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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. Antiproliferative effect of gold(I compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells

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    Nam-Hoon Kim

    2013-01-01

    Full Text Available Signal transducer and activator of transcription 3 (STAT3 andtelomerase are considered attractive targets for anticancertherapy. The in vitro anticancer activity of the gold(I compoundauranofin was investigated using MDA-MB 231 human breastcancer cells, in which STAT3 is constitutively active. In cellculture, auranofin inhibited growth in a dose-dependent manner,and N-acetyl-L-cysteine (NAC, a scavenger of reactive oxygenspecies (ROS, markedly blocked the effect of auranofin.Incorporation of 5-bromo-2’-deoxyuridine into DNA andanchorage-independent cell growth on soft agar were decreasedby auranofin treatment. STAT3 phosphorylation and telomeraseactivity were also attenuated in cells exposed to auranofin, butNAC pretreatment restored STAT3 phosphorylation andtelomerase activity in these cells. These findings indicate thatauranofin exerts in vitro antitumor effects in MDA-MB 231 cellsand its activity involves inhibition of STAT3 and telomerase.Thus, auranofin shows potential as a novel anticancer drug thattargets STAT3 and telomerase. [BMB Reports 2013; 46(1: 59-64

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

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    Ryuta Tobe

    2011-09-01

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

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

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    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.

  5. 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 ...

  6. Selenoprotein-Transgenic Chlamydomonas reinhardtii

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    Jiazuan Ni

    2013-02-01

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

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

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    Christina A Bulman

    2015-02-01

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

  8. 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

  9. 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 ...

  10. 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

  11. 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.

  12. 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

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

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    Jocelyn M Madeira

    2015-01-01

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

  14. 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.

  15. Ebola viral selenoproteins: a metallomics analysis

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    Somsri Wiwanitkit

    2015-01-01

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

  16. Selenoprotein P in colitis-associated carcinoma

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    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. Overexpression of human selenoprotein H in neuronal cells enhances mitochondrial biogenesis and function through activation of protein kinase A, protein kinase B, and cyclic adenosine monophosphate response element-binding protein pathway.

    Science.gov (United States)

    Mehta, Suresh L; Mendelev, Natalia; Kumari, Santosh; Andy Li, P

    2013-03-01

    Mitochondrial biogenesis is activated by nuclear encoded transcription co-activator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is regulated by several upstream factors including protein kinase A and Akt/protein kinase B. We have previously shown that selenoprotein H enhances the levels of nuclear regulators for mitochondrial biogenesis, increases mitochondrial mass and improves mitochondrial respiratory rate, under physiological condition. Furthermore, overexpression of selenoprotein H protects neuronal HT22 cells from ultraviolet B irradiation-induced cell damage by lowering reactive oxygen species production, and inhibiting activation of caspase-3 and -9, as well as p53. The objective of this study is to identify the cell signaling pathways by which selenoprotein H initiates mitochondrial biogenesis. We first confirmed our previous observation that selenoprotein H transfected HT22 cells increased the protein levels of nuclear-encoded mitochondrial biogenesis factors, peroxisome proliferator-activated receptor γ coactivator-1α, nuclear respiratory factor 1 and mitochondrial transcription factor A. We then observed that total and phosphorylation of protein kinase A, Akt/protein kinase B and cyclic adenosine monophosphate response element-binding protein (CREB) were significantly increased in selenoprotein H transfected cells compared to vector transfected HT22 cells. To verify whether the observed stimulating effects on mitochondrial biogenesis pathways are caused by selenoprotein H and mediated through CREB, we knocked down selenoprotein H mRNA level using siRNA and inhibited CREB with napthol AS-E phosphate in selenoprotein H transfected cells and repeated the measurements of the aforementioned biomarkers. Our results revealed that silencing of selenoprotein H not only decreased the protein levels of PGC-1α, nuclear respiratory factor 1 and mitochondrial transcription factor A, but also decreased the total and

  20. Relevance of selenoprotein transcripts for selenium status in humans.

    Science.gov (United States)

    Reszka, Edyta; Jablonska, Ewa; Gromadzinska, Jolanta; Wasowicz, Wojciech

    2012-04-01

    The most commonly used methods for assessing the selenium (Se) status in humans involve analysis of Se concentration, selenoprotein activity, and concentration in the blood and its compartments. Recently, it has been suggested that the expression of selenoprotein mRNA in circulating blood leukocytes could differently reflect Se status, due to prioritization of specific selenoprotein synthesis in response to dietary Se supply. Whereas the Se levels required for optimization of selenoprotein P level and plasma glutathione peroxidise activity are well known, estimation of Se level that is required for maximal mRNA expression of selenoprotein in humans is the subject of current investigations. Studies on rats suggest that whole blood selenoprotein mRNA level can be used as the relevant molecular biomarker for assessing Se status, and suboptimal Se intake may be sufficient to achieve effective expression. Human studies, however, did not confirm this hypothesis. According to studies on rodents and humans discussed in this review, it appears that suboptimal Se intake may be sufficient to satisfy molecular requirements of Se and it is lower than current recommended dietary intake in humans. The use of selenoprotein transcripts as a molecular biomarker of Se status requires further studies on a large group of healthy individuals with different baseline Se, including data regarding genetic polymorphism of selenoproteins and data regarding potential modifiers of Se metabolism. PMID:21898179

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

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    Charles E Chapple

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

  2. 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...

  3. 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)-...

  4. Altered hippocampus synaptic function in selenoprotein P deficient mice

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    Peters Melinda M

    2006-09-01

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

  5. 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

  6. Determination and distribution of human plasma selenoproteins

    Energy Technology Data Exchange (ETDEWEB)

    Plecko, T.; Nordmann, S.; Ruekgauer, M.; Kruse-Jarres, J.D. [Institute for Clinical Chemistry and Laboratory Medicine, Stuttgart (Germany)

    1999-03-01

    Major portions of plasma-selenium are incorporated in the proteins glutathione peroxidase (GSH-Px), selenoprotein P (Sel P) and albumin. A chromatographic method, adapted from a procedure by Harrison et al. [6], uses heparin- and blue-sepharose to separate the three protein fractions. The determination of selenium was carried out by electrothermal atomic absorption spectroscopy (ETAAS) using the Zeeman effect. The selenium distribution of 17 healthy subjects was 68 {+-} 7% of the total plasma selenium associated to Sel P, 25 {+-} 4% associated to p-GSH-Px and 7{+-}4% associated to albumin. The recovery of selenium was 99 {+-} 4%. For precision measurements a plasma pool has been separated seven times. The selectivity of this method was monitored by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and GSH-Px activity measurements. A fast method, adapted for clinical applications, is described which allows to determine the human plasma selenium distribution in about an hour. (orig.) With 2 tabs., 8 refs.

  7. Redox effects and cytotoxic profiles of MJ25 and auranofin towards malignant melanoma cells

    Science.gov (United States)

    Drummond, Catherine J.; McCarthy, Anna R.; Higgins, Maureen; Campbell, Johanna; Brodin, Bertha; Arnér, Elias S.J.; Laín, Sonia

    2015-01-01

    Malignant melanoma is the most dangerous type of skin cancer. Although recent progress in treatment has been achieved, lack of response, drug resistance and relapse remain major problems. The tumor suppressor p53 is rarely mutated in melanoma, yet it is inactive in the majority of cases due to dysregulation of upstream pathways. Thus, we screened for compounds that can activate p53 in melanoma cells. Here we describe effects of the small molecule MJ25 (2-{[2-(1,3-benzothiazol-2-ylsulfonyl)ethyl]thio}-1,3-benzoxazole), which increased the level of p53-dependent transactivation both as a single agent and in combination with nutlin-3. Furthermore, MJ25 showed potent cytotoxicity towards melanoma cell lines, whilst having weaker effects against human normal cells. MJ25 was also identified in an independent screen as an inhibitor of thioredoxin reductase 1 (TrxR1), an important selenoenzyme in the control of oxidative stress and redox regulation. The well-characterized TrxR inhibitor auranofin, which is FDA-approved and currently in clinical trials against leukemia and a number of solid cancers, displayed effects comparable with MJ25 on cells and led to eradication of cultured melanoma cells at low micromolar concentrations. In conclusion, auranofin, MJ25 or other inhibitors of TrxR1 should be evaluated as candidate compounds or leads for targeted therapy of malignant melanoma. PMID:26029997

  8. 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

  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. 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 ...

  11. 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 ...

  12. 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...

  13. 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 ...

  14. 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

  15. 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

  16. 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...

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

    Institute of Scientific and Technical Information of China (English)

    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 devel-oped 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 cys-teine-containing homologs of selenoprotein genes.Our results showed that 11365 genes were termi-nated with TGA codons,918 of which contained SECIS elements.Similarity search revealed that 58 genes contained Sec/Cys pairs and similar flanking regions around in-frame TGA codons.Finally,7 genes were found to fully meet requirements for selenoproteins,although they have not been anno-tated as selenoproteins in NCBI databases.Deduced from their basic properties,the newly found se-lenoproteins 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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 ...

  3. 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 ...

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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...

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

    Science.gov (United States)

    Sunde, Roger A; Sunde, Gavin R; Sunde, Colin M; Sunde, Milton L; Evenson, Jacqueline K

    2015-01-01

    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.

  12. 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...

  13. Selenoprotein gene expression during selenium-repletion of selenium-deficient rats.

    Science.gov (United States)

    Bermano, G; Nicol, F; Dyer, J A; Sunde, R A; Beckett, G J; Arthur, J R; Hesketh, J E

    1996-03-01

    Selenium repletion of selenium-deficient rats with 20 micrograms selenium / kg body weight as Na2SeO3 was used as a model to investigate the mechanisms that control the distribution of the trace element to specific selenoproteins in liver and thyroid. Cytosolic glutathione peroxidase (cGSHPx), phospholipid hydroperoxide glutathione peroxidase (PHGSHPx), and iodothyronine 5'-deiodinase (IDI) activities were all transiently increased in liver 16 to 32 h after ip injection with selenium. However, only cGSHPx and PHGSHPx activities increased in the thyroid where IDI activity was already increased by selenium deficiency. These responses were owing to synthesis of the seleoproteins on newly synthesised and/or existing mRNAs. The selenoprotein mRNAs in the thyroid gland were increased two- and threefold after the transitory increases in selenoprotein activity. In contrast, there were parallel changes in selenoprotein mRNAs and enzyme activities in the liver, with no prolonged rises in mRNA levels. The organ differences suggest that increased thryotrophin (TSH) concentrations, which are known to induce thyrodial IDI and mRNA, may control the mRNAs for all the thyroidal selenoproteins investigated and be a major mechanism for the preservation of thyroidal selenoproteins when selenium supplies are limited. PMID:8727669

  14. 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.

  15. 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.

  16. Selenoprotein P mRNA expression in human hepatic tissues

    Institute of Scientific and Technical Information of China (English)

    Chun-Li Li; Ke-Jun Nan; Tao Tian; Chen-Guang Sui; Yan-Fang Liu

    2007-01-01

    AIM: To investigate the expression of Selenoprotein P mRNA (SePmRNA) in tissues of normal liver, liver cirrhosis and hepatocellular carcinoma (HCC), and its relationship with HCC occurrence and development.METHODS: The expression of SePmRNA in tissues of normal liver, liver cirrhosis and HCC were detected by in situ hybridization using a cDNA probe.RESULTS: The enzyme digesting products of pBluescript-Human Selenoprotein P were evaluated by electrophoresis.The positive expression of SePmRNA was found in the tissues of normal liver,liver cirrhosis and HCC.The expression of SeP mRNA was found in hepatic interstitial substance,especially in endothelial cells and lymphocytes of vasculature.The positive rate of SePmRNA in normal liver tissue was 84.6% (11/13) and the positive signals appeared in the nucleus and cytoplasm,mostly in the nucleolus,and the staining granules were larger in the nucleolus and around the nucleus.The positive rate of SePmRNA in liver cirrhosis tissue was 45.O% (9/20) and the positive signals were mainly in the nucleolus and cytoplasm,being less around the nucleus and inner nucleus than that in normal liver tissue. The positive rate of SePmRNA in HCC tissue was 30.0% (9/30) and the positive signals were in the cytoplasm, but less in the nucleus.CONCLUSION: SePmRNA expression in the tissues of normal liver and HCC is significantly different (84.6% vs 30.0%, P = 0.003), suggesting that SeP might play a role in the occurrence and development of HCC.

  17. 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

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

    DEFF Research Database (Denmark)

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

    2009-01-01

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

  19. Selenoprotein P and neurodegeneration%硒蛋白P与神经退行性变化

    Institute of Scientific and Technical Information of China (English)

    李菲; 安书成

    2013-01-01

    Selenoprotein P plays an important role in the transportation and homeostasis of selenium (Se). It is mainly distributed in the cerebellum, olfactory bulb, hippocampus and frontal cortex. The expression of selenoprotein P is observed in both neurons and astrocytes. Selenopotein P can protect nerves and is also important for maintaining the normal function of brain. The genetic deletion of selenoprotein P in mice can result in neurological dysfunction and even death. Selenoprotein P is also involved in neurodegeneration diseases including Alzheimer's disease, Parkinson's disease, and seizures. This paper focuses on the role of selenoprotein P in neurodegenerative changes.%硒蛋白P (selenoprotein P,SelP)对于硒转运及维持硒水平稳定非常重要.硒蛋白P主要分布于小脑、嗅球、海马区和额叶皮质,神经元和星形胶质细胞中均有其表达,对神经细胞具有保护作用,在维持正常的脑功能中发挥着重要作用.硒蛋白P基因敲除导致小鼠神经损伤,甚至死亡.硒蛋白P与阿尔茨海默症、帕金森综合征、癫痫等神经退行性疾病的发生有关.重点介绍硒蛋白P在神经退行性变化方面的作用.

  20. 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...

  1. 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 (...

  2. 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...

  3. 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.

  4. Expression of Selenoprotein Genes Is Affected by Obesity of Pigs Fed a High-Fat Diet123

    Science.gov (United States)

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

    2015-01-01

    Background: Relations of the 25 mammalian selenoprotein genes with obesity and the associated inflammation remain unclear. Objective: This study explored impacts of high-fat diet-induced obesity on inflammation and expressions of selenoprotein and obesity-related genes in 10 tissues of pigs. Methods: Plasma and 10 tissues were collected from pigs (n = 10) fed a corn-soy–based control diet or that diet containing 3–7% lard from weanling to finishing (180 d). Plasma concentrations (n = 8) of cytokines and thyroid hormones and tissue mRNA abundance (n = 4) of 25 selenoprotein genes and 16 obesity-related genes were compared between the pigs fed the control and high-fat diets. Stepwise regression was applied to analyze correlations among all these measures, including the previously reported body physical and plasma biochemical variables. Results: The high-fat diet elevated (P < 0.05) plasma concentrations of tumor necrosis factor α, interleukin-6, leptin, and leptin receptor by 29–42% and affected (P < 0.05–0.1) tissue mRNA levels of the selenoprotein and obesity-related genes in 3 patterns. Specifically, the high-fat diet up-regulated 12 selenoprotein genes in 6 tissues, down-regulated 13 selenoprotein genes in 7 tissues, and exerted no effect on 5 genes in any tissue. Body weights and plasma triglyceride concentrations of pigs showed the strongest regressions to tissue mRNA abundances of selenoprotein and obesity-related genes. Among the selenoprotein genes, selenoprotein V and I were ranked as the strongest independent variables for the regression of phenotypic and plasma measures. Meanwhile, agouti signaling protein, adiponectin, and resistin genes represented the strongest independent variables of the obesity-related genes for the regression of tissue selenoprotein mRNA. Conclusions: The high-fat diet induced inflammation in pigs and affected their gene expression of selenoproteins associated with thioredoxin and oxidoreductase systems, local tissue

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

    NARCIS (Netherlands)

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

    2009-01-01

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

  7. 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

  8. 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.

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

    Science.gov (United States)

    Zhu, Hui; Sun, Sheng-Nan; Zheng, Jing; Fan, Hui-Hui; Wu, Hong-Mei; Chen, Song-Fang; Cheng, Wen-Hsing; Zhu, Jian-Hong

    2016-01-01

    Genes of selenoproteome have been increasingly implicated in various aspects of neurobiology and neurological disorders, but remain largely elusive in Parkinson’s disease (PD). In this study, we investigated the selenotranscriptome (24 selenoproteins in total) in five brain regions (cerebellum, substantia nigra, cortex, pons and hippocampus) by real time qPCR in a two-phase manner using a mouse model of chronic PD. A wide range of changes in selenotranscriptome was observed in a manner depending on selenoproteins and brain regions. While Selv mRNA was not detectable and Dio1& 3 mRNA levels were not affected, 1, 11 and 9 selenoproteins displayed patterns of increase only, decrease only, and mixed response, respectively, in these brain regions of PD mice. In particular, the mRNA expression of Gpx1-4 showed only a decreased trend in the PD mouse brains. In substantia nigra, levels of 17 selenoprotein mRNAs were significantly decreased whereas no selenoprotein was up-regulated in the PD mice. In contrast, the majority of selenotranscriptome did not change and a few selenoprotein mRNAs that respond displayed a mixed pattern of up- and down-regulation in cerebellum, cortex, hippocampus, and/or pons of the PD mice. Gpx4, Sep15, Selm, Sepw1, and Sepp1 mRNAs were most abundant across all these five brain regions. Our results showed differential responses of selenoproteins in various brain regions of the PD mouse model, providing critical selenotranscriptomic profiling for future functional investigation of individual selenoprotein in PD etiology. PMID:27656880

  10. 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 ...

  11. 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

  12. 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.

  13. 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

  14. 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...

  15. 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.

  16. 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

  17. 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...

  18. 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.

  19. 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 ( 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.

  20. 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

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

    DEFF Research Database (Denmark)

    Sidenius, U; Gammelgaard, Bente

    2000-01-01

    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......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...

  2. 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...

  3. 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...

  4. 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...

  5. 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...

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

    DEFF Research Database (Denmark)

    Sidenius, U; Farver, O; Jøns, O;

    1999-01-01

    and the fractionation was followed by analysis of the collected fractions for selenium by inductively coupled plasma mass spectrometry. By the combination of immobilized Co2+ affinity chromatography and heparin affinity chromatography a simple method was developed yielding a 14,800-fold enrichment of selenoprotein P...

  7. 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...

  8. 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

  9. 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

  10. Selenoprotein P Is the Major Selenium Transport Protein in Mouse Milk

    Science.gov (United States)

    Hill, Kristina E.; Motley, Amy K.; Winfrey, Virginia P.; Burk, Raymond F.

    2014-01-01

    Selenium is transferred from the mouse dam to its neonate via milk. Milk contains selenium in selenoprotein form as selenoprotein P (Sepp1) and glutathione peroxidase-3 (Gpx3) as well as in non-specific protein form as selenomethionine. Selenium is also present in milk in uncharacterized small-molecule form. We eliminated selenomethionine from the mice in these experiments by feeding a diet that contained sodium selenite as the source of selenium. Selenium-replete dams with deletion of Sepp1 or Gpx3 were studied to assess the effects of these genes on selenium transfer to the neonate. Sepp1 knockout caused a drop in milk selenium to 27% of the value in wild-type milk and a drop in selenium acquisition by the neonates to 35%. In addition to decreasing milk selenium by eliminating Sepp1, deletion of Sepp1 causes a decline in whole-body selenium, which likely also contributes to the decreased transfer of selenium to the neonate. Deletion of Gpx3 did not decrease milk selenium content or neonate selenium acquisition by measurable amounts. Thus, when the dam is fed selenium-adequate diet (0.25 mg selenium/kg diet), milk Sepp1 transfers a large amount of selenium to neonates but the transfer of selenium by Gpx3 is below detection by our methods. PMID:25068390

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

    Directory of Open Access Journals (Sweden)

    Kristina E Hill

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

  12. 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....

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

    Science.gov (United States)

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

    2013-11-01

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

  14. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Goodrich, Jaclyn M.; Wang, Yi [Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109 (United States); Gillespie, Brenda [Department of Biostatistics, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109 (United States); Werner, Robert [Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109 (United States); Department of Physical Medicine and Rehabilitation, University of Michigan, 325 E. Eisenhower Parkway Suite 100, Ann Arbor, MI 48108 (United States); Franzblau, Alfred [Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109 (United States); Basu, Niladri, E-mail: niladri@umich.edu [Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109 (United States)

    2011-12-15

    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 Prime ), or both (SEPP1 3 Prime 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: Black-Right-Pointing-Pointer We explore the influence of 15 polymorphisms on urine and hair Hg levels. Black-Right-Pointing-Pointer Urine and hair Hg levels in dental professionals were similar to the US population. Black-Right-Pointing-Pointer GSTT1 and SEPP1 polymorphisms associated with urine Hg levels. Black

  16. 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

  17. 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

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

    Directory of Open Access Journals (Sweden)

    Díaz-Rubio Manuel

    2008-07-01

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

  19. 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

  20. 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

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

    Directory of Open Access Journals (Sweden)

    Andrew J Goldson

    Full Text Available 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 FINDINGS: A 12 week human dietary intervention study was undertaken in 119 volunteers who received placebo, 50, 100 or 200 µg/day Se-enriched yeast (Se-yeast or meals containing unenriched or Se-enriched onions (50 µg/day. Gene expression was quantified in RNA samples extracted from human peripheral blood mononuclear cells (PBMC's using quantitative RT-PCR. There was a significant increase in SEPW1 mRNA in the Se-enriched onion group (50 µg/day compared with the unenriched onion group. SEPR and SEPW1 did not change significantly over the duration of the supplementation period in the control or Se-yeast groups, except at week 10 when SEPW1 mRNA levels were significantly lower in the 200 µg/day Se-yeast group compared to the placebo group. Levels of SEPS1 mRNA increased significantly 7 days after the influenza vaccine challenge, the magnitude of the increase in SEPS1 gene expression was dose-dependent, with a significantly greater response with higher Se supplementation. CONCLUSIONS: This novel finding provides preliminary evidence for a role of SEPS1 in the immune response, and further supports the relationship between Se status and immune function. TRIAL REGISTRATION: ClinicalTrials.gov [NCT00279812].

  2. 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...

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

    DEFF Research Database (Denmark)

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

    2000-01-01

    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...

  4. 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

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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...

  10. 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 ...

  11. 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

  12. 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

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

    Directory of Open Access Journals (Sweden)

    Rachel M Taylor

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

  14. 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.

  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. 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

  17. 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

  18. 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...

  19. 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...

  20. Expression of selenoprotein-coding genes SEPP1, SEP15 and hGPX1 in non-small cell lung cancer.

    Science.gov (United States)

    Gresner, Peter; Gromadzinska, Jolanta; Jablonska, Ewa; Kaczmarski, Jacek; Wasowicz, Wojciech

    2009-07-01

    Aim of the study was to investigate the mRNA expression level of selenoprotein P (SEPP1), 15-kDa selenoprotein (SEP15) and glutathione peroxidase 1 (hGPX1) in paired malignant and non-malignant tissue. To achieve this goal, the quantitative real-time PCR technique was utilized in paired tissue samples from 33 non-small cell lung cancer (NSCLC) patients. Simultaneously, the activity of glutathione peroxidases (GPX) and the level of thiobarbituric acid-reactive species (TBARS) in paired tissue specimens and the blood plasma selenium level was measured. We found significant down-regulation of SEPP1 expression level in tumorous lung tissue (2.732-fold; p<0.001). The expression of hGPX1 and SEP15 in tumorous tissue remained unchanged compared to healthy tissue. The level of TBARS in malignant tissue was significantly increased (p<0.005) and negatively correlated with SEPP1 expression level (R(S)=-0.3238; p<0.05). The activity of GPX in malignant tissue was significantly increased compared to the non-malignant one (p<0.005) and negatively correlated with the expression level of SEPP1. It seems possible, that the down-regulation of SEPP1 expression may lead to an increased oxidative stress possibly resulting in lung carcinogenesis. Increased activity of GPX in tumorous lung tissue seems to be a feedback mechanism. PMID:19058871

  1. 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.

  2. 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

  3. 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

  4. 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。

  5. Selenium Alleviates Aflatoxin B₁-Induced Immune Toxicity through Improving Glutathione Peroxidase 1 and Selenoprotein S Expression in Primary Porcine Splenocytes.

    Science.gov (United States)

    Hao, Shu; Hu, Junfa; Song, Suquan; Huang, Da; Xu, Haibing; Qian, Gang; Gan, Fang; Huang, Kehe

    2016-02-17

    Selenium (Se) is generally known as an essential micronutrient and antioxidant for humans and animals. Aflatoxin B1 (AFB1) is a frequent contaminant of food and feed, causing immune toxicity and hepatotoxicity. Little has been done about the mechanisms of how Se protects against AFB1-induced immune toxicity. The aim of this present study is to investigate the protective effects of Se against AFB1 and the underlying mechanisms. The primary splenocytes isolated from healthy pigs were stimulated by anti-pig-CD3 monoclonal antibodies and treated by various concentrations of different Se forms and AFB1. The results showed that Se supplementation alleviated the immune toxicity of AFB1 in a dose-dependent manner, as demonstrated by increasing T-cell proliferation and interleukin-2 production. Addition of buthionine sulfoximine abrogated the protective effects of SeMet against AFB1. SeMet enhanced mRNA and protein expression of glutathione peroxidase 1 (GPx1), selenoprotein S (SelS), and thioredoxin reductase 1 without and with AFB1 treatments. Furthermore, knockdown of GPx1 and SelS by GPx1-specific siRNA and SelS-specific siRNA diminished the protective effects of SeMet against AFB1-induced immune toxicity. It is concluded that SeMet diminishes AFB1-induced immune toxicity through increasing antioxidant ability and improving GPx1 and SelS expression in splenocytes. This study suggests that organic selenium may become a promising supplementation to protect humans and animals against the decline in immunity caused by AFB1.

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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

  12. Se-Hg Dual-element Labeling Strategy for Selectively Recognizing Selenoprotein and Selenopeptide%硒-汞双元素标记策略识别硒蛋白/多肽

    Institute of Scientific and Technical Information of China (English)

    徐明; 杨利民; 王秋泉

    2015-01-01

    提出并发展了一种基于电感耦合等离子体质谱( ICP-MS)的双元素标签标记策略来选择性识别和检测硒蛋白/多肽,其中内源元素硒( Se)作为硒蛋白/多肽分子的识别元素,外源元素汞( Hg)作为硒蛋白/多肽和含硒蛋白/多肽分子的区分元素。通过对硒代半胱氨酸(SeCys)和谷胱甘肽过氧化酶1(GPx1)两种模型分子的研究,外源邻羧基苯硫甲基汞( CH3 Hg-THI )动态解离的 CH3 Hg+能够选择性标记硒代半胱氨酸残基( SeCys)中硒醇基(-SeH),但不能标记含硒蛋白/多肽分子的硒代蛋氨酸残基( SeMet)中的—SeCH3,进而依据Se和Hg的ICP-MS信号识别和检测硒蛋白/多肽。本方法应用于富硒酵母水溶性提取液的分析,结果表明,提取液中的硒蛋白/多肽能够被有效识别和检测,验证了Se-Hg双元素标签标记策略的发展是ICP-MS识别和检测硒蛋白/多肽的一种可行且优越的途径。%An endogenous element-label plus exogenous element-tag strategy was proposed for inductively coupled plasma mass spectrometry ( ICP-MS) to screen and discriminate a family of ultratrace but biological important biomolecules. The feasibility of this novel idea has been demonstrated when setting seleno ( SeCys) and Se-containing ( SeMet) proteins ( peptides) as an example. Se-label naturally occurring in the biomole-cules acts an identifier for picking them up out of large amount of various coexisting proteins ( peptides) , and CH3 Hg-tag that can bind to SeCys but not SeMet fulfills the task of discriminating seleno and Se-containing ones based on the Se and Hg signals on ICP-MS. After confirmed using SeCys and GPx1, the Se-Hg dual-element labeling strategy together with ICP-MS was applied to screen and discriminate seleno and Se-contai-ning proteins ( peptides) in the water-soluble extracts of Se-enriched yeast, and seven selenoproteins ( pep-tides) were detected with both 202 Hg and 82 Se signals out of fifteen Se

  13. 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 ...

  14. 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...

  15. 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

  16. 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...

  17. 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...

  18. 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.

  19. 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

  20. 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

  1. Chemical Inhibition of Autophagy

    DEFF Research Database (Denmark)

    Baek, Eric; Lin Kim, Che; Gyeom Kim, Mi;

    2016-01-01

    Chinese hamster ovary (CHO) cells activate and undergo apoptosis and autophagy for various environmental stresses. Unlike apoptosis, studies on increasing the production of therapeutic proteins in CHO cells by targeting the autophagy pathway are limited. In order to identify the effects of chemical...... autophagy inhibitors on the specific productivity (qp), nine chemical inhibitors that had been reported to target three different phases of autophagy (metformin, dorsomorphin, resveratrol, and SP600125 against initiation and nucleation; 3-MA, wortmannin, and LY294002 against elongation, and chloroquine...... significantly increased the qp of DG44-Fc and DUKX-Fc. In contrast, for DG44-Ab, only 3-MA significantly increased the qp. The autophagy-inhibiting activity of the nine chemical inhibitors on the rCHO cell lines was evaluated through Western blot analysis and flow cytometry. Unexpectedly, some chemical...

  2. 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 ...

  3. 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…

  4. 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.

  5. 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

  6. 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...

  7. 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 ...

  8. Treatment of chronic discoid lupus erythematosus with an oral gold compound (auranofin).

    Science.gov (United States)

    Dalziel, K; Going, G; Cartwright, P H; Marks, R; Beveridge, G W; Rowell, N R

    1986-08-01

    Twenty-three patients with severe longstanding discoid lupus erythematosus, unresponsive to conventional treatments, were treated with oral gold in a multicentre open study. Nineteen patients showed clinical improvement and in four of these there was complete resolution of lesions. Adverse reactions were generally mild and self limiting.

  9. 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...

  10. 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

  11. 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.

  12. 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.

  13. Islam Does Not Inhibit Science.

    Science.gov (United States)

    Shanavas, T. O.

    1999-01-01

    Compares the science/religion relationship in both Christian and Islamic countries. Presents Muslim scholars' ideas about the presence of humans on earth. Presents ideas on active nature, Noah's curse, and the age of the universe. Refutes the notion that Islam inhibited science and advocates the belief that Islam promoted science. (YDS)

  14. 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 Pl...

  15. 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.

  16. Conditioned inhibition and reinforcement rate.

    Science.gov (United States)

    Harris, Justin A; Kwok, Dorothy W S; Andrew, Benjamin J

    2014-07-01

    We investigated conditioned inhibition in a magazine approach paradigm. Rats were trained on a feature negative discrimination between an auditory conditioned stimulus (CS) reinforced at one rate versus a compound of that CS and a visual stimulus (L) reinforced at a lower rate. This training established L as a conditioned inhibitor. We then tested the inhibitory strength of L by presenting it in compound with other auditory CSs. L reduced responding when tested with a CS that had been reinforced at a high rate, but had less or even no inhibitory effect when tested with a CS that had been reinforced at a low rate. The inhibitory strength of L was greater if it signaled a decrease in reinforcement from an already low rate than if it signaled an equivalent decrease in reinforcement from a high rate. We conclude that the strength of inhibition is not a linear function of the change in reinforcement that it signals. We discuss the implications of this finding for models of learning (e.g., Rescorla & Wagner, 1972) that identify inhibition with a difference (subtraction) rule.

  17. Using chemical approaches to study selenoproteins - focus on thioredoxin reductases

    OpenAIRE

    Hondal, Robert J.

    2009-01-01

    The study of selenocysteine-containing proteins is difficult due to the problems associated with the heterologous production of these proteins. These problems are due to the intricate recoding mechanism used by cells to translate the UGA codon as a sense codon for selenocysteine. The process is further complicated by the fact that eukaryotes and prokaryotes have different UGA recoding machineries.

  18. 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...

  19. 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...

  20. 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

  1. 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

  2. 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.

  3. Suramin inhibits EV71 infection.

    Science.gov (United States)

    Wang, Yaxin; Qing, Jie; Sun, Yuna; Rao, Zihe

    2014-03-01

    Enterovirus-71 (EV71) is one of the major causative reagents for hand-foot-and-mouth disease. In particular, EV71 causes severe central nervous system infections and leads to numerous dead cases. Although several inactivated whole-virus vaccines have entered in clinical trials, no antiviral agent has been provided for clinical therapy. In the present work, we screened our compound library and identified that suramin, which has been clinically used to treat variable diseases, could inhibit EV71 proliferation with an IC50 value of 40 μM. We further revealed that suramin could block the attachment of EV71 to host cells to regulate the early stage of EV71 infection, as well as affected other steps of EV71 life cycle. Our results are helpful to understand the mechanism for EV71 life cycle and provide a potential for the usage of an approved drug, suramin, as the antiviral against EV71 infection.

  4. 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.

  5. 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...

  6. 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...

  7. Reduced surround inhibition in musicians.

    Science.gov (United States)

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

    2012-06-01

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

  8. 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,

  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. 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

  11. 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…

  12. A Qualitative Approach to Enzyme Inhibition

    Science.gov (United States)

    Waldrop, Grover L.

    2009-01-01

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

  13. Inhibited and Uninhibited Types of Children.

    Science.gov (United States)

    Kagan, Jerome; And Others

    1989-01-01

    Investigates the preservation of inhibited and uninhibited behaviors in 100 children of 14, 20, 32, and 48 months. Children who had been extremely inhibited or uninhibited at 14 and 20 months differed significantly at 4 years of age in behavior and cardiac acceleration. (RJC)

  14. 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…

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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.

  20. Cellulase Inhibition by High Concentrations of Monosaccharides

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  1. 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.

  2. 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

  3. Lobelane inhibits methamphetamine-evoked dopamine release via inhibition of the vesicular monoamine transporter-2.

    Science.gov (United States)

    Nickell, Justin R; Krishnamurthy, Sairam; Norrholm, Seth; Deaciuc, Gabriela; Siripurapu, Kiran B; Zheng, Guangrong; Crooks, Peter A; Dwoskin, Linda P

    2010-02-01

    Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [(3)H]dihydrotetrabenazine binding, inhibition of [(3)H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (K(i) = 45 nM) inhibiting vesicular [(3)H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC(50) = 0.65 microM; I(max) = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC(50) = 0.42 microM, I(max) = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for

  4. Lobelane Inhibits Methamphetamine-Evoked Dopamine Release via Inhibition of the Vesicular Monoamine Transporter-2S⃞

    Science.gov (United States)

    Nickell, Justin R.; Krishnamurthy, Sairam; Norrholm, Seth; Deaciuc, Gabriela; Siripurapu, Kiran B.; Zheng, Guangrong; Crooks, Peter A.

    2010-01-01

    Lobeline is currently being evaluated in clinical trials as a methamphetamine abuse treatment. Lobeline interacts with nicotinic receptor subtypes, dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Methamphetamine inhibits VMAT2 and promotes dopamine (DA) release from synaptic vesicles, resulting ultimately in increased extracellular DA. The present study generated structure-activity relationships by defunctionalizing the lobeline molecule and determining effects on [3H]dihydrotetrabenazine binding, inhibition of [3H]DA uptake into striatal synaptic vesicles and synaptosomes, the mechanism of VMAT2 inhibition, and inhibition of methamphetamine-evoked DA release. Compared with lobeline, the analogs exhibited greater potency inhibiting DA transporter (DAT) function. Saturated analogs, lobelane and nor-lobelane, exhibited high potency (Ki = 45 nM) inhibiting vesicular [3H]DA uptake, and lobelane competitively inhibited VMAT2 function. Lobeline and lobelane exhibited 67- and 35-fold greater potency, respectively, in inhibiting VMAT2 function compared to DAT function. Lobelane potently decreased (IC50 = 0.65 μM; Imax = 73%) methamphetamine-evoked DA overflow, and with a greater maximal effect compared with lobeline (IC50 = 0.42 μM, Imax = 56.1%). These results provide support for VMAT2 as a target for inhibition of methamphetamine effects. Both trans-isomers and demethylated analogs of lobelane had reduced or unaltered potency inhibiting VMAT2 function and lower maximal inhibition of methamphetamine-evoked DA release compared with lobelane. Thus, defunctionalization, cis-stereochemistry of the side chains, and presence of the piperidino N-methyl are structural features that afford greatest inhibition of methamphetamine-evoked DA release and enhancement of selectivity for VMAT2. The current results reveal that lobelane, a selective VMAT2 inhibitor, inhibits methamphetamine-evoked DA release and is a promising lead for the development of a

  5. 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

  6. 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

  7. 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...

  8. 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 =...

  9. 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...

  10. 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....

  11. Inhibited solid propellant composition containing beryllium hydride

    Science.gov (United States)

    Thompson, W. W. (Inventor)

    1978-01-01

    An object of this invention is to provide a composition of beryllium hydride and carboxy-terminated polybutadiene which is stable. Another object of this invention is to provide a method for inhibiting the reactivity of beryllium hydride toward carboxy-terminated polybutadiene. It was found that a small amount of lecithin inhibits the reaction of beryllium hydride with the acid groups in carboxy terminated polybutadiene.

  12. Inhibition of Heme Peroxidases by Melamine

    Directory of Open Access Journals (Sweden)

    Pattaraporn Vanachayangkul

    2012-01-01

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

  13. Scale Inhibition of Green Inhibitor Polyepoxysuccinic Sodium

    Institute of Scientific and Technical Information of China (English)

    Feng Hui-xia; Wang Yi; Yu Shu-rong; Liang Bao-feng

    2004-01-01

    Polyepoxysuccinic acid (PESA) is the green water treatment agents recognized all over the world[1-3]. It is found that when PESA is used alone, it had good scale inhibition. PESA should be included in the category of green scale inhibitor.PESA is synthesized with maleicanhydride in the presence of catalysts. The effect on scale-in-hibiting property of the product from amount and feed times of catalyst, the reaction temperature, the reaction time were investigated. The optimum reaction conditions are as follows:n(maleic anhydride):n(Ca(OH)2):n(NaOH)=1:0.05-0.2:0.5, reaction temperature 95C, reaction time 4h.In all the references about PESA, PESA is researched as a kind of highly effective scale inhibitor or chelate. In this paper, the performance of scale inhibition of PESA is evaluated by scale static inhibitor.The results are shown in Figture1.It is evident from our experimental data (Figture1) that when inhibition for CaCO3.With the increase of PESA dosage, scale inhibition increases. When dosage is more than 6mg/L, inhibition efficiency is over 50%. The formulas give scale inhibition efficiency more than 95% at 12mg/L of total dosage.

  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. 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.

  16. Importance of cadmium speciation in nitrification inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Semerci, Neslihan [Marmara University, Department of Environmental Engineering, 34722 Kuyubasi, Istanbul (Turkey)]. E-mail: yazici@eng.marmara.edu.tr; Cecen, Ferhan [Bogazici University, Institute of Environmental Sciences, Bebek, Istanbul (Turkey)

    2007-08-17

    In this study, the influence of Cd speciation on nitrification inhibition was investigated in batch suspended growth activated sludge systems which contain biomass enriched in terms of nitrifiers. For this purpose, parallel measurements of specific oxygen uptake rates (SOUR), ammonium utilization rates (q{sub NH{sub 4}-N}) and Cd uptake were carried out. Cd speciation was adjusted with a strong complexing agent, ethylenediaminetetraacetic acid (EDTA). Free and biosorbed Cd concentrations were theoretically determined by using the MINEQL+ program and the Cd adsorption constant, whereas labile Cd was determined by voltammetric measurements. The presence of EDTA decreased nitrification inhibition by lowering the available Cd species and by preventing biosorption of Cd. Almost complete recovery from inhibition was attained by EDTA addition to nitrifying bacteria which were inhibited by Cd for a certain time. These results suggested that the sites sensitive to Cd were rather located on the surface of bacterial cell than inside. Nitrification inhibition depended on equilibrium concentrations of free (Cd{sup 2+}), labile (Cd{sub volt}) and biosorbed Cd (Cd{sub volt}) and did not correlate with the total Cd. The measurement of labile metal by voltammetry in inhibition studies is a promising approach since it is easy to apply in practice.

  17. Phosphatidic acid inhibits blue light-induced stomatal opening via inhibition of protein phosphatase 1 [corrected].

    Science.gov (United States)

    Takemiya, Atsushi; Shimazaki, Ken-ichiro

    2010-08-01

    Stomata open in response to blue light under a background of red light. The plant hormone abscisic acid (ABA) inhibits blue light-dependent stomatal opening, an effect essential for promoting stomatal closure in the daytime to prevent water loss. However, the mechanisms and molecular targets of this inhibition in the blue light signaling pathway remain unknown. Here, we report that phosphatidic acid (PA), a phospholipid second messenger produced by ABA in guard cells, inhibits protein phosphatase 1 (PP1), a positive regulator of blue light signaling, and PA plays a role in stimulating stomatal closure in Vicia faba. Biochemical analysis revealed that PA directly inhibited the phosphatase activity of the catalytic subunit of V. faba PP1 (PP1c) in vitro. PA inhibited blue light-dependent stomatal opening but did not affect red light- or fusicoccin-induced stomatal opening. PA also inhibited blue light-dependent H(+) pumping and phosphorylation of the plasma membrane H(+)-ATPase. However, PA did not inhibit the autophosphorylation of phototropins, blue light receptors for stomatal opening. Furthermore, 1-butanol, a selective inhibitor of phospholipase D, which produces PA via hydrolysis of phospholipids, diminished the ABA-induced inhibition of blue light-dependent stomatal opening and H(+) pumping. We also show that hydrogen peroxide and nitric oxide, which are intermediates in ABA signaling, inhibited the blue light responses of stomata and that 1-butanol diminished these inhibitions. From these results, we conclude that PA inhibits blue light signaling in guard cells by PP1c inhibition, accelerating stomatal closure, and that PP1 is a cross talk point between blue light and ABA signaling pathways in guard cells.

  18. 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...

  19. 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...

  20. 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.

  1. Matrix metalloproteinase inhibition in atherosclerosis and stroke.

    Science.gov (United States)

    Roycik, M D; Myers, J S; Newcomer, R G; Sang, Q-X A

    2013-09-01

    Matrix metalloproteinases (MMPs) are a family of tightly regulated, zinc-dependent proteases that degrade extracellular matrix (ECM), cell surface, and intracellular proteins. Vascular remodeling, whether as a function of normal physiology or as a consequence of a myriad of pathological processes, requires degradation of the ECM. Thus, the expression and activity of many MMPs are up-regulated in numerous conditions affecting the vasculature and often exacerbate vascular dysfunction. A growing body of evidence supports the rationale of using MMP inhibitors for the treatment of cardiovascular diseases, stroke, and chronic vascular dementia. This manuscript will examine promising targets for MMP inhibition in atherosclerosis and stroke, reviewing findings in preclinical animal models and human patient studies. Strategies for MMP inhibition have progressed beyond chelating the catalytic zinc to functional blocking antibodies and peptides that target either the active site or exosites of the enzyme. While the inhibition of MMP activity presents a rational therapeutic avenue, the multiplicity of roles for MMPs and the non-selective nature of MMP inhibitors that cause unintended side-effects hinder full realization of MMP inhibition as therapy for vascular disease. For optimal therapeutic effects to be realized, specific targets for MMP inhibition in these pathologies must first be identified and then attacked by potent and selective agents during the most appropriate timepoint.

  2. 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

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

    Science.gov (United States)

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

    2015-01-01

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

  4. 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.

  5. Vanadium inhibition of serine and cysteine proteases.

    Science.gov (United States)

    Guerrieri, N; Cerletti, P; De Vincentiis, M; Salvati, A; Scippa, S

    1999-03-01

    A study was made on the effect of vanadium, in both the tetravalent state in vanadyl sulphate and in the pentavalent state in sodium meta-vanadate, and ortho-vanadate, on the proteolysis of azocasein by two serine proteases, trypsin and subtilisin and two cysteine proteases bromelain and papain. Also the proteolysis of bovine azoalbumin by serine proteases was considered. An inhibitory effect was present in all cases, except meta-vanadate with subtilisin. The oxidation level of vanadium by itself did not determine the inhibition kinetics, which also depended on the type and composition of the vanadium containing molecule and on the enzyme assayed. The pattern of inhibition was similar for proteases belonging to the same class. The highest inhibition was obtained with meta-vanadate on papain and with vanadyl sulphate on bromelain.

  6. 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

  7. 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

  8. Product inhibition of five Hypocrea jecorina cellulases

    DEFF Research Database (Denmark)

    Murphy, Leigh; Westh, Peter; Bohlin, Christina;

    2013-01-01

    Product inhibition of cellulolytic enzymes has been deemed a critical factor in the industrial saccharification of cellulosic biomass. Several investigations have addressed this problem using crude enzyme preparations or commercial (mixed) cellulase products, but quantitative information...... cellulose may be monitored by calorimetry. The key advantage of this approach is that it directly measures the rate of hydrolysis while being essentially blind to the background of added product. We investigated the five major cellulases from Hypocrea jecorina (anamorph: Tricoderma reesei), Cel7A (formerly...... by cellobiose, but showed the highest sensitivity to glucose among all investigated enzymes. The endoglucanases Cel12A and Cel7B were moderately inhibited by cellobiose (IC50 = 60–80 mM), and weakly inhibited by glucose (IC50 = 350–380 mM). The highest resistance to both products was found for Cel5A, which...

  9. Inhibition of Henipavirus infection by RNA interference.

    Science.gov (United States)

    Mungall, Bruce A; Schopman, Nick C T; Lambeth, Luke S; Doran, Tim J

    2008-12-01

    Nipah virus (NiV) and Hendra virus (HeV) are recently emerged zoonotic paramyxoviruses exclusively grouped within a new genus, Henipavirus. These viruses cause fatal disease in a wide range of species, including humans. Both NiV and HeV have continued to re-emerge sporadically in Bangladesh and Australia, respectively. There are currently no therapeutics or vaccines available to treat Henipavirus infection and both are classified as BSL4 pathogens. RNA interference (RNAi) is a process by which double-stranded RNA directs sequence-specific degradation of messenger RNA in animal and plant cells. Small interfering RNAs (siRNAs) mediate RNAi by inhibiting gene expression of homologous mRNA and our preliminary studies suggest RNAi may be a useful approach to developing novel therapies for these highly lethal pathogens. Eight NiV siRNA molecules (four L and four N gene specific), two HeV N gene specific, and two non-specific control siRNA molecules were designed and tested for their ability to inhibit a henipavirus minigenome replication system (which does not require the use of live virus) in addition to live virus infections in vitro. In the minigenome assay three out of the four siRNAs that targeted the L gene of NiV effectively inhibited replication. In contrast, only NiV N gene siRNAs were effective in reducing live NiV replication, suggesting inhibition of early, abundantly expressed gene transcripts may be more effective than later, less abundant transcripts. Additionally, some of the siRNAs effective against NiV infection were only partially effective inhibitors of HeV infection. An inverse correlation between the number of nucleotide mismatches and the efficacy of siRNA inhibition was observed. The demonstration that RNAi effectively inhibits henipavirus replication in vitro, is a novel approach and may provide an effective therapy for these highly lethal, zoonotic pathogens. PMID:18687361

  10. Inhibition of microbial arsenate reduction by phosphate.

    Science.gov (United States)

    Slaughter, Deanne C; Macur, Richard E; Inskeep, William P

    2012-03-20

    The ratio of arsenite (As(III)) to arsenate (As(V)) in soils and natural waters is often controlled by the activity of As-transforming microorganisms. Phosphate is a chemical analog to As(V) and, consequently, may competitively inhibit microbial uptake and enzymatic binding of As(V), thus preventing its reduction to the more toxic, mobile, and bioavailable form - As(III). Five As-transforming bacteria isolated either from As-treated soil columns or from As-impacted soils were used to evaluate the effects of phosphate on As(V) reduction and As(III) oxidation. Cultures were initially spiked with various P:As ratios, incubated for approximately 48 h, and analyzed periodically for As(V) and As(III) concentration. Arsenate reduction was inhibited at high P:As ratios and completely suppressed at elevated levels of phosphate (500 and 1,000 μM; P inhibition constant (K(i))∼20-100 μM). While high P:As ratios effectively shut down microbial As(V) reduction, the expression of the arsenate reductase gene (arsC) was not inhibited under these conditions in the As(V)-reducing isolate, Agrobacterium tumefaciens str. 5B. Further, high phosphate ameliorated As(V)-induced cell growth inhibition caused by high (1mM) As pressure. These results indicate that phosphate may inhibit As(V) reduction by impeding As(V) uptake by the cell via phosphate transport systems or by competitively binding to the active site of ArsC. PMID:21741807

  11. 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

  12. 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...

  13. 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)

  14. 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...

  15. 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...

  16. 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 subst......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...

  17. Silver-Palladium Surfaces Inhibit Biofilm Formation

    DEFF Research Database (Denmark)

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

    2009-01-01

    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...

  18. Inhibition of denitrification by ultraviolet radiation

    Science.gov (United States)

    Mancinelli, R. L.; White, M. R.

    It has been shown that UV-A (λ = 320- 400 nm) and UV-B (λ = 280 - 320 nm) inhibit photosynthesis, nitrogen fixation and nitrification. The purpose of this study was to determine the effects, if any, on denitrification in a microbial community inhabiting the intertidal. The community studied is the microbial mat consisting primarily of Lyngbya that inhabits the Pacific marine intertidal, Baja California, Mexico. Rates of denitrification were determined using the acetylene blockage technique. Pseudomonas fluorescens (ATCC # 17400) was used as a control organism, and treated similarly to the mat samples. Samples were incubated either beneath a PAR transparent, UV opaque screen (OP3), or a mylar screen to block UV-B, or a UV transparent screen (UVT) for 2 to 3 hours. Sets of samples were also treated with nitrapyrin to inhibit nitrification, or DCMU to inhibit photosynthesis and treated similarly. Denitrification rates were greater in the UV protected samples than in the UV exposed samples the mat samples as well as for the Ps. fluorescens cultures. Killed controls exhibited no activity. In the DCMU and nitrapyrin treated samples denitrification rates were the same as in the untreated samples. These data indicate that denitrification is directly inhibited by UV radiation.

  19. 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…

  20. Acidosis inhibits mineralization in human osteoblasts.

    Science.gov (United States)

    Takeuchi, Shoko; Hirukawa, Koji; Togari, Akifumi

    2013-09-01

    Osteoblasts and osteoclasts maintain bone volume. Acidosis affects the function of these cells including mineral metabolism. We examined the effect of acidosis on the expression of transcription factors and mineralization in human osteoblasts in vitro. Human osteoblasts (SaM-1 cells) derived from the ulnar periosteum were cultured with α-MEM containing 50 μg/ml ascorbic acid and 5 mM β-glycerophosphate (calcifying medium). Acidosis was induced by incubating the SaM-1 cells in 10 % CO₂ (pH approximately 7.0). Mineralization, which was augmented by the calcifying medium, was completely inhibited by acidosis. Acidosis depressed c-Jun mRNA and increased osteoprotegerin (OPG) production in a time-dependent manner. Depressing c-Jun mRNA expression using siRNA increased OPG production and inhibited mineralization. In addition, depressing OPG mRNA expression with siRNA enhanced mineralization in a dose-dependent manner. Acidosis or the OPG protein strongly inhibited mineralization in osteoblasts from neonatal mice. The present study was the first to demonstrate that acidosis inhibited mineralization, depressed c-Jun mRNA expression, and induced OPG production in human osteoblasts. These results suggest that OPG is involved in mineralization via c-Jun in human osteoblasts.

  1. 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.

  2. 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

  3. Mechanism of dissolution inhibition in phenolic resins

    Science.gov (United States)

    Lin, Chen-Chy; Yeh, Tung-Feng; Reiser, Arnost; Honda, Kenji; Beauchemin, Bernard T., Jr.

    1993-09-01

    It was suggested in an earlier communication that dissolution inhibition in phenolic resins comes about through the blocking of some of the hydrophilic OH-groups by a hydrophobic effect of the inhibitors. Honda et al. have shown that the hydrophobicity of the additive is not a sufficient condition, and that the polar groups of the inhibitor, such as the diazoquinone function, play an important role in the inhibition effect. They found that additives with very similar skeletal structures, but differing in the polar anchor group, have very different inhibition efficiencies in a common novolac resin. In this study we investigate the interaction between phenols and the anchor groups of the inhibitors by determining the equilibrium constants of their association reaction. From this, the fraction of bound acceptor groups (inhibitors) can be estimated for the casting solution of the films at the point of solidification. It can be shown that this fraction correlates quite satisfactorily with the inhibition effect of the additives used in Honda's study.

  4. Stress kinase inhibition modulates acute experimental pancreatitis

    Institute of Scientific and Technical Information of China (English)

    F. Fleischer; R. Dabew; B. Goke; ACC Wagner

    2001-01-01

    AIM To examine the role of p38 during acute experimental cerulein pancreatitis.METHODS Rats were treated with cerulein with or without a specific JNK inhibitor (CEP1347)andy or a specific p38 inhbitor (SB203380) and pancreatic stress kinase activity wasdetermined. Parameters to assess pancreatitis included trypsin, amylase, lipase, pancreatic weight and histology.RESULTS JNK inhibition with CEP1347ameliorated pancreatitis, reducing pancreatic edema. In contrast, p38 inhibition with SB203580aggravated pancreatitis with higher trypsinlevels and, with induction of acinar necrosis not normally found after cerulein hyperstimulation.Simultaneous treatment with both CEP1347 and SB203580 mutually abolished the effects of either compound on cerulein pancreatitis.CONCLUSION Stress kinases modulatepancreatitis differentially. JNK seems to promote pancreatitis development, possibly by supporting inflammatory reactions such as edema formation while its inhibition ameliorates pancreatitis. In contrast, p38 may help reduce organ destruction while inhibition of p38 during induction of cerulein pancreatitis leads to the occurrence of acinar necrosis.

  5. 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.

  6. 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...

  7. 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...

  8. 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,…

  9. Hemagglutinin inhibition assay with swine sera

    Science.gov (United States)

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

  10. 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

  11. Cerebellar cortical inhibition and classical eyeblink conditioning.

    Science.gov (United States)

    Bao, Shaowen; Chen, Lu; Kim, Jeansok J; Thompson, Richard F

    2002-02-01

    The cerebellum is considered a brain structure in which memories for learned motor responses (e.g., conditioned eyeblink responses) are stored. Within the cerebellum, however, the relative importance of the cortex and the deep nuclei in motor learning/memory is not entirely clear. In this study, we show that the cerebellar cortex exerts both basal and stimulus-activated inhibition to the deep nuclei. Sequential application of a gamma-aminobutyric acid type A receptor (GABA(A)R) agonist and a noncompetitive GABA(A)R antagonist allows selective blockade of stimulus-activated inhibition. By using the same sequential agonist and antagonist methods in behaving animals, we demonstrate that the conditioned response (CR) expression and timing are completely dissociable and involve different inhibitory inputs; although the basal inhibition modulates CR expression, the conditioned stimulus-activated inhibition is required for the proper timing of the CR. In addition, complete blockade of cerebellar deep nuclear GABA(A)Rs prevents CR acquisition. Together, these results suggest that different aspects of the memories for eyeblink CRs are encoded in the cerebellar cortex and the cerebellar deep nuclei.

  12. 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…

  13. 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

  14. WEE1 inhibition sensitizes osteosarcoma to radiotherapy

    Directory of Open Access Journals (Sweden)

    Helder Marco N

    2011-04-01

    Full Text Available Abstract Background The use of radiotherapy in osteosarcoma (OS is controversial due to its radioresistance. OS patients currently treated with radiotherapy generally are inoperable, have painful skeletal metastases, refuse surgery or have undergone an intralesional resection of the primary tumor. After irradiation-induced DNA damage, OS cells sustain a prolonged G2 cell cycle checkpoint arrest allowing DNA repair and evasion of cell death. Inhibition of WEE1 kinase leads to abrogation of the G2 arrest and could sensitize OS cells to irradiation induced cell death. Methods WEE1 expression in OS was investigated by gene-expression data analysis and immunohistochemistry of tumor samples. WEE1 expression in OS cell lines and human osteoblasts was investigated by Western blot. The effect of WEE1 inhibition on the radiosensitivity of OS cells was assessed by cell viability and caspase activation analyses after combination treatment. The presence of DNA damage was visualized using immunofluorescence microscopy. Cell cycle effects were investigated by flow cytometry and WEE1 kinase regulation was analyzed by Western blot. Results WEE1 expression is found in the majority of tested OS tissue samples. Small molecule drug PD0166285 inhibits WEE1 kinase activity. In the presence of WEE1-inhibitor, irradiated cells fail to repair their damaged DNA, and show higher levels of caspase activation. The inhibition of WEE1 effectively abrogates the irradiation-induced G2 arrest in OS cells, forcing the cells into premature, catastrophic mitosis, thus enhancing cell death after irradiation treatment. Conclusion We show that PD0166285, a small molecule WEE1 kinase inhibitor, can abrogate the G2 checkpoint in OS cells, pushing them into mitotic catastrophe and thus sensitizing OS cells to irradiation-induced cell death. This suggests that WEE1 inhibition may be a promising strategy to enhance the radiotherapy effect in patients with OS.

  15. 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...

  16. 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...

  17. 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

  18. 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...

  19. 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...

  20. 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

  1. 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......BACKGROUND AND PURPOSE: Cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Potent active site-directed inhibitors have been developed and showed variable success in clinical trials. These inhibitors block the entire activity of CatK and thus may interfere with other...... 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...

  2. 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

  3. Sulfate inhibition effect on sulfate reducing bacteria

    Directory of Open Access Journals (Sweden)

    Sulaiman Al Zuhair

    2008-12-01

    Full Text Available There is an increasing interest in the potential of bacterial sulfate reduction as an alternative method for sulfate removal from wastewater. Under anaerobic conditions, sulfate-reducing bacteria (SRB utilize sulfate to oxidize organic compounds and generate sulfide (S2-. SRB were successfully isolated from sludge samples obtained from a local petroleum refinery, and used for sulfate removal. The effects of initial sulfate concentration, temperature and pH on the rate of bacterial growth and anaerobic sulfate removal were investigated and the optimum conditions were identified. The experimental data were used to determine the parameters of two proposed kinetic model, which take into consideration substrate inhibition effect. Keywords: Sulfate Reducing Bacteria, Sulfate, Kinetic Model, Biotreatement, Inhibition Received: 31 August 2008 / Received in revised form: 18 September 2008, Accepted: 18 September 2008 Published online: 28 September 2008

  4. 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.

  5. Proton pump inhibitors inhibit pancreatic secretion

    DEFF Research Database (Denmark)

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

    2015-01-01

    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...... 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 major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3-, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3- secretion. We propose that proton transport is driving secretion, and that in addition...

  6. AMPA receptor inhibition by synaptically released zinc.

    Science.gov (United States)

    Kalappa, Bopanna I; Anderson, Charles T; Goldberg, Jacob M; Lippard, Stephen J; Tzounopoulos, Thanos

    2015-12-22

    The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.

  7. 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....... In addition, combination treatment seemed safe and effective also in patients with impaired kidney function. These initial findings formed the basis for the design of a large morbidity and mortality trial investigating aliskiren as add-on to standard treatment. The study has just concluded, but 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 inhibition in chronic...

  8. 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.

  9. Non-Classical Inhibition of Carbonic Anhydrase

    Science.gov (United States)

    Lomelino, Carrie L.; Supuran, Claudiu T.; McKenna, Robert

    2016-01-01

    Specific isoforms from the carbonic anhydrase (CA) family of zinc metalloenzymes have been associated with a variety of diseases. Isoform-specific carbonic anhydrase inhibitors (CAIs) are therefore a major focus of attention for specific disease treatments. Classical CAIs, primarily sulfonamide-based compounds and their bioisosteres, are examined as antiglaucoma, antiepileptic, antiobesity, antineuropathic pain and anticancer compounds. However, many sulfonamide compounds inhibit all CA isoforms nonspecifically, diluting drug effectiveness and causing undesired side effects due to off-target inhibition. In addition, a small but significant percentage of the general population cannot be treated with sulfonamide-based compounds due to a sulfa allergy. Therefore, CAIs must be developed that are not only isoform specific, but also non-classical, i.e. not based on sulfonamides, sulfamates, or sulfamides. This review covers the classes of non-classical CAIs and the recent advances in the development of isoform-specific inhibitors based on phenols, polyamines, coumarins and their derivatives. PMID:27438828

  10. 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.

  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. 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...

  13. 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

  14. 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 ...

  15. 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

  16. 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...

  17. 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...

  18. 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.

  19. Caffeine Inhibits Acetylcholinesterase, But Not Butyrylcholinesterase

    Directory of Open Access Journals (Sweden)

    Petr Dobes

    2013-05-01

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

  20. Celecoxib transiently inhibits cellular protein synthesis.

    Science.gov (United States)

    Pyrko, Peter; Kardosh, Adel; Schönthal, Axel H

    2008-01-15

    To uncover the full spectrum of its pharmacological activities, the selective COX-2 inhibitor celecoxib is routinely being used at concentrations of up to 100 microM in cell culture. At these elevated concentrations, several COX-2-independent effects were identified, although many details of these events have remained unclear. Here, we report a COX-2-independent effect of celecoxib that might have profound consequences for the interpretation of previous results obtained at elevated concentrations of this drug in vitro. We found that celecoxib rapidly inhibits general protein translation at concentrations as low as 30 microM. This appears to be a consequence of endoplasmic reticulum (ER) stress and entails the phosphorylation and inactivation of eukaryotic translation initiation factor 2 alpha (eIF2alpha). These effects were not achieved by other coxibs (rofecoxib, valdecoxib) or traditional NSAIDs (indomethacin, flurbiprofen), but were mimicked by the COX-2-inactive celecoxib analog, 2,5-dimethyl-celecoxib (DMC), indicating COX-2 independence. Considering the obvious impact of blocked translation on cellular function, we provide evidence that this severe inhibition of protein synthesis might suffice to explain some of the previously reported COX-2-independent effects of celecoxib, such as the down-regulation of the essential cell cycle regulatory protein cyclin D, which is a short-lived protein that rapidly disappears in response to the inhibition of protein synthesis. Taken together, our findings establish ER stress-induced inhibition of general translation as a critical outcome of celecoxib treatment in vitro, and suggest that this effect needs to be considered when interpreting observations from the use of this drug in cell culture. PMID:17920040

  1. 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...

  2. 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 ...

  3. 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

  4. 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.

  5. Inhibition of topoisomerase II by liriodenine.

    Science.gov (United States)

    Woo, S H; Reynolds, M C; Sun, N J; Cassady, J M; Snapka, R M

    1997-08-15

    The cytotoxic oxoaporphine alkaloid liriodenine, isolated from Cananga odorata, was found to be a potent inhibitor of topoisomerase II (EC 5.99.1.3) both in vivo and in vitro. Liriodenine treatment of SV40 (simian virus 40)-infected CV-1 cells caused highly catenated SV40 daughter chromosomes, a signature of topoisomerase II inhibition. Strong catalytic inhibition of topoisomerase II by liriodenine was confirmed by in vitro assays with purified human topoisomerase II and kinetoplast DNA. Liriodenine also caused low-level protein-DNA cross-links to pulse-labeled SV40 chromosomes in vivo, suggesting that it may be a weak topoisomerase II poison. This was supported by the finding that liriodenine caused topoisomerase II-DNA cross-links in an in vitro assay for topoisomerase II poisons. Verapamil did not increase either liriodenine-induced protein-DNA cross-links or catalytic inhibition of topoisomerase II in SV40-infected cells. This indicates that liriodenine is not a substrate for the verapamil-sensitive drug efflux pump in CV-1 cells. PMID:9313773

  6. 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

  7. 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

  8. Allosteric Inhibition of Human Immunodeficiency Virus Integrase

    Science.gov (United States)

    Gupta, Kushol; Brady, Troy; Dyer, Benjamin M.; Malani, Nirav; Hwang, Young; Male, Frances; Nolte, Robert T.; Wang, Liping; Velthuisen, Emile; Jeffrey, Jerry; Van Duyne, Gregory D.; Bushman, Frederic D.

    2014-01-01

    HIV-1 replication in the presence of antiviral agents results in evolution of drug-resistant variants, motivating the search for additional drug classes. Here we report studies of GSK1264, which was identified as a compound that disrupts the interaction between HIV-1 integrase (IN) and the cellular factor lens epithelium-derived growth factor (LEDGF)/p75. GSK1264 displayed potent antiviral activity and was found to bind at the site occupied by LEDGF/p75 on IN by x-ray crystallography. Assays of HIV replication in the presence of GSK1264 showed only modest inhibition of the early infection steps and little effect on integration targeting, which is guided by the LEDGF/p75·IN interaction. In contrast, inhibition of late replication steps was more potent. Particle production was normal, but particles showed reduced infectivity. GSK1264 promoted aggregation of IN and preformed LEDGF/p75·IN complexes, suggesting a mechanism of inhibition. LEDGF/p75 was not displaced from IN during aggregation, indicating trapping of LEDGF/p75 in aggregates. Aggregation assays with truncated IN variants revealed that a construct with catalytic and C-terminal domains of IN only formed an open polymer associated with efficient drug-induced aggregation. These data suggest that the allosteric inhibitors of IN are promising antiviral agents and provide new information on their mechanism of action. PMID:24904063

  9. 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).

  10. 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.

  11. Deubiquitinase inhibition as a cancer therapeutic strategy.

    Science.gov (United States)

    D'Arcy, Padraig; Wang, Xin; Linder, Stig

    2015-03-01

    The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS has made this an attractive target for development of drugs that show selectivity for tumor cells. Deubiquitinases (DUBs, ubiquitin isopeptidases) are components of the UPS that catalyze the removal of ubiquitin moieties from target proteins or polyubiquitin chains, resulting in altered signaling or changes in protein stability. A number of DUBs regulate processes associated with cell proliferation and apoptosis, and as such represent candidate targets for cancer therapeutics. The majority of DUBs are cysteine proteases and are likely to be more "druggable" than E3 ligases. Cysteine residues in the active sites of DUBs are expected to be reactive to various electrophiles. Various compounds containing α,β-unsaturated ketones have indeed been demonstrated to inhibit cellular DUB activity. Inhibition of proteasomal cysteine DUB enzymes (i.e. USP14 and UCHL5) can be predicted to be particularly cytotoxic to cancer cells as it leads to blocking of proteasome function and accumulation of proteasomal substrates. We here provide an overall review of DUBs relevant to cancer and of various small molecules which have been demonstrated to inhibit DUB activity.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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...

  18. 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 ...

  19. 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...

  20. 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...

  1. 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...

  2. Selenium and its' role in the maintenance of genomic stability.

    Science.gov (United States)

    Ferguson, Lynnette R; Karunasinghe, Nishi; Zhu, Shuotun; Wang, Alice H

    2012-05-01

    Selenium (Se) is an essential micronutrient for humans, acting as a component of the unusual amino acids, selenocysteine (Se-Cys) and selenomethionine (Se-Met). Where Se levels are low, the cell cannot synthesise selenoproteins, although some selenoproteins and some tissues are prioritised over others. Characterised functions of known selenoproteins, include selenium transport (selenoprotein P), antioxidant/redox properties (glutathione peroxidases (GPxs), thioredoxin reductases and selenoprotein P) and anti-inflammatory properties (selenoprotein S and GPx4). Various forms of Se are consumed as part of a normal diet, or as a dietary supplement. Supplementation of tissue culture media, animal or human diets with moderate levels of certain Se compounds may protect against the formation of DNA adducts, DNA or chromosome breakage, and chromosome gain or loss. Protective effects have also been shown on mitochondrial DNA, and on telomere length and function. Some of the effects of Se compounds on gene expression may relate to modulation of DNA methylation or inhibition of histone deacetylation. Despite a large number of positive effects of selenium and selenoproteins in various model systems, there have now been some human clinical trials that have shown adverse effects of Se supplementation, according to various endpoints. Too much Se is as harmful as too little, with animal models showing a "U"-shaped efficacy curve. Current recommended daily allowances differ among countries, but are generally based on the amount of Se necessary to saturate GPx enzymes. However, increasing evidence suggests that other enzymes may be more important than GPx for Se action, that optimal levels may depend upon the form of Se being ingested, and vary according to genotype. New paradigms, possibly involving nutrigenomic tools, will be necessary to optimise the forms and levels of Se desirable for maximum protection of genomic stability in all humans.

  3. 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.

  4. 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

  5. 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

  6. 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

  7. Inhibiting Mycobacterium tuberculosis within and without.

    Science.gov (United States)

    Cole, Stewart T

    2016-11-01

    Tuberculosis remains a scourge of global health with shrinking treatment options due to the spread of drug-resistant strains of Mycobacterium tuberculosis Intensive efforts have been made in the past 15 years to find leads for drug development so that better, more potent drugs inhibiting new targets could be produced and thus shorten treatment duration. Initial attempts focused on repurposing drugs that had been developed for other therapeutic areas but these agents did not meet their goals in clinical trials. Attempts to find new lead compounds employing target-based screens were unsuccessful as the leads were inactive against M. tuberculosis Greater success was achieved using phenotypic screening against live tubercle bacilli and this gave rise to the drugs bedaquiline, pretomanid and delamanid, currently in phase III trials. Subsequent phenotypic screens also uncovered new leads and targets but several of these targets proved to be promiscuous and inhibited by a variety of seemingly unrelated pharmacophores. This setback sparked an interest in alternative screening approaches that mimic the disease state more accurately. Foremost among these were cell-based screens, often involving macrophages, as these should reflect the bacterium's niche in the host more faithfully. A major advantage of this approach is its ability to uncover functions that are central to infection but not necessarily required for growth in vitro For instance, inhibition of virulence functions mediated by the ESX-1 secretion system severely attenuates intracellular M. tuberculosis, preventing intercellular spread and ultimately limiting tissue damage. Cell-based screens have highlighted the druggability of energy production via the electron transport chain and cholesterol metabolism. Here, I review the scientific progress and the pipeline, but warn against over-optimism due to the lack of industrial commitment for tuberculosis drug development and other socio-economic factors.This article is

  8. 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.

  9. 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.

  10. Inhibiting bacterial toxins by channel blockage.

    Science.gov (United States)

    Bezrukov, Sergey M; Nestorovich, Ekaterina M

    2016-03-01

    Emergent rational drug design techniques explore individual properties of target biomolecules, small and macromolecule drug candidates, and the physical forces governing their interactions. In this minireview, we focus on the single-molecule biophysical studies of channel-forming bacterial toxins that suggest new approaches for their inhibition. We discuss several examples of blockage of bacterial pore-forming and AB-type toxins by the tailor-made compounds. In the concluding remarks, the most effective rationally designed pore-blocking antitoxins are compared with the small-molecule inhibitors of ion-selective channels of neurophysiology.

  11. Basis of pyruvate inhibition in Thiobacillus thiooxidans.

    Science.gov (United States)

    Rao, G S; Berger, L R

    1970-05-01

    Addition of 10(-3)m pyruvic acid to cultures of Thiobacillus thiooxidans, at pH 2.3, results in its rapid intracellular accumulation and in the cessation of sulfur oxidation, CO(2) fixation, and oxygen consumption; at pH 7.0, pyruvate neither inhibits oxygen uptake nor accumulates appreciably intracellularly. Pyruvate does not affect CO(2) fixation in cell-free extracts. The data suggest that the cells of T. thiooxidans are passively permeable to pyruvic acid at low pH. Thus entry of pyruvic acid causes accumulation of pyruvate with a concomitant decrease in intracellular pH.

  12. 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].

  13. Thiol-dependent inhibition of RNA synthesis in vitro by acridines: structure-inhibition relationships.

    Science.gov (United States)

    Gniazdowski, M; Szmigiero, L; Wilmańska, D

    1982-01-01

    In the presence of sulfhydryl compounds an anticancer drug, 1-nitro-9-aminoalkylacridine derivative, forms with DNA irreversible, probably covalent, complexes of decreased template properties. Five 9-substituted 1-nitro-9-aminoacridine derivatives of cytostatic activity show irreversible thiol-dependent inhibitory effects on the RNA synthesis in vitro system while equal inhibition is observed both in the presence and in the absence of dithiothreitol with biologically inactive analogues of nitrocrine. In the absence of sulfhydryl compounds the inhibition depends on the planarity of the acridine ring. Hence, both 1-nitro-9-aminoalkylacridine and tetrahydroacridine derivatives show low inhibitory effect. PMID:6174208

  14. Optogenetic and chemogenetic strategies for sustained inhibition of pain

    Science.gov (United States)

    Iyer, Shrivats M.; Vesuna, Sam; Ramakrishnan, Charu; Huynh, Karen; Young, Stephanie; Berndt, Andre; Lee, Soo Yeun; Gorini, Christopher J.; Deisseroth, Karl; Delp, Scott L.

    2016-01-01

    Spatially targeted, genetically-specific strategies for sustained inhibition of nociceptors may help transform pain science and clinical management. Previous optogenetic strategies to inhibit pain have required constant illumination, and chemogenetic approaches in the periphery have not been shown to inhibit pain. Here, we show that the step-function inhibitory channelrhodopsin, SwiChR, can be used to persistently inhibit pain for long periods of time through infrequent transdermally delivered light pulses, reducing required light exposure by >98% and resolving a long-standing limitation in optogenetic inhibition. We demonstrate that the viral expression of the hM4D receptor in small-diameter primary afferent nociceptor enables chemogenetic inhibition of mechanical and thermal nociception thresholds. Finally, we develop optoPAIN, an optogenetic platform to non-invasively assess changes in pain sensitivity, and use this technique to examine pharmacological and chemogenetic inhibition of pain. PMID:27484850

  15. Calcineurin/NFAT signalling inhibits myeloid haematopoiesis.

    Science.gov (United States)

    Fric, Jan; Lim, Clarice X F; Koh, Esther G L; Hofmann, Benjamin; Chen, Jinmiao; Tay, Hock Soon; Mohammad Isa, Siti Aminah Bte; Mortellaro, Alessandra; Ruedl, Christiane; Ricciardi-Castagnoli, Paola

    2012-04-01

    Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signalling can also mediate granulocyte and dendritic cell (DC) activation, but it is unknown whether NFAT influences their development from progenitors. Here, we report a novel role for calcineurin/NFAT signalling as a negative regulator of myeloid haematopoiesis. Reconstituting lethally irradiated mice with haematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells in media supplemented with Flt3-L in the presence of the calcineurin/NFAT inhibitor Cyclosporin A increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. In conclusion, these results provide evidence that calcineurin/NFAT signalling negatively regulates myeloid lineage development. The finding that inhibition of NFAT enhances myeloid development provides a novel insight into understanding how the treatment with drugs targeting calcineurin/NFAT signalling influence the homeostasis of the innate immune system.

  16. 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

  17. 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

  18. Safrole oxide inhibits angiogenesis by inducing apoptosis.

    Science.gov (United States)

    Zhao, Jing; Miao, Junying; Zhao, Baoxiang; Zhang, Shangli; Yin, Deling

    2005-06-01

    Our previous studies indicate that 3, 4-(methylenedioxy)-1-(2', 3'-epoxypropyl)-benzene (safrole oxide), a newly synthesized compound, induces apoptosis in vascular endothelial cells (VECs) and A549 lung cancer cells. To our knowledge, the inhibition of angiogenesis by safrole oxide has not been reported yet. We report here that cultured rat aorta treated with safrole oxide exhibited a significant microvessel reduction as determined by counting the number of microvessels in a phase contrast microscope. There were more microvessels formed in the presence of A549 lung cancer cells in rat aorta model, while a dramatic inhibition of angiogenesis was obtained by adding 220-450 micromol l(-1) of safrole oxide to the growth medium (Psafrole oxide produced only some abortive endothelial cells but not microvessels. Furthermore, safrole oxide induced antiangiogenic effect in the chorioallantoic membranes (CAM) as a dose dependent manner. Eggs treated with 2-11 micromol 100 microl(-1) per egg of the safrole oxide for 48 h exhibited a significant reduction in blood vessel area of the CAM, a process likely mediated by apoptosis as demonstrated by DNA fragmentation. Our results suggest that safrole oxide has antiangiogenic activity and this effect might occur by induction of cellular apoptosis.

  19. Understanding biocatalyst inhibition by carboxylic acids

    Directory of Open Access Journals (Sweden)

    Laura R Jarboe

    2013-09-01

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

  20. 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

  1. 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

  2. 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

  3. GABAergic inhibition in visual cortical plasticity

    Directory of Open Access Journals (Sweden)

    Alessandro Sale

    2010-03-01

    Full Text Available Experience is required for the shaping and refinement of developing neural circuits during well defined periods of early postnatal development called critical periods. Many studies in the visual cortex have shown that intracortical GABAergic circuitry plays a crucial role in defining the time course of the critical period for ocular dominance plasticity. With the end of the critical period, neural plasticity wanes and recovery from the effects of visual defects on visual acuity (amblyopia or binocularity is much reduced or absent. Recent results pointed out that intracortical inhibition is a fundamental limiting factor for adult cortical plasticity and that its reduction by means of different pharmacological and environmental strategies makes it possible to greatly enhance plasticity in the adult visual cortex, promoting ocular dominance plasticity and recovery from amblyopia. Here we focus on the role of intracortical GABAergic circuitry in controlling both developmental and adult cortical plasticity. We shall also discuss the potential clinical application of these findings to neurological disorders in which synaptic plasticity is compromised because of excessive intracortical inhibition.

  4. Transcriptional inhibition by the retinoblastoma protein

    DEFF Research Database (Denmark)

    Fattaey, A; Helin, K; Harlow, E

    1993-01-01

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

  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. Chromosome tips damaged in anaphase inhibit cytokinesis.

    Directory of Open Access Journals (Sweden)

    Norman M Baker

    Full Text Available Genome maintenance is ensured by a variety of biochemical sensors and pathways that repair accumulated damage. During mitosis, the mechanisms that sense and resolve DNA damage remain elusive. Studies have demonstrated that damage accumulated on lagging chromosomes can activate the spindle assembly checkpoint. However, there is little known regarding damage to DNA after anaphase onset. In this study, we demonstrate that laser-induced damage to chromosome tips (presumptive telomeres in anaphase of Potorous tridactylis cells (PtK2 inhibits cytokinesis. In contrast, equivalent irradiation of non-telomeric chromosome regions or control irradiations in either the adjacent cytoplasm or adjacent to chromosome tips near the spindle midzone during anaphase caused no change in the eventual completion of cytokinesis. Damage to only one chromosome tip caused either complete absence of furrow formation, a prolonged delay in furrow formation, or furrow regression. When multiple chromosome tips were irradiated in the same cell, the cytokinesis defects increased, suggesting a potential dose-dependent mechanism. These results suggest a mechanism in which dysfunctional telomeres inhibit mitotic exit.

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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.

  14. Menthol inhibits the perception of warmth.

    Science.gov (United States)

    Green, B G

    1986-01-01

    The effect of l-menthol on the ability to perceive gradual increases in skin temperature was measured in two experiments. Experiment 1 established that suprathreshold sensations of warmth generated on the vermilion border of the lip could be significantly attenuated by exposure to menthol in concentrations of 0.2 and 2.0% (in mineral oil). Experiment 2 demonstrated that exposure to the 2.0% menthol solution caused the threshold for warmth to rise significantly whereas the threshold for heat pain was unchanged. Although masking of sensations of warmth by menthol-induced sensations of cold is discussed as a possible explanation for the results, a direct effect of the menthol molecule on warm receptors (i.e., inhibition or desensitization) is considered a more likely explanation.

  15. 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

  16. 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.

  17. Inhibition of cyclodextrins on α-galactosidase.

    Science.gov (United States)

    Yao, Di; Zhu, Zhenzhou; Cai, Hongyan; Chen, Xuan; Sun, Wei; Barba, Francisco J; Li, Fang; Shen, Wangyang; Ding, Wenping

    2017-02-15

    This work successfully investigated the effects of different influential factors and hydrophobic cavities of cyclodextrins (CDs) on α-galactosidase (α-Gal) by detecting α-Gal activity. The highest inhibitory concentration of three kinds of CDs (α-, β-, and γ-CD) on α-Gal was 10mM. Moreover, the highest inhibition of α-Gal was obtained under the following conditions: reaction time of 90min, temperature of 30°C, and pH 6.0. Compared with other CDs, β-CD showed more ability to interact with α-Gal due to its appropriate cavity geometric dimensions. From circular dichroism and nuclear magnetic resonance it was observed that β-CD changed the secondary structure of α-Gal and formed a hydrogen bond with this enzyme. PMID:27664608

  18. Transcranial magnetic stimulation (TMS) inhibits cortical dendrites.

    Science.gov (United States)

    Murphy, Sean C; Palmer, Lucy M; Nyffeler, Thomas; Müri, René M; Larkum, Matthew E

    2016-03-18

    One of the leading approaches to non-invasively treat a variety of brain disorders is transcranial magnetic stimulation (TMS). However, despite its clinical prevalence, very little is known about the action of TMS at the cellular level let alone what effect it might have at the subcellular level (e.g. dendrites). Here, we examine the effect of single-pulse TMS on dendritic activity in layer 5 pyramidal neurons of the somatosensory cortex using an optical fiber imaging approach. We find that TMS causes GABAB-mediated inhibition of sensory-evoked dendritic Ca(2+) activity. We conclude that TMS directly activates fibers within the upper cortical layers that leads to the activation of dendrite-targeting inhibitory neurons which in turn suppress dendritic Ca(2+) activity. This result implies a specificity of TMS at the dendritic level that could in principle be exploited for investigating these structures non-invasively.

  19. 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

  20. 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

  1. 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.

  2. [Inhibition of aromatics on ammonia-oxidizing activity of sediment].

    Science.gov (United States)

    Dong, Chun-hong; Hu, Hong-ying; Wei, Dong-bin; Huang, Xia; Qian, Yi

    2004-03-01

    The inhibition of 24 aromatics on ammonia-oxidizing activity of nitrifying bacteria in sediment was measured. The effects of the kind, number and position of substituted groups on ammonia-oxidizing activity of nitrifying bacteria were discussed. The inhibition of mono-substituted benzenes on ammonia-oxidizing activity of nitrifying bacteria were in order of -OH > -NO2 > -NH2 > -Cl > -CH3 > -H. The position of substituted groups of di-substituted benzenes also affected the inhibition, and the inhibitions of dimethylbenzenes(xylene) were in order of meta-> ortho-> para-. The increase in number of substituted group on benzene-ring enhanced the inhibition of aromatics studied in this study on nitrifying bacteria. There was a linear relationship between inhibition (IC50, mumol.L-1) of aromatics on ammonia-oxidizing activity and total electronegativity (sigma E) of aromatics: lgIC50 = 14.72 - 0.91 sigma E.

  3. 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.

  4. 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

  5. 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.

  6. 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...

  7. 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...

  8. 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.

  9. Response inhibition in pedophilia: an FMRI pilot study

    OpenAIRE

    Habermeyer, Benedikt; Esposito, Fabrizio; Händel, Nadja; Lemoine, Patrick; Kuhl, Hans Christian; Klarhöfer, Markus; Mager, Ralph; Mokros, Andreas; Dittmann, Volker; Seifritz, Erich; Graf, Marc

    2013-01-01

    Background: The failure to inhibit pleasurable but inappropriate urges is associated with frontal lobe pathology and has been suggested as a possible cause of pedophilic behavior. However, imaging and neuropsychological findings about frontal pathology in pedophilia are heterogeneous. In our study we therefore address inhibition behaviorally and by means of functional imaging, aiming to assess how inhibition in pedophilia is related to a differential recruitment of frontal brain areas. Method...

  10. 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...

  11. 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...

  12. 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...

  13. 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...

  14. Acute inhibition of corticosteroidogenesis by inhibitors of calmodulin action.

    Science.gov (United States)

    Carsia, R V; Moyle, W R; Wolff, D J; Malamed, S

    1982-11-01

    To identify the possible role of calmodulin in ACTH function, we tested the ability of chlorpromazine (CP) and other calmodulin antagonists to inhibit steroidogenesis of isolated adrenocortical cells of the rat. CP reversibly inhibited maximal ACTH-induced corticosterone (B) production. The presence of the drug did not alter the ED50 of ACTH stimulation (3.2 X 10(3) pg/ml), suggesting that it inhibited ACTH-induced steroidogenesis in a noncompetitive manner. The CP concentration required for half-maximal inhibition was 8.2 microM, a value close to the dissociation constant of the CP-calmodulin complex (5.3 microM). Concentrations greater than 40 microM resulted in complete inhibition. Similar concentrations of CP inhibited ACTH-induced cAMP accumulation in a dose-dependent manner, indicating an effect of the drug on early events in ACTH action. In addition, CP also apparently acted at a site distal to the point of cAMP formation, as shown by the finding that it inhibited cAMP-induced B production. CP inhibition of ACTH-induced B production was independent of the Ca2+ concentration, suggesting that the drug did not compete with Ca2+ directly. Concentrations of CP greater than 20 microM inhibited protein synthesis as measured by leucine incorporation into cellular proteins. Thus, although the inhibitory effect of high concentrations of CP on steroidogenesis might be explained by an effect on protein synthesis, the inhibition seen at 10 microM appeared to be independent of protein synthesis. Other antagonists of calmodulin action inhibited maximal ACTH-induced B production with the following relative potencies: trifluoperazine greater than CP greater than haloperidol greater than chlordiazepoxide. This order is similar to that reported for inhibition of calmodulin-activated phosphodiesterase and for binding to calmodulin. These findings suggest that calmodulin may modulate the effect of ACTH on steroidogenesis at multiple sites.

  15. 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.

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

    Science.gov (United States)

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

    2013-11-01

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

  17. 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

  18. Inhibition behavior for copper corrosion by photoelectrochemical methods

    Institute of Scientific and Technical Information of China (English)

    徐群杰; 周国定

    2003-01-01

    The application of photoelectrochemical methods in the inhibition effects for copper corrosion was described. The methods include cyclic voltammetry photocurrent measurements, intensity modulated photocurrent spectrum(IMPS) and laser-scanning photoelectrochemical microscopic method(PEM) which have been applied to the evaluation of inhibitors and inhibition behavior. The inhibition effect of BTA for copper corrosion is better than that of 4CBTA, 5CBTA, CBT-1, PTD, BT-250, CBTME and CBTBE at the same concentration. The inhibition mechanism of the derivatives of BTA with-COOH group(4CBTA, 5CBTA, CBT-1) is different from those with estergroup(CBTME, CBTBE).

  19. 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...... and biofouling inhibiting mechanism of these surfaces. In this study, the evidence is presented that the inhibiting effect can be caused by the electrochemical interactions and/or electric field between Pd and Ag/AgCl combined with an organic environment....

  20. Schedule of Punishment and Inhibition of Aggression in Children

    Science.gov (United States)

    Parke, Ross D.; Deur, Jan L.

    1972-01-01

    Data showed that consistent punishment resulted in faster inhibition than inconsistent punishment; subjects who were punished showed less persistence than subjects placed on an extinction schedule. (Authors)

  1. 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...

  2. 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...

  3. 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...

  4. 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...

  5. Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis

    Directory of Open Access Journals (Sweden)

    Li Q

    2013-07-01

    Full Text Available Qingli Li,1,2 Mark J Lambrechts,1 Qiuyang Zhang,1 Sen Liu,1 Dongxia Ge,1 Rutie Yin,2 Mingrong Xi,2 Zongbing You1 1Departments of Structural and Cellular Biology and Orthopaedic Surgery, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, and Tulane Center for Aging, Tulane University Health Sciences Center, New Orleans, LA, USA; 2Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA, are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy. Keywords: serine hydroxymethyltransferase, prostate cancer, apoptosis

  6. Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF-κB activation.

    Science.gov (United States)

    Ma, Jianqun; Xu, Hai; Wu, Jun; Qu, Changfa; Sun, Fenglin; Xu, Shidong

    2015-12-01

    Linalool, a natural compound that exists in the essential oils of several aromatic plants species, has been reported to have anti-inflammatory effects. However, the effects of linalool on cigarette smoke (CS)-induced acute lung inflammation have not been reported. In the present study, we investigated the protective effects of linalool on CS-induced acute lung inflammation in mice. Linalool was given i.p. to mice 2h before CS exposure daily for five consecutive days. The numbers of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF) were measured. The production of TNF-α, IL-6, IL-1β, IL-8 and MCP-1 were detected by ELISA. The expression of NF-κB was detected by Western blotting. Our results showed that treatment of linalool significantly attenuated CS-induced lung inflammation, coupled with inhibited the infiltration of inflammatory cells and TNF-α, IL-6, IL-1β, IL-8 and MCP-1 production. Meanwhile, treatment of linalool inhibited CS-induced lung MPO activity and pathological changes. Furthermore, linalool suppressed CS-induced NF-κB activation in a dose-dependent manner. In conclusion, our results demonstrated that linalool protected against CS-induced lung inflammation through inhibiting CS-induced NF-κB activation.

  7. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration.

    Science.gov (United States)

    Detaille, D; Vial, G; Borel, A-L; Cottet-Rouselle, C; Hallakou-Bozec, S; Bolze, S; Fouqueray, P; Fontaine, E

    2016-01-01

    Imeglimin is the first in a new class of oral glucose-lowering agents, having recently completed its phase 2b trial. As Imeglimin did show a full prevention of β-cell apoptosis, and since angiopathy represents a major complication of diabetes, we studied Imeglimin protective effects on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments (exposure to high glucose and oxidizing agent tert-butylhydroperoxide) which led to mitochondrial permeability transition pore (PTP) opening, cytochrome c release and cell death. These events were fully prevented by Imeglimin treatment. This protective effect on cell death occurred without any effect on oxygen consumption rate, on lactate production and on cytosolic redox or phosphate potentials. Imeglimin also dramatically decreased reactive oxygen species production, inhibiting specifically reverse electron transfer through complex I. We conclude that Imeglimin prevents hyperglycemia-induced cell death in HMEC-1 through inhibition of PTP opening without inhibiting mitochondrial respiration nor affecting cellular energy status. Considering the high prevalence of macrovascular and microvascular complications in type 2 diabetic subjects, these results together suggest a potential benefit of Imeglimin in diabetic angiopathy. PMID:27551496

  8. 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 ...

  9. Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells

    Institute of Scientific and Technical Information of China (English)

    Peng-fei GE; Ji-zhou ZHANG; Xiao-fei WANG; Fan-kai MENG; Wen-chen LI; Yong-xin LUAN; Feng LING; Yi-nan LUO

    2009-01-01

    Aim:The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation.Recent studies suggest that proteasome inhibitors may reduce tumor growth and activate autophagy.Due to the dual roles of autophagy in tumor cell survival and death,the effect of autophagy on the destiny of glioma cells remains unclear.In this study,we sought to investigate whether inhibition of the proteasome can induce autophagy and the effects of autophagy on the fate of human SHG-44 glioma cells.Methods:The proteasome inhibitor MG-132 was used to induce autophagy in SHG-44 glioma cells,and the effect of autophagy on the survival of SHG-44 glioma cells was investigated using an autophagy inhibitor 3-MA.Cell viability was measured by MTT assay.Apoptosis and cell cycle were detected by flow cytometry.The expression of autophagy related proteins was determined by Western blot.Results:MG-132 inhibited cell proliferation,induced cell death and cell cycle arrest at G~JM phase,and activated autophagy in SHG-44 glioma cells.The expression of autophagy-related Beclin-1 and LC3-1 was significantly up-regulated and part of LC3-1 was converted into LC3-11.However,when SHG-44 glioma cells were co-treated with MG-132 and 3-MA,the cells became less viable,but cell death and cell numbers at G2/M phase increased.Moreover,the accumulation of acidic vesicular organelles was decreased,the expression of Beclin-1 and LC3 was significantly down-regulated and the conversion of LC3-11 from LC3-1 was also inhibited.Conclusion:Inhibition of the proteasome can induce autophagy in human SHG-44 glioma cells,and inhibition of autophagy increases cell death.This discovery may shed new light on the effect of autophagy on modulating the fate of SHG-44 glioma cells.

  10. Pharmacologic inhibition of lactate production prevents myofibroblast differentiation.

    Science.gov (United States)

    Kottmann, Robert Matthew; Trawick, Emma; Judge, Jennifer L; Wahl, Lindsay A; Epa, Amali P; Owens, Kristina M; Thatcher, Thomas H; Phipps, Richard P; Sime, Patricia J

    2015-12-01

    Myofibroblasts are one of the primary cell types responsible for the accumulation of extracellular matrix in fibrosing diseases, and targeting myofibroblast differentiation is an important therapeutic strategy for the treatment of pulmonary fibrosis. Transforming growth factor-β (TGF-β) has been shown to be an important inducer of myofibroblast differentiation. We previously demonstrated that lactate dehydrogenase and its metabolic product lactic acid are important mediators of myofibroblast differentiation, via acid-induced activation of latent TGF-β. Here we explore whether pharmacologic inhibition of LDH activity can prevent TGF-β-induced myofibroblast differentiation. Primary human lung fibroblasts from healthy patients and those with pulmonary fibrosis were treated with TGF-β and or gossypol, an LDH inhibitor. Protein and RNA were analyzed for markers of myofibroblast differentiation and extracellular matrix generation. Gossypol inhibited TGF-β-induced expression of the myofibroblast marker α-smooth muscle actin (α-SMA) in a dose-dependent manner in both healthy and fibrotic human lung fibroblasts. Gossypol also inhibited expression of collagen 1, collagen 3, and fibronectin. Gossypol inhibited LDH activity, the generation of extracellular lactic acid, and the rate of extracellular acidification in a dose-dependent manner. Furthermore, gossypol inhibited TGF-β bioactivity in a dose-dependent manner. Concurrent treatment with an LDH siRNA increased the ability of gossypol to inhibit TGF-β-induced myofibroblast differentiation. Gossypol inhibits TGF-β-induced myofibroblast differentiation through inhibition of LDH, inhibition of extracellular accumulation of lactic acid, and inhibition of TGF-β bioactivity. These data support the hypothesis that pharmacologic inhibition of LDH may play an important role in the treatment of pulmonary fibrosis.

  11. 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

  12. Inhibition of Complement Retards Ankylosing Spondylitis Progression

    Science.gov (United States)

    Yang, Chaoqun; Ding, Peipei; Wang, Qingkai; Zhang, Long; Zhang, Xin; Zhao, Jianquan; Xu, Enjie; Wang, Na; Chen, Jianfeng; Yang, Guang; Hu, Weiguo; Zhou, Xuhui

    2016-01-01

    Ankylosing spondylitis (AS) is a chronic axial spondyloarthritis (SpA) resulting in back pain and progressive spinal ankyloses. Currently, there are no effective therapeutics targeting AS largely due to elusive pathogenesis mechanisms, even as potential candidates such as HLA-B27 autoantigen have been identified. Herein, we employed a proteoglycan (PG)-induced AS mouse model together with clinical specimens, and found that the complement system was substantially activated in the spinal bone marrow, accompanied by a remarkable proportion alteration of neutrophils and macrophage in bone marrow and spleen, and by the significant increase of TGF-β1 in serum. The combined treatment with a bacteria-derived complement inhibitor Efb-C (C-terminal of extracellular fibrinogen-binding protein of Staphylococcus aureus) remarkably retarded the progression of mouse AS by reducing osteoblast differentiation. Furthermore, we demonstrated that two important modulators involved in AS disease, TGF-β1 and RANKL, were elevated upon in vitro complement attack in osteoblast and/or osteoclast cells. These findings further unravel that complement activation is closely related with the pathogenesis of AS, and suggest that complement inhibition may hold great potential for AS therapy. PMID:27698377

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. Aspirin, cyclooxygenase inhibition and colorectal cancer.

    Science.gov (United States)

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

    2014-02-01

    Colorectal cancer (CRC) is the third most common type of cancer worldwide. Screening measures are far from adequate and not widely available in resource-poor 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 a limited and rapidly reversible inhibitory effect on COX-2 and/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.

  20. 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.

  1. 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.

  2. 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)

  3. 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.

  4. Inhibition of foodborne pathogens by pomegranate juice.

    Science.gov (United States)

    Haghayeghi, Koorosh; Shetty, Kalidas; Labbé, Ronald

    2013-05-01

    Pomegranates have health-promoting benefits because of their polyphenol constituents. Previous studies have demonstrated the antimicrobial activity of aqueous and organic extracts of pomegranate components and by-products. We sought to determine the antimicrobial activity against 40 foodborne pathogens representing eight bacterial species using juice itself. In addition, we sought to determine the synergistic antimicrobial activity between pomegranate juice and other plant products displaying antimicrobial activity. The antimicrobial activity of pomegranate juice was dependent on the test organism, which varied to highly susceptible (four Gram-positive species) to unaffected (Salmonella and Escherichia coli O157:H7). Two Gram-negative species, which were inhibited were Helicobacter pylori and Vibrio parahemolyticus. No synergistic antimicrobial activity was seen between pomegranate and either barberry, oregano, or cranberry. The antimicrobial activity of pomegranate juice is dependent on the test organism and extraction method. The sensitivity of H. pylori suggests that pomegranate juice may be an alternative or supplemental treatment for gastric ulcers caused by this organism.

  5. Decoupled echo state networks with lateral inhibition.

    Science.gov (United States)

    Xue, Yanbo; Yang, Le; Haykin, Simon

    2007-04-01

    Building on some prior work, in this paper we describe a novel structure termed the decoupled echo state network (DESN) involving the use of lateral inhibition. Two low-complexity implementation schemes, namely, the DESN with reservoir prediction (DESN + RP) and DESN with maximum available information (DESN + MaxInfo), are developed: (1) In the multiple superimposed oscillator (MSO) problem, DESN + MaxInfo exhibits three important attributes: lower generalization mean-square error (MSE), better robustness with respect to the random generation of reservoir weight matrix and feedback connections, and robustness to variations in the sparseness of reservoir weight matrix, compared to DESN + RP. (2) For a noiseless nonlinear prediction task, DESN + RP outperforms the DESN + MaxInfo and single reservoir-based ESN approach in terms of lower prediction MSE and better robustness to a change in the number of inputs and sparsity of the reservoir weight matrix. Finally, in a real-life prediction task using noisy sea clutter data, both schemes exhibit higher prediction accuracy and successful design ratio than a conventional ESN with a single reservoir.

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

    Science.gov (United States)

    George, Tim; Wiley, Jennifer

    2016-01-01

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

  7. 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

  8. Underlying Personality Characteristics of Behavioral Inhibition in Children

    Science.gov (United States)

    Muris, Peter; Dietvorst, Roeland

    2006-01-01

    Behavioral inhibition refers to the tendency of children to be unusually shy and to react with fear and withdrawal in situations that are novel and/or unfamiliar, and is generally regarded as a vulnerability factor for developing anxiety disorders. The present study investigated the hypothesis that behavioral inhibition is characterized by a…

  9. 46 CFR 153.912 - Certificate of inhibition or stabilization.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 5 2010-10-01 2010-10-01 false Certificate of inhibition or stabilization. 153.912 Section 153.912 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CERTAIN BULK DANGEROUS... Documents and Cargo Information § 153.912 Certificate of inhibition or stabilization. (a) When a cargo...

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

    NARCIS (Netherlands)

    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

  11. 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

  12. 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…

  13. 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…

  14. 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…

  15. 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…

  16. The Root-inhibiting Substance of Allium Cepa

    NARCIS (Netherlands)

    Stolk, Anth.

    1953-01-01

    Whereas scientific research on inhibiting substances has mainly occupied itself with the effect of these substances on the germination process, I was able to demonstrate the presence of a root-inhibiting agent during my studies on root formation in Fuchsia hybrida and Pelargonium zonale (Stolk, 1952

  17. The Inhibition of Pretend Play and Its Implications for Development.

    Science.gov (United States)

    Gordon, Debra E.

    1993-01-01

    Describes four kinds of pretend play inhibition observed in children from three to nine years of age. Proposes hypotheses regarding potential causes and developmental sequelae of pretend play difficulties, in both cognitive and socioaffective realms. Discusses the implications of children's pretend play inhibition for examining relationships…

  18. 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

  19. 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....

  20. 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...

  1. 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.

  2. . Psychological predictors of inhibition development in educational environments

    Directory of Open Access Journals (Sweden)

    Symanyuk, Elvira E.

    2016-09-01

    Full Text Available This article examines psychological predictors of inhibition in educational environments as well as various aspects of pedagogical communication, including facilitation, which is aimed at enhancing educational effectiveness and developing students by means of using a particular communication style and the teacher’s personality. The need to study inhibition (the deterioration of teacher-children interactions; the negation of a student’s individuality; the inability to understand and accept students’ viewpoints; teacher-provoked conflicts; and emotional callousness is substantiated. The essence of psychological predictors as independent variables, changes in which lead to changes in other dependent variables, allowing the prediction of inhibition development, is explained. The research objective was to identify psychological predictors of the development of inhibition in pedagogical communication. An empirical study was conducted using standardized techniques for diagnosing communicative attitudes (V. Boyko, developing general communicative tolerance (V. Boyko, identifying aggressiveness (A. Asinger, identifying the level of empathy (V. Boyko, and identifying the degree of pedagogical inhibition (L. Polosova. The sample contained 375 teachers from Yekaterinburg educational institutions, with participant selection made using stratified sampling. The teacher’s personality features (a negative communicative attitude, low communicative tolerance and empathy, and higher levels of aggression were shown to be key predictors of inhibition, which itself was found to depend on the length of teaching experience. At the beginning of one’s professional teaching career, the level of inhibition is minimal. However, the level of inhibition reaches its maximum level after 5-10 years of teaching, and after 20 years, there is a sharp decrease in the level of inhibition. The conclusion of this study stresses the importance of developing strategies to

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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…

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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.

  14. Neural correlates of central inhibition during physical fatigue.

    Directory of Open Access Journals (Sweden)

    Masaaki Tanaka

    Full Text Available Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG. Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs in the posterior cingulated cortex (PCC, with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue.

  15. Malonate inhibits virulence gene expression in Vibrio cholerae.

    Science.gov (United States)

    Minato, Yusuke; Fassio, Sara R; Häse, Claudia C

    2013-01-01

    We previously found that inhibition of the TCA cycle, either through mutations or chemical inhibition, increased toxT transcription in Vibrio cholerae. In this study, we found that the addition of malonate, an inhibitor of succinate dehydrogenase (SDH), decreased toxT transcription in V. cholerae, an observation inconsistent with the previous pattern observed. Unlike another SDH inhibitor, 2-thenoyltrifluoroacetone (TTFA), which increased toxT transcription and slightly inhibited V. cholerae growth, malonate inhibited toxT transcription in both the wild-type strain and TCA cycle mutants, suggesting malonate-mediated inhibition of virulence gene expression is independent to TCA cycle activity. Addition of malonate also inhibited ctxB and tcpA expressions but did not affect aphA, aphB, tcpP and toxR expressions. Malonate inhibited cholera toxin (CT) production in both V. cholerae classical biotype strains O395N1 and CA401, and El Tor biotype strain, N16961. Consistent with previous reports, we confirmed that these strains of V. cholerae did not utilize malonate as a primary carbon source. However, we found that the addition of malonate to the growth medium stimulated V. cholerae growth. All together, these results suggest that metabolizing malonate as a nutrient source negatively affects virulence gene expression in V. cholerae.

  16. Methylene Blue Inhibits Caspases by Oxidation of the Catalytic Cysteine.

    Science.gov (United States)

    Pakavathkumar, Prateep; Sharma, Gyanesh; Kaushal, Vikas; Foveau, Bénédicte; LeBlanc, Andrea C

    2015-09-24

    Methylene blue, currently in phase 3 clinical trials against Alzheimer Disease, disaggregates the Tau protein of neurofibrillary tangles by oxidizing specific cysteine residues. Here, we investigated if methylene blue can inhibit caspases via the oxidation of their active site cysteine. Methylene blue, and derivatives, azure A and azure B competitively inhibited recombinant Caspase-6 (Casp6), and inhibited Casp6 activity in transfected human colon carcinoma cells and in serum-deprived primary human neuron cultures. Methylene blue also inhibited recombinant Casp1 and Casp3. Furthermore, methylene blue inhibited Casp3 activity in an acute mouse model of liver toxicity. Mass spectrometry confirmed methylene blue and azure B oxidation of the catalytic Cys163 cysteine of Casp6. Together, these results show a novel inhibitory mechanism of caspases via sulfenation of the active site cysteine. These results indicate that methylene blue or its derivatives could (1) have an additional effect against Alzheimer Disease by inhibiting brain caspase activity, (2) be used as a drug to prevent caspase activation in other conditions, and (3) predispose chronically treated individuals to cancer via the inhibition of caspases.

  17. Influence of supraliminal reward information on unconsciously triggered response inhibition.

    Science.gov (United States)

    Diao, Liuting; Ding, Cody; Qi, Senqing; Zeng, Qinghong; Huang, Bo; Xu, Mengsi; Fan, Lingxia; Yang, Dong

    2014-01-01

    Although executive functions (e.g., response inhibition) are often thought to interact consciously with reward, recent studies have demonstrated that they can also be triggered by unconscious stimuli. Further research has suggested a close relationship between consciously and unconsciously triggered response inhibition. To date, however, the effect of reward on unconsciously triggered response inhibition has not been explored. To address this issue, participants in this study performed runs of a modified Go/No-Go task during which they were exposed to both high and low value monetary rewards presented both supraliminally and subliminally. Participants were informed that they would earn the reward displayed if they responded correctly to each trial of the run. According to the results, when rewards were presented supraliminally, a greater unconsciously triggered response inhibition was observed for high-value rewards than for low-value rewards. In contrast, when rewards were presented subliminally, no enhanced unconsciously triggered response inhibition was observed. Results revealed that supraliminal and subliminal rewards have distinct effects on unconsciously triggered response inhibition. These findings have important implications for extending our understanding of the relationship between reward and response inhibition. PMID:25268227

  18. 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

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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...

  4. Irreversible inhibition of RANK expression as a possible mechanism for IL-3 inhibition of RANKL-induced osteoclastogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Khapli, Shruti M.; Tomar, Geetanjali B.; Barhanpurkar, Amruta P.; Gupta, Navita; Yogesha, S.D.; Pote, Satish T. [National Center for Cell Science, University of Pune Campus, Pune 411 007 (India); Wani, Mohan R., E-mail: mohanwani@nccs.res.in [National Center for Cell Science, University of Pune Campus, Pune 411 007 (India)

    2010-09-03

    Research highlights: {yields} IL-3 inhibits receptor activator of NF-{kappa}B ligand (RANKL)-induced osteoclastogenesis. {yields} IL-3 inhibits RANKL-induced JNK activation. {yields} IL-3 down-regulates expression of c-Fos and NFATc1 transcription factors. {yields} IL-3 down-regulates RANK expression posttranscriptionally and irreversibly. {yields} IL-3 inhibits in vivo RANK expression. -- Abstract: IL-3, a cytokine secreted by activated T lymphocytes, stimulates the proliferation, differentiation and survival of pluripotent hematopoietic stem cells. In this study, we investigated the mechanism of inhibitory action of IL-3 on osteoclast differentiation. We show here that IL-3 significantly inhibits receptor activator of NF-{kappa}B (RANK) ligand (RANKL)-induced activation of c-Jun N-terminal kinase (JNK). IL-3 down-regulates expression of c-Fos and nuclear factor of activated T cells (NFATc1) transcription factors. In addition, IL-3 down-regulates RANK expression posttranscriptionally in both purified osteoclast precursors and whole bone marrow cells. Furthermore, the inhibitory effect of IL-3 on RANK expression was irreversible. Interestingly, IL-3 inhibits in vivo RANK expression in mice. Thus, we provide the first evidence that IL-3 irreversibly inhibits RANK expression that results in inhibition of important signaling molecules induced by RANKL.

  5. MK615 inhibits pancreatic cancer cell growth by dual inhibition of Aurora A and B kinases

    Institute of Scientific and Technical Information of China (English)

    Toshie Okada; Tokihiko Sawada; Tatsushi Osawa; Masakazu Adachi; Keiichi Kubota

    2008-01-01

    AIM:To investigate the anti-neoplastic effect of MK615,an anti-neoplastic compound isolated from Japanese apricot,against human pancreatic cancer cells in vitro.METHODS:Three human pancreatic cancer cell lines PANC-1,PK-1,and PK45H were cultured with MK615 at concentrations of 600,300,150,and O μg/mL.Growth inhibition was evaluated by cell proliferation assay,and killing activity was determined by lactate dehydrogenase (LDH) assay.Expression of Aurora A and B kinases was detected by real-time polymerase chain reaction (PCR) and Western blotting.Cell cycle stages were evaluated by flow cytometry.RESULTS:The growth inhibitory rates of MK615 at 150,300,and 600 μg/mL were 2.3% ± 0.9%,8.9% ±3.2% and 67.1% ± 8.1% on PANC1 cells,1.3% ± 0.3%,8.7% ± 4.1% and 45.7 ± 7.6% on PK1 cells,and 1.2 ±0.8%,9.1% ± 2.1% and 52.1% ± 5.5% on PK45H cells,respectively (P<0.05).The percentage cytotoxicities of MK615 at 0,150,300,and 600 μg/mL were 19.6% ±1.3%,26.7% ± 1.8%,25.5% ± 0.9% and 26.4% ± 0.9%in PANC1 cells,19.7% ± 1.3%,24.7% ± 0.8%,25.9% ±0.9% and 29.9% ± 1.1% in PK1 cells,and 28.0% ± 0.9%,31.2% ± 0.9%,30.4% ± 1.1% and 35.3 ± 1.0% in PK45H cells,respectively (P<0.05).Real-time PCR and Western blotting showed that MK615 dually inhibited the expression of Aurora A and B kinases.Cell cycle analysis revealed that MK615 increased the population of cells in G2/M phase.CONCLUSION:MK615 exerts an anti-neoplastic effect on human pancreatic cancer cells in vitro by dual inhibition of Aurora A and B kinases.

  6. 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.

  7. 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].

  8. What about inhibition in the Wisconsin Card Sorting Test?

    Science.gov (United States)

    Steinmetz, Jean-Paul; Houssemand, Claude

    2011-05-01

    The commercially available Wisconsin Card Sorting Test (WCST) is one of the most commonly used tests for assessing executive functions within clinical settings. Importantly, however, it remains relatively unclear exactly what processes are assessed by the test. Conceptually, increased perseverative errors in sorting cards are usually related to deficient inhibition processes. Empirically, evidence supporting this conclusion is limited. In a sample of 38 healthy adults we addressed the question to what extent inhibition mechanisms assessed by the go/no-go and the stop-signal paradigm are related to WCST performances. Inhibition-related scores were found to predict non-perseverative errors better than perseverative errors. Consequently we conclude that the non-perseverative errors score reflects processes that are partly dependent on inhibition functions.

  9. Mildiomycin: a nucleoside antibiotic that inhibits protein synthesis.

    Science.gov (United States)

    Feduchi, E; Cosín, M; Carrasco, L

    1985-03-01

    Mildiomycin, a new nucleoside antibiotic, selectively inhibits protein synthesis in HeLa cells, and is less active in the inhibition of RNA or DNA synthesis. An increased inhibition of translation by mildiomycin is observed in cultured HeLa cells when they are permeabilized by encephalomyocarditis virus. This observation suggests that this antibiotic does not easily pass through the cell membrane, as occurs with other nucleoside and aminoglycoside antibiotics. The inhibition of translation is also observed in cell-free systems, such as endogenous protein synthesis in a rabbit reticulocyte lysate or the synthesis of polyphenylalanine directed by poly (U). Finally the mode of action of mildiomycin was investigated and the results suggest that the compound blocks the peptidyl-transferase center.

  10. 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.

  11. 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.

  12. 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.

  13. The neural basis of inhibition in cognitive control.

    Science.gov (United States)

    Aron, Adam R

    2007-06-01

    The concept of "inhibition" is widely used in synaptic, circuit, and systems neuroscience, where it has a clear meaning because it is clearly observable. The concept is also ubiquitous in psychology. One common use is to connote an active/willed process underlying cognitive control. Many authors claim that subjects execute cognitive control over unwanted stimuli, task sets, responses, memories, and emotions by inhibiting them, and that frontal lobe damage induces distractibility, impulsivity, and perseveration because of damage to an inhibitory mechanism. However, with the exception of the motor domain, the notion of an active inhibitory process underlying cognitive control has been heavily challenged. Alternative explanations have been provided that explain cognitive control without recourse to inhibition as concept, mechanism, or theory. This article examines the role that neuroscience can play when examining whether the psychological concept of active inhibition can be meaningfully applied in cognitive control research.

  14. Aging and vigilance: who has the inhibition deficit?

    Science.gov (United States)

    Brache, Kristina; Scialfa, Charles; Hudson, Carl

    2010-04-01

    The present study compared 18 younger (M = 21.00 years) and 17 older adults (M = 64.29 years) in a modified vigilance task that required the inhibition of a routinized response. The task was a 50-min simulation of industrial inspection, wherein observers were presented with simple displays labeled "good" and "bad" parts. General linear modeling indicated that younger adults showed a doubling of inhibition failures over time (from 19% to 43%); older adults' inhibition failures held constant at approximately 17.5%. In both age groups, those who responded most quickly were also most error-prone. A control experiment, using the traditional vigilance task requiring a response to infrequent "bad" parts, found only small age differences in accuracy and these also favored older adults. This research suggests that younger adults may demonstrate larger inhibition failures when the routinized responses on simple tasks must be suppressed. There are several implications for theory, industrial design, and cognitive assessment.

  15. 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

  16. 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

  17. 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…

  18. Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Yoon Sun; Jung, Hye Jin [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Seok, Seung Hyeok [Department of Microbiology and Immunology, Institute for Experimental Animals, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Payumo, Alexander Y.; Chen, James K. [Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305 (United States); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2013-04-19

    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.

  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. Motivating inhibition - reward prospect speeds up response cancellation.

    Science.gov (United States)

    Boehler, Carsten N; Hopf, Jens-Max; Stoppel, Christian M; Krebs, Ruth M

    2012-12-01

    Reward prospect has been demonstrated to facilitate various cognitive and behavioral operations, particularly by enhancing the speed and vigor of processes linked to approaching reward. Studies in this domain typically employed task regimes in which participants' overt responses are facilitated by prospective rewards. In contrast, we demonstrate here that even the cancellation of a motor response can be accelerated by reward prospect, thus signifying reward-related benefits on restraint rather than approach behavior. Importantly, this facilitation occurred independent of strategy-related adjustments of response speed, which are known to systematically distort the estimation of response-cancellation speed. The fact that motivational factors can indeed facilitate response inhibition is not only relevant for understanding how motivation and response inhibition interact in healthy participants but also for work on various patient groups that display response-inhibition deficits, suggesting that core differences in the ability to inhibit motor responses have to be differentiated from motivational factors.

  1. 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

  2. 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

  3. Electrochemical impedance spectroscopy study on corrosion inhibition of benzyltriethylammonium chloride

    Science.gov (United States)

    Idris, Mohd Nazri; Daud, Abdul Razak; Othman, Norinsan Kamil

    2013-11-01

    Electrochemical Impedance Spectroscopy (EIS) was employed to study the corrosion inhibition behavior of benzyltriethylammonium chloride (BTC) for carbon steel corrosion. The inhibition efficiency was investigated in 1.0 M HCl solution at room temperature (25°C) by varying the BTC concentration. EIS results indicated that the double layer capacitance of electrolyte/carbon steel interface decreases with the increasing of BTC concentration and consequently enhances the polarization resistance of equivalence Randles circuit. The results indicated that inhibition efficiency of as high as 65% could be achieved when 10mM BTC was present in 1.0 M HCl solution as compared to inhibitor-free solution. The inhibition process of BTC on the carbon steel corrosion was found to obey Langmuir adsorption isotherm. This study revealed that BTC is suitable to be used as a corrosion inhibitor in acid media.

  4. 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...

  5. 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...

  6. 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...

  7. 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...

  8. 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

  9. 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...

  10. 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 ...

  11. 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...

  12. 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...

  13. Novel antimicrobial peptides that inhibit gram positive bacterial exotoxin synthesis.

    Directory of Open Access Journals (Sweden)

    Joseph A Merriman

    Full Text Available Gram-positive bacteria, such as Staphylococcus aureus, cause serious human illnesses through combinations of surface virulence factors and secretion of exotoxins. Our prior studies using the protein synthesis inhibitor clindamycin and signal transduction inhibitors glycerol monolaurate and α-globin and β-globin chains of hemoglobin indicate that their abilities to inhibit exotoxin production by S. aureus are separable from abilities to inhibit growth of the organism. Additionally, our previous studies suggest that inhibition of exotoxin production, in absence of ability to kill S. aureus and normal flora lactobacilli, will prevent colonization by pathogenic S. aureus, while not interfering with lactobacilli colonization. These disparate activities may be important in development of novel anti-infective agents that do not alter normal flora. We initiated studies to explore the exotoxin-synthesis-inhibition activity of hemoglobin peptides further to develop potential agents to prevent S. aureus infections. We tested synthesized α-globin chain peptides, synthetic variants of α-globin chain peptides, and two human defensins for ability to inhibit exotoxin production without significantly inhibiting S. aureus growth. All of these peptides were weakly or not inhibitory to bacterial growth. However, the peptides were inhibitory to exotoxin production with increasing activity dependent on increasing numbers of positively-charged amino acids. Additionally, the peptides could be immobilized on agarose beads or have amino acid sequences scrambled and still retain exotoxin-synthesis-inhibition. The peptides are not toxic to human vaginal epithelial cells and do not inhibit growth of normal flora L. crispatus. These peptides may interfere with plasma membrane signal transduction in S. aureus due to their positive charges.

  14. 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...

  15. 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 ...

  16. 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 ...

  17. 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...

  18. 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...

  19. 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...

  20. 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.

  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. 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

  3. 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.

  4. Glycine transporter-1 inhibition preceding extinction training inhibits reacquisition of cocaine seeking.

    Science.gov (United States)

    Achat-Mendes, Cindy; Nic Dhonnchadha, Bríd Á; Platt, Donna M; Kantak, Kathleen M; Spealman, Roger D

    2012-12-01

    Cognitive enhancers that act by increasing glycine transmission might be useful adjuncts to cocaine-cue extinction training to deter relapse. The study investigated the effects of combining treatments of the glycine transporter-1 (GlyT-1) inhibitor, Org24598, with extinction training on the subsequent reacquisition of cocaine self-administration. Squirrel monkeys and rats were trained to self-administer cocaine under a second-order schedule of intravenous drug injection in which responding was maintained by cocaine injections and a cocaine-paired visual stimulus. During three weekly extinction sessions, saline was substituted for cocaine but responding still produced the cocaine-paired stimulus. Subjects were treated with Org24598 or vehicle, either before or after each extinction session. One week later, cocaine injections were restored, and reacquisition of cocaine self-administration was evaluated over 15 sessions. Compared with vehicle, administration of Org24598 (1.0 mg/kg in monkeys; 3.0 or 7.5 mg/kg in rats) before each extinction session significantly inhibited reacquisition of cocaine self-administration in each species. In contrast, administration of Org24598 (1.0 mg/kg in monkeys) following, rather than preceding, each extinction session did not affect reacquisition compared with vehicle. When extinction training was replaced by cocaine self-administration or abstinence control conditions, treatment with the same doses of Org24598 resulted in reacquisition that was significantly more rapid than the reacquisition observed when Org24598 was administered before extinction training sessions. The results support the potential clinical utility of GlyT-1 inhibitor pretreatments combined with cocaine-cue extinction training to inhibit relapse.

  5. 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.

  6. Inhibition of Bacillus subtilis growth and sporulation by threonine.

    Science.gov (United States)

    Lamb, D H; Bott, K F

    1979-01-01

    A 1-mg/ml amount of threonine (8.4 mM) inhibited growth and sporulation of Bacillus subtilis 168. Inhibition of sporulation was efficiently reversed by valine and less efficiently by pyruvate, arginine, glutamine, and isoleucine. Inhibition of vegetative growth was reversed by asparate and glutamate as well as by valine, arginine, or glutamine. Cells in minimal growth medium were inhibited only transiently by very high concentrations of threonine, whereas inhibition of sporulation was permanent. Addition of threonine prevented the normal increase in alkaline phosphatase and reduced the production of extracellular protease by about 50%, suggesting that threonine blocked the sporulation process relatively early. 2-Ketobutyrate was able to mimic the effect of threonine on sporulation. Sporulation in a strain selected for resistance to azaleucine was partially resistant. Seventy-five percent of the mutants selected for the ability to grow vegetatively in the presence of high threonine concentrations were found to be simultaneously isoleucine auxotrophs. In at least one of these mutants, the threonine resistance phenotpye could not be dissociated from the isoleucine requirement by transformation. This mutation was closely linked to a known ilvA mutation (recombination index, 0.16). This strain also had reduced intracellular threonine deaminase activity. These results suggest that threonine inhibits B. subtilis by causing valine starvation.

  7. Unconsciously triggered response inhibition requires an executive setting.

    Science.gov (United States)

    Chiu, Yu-Chin; Aron, Adam R

    2014-02-01

    Much research on response inhibition has focused on a consciously triggered variety (i.e., outright stopping of action). However, recent studies have shown that response inhibition can also be triggered unconsciously. For example, van Gaal, Ridderinkhof, Scholte, and Lamme (2010) showed that an unconscious no-go prime slowed down ongoing behavior, at least when outright stopping was sometimes required (i.e., in an executive setting). Here we replicated that result but also went further by including a condition with no executive setting. Then there was no slowing following a no-go prime. These results support the hypothesis that an executive setting is necessary for unconsciously triggered inhibition. We speculate that this arises from the fact that when the context includes outright stopping, the brain network for response inhibition is primed, and it can be triggered by the unconscious prime. The result has theoretical implications for the distinction between conscious and unconscious response inhibition and also clinical implications for how to train response inhibition so that it is instantiated automatically.

  8. 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.

  9. Palmitoylethanolamide Inhibits Glutamate Release in Rat Cerebrocortical Nerve Terminals

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    Tzu-Yu Lin

    2015-03-01

    Full Text Available The effect of palmitoylethanolamide (PEA, an endogenous fatty acid amide displaying neuroprotective actions, on glutamate release from rat cerebrocortical nerve terminals (synaptosomes was investigated. PEA inhibited the Ca2+-dependent release of glutamate, which was triggered by exposing synaptosomes to the potassium channel blocker 4-aminopyridine. This release inhibition was concentration dependent, associated with a reduction in cytosolic Ca2+ concentration, and not due to a change in synaptosomal membrane potential. The glutamate release-inhibiting effect of PEA was prevented by the Cav2.1 (P/Q-type channel blocker ω-agatoxin IVA or the protein kinase A inhibitor H89, not affected by the intracellular Ca2+ release inhibitors dantrolene and CGP37157, and partially antagonized by the cannabinoid CB1 receptor antagonist AM281. Based on these results, we suggest that PEA exerts its presynaptic inhibition, likely through a reduction in the Ca2+ influx mediated by Cav2.1 (P/Q-type channels, thereby inhibiting the release of glutamate from rat cortical nerve terminals. This release inhibition might be linked to the activation of presynaptic cannabinoid CB1 receptors and the suppression of the protein kinase A pathway.

  10. Targeted Inhibition of Multiple Receptor Tyrosine Kinases in Mesothelioma

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    Wen-Bin Ou

    2011-01-01

    Full Text Available The receptor tyrosine kinases (RTKs epidermal growth factor receptor (EGFR and MET are activated in subsets of mesothelioma, suggesting that these kinases might represent novel therapeutic targets in this notoriously chemotherapy-resistant cancer. However, clinical trials have shown little activity for EGFR inhibitors in mesothelioma. Despite the evidence for RTK activation in mesothelioma pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. Using phospho-RTK and immunoblot assays, we herein demonstrate activation of multiple RTKs (EGFR, MET, AXL, and ERBB3 in individual mesothelioma cell lines but not in normal mesothelioma cells. Inhibition of mesothelioma multi-RTK signaling was accomplished using combinations of RTK direct inhibitors or by inhibition of the RTK chaperone, heat shock protein 90 (HSP90. Multi-RTK inhibition by the HSP90 inhibitor 17-allyloamino-17demethoxygeldanamycin (17-AAG had a substantially greater effect on mesothelioma proliferation and survival compared with inhibition of individual activated RTKs. HSP90 inhibition also suppressed phosphorylation of down-stream signaling intermediates (AKT, mitogen-activated protein kinase, and S6; upregulated the p53, p21, and p27 cell cycle checkpoints; induced G2 phase arrest; induced caspase 3/7 activity; and led to an increase in the sub-G1 apoptotic population. These compelling proapoptotic and antiproliferative responses indicate that HSP90 inhibition warrants clinical evaluation as a novel therapeutic strategy in mesothelioma.

  11. 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

  12. The Inhibition of Lipase and Glucosidase Activities by Acacia Polyphenol

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    Nobutomo Ikarashi

    2011-01-01

    Full Text Available Acacia polyphenol (AP extracted from the bark of the black wattle tree (Acacia mearnsii is rich in unique catechin-like flavan-3-ols, such as robinetinidol and fisetinidol. In an in vitro study, we measured the inhibitory activity of AP on lipase and glucosidase. In addition, we evaluated the effects of AP on absorption of orally administered olive oil, glucose, maltose, sucrose and starch solution in mice. We found that AP concentration-dependently inhibited the activity of lipase, maltase and sucrase with an IC50 of 0.95, 0.22 and 0.60 mg ml−1, respectively. In ICR mice, olive oil was administered orally immediately after oral administration of AP solution, and plasma triglyceride concentration was measured. We found that AP significantly inhibited the rise in plasma triglyceride concentration after olive oil loading. AP also significantly inhibited the rise in plasma glucose concentration after maltose and sucrose loading, and this effect was more potent against maltose. AP also inhibited the rise in plasma glucose concentration after glucose loading and slightly inhibited it after starch loading. Our results suggest that AP inhibits lipase and glucosidase activities, which leads to a reduction in the intestinal absorption of lipids and carbohydrates.

  13. Highly reflective reasoners show no signs of belief inhibition.

    Science.gov (United States)

    Svedholm-Häkkinen, Annika M

    2015-01-01

    The processes underlying individual differences in reasoning performance are not entirely understood. What do people who do well on reasoning tasks where beliefs and logic conflict do differently from other people? Because abundant evidence shows that even poorer reasoners detect these conflicts, it has been suggested that individual differences in reasoning performance arise from inhibition failures later in the reasoning process. The present paper argues that a minority of highly skilled reasoners may deviate from this general reasoning process from an early stage. Two studies investigated signs of belief inhibition using a lexical access paradigm (Study 1) and a negative priming paradigm (Study 2). Study 1 showed that while other people exhibited signs of belief inhibition following a belief-logic conflict, people with the highest disposition for cognitive reflection did not. In Study 2, this finding was replicated and similar results were also obtained when comparing groups with higher and lower general cognitive ability. Two possible explanations are discussed. The reasoners with a highly reflective cognitive style or high general cognitive ability may have engaged and inhibited belief processing but if so, they may have been exceptionally efficient at recovering from it, wherefore no belief inhibition effects were found. An alternative account is that these reasoners started Type 2 processing directly, without first engaging in and then inhibiting belief-based processing. Under either explanation, the results indicate that individual differences in reasoning may partly arise from differences that occur early in the reasoning process.

  14. Cocaine Inhibition of Nicotinic Acetylcholine ReceptorsInfluences Dopamine Release

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    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.

  15. Cocaine inhibition of nicotinic acetylcholine receptors influences dopamine release.

    Science.gov (United States)

    Acevedo-Rodriguez, Alexandra; Zhang, Lifen; Zhou, Fuwen; Gong, Suzhen; Gu, Howard; De Biasi, Mariella; Zhou, Fu-Ming; 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 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. PMID:25237305

  16. Posterior insular cortex is necessary for conditioned inhibition of fear.

    Science.gov (United States)

    Foilb, Allison R; Flyer-Adams, Johanna G; Maier, Steven F; Christianson, John P

    2016-10-01

    Veridical detection of safety versus danger is critical to survival. Learned signals for safety inhibit fear, and so when presented, reduce fear responses produced by danger signals. This phenomenon is termed conditioned inhibition of fear. Here, we report that CS+/CS- fear discrimination conditioning over 5 days in rats leads the CS- to become a conditioned inhibitor of fear, as measured by the classic tests of conditioned inhibition: summation and retardation of subsequent fear acquisition. We then show that NMDA-receptor antagonist AP5 injected to posterior insular cortex (IC) before training completely prevented the acquisition of a conditioned fear inhibitor, while intra-AP5 to anterior and medial IC had no effect. To determine if the IC contributes to the recall of learned fear inhibition, injections of the GABAA agonist muscimol were made to posterior IC before a summation test. This resulted in fear inhibition per se, which obscured inference to the effect of IC inactivation with recall of the safety cue. Control experiments sought to determine if the role of the IC in conditioned inhibition learning could be reduced to simpler fear discrimination function, but fear discrimination and recall were unaffected by AP5 or muscimol, respectively, in the posterior IC. These data implicate a role of posterior IC in the learning of conditioned fear inhibitors.

  17. 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:

  18. Allosteric Inhibition of Factor XIIIa. Non-Saccharide Glycosaminoglycan Mimetics, but Not Glycosaminoglycans, Exhibit Promising Inhibition Profile.

    Science.gov (United States)

    Al-Horani, Rami A; Karuturi, Rajesh; Lee, Michael; Afosah, Daniel K; Desai, Umesh R

    2016-01-01

    Factor XIIIa (FXIIIa) is a transglutaminase that catalyzes the last step in the coagulation process. Orthostery is the only approach that has been exploited to design FXIIIa inhibitors. Yet, allosteric inhibition of FXIIIa is a paradigm that may offer a key advantage of controlled inhibition over orthosteric inhibition. Such an approach is likely to lead to novel FXIIIa inhibitors that do not carry bleeding risks. We reasoned that targeting a collection of basic amino acid residues distant from FXIIIa's active site by using sulfated glycosaminoglycans (GAGs) or non-saccharide GAG mimetics (NSGMs) would lead to the discovery of the first allosteric FXIIIa inhibitors. We tested a library of 22 variably sulfated GAGs and NSGMs against human FXIIIa to discover promising hits. Interestingly, although some GAGs bound to FXIIIa better than NSGMs, no GAG displayed any inhibition. An undecasulfated quercetin analog was found to inhibit FXIIIa with reasonable potency (efficacy of 98%). Michaelis-Menten kinetic studies revealed an allosteric mechanism of inhibition. Fluorescence studies confirmed close correspondence between binding affinity and inhibition potency, as expected for an allosteric process. The inhibitor was reversible and at least 9-fold- and 26-fold selective over two GAG-binding proteins factor Xa (efficacy of 71%) and thrombin, respectively, and at least 27-fold selective over a cysteine protease papain. The inhibitor also inhibited the FXIIIa-mediated polymerization of fibrin in vitro. Overall, our work presents the proof-of-principle that FXIIIa can be allosterically modulated by sulfated non-saccharide agents much smaller than GAGs, which should enable the design of selective and safe anticoagulants. PMID:27467511

  19. 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...

  20. 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

  1. 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.

  2. Response inhibition and its relation to multidimensional impulsivity.

    Science.gov (United States)

    Wilbertz, Tilmann; Deserno, Lorenz; Horstmann, Annette; Neumann, Jane; Villringer, Arno; Heinze, Hans-Jochen; Boehler, Carsten N; Schlagenhauf, Florian

    2014-12-01

    Impulsivity is a multidimensional construct that has been suggested as a vulnerability factor for several psychiatric disorders, especially addiction disorders. Poor response inhibition may constitute one facet of impulsivity. Trait impulsivity can be assessed by self-report questionnaires such as the widely used Barratt Impulsiveness Scale (BIS-11). However, regarding the multidimensionality of impulsivity different concepts have been proposed, in particular the UPPS self-report questionnaire ('Urgency', 'Lack of Premeditation', 'Lack of Perseverance', 'Sensation Seeking') that is based on a factor analytic approach. The question as to which aspects of trait impulsivity map on individual differences of the behavioral and neural correlates of response inhibition so far remains unclear. In the present study, we investigated 52 healthy individuals that scored either very high or low on the BIS-11 and underwent a reward-modulated Stop-signal task during fMRI. Neither behavioral nor neural differences were observed with respect to high- and low-BIS groups. In contrast, UPPS subdomain Urgency best explained inter-individual variability in SSRT scores and was further negatively correlated to right IFG/aI activation in 'Stop>Go' trials - a key region for response inhibition. Successful response inhibition in rewarded compared to nonrewarded stop trials yielded ventral striatal (VS) activation which might represent a feedback signal. Interestingly, only participants with low Urgency scores were able to use this VS feedback signal for better response inhibition. Our findings indicate that the relationship of impulsivity and response inhibition has to be treated carefully. We propose Urgency as an important subdomain that might be linked to response inhibition as well as to the use of reward-based neural signals. Based on the present results, further studies examining the influence of impulsivity on psychiatric disorders should take into account Urgency as an important

  3. Inhibition of 5-Lipoxygenase Pathway Attenuates Acute Liver Failure by Inhibiting Macrophage Activation

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    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.

  4. 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.

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

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    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.

  6. Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma

    Science.gov (United States)

    Kassam, Amin B.; Park, Myung-Jin; Gardner, Paul; Prevedello, Daniel; Henry, Stephanie; Horbinski, Craig; Beumer, Jan H.; Tawbi, Hussein; Williams, Brian J.; Shaffrey, Mark E.; Egorin, Merrill J.; Abounader, Roger; Park, Deric M.

    2015-01-01

    Background The majority of chordomas show activation of the platelet-derived growth factor receptor (PDGFR). Based on in vitro intertumoral variation in response to recombinant PDGF protein and PDGFR inhibition, and variable tumor response to imatinib, we hypothesized that chordomas resistant to PDGFR inhibition may possess downstream activation of the pathway. Methods Molecular profiling was performed on 23 consecutive chordoma primary tissue specimens. Primary cultures established from 20 of the 23 specimens, and chordoma cell lines, UCH-1 and UCH-2, were used for in vitro experiments. Results Loss of heterozygosity (LOH) at the phosphatase and tensin homolog (PTEN) locus was observed in 6 specimens (26%). PTEN disruption statistically correlated with increased Ki-67 proliferation index, an established marker of poor outcome for chordoma. Compared to wild type, PTEN deficient chordomas displayed increased proliferative rate, and responded less favorably to PDGFR inhibition. PTEN gene restoration abrogated this growth advantage. Chordomas are characterized by intratumoral hypoxia and local invasion, and histone deacetylase (HDAC) inhibitors are capable of attenuating both hypoxic signaling and cell migration. The combination of PDGFR and HDAC inhibition effectively disrupted growth and invasion of PTEN deficient chordoma cells. Conclusions Loss of heterozygosity of the PTEN gene seen in a subset of chordomas is associated with aggressive in vitro behavior and strongly correlates with increased Ki-67 proliferative index. Combined inhibition of PDGFR and HDAC attenuates proliferation and invasion in chordoma cells deficient for PTEN. PMID:26247786

  7. Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma.

    Directory of Open Access Journals (Sweden)

    Dae-Hee Lee

    Full Text Available The majority of chordomas show activation of the platelet-derived growth factor receptor (PDGFR. Based on in vitro intertumoral variation in response to recombinant PDGF protein and PDGFR inhibition, and variable tumor response to imatinib, we hypothesized that chordomas resistant to PDGFR inhibition may possess downstream activation of the pathway.Molecular profiling was performed on 23 consecutive chordoma primary tissue specimens. Primary cultures established from 20 of the 23 specimens, and chordoma cell lines, UCH-1 and UCH-2, were used for in vitro experiments.Loss of heterozygosity (LOH at the phosphatase and tensin homolog (PTEN locus was observed in 6 specimens (26%. PTEN disruption statistically correlated with increased Ki-67 proliferation index, an established marker of poor outcome for chordoma. Compared to wild type, PTEN deficient chordomas displayed increased proliferative rate, and responded less favorably to PDGFR inhibition. PTEN gene restoration abrogated this growth advantage. Chordomas are characterized by intratumoral hypoxia and local invasion, and histone deacetylase (HDAC inhibitors are capable of attenuating both hypoxic signaling and cell migration. The combination of PDGFR and HDAC inhibition effectively disrupted growth and invasion of PTEN deficient chordoma cells.Loss of heterozygosity of the PTEN gene seen in a subset of chordomas is associated with aggressive in vitro behavior and strongly correlates with increased Ki-67 proliferative index. Combined inhibition of PDGFR and HDAC attenuates proliferation and invasion in chordoma cells deficient for PTEN.

  8. 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.

  9. 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

  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. Paeoniflorin inhibits macrophage-mediated lung cancer metastasis.

    Science.gov (United States)

    Wu, Qi; Chen, Gang-Ling; Li, Ya-Juan; Chen, Yang; Lin, Fang-Zhen

    2015-12-01

    Alternatively activated macrophages are more frequently involved in tumor growth, angiogenesis, and immunosuppression. A previous study showed that paeoniflorin, the major active constituent of Paeonia lactiflora Pallas, can inhibit tumor growth and lung metastases of Lewis lung tumor-bearing mice. This study tried to investigate whether paeoniflorin inhibited lung cancer metastasis by inhibiting the alternative activation of macrophages (M2 macrophage). Using a viability assay, the cytotoxicity of paeoniflorin on Lewis lung cancer cells and peritoneal macrophages were investigated. In vitro scratch wound and in vivo lung metastasis experiments were used to test the ability to inhibit the migration of paeoniflorin and the function of M2 macrophages. Flow cytometry was performed to test the cell cycle of Lewis lung cancer cells, and to test the M2 macrophages in peritoneal macrophages and subcutaneous transplantable tumor. It was found that paeoniflorin showed no inhibitory effect on the growth of Lewis lung cancer cells and peritoneal macrophages of mouse in vitro. Paeoniflorin could attenuate the migration of LLC stimulated by alternatively activated macrophages (stimulated for 24 h and 48 h, paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P lung cancer cells (paeoniflorin 100 μmol·L(-1), P lung metastasis of Lewis lung cancer cells xenograft and decrease the numbers of M2 macrophages in subcutaneous xenograft tumour in vivo (paeoniflorin 20, 40 mg·kg(-1), P lung metastasis of Lewis lung cancer cells xenograft partly through inhibiting the alternative activation of macrophages.

  12. Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer.

    Science.gov (United States)

    Wu, Buchu; Hu, Ke; Li, Shu; Zhu, Jing; Gu, Liying; Shen, Haoran; Hambly, Brett D; Bao, Shisan; Di, Wen

    2012-01-01

    Dihydroartiminisin (DHA), the active component of a Chinese herb (Artemisia annua), has been utilised as an anti-malarial drug since ancient China. DHA has also been shown to inhibit proliferation of cancer in vitro. However, the capacity of DHA to inhibit the development of ovarian cancer is still unclear. The adhesion, invasion, and migration of human ovarian cancer cell line (HO8910PM) was determined following DHA treatment in vitro, using Matrigel coated plate, transwell membrane chamber, and wound healing models, respectively. A mouse ovarian cancer model was established by orthotopic inoculation of HO8910PM cell line in nude mice. The growth and metastasis in vivo was determined 8 weeks post-implantation in response to DHA treatment. The expression of phosphorylated focal adhesion kinase (pFAK) and matrix metalloproteinases (MMP-2 and MMP-9) was evaluated using Western blotting. The expression of Von Willebrand factor (vWF) and infiltration of macrophages were determined, using immunohistochemistry. DHA inhibits ovarian cancer cell proliferation, adhesion, migration and invasion in vitro in a dose-dependent manner, consistent with decreased expression of pFAK and MMP-2, but not MMP-9. DHA inhibited metastasis significantly in vivo, associated with reduced vWF expression and macrophage infiltration. In conclusion, DHA inhibits the development of ovarian cancer, in part via down-regulating pFAK, MMP-2, vWF and macrophage infiltration. PMID:22025319

  13. Menthol binding and inhibition of α7-nicotinic acetylcholine receptors.

    Directory of Open Access Journals (Sweden)

    Abrar Ashoor

    Full Text Available Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the α7 subunit of the nicotinic acetylcholine (nACh receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit α7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca(2+-dependent Cl(- channels, since menthol inhibition remained unchanged by intracellular injection of the Ca(2+ chelator BAPTA and perfusion with Ca(2+-free bathing solution containing Ba(2+. Furthermore, increasing ACh concentrations did not reverse menthol inhibition and the specific binding of [(125I] α-bungarotoxin was not attenuated by menthol. Studies of α7- nACh receptors endogenously expressed in neural cells demonstrate that menthol attenuates α7 mediated Ca(2+ transients in the cell body and neurite. In conclusion, our results suggest that menthol inhibits α7-nACh receptors in a noncompetitive manner.

  14. 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

  15. Organo-selenium-containing dental sealant inhibits bacterial biofilm.

    Science.gov (United States)

    Tran, P; Hamood, A; Mosley, T; Gray, T; Jarvis, C; Webster, D; Amaechi, B; Enos, T; Reid, T

    2013-05-01

    Oral bacteria, including Streptococcus mutans and Streptococcus salivarius, contribute to tooth decay and plaque formation; therefore, it is essential to develop strategies to prevent dental caries and plaque formation. We recently showed that organo-selenium compounds covalently attached to different biomaterials inhibited bacterial biofilms. Our current study investigates the efficacy of an organo-selenium dental sealant (SeLECT-Defense(TM) sealant) in inhibiting S. mutans and S. salivarius biofilm formation in vitro. The organo-selenium was synthesized and covalently attached to dental sealant material via standard polymer chemistry. By colony-forming unit (CFU) assay and confocal microscopy, SeLECT-Defense(TM) sealant was found to completely inhibit the development of S. mutans and S. salivarius biofilms. To assess the durability of the anti-biofilm effect, we soaked the SeLECT-Defense(TM) sealant in PBS for 2 mos at 37°C and found that the biofilm-inhibitory effect was not diminished after soaking. To determine if organo-selenium inhibits bacterial growth under the sealant, we placed SeLECT-Defense sealant over a lawn of S. mutans. In contrast to a control sealant, SeLECT-Defense(TM) sealant completely inhibited the growth of S. mutans. These results suggest that the inhibitory effect of SeLECT-Defense(TM) sealant against S. mutans and S. salivarius biofilms is very effective and durable.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. Sirolimus and Auranofin in Treating Patients With Advanced or Recurrent Non-Small Cell Lung Cancer or Small Cell Lung Cancer

    Science.gov (United States)

    2016-08-25

    Extensive Stage Small Cell Lung Carcinoma; Lung Adenocarcinoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Small Cell Lung Carcinoma; Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

  2. Gold Nanoparticles and Microwave Irradiation Inhibit Beta-Amyloid Amyloidogenesis

    Directory of Open Access Journals (Sweden)

    Bastus Neus

    2008-01-01

    Full Text Available Abstract Peptide-Gold nanoparticles selectively attached to β-amyloid protein (Aβ amyloidogenic aggregates were irradiated with microwave. This treatment produces dramatic effects on the Aβ aggregates, inhibiting both the amyloidogenesis and the restoration of the amyloidogenic potential. This novel approach offers a new strategy to inhibit, locally and remotely, the amyloidogenic process, which could have application in Alzheimer’s disease therapy. We have studied the irradiation effect on the amyloidogenic process in the presence of conjugates peptide-nanoparticle by transmission electronic microscopy observations and by Thioflavine T assays to quantify the amount of fibrils in suspension. The amyloidogenic aggregates rather than the amyloid fibrils seem to be better targets for the treatment of the disease. Our results could contribute to the development of a new therapeutic strategy to inhibit the amyloidogenic process in Alzheimer’s disease.

  3. Group remembering: does social loafing underlie collaborative inhibition?

    Science.gov (United States)

    Weldon, M S; Blair, C; Huebsch, P D

    2000-11-01

    When people collaborate to recall information, they experience collaborative inhibition, a deficit in recall relative to nominal groups (the pooled, nonredundant recall of individuals working alone). That is, people recalling in groups do not perform up to their potential. Collaborative inhibition may be due to retrieval interference (e.g., B. H. Basden, D. R. Basden, S. Bryner, & R. L. Thomas, 1997) or to motivational factors such as social loafing in the group situation. Five experiments examined the role of motivational factors by varying monetary incentives, recall criterion, personal accountability, group cohesion, and group gender. Increasing motivation sometimes increased the overall level of recall but failed to eliminate the collaborative inhibition effect. The results suggest that collaboration interferes with an individual's ability to reconstruct his or her knowledge. PMID:11185783

  4. 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.

  5. Inhibitive Effects of Quercetin on Rabbit Tenon Capsule Fibroblasts Proliferation

    Institute of Scientific and Technical Information of China (English)

    Su Liu; Lin Chen

    2005-01-01

    Purpose:To study the inhibitive effects of quercetin (QU) on the fibroblasts proliferation of rabbit Tenon's capsule and its mechanism.Methods: Cultured fibroblasts were exposed to different concentrations of QU solution and investigated by microculture tetrazolium (MTT) assay. The effect of QU was obser ved on cells cycle using the flow cytometer. Besults: QU can suppress the proliferation of rabbit Tenon's capsule fibroblasts in vitro and show a dose-time dependent tendency.Flow cytometer results showed 26.92% cell increase in G1 phase, 23.50% decrease in S phase and 3.42% decrease in G2 phase.Conclusions: QU can suppress the proliferation of rabbit Tenon's capsule fibroblasts in vitro and show a dose-time dependent tendency. QU may effect all phase of cell cycle and inhibit cell proliferation by inhibiting G1 phase transitting to S phase and G2 phase.

  6. Tyrosinase inhibition kinetic studies of standardized extract of Berberis aristata.

    Science.gov (United States)

    Biswas, Rajarshi; Mukherjee, Pulok K; Chaudhary, Sushil K

    2016-06-01

    The stem bark and wood of Berberis aristata DC (Daruharidra) are one of the principal ingredients of traditional skin lighting and exfoliating scrub preparation in India. The standardised extract of B. aristata was screened to evaluate their in vitro antityrosinase activity and inhibition kinetics. Phytochemical and pharmacological studies were carried out with different solvent fractions of the methanol extract of B. aristata (MEBA). RP-HPLC analysis was used to determine the berberine content in extract and fractions of B. aristata. MEBA showed maximum berberine content. Extract and fractions of B. aristata contain the maximum amount of alkaloids than other constituents. In tyrosinase inhibition assay, MEBA was found to possess highest dose-dependent monophenolase and moderate diphenolase activity. The enzyme kinetic study revealed that MEBA possessed mixed type inhibition of monophenolase activity of tyrosinase. These bioactivities indicate that the MEBA has antihyperpigmentation potential in human skin. PMID:26212353

  7. Aedes aegypti D7 Saliva Protein Inhibits Dengue Virus Infection

    Science.gov (United States)

    Conway, Michael J.; Londono-Renteria, Berlin; Troupin, Andrea; Watson, Alan M.; Klimstra, William B.; Fikrig, Erol; Colpitts, Tonya M.

    2016-01-01

    Aedes aegypti is the primary vector of several medically relevant arboviruses including dengue virus (DENV) types 1–4. Ae. aegypti transmits DENV by inoculating virus-infected saliva into host skin during probing and feeding. Ae. aegypti saliva contains over one hundred unique proteins and these proteins have diverse functions, including facilitating blood feeding. Previously, we showed that Ae. aegypti salivary gland extracts (SGEs) enhanced dissemination of DENV to draining lymph nodes. In contrast, HPLC-fractionation revealed that some SGE components inhibited infection. Here, we show that D7 proteins are enriched in HPLC fractions that are inhibitory to DENV infection, and that recombinant D7 protein can inhibit DENV infection in vitro and in vivo. Further, binding assays indicate that D7 protein can directly interact with DENV virions and recombinant DENV envelope protein. These data reveal a novel role for D7 proteins, which inhibits arbovirus transmission to vertebrates through a direct interaction with virions. PMID:27632170

  8. Image enhancement algorithm based on improved lateral inhibition network

    Science.gov (United States)

    Yun, Haijiao; Wu, Zhiyong; Wang, Guanjun; Tong, Gang; Yang, Hua

    2016-05-01

    There is often substantial noise and blurred details in the images captured by cameras. To solve this problem, we propose a novel image enhancement algorithm combined with an improved lateral inhibition network. Firstly, we built a mathematical model of a lateral inhibition network in conjunction with biological visual perception; this model helped to realize enhanced contrast and improved edge definition in images. Secondly, we proposed that the adaptive lateral inhibition coefficient adhere to an exponential distribution thus making the model more flexible and more universal. Finally, we added median filtering and a compensation measure factor to build the framework with high pass filtering functionality thus eliminating image noise and improving edge contrast, addressing problems with blurred image edges. Our experimental results show that our algorithm is able to eliminate noise and the blurring phenomena, and enhance the details of visible and infrared images.

  9. Inhibition of Naja kaouthia venom activities by plant polyphenols.

    Science.gov (United States)

    Pithayanukul, Pimolpan; Ruenraroengsak, Pakatip; Bavovada, Rapepol; Pakmanee, Narumol; Suttisri, Rutt; Saen-oon, Suwipa

    2005-03-21

    Plant polyphenols from the aqueous extracts of Pentace burmanica, Pithecellobium dulce, Areca catechu and Quercus infectoria were tested for their inhibitory activities against Naja kaouthia (NK) venom by in vitro neutralization method. The first three extracts could completely inhibit the lethality of the venom at 4 LD50 concentration and the venom necrotizing activity at the minimum necrotizing dose while also inhibited up to 90% of the acetylcholinesterase activity of NK venom at much lower tannin concentrations than that of Quercus infectoria. The ED50 of plant tannins in inhibiting NK venom activities varied according to condensed tannins and their content in the extracts. Molecular docking of the complexes between alpha-cobratoxin and either hydrolysable or condensed tannins at their lowest energetic conformations were proposed. The anti-venom activities of these plant polyphenols by selectively blocking the nicotinic acetylcholine receptor and non-selectively by precipitation of the venom proteins were suggested. PMID:15740891

  10. Inhibition of MMP-13 with modified polymer particles

    Science.gov (United States)

    Tran, Hai; Bratlie, Kaitlin M.

    2016-06-01

    Matrix metalloproteinases (MMPs) are proteases that destroy the extracellular matrix and have important roles in the foreign body response, wound healing, and disease. Of particular importance is the chronic wound environment in which MMP activity is increased, resulting in destruction of the de novo extracellular matrix. One potential treatment of these wounds would be to use dressings that are capable of inhibiting MMP activity. In this study, we examined the effect of seven polymer modifiers (2-amino-3-guanidinopropionic acid, arginine, carnitine, citrulline, creatine, 3-guanidino propionic acid, and Nw-nitro-L-arginine) on MMP-13 activity. MMP-13 is a collagenase that is present in chronic wounds and is zinc dependent. Our results showed that these polymer modifiers were able to inhibit MMP-13 activity to varying degrees. The mechanism of inhibition appears to be binding zinc to the modifiers.

  11. Language dominance and inhibition abilities in bilingual older adults*

    Science.gov (United States)

    GORAL, MIRA; CAMPANELLI, LUCA; SPIRO, AVRON

    2016-01-01

    This study aimed to examine the so-called bilingual advantage in older adults’ performance in three cognitive domains and to identify whether language use and bilingual type (dominant vs. balanced) predicted performance. The participants were 106 Spanish–English bilinguals ranging in age from 50 years to 84 years. Three cognitive domains were examined (each by a single test): inhibition (the Simon task), alternating attention (the Trail Making test), and working memory (Month Ordering). The data revealed that age was negatively correlated to performance in each domain. Bilingual type – balanced vs. dominant – predicted performance and interacted with age only on the inhibition measure (the Simon task). Balanced bilinguals showed age-related inhibition decline (i.e., greater Simon effect with increasing age); in contrast, dominant bilinguals showed little or no age-related change. The findings suggest that bilingualism may offer cognitive advantage in older age only for a subset of bilinguals.

  12. Genetic influences on the acquisition and inhibition of fear.

    Science.gov (United States)

    Wendt, Julia; Neubert, Jörg; Lindner, Katja; Ernst, Florian D; Homuth, Georg; Weike, Almut I; Hamm, Alfons O

    2015-12-01

    As a variant of the Pavlovian fear conditioning paradigm the conditional discrimination design allows for a detailed investigation of fear acquisition and fear inhibition. Measuring fear-potentiated startle responses, we investigated the influence of two genetic polymorphisms (5-HTTLPR and COMT Val(158)Met) on fear acquisition and fear inhibition which are considered to be critical mechanisms for the etiology and maintenance of anxiety disorders. 5-HTTLPR s-allele carriers showed a more stable potentiation of the startle response during fear acquisition. Homozygous COMT Met-allele carriers, which had demonstrated delayed extinction in previous investigations, show deficient fear inhibition in presence of a learned safety signal. Thus, our results provide further evidence that 5-HTTLPR and COMT Val(158)Met genotypes influence the vulnerability for the development of anxiety disorders via different mechanisms.

  13. Corrosion inhibition of aluminum 6063 using some pharmaceutical compounds

    Energy Technology Data Exchange (ETDEWEB)

    Fouda, A.S. [Department of Chemistry, Faculty of Science, El-Mansoura University, El-Mansoura 35516 (Egypt)], E-mail: asfouda@mans.edu.eg; Al-Sarawy, A.A. [Department of Chemistry, Faculty of Engineering, El-Mansoura University, El-Mansoura (Egypt); Ahmed, F.Sh. [Department of Chemistry, Faculty of Science (Demitta), El-Mansoura University, El-Mansoura (Egypt); El-Abbasy, H.M. [Department of Chemistry, Faculty of Science, El-Mansoura University, El-Mansoura 35516 (Egypt)

    2009-03-15

    The corrosion inhibition characteristics of some pharmaceutical compounds on aluminum 6063 in 0.5 mol l{sup -1} H{sub 3}PO{sub 4} has been studied using weight loss and galvanostatic polarization techniques. Results showed that the inhibition occurs through adsorption of the inhibitor molecules on the metal surface. The inhibition efficiency increased with increasing inhibitor concentration, but decreased with increasing temperature. The adsorption of first group pharmaceutical compounds on the metal surface is found to obey Frumkin's adsorption isotherm, but the adsorption of second group pharmaceutical compounds is found to obey Temkin's adsorption isotherm. Thermodynamic parameters for adsorption process were determined. Galvanostatic polarization studies showed that first and second groups' pharmaceutical compounds are mixed-type inhibitors and the results obtained from the two techniques are in good agreement.

  14. Repellents inhibit P450 enzymes in Stegomyia (Aedes aegypti.

    Directory of Open Access Journals (Sweden)

    Gloria Isabel Jaramillo Ramirez

    Full Text Available The primary defence against mosquitoes and other disease vectors is often the application of a repellent. Despite their common use, the mechanism(s underlying the activity of repellents is not fully understood, with even the mode of action of DEET having been reported to be via different mechanisms; e.g. interference with olfactory receptor neurones or actively detected by olfactory receptor neurones on the antennae or maxillary palps. In this study, we discuss a novel mechanism for repellence, one of P450 inhibition. Thirteen essential oil extracts from Colombian plants were assayed for potency as P450 inhibitors, using a kinetic fluorometric assay, and for repellency using a modified World Health Organisation Pesticide Evaluations Scheme (WHOPES arm-in cage assay with Stegomyia (Aedes aegypti mosquitoes. Bootstrap analysis on the inhibition analysis revealed a significant correlation between P450-inhibition and repellent activity of the oils.

  15. Somatosensory integration controlled by dynamic thalamocortical feed-forward inhibition.

    Science.gov (United States)

    Gabernet, Laetitia; Jadhav, Shantanu P; Feldman, Daniel E; Carandini, Matteo; Scanziani, Massimo

    2005-10-20

    The temporal features of tactile stimuli are faithfully represented by the activity of neurons in the somatosensory cortex. However, the cellular mechanisms that enable cortical neurons to report accurate temporal information are not known. Here, we show that in the rodent barrel cortex, the temporal window for integration of thalamic inputs is under the control of thalamocortical feed-forward inhibition and can vary from 1 to 10 ms. A single thalamic fiber can trigger feed-forward inhibition and contacts both excitatory and inhibitory cortical neurons. The dynamics of feed-forward inhibition exceed those of each individual synapse in the circuit and are captured by a simple disynaptic model of the thalamocortical projection. The variations in the integration window produce changes in the temporal precision of cortical responses to whisker stimulation. Hence, feed-forward inhibitory circuits, classically known to sharpen spatial contrast of tactile inputs, also increase the temporal resolution in the somatosensory cortex.

  16. Quantum Chemical Study on the Corrosion Inhibition of Some Oxadiazoles

    Directory of Open Access Journals (Sweden)

    Hong Ju

    2015-01-01

    Full Text Available Quantum chemical calculations based on DFT method were performed on three nitrogen-bearing heterocyclic compounds used as corrosion inhibitors for the mild steel in acid media to determine the relationship between the molecular structure of inhibitors and inhibition efficiency. The structural parameters, such as energy and distribution of highest occupied molecular orbital (HOMO and lowest unoccupied molecular orbital (LUMO, the charge distribution of the studied inhibitors, the absolute electronegativity (χ values, and the fraction of electrons (ΔN transfer from inhibitors to mild steel were also calculated and correlated with inhibition efficiencies. The results showed that the inhibition efficiency of inhibitors increased with the increase in energy of HOMO and decrease in energy gap of frontier molecular orbital, and the areas containing N and O atoms are most possible sites for bonding the steel surface by donating electrons to the mild steel.

  17. Ketamine protects acetylcholinesterase against inhibition by propoxur and phoxim.

    Science.gov (United States)

    Koutsoviti-Papadopoulou, M; Kounenis, G; Elezoglou, V

    1994-01-01

    In the present study the effect of ketamine on the contractions caused by propoxur and phoxim on the isolated guinea pig ileum was investigated. Ketamine was found able to inhibit in a concentration-dependent manner the contractile responses of the ileum to propoxur and phoxim, while it did not significantly modify the contractions induced by acetylcholine. Propoxur and phoxim augmented the contractile responses induced by acetylcholine in the presence of acetylcholinesterase. This augmentation was prevented by ketamine, in a concentration-dependent manner. These findings suggest that ketamine inhibits the contractile effect of propoxur and phoxim on the guinea pig ileum and this inhibition seems to be associated with the protection of acetylcholinesterase against the action of these two compounds.

  18. Inhibition of the anaerobic digestion process by linear alkylbenzene sulfonates

    DEFF Research Database (Denmark)

    Gavala, Hariklia N.; Ahring, Birgitte Kiær

    2002-01-01

    it is important to investigate the effect of these xenobiotic compounds on an anaerobic environment. The inhibitory effect of Linear Alkylbenzene Sulfonates (LAS) on the acetogenic and methanogenic step of the anaerobic digestion process was studied. LAS inhibit both acetogenesis from propionate...... and methanogenesis from acetate and hydrogen and it is shown that the propionate-utilising bacteria are more sensitive to the presence of LAS than the acetoclastic methanogens. It has been proven that the inhibition intensity depends on the solids concentration and thus the term "biomass specific LAS concentration......" has been introduced in order to describe the phenomenon better. Conclusively, it is believed that the inhibitory effect of LAS is the main reason that anaerobic microbial enrichments on LAS have not been succeeded yet. Also, the inhibition caused by LAS on the acetogenic and methanogenic step...

  19. Corrosion Inhibition of High Speed Steel by Biopolymer HPMC Derivatives

    Directory of Open Access Journals (Sweden)

    Shih-Chen Shi

    2016-07-01

    Full Text Available The corrosion inhibition characteristics of the derivatives of biopolymer hydroxypropyl methylcellulose (HPMC, hydroxypropyl methylcellulose phthalate (HPMCP, and hydroxypropyl methylcellulose acetate succinate (HPMCAS film are investigated. Based on electrochemical impedance spectroscopic measurements and potentiodynamic polarization, the corrosion inhibition performance of high speed steel coated with HPMC derivatives is evaluated. The Nyquist plot and Tafel polarization demonstrate promising anti-corrosion performance of HPMC and HPMCP. With increasing film thickness, both materials reveal improvement in corrosion inhibition. Moreover, because of a hydrophobic surface and lower moisture content, HPMCP shows better anti-corrosion performance than HPMCAS. The study is of certain importance for designing green corrosion inhibitors of high speed steel surfaces by the use of biopolymer derivatives.

  20. Ribavirin Inhibits Parrot Bornavirus 4 Replication in Cell Culture.

    Science.gov (United States)

    Musser, Jeffrey M B; Heatley, J Jill; Koinis, Anastasia V; Suchodolski, Paulette F; Guo, Jianhua; Escandon, Paulina; Tizard, Ian R

    2015-01-01

    Parrot bornavirus 4 is an etiological agent of proventricular dilatation disease, a fatal neurologic and gastrointestinal disease of psittacines and other birds. We tested the ability of ribavirin, an antiviral nucleoside analog with antiviral activity against a range of RNA and DNA viruses, to inhibit parrot bornavirus 4 replication in duck embryonic fibroblast cells. Two analytical methods that evaluate different products of viral replication, indirect immunocytochemistry for viral specific nucleoprotein and qRT-PCR for viral specific phosphoprotein gene mRNA, were used. Ribavirin at concentrations between 2.5 and 25 μg/mL inhibited parrot bornavirus 4 replication, decreasing viral mRNA and viral protein load, in infected duck embryonic fibroblast cells. The addition of guanosine diminished the antiviral activity of ribavirin suggesting that one possible mechanism of action against parrot bornavirus 4 may likely be through inosine monophosphate dehydrogenase inhibition. This study demonstrates parrot bornavirus 4 susceptibility to ribavirin in cell culture. PMID:26222794