (English)

    Xue-Song Liang; Jian-Qi Lian; Yong-Xing Zhou; Qing-He Nie; Chun-Qiu Hao

    2003-01-01

    AIM: To investigate the anti-virus infection activity of internal ribosome entry site (IRES) specific inhibitor RNA (IRNA).METHODS: IRNA eukaryotic vector pcRz-IRNA or mIRNA eukaryotic vector pcRz-mIRNA was tansfected into human hepatocarcinoma cells (HHCC), then selected with neomycin G418 for 4 to 8 weeks, and then infected with polio virus vaccinas line. The cytopethogenesis effect was investigated and the cell extract was collected. At last the polio virus titer of different cells was determined by plaque assay.RESULTS: Constitutive expression of IRNA was not detrimental to cell growth. HCV IRES-mediated capindependent translation was markedly inhibited in cells constitutively expressing IRNA compared to control hepatoma cells. However, cap-dependent translation was not significantly affected in these cell line. Additionally, HHCC cells constitutively expressing IRNA became refractory to infection of polio virus.CONCLUSION: IRES specific IRNA can inhibit HCV IRES mediated translation and poliovirus replication.

  8. DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

    OpenAIRE

    Asmis, L; Tanner, F C; Sudano, I; Lüscher, T F; Camici, G G

    2010-01-01

    Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents. Methods and resul...

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

    OpenAIRE

    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 oth...

  10. Spatially Reciprocal Inhibition of Inhibition within a Stimulus Selection Network in the Avian Midbrain

    OpenAIRE

    C Alex Goddard; Mysore, Shreesh P.; Bryant, Astra S.; Huguenard, John R.; Knudsen, Eric I

    2014-01-01

    Reciprocal inhibition between inhibitory projection neurons has been proposed as the most efficient circuit motif to achieve the flexible selection of one stimulus among competing alternatives. However, whether such a motif exists in networks that mediate selection is unclear. Here, we study the connectivity within the nucleus isthmi pars magnocellularis (Imc), a GABAergic nucleus that mediates competitive selection in the midbrain stimulus selection network. Using laser photostimulation of c...

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

    OpenAIRE

    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...

  12. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3

    OpenAIRE

    Nelson, Erik A.; Walker, Sarah R.; Kepich, Alicia; Gashin, Laurie B.; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C.; Frank, David A.

    2008-01-01

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Ni...

  13. Comparison of inhibition of Escherichia coli topoisomerase IV by quinolones with DNA gyrase inhibition.

    OpenAIRE

    Hoshino, K; Kitamura, A; Morrissey, I.; Sato, K.; Kato, J; Ikeda, H.

    1994-01-01

    In order to examine the inhibitory activities of quinolones against topoisomerase IV, both subunits of this enzyme, ParC and ParE, were purified from Escherichia coli. The specific activity of topoisomerase IV decatenation was found to be more than five times greater than that of topoisomerase IV relaxation. Thus, the decatenation activity of topoisomerase IV seems the most relevant activity for use in studies of drug inhibition of this enzyme. Although topoisomerase IV was less sensitive to ...

  14. Fluoxetine-induced inhibition of synaptosomal [3H]5-HT release: Possible Ca2+-channel inhibition

    International Nuclear Information System (INIS)

    Fluoxetine, a selective 5-Ht uptake inhibitor, inhibited 15 mM K+-induced [3H]5-HT release from rat spinal cord and cortical synaptosomes at concentrations > 0.5 uM. This effect reflected a property shared by another selective 5-HT uptake inhibitor paroxetine but not by less selective uptake inhibitors such as amitriptyline, desipramine, imipramine or nortriptyline. Inhibition of release by fluoxetine was inversely related to both the concentration of K+ used to depolarize the synaptosomes and the concentration of external Ca2+. Experiments aimed at determining a mechanism of action revealed that fluoxetine did not inhibit voltage-independent release of [3H]5-HT release induced by the Ca2+-ionophore A 23187 or Ca2+-independent release induced by fenfluramine. Moreover the 5-HT autoreceptor antagonist methiothepin did not reverse the inhibitory actions of fluoxetine on K+-induced release. Further studies examined the effects of fluoxetine on voltage-dependent Ca2+ channels and Ca2+ entry

  15. Mullerian Inhibiting Substance inhibits cervical cancer cell growth via a pathway involving p130 and p107

    OpenAIRE

    Barbie, Thanh U.; Barbie, David A; MacLaughlin, David T.; Maheswaran, Shyamala; Donahoe, Patricia K.

    2003-01-01

    In addition to causing regression of the Mullerian duct in the male embryo, Mullerian Inhibiting Substance (MIS) inhibits the growth of epithelial ovarian cancer cells, which are known to be of Mullerian origin. Because the uterine cervix is derived from the same Mullerian duct precursor as the epithelium of the ovary, we tested the hypothesis that cervical cancer cells might also respond to MIS. A number of cervical cancer cell lines express the MIS type II receptor, and MIS inhibits the gro...

  16. Positional Isomers of Aspirin Are Equally Potent in Inhibiting Colon Cancer Cell Growth: Differences in Mode of Cyclooxygenase Inhibition

    OpenAIRE

    Kodela, Ravinder; Chattopadhyay, Mitali; Goswami, Satindra; Gan, Zong Yuan; Rao, Praveen P.N.; Nia, Kamran V.; Velázquez-Martínez, Carlos A.; Kashfi, Khosrow

    2013-01-01

    We compared the differential effects of positional isomers of acetylsalicylic acid (o-ASA, m-ASA, and p-ASA) on cyclooxygenase (COX) inhibition, gastric prostaglandin E2 (PGE2), malondialdehyde, tumor necrosis factor-alpha (TNF-α) levels, superoxide dismutase (SOD) activity, human adenocarcinoma colon cancer cell growth inhibition, cell proliferation, apoptosis, and cell-cycle progression. We also evaluated the gastric toxicity exerted by ASA isomers. All ASA isomers inhibit COX enzymes, but ...

  17. Inhibition of Escherichia coli ATP synthase by amphibian antimicrobial peptides.

    Science.gov (United States)

    Laughlin, Thomas F; Ahmad, Zulfiqar

    2010-04-01

    Previously melittin, the alpha-helical basic honey bee venom peptide, was shown to inhibit F(1)-ATPase by binding at the beta-subunit DELSEED motif of F(1)F(o)-ATP synthase. Herein, we present the inhibitory effects of the basic alpha-helical amphibian antimicrobial peptides, ascaphin-8, aurein 2.2, aurein 2.3, carein 1.8, carein 1.9, citropin 1.1, dermaseptin, maculatin 1.1, maganin II, MRP, or XT-7, on purified F(1) and membrane bound F(1)F(0)Escherichia coli ATP synthase. We found that the extent of inhibition by amphibian peptides is variable. Whereas MRP-amide inhibited ATPase essentially completely (approximately 96% inhibition), carein 1.8 did not inhibit at all (0% inhibition). Inhibition by other peptides was partial with a range of approximately 13-70%. MRP-amide was also the most potent inhibitor on molar scale (IC(50) approximately 3.25 microM). Presence of an amide group at the c-terminal of peptides was found to be critical in exerting potent inhibition of ATP synthase ( approximately 20-40% additional inhibition). Inhibition was fully reversible and found to be identical in both F(1)F(0) membrane preparations as well as in isolated purified F(1). Interestingly, growth of E. coli was abrogated in the presence of ascaphin-8, aurein 2.2, aurein 2.3, citropin 1.1, dermaseptin, magainin II-amide, MRP, MRP-amide, melittin, or melittin-amide but was unaffected in the presence of carein 1.8, carein 1.9, maculatin 1.1, magainin II, or XT-7. Hence inhibition of F(1)-ATPase and E. coli cell growth by amphibian antimicrobial peptides suggests that their antimicrobial/anticancer properties are in part linked to their actions on ATP synthase. PMID:20100509

  18. Inhibition of angiogenesis by S-adenosylmethionine

    International Nuclear Information System (INIS)

    Highlights: → Effects of S-adenosylmethionine (SAM) were investigated in endothelial cells. → Our results showed that SAM decreased proliferation of endothelial cells. → SAM influentially inhibited the percentage of cell migration. → SAM probably stopped migration as independent from its effects on proliferation. → SAM was shown to suppress in vitro angiogenesis. -- Abstract: Metastasis is a leading cause of mortality and morbidity in cancer. One of the steps in metastasis process is the formation of new blood vessels. Aberrant DNA methylation patterns are common in cancer cells. In recent studies, S-adenosylmethionine (SAM), which is a DNA methylating agent, has been found to have inhibitory effects on some carcinoma cells in vivo and in vitro. In the present study, we have used SAM to investigate whether it is effective against angiogenesis in vitro. Our results have shown that SAM can reduce the formation and organization of capillary-like structures of endothelial cells in tumoral environment. Besides, we have found SAM can block endothelial cell proliferation and the migration of cells towards growth factors-rich media. In conclusion, our study suggests that SAM may be used against angiogenesis as a natural bio-product.

  19. Pain inhibits pain; human brainstem mechanisms.

    Science.gov (United States)

    Youssef, A M; Macefield, V G; Henderson, L A

    2016-01-01

    Conditioned pain modulation is a powerful analgesic mechanism, occurring when a painful stimulus is inhibited by a second painful stimulus delivered at a different body location. Reduced conditioned pain modulation capacity is associated with the development of some chronic pain conditions and the effectiveness of some analgesic medications. Human lesion studies show that the circuitry responsible for conditioned pain modulation lies within the caudal brainstem, although the precise nuclei in humans remain unknown. We employed brain imaging to determine brainstem sites responsible for conditioned pain modulation in 54 healthy individuals. In all subjects, 8 noxious heat stimuli (test stimuli) were applied to the right side of the mouth and brain activity measured using functional magnetic resonance imaging. This paradigm was then repeated. However, following the fourth noxious stimulus, a separate noxious stimulus, consisting of an intramuscular injection of hypertonic saline into the leg, was delivered (conditioning stimulus). During this test and conditioning stimulus period, 23 subjects displayed conditioned pain modulation analgesia whereas 31 subjects did not. An individual's analgesic ability was not influenced by gender, pain intensity levels of the test or conditioning stimuli or by psychological variables such as pain catastrophizing or fear of pain. Brain images were processed using SPM8 and the brainstem isolated using the SUIT toolbox. Significant increases in signal intensity were determined during each test stimulus and compared between subjects that did and did not display CPM analgesia (pmechanisms responsible for the maintenance of persistent pain conditions thought to involve altered analgesic circuitry. PMID:26343321

  20. Prepulse inhibition deficits in women with PTSD.

    Science.gov (United States)

    Pineles, Suzanne L; Blumenthal, Terry D; Curreri, Andrew J; Nillni, Yael I; Putnam, Katherine M; Resick, Patricia A; Rasmusson, Ann M; Orr, Scott P

    2016-09-01

    Prepulse inhibition (PPI) is an automatic and preattentive process, whereby a weak stimulus attenuates responding to a sudden and intense startle stimulus. PPI is a measure of sensorimotor filtering, which is conceptualized as a mechanism that facilitates processing of an initial stimulus and is protective from interruption by a later response. Impaired PPI has been found in (a) healthy women during the luteal phase of the menstrual cycle, and (b) individuals with types of psychopathology characterized by difficulty suppressing and filtering sensory, motor, or cognitive information. In the current study, 47 trauma-exposed women with or without posttraumatic stress disorder (PTSD) completed a PPI session during two different phases of the menstrual cycle: the early follicular phase, when estradiol and progesterone are both low, and the midluteal phase, when estradiol and progesterone are both high. Startle stimuli were 100 dB white noise bursts presented for 50 ms, and prepulses were 70 dB white noise bursts presented for 20 ms that preceded the startle stimuli by 120 ms. Women with PTSD showed deficits in PPI relative to the healthy trauma-exposed participants. Menstrual phase had no effect on PPI. These results provide empirical support for individuals with PTSD having difficulty with sensorimotor filtering. The potential utility of PPI as a Research Domain Criteria (RDoC) phenotype is discussed. PMID:27237725

  1. Inhibition of dextromethorphan metabolism by moclobemide.

    Science.gov (United States)

    Härtter, S; Dingemanse, J; Baier, D; Ziegler, G; Hiemke, C

    1998-01-01

    This pilot study was conducted to evaluate the potential of the new antidepressant moclobemide to inhibit the cytochrome enzyme P4502D6 (CYP2D6) using the cough suppressant dextromethorphan as a substrate in four extensive metabolizers (EM) of debrisoquine. The subjects received seven oral doses of 20 mg dextromethorphan at 4-h intervals over 2 days (1 and 2) and subsequently moclobemide (300 mg b.i.d.) for 9 days. On days 10 and 11, they received seven doses of 20 mg dextromethorphan in addition to moclobemide. During monotreatment and combined treatment, blood was collected on days 2 and 11, respectively, for determination of dextromethorphan and its demethylated metabolites using automated high-performance liquid chromatography with column switching. Concurrent administration of moclobemide markedly reduced the O-demethylation of dextromethorphan, whereas the N-demethylation of dextrorphan to hydroxymorphinan was not affected. The findings indicate that moclobemide can affect the pharmacokinetics of drugs that are mainly metabolized by CYP2D6. PMID:9489930

  2. PARP inhibition and postinfarction myocardial remodeling.

    Science.gov (United States)

    Halmosi, Robert; Deres, Laszlo; Gal, Roland; Eros, Krisztian; Sumegi, Balazs; Toth, Kalman

    2016-08-01

    Coronary artery disease accounts for the greatest proportion of cardiovascular diseases therefore it is the major cause of death worldwide. Its therapeutic importance is indicated by still high mortality of myocardial infarction, which is one of the most severe forms of CVDs. Moreover, the risk of developing heart failure is very high among survivors. Heart failure is accompanied by high morbidity and mortality rate, therefore this topic is in the focus of researchers' interest. After a myocardial infarct, at first ventricular hypertrophy develops as a compensatory mechanism to decrease wall stress but finally leads to left ventricular dilation. This phenomenon is termed as myocardial remodeling. The main characteristics of underlying mechanisms involve cardiomyocyte growth, vessel changes and increased collagen production, in all of which several mechanical stress induced neurohumoral agents, oxidative stress and signal transduction pathways are involved. The long term activation of these processes ultimately leads to left ventricular dilation and heart failure with decreased systolic function. Oxidative stress causes DNA breaks producing the activation of nuclear poly(ADP-ribose) polymerase-1 (PARP-1) enzyme that leads to energy depletion and unfavorable modulation of different kinase cascades (Akt-1/GSK-3β, MAPKs, various PKC isoforms) and thus it promotes the development of heart failure. Therefore inhibition of PARP enzyme could offer a promising new therapeutical approach to prevent the onset of heart failure among postinfarction patients. The purpose of this review is to give a comprehensive summary about the most significant experimental results and mechanisms in postinfarction remodeling. PMID:27392900

  3. Acetylcholinesterase-inhibiting Alkaloids from Zephyranthes concolor

    Directory of Open Access Journals (Sweden)

    Sebastien Arseneau

    2011-11-01

    Full Text Available The bulbs and aerial parts of Zephyranthes concolor (Lindl. Benth. & Hook. f. (Amaryllidaceae, an endemic species to Mexico, were found to contain the alkaloids chlidanthine, galanthamine, galanthamine N-oxide, lycorine, galwesine, and epinorgalanthamine. Since currently only partial and low resolution 1H-NMR data for chlidanthine acetate are available, and none for chlidanthine, its 1D and 2D high resolution 1H- and 13C-NMR spectra were recorded. Unambiguous assignations were achieved with HMBC, and HSQC experiments, and its structure was corroborated by X-ray diffraction. Minimum energy conformation for structures of chlidanthine, and its positional isomer galanthamine, were calculated by molecular modelling. Galanthamine is a well known acetylcholinesterase inhibitor; therefore, the isolated alkaloids were tested for this activity. Chlidanthine and galanthamine N-oxide inhibited electric eel acetylcholinesterase (2.4 and 2.6 × 10−5 M, respectively, indicating they are about five times less potent than galanthamine, while galwesine was inactive at 10−3 M. Inhibitory activity of HIV-1 replication, and cytotoxicity of the isolated alkaloids were evaluated in human MT-4 cells; however, the alkaloids showed poor activity as compared with standard anti-HIV drugs, but most of them were not cytotoxic.

  4. 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.

  5. 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.

  6. Aspirin, cyclooxygenase inhibition and colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Carlos; Sostres; Carla; Jerusalen; Gargallo; Angel; Lanas

    2014-01-01

    Colorectal cancer(CRC)is the third most common type of cancer worldwide.Screening measures are far from adequate and not widely available in resourcepoor settings.Primary prevention strategies therefore remain necessary to reduce the risk of developing CRC.Increasing evidence from epidemiological studies,randomized clinical trials and basic science supports the effectiveness of aspirin,as well as other non-steroidal anti-inflammatory drugs,for chemoprevention of several types of cancer,including CRC.This includes the prevention of adenoma recurrence and reduction of CRC incidence and mortality.The detectable benefit of daily low-dose aspirin(at least 75 mg),as used to prevent cardiovascular disease events,strongly suggests that its antiplatelet action is central to explaining its antitumor efficacy.Daily low-dose aspirin achieves complete and persistent inhibition of cyclooxygenase(COX)-1 in platelets(in pre-systemic circulation)while causing alimited and rapidly reversible inhibitory effect on COX-2and/or COX-1 expressed in nucleated cells.Aspirin has a short half-life in human circulation(about 20 minutes);nucleated cells have the ability to resynthesize acetylated COX isozymes within a few hours,while platelets do not.COX-independent mechanisms of aspirin have been suggested to explain its chemopreventive effects but this concept remains to be demonstrated in vivo at clinical doses.

  7. Simvastatin inhibits CD44 fragmentation in chondrocytes.

    Science.gov (United States)

    Terabe, Kenya; Takahashi, Nobunori; Takemoto, Toki; Knudson, Warren; Ishiguro, Naoki; Kojima, Toshihisa

    2016-08-15

    In human osteoarthritic chondrocytes, the hyaluronan receptor CD44 undergoes proteolytic cleavage at the cell surface. CD44 cleavage is thought to require transit of CD44 into cholesterol-rich lipid rafts. The purpose of this study was to investigate whether statins exert a protective effect on articular chondrocytes due to diminution of cholesterol. Three model systems of chondrocytes were examined including human HCS-2/8 chondrosarcoma cells, human osteoarthritic chondrocytes and normal bovine articular chondrocytes. Treatment with IL-1β + Oncostatin M resulted in a substantial increase in CD44 fragmentation in each of the three chondrocyte models. Pre-incubation with simvastatin prior to treatment with IL-1β + Oncostatin M decreased the level of CD44 fragmentation, decreased the proportion of CD44 that transits into the lipid raft fractions, decreased ADAM10 activity and diminished the interaction between CD44 and ADAM10. In HCS-2/8 cells and bovine articular chondrocytes, fragmentation of CD44 was blocked by the knockdown of ADAM10. Inhibition of CD44 fragmentation by simvastatin also resulted in improved retention of pericellular matrix. Addition of cholesterol and farnesyl-pyrophosphate reversed the protective effects of simvastatin. Thus, the addition of simvastatin exerts positive effects on chondrocytes including reduced CD44 fragmentation and enhanced the retention of pericellular matrix. PMID:27242325

  8. Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst

    Indian Academy of Sciences (India)

    David Alan Thompson; Bruce D Hammock

    2007-03-01

    The leukotoxins [9(10)- and 12(13)-EpOME] are produced by activated inflammatory leukocytes such as neutrophils. High EpOME levels are observed in disorders such as acute respiratory distress syndrome and in patients with extensive burns. Although the physiological significance of the EpOMEs remains poorly understood, in some systems, the EpOMEs act as a protoxin, with their corresponding epoxide hydrolase metabolites, 9,10- and 12,13-DiHOME, specifically exerting toxicity. Both the EpOMEs and the DiHOMEs were also recently shown to have neutrophil chemotactic activity. We evaluated whether the neutrophil respiratory burst, a surge of oxidant production thought to play an important role in limiting certain bacterial and fungal infections, is modulated by members of the EpOME metabolic pathway. We present evidence that the DiHOMEs suppress the neutrophil respiratory burst by a mechanism distinct from that of respiratory burst inhibitors such as cyclosporin H or lipoxin A4, which inhibit multiple aspects of neutrophil activation.

  9. Cisplatin inhibits bone healing during distraction osteogenesis.

    Science.gov (United States)

    Stine, Kimo C; Wahl, Elizabeth C; Liu, Lichu; Skinner, Robert A; Vanderschilden, Jacquelyn; Bunn, Robert C; Montgomery, Corey O; Suva, Larry J; Aronson, James; Becton, David L; Nicholas, Richard W; Swearingen, Christopher J; Lumpkin, Charles K

    2014-03-01

    Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non-cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five-dose CDP regimen (2 mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice (p CDP regimen were observed in TNFR1KO mice. The two-dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri-operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP. PMID:24259375

  10. Advances in Bacterial Methionine Aminopeptidase Inhibition.

    Science.gov (United States)

    Helgren, Travis R; Wangtrakuldee, Phumvadee; Staker, Bart L; Hagen, Timothy J

    2016-01-01

    Methionine aminopeptidases (MetAPs) are metalloenzymes that cleave the N-terminal methionine from newly synthesized peptides and proteins. These MetAP enzymes are present in bacteria, and knockout experiments have shown that MetAP activity is essential for cell life, suggesting that MetAPs are good antibacterial drug targets. MetAP enzymes are also present in the human host and selectivity is essential. There have been significant structural biology efforts and over 65 protein crystal structures of bacterial MetAPs are deposited into the PDB. This review highlights the available crystallographic data for bacterial MetAPs. Structural comparison of bacterial MetAPs with human MetAPs highlights differences that can lead to selectivity. In addition, this review includes the chemical diversity of molecules that bind and inhibit the bacterial MetAP enzymes. Analysis of the structural biology and chemical space of known bacterial MetAP inhibitors leads to a greater understanding of this antibacterial target and the likely development of potential antibacterial agents. PMID:26268344

  11. Inhibition of oxidation in nuclear graphite

    International Nuclear Information System (INIS)

    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 oxidising 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 postulated 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 deg. C. The proposed addition of B4C to graphite components in the nuclear core would necessarily be enriched in B-11 isotope in order to minimise 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. (authors)

  12. Hsp90 inhibition decreases mitochondrial protein turnover.

    Directory of Open Access Journals (Sweden)

    Daciana H Margineantu

    Full Text Available BACKGROUND: Cells treated with hsp90 inhibitors exhibit pleiotropic changes, including an expansion of the mitochondrial compartment, accompanied by mitochondrial fragmentation and condensed mitochondrial morphology, with ultimate compromise of mitochondrial integrity and apoptosis. FINDINGS: We identified several mitochondrial oxidative phosphorylation complex subunits, including several encoded by mtDNA, that are upregulated by hsp90 inhibitors, without corresponding changes in mRNA abundance. Post-transcriptional accumulation of mitochondrial proteins observed with hsp90 inhibitors is also seen in cells treated with proteasome inhibitors. Detailed studies of the OSCP subunit of mitochondrial F1F0-ATPase revealed the presence of mono- and polyubiquitinated OSCP in mitochondrial fractions. We demonstrate that processed OSCP undergoes retrotranslocation to a trypsin-sensitive form associated with the outer mitochondrial membrane. Inhibition of proteasome or hsp90 function results in accumulation of both correctly targeted and retrotranslocated mitochondrial OSCP. CONCLUSIONS: Cytosolic turnover of mitochondrial proteins demonstrates a novel connection between mitochondrial and cytosolic compartments through the ubiquitin-proteasome system. Analogous to defective protein folding in the endoplasmic reticulum, a mitochondrial unfolded protein response may play a role in the apoptotic effects of hsp90 and proteasome inhibitors.

  13. 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.

  14. Bromodomains: Structure, function and pharmacology of inhibition.

    Science.gov (United States)

    Ferri, Elena; Petosa, Carlo; McKenna, Charles E

    2016-04-15

    Bromodomains are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation. The human proteome comprises 46 bromodomain-containing proteins with a total of 61 bromodomains, which, despite highly conserved structural features, recognize a wide array of natural peptide ligands. Over the past five years, bromodomains have attracted great interest as promising new epigenetic targets for diverse human diseases, including inflammation, cancer, and cardiovascular disease. The demonstration in 2010 that two small molecule compounds, JQ1 and I-BET762, potently inhibit proteins of the bromodomain and extra-terminal (BET) family with translational potential for cancer and inflammatory disease sparked intense efforts in academia and pharmaceutical industry to develop novel bromodomain antagonists for therapeutic applications. Several BET inhibitors are already in clinical trials for hematological malignancies, solid tumors and cardiovascular disease. Currently, the field faces the challenge of single-target selectivity, especially within the BET family, and of overcoming problems related to the development of drug resistance. At the same time, new trends in bromodomain inhibitor research are emerging, including an increased interest in non-BET bromodomains and a focus on drug synergy with established antitumor agents to improve chemotherapeutic efficacy. This review presents an updated view of the structure and function of bromodomains, traces the development of bromodomain inhibitors and their potential therapeutic applications, and surveys the current challenges and future directions of this vibrant new field in drug discovery. PMID:26707800

  15. Photorespiration and Oxygen Inhibition of Photosynthesis in Chlorella pyrenoidosa.

    Science.gov (United States)

    Shelp, B J; Canvin, D T

    1980-05-01

    The inhibition of photosynthesis by O(2) in air-grown Chlorella pyrenoidosa was investigated using three experimental techniques (artificial leaf, aqueous method, and O(2) electrode) to measure carbon assimilation. CO(2) response curves were determined under different O(2), pH, and temperature conditions. Regardless of the experimental technique and condition, O(2) inhibition was not evident until a concentration of 50% was reached; V(max) values were reduced whereas K(m) (CO(2)) values were unaffected by the increasing O(2) concentration. The response of photosynthesis to O(2) was independent of CO(2) and HCO(3) (-) concentrations as well as temperature. Relative rates of photosynthesis showed a 4 to 5% stimulation in 2% O(2), a 12% inhibition in 50% O(2), and a 24% inhibition in 100% O(2). The inhibition by 50% O(2) was still reversible after 20 minutes exposure whereas 100% O(2) caused irreversible inhibition after only 4 minutes.The O(2) inhibition is discussed in terms of the oxygenase reaction and a Mehler reaction supporting pseudocyclic electron flow. The results are inconsistent with the proposals that photorespiration exists in these algae and that a CO(2)-concentrating mechanism suppresses the O(2) inhibition of photosynthesis. PMID:16661282

  16. Ordering kinetics in model systems with inhibited interfacial adsorption

    DEFF Research Database (Denmark)

    Willart, J.-F.; Mouritsen, Ole G.; Naudts, J.; Descamps, M.

    1992-01-01

    The ordering kinetics in two-dimensional Ising-like spin moels with inhibited interfacial adsorption are studied by computer-simulation calculations. The inhibited interfacial adsorption is modeled by a particular interfacial adsorption condition on the structure of the domain wall between...

  17. Toxic action of organophosphorus compounds and esterase inhibition in houseflies

    NARCIS (Netherlands)

    Asperen, K. van

    1960-01-01

    The paper deals with investigations on the inhibition in vivo of the cholin-esterase and the aliesterase in houseflies poisoned by treatment with organophosphorus insecticides. The kinetics of the inhibition of esterases by DDVP, paraoxon and diazoxon in the presence and in the absence of substrate

  18. Executive functioning in boys with ADHD: primarily an inhibition deficit?

    NARCIS (Netherlands)

    Scheres, A.P.J.; Oosterlaan, J.; Geurts, H.M.; Morein-Zamir, S.; Meiran, N.; Vlasveld, L.; Sergeant, J.A.

    2004-01-01

    This study was aimed at: (1) testing whether boys with Attention Deficit/Hyperactivity Disorder (ADHD) demonstrate a deficit in response inhibition and deficits in other executive functions (EF), or alternatively, demonstrate a deficit in only response inhibition; (2) investigating which role associ

  19. The Affective Consequences of Cognitive Inhibition: Devaluation or Neutralization?

    Science.gov (United States)

    Frischen, Alexandra; Ferrey, Anne E.; Burt, Dustin H. R.; Pistchik, Meghan; Fenske, Mark J.

    2012-01-01

    Affective evaluations of previously ignored visual stimuli are more negative than those of novel items or prior targets of attention or response. This has been taken as evidence that inhibition has negative affective consequences. But inhibition could act instead to attenuate or "neutralize" preexisting affective salience, predicting opposite…

  20. 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…

  1. Distractor Inhibition: Principles of Operation during Selective Attention

    Science.gov (United States)

    Wyatt, Natalie; Machado, Liana

    2013-01-01

    Research suggests that although target amplification acts as the main determinant of the efficacy of selective attention, distractor inhibition contributes under some circumstances. Here we aimed to gain insight into the operating principles that regulate the use of distractor inhibition during selective attention. The results suggest that, in…

  2. Men in the Triangle: Grief, Inhibition, and Defense

    Science.gov (United States)

    Clayton, Robert E.

    2015-01-01

    Inhibition of emotional experience is a widely acknowledged characteristic of many Western-raised men. While this affective inhibition may impact men chronically in many ways, it becomes particularly salient when men are bereaved or otherwise grieving and are unable fully to experience normative emotional responses to loss. This article briefly…

  3. 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.

  4. Corrosion inhibition of carbon steel by sodium metavanadate

    Directory of Open Access Journals (Sweden)

    VIJAYA GOPAL SRIBHARATHY

    2012-08-01

    Full Text Available The inhibition efficiency of sodium metavanadate (SMV-adipic acid (AA system in controlling corrosion of carbon steel in an aqueous solution containing 60 ppm of Cl- has been evaluated by weight-loss method; 250 ppm of SMV exhibits inhibition efficiency of 56 %. Addition of adipic acid to SMV improves the inhibition efficiency of the system. The formulation consisting of 250 ppm of SMV and 250 ppm of adipic acid has inhibition efficiency of 98 %. A synergistic effect exists between SMV and adipic acid with the synergism parameters greater than 1. Mecha¬nistic aspects of corrosion inhibition have been studied by electrochemical methods like potentiodynamic polarization and electrochemical impedance spectroscopy. FTIR spectra reveal that the protective film consists of Fe2+-SMV complex and Fe2+-adipic acid complex. The protective film has been analyzed by fluorescence spectra, SEM and EDAX.

  5. Corrosion inhibition of mild steel in HCL solution by pectin

    International Nuclear Information System (INIS)

    Highlights: • Pectin is an efficient inhibitor for mild steel corrosion in HCl. • Inhibition results from surface geometric blocking by chemisorbed species. • UV–visible data point to the formation of a complex between pectin and Fe2+ ions. - Abstract: This work describes the successful performance of pectin as an eco-friendly corrosion inhibitor for mild steel in HCl solution. The inhibition mechanism is discussed considering thermodynamics of adsorption and kinetics of the electrochemical reactions. Inhibition efficiency increases with temperature while the activation energy for the corrosion rate decreases with the addition of pectin. Pectin is a mixed-type inhibitor and the mode of inhibition results from the geometric blocking effect of chemisorbed inhibitive species at the metal surface. Spectroscopic analysis points to the formation of a complex between pectin and Fe2+ ions released during the corrosion reaction

  6. Gliclazide directly inhibits arginine-induced glucagon release

    DEFF Research Database (Denmark)

    Cejvan, Kenan; Coy, David H; Holst, Jens Juul;

    2002-01-01

    Arginine-stimulated insulin and somatostatin release is enhanced by the sulfonylurea gliclazide. In contrast, gliclazide inhibits the glucagon response. The aim of the present study was to investigate whether this inhibition of glucagon release was mediated by a direct suppressive effect of...... specific antagonist of type 2 somatostatin receptor, DC-41-33 (2 micro mol/l), which fully antagonizes the suppressive somatostatin effect on rat A cells. Gliclazide (30 micro mol/l) inhibited glucagon release by 54% in the perfusion experiments, whereas the somatostatin response was nearly abolished. In...... islet perifusions with DC-41-33, arginine-induced glucagon release was inhibited by 66%. We therefore concluded that gliclazide inhibits glucagon release by a direct action on the pancreatic A cell....

  7. Antiarrhythmic Mechanisms of SK Channel Inhibition in the Rat Atrium

    DEFF Research Database (Denmark)

    Skibsbye, Lasse; Wang, Xiaodong; Axelsen, Lene Nygaard;

    2015-01-01

    period (ERP) and slowing the conduction velocity. We therefore aimed at elucidating these properties of SK channel inhibition and the underlying antiarrhythmic mechanisms by using; microelectrode action potential recordings and conduction velocity measurements in isolated rat atrium. Automated patch-clamping...... and two-electrode voltage-clamp was used to access INa and IK,ACh respectively. RESULTS: The SK channel inhibitor N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) exhibited antiarrhythmic effects. ICA prevented electrically induced runs of atrial fibrillation in the isolated right atrium and...... channel inhibition by ICA (10-30 µM) demonstrated prominent depression of other sodium channel-dependent parameters. ICA did not inhibit IK,ACh, but at concentrations above 10 µM ICA use-dependently inhibited INa. CONCLUSION: SK channel inhibition modulates multiple parameters of the action potential. It...

  8. Pancreatic polypepetide inhibits pancreatic enzyme secretion via a cholinergic pathway

    International Nuclear Information System (INIS)

    In rat pancreatic slices, rat pancreatic polypeptide (PP) or C-terminal hexapeptide of PP [PP-(31-36)] inhibited potassium-stimulated amylase release in a dose-dependent manner. The inhibition was unaffected by addition of hexamethonium but blocked by atropine. In contrast, PP-(31-36) did not have any effect on acetylcholine- or cholecystokinin octapeptide-stimulated amylase release. In addition, when pancreatic slices were incubated with [3H]choline, PP-(31-36) inhibited the potassium-evoked release of synthesized [3H]acetylcholine in a dose-dependent manner. The inhibitory action of PP was unaffected by adrenergic, dopaminergic, or opioid receptor antagonists. Thus PP inhibits pancreatic enzyme secretion via presynaptic modulation of acetylcholine release. This newly identified pathway provides a novel mechanism for hormonal inhibition of pancreatic enzyme secretion via modulation of the classic neurotransmitter function

  9. Inhibition of dextran and mutan synthesis by cycloisomaltooligosaccharides.

    Science.gov (United States)

    Kobayashi, M; Funane, K; Oguma, T

    1995-10-01

    Novel cyclic isomaltooligosaccharides, cyclodextran, strongly inhibited the dextransucrase reaction. The inhibition was dependent on the cyclodextran concentration and greatly enhanced by the first incubation at 30 degrees for 30 min. Cyclodextran-heptaose and -octaose were competitive inhibitors for sucrose yielding Ki's of 0.25 and 0.64 mM, respectively. Both reducing sugar and dextran producing activities of dextransucrase were almost equally inhibited by the cyclodextrans. Although gamma-cyclodextrin, palatinose, sucrose-monocaprate, and maltitol gave 5-35% inhibition, cyclodextran-heptaose gave 95% inhibition. Moreover, water-insoluble glucan (mutan) synthesis by the glucosyltransferase from Streptococcus mutans was significantly repressed by the addition of cyclodextran. PMID:8534976

  10. Sulindac Sulfide, but Not Sulindac Sulfone, Inhibits Colorectal Cancer Growth

    Directory of Open Access Journals (Sweden)

    Christopher S. Williams

    1999-06-01

    Full Text Available Sulindac sulfide, a metabolite of the nonsteroidal antiinflammatory drug (NSAID sulindac sulfoxide, is effective at reducing tumor burden in both familial adenomatous polyposis patients and in animals with colorectal cancer. Another sulindac sulfoxide metabolite, sulindac sulfone, has been reported to have antitumor properties without inhibiting cyclooxygenase activity. Here we report the effect of sulindac sulfone treatment on the growth of colorectal carcinoma cells. We observed that sulindac sulfide or sulfone treatment of HCA-7 cells led to inhibition of prostaglandin E2 production. Both sulindac sulfide and sulfone inhibited HCA-7 and HCT-116 cell growth in vitro. Sulindac sulfone had no effect on the growth of either HCA-7 or HCT-116 xenografts, whereas the sulfide derivative inhibited HCA-7 growth in vivo. Both sulindac sulfide and sulfone inhibited colon carcinoma cell growth and prostaglandin production in vitro, but sulindac sulfone had no effect on the growth of colon cancer cell xenografts in nude mice.

  11. 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…

  12. Substrate inhibition in Pseudomonas oxalaticus OX1 : a kinetic study of growth inhibition by oxalate and formate using extended cultures

    NARCIS (Netherlands)

    Dijkhuizen, L.; Harder, W.

    1975-01-01

    Pseudomonas oxalaticus OX1 has been grown in a mineral salts medium with oxalate or formate as the sole source of carbon and energy. At concentrations of these substrates above 50 mM inhibition of growth was indicated by a long and variable lag phase in batch culture. This inhibition was further stu

  13. Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway.

    Science.gov (United States)

    Zheng, Jie; Son, Dong Ju; Gu, Sun Mi; Woo, Ju Rang; Ham, Young Wan; Lee, Hee Pom; Kim, Wun Jae; Jung, Jae Kyung; Hong, Jin Tae

    2016-01-01

    Piperlongumine has anti-cancer activity in numerous cancer cell lines via various signaling pathways. But there has been no study regarding the mechanisms of PL on the lung cancer yet. Thus, we evaluated the anti-cancer effects and possible mechanisms of PL on non-small cell lung cancer (NSCLC) cells in vivo and in vitro. Our findings showed that PL induced apoptotic cell death and suppressed the DNA binding activity of NF-κB in a concentration dependent manner (0-15 μM) in NSCLC cells. Docking model and pull down assay showed that PL directly binds to the DNA binding site of nuclear factor-κB (NF-κB) p50 subunit, and surface plasmon resonance (SPR) analysis showed that PL binds to p50 concentration-dependently. Moreover, co-treatment of PL with NF-κB inhibitor phenylarsine oxide (0.1 μM) or p50 siRNA (100 nM) augmented PL-induced inhibitory effect on cell growth and activation of Fas and DR4. Notably, co-treatment of PL with p50 mutant plasmid (C62S) partially abolished PL-induced cell growth inhibition and decreased the enhanced expression of Fas and DR4. In xenograft mice model, PL (2.5-5 mg/kg) suppressed tumor growth of NSCLC dose-dependently. Therefore, these results indicated that PL could inhibit lung cancer cell growth via inhibition of NF-κB signaling pathway in vitro and in vivo. PMID:27198178

  14. 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.

  15. Stat3 inhibition in neural lineage cells.

    Science.gov (United States)

    Chiba, Tomohiro; Mack, Laura; Delis, Natalia; Brill, Boris; Groner, Bernd

    2012-06-01

    Abstract Deregulation of signal transducer and activator of transcription 3 (Stat3) is attracting attentions in neurological disorders of elderly populations, e.g., Stat3 is inactivated in hippocampal neurons of Alzheimer's disease (AD) brains, whereas it is often constitutively activated in glioblastoma multiforme (GBM), correlating with poor prognosis. Stat3-inhibiting drugs have been intensively developed for chemotherapy based on the fact that GBM, in many cases, are "addicted" to Stat3 activation. Stat3 inhibitors, however, potentially have unfavorable side effects on postmitotic neurons, normal permanent residents in the central nervous system. It is, therefore, of great importance to address detailed cellular responses of neural lineage cells including normal neurons, astrocytes, and neuronal/glial cancer cell lines to several classes of Stat3 inhibitors focusing on their effective concentrations. Here, we picked up five human and mouse cancer cell lines (Neuro-2a and SH-SY5Y neuroblastoma cell lines and Tu-9648, U-87MG, and U-373MG glioblastoma cell lines) and treated with various Stat3 inhibitors. Among them, Stattic, FLLL31, and resveratrol potently suppressed P-Stat3 and cell viability in all the tested cell lines. Stat3 knockdown or expression of dominant-negative Stat3 further sensitized cells to the inhibitors. Expression of familial AD-related mutant amyloid precursor protein sensitized neuronal cells, not glial cells, to Stat3 inhibitors by reducing P-Stat3 levels. Primary neurons and astrocytes also responded to Stat3 inhibitors with similar sensitivities to those observed in cancer cell lines. Thus, Stat3 inhibitors should be carefully targeted to GBM cells to avoid potential neurotoxicity leading to AD-like neuropsychiatric dysfunctions. PMID:25436682

  16. Caries inhibition by fluoride-releasing primers.

    Science.gov (United States)

    Kerber, L J; Donly, K J

    1993-10-01

    This study evaluated the caries inhibition of dentin primers with the addition of fluoride. Two standardized Class V preparations were placed in 20 molars, the gingival margin placed below the cementoenamel junction and the occlusal margin placed in enamel. Two dentin primers (Syntac and ScotchPrep) were placed in equal numbers of 20 preparations, according to manufacturer's instructions. Ammonium fluoride (10% by weight) was then added to these primers and they were placed in the remaining 20 preparations, opposing the non-fluoridated primer of the same system. All teeth were then restored with a non-fluoridated resin composite. All teeth were subjected to an artificial caries challenge (pH 4.2) for 5 days. Sections of 100 microns were obtained, photographed under polarized light microscopy, then demineralized areas were quantitated by digitization. Results demonstrated the mean areas (mm2 +/- S.D.) demineralization at 0.25 mm, 0.5 mm and 1.0 mm from the restoration margin to be: Syntac/fluoride (1.44 +/- 0.49, 1.68 +/- 0.54, 3.72 +/- 0.74); Syntac (1.99 +/- 0.58, 1.50 +/- 0.35, 2.98 +/- 1.26); ScotchPrep/fluoride (1.23 +/- 0.68, 1.55 +/- 0.64, 3.08 +/- 1.16); ScotchPrep (1.90 +/- 0.83, 1.71 +/- .038, 3.36 +/- 0.62). A paired t-test indicated primers with fluoride to demonstrate significantly less demineralization 0.25 mm from the restoration margin (P < 0.07). PMID:7880460

  17. Risedronate inhibits human osteosarcoma cell invasion

    Directory of Open Access Journals (Sweden)

    Jung Sung

    2009-07-01

    Full Text Available Abstract Background Osteosarcoma is a highly malignant bone tumor and is the most commonly encountered malignant bone tumor in children and adolescents. Furthermore, significant numbers of patients eventually develop pulmonary metastases and succumb to the disease even after conventional multi-agent chemotherapy and surgical excision. Several solid tumors display enhanced expression of matrix metalloproteinases (MMPs, and recently clinical trials have been initiated on MMP-inhibitors. On the other hand, bisphosphonates (BPs, which have a profound effect on bone resorption, are widely used to treat osteoclast-mediated bone diseases. BPs are also known to inhibit tumor growths and metastases in some tumors such as breast cancer, renal cell carcinoma, and prostate cancer. Methods Two osteosarcoma cell lines (SaOS-2 and U2OS were treated with risedronate (0, 0.1, 1, 10 μM for 48 hours. Cell viabilities were determined using MTT assay, the mRNA levels of MMP-2 and MMP-9 were analyzed by reverse-transcription polymerase chain reaction, the amount of MMP-2 and MMP-9 protein were analyzed by Westernblot, the activities of MMP-2 and MMP-9 were observed by Gelatin zymography, and Matrigel invasion assays were used to investigate the invasive potential of osteosarcoma cell lines before and after risedronate treatment. Results The invasiveness of osteosarcoma cell lines (SaOS-2, U2OS were reduced in a dose dependent manner follow 48 hour treatment of up to 10 μM of the risedronate at which concentration no cytotoxicity occurred. Furthermore, the gelatinolytic activities and protein and mRNA levels of MMP-2 and MMP-9 were also suppressed by increasing risedronate concentrations. Conclusion Given that MMP-2 and MMP-9 are instrumental in tumor cell invasion, our results suggest the risedronate could reduce osteosarcoma cell invasion.

  18. Inhibition and anti-inhibition effects of electron scavengers in hydrocarbons revisited

    International Nuclear Information System (INIS)

    Positronium formation experiments in n-hexane were performed with C2H5Br and CCl4 as inhibitors and others (decalin, tetralin, benzene, naphthalene, phenanthrene) as anti-inhibitors. Although the results can be interpreted in terms of the anti-recombination and anti-inhibition, it is necessary to consider further some new aspects of intra-spur reactions such as shallow trapping of e+ and secondary reactions of Ps. The data thus interpreted correlate excellently with the data of radiation chemistry. (author)

  19. Saccharin and Cyclamate Inhibit Binding of Epidermal Growth Factor

    Science.gov (United States)

    Lee, L. S.

    1981-02-01

    The binding of 125I-labeled mouse epidermal growth factor (EGF) to 18 cell lines, including HeLa (human carcinoma), MDCK (dog kidney cells), HTC (rat hepatoma), K22 (rat liver), HF (human foreskin), GM17 (human skin fibroblasts), XP (human xeroderma pigmentosum fibroblasts), and 3T3-L1 (mouse fibroblasts), was inhibited by saccharin and cyclamate. The human cells were more sensitive to inhibition by these sweeteners than mouse or rat cells. EGF at doses far above the physiological levels reversed the inhibition in rodent cells but not in HeLa cells. In HeLa cells, the doses of saccharin and cyclamate needed for 50% inhibition were 3.5 and 9.3 mg/ml, respectively. Glucose, 2-deoxyglucose, sucrose, and xylitol did not inhibit EGF binding. Previous studies have shown that phorbol esters, strongly potent tumor promoters, also inhibit EGF binding to tissue culture cells. To explain the EGF binding inhibition by such greatly dissimilar molecules as phorbol esters, saccharin, and cyclamate, it is suggested that they operate through the activation of a hormone response control unit.

  20. 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

    2015-01-01

    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. PMID:26400108

  1. 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. PMID:24607865

  2. Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of STAT3 signaling pathway.

    Science.gov (United States)

    Cai, Qiaoyan; Lin, Jiumao; Wei, Lihui; Zhang, Ling; Wang, Lili; Zhan, Youzhi; Zeng, Jianwei; Xu, Wei; Shen, Aling; Hong, Zhenfeng; Peng, Jun

    2012-01-01

    Signal Transducer and Activator of Transcription 3 (STAT3), a common oncogenic mediator, is constitutively activated in many types of human cancers; therefore it is a major focus in the development of novel anti-cancer agents. Hedyotis diffusa Willd has been used as a major component in several Chinese medicine formulas for the clinical treatment of colorectal cancer (CRC). However, the precise mechanism of its anti-tumor activity remains largely unclear. Using a CRC mouse xenograft model, in the present study we evaluated the effect of the ethanol extract of Hedyotis diffusa Willd (EEHDW) on tumor growth in vivo and investigated the underlying molecular mechanisms. We found that EEHDW reduced tumor volume and tumor weight, but had no effect on body weight gain in CRC mice, demonstrating that EEHDW can inhibit CRC growth in vivo without apparent adverse effect. In addition, EEHDW treatment suppressed STAT3 phosphorylation in tumor tissues, which in turn resulted in the promotion of cancer cell apoptosis and inhibition of proliferation. Moreover, EEHDW treatment altered the expression pattern of several important target genes of the STAT3 signaling pathway, i.e., decreased expression of Cyclin D1, CDK4 and Bcl-2 as well as up-regulated p21 and Bax. These results suggest that suppression of the STAT3 pathway might be one of the mechanisms by which EEHDW treats colorectal cancer. PMID:22754353

  3. Andrographolide inhibits multiple myeloma cells by inhibiting the TLR4/NF-κB signaling pathway.

    Science.gov (United States)

    Gao, Hui; Wang, Jianrong

    2016-02-01

    Andrographolide is an active component from the extract of Andrographis paniculata [(Burm.f) Nees], a medicinal plant from the Acanthaceae family. Pharmacological studies have revealed that andrographolide possesses anti-bacterial, anti-inflammatory, anti-viral, immune regulatory and hepatoprotective properties, and is efficacious in the treatment of cardiovascular diseases, while exhibiting low toxicity and low cost. The present study aimed to determine the inhibitory effects of andrographolide on the growth of multiple myeloma (MM) cells and its possible impact on the Toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling pathway. Cell proliferation was detected using an MTT assay, cellular apoptosis was measured using flow cytometry, and caspase-9/3 activation were assessed using colorimetric assay kits. Furthermore, TLR4 and NF-κB protein expression was determined by western blot analysis. The results revealed that andrographolide reduced the proliferation, while increasing cellular apoptosis and caspase-9/3 activation of MM cells, in addition to downregulating the expression of TLR4 and NF-κB protein. Of note, TLR4- or NF-κB-targeting small-interfering (si)RNA enhanced the andrographolide-induced inhibition of cell proliferation and induction of apoptosis of MM cells. The results of the present study therefore suggested that andrographolide inhibited multiple myeloma cells via the TLR4/NF-κB signaling pathway. PMID:26707811

  4. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3.

    Science.gov (United States)

    Nelson, Erik A; Walker, Sarah R; Kepich, Alicia; Gashin, Laurie B; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C; Frank, David A

    2008-12-15

    Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. PMID:18824601

  5. Inhibition of gravitropism in oat coleoptiles by calcium chelation

    Science.gov (United States)

    Roux, S. J.

    1984-01-01

    Some cellular event necessary for gravitropism is inhibited by EGTA without interferring with the overall growth. Calcium relieves this inhibition and demonstrates both that inhibition is reversible and was probably due to a reduction in the ability to free calcium required for one or more at the transduction steps of gravitropism. At the near neutral pH used, EGTA is charged and would not be expected to readily cross the membrane. One of its primary effects, then, is probably the bringing of free calcium in the apoplastic space exterior to the cell membranes.

  6. Inhibition of Copper Corrosion by Flavonoids in Nitric Acid

    OpenAIRE

    Mahmoud A. Al-Qudah

    2011-01-01

    A study has been made to investigate the effect of some substituted flavonoids on copper dissolution in 2.0 M HNO3 for 4.0 hours at different temperatures by the weight loss method. Percentage of inhibition increases as concentration of the flavonoids increases and reaches a maximum value, due to the formation of a monolayer film on the surface of the metal. 92% Inhibition was observed in some of these flavonoids. As temperature increases, percentage of inhibition decreases. Energy of activat...

  7. Endocannabinoids inhibit the growth of free-living amoebae.

    Science.gov (United States)

    Dey, Rafik; Pernin, Pierre; Bodennec, Jacques

    2010-07-01

    The cannabinoid Delta(9)-tetrahydrocannabinol inhibits the growth of some pathogenic amoebae in vitro and exacerbates amoebic encephalitis in animal models. However, the effects of endogenous cannabinoids on amoebae remain unknown. Therefore, we tested several endocannabinoids (N-acyl ethanolamines and 2-O-acyl glycerol) on different genera of amoebae. The results showed that all of the endocannabinoids tested inhibit amoebic growth at subpharmacological doses, with 50% inhibitory concentrations ranging from 15 to 20 microM. A nonhydrolyzable endocannabinoid had similar effects, showing that the inhibition seen results from endocannabinoids per se rather than from a catabolic product. PMID:20479202

  8. Endocannabinoids Inhibit the Growth of Free-Living Amoebae▿

    Science.gov (United States)

    Dey, Rafik; Pernin, Pierre; Bodennec, Jacques

    2010-01-01

    The cannabinoid Δ9-tetrahydrocannabinol inhibits the growth of some pathogenic amoebae in vitro and exacerbates amoebic encephalitis in animal models. However, the effects of endogenous cannabinoids on amoebae remain unknown. Therefore, we tested several endocannabinoids (N-acyl ethanolamines and 2-O-acyl glycerol) on different genera of amoebae. The results showed that all of the endocannabinoids tested inhibit amoebic growth at subpharmacological doses, with 50% inhibitory concentrations ranging from 15 to 20 μM. A nonhydrolyzable endocannabinoid had similar effects, showing that the inhibition seen results from endocannabinoids per se rather than from a catabolic product. PMID:20479202

  9. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation

    OpenAIRE

    De Petrocellis, Luciano; Melck, Dominique; Palmisano, Antonella; Bisogno, Tiziana; Laezza, Chiara; Bifulco, Maurizio; Di Marzo, Vincenzo

    1998-01-01

    Anandamide was the first brain metabolite shown to act as a ligand of “central” CB1 cannabinoid receptors. Here we report that the endogenous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently inhibited the proliferation of MCF-7 and EFM-19 cells with IC50 values between 0.5 and 1.5 μM and 83–92% maximal inhibition at 5–10 μM. The proliferation of several other nonmammary tumoral cell lines was not affected by 10 ...

  10. 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...... the potential difference between silver and palladium while contacting with an electrolyte, the surface can form numerous discrete anodic and cathodic areas, so that an inhibiting reaction can occur. In this paper, a series of electrochemical and biological investigations were conducted to study the...

  11. Inhibition Mechanism of Cholinesterases by Carbamate: A Theoretical Study

    Institute of Scientific and Technical Information of China (English)

    YAO Yuan; LI Ze-sheng

    2008-01-01

    The density functional theory at the B3LYP/6-311G(d,p) level was applied to exploring the inhibition mechanism of cholinesterases by carbamate.The results indicate that the inhibition reactions with or without the catalytic effect of the catalytic triad in cholinesterases underwent a two-step addition-elimination mechanism,which is in good agreement with the proposed mechanism.The solvent has a strong effect on the inhibition reactions and the reaction with the catalytic triad in the solvent phase is close to the real reaction under biological condition.

  12. Curcumin inhibits amygdaloid kindled seizures in rats

    Institute of Scientific and Technical Information of China (English)

    DU Peng; LI Xin; LIN Hao-jie; PENG Wei-feng; LIU Jian-ying; MA Yu; FAN Wei; WANG Xin

    2009-01-01

    Background Curcumin can reduce the severity of seizures induced by kainate acid (KA), but the role of curcumin in amygdaloid kindled models is still unknown. This study aimed to explore the effect of curcumin on the development of kindling in amygdaloid kindled rats.Methods With an amygdaloid kindled Sprague-Dawley (SD) rat model and an electrophysiological method, differentdoses of curcumin (10 mg·kg-1·d-1 and 30 mg·kg-1·d-1as low dose groups, 100 mg·kg-1·d-1 and 300 mg·kg-1·d-1 as high dose groups) were administrated intraperitoneally during the whole kindling days, by comparison with the course of kindling, afterdischarge (AD) thresholds and the number of Ads to reach the stages of class Ⅰ to Ⅴ seizures in the rats between control and experimental groups. One-way or two-way ANOVA and Fisher's least significant difference post hoc test were used for statistical analyses.Results Curcumin (both 100 mg·kg-1·d-1 and 300 mg·kg-1·d-1) significantly inhibited the behavioral seizure development in the (19.80±9.25) and (21.70±9.21) stimulations respectively required to reach the kindled state. Rats treated with 100 mg·kg-1·d-1 curcumin 30 minutes before kindling stimulation showed an obvious increase in the stimulation current intensity required to evoke AD from (703.3±85.9) μA to (960.0±116.5) μA during the progression to class Ⅴ seizures. Rats treated with 300 mg·kg-1·d-1 curcumin showed a significant increase in the stimulation current intensity required to evoke AD from (735.0±65.2) μA to (86±7.093.4) μA during the progression to class Ⅴ seizures. Rats treated with 300 mg·kg-1·d-1 curcumin required much more evoked Ads to reach the stage of class both Ⅳ (as (199.83±12.47) seconds) and Ⅴ seizures (as (210.66±10.68) seconds). Rats treated with 100 mg·kg-1·d-1 curcumin required much more evoked Ads to reach the stage of class V seizures (as (219.56±18.24) seconds). Conclusion Our study suggests that curcumin has a potential

  13. FOXP3 Inhibits HIV-1 Infection of CD4 T-cells via Inhibition of LTR Transcriptional Activity

    OpenAIRE

    Selliah, Nithianandan; Zhang, Mingce; White, Sara; Zoltick, Philip; Sawaya, Bassel E.; Finkel, Terri H.; Cron, Randy Q

    2008-01-01

    FOXP3 is a necessary transcription factor for the development and function of CD4+ regulatory T-cells (Tregs). The role of Tregs in HIV-1 infection remains unclear. Here, we show expression of FOXP3 in primary human CD4 T-cells significantly inhibits HIV-1 infection. Since FOXP3 inhibits NFAT activity, and NFAT proteins contribute to HIV-1 transcription, we explore a transcriptional repressive function of HIV-1 LTR by FOXP3. Over-expression of FOXP3 in primary CD4 T-cells inhibits wild-type H...

  14. mTOR inhibition in management of advanced breast cancer

    Directory of Open Access Journals (Sweden)

    Shona Nag

    2012-01-01

    Full Text Available The mTOR pathway is becoming increasingly important in several cancers including breast cancer. This review will focus on the role of its inhibition in the management of advanced breast cancer.

  15. Cross inhibition improves activity selection when switching incurs time costs

    Institute of Scientific and Technical Information of China (English)

    James A.R.MARSHALL; Angélique FAVREAU-PEIGN(E); Lutz FROMHAGE; John M.MCNAMARA; Lianne F.S.MEAH; Alasdair I.HOUSTON

    2015-01-01

    We consider a behavioural model of an animal choosing between two activities,based on positive feedback,and examine the effect of introducing cross inhibition between the motivations for the two activities.While cross-inhibition has previously been included in models of decision making,the question of what benefit it may provide to an animal's activity selection behaviour has not previously been studied.In neuroscience and in collective behaviour cross-inhibition,and other equivalent means of coupling evidence-accumulating pathways,have been shown to approximate statistically-optimal decision-making and to adaptively break deadlock,thereby improving decision performance.Switching between activities is an ongoing decision process yet here we also find that cross-inhibition robustly improves its efficiency,by reducing the frequency of costly switches between behaviours [Current Zoology 61 (2):242-250,2015].

  16. Inhibition efficiency of urine towards stone forming minerals.

    Directory of Open Access Journals (Sweden)

    Dr. Seema Jawalekar,

    2010-02-01

    Full Text Available Urine specimens were collected from 100 normal individuals and 100 kidney stone patients and analysed spectrophotometrically for common stone promoters like oxalate, calcium, uric acid and phosphate and stone inhibitors like citrate and magnesium. Inhibition efficiency by these inhibitors exiting in urine samples towards the mineralisation of urinary stone forming minerals like calcium oxalate ,phosphate or carbonate has been studied in an experimental model. The results were presented as mean ± SD, student’s t test was used for statistical analysis. Hypocitraturia and hyperoxaluria were the common bnormalities in the stone formers. Kidney stone patients had significantly higher urinary oxalate, calcium and uric acid and lower phosphate than normal individuals. The efficiency is markedly higher for phosphate, carbonate and urates by healthy urine samples.For the stubborn mineral oxalate has low inhibition efficiency. The urine of stone formers show very little inhibition. This implies that inhibition of crystal growth is proportional to the concentration of inhibitory factor present.

  17. Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones.

    Science.gov (United States)

    McKee, E E; Ferguson, M; Bentley, A T; Marks, T A

    2006-06-01

    The effects of a variety of oxazolidinones, with different antibacterial potencies, including linezolid, on mitochondrial protein synthesis were determined in intact mitochondria isolated from rat heart and liver and rabbit heart and bone marrow. The results demonstrate that a general feature of the oxazolidinone class of antibiotics is the inhibition of mammalian mitochondrial protein synthesis. Inhibition was similar in mitochondria from all tissues studied. Further, oxazolidinones that were very potent as antibiotics were uniformly potent in inhibiting mitochondrial protein synthesis. These results were compared to the inhibitory profiles of other antibiotics that function by inhibiting bacterial protein synthesis. Of these, chloramphenicol and tetracycline were significant inhibitors of mammalian mitochondrial protein synthesis while the macrolides, lincosamides, and aminoglycosides were not. Development of future antibiotics from the oxazolidinone class will have to evaluate potential mitochondrial toxicity. PMID:16723564

  18. Inhibition of coagulation factors by recombinant barley serpin BSZx

    DEFF Research Database (Denmark)

    Dahl, Søren Weis; Rasmussen, S.K.; Petersen, L..C.;

    1996-01-01

    leukocytes, a fungal trypsin and three subtilisins, Thrombin, plasma kallikrein, factor VIIa/tissue factor and factor Xa were inhibited by BSZx at heparin independent association rates (k(ass)) of 4.5 x 10(3)-1.3 x 10(5) M(-1) s(-1) at 22 degrees C. Only factor Xa turned a significant fraction of BSZx over...... as substrate, Complexes of these proteinase with BSZx resisted boiling in SDS, and amino acid sequencing showed that cleavage in the reactive center loop only occurred after P-1 Arg. Activated protein C and leukocyte elastase were slowly inhibited by BSZx (k(ass) = 1-2 x 10(2) M(-1) s(-1)) whereas...... factor XIIa, urokinase and tissue type plasminogen activator, plasmin and pancreas kallikrein and elastase were not or only weakly affected, The inhibition pattern with mammalian proteinases reveal a specificity of BSZx similar to that of antithrombin III. Trypsin from Fusarium was not inhibited while...

  19. A Broad Dynamical Model for Pattern Formation by Lateral Inhibition

    CERN Document Server

    Arcak, Murat

    2012-01-01

    Many patterning events in multi-cellular organisms rely on cell-to-cell contact signaling, such as the Notch pathway in metazoans. A particularly interesting phenomenon in this form of communication is lateral inhibition where a cell that adopts a particular fate inhibits its immediate neighbors from doing the same. Dynamical models are of great interest for understanding the circuit topologies involved in lateral inhibition and for predicting the associated patterns. Several simplified models have been employed for Notch signalling pathways in the literature. The objective of this paper is to present an abstract dynamical model that captures the essential features of lateral inhibition and to demonstrate with dynamical systems techniques that these features indeed lead to patterning.

  20. 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...... seven fold decreased whereas K M was unaffected in the presence of 10 microM Zn2+. The inhibitory effect of Zn2+ on APC activity was also observed when factor Va was used as a substrate in an assay coupled to a prothrombinase assay. The interaction of Zn2+ with APC was accompanied by a reversible...... fold enhanced, presumably due to the Ca2+-induced conformational change affecting the conformation of the Zn2+-binding site. The inhibition mechanism was non-competitive both in the absence and presence of Ca2+. Comparisons of sequences and structures suggested several possible sites for zinc binding...

  1. Corrosion inhibition in the presence of microbial corrosion

    Energy Technology Data Exchange (ETDEWEB)

    Videla, H.A. [Univ. of La Plata (Argentina). Dept. of Chemistry

    1996-12-01

    Microorganisms influence corrosion by changing the electrochemical conditions at the metal/solution interface. These changes may have different effects, ranging from the induction of localized corrosion to corrosion inhibition. The key to the alteration of conditions at a metal surface and hence, the enhancement or inhibition of corrosion is the formation of a biofilm. On a biologically conditioned metal surface microorganisms can induce corrosion inhibition in several ways: (a) by neutralizing the action of a corrosive substance already present in the medium; (b) by stabilizing a protective film on a metal surface or (c) by inducing a decrease in the medium aggressiveness. Seldomly mentioned in the literature, microbial inhibition of corrosion could be a potentially useful tool to counteract many of the biodeterioration cases encountered in practice.

  2. Response inhibition is associated with white matter microstructure in children

    DEFF Research Database (Denmark)

    Madsen, Kathrine Skak; Baaré, William; Vestergaard, Martin;

    2010-01-01

    Cognitive control of thoughts, actions and emotions is important for normal behaviour and the development of such control continues throughout childhood and adolescence. Several lines of evidence suggest that response inhibition is primarily mediated by a right-lateralized network involving...... the relationship between response inhibition, as measured with the stop-signal task, and indices of regional white matter microstructure in typically-developing children. We hypothesized that better response inhibition performance would be associated with higher fractional anisotropy (FA) in fibre tracts within...... right IFG and preSMA after controlling for age. Mean FA and diffusivity values were extracted from right and left IFG and preSMA. As hypothesized, faster response inhibition was significantly associated with higher FA and lower perpendicular diffusivity in both the right IFG and the right pre...

  3. Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

    International Nuclear Information System (INIS)

    Highlights: ► This is the first functional characterization of UQCRB in vivo model. ► Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ► UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases

  4. Corrosion Inhibition of a Green Scale Inhibitor Polyepoxysuccinic Acid

    Institute of Scientific and Technical Information of China (English)

    Rong Chun XIONG; Qing ZHOU; Gang WEI

    2003-01-01

    The corrosion inhibition of a green scale inhibitor, polyepoxysuccinic acid (PESA) wasstudied based on dynamic tests. It is found that when PESA is used alone, it had good corrosioninhibition. So, PESA should be included in the category of corrosion inhibitors. It is not only akind of green scale inhibitor, but also a green corrosion inhibitor. The synergistic effect betweenPESA and Zn2+ or sodium gluconate is poor. However, the synergistic effect among PESA, Zn2+and sodium gluconate is excellent, and the corrosion inhibition efficiency for carbon steel is higherthan 99%. Further study of corrosion inhibition mechanism reveals that corrosion inhibition ofPESA is not affected by carboxyl group, but by the oxygen atom inserted The existence ofoxygen atom in PESA molecular structure makes it easy to form stable chelate with pentacyclicstructure.

  5. Mathematical Modelling Of Cyanide Inhibition on Cassava Wastewater Treatment

    OpenAIRE

    E. Onukwugha

    2013-01-01

    Anaerobic Baffled Reactors (ABR) is used to evaluate the extent of cyanide inhibition of cassava wastewater treatment. The reactor has aspect ratio of 4:1:1. Kinetic analyses of specific growth rate μmax and half saturation constant

  6. Flagging Drugs That Inhibit the Bile Salt Export Pump.

    Science.gov (United States)

    Montanari, Floriane; Pinto, Marta; Khunweeraphong, Narakorn; Wlcek, Katrin; Sohail, M Imran; Noeske, Tobias; Boyer, Scott; Chiba, Peter; Stieger, Bruno; Kuchler, Karl; Ecker, Gerhard F

    2016-01-01

    The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis. Predictive computational models of BSEP inhibition may allow for fast identification of potentially harmful compounds in large databases. This article presents a predictive in silico model based on physicochemical descriptors that is able to flag compounds as potential BSEP inhibitors. This model was built using a training set of 670 compounds with available BSEP inhibition potencies. It successfully predicted BSEP inhibition for two independent test sets and was in a further step used for a virtual screening experiment. After in vitro testing of selected candidates, a marketed drug, bromocriptin, was identified for the first time as BSEP inhibitor. This demonstrates the usefulness of the model to identify new BSEP inhibitors and therefore potential cholestasis perpetrators. PMID:26642869

  7. Transcriptome dynamics of the microRNA inhibition response

    DEFF Research Database (Denmark)

    Wen, Jiayu; Leucci, Elenora; Vendramin, Roberto; Kauppinen, Sakari; Lund, Anders H; Krogh, Anders; Parker, Brian J

    2015-01-01

    We report a high-resolution time series study of transcriptome dynamics following antimiR-mediated inhibition of miR-9 in a Hodgkin lymphoma cell-line-the first such dynamic study of the microRNA inhibition response-revealing both general and specific aspects of the physiological response. We show...... validate the key observations with independent time series qPCR and we experimentally validate key predicted miR-9 targets. Methodologically, we developed sensitive functional data analytic predictive methods to analyse the weak response inherent in microRNA inhibition experiments. The methods of this...... study will be applicable to similar high-resolution time series transcriptome analyses and provides the context for more accurate experimental design and interpretation of future microRNA inhibition studies....

  8. Inhibition of osteoclastogenesis by mechanically loaded osteocytes: involvement of MEPE

    NARCIS (Netherlands)

    R.N. Kulkarni; A.D. Bakker; V. Everts; J. Klein Nulend

    2010-01-01

    In regions of high bone loading, the mechanoresponsive osteocytes inhibit osteoclastic bone resorption by producing signaling molecules. One possible candidate is matrix extracellular phosphoglycoprotein (MEPE) because acidic serine- and aspartate-rich MEPE-associated motif peptides upregulate osteo

  9. Beyond Behavioral Inhibition: Etiological Factors in Childhood Anxiety

    Science.gov (United States)

    Manassis, Katharina; Hudson, Jennifer L.; Webb, Alicia; Albano, Anne Marie

    2004-01-01

    Theoretical models of childhood anxiety have emphasized temperamental vulnerability, principally behavioral inhibition, and its interaction with various environmental factors promoting anxiety (for example, overprotective parenting, insecure attachment, life stress). Although clearly establishing the importance of both nature and nurture in…

  10. Inhibition of Porcine Small Intestinal Sucrase by Validamine

    Institute of Scientific and Technical Information of China (English)

    郑裕国; 申屠旭萍; 沈寅初

    2005-01-01

    As an important medicinal intermediate with broad uses, validamine, an aminocyclitol, isolated from the enzymolysis broth of validamycins, has gained more and more attention. The absolute configuration of validamine is similar to that of α-D-glucose, and it demonstrates powerful inhibition activity on glycosidase. In this paper, the inhibitory effect of validamine on porcine small intestinal sucrase was investigated. Validamine was found to be a potent, competitive inhibitor to porcine small intestinal sucrase in vitro with an IC50 value of 6.85 × 10-4 mol·L-1. Validamine exhibited a dose-dependent inhibition effect on porcine small intestinal sucrase, whereby the inhibition interaction of validamine and porcine small intestinal sucrase was a fast binding process. The inhibition of validamine on porcine small intestinal sucrase was pH-dependent.

  11. Prepotent response inhibition predicts treatment outcome in attention deficit/hyperactivity disorder

    NARCIS (Netherlands)

    S. van der Oord; H.M. Geurts; P.J.M. Prins; P.M.G. Emmelkamp; J. Oosterlaan

    2012-01-01

    Objective: Inhibition deficits, including deficits in prepotent response inhibition and interference control, are core deficits in ADHD. The predictive value of prepotent response inhibition and interference control was assessed for outcome in a 10-week treatment trial with methylphenidate. Methods:

  12. Inhibition of bacteria contaminating alcoholic fermentations by killer yeasts

    OpenAIRE

    Maria Cristina Meneghin; Vanda Renata Reis; Sandra Regina Ceccato-Antonini

    2010-01-01

    The aim of this work was to study the in vitro antibacterial activity possessed by killer yeast strains against bacteria contaminating alcoholic fermentation (Bacillus subtilis, Lactobacillus plantarum, Lactobacillus fermentum and Leuconostoc mesenteroides), in cell X cell and cell X crude toxin preparations. The bacteria were not inhibited by any S. cerevisiae killer strains (5 out of 11). The inhibition caused by two crude toxin preparations (Trichosporon figueirae and Candida sp) against L...

  13. The role of non-CRF inhibition in contour detection

    OpenAIRE

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

    2003-01-01

    We propose a biologically motivated computational step, called non-classical receptive field (non-CRF) inhibition, to improve the performance of contour detectors. Non-CRF inhibition is exhibited by 80% of the orientation selective neurons in the primary visual cortex of macaque monkeys and has been demonstrated to influence the visual perception of man as well. We introduce an image processing operator, the bar cell operator, which consists of a Gabor energy operator augmented with non-CRF i...

  14. Inhibition of Mammalian Mitochondrial Protein Synthesis by Oxazolidinones

    OpenAIRE

    McKee, E. E.; Ferguson, M; Bentley, A T; Marks, T. A.

    2006-01-01

    The effects of a variety of oxazolidinones, with different antibacterial potencies, including linezolid, on mitochondrial protein synthesis were determined in intact mitochondria isolated from rat heart and liver and rabbit heart and bone marrow. The results demonstrate that a general feature of the oxazolidinone class of antibiotics is the inhibition of mammalian mitochondrial protein synthesis. Inhibition was similar in mitochondria from all tissues studied. Further, oxazolidinones that wer...

  15. A Nonantibiotic Chemically Modified Tetracycline (CMT-3) Inhibits Intimal Thickening

    OpenAIRE

    Islam, Muzharul M.; Franco, Christopher D.; Courtman, David W.; Bendeck, Michelle P.

    2003-01-01

    Recent research has shown that the tetracycline antibiotics are pluripotent drugs that inhibit the activity of matrix metalloproteinases (MMPs) and affect many cellular functions including proliferation, migration, and matrix remodeling. We have shown that doxycycline inhibits MMP activity and intimal thickening after injury of the rat carotid artery, however we do not know whether these effects are because of the antibiotic, anti-MMP, or other actions of doxycycline. Recently, chemically mod...

  16. Inhibition of human lymphoproliferative responses by mycobacterial phenolic glycolipids.

    OpenAIRE

    Fournie, J J; Adams, E; Mullins, R J; Basten, A

    1989-01-01

    The effect of mycobacterial phenolic glycolipids from Mycobacterium leprae, M. bovis BCG, and M. kansasii on in vitro proliferative responses by human blood mononuclear cells from healthy BCG vaccinees was investigated. All three phenolic glycolipids inhibited proliferation in a concentration-dependent manner. Inhibition was independent of the stimulus used and involved neither antigen-presenting cells nor antigen-specific CD8+ suppressor T cells. It was concluded that the phenomenon may be a...

  17. Intracortical inhibition of the motor cortex is normal in chorea

    OpenAIRE

    HANAJIMA, R; Ugawa, Y; Y. Terao; Furubayashi, T.; Machii, K; Shiio, Y.; H. Enomoto; Uesugi, H.; Mochizuki, H.; Kanazawa, I

    1999-01-01

    Intracortical inhibition of the motor cortex was investigated using a paired pulse magnetic stimulation method in 14 patients with chorea caused by various aetiologies (six patients with Huntington's disease, one with chorea acanthocytosis, a patient with systemic lupus erythematosus with a vascular lesion in the caudate, three with senile chorea and three with chorea of unknown aetiology). The time course and amount of inhibition was the same in the patients as in normal su...

  18. Tristetraprolin inhibits gastric cancer progression through suppression of IL-33

    OpenAIRE

    Kaiyuan Deng; Hao Wang; Ting Shan; Yigang Chen; Hong Zhou; Qin Zhao; Jiazeng Xia

    2016-01-01

    Tristetraprolin (TTP) is an adenine/uridine (AU)-rich element (ARE)-binding protein that can induce degradation of mRNAs. In this study, we report that TTP suppresses the expression of interleukin-33 (IL-33), a tumor-promoting inflammatory cytokine, and thereby inhibits the progression of gastric cancer (GC). Overexpression of TTP decreased the level of IL-33, whereas knockdown of TTP increased IL-33 levels. We also discovered that TTP inhibited the proliferation, migration, and invasion of G...

  19. Inhibition of airway surface fluid absorption by cholinergic stimulation

    OpenAIRE

    Nam Soo Joo; Krouse, Mauri E.; Jae Young Choi; Hyung-Ju Cho; Wine, Jeffrey J.

    2016-01-01

    In upper airways airway surface liquid (ASL) depth and clearance rates are both increased by fluid secretion. Secretion is opposed by fluid absorption, mainly via the epithelial sodium channel, ENaC. In static systems, increased fluid depth activates ENaC and decreased depth inhibits it, suggesting that secretion indirectly activates ENaC to reduce ASL depth. We propose an alternate mechanism in which cholinergic input, which causes copious airway gland secretion, also inhibits ENaC-mediated ...

  20. Firing regulation of fast-spiking interneurons by autaptic inhibition

    OpenAIRE

    Guo, Daqing; Chen, Mingming; Perc, Matjaz; Wu, Shengdun; Xia, Chuan; Zhang, Yangsong; Xu, Peng; Xia, Yang; Yao, Dezhong

    2016-01-01

    Fast-spiking (FS) interneurons in the brain are self-innervated by powerful inhibitory GABAergic autaptic connections. By computational modelling, we investigate how autaptic inhibition regulates the firing response of such interneurons. Our results indicate that autaptic inhibition both boosts the current threshold for action potential generation as well as modulates the input-output gain of FS interneurons. The autaptic transmission delay is identified as a key parameter that controls the f...

  1. Strategic modulation of response inhibition in task-switching

    OpenAIRE

    Kai RobinGrzyb

    2013-01-01

    Residual activations from previous task performance usually prime the system toward response repetition. However, when the task switches, the repetition of a response (RR) produces longer reaction times and higher error rates. Some researchers assumed that these RR costs reflect strategic inhibition of just executed responses and that this serves for preventing perseveration errors. We investigated whether the basic level of response inhibition is adapted to the overall risk of response perse...

  2. Delta-Notch Lateral Inhibition within the Organ of Corti

    International Nuclear Information System (INIS)

    Lateral inhibition is described as an emergent property of the Delta-Notch signalling network. Two separate model representations of lateral inhibition are proposed for different purposes. One provides information about bioenergetics while the other has the capability to produce a physical representation. It is proposed that both can be used in further studies of the sensory pathways in the human connectome model of brain function

  3. Endocannabinoids Inhibit the Growth of Free-Living Amoebae▿

    OpenAIRE

    Dey, Rafik; Pernin, Pierre; Bodennec, Jacques

    2010-01-01

    The cannabinoid Δ9-tetrahydrocannabinol inhibits the growth of some pathogenic amoebae in vitro and exacerbates amoebic encephalitis in animal models. However, the effects of endogenous cannabinoids on amoebae remain unknown. Therefore, we tested several endocannabinoids (N-acyl ethanolamines and 2-O-acyl glycerol) on different genera of amoebae. The results showed that all of the endocannabinoids tested inhibit amoebic growth at subpharmacological doses, with 50% inhibitory concentrations ra...

  4. Inhibition of OCTN2-Mediated Transport of Carnitine by Etoposide

    OpenAIRE

    Hu, Chaoxin; Lancaster, Cynthia S.; Zuo, Zhili; Hu, Shuiying; Chen, Zhaoyuan; Rubnitz, Jeffrey E; Baker, Sharyn D.; Sparreboom, Alex

    2012-01-01

    OCTN2 is a bifunctional transporter that reabsorbs filtered carnitine in a sodium dependent manner and secretes organic cations into urine as a proton antiport mechanism. We hypothesized that inhibition of OCTN2 by anticancer drugs can influence carnitine resorption. OCTN2-mediated transport inhibition by anticancer drugs was assessed using cells transfected with human OCTN2 (hOCTN2) or mouse Octn2 (mOctn2). Excretion of carnitine and acetylcarnitine was measured in urine collected from mice ...

  5. Corrosion inhibition performance of a ionic liquid surfactant Br

    OpenAIRE

    Jing LIU; Dishun ZHAO; LIU, RAN; Wang, Ming; Peibing REN

    2016-01-01

    In order to study the novel green organic mercury-substituting inhibitors, the ionic liquid surfactant 1-methyl-3-dodecyl imidazole bromide ( Br) is synthesized with N-methyl imidazole and 1-bromodecane as raw materials. The corrosion inhibition of Br for zinc in zinc-manganese batteries is investigated using electrochemical methods and weight loss methods. The results show that corrosion inhibition efficiency increases with the increase of the concentration of Br, and when the concentration ...

  6. Implementation Intentions Facilitate Response Inhibition in Children with ADHD

    OpenAIRE

    Gawrilow, Caterina; Gollwitzer, Peter M.

    2008-01-01

    Attention Deficit/Hyperactivity Disorder (ADHD) is associated with action control problems such as failure to inhibit inappropriate responses. Two studies investigated whether self-regulation by implementation intentions (if-then plans; Gollwitzer, P. M. (1999). Implementation intentions: Strong effects of simple plans. American Psychologist, 54, 493 503) facilitates response inhibition in children with ADHD. In Study 1, children with ADHD who furnished a suppression goal with implementation ...

  7. Inhibition of virulence potential of Vibrio cholerae by natural compounds

    OpenAIRE

    Yamasaki, Shinji; Asakura, Masahiro; Neogi, Sucharit Basu; Hinenoya, Atsushi; Iwaoka, Emiko; Aoki, Shunji

    2011-01-01

    The rise in multi-drug resistant Vibrio cholerae strains is a big problem in treatment of patients suffering from severe cholera. Only a few studies have evaluated the potential of natural compounds against V. cholerae. Extracts from plants like ‘neem’, ‘guazuma’, ‘daio’, apple, hop, green tea and elephant garlic have been shown to inhibit bacterial growth or the secreted cholera toxin (CT). However, inhibiting bacterial growth like common antimicrobial agents may also impose selective pressu...

  8. Attentional lapse and inhibition control in adults with Williams Syndrome.

    OpenAIRE

    Greer, J; Riby, D. M.; Hamiliton, C.; Riby, L. M.

    2013-01-01

    Research exploring cognitive processing associated with Williams Syndrome (WS) has suggested that executive functioning deficits exist across the developmental spectrum. Such executive functions include problem solving, planning, dividing attention and inhibiting responses. Within a framework of executive functions, the aim of the current study was to explore attentional lapse and inhibition skills in older adults with WS (n = 20; aged 36–61 yr) and consider the implications of deficits withi...

  9. Sodium Fluoride Inhibits MMP-2 and MMP-9

    OpenAIRE

    Kato, M.T.; Bolanho, A.; Zarella, B.L.; Salo, T.; Tjäderhane, L.; Buzalaf, M.A.R.

    2014-01-01

    The importance of fluoride (F) in preventing dental caries by favorably interfering in the demineralization-remineralization processes is well-established, but its ability to inhibit matrix metalloproteinases (MMPs), which could also help to prevent dentin caries, has not been investigated. This study assessed the ability of F to inhibit salivary and purified human gelatinases MMPs-2 and -9. Saliva was collected from 10 healthy individuals. Pooled saliva was centrifuged, and supernatants were...

  10. Inhibition of macrophage phagosome-lysosome fusion by Salmonella typhimurium.

    OpenAIRE

    Buchmeier, N A; Heffron, F

    1991-01-01

    Salmonella typhimurium-infected macrophages were examined by electron microscopy to determine whether intracellular survival of S. typhimurium is associated with failure of bacteria containing phagosomes to fuse with secondary lysosomes. S. typhimurium 14028 actively inhibited phagosome-lysosome fusion and appeared to preferentially divide within unfused phagocytic vesicles. In comparison with Escherichia coli, S. typhimurium inhibited phagosome-lysosome fusion in peritoneal macrophages, J774...

  11. Facilitation versus inhibition in non-spatial attribute discrimination tasks

    OpenAIRE

    Hu, Frank K.; Samuel, Arthur G.

    2011-01-01

    Inhibition of Return is a delay in initiating attentional shifts to previously inspected locations. It has been explained as a mechanism to facilitate visual search of a scene by inhibiting the allocation of attention to locations that have already been examined. We (Hu, Samuel, & Chan, Journal of Experimental Psychology: General, 2010) recently demonstrated that similar processing costs can appear when a non-spatial attribute (color or shape) repeats—detection of a target stimulus was slower...

  12. Inhibition of Brevibacterium linens by Probiotics from Dairy Products

    OpenAIRE

    Knox, Alison M.; Viljoen, Bennie C.; Lourens-Hattingh, Analie

    2005-01-01

    Brevibacterium linens is an important species in dairy products rendering a specific taste and aroma to numerous smear ripened and blue veined cheeses due to proteolysis. However, the presence of the species in South African blue veined cheeses is undesirable and consumers demand the product void of the species. Accordingly, numerous methods including microbial inhibition using fungi and bacterial probiotic cultures with possible inhibitory effects were applied in an attempt to inhibit the sp...

  13. Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML

    OpenAIRE

    Zaitseva, Lyubov; Murray, Megan Y; Shafat, Manar S.; Lawes, Matthew J.; MacEwan, David J.; Bowles, Kristian M.; Rushworth, Stuart A.

    2014-01-01

    Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/C...

  14. Platelet inhibition with Ticlopidine in atherosclerotic intermittent claudication.

    OpenAIRE

    Aukland, A; Hurlow, R. A.; George, A J; Stuart, J

    1982-01-01

    Fifty-one men with atherosclerotic intermittent claudication and haemorheological abnormalities completed a double-blind, one-year randomised trial of Ticlopidine (500 mg/day), a new antiplatelet agent. Ticlopidine caused significant inhibition of platelet aggregation but did not fully correct abnormalities of coagulation, viscosity, and fibrinolysis. There was no significant improvement in walking ability, Doppler ankle-pressure indices, or calf blood flow. Sustained platelet inhibition for ...

  15. Delta-Notch Lateral Inhibition within the Organ of Corti

    Science.gov (United States)

    Summers, R.; Abdulla, T.; Luff, R.

    2013-09-01

    Lateral inhibition is described as an emergent property of the Delta-Notch signalling network. Two separate model representations of lateral inhibition are proposed for different purposes. One provides information about bioenergetics while the other has the capability to produce a physical representation. It is proposed that both can be used in further studies of the sensory pathways in the human connectome model of brain function.

  16. Selective inhibition of DNA amplification in nonadhering Mycoplasma pneumoniae cultures

    Energy Technology Data Exchange (ETDEWEB)

    Zigangirova, N.A.; Solov`eva, S.V.; Rakovskaya, I.V. [Gamaleya Scientific Research Institute of Epidemiology and Microbiology, Moscow (Russian Federation)] [and others

    1995-08-01

    Inhibition of amplification of various genome regions of Mycoplasma pneumoniae was observed in the polymerase chain reaction, and was dependent on cultivation conditions. A protein stably associated with DNA is responsible for the inhibitory effect. It is assumed that when the protein selectively associates with separate DNA regions, it can inhibit genes encoding pathogenicity factors, thus promoting mycoplasma transformation into persistent variants. 16 refs., 2 figs.

  17. Individual Differences in Fear Potentiated Startle in Behaviorally Inhibited Children

    OpenAIRE

    Barker, Tyson V.; Reeb-Sutherland, Bethany; Fox, Nathan A.

    2013-01-01

    Behavioral inhibition (BI) is a temperament characterized during early childhood by increased fearfulness to novelty, social reticence to unfamiliar peers, and heightened risk for the development of anxiety. Heightened startle responses to safety cues have been found among behaviorally inhibited adolescents who have an anxiety disorder suggesting that this measure may serve as a biomarker for the development of anxiety amongst this risk population. However, it is unknown if these aberrant sta...

  18. Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation.

    OpenAIRE

    Corr, P B; Creer, M H; Yamada, K.A.; Saffitz, J E; Sobel, B. E.

    1989-01-01

    Hypoxia in isolated myocytes results in accumulation of long-chain acylcarnitines (LCA) in sarcolemma. Inhibition of carnitine acyltransferase I (CAT-I) with sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA) prevents both the accumulation of LCA in the sarcolemma and the initial electrophysiologic derangements associated with hypoxia. Another amphiphilic metabolite, lysophosphatidylcholine (LPC), accumulates in the ischemic heart in vivo, in part because of inhibition of its c...

  19. Fluoride inhibits the antimicrobial peroxidase systems in human whole saliva.

    Science.gov (United States)

    Hannuksela, S; Tenovuo, J; Roger, V; Lenander-Lumikari, M; Ekstrand, J

    1994-01-01

    Fluoride (F-) ions at concentrations present in vivo at the plaque/enamel interface (0.05-10 mM) inhibited the activities of lactoperoxidase (LP), myeloperoxidase (MP) and total salivary peroxidase (TSP) in a pH- and dose-dependent way. The inhibition was observed only at pH or = 0.1 mM. At pH 5.5 LP activity was inhibited by 85% and MP by 34% with 10 mM F-. TSP activity was also inhibited only at low pH (5.5) by approximately 25%. Furthermore, the generation of the actual antimicrobial agent in vivo, hypothiocyanite (HOSCN/OSCN-), of the oral peroxidase systems was inhibited by F-, again at low pH (5.0-5.5) both in buffer (by 45%) and in saliva (by 15%). This inhibition was observed only with the highest F- concentrations studied (5-10 mM). Fluoridated toothpaste (with 0.10 or 0.14% F) mixed with saliva did not inhibit TSP or HOSCN/OSCN- generation. This may have been due to the 'buffering' effect of toothpaste which did not allow salivary pH to drop below 5.9. We conclude that the F- ions in acidic fluoride products, e.g. in gels or varnishes (but not in toothpastes), may have the potential to locally inhibit the generation of a nonimmune host defense factor, HOSCN/OSCN/SCN-, produced by oral peroxidase systems. The possible clinical significance of this finding remains to be shown. PMID:7850846

  20. 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.

  1. DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

    International Nuclear Information System (INIS)

    Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents. Methods and results: Human venous blood from healthy volunteers was collected in citrated tubes and platelet activation was studied by cone and platelet analyzer (CPA) and rapid-platelet-function-assay (RPFA). CPA analysis showed that DMSO-treated platelets exhibit a lower adherence in response to shear stress (-15.54 ± 0.9427%, n = 5, P < 0.0001 versus control). Additionally, aggregometry studies revealed that DMSO-treated, arachidonate-stimulated platelets had an increased lag phase (18.0% ± 4.031, n = 9, P = 0.0004 versus control) as well as a decreased maximal aggregation (-6.388 ± 2.212%, n = 6, P = 0.0162 versus control). Inhibitory action of DMSO could be rescued by exogenous thromboxane A2 and was mediated, at least in part, by COX-1 inhibition. Conclusions: Clinically relevant concentrations of DMSO impair platelet activation by a thromboxane A2-dependent, COX-1-mediated effect. This finding may be crucial for the previously reported anti-thrombotic property displayed by DMSO. Our findings support a role for DMSO as a novel drug to prevent not only proliferation, but also thrombotic complications of drug eluting stents.

  2. Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition.

    Science.gov (United States)

    Kahle, Kristopher T; Schmouth, Jean-François; Lavastre, Valérie; Latremoliere, Alban; Zhang, Jinwei; Andrews, Nick; Omura, Takao; Laganière, Janet; Rochefort, Daniel; Hince, Pascale; Castonguay, Geneviève; Gaudet, Rébecca; Mapplebeck, Josiane C S; Sotocinal, Susana G; Duan, JingJing; Ward, Catherine; Khanna, Arjun R; Mogil, Jeffrey S; Dion, Patrick A; Woolf, Clifford J; Inquimbert, Perrine; Rouleau, Guy A

    2016-01-01

    HSN2is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking theHsn2exon ofWnk1 Although these mice had normal spinal neuron and peripheral sensory neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K(+)-Cl(-)cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr(906)and Thr(1007), resulting in an associated loss of GABA (γ-aminobutyric acid)-mediated inhibition of spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl(-)such that GABA signaling resulted in a less hyperpolarized state (increased neuronal activity) rather than a more hyperpolarized state (decreased neuronal activity) in mouse spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr(906)and Thr(1007)phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured spinal cord lamina II neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury. PMID:27025876

  3. Combined MET inhibition and topoisomerase I inhibition block cell growth of small cell lung cancer.

    Science.gov (United States)

    Rolle, Cleo E; Kanteti, Rajani; Surati, Mosmi; Nandi, Suvobroto; Dhanasingh, Immanuel; Yala, Soheil; Tretiakova, Maria; Arif, Qudsia; Hembrough, Todd; Brand, Toni M; Wheeler, Deric L; Husain, Aliya N; Vokes, Everett E; Bharti, Ajit; Salgia, Ravi

    2014-03-01

    Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)-induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC. PMID:24327519

  4. DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

    Energy Technology Data Exchange (ETDEWEB)

    Asmis, Lars [Institute for Clinical Hematology, University Hospital Zuerich, Zuerich (Switzerland); Tanner, Felix C. [Cardiovascular Research, Physiology Institute, University of Zuerich, Zuerich (Switzerland); Center for Integrative Human Physiology, University of Zuerich, Zuerich (Switzerland); Cardiology, Cardiovascular Center, University Hospital Zuerich, Zuerich (Switzerland); Sudano, Isabella [Cardiology, Cardiovascular Center, University Hospital Zuerich, Zuerich (Switzerland); Luescher, Thomas F. [Cardiovascular Research, Physiology Institute, University of Zuerich, Zuerich (Switzerland); Center for Integrative Human Physiology, University of Zuerich, Zuerich (Switzerland); Cardiology, Cardiovascular Center, University Hospital Zuerich, Zuerich (Switzerland); Camici, Giovanni G., E-mail: giovannic@access.uzh.ch [Cardiovascular Research, Physiology Institute, University of Zuerich, Zuerich (Switzerland); Center for Integrative Human Physiology, University of Zuerich, Zuerich (Switzerland)

    2010-01-22

    Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents. Methods and results: Human venous blood from healthy volunteers was collected in citrated tubes and platelet activation was studied by cone and platelet analyzer (CPA) and rapid-platelet-function-assay (RPFA). CPA analysis showed that DMSO-treated platelets exhibit a lower adherence in response to shear stress (-15.54 {+-} 0.9427%, n = 5, P < 0.0001 versus control). Additionally, aggregometry studies revealed that DMSO-treated, arachidonate-stimulated platelets had an increased lag phase (18.0% {+-} 4.031, n = 9, P = 0.0004 versus control) as well as a decreased maximal aggregation (-6.388 {+-} 2.212%, n = 6, P = 0.0162 versus control). Inhibitory action of DMSO could be rescued by exogenous thromboxane A2 and was mediated, at least in part, by COX-1 inhibition. Conclusions: Clinically relevant concentrations of DMSO impair platelet activation by a thromboxane A2-dependent, COX-1-mediated effect. This finding may be crucial for the previously reported anti-thrombotic property displayed by DMSO. Our findings support a role for DMSO as a novel drug to prevent not only proliferation, but also thrombotic complications of drug eluting stents.

  5. Inhibition of mTOR Signal Reduces Epileptogenesis by Inhibiting Early Inflammatory Responses

    Directory of Open Access Journals (Sweden)

    Haiju Zhang

    2015-09-01

    Full Text Available Accumulating evidence suggests that brain inflammation is an important mechanism that promotes epileptogenesis and seizure development. This topic was inspired from the tuberous sclerosis (TSC, in the pathogenesis of the deletion of Tsc1/2 gene induced by the mammalian target of rapamycin (mTOR abnormal activation signal, which is associated with intractable epilepsy. mTOR specific inhibitor can reduce TSC subependymal nodules, and seizures eased. While the mTOR inhibitors are also powerful immunosuppressant, we presumed that mTOR signal abnormal activation was involved in the chronic epileptogenesis after seizures, whether mTOR inhibitors could prevent the epileptogenesis by inhibiting the early inflammatory factors via mTOR signal. We induced seizures in rats (P10d by intraperitoneal injection kainic acid (KA, and pretreatment of rapamycin was given intraperitoneally (6 mg/kg/day under isoflurane anesthesia for 3 consecutive days prior to kainate injection, once daily for 7 days. The experiment rats were divided into KA group, KA+RAP group and Control group. We observed the difference of chronic spontaneous seizures (SRS occurred in the groups. This study will research the alteration of the mTOR signal after seizures in immature rats. We also study the effects of mTOR inhibitors on astrocytes, microglia and early inflammatory factors such as IL-1β, COX-2, TGF- 1 after KA induced-SE. mTOR inhibitors can reduce the occurrence of SRS in chronic phase, and inhibit the gene and protein expression of early inflammatory cytokines of IL-1, TGF-1 and COX-2 level, Which may provide new ideas and methods to prevent the formation of chronic epilepsy.

  6. Cocaine Inhibition of Nicotinic Acetylcholine ReceptorsInfluences Dopamine Release

    Directory of Open Access Journals (Sweden)

    Alexandra eAcevedo-Rodriguez

    2014-09-01

    Full Text Available Nicotinic acetylcholine receptors (nAChRs potently regulate dopamine (DA release in the striatum and alter cocaine’s ability to reinforce behaviors. Since cocaine is a weak nAChR inhibitor, we hypothesized that cocaine may alter DA release by inhibiting the nAChRs in DA terminals in the striatum and thus contribute to cocaine's reinforcing properties primarily associated with the inhibition of DA transporters. We found that biologically relevant concentrations of cocaine can mildly inhibit nAChR-mediated currents in midbrain DA neurons and consequently alter DA release in the dorsal and ventral striatum. At very high concentrations, cocaine also inhibits voltage-gated Na channels in DA neurons. Furthermore, our results show that partial inhibition of nAChRs by cocaine reduces evoked DA release. This diminution of DA release via nAChR inhibition more strongly influences release evoked at low or tonic stimulation frequencies than at higher (phasic stimulation frequencies, particularly in the dorsolateral striatum. This cocaine-induced shift favoring phasic DA release may contribute to the enhanced saliency and motivational value of cocaine-associated memories and behaviors.

  7. Oxidative stress inhibits axonal transport: implications for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Fang Cheng

    2012-06-01

    Full Text Available Abstract Background Reactive oxygen species (ROS released by microglia and other inflammatory cells can cause axonal degeneration. A reduction in axonal transport has also been implicated as a cause of axonal dystrophies and neurodegeneration, but there is a paucity of experimental data concerning the effects of ROS on axonal transport. We used live cell imaging to examine the effects of hydrogen peroxide on the axonal transport of mitochondria and Golgi-derived vesicles in cultured rat hippocampal neurons. Results Hydrogen peroxide rapidly inhibited axonal transport, hours before any detectable changes in mitochondrial morphology or signs of axonal degeneration. Mitochondrial transport was affected earlier and was more severely inhibited than the transport of Golgi-derived vesicles. Anterograde vesicle transport was more susceptible to peroxide inhibition than retrograde transport. Axonal transport partially recovered following removal of hydrogen peroxide and local application of hydrogen peroxide inhibited transport, suggesting that the effects were not simply a result of nerve cell death. Sodium azide, an ATP synthesis blocker, had similar effects on axonal transport, suggesting that ATP depletion may contribute to the transport inhibition due to hydrogen peroxide. Conclusions These results indicate that inhibition of axonal transport is an early consequence of exposure to ROS and may contribute to subsequent axonal degeneration.

  8. Iron chelators ICL670 and 311 inhibit HIV-1 transcription

    International Nuclear Information System (INIS)

    HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics

  9. Oral zinc sulfate solutions inhibit sweet taste perception.

    Science.gov (United States)

    Keast, Russell S J; Canty, Thomas M; Breslin, Paul A S

    2004-07-01

    We investigated the ability of zinc sulfate (5, 25, 50 mM) to inhibit the sweetness of 12 chemically diverse sweeteners, which were all intensity matched to 300 mM sucrose [800 mM glucose, 475 mM fructose, 3.25 mM aspartame, 3.5 mM saccharin, 12 mM sodium cyclamate, 14 mM acesulfame-K, 1.04 M sorbitol, 0.629 mM sucralose, 0.375 mM neohesperidin dihydrochalcone (NHDC), 1.5 mM stevioside and 0.0163 mM thaumatin]. Zinc sulfate inhibited the sweetness of most compounds in a concentration dependent manner, peaking with 80% inhibition by 50 mM. Curiously, zinc sulfate never inhibited the sweetness of Na-cyclamate. This suggests that Na-cyclamate may access a sweet taste mechanism that is different from the other sweeteners, which were inhibited uniformly (except thaumatin) at every concentration of zinc sulfate. We hypothesize that this set of compounds either accesses a single receptor or multiple receptors that are inhibited equally by zinc sulfate at each concentration. PMID:15269123

  10. 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. PMID:19004764

  11. 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.

  12. Gingival tissue-produced inhibition of platelet aggregation and the loss of inhibition in streptozotocin-induced diabetic rats

    International Nuclear Information System (INIS)

    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 [1-14C]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. (author)

  13. An improved substrate cocktail for assessing direct inhibition and time-dependent inhibition of multiple cytochrome P450s

    OpenAIRE

    Chen, Zhong-hua; Zhang, Su-xing; Long, Na; Lin, Li-shan; Tao CHEN; Zhang, Fei-peng; Lv, Xue-Qin; Ye, Pei-zhen; Li, Ning; Zhang, Ke-Zhi

    2016-01-01

    Aim: The substrate cocktail is frequently used to evaluate cytochrome P450 (CYP) enzyme-mediated drug interactions and potential interactions among the probe substrates. Here, we re-optimized the substrate cocktail method to increase the reliability and accuracy of screening for candidate compounds and expanded the method from a direct CYP inhibition assay to a time-dependent inhibition (TDI) assay. Methods: In the reaction mixtures containing human liver microsome (0.1 mg/mL), both the conce...

  14. The links between dyslexia and inhibition deficits: do dyslexic children with an inhibition deficit have a specific reading profile?

    OpenAIRE

    Verhaegen, Clémence; Schelstraete, Marie-Anne; Noël, Marie-Pascale

    2010-01-01

    The present study focused on the nature of the reading disability of children with both dyslexia and inhibition deficit. Van der Schoot et al. (2000; 2004); Nossent et al. (2005); Nossent and Deroux (2006) showed that these children tended more to guess the words they read because these “guessers” found difficulties in suppressing false candidate words that are activated in the lexicon. To test this account, dyslexic children with and without inhibition deficit were presented a sentence readi...

  15. Damnacanthal inhibits the NF-κB/RIP-2/caspase-1 signal pathway by inhibiting p56lck tyrosine kinase.

    Science.gov (United States)

    Kim, Min-Ho; Jeong, Hyun-Ja

    2014-10-01

    Damnacanthal is a major constituent of Morinda citrifolia L. (noni) and exhibits anti-cancer and anti-inflammatory activities. However, the effects of damnacanthal on allergic diseases have not been determined. In this study, we investigated the effect of damnacanthal on mast cell-mediated allergic inflammatory responses. Damnacanthal significantly and dose-dependently inhibited compound 48/80-induced systemic anaphylactic shock, histamine release and intracellular calcium levels. In particular, IgE-mediated passive cutaneous anaphylaxis was significantly inhibited by the oral administration of damnacanthal. In addition, we report for the first time that p56lck tyrosine kinase was expressed in phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-stimulated mast cells. Furthermore, damnacanthal inhibited the up-regulation of p56lck tyrosine kinase activity by PMACI and repressed PMACI-induced histidine decarboxylase expression and activity. Damnacanthal also inhibited PMACI-induced interleukin (IL)-1β, IL-6 and tumor necrosis factor-α expressions by suppressing nuclear factor-kappa B (NF-κB) activation and suppressed the activation of caspase-1 and the expression of receptor interacting protein-2. This study shows damnacanthal inhibits the NF-κB/receptor-interacting protein-2/caspase-1 signal pathway by inhibiting p56lck tyrosine kinase and suggests that damnacanthal has potential for the treatment of mast cell-mediated allergic disorders. PMID:25139491

  16. Curcumin directly inhibits the transport activity of GLUT1.

    Science.gov (United States)

    Gunnink, Leesha K; Alabi, Ola D; Kuiper, Benjamin D; Gunnink, Stephen M; Schuiteman, Sam J; Strohbehn, Lauren E; Hamilton, Kathryn E; Wrobel, Kathryn E; Louters, Larry L

    2016-06-01

    Curcumin, a major ingredient in turmeric, has a long history of medicinal applications in a wide array of maladies including treatment for diabetes and cancer. Seemingly counterintuitive to the documented hypoglycemic effects of curcumin, however, a recent report indicates that curcumin directly inhibits glucose uptake in adipocytes. The major glucose transporter in adipocytes is GLUT4. Therefore, this study investigates the effects of curcumin in cell lines where the major transporter is GLUT1. We report that curcumin has an immediate inhibitory effect on basal glucose uptake in L929 fibroblast cells with a maximum inhibition of 80% achieved at 75 μM curcumin. Curcumin also blocks activation of glucose uptake by azide, glucose deprivation, hydroxylamine, or phenylarsine oxide. Inhibition does not increase with exposure time and the inhibitory effects reverse within an hour. Inhibition does not appear to involve a reaction between curcumin and the thiol side chain of a cysteine residue since neither prior treatment of cells with iodoacetamide nor curcumin with cysteine alters curcumin's inhibitory effects. Curcumin is a mixed inhibitor reducing the Vmax of 2DG transport by about half with little effect on the Km. The inhibitory effects of curcumin are not additive to the effects of cytochalasin B and 75 μM curcumin actually reduces specific cytochalasin B binding by 80%. Taken together, the data suggest that curcumin binds directly to GLUT1 at a site that overlaps with the cytochalasin B binding site and thereby inhibits glucose transport. A direct inhibition of GLUT proteins in intestinal epithelial cells would likely reduce absorption of dietary glucose and contribute to a hypoglycemic effect of curcumin. Also, inhibition of GLUT1 activity might compromise cancer cells that overexpress GLUT1 and be another possible mechanism for the documented anticancer effects of curcumin. PMID:27039889

  17. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation

    Directory of Open Access Journals (Sweden)

    Maharjan Anu S

    2010-11-01

    Full Text Available Abstract Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF-α accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN-α, IFN-γ, interleukin (IL-12, aggregated immunoglobulin G (IgG or serum amyloid P (SAP, factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-α, IFN-γ, granulocyte colony-stimulating factor and tumor growth factor β1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes. Conclusions Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure.

  18. 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

  19. Supramolecular nanofibrils inhibit cancer progression in vitro and in vivo

    Science.gov (United States)

    Kuang, Yi; Du, Xuewen; Zhou, Jie; Xu, Bing

    2014-01-01

    The recent discovery of the inverse comorbidity between cancer and Alzheimer’s disease implies that one may use amyloids to inhibit tumors. During the conversion of a dipeptide segment (Phe-Phe) in β-amyloid into a supramolecular hydrogelator, we obtained a small molecule (1) that can self-assembly into nanofibrils via multiple intermolecular hydrogen bonding and aromatic-aromatic interactions. Interestingly, while the monomers of 1 are innocuous, the nanofibrils formed by 1 can selectively inhibit the growth of glioblastoma cells over neuronal cells. To further assess the potential of this small molecular nanofibrils as anti-cancer agent, we exam the biological activity of the nanofibrils and demonstrate that the nanofibrils of 1 efficiently inhibit the progression of cancer cells (e.g., HeLa cells) both in cell assays and on xenograft mice model. This work suggests that nanofibrils derived from core motif of amyloid are effective agents for inhibiting cancer progression. Thus, this work contributes to a new approach that uses supramolecular nanofibrils as de novo molecular amyloids for inhibiting the growth of cancer cells. PMID:24574174

  20. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

    International Nuclear Information System (INIS)

    Research highlights: → Igf1r is overexpressed and activated in a Sonic Hedgehog driven model of medulloblastoma. → Picropodophyllin targets and abrogates IGF signaling in medulloblastoma. → Picropodophyllin inhibits medulloblastoma tumor cell growth by induction of apoptosis. -- Abstract: The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.

  1. Magnetic fields and thermal flux inhibition in inertial confinement fusion

    International Nuclear Information System (INIS)

    Of critical concern in directly driven laser fusion systems is the understanding of electron thermal transport between the region where laser light is absorbed and the ablation layer where the high pressures which accelerate the imploding shell are generated. Evidence has accumulated over the past several years which indicates that the heat flow may be strongly inhibited. Computer hydrodynamics models used to interpret experimental results have typically employed, in an ad hoc fashion, strong flux-limited diffusion which has led to fairly widespread acceptance of a flux inhibition value near f=0.03. It is shown in this paper that the observed flux inhibition can stem directly from the strong magnetic fields generated at the ablation layer as a result of modest laser asymmetries. These fields are shed from the ablation layer and fill the overdense region which strongly influences the thermal transport. The self-consistent numerical simulation of thermal transport in this environment shows strong thermal flux inhibition as interpreted from the following computational measurements: (1) reduced ablation pressures, (2) reduced implosion velocities, (3) reduced mass ablation rates, (4) density profile flattening, and (5) reduced classical absorption; all of which have been experimentally observed. The mass ablation rates obtained from the self-consistent two-dimensional model agree well with a one-dimensional model using an imposed flux inhibition factor of 0.03. (author)

  2. Acetaldehyde inhibition of protein synthesis in isolated rat pancreatic acini

    International Nuclear Information System (INIS)

    Exposure of isolated dispersed pancreatic acini to increasing concentrations of ethanol (5 to 500 mM) or acetaldehyde (0.5 to 100 mM) produced a progressive inhibition of [3H]leucine incorporation into both cellular (those remaining in the cell) and secretory (those released into the medium) proteins. Whereas 500 mM ethanol caused 90-95% inhibition in the synthesis of cellular and secretory proteins, the concentration of acetaldehyde needed to produce a similar inhibition was found to be 50 mM. All subsequent experiments were performed with 12.5 mM acetaldehyde, a concentration that consistently inhibited acinar protein synthesis by about 50%. The acetaldehyde-mediated inhibition of acinar protein synthesis was partially normalized when this metabolite was removed after 30 min during a 90-min incubation period. In the presence of acetaldehyde, the secretion of 3H-pulse-labeled proteins, but not amylase, trypsinogen, or chymotrypsinogen, was greatly depressed. Acetaldehyde also caused a marked reduction in [3H]uridine incorporation into acinar RNA. The entry of [3H]uridine, [3H]leucine, and [3H]aminoisobutyric acid into isolated acini was found to be slightly (15-25%) decreased by acetaldehyde. It is concluded that acetaldehyde exerts a direct toxic effect on isolated dispersed pancreatic acini as evidenced by diminution of both protein and RNA synthesis and decreased secretion of the newly synthesized proteins. This inhibitory effect of acetaldehyde could be partially reversed

  3. Recruitment of Perisomatic Inhibition during Spontaneous Hippocampal Activity In Vitro.

    Directory of Open Access Journals (Sweden)

    Anna Beyeler

    Full Text Available It was recently shown that perisomatic GABAergic inhibitory postsynaptic potentials (IPSPs originating from basket and chandelier cells can be recorded as population IPSPs from the hippocampal pyramidal layer using extracellular electrodes (eIPSPs. Taking advantage of this approach, we have investigated the recruitment of perisomatic inhibition during spontaneous hippocampal activity in vitro. Combining intracellular and extracellular recordings from pyramidal cells and interneurons, we confirm that inhibitory signals generated by basket cells can be recorded extracellularly, but our results suggest that, during spontaneous activity, eIPSPs are mostly confined to the CA3 rather than CA1 region. CA3 eIPSPs produced the powerful time-locked inhibition of multi-unit activity expected from perisomatic inhibition. Analysis of the temporal dynamics of spike discharges relative to eIPSPs suggests significant but moderate recruitment of excitatory and inhibitory neurons within the CA3 network on a 10 ms time scale, within which neurons recruit each other through recurrent collaterals and trigger powerful feedback inhibition. Such quantified parameters of neuronal interactions in the hippocampal network may serve as a basis for future characterisation of pathological conditions potentially affecting the interactions between excitation and inhibition in this circuit.

  4. Development of an inhibitive enzyme assay for copper.

    Science.gov (United States)

    Shukor, M Y; Bakar, N A; Othman, A R; Yunus, I; Shamaan, N A; Syed, M A

    2009-01-01

    In this work the development of an inhibitive assay for copper using the molybdenum-reducing enzyme assay is presented. The enzyme is assayed using 12-molybdophosphoric acid at pH 5.0 as an electron acceptor substrate and NADH as the electron donor substrate. The enzyme converts the yellowish solution into a deep blue solution. The assay is based on the ability of copper to inhibit the molybdenum-reducing enzyme from the molybdate-reducing Serratia sp. Strain DRY5. Other heavy metals tested did not inhibit the enzyme at 10 mg l(-1). The best model with high regression coefficient to measure copper inhibition is one-phase binding. The calculated IC50 (concentration causing 50% inhibition) is 0.099 mg l(-1) and the regression coefficient is 0.98. The comparative LC50, EC50 and IC50 data for copper in different toxicity tests show that the IC50 value for copper in this study is lower than those for immobilized urease, bromelain, Rainbow trout, R. meliloti, Baker's Yeast dehydrogenase activity Spirillum volutans, P. fluorescens, Aeromonas hydrophilia and synthetic activated sludge assays. However the IC50 value is higher than those for Ulva pertusa and papain assays, but within the reported range for Daphnia magna and Microtox assays. PMID:20112861

  5. Thiazolidinediones inhibit REG Iα gene transcription in gastrointestinal cancer cells

    International Nuclear Information System (INIS)

    REG (Regenerating gene) Iα protein functions as a growth factor for gastrointestinal cancer cells, and its mRNA expression is strongly associated with a poor prognosis in gastrointestinal cancer patients. We here demonstrated that PPARγ-agonist thiazolidinediones (TZDs) inhibited cell proliferation and REG Iα protein/mRNA expression in gastrointestinal cancer cells. TZDs inhibited the REG Iα gene promoter activity, via its cis-acting element which lacked PPAR response element and could not bind to PPARγ, in PPARγ-expressing gastrointestinal cancer cells. The inhibition was reversed by co-treatment with a specific PPARγ-antagonist GW9662. Although TZDs did not inhibit the REG Iα gene promoter activity in PPARγ-non-expressing cells, PPARγ overexpression in the cells recovered their inhibitory effect. Taken together, TZDs inhibit REG Iα gene transcription through a PPARγ-dependent pathway. The TZD-induced REG Iα mRNA reduction was abolished by cycloheximide, indicating the necessity of novel protein(s) synthesis. TZDs may therefore be a candidate for novel anti-cancer drugs for patients with gastrointestinal cancer expressing both REG Iα and PPARγ.

  6. A study of PCR inhibition mechanisms using real time PCR.

    Science.gov (United States)

    Opel, Kerry L; Chung, Denise; McCord, Bruce R

    2010-01-01

    In this project, real time polymerase chain reaction (PCR) was utilized to study the mechanism of PCR inhibition through examination of the effect of amplicon length, melting temperature, and sequence. Specifically designed primers with three different amplicon lengths and three different melting temperatures were used to target a single homozygous allele in the HUMTH01 locus. The effect on amplification efficiency for each primer pair was determined by adding different concentrations of various PCR inhibitors to the reaction mixture. The results show that a variety of inhibition mechanisms can occur during the PCR process depending on the type of co-extracted inhibitor. These include Taq inhibition, DNA template binding, and effects on reaction efficiency. In addition, some inhibitors appear to affect the reaction in more than one manner. Overall we find that amplicon size and melting temperature are important in some inhibition mechanisms and not in others and the key issue in understanding PCR inhibition is determining the identity of the interfering substance. PMID:20015162

  7. IGFBP-3, hypoxia and TNF-α inhibit adiponectin transcription

    International Nuclear Information System (INIS)

    The thiazolidinedione rosiglitazone, an agonist ligand for the nuclear receptor PPAR-γ, improves insulin sensitivity in part by stimulating transcription of the insulin-sensitizing adipokine adiponectin. It activates PPAR-γ-RXR-α heterodimers bound to PPAR-γ response elements in the adiponectin promoter. Rosiglitazone-stimulated adiponectin protein synthesis in 3T3-L1 mouse adipocytes has been shown to be inhibited by IGFBP-3, which can be induced by hypoxia and the proinflammatory cytokine, TNF-α, two inhibitors of adiponectin transcription. The present study demonstrates that IGFBP-3, the hypoxia-mimetic agent cobalt chloride, and TNF-α inhibit rosiglitazone-induced adiponectin transcription in mouse embryo fibroblasts that stably express PPAR-γ2. Native IGFBP-3 can bind RXR-α and inhibited rosiglitazone stimulated promoter activity, whereas an IGFBP-3 mutant that does not bind RXR-α did not. These results suggest that IGFBP-3 may mediate the inhibition of adiponectin transcription by hypoxia and TNF-α, and that IGFBP-3 binding to RXR-α may be required for the observed inhibition.

  8. AI-2 of Aggregatibacter actinomycetemcomitans Inhibits Candida albicans Biofilm Formation

    Directory of Open Access Journals (Sweden)

    Endang W. Bachtiar

    2014-07-01

    Full Text Available Aggregatibacter actinomycetemcomitans, a Gram-negative bacterium, and Candida albicans, a polymorphic fungus, are both commensals of the oral cavity but both are opportunistic pathogens that can cause oral diseases. A. actinomycetemcomitans produces a quorum-sensing molecule called autoinducer-2 (AI-2, synthesized by LuxS, that plays an important role in expression of virulence factors, in intra- but also in interspecies communication. The aim of this study was to investigate the role of AI-2 based signaling in the interactions between C. albicans and A. actinomycetemcomitans. A. actinomycetemcomitans adhered to C. albicans and inhibited biofilm formation by means of a molecule that was secreted during growth. C. albicans biofilm formation increased significantly when co-cultured with A. actinomycetemcomitans luxS, lacking AI-2 production. Addition of wild-type-derived spent medium or synthetic AI-2 to spent medium of the luxS strain, restored inhibition of C. albicans biofilm formation to wild-type levels. Addition of synthetic AI-2 significantly inhibited hypha formation of C. albicans possibly explaining the inhibition of biofilm formation. AI-2 of A. actinomycetemcomitans is synthesized by LuxS, accumulates during growth and inhibits C. albicans hypha- and biofilm formation. Identifying the molecular mechanisms underlying the interaction between bacteria and fungi may provide important insight into the balance within complex oral microbial communities.

  9. Inhibition of Voltage-Gated Calcium Channels by RGK Proteins.

    Science.gov (United States)

    Buraei, Zafir; Yang, Jian

    2015-01-01

    Due to their essential biological roles, voltage-gated calcium channels (VGCCs) are regulated by a myriad of molecules and mechanisms. Fifteen years ago, RGK proteins were discovered to bind the VGCC β subunit (Cavβ) and potently inhibit high-voltage activated Ca(2+) channels. RGKs (Rad, Rem, Rem2 and Gem/Kir) are a family of monomeric small GTPases belonging to the superfamily of Ras GTPases. They exert dual inhibitory effects on VGCCs, decreasing surface expression and suppressing surface channels through immobilization of the voltage sensor or reduction of channel open probability. While Cavβ is required for all forms of RGK inhibition, not all inhibition is mediated by the RGK-Cavβ interaction. Some RGK proteins also interact directly with the pore-forming α1 subunit of some types of VGCCs (Cavα1). Importantly, RGK proteins tonically inhibit VGCCs in native cells, regulating cardiac and neural functions. This minireview summarizes the mechanisms, molecular determinants, and physiological impact of RGK inhibition of VGCCs. PMID:25966691

  10. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Ohshima-Hosoyama, Sachiko; Hosoyama, Tohru; Nelon, Laura D. [Greehey Children' s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Keller, Charles, E-mail: keller@ohsu.edu [Greehey Children' s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229 (United States)

    2010-09-03

    Research highlights: {yields} Igf1r is overexpressed and activated in a Sonic Hedgehog driven model of medulloblastoma. {yields} Picropodophyllin targets and abrogates IGF signaling in medulloblastoma. {yields} Picropodophyllin inhibits medulloblastoma tumor cell growth by induction of apoptosis. -- Abstract: The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.

  11. IGFBP-3, hypoxia and TNF-{alpha} inhibit adiponectin transcription

    Energy Technology Data Exchange (ETDEWEB)

    Zappala, Giovanna, E-mail: zappalag@mail.nih.gov [Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD (United States); Rechler, Matthew M. [Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD (United States); Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD (United States)

    2009-05-15

    The thiazolidinedione rosiglitazone, an agonist ligand for the nuclear receptor PPAR-{gamma}, improves insulin sensitivity in part by stimulating transcription of the insulin-sensitizing adipokine adiponectin. It activates PPAR-{gamma}-RXR-{alpha} heterodimers bound to PPAR-{gamma} response elements in the adiponectin promoter. Rosiglitazone-stimulated adiponectin protein synthesis in 3T3-L1 mouse adipocytes has been shown to be inhibited by IGFBP-3, which can be induced by hypoxia and the proinflammatory cytokine, TNF-{alpha}, two inhibitors of adiponectin transcription. The present study demonstrates that IGFBP-3, the hypoxia-mimetic agent cobalt chloride, and TNF-{alpha} inhibit rosiglitazone-induced adiponectin transcription in mouse embryo fibroblasts that stably express PPAR-{gamma}2. Native IGFBP-3 can bind RXR-{alpha} and inhibited rosiglitazone stimulated promoter activity, whereas an IGFBP-3 mutant that does not bind RXR-{alpha} did not. These results suggest that IGFBP-3 may mediate the inhibition of adiponectin transcription by hypoxia and TNF-{alpha}, and that IGFBP-3 binding to RXR-{alpha} may be required for the observed inhibition.

  12. Mesencephalic stimulation elicits inhibition of phrenic nerve activity in cat.

    Science.gov (United States)

    Gallman, E A; Lawing, W L; Millhorn, D E

    1991-05-01

    1. Previous work from this laboratory has indicated that the mesencephalon is the anatomical substrate for a mechanism capable of inhibiting central respiratory drive in glomectomized cats for periods of up to 1 h or more following brief exposure to systemic hypoxia; phrenic nerve activity was used as an index of central respiratory drive. 2. The present study was undertaken to further localize the region responsible for the observed post-hypoxic inhibition of respiratory drive. We studied the phrenic nerve response to stimulations of the mesencephalon in anaesthetized, paralysed peripherally chemo-denervated cats with end-expired PCO2 and body temperature servo-controlled. 3. Stimulations of two types were employed. Electrical stimulation allowed rapid determination of sites from which phrenic inhibition could be elicited. Microinjections of excitatory amino acids were used subsequently in order to confine excitation to neuronal cell bodies and not axons of passage. 4. Stimulation of discrete regions of the ventromedial aspect of the mesencephalon in the vicinity of the red nucleus produced substantial inhibition of phrenic activity which lasted up to 45 min. Stimulation of other areas of the mesencephalon either produced no phrenic inhibition or resulted in a slight stimulation of phrenic activity. 5. The results are discussed in the context of the central respiratory response to hypoxia. PMID:1676420

  13. Thyroid peroxidase activity is inhibited by amino acids

    Directory of Open Access Journals (Sweden)

    D.P. Carvalho

    2000-03-01

    Full Text Available Normal in vitro thyroid peroxidase (TPO iodide oxidation activity was completely inhibited by a hydrolyzed TPO preparation (0.15 mg/ml or hydrolyzed bovine serum albumin (BSA, 0.2 mg/ml. A pancreatic hydrolysate of casein (trypticase peptone, 0.1 mg/ml and some amino acids (cysteine, tryptophan and methionine, 50 µM each also inhibited the TPO iodide oxidation reaction completely, whereas casamino acids (0.1 mg/ml, and tyrosine, phenylalanine and histidine (50 µM each inhibited the TPO reaction by 54% or less. A pancreatic digest of gelatin (0.1 mg/ml or any other amino acid (50 µM tested did not significantly decrease TPO activity. The amino acids that impair iodide oxidation also inhibit the TPO albumin iodination activity. The inhibitory amino acids contain side chains with either sulfur atoms (cysteine and methionine or aromatic rings (tyrosine, tryptophan, histidine and phenylalanine. Among the amino acids tested, only cysteine affected the TPO guaiacol oxidation reaction, producing a transient inhibition at 25 or 50 µM. The iodide oxidation inhibitory activity of cysteine, methionine and tryptophan was reversed by increasing iodide concentrations from 12 to 18 mM, while no such effect was observed when the cofactor (H2O2 concentration was increased. The inhibitory substances might interfere with the enzyme activity by competing with its normal substrates for their binding sites, binding to the free substrates or reducing their oxidized form.

  14. Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces atresia, and inhibits steroid hormone production in cultured mouse antral follicles

    Energy Technology Data Exchange (ETDEWEB)

    Hannon, Patrick R., E-mail: phannon2@illinois.edu; Brannick, Katherine E., E-mail: kbran@illinois.edu; Wang, Wei, E-mail: Wei.Wang2@covance.com; Gupta, Rupesh K., E-mail: drrupesh@yahoo.com; Flaws, Jodi A., E-mail: jflaws@illinois.edu

    2015-04-01

    Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental toxicant found in consumer products that causes ovarian toxicity. Antral follicles are the functional ovarian units and must undergo growth, survival from atresia, and proper regulation of steroidogenesis to ovulate and produce hormones. Previous studies have determined that DEHP inhibits antral follicle growth and decreases estradiol levels in vitro; however, the mechanism by which DEHP elicits these effects is unknown. The present study tested the hypothesis that DEHP directly alters regulators of the cell cycle, apoptosis, and steroidogenesis to inhibit antral follicle functionality. Antral follicles from adult CD-1 mice were cultured with vehicle control or DEHP (1–100 μg/ml) for 24–96 h to establish the temporal effects of DEHP on the follicle. Following 24–96 h of culture, antral follicles were subjected to gene expression analysis, and media were subjected to measurements of hormone levels. DEHP increased the mRNA levels of cyclin D2, cyclin dependent kinase 4, cyclin E1, cyclin A2, and cyclin B1 and decreased the levels of cyclin-dependent kinase inhibitor 1A prior to growth inhibition. Additionally, DEHP increased the mRNA levels of BCL2-associated agonist of cell death, BCL2-associated X protein, BCL2-related ovarian killer protein, B-cell leukemia/lymphoma 2, and Bcl2-like 10, leading to an increase in atresia. Further, DEHP decreased the levels of progesterone, androstenedione, and testosterone prior to the decrease in estradiol levels, with decreased mRNA levels of side-chain cleavage, 17α-hydroxylase-17,20-desmolase, 17β-hydroxysteroid dehydrogenase, and aromatase. Collectively, DEHP directly alters antral follicle functionality by inhibiting growth, inducing atresia, and inhibiting steroidogenesis. - Highlights: • DEHP inhibits antral follicle growth by dysregulating cell cycle regulators. • DEHP induces antral follicle atresia by dysregulating apoptosis regulators. • DEHP

  15. Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition

    Science.gov (United States)

    Mimura, Naoya; Hideshima, Teru; Shimomura, Toshiyasu; Suzuki, Rikio; Ohguchi, Hiroto; Rizq, Ola; Kikuchi, Shohei; Yoshida, Yasuhiro; Cottini, Francesca; Jakubikova, Jana; Cirstea, Diana; Gorgun, Gullu; Minami, Jiro; Tai, Yu-Tzu; Richardson, Paul G.; Utsugi, Teruhiro; Iwama, Atsushi; Anderson, Kenneth C.

    2014-01-01

    The PI3K/Akt pathway plays a crucial role in the pathogenesis of multiple myeloma (MM) in the bone marrow (BM) milieu. However, efficacy of selective and potent Akt inhibition has not yet been fully elucidated. In this study, we therefore examined the biologic impact of selective and potent Akt inhibition by a novel allosteric inhibitor TAS-117. TAS-117 induced significant growth inhibition, associated with downregulation of phosphorylated Akt (p-Akt), selectively in MM cell lines with high baseline p-Akt. Cytotoxicity of TAS-117 was also observed in patients MM cells, but not in normal peripheral blood mononuclear cells. Importantly, TAS-117 induced significant cytotoxicity in MM cells even in the presence of BM stromal cells, associated with inhibition of IL-6 secretion. Oral administration of TAS-117 significantly inhibited human MM cell growth in murine xenograft models. TAS-117 triggered apoptosis and autophagy, as well as induction of endoplasmic reticulum (ER) stress response with minimal expression of CHOP, a fatal ER-stress marker. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity, associated with increased CHOP and PARP cleavage and blockade of bortezomib-induced p-Akt, suggesting that TAS-117 augments bortezomib-induced ER stress and apoptotic signaling. Carfilzomib-induced cytotoxicity was similarly enhanced by TAS-117. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity in vivo, associated with prolonged host survival. Our results show that selective and potent Akt inhibition by TAS-117 triggers anti-MM activities in vitro and in vivo, as well as enhances cytotoxicity of proteasome inhibition, providing the preclinical framework for clinical evaluation of selective Akt inhibitors, alone and in combination with proteasome inhibitors in MM. PMID:24934808

  16. Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces atresia, and inhibits steroid hormone production in cultured mouse antral follicles

    International Nuclear Information System (INIS)

    Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental toxicant found in consumer products that causes ovarian toxicity. Antral follicles are the functional ovarian units and must undergo growth, survival from atresia, and proper regulation of steroidogenesis to ovulate and produce hormones. Previous studies have determined that DEHP inhibits antral follicle growth and decreases estradiol levels in vitro; however, the mechanism by which DEHP elicits these effects is unknown. The present study tested the hypothesis that DEHP directly alters regulators of the cell cycle, apoptosis, and steroidogenesis to inhibit antral follicle functionality. Antral follicles from adult CD-1 mice were cultured with vehicle control or DEHP (1–100 μg/ml) for 24–96 h to establish the temporal effects of DEHP on the follicle. Following 24–96 h of culture, antral follicles were subjected to gene expression analysis, and media were subjected to measurements of hormone levels. DEHP increased the mRNA levels of cyclin D2, cyclin dependent kinase 4, cyclin E1, cyclin A2, and cyclin B1 and decreased the levels of cyclin-dependent kinase inhibitor 1A prior to growth inhibition. Additionally, DEHP increased the mRNA levels of BCL2-associated agonist of cell death, BCL2-associated X protein, BCL2-related ovarian killer protein, B-cell leukemia/lymphoma 2, and Bcl2-like 10, leading to an increase in atresia. Further, DEHP decreased the levels of progesterone, androstenedione, and testosterone prior to the decrease in estradiol levels, with decreased mRNA levels of side-chain cleavage, 17α-hydroxylase-17,20-desmolase, 17β-hydroxysteroid dehydrogenase, and aromatase. Collectively, DEHP directly alters antral follicle functionality by inhibiting growth, inducing atresia, and inhibiting steroidogenesis. - Highlights: • DEHP inhibits antral follicle growth by dysregulating cell cycle regulators. • DEHP induces antral follicle atresia by dysregulating apoptosis regulators. • DEHP

  17. Inhibition of 5-Lipoxygenase Pathway Attenuates Acute Liver Failure by Inhibiting Macrophage Activation

    Directory of Open Access Journals (Sweden)

    Lu Li

    2014-01-01

    Full Text Available This study aimed to investigate the role of 5-lipoxygenase (5-LO in acute liver failure (ALF and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN/lipopolysaccharide (LPS. Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor, 24 hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT, aspartate transaminase (AST, total bilirubin (Tbil, and tumor necrosis factor- (TNF-α. Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8 hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF-α was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition.

  18. Eriodictyol Inhibits RANKL-Induced Osteoclast Formation and Function Via Inhibition of NFATc1 Activity.

    Science.gov (United States)

    Song, Fangming; Zhou, Lin; Zhao, Jinmin; Liu, Qian; Yang, Mingli; Tan, Renxiang; Xu, Jun; Zhang, Ge; Quinn, Julian M W; Tickner, Jennifer; Huang, Yuanjiao; Xu, Jiake

    2016-09-01

    Receptor activator of nuclear factor kappa-B ligand (RANKL) induces differentiation and function of osteoclasts through triggering multiple signaling cascades, including NF-κB, MAPK, and Ca(2+) -dependent signals, which induce and activate critical transcription factor NFATc1. Targeting these signaling cascades may serve as an effective therapy against osteoclast-related diseases. Here, by screening a panel of natural plant extracts with known anti-inflammatory, anti-tumor, or anti-oxidant properties for possible anti-osteoclastogenic activities we identified Eriodictyol. This flavanone potently suppressed RANKL-induced osteoclastogenesis and bone resorption in a dose-dependent manner without detectable cytotoxicity, suppressing RANKL-induced NF-κB, MAPK, and Ca(2+) signaling pathways. Eriodictyol also strongly inhibited RANKL-induction of c-Fos levels (a critical component of AP-1 transcription factor required by osteoclasts) and subsequent activation of NFATc1, concomitant with reduced expression of osteoclast specific genes including cathepsin K (Ctsk), V-ATPase-d2 subunit, and tartrate resistant acid phosphatase (TRAcP/Acp5). Taken together, these data provide evidence that Eriodictyol could be useful for the prevention and treatment of osteolytic disorders associated with abnormally increased osteoclast formation and function. J. Cell. Physiol. 231: 1983-1993, 2016. © 2016 Wiley Periodicals, Inc. PMID:26754483

  19. Modeling of laccase inhibition by formetanate pesticide using theoretical approaches.

    Science.gov (United States)

    Martins, Ana C V; Ribeiro, Francisco W P; Zanatta, Geancarlo; Freire, Valder N; Morais, Simone; de Lima-Neto, Pedro; Correia, Adriana N

    2016-04-01

    The inhibition of laccase enzymatic catalytic activity by formetanate hydrochloride (FMT) was investigated by cyclic voltammetry and by quantum chemical calculations based on density functional theory with a protein fragmentation approach. The cyclic voltammograms were obtained using a biosensor prepared by enzyme immobilization on gold electrodes modified with gold nanoparticles and 4-aminophenol as the target molecule. The decrease in the peak current in the presence of FMT was used to characterize the inhibition process. The calculations identified Asp206 as the most relevant moiety in the interaction of FMT with the laccase enzymatic ligand binding domain. The amino acid residue Cys453 was important, because the Cys453-FMT interaction energy was not affected by the dielectric constant, although it was not a very close residue. This study provides an overview of how FMT inhibits laccase catalytic activity. PMID:26720841

  20. Inhibiting effect of melittin on pathogens of crops

    Institute of Scientific and Technical Information of China (English)

    PAN LingZi; NA Jie; XING Zhuo; FANG HongJun; WANG GuanLin

    2007-01-01

    The spectrum of antimicrobial effects of melittin were investigated on 19 pathogens by using a cylinder-plate method with serial dilutions. Bacteriostatic efficiency and possible mechanistic effects were monitored via growth curves. The mechanism of inhibition was further analyzed by SDS-PAGE, flow cytometry and electron microscopy. Melittin had a wide inhibition spectrum and killed pathogens effectively, and bacteriostatic action was influenced by factors such as pH and temperature. We elucidated three inhibitory mechanisms: melittin integrated with the cell membrane causing cell bursting and cytoplasm release, inhibited the synthesis of proteins and caused the cytoplasm to condense, and delayed pathogens in phase I (or phase G1) so that they could not complete the cell cycle. These results suggest that melittin could serve as a broad-spectrum biological pesticide with fast-action and high-efficiency.