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Sample records for terpenoid drug candidates

  1. High-throughput testing of terpenoid biosynthesis candidate genes using transient expression in Nicotiana benthamiana

    DEFF Research Database (Denmark)

    Bach, Søren Spanner; Bassard, Jean-Étienne André; Andersen-Ranberg, Johan

    2014-01-01

    To respond to the rapidly growing number of genes putatively involved in terpenoid metabolism, a robust high-throughput platform for functional testing is needed. An in planta expression system offers several advantages such as the capacity to produce correctly folded and active enzymes localized...

  2. Volatile terpenoids as potential drug leads in Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Wojtunik-Kulesza Karolina A.

    2017-12-01

    Full Text Available Alzheimer’s disease (AD is by far the most prevalent of all known forms of dementia. Despite wide-spread research, the main causes of emergence and development of AD have not been fully recognized. Natural, low-molecular, lipophilic terpenoids constitute an interesting group of secondary plant metabolites, that exert biological activities of possible use in the prevention and treatment of AD. In order to identify secondary metabolites possessing both antioxidant activity and the potential to increase the level of acetylcholine, selected terpenoids have been screened for possible acetylcholinesterase inhibitory activity by use of two methods, namely Marston (chromatographic assay and Ellman (spectrophotometric assay. In order to describe the interaction between terpenes and AChE active gorge, molecular docking simulations were performed. Additionally, all analyzed terpenes were also evaluated for their cytotoxic properties against two normal cell lines using MTT assay. The obtained results show that: carvone (6, pulegone (8 and γ-terpinene (7 possess desirable AChE inhibitory activity. MTT assay revealed low or lack of cytotoxicity of these metabolites. Thus, among the investigated terpenes, carvone (6, pulegone (8 and y-terpinene (7 can be recognized as compounds with most promising activities in the development of multi-target directed ligands.

  3. Terpenoids for medicine

    NARCIS (Netherlands)

    Fischedick, Justin

    2013-01-01

    This thesis is concerns research on monoterpenoids, sesquiterpenoids, and diterpenoids with medicinal properties. Terpenoids from commond herbs as well as Cannabis sativa, Inula britannica, Tanacetum parthenium, and Salvia officinalis were investigated

  4. Pharmacology of biosimilar candidate drugs in rheumatology: a literature review.

    Science.gov (United States)

    Araújo, F; Cordeiro, I; Teixeira, F; Gonçalves, J; Fonseca, J E

    2014-01-01

    To review current evidence concerning pharmacology of biosimilar candidates to be used in rheumatology. A PubMed search up to August 2013 was performed using relevant search terms to include all studies assessing pharmacological properties of biosimilar candidates to be used in rheumatology. Data on study characteristics, type of intervention, pharmacokinetics (PK), pharmacodynamics (PD) and bioequivalence ratios was extracted. Of 280 articles screened, 5 fulfilled our inclusion criteria. Two trials, PLANETAS and PLANETRA, compared CT-P13 and infliximab in patients with active ankylosing spondylitis and rheumatoid arthritis, respectively. PK bioequivalence was demonstrated in the phase 1 PLANETAS trial by highly comparable area under the curve (AUC) and maximum drug concentrations (Cmax), whose geometric mean ratios fell between the accepted bioequivalence range of 80-125%. Equivalence in efficacy and safety was demonstrated in the phase 3 PLANETRA trial. Two phase 1 trials comparing etanercept biosimilar candidates TuNEX and HD203 in healthy volunteers showed a high degree of similarity in AUC and Cmax, with respective geometric mean ratios between PK bioequivalence range. The last included trial referred to GP2013, a rituximab biosimilar candidate, which demonstrated PK and PD bioequivalence to reference product in three different dosing regimens in cynomolgus monkeys. Infliximab, etanercept and rituximab biosimilar candidates have demonstrated PK bioequivalence in the trials included in this review. CT-P13 has recently been approved for use in the European market and the remaining biosimilar candidates are currently being tested in patients with rheumatoid arthritis.

  5. A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

    DEFF Research Database (Denmark)

    Marstrand, T T; Borup, R; Willer, A

    2010-01-01

    regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost...

  6. Salicytamide: a New Anti-inflammatory Designed Drug Candidate.

    Science.gov (United States)

    Guedes, Karen Marinho Maciel; Borges, Rosivaldo Santos; Fontes-Júnior, Enéas Andrade; Silva, Andressa Santa Brigida; Fernandes, Luanna Melo Pereira; Cartágenes, Sabrina Carvalho; Pinto, Ana Carla Godinho; Silva, Mallone Lopes; Queiroz, Luana Melo Diogo; Vieira, José Luís Fernandes; Sousa, Pergentino José Cunha; Maia, Cristiane Socorro Ferraz

    2018-04-13

    Salicytamide is a new drug developed through molecular modelling and rational drug design by the molecular association of paracetamol and salicylic acid. This study was conducted to assess the acute oral toxicity, antinociceptive, and antioedematogenic properties of salicytamide. Acute toxicity was based on the OECD 423 guidelines. Antinociceptive properties were investigated using the writhing, hot plate and formalin tests in Swiss mice. Antioedematogenic properties were evaluated using the carrageenan-induced paw oedema model and croton oil-induced dermatitis in Wistar rats. Salicytamide did not promote behavioural changes or animal deaths during acute oral toxicity evaluation. Furthermore, salicytamide exhibited peripheral antinociceptive activity as evidenced by the reduction in writhing behaviour (ED50 = 4.95 mg/kg) and licking time in the formalin test's inflammatory phase. Also, salicytamide elicited central antinociceptive activity on both hot plate test and formalin test's neurogenic phase. Additionally, salicytamide was effective in reducing carrageenan or croton oil-induced oedema formation. Overall, we have shown that salicytamide, proposed here as a new NSAID candidate, did not induce oral acute toxicity and elicited both peripheral antinociceptive effects (about 10-25 times more potent than its precursors in the writhing test) and antioedematogenic properties. Salicytamide also presented central antinociceptive activity, which seems to be mediated through opioid-independent mechanisms. These findings reveal salicytamide as a promising antinociceptive/antioedematogenic drug candidate.

  7. Potential drug development candidates for human soil-transmitted helminthiases.

    Directory of Open Access Journals (Sweden)

    Piero Olliaro

    2011-06-01

    Full Text Available Few drugs are available for soil-transmitted helminthiasis (STH; the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives.We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI statements, European Public Assessment Reports (EPAR and published literature. Concomitantly, we developed a target product profile (TPP against which the products were compared.The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files.Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made.

  8. Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

    Directory of Open Access Journals (Sweden)

    Miguel Angel Moreno

    2014-12-01

    Full Text Available Leishmania infantum is the etiological agent of zoonotic visceral leishmaniasis in the Mediterranean basin. The disease is fatal without treatment, which has been based on antimonial pentavalents for more than 60 years. Due to resistances, relapses and toxicity to current treatment, the development of new drugs is required. The structure of the L. infantum tyrosine aminotransferase (LiTAT has been recently solved showing important differences with the mammalian orthologue. The characterization of LiTAT is reported herein. This enzyme is cytoplasmic and is over-expressed in the more infective stages and nitric oxide resistant parasites. Unlike the mammalian TAT, LiTAT is able to use ketomethiobutyrate as co-substrate. The pharmacophore model of LiTAT with this specific co-substrate is described herein. This may allow the identification of new inhibitors present in the databases. All the data obtained support that LiTAT is a good target candidate for the development of new anti-leishmanial drugs.

  9. Prediction methods and databases within chemoinformatics: emphasis on drugs and drug candidates

    DEFF Research Database (Denmark)

    Jonsdottir, Svava Osk; Jorgensen, FS; Brunak, Søren

    2005-01-01

    about drugs and drug candidates, and of databases with relevant properties. Access to experimental data and numerical methods for selecting and utilizing these data is crucial for developing accurate predictive in silico models. Many interesting predictive methods for classifying the suitability......MOTIVATION: To gather information about available databases and chemoinformatics methods for prediction of properties relevant to the drug discovery and optimization process. RESULTS: We present an overview of the most important databases with 2-dimensional and 3-dimensional structural information...... of chemical compounds as potential drugs, as well as for predicting their physico-chemical and ADMET properties have been proposed in recent years. These methods are discussed, and some possible future directions in this rapidly developing field are described....

  10. The synthesis and characterization of novel brush-type chiral stationary phase based on terpenoid selector for resolution of chiral drugs

    Directory of Open Access Journals (Sweden)

    Wang Dao-Cai

    2016-01-01

    Full Text Available In the light of the chiral resolution mechanism and structures of brush-type CSP, a new chiral selector 4′-carboxyl-1′-ursolic methyl ester-3β-yl-benzoate has been prepared. Then the terpenoid chiral selector was covalently linked to 3-aminopropyl silica gel. Its structure identification data are provided by 1H NMR, MS and elementary analysis. The enantiodiscriminating capability of the brush-type CSP was evaluated by static adsorption experiment with methyl mandelate, aniline derivative of mandelic acid, benzoin and ibuprofen. Experimental results demonstrated that the chiral selector has selectivity, and the enantiomers of methyl mandelate and ibuprofen could be separated on the CSP, which indicated that the novel brush-type CSP possess a bright prospects for chiral separation potentially.

  11. Candidate genes for cross-resistance against DNA-damaging drugs

    DEFF Research Database (Denmark)

    Wittig, Rainer; Nessling, Michelle; Will, Rainer D

    2002-01-01

    Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA...... as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs....

  12. Zeolites: promising candidates for drug delivery systems (DDSs)

    OpenAIRE

    Vilaça, Natália; Amorim, Ricardo; Baltazar, Fátima; Fonseca, António Manuel; Neves, Isabel C.

    2012-01-01

    [Excerpt] The aim of controlled drug delivery systems (DDSs) is to administer the necessary amount of drug safely and effectively to specific sites in the human body and to regulate the temporal drug profile for maximum therapeutic benefits.[1] Zeolites are crystalline aluminosilicates solids with very regular microporous structures and they have been recently considered for medical use due to their biological properties and stability in biological environments.[1,2] The large variety in ...

  13. A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

    Science.gov (United States)

    Eleuteri, C.; Olla, S.; Veroni, C.; Umeton, R.; Mechelli, R.; Romano, S.; Buscarinu, Mc.; Ferrari, F.; Calò, G.; Ristori, G.; Salvetti, M.; Agresti, C.

    2017-04-01

    There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

  14. Cancer in silico drug discovery: a systems biology tool for identifying candidate drugs to target specific molecular tumor subtypes.

    Science.gov (United States)

    San Lucas, F Anthony; Fowler, Jerry; Chang, Kyle; Kopetz, Scott; Vilar, Eduardo; Scheet, Paul

    2014-12-01

    Large-scale cancer datasets such as The Cancer Genome Atlas (TCGA) allow researchers to profile tumors based on a wide range of clinical and molecular characteristics. Subsequently, TCGA-derived gene expression profiles can be analyzed with the Connectivity Map (CMap) to find candidate drugs to target tumors with specific clinical phenotypes or molecular characteristics. This represents a powerful computational approach for candidate drug identification, but due to the complexity of TCGA and technology differences between CMap and TCGA experiments, such analyses are challenging to conduct and reproduce. We present Cancer in silico Drug Discovery (CiDD; scheet.org/software), a computational drug discovery platform that addresses these challenges. CiDD integrates data from TCGA, CMap, and Cancer Cell Line Encyclopedia (CCLE) to perform computational drug discovery experiments, generating hypotheses for the following three general problems: (i) determining whether specific clinical phenotypes or molecular characteristics are associated with unique gene expression signatures; (ii) finding candidate drugs to repress these expression signatures; and (iii) identifying cell lines that resemble the tumors being studied for subsequent in vitro experiments. The primary input to CiDD is a clinical or molecular characteristic. The output is a biologically annotated list of candidate drugs and a list of cell lines for in vitro experimentation. We applied CiDD to identify candidate drugs to treat colorectal cancers harboring mutations in BRAF. CiDD identified EGFR and proteasome inhibitors, while proposing five cell lines for in vitro testing. CiDD facilitates phenotype-driven, systematic drug discovery based on clinical and molecular data from TCGA. ©2014 American Association for Cancer Research.

  15. Identify drug repurposing candidates by mining the protein data bank.

    Science.gov (United States)

    Moriaud, Fabrice; Richard, Stéphane B; Adcock, Stewart A; Chanas-Martin, Laetitia; Surgand, Jean-Sébastien; Ben Jelloul, Marouane; Delfaud, François

    2011-07-01

    Predicting off-targets by computational methods is gaining increasing interest in early-stage drug discovery. Here, we present a computational method based on full 3D comparisons of 3D structures. When a similar binding site is detected in the Protein Data Bank (PDB) (or any protein structure database), it is possible that the corresponding ligand also binds to that similar site. On one hand, this target hopping case is probably rare because it requires a high similarity between the binding sites. On the other hand, it could be a strong rational evidence to highlight possible off-target reactions and possibly a potential undesired side effect. This target-based drug repurposing can be extended a significant step further with the capability of searching the full surface of all proteins in the PDB, and therefore not relying on pocket detection. Using this approach, we describe how MED-SuMo reproduces the repurposing of tadalafil from PDE5A to PDE4A and a structure of PDE4A with tadalafil. Searching for local protein similarities generates more hits than for whole binding site similarities and therefore fragment repurposing is more likely to occur than for drug-sized compounds. In this work, we illustrate that by mining the PDB for proteins sharing similarities with the hinge region of protein kinases. The experimentally validated examples, biotin carboxylase and synapsin, are retrieved. Further to fragment repurposing, this approach can be applied to the detection of druggable sites from 3D structures. This is illustrated with detection of the protein kinase hinge motif in the HIV-RT non-nucleosidic allosteric site.

  16. Terpenoids and Their Biosynthesis in Cyanobacteria

    Directory of Open Access Journals (Sweden)

    Bagmi Pattanaik

    2015-01-01

    Full Text Available Terpenoids, or isoprenoids, are a family of compounds with great structural diversity which are essential for all living organisms. In cyanobacteria, they are synthesized from the methylerythritol-phosphate (MEP pathway, using glyceraldehyde 3-phosphate and pyruvate produced by photosynthesis as substrates. The products of the MEP pathway are the isomeric five-carbon compounds isopentenyl diphosphate and dimethylallyl diphosphate, which in turn form the basic building blocks for formation of all terpenoids. Many terpenoid compounds have useful properties and are of interest in the fields of pharmaceuticals and nutrition, and even potentially as future biofuels. The MEP pathway, its function and regulation, and the subsequent formation of terpenoids have not been fully elucidated in cyanobacteria, despite its relevance for biotechnological applications. In this review, we summarize the present knowledge about cyanobacterial terpenoid biosynthesis, both regarding the native metabolism and regarding metabolic engineering of cyanobacteria for heterologous production of non-native terpenoids.

  17. Terpenoids and Their Biosynthesis in Cyanobacteria

    Science.gov (United States)

    Pattanaik, Bagmi; Lindberg, Pia

    2015-01-01

    Terpenoids, or isoprenoids, are a family of compounds with great structural diversity which are essential for all living organisms. In cyanobacteria, they are synthesized from the methylerythritol-phosphate (MEP) pathway, using glyceraldehyde 3-phosphate and pyruvate produced by photosynthesis as substrates. The products of the MEP pathway are the isomeric five-carbon compounds isopentenyl diphosphate and dimethylallyl diphosphate, which in turn form the basic building blocks for formation of all terpenoids. Many terpenoid compounds have useful properties and are of interest in the fields of pharmaceuticals and nutrition, and even potentially as future biofuels. The MEP pathway, its function and regulation, and the subsequent formation of terpenoids have not been fully elucidated in cyanobacteria, despite its relevance for biotechnological applications. In this review, we summarize the present knowledge about cyanobacterial terpenoid biosynthesis, both regarding the native metabolism and regarding metabolic engineering of cyanobacteria for heterologous production of non-native terpenoids. PMID:25615610

  18. Drug repurposing: a systematic approach to evaluate candidate oral neuroprotective interventions for secondary progressive multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Hanna M Vesterinen

    Full Text Available To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis.Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action.We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil as lead candidates for clinical evaluation.We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders.

  19. Metabolic engineering for improved heterologous terpenoid biosynthesis

    NARCIS (Netherlands)

    Ryden, A.; Melillo, E.; Czepnik, M.; Kayser, O.

    Terpenoids belong to the largest class of natural compounds and are produced in all living organisms. The isoprenoid skeleton is based on assembling of C5 building blocks, but the biosynthesis of a great variety of terpenoids ranging from monoterpenoids to polyterpenoids is not fully understood

  20. Characterization of terpenoid volatiles from cultivars of eastern hemlock (Tsuga canadensis).

    Science.gov (United States)

    Lagalante, Anthony F; Montgomery, Michael E; Calvosa, Frank C; Mirzabeigi, Michael N

    2007-12-26

    The volatile terpenoid fraction from needles in 13 cultivars of Tsuga canadensis L. (Carriere) was analyzed by gas chromatography with mass spectrometry (GC-MS). The results of this study are considered along with previously reported results for foliar terpenoid levels of the Asian (T. sieboldii, T. chinensis, T. diversifolia), western North American (T. mertensiana, T. heterophylla), and eastern North American species (T. canadensis, T. caroliniana) of hemlock to draw conclusions about the potential of cultivar host resistance to the hemlock woolly adelgid (Adelges tsugae Annand). It is suggested that hemlocks in eastern North America have adapted their terpenoid chemistry for protection against endemic defoliators and that this has made them vulnerable to non-native, sucking pests such as adelgids and scales. Some cultivars of T. canadensis have a terpenoid profile that resembles that of the resistant noneastern North American species and are candidates for biological screening for resistance. Among the cultivars, the variation in terpenoid chemistry did not absolutely correspond with the considerable differences in morphological characters observed, indicating that the terpenoid chemistry is not definitively coupled with hemlock morphology.

  1. A Novel Terpenoid from Elephantopus Scaber – Antibacterial Activity on Staphylococcus Aureus: A Substantiate Computational Approach

    Science.gov (United States)

    Daisy, P.; Mathew, Salu; Suveena, S.; Rayan, Nirmala A.

    2008-01-01

    Staphylococcus aureus has gained much attention in the last decade as it is a major cause of the Urinary Tract Infection in Diabetic patients. The Extended Spectrum β-Lactamases (ESβL) producers are highly resistant to several conventional antibiotics. This limits the therapeutic options.Hence efforts are now taken to screen few medicinal plants, which are both economic and less toxic. Among the several plants screened, we have chosen the acetone extract of Elephantopus scaber from which we purified a new terpenoid for our study. Its structure was generated using CHEMSKETCH software and the activity prediction was done using PASS PREDICTION software. We have confirmed the mechanism of anti-bacterial effect of terpenoid using Computer – Aided Drug Design (CADD) with computational methods to simulate drug – receptor interactions. The Protein-Ligand interaction plays a significant role in the structural based drug designing. In this present study we have taken the Autolysin, the bacteriolytic enzyme, that digest the cell wall peptidoglycon. The autolysin and terpenoid were docked using HEX docking software and the docking score with minimum energy value of -209.54 was calculated. It infers that the terpenoid can inhibit the activity of autolysin by forming a strong atomic interaction with the active site residues. Hence the terpenoid can act as a drug for bacterial infections. Further investigations can be carried out to predict the activity of terpeniod on other targets. PMID:23675090

  2. Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?

    Science.gov (United States)

    Gopalakrishnan, Ranganath; Frolov, Andrey I; Knerr, Laurent; Drury, William J; Valeur, Eric

    2016-11-10

    Over the past decade, foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino acid based backbones, have been the most studied from a therapeutic perspective, while polyaromatic foldamers have barely evolved from their nascency and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targets or provide chemical biology tools. The potential of foldamer drug candidates reaching the clinic is still a stretch. Nevertheless, advances in the field have demonstrated their potential for the discovery of next generation therapeutics. In this perspective, the current knowledge of foldamers is reviewed in a drug discovery context. Recent advances in the early phases of drug discovery including hit finding, target validation, and optimization and molecular modeling are discussed. In addition, challenges and focus areas are debated and gaps highlighted.

  3. Candidate Targets for New Anti-Virulence Drugs: Selected Cases of Bacterial Adhesion and Biofilm Formation

    DEFF Research Database (Denmark)

    Klemm, Per; Hancock, Viktoria; Kvist, Malin

    2007-01-01

    is particularly problematic in medical contexts because biofilm-associated bacteria are particularly hard to eradicate. Several promising candidate drugs that target bacterial adhesion and biofilm formation are being developed. Some of these might be valuable weapons for fighting infectious diseases in the future...... formation are highly attractive targets for new drugs. Specific adhesion provides bacteria with target selection and prevents removal by hydrodynamic flow forces. Bacterial adhesion is of paramount importance for bacterial pathogenesis. Adhesion is also the first step in biofilm formation. Biofilm formation...

  4. In silico discovery of terpenoid metabolism in Cannabis sativa.

    Science.gov (United States)

    Massimino, Luca

    2017-01-01

    Due to their efficacy, cannabis based therapies are currently being prescribed for the treatment of many different medical conditions. Interestingly, treatments based on the use of cannabis flowers or their derivatives have been shown to be very effective, while therapies based on drugs containing THC alone lack therapeutic value and lead to increased side effects, likely resulting from the absence of other pivotal entourage compounds found in the Phyto-complex. Among these compounds are terpenoids, which are not produced exclusively by cannabis plants, so other plant species must share many of the enzymes involved in their metabolism. In the present work, 23,630 transcripts from the canSat3 reference transcriptome were scanned for evolutionarily conserved protein domains and annotated in accordance with their predicted molecular functions. A total of 215 evolutionarily conserved genes encoding enzymes presumably involved in terpenoid metabolism are described, together with their expression profiles in different cannabis plant tissues at different developmental stages. The resource presented here will aid future investigations on terpenoid metabolism in Cannabis sativa .

  5. Terpenoids in plant signaling, chemical ecology

    NARCIS (Netherlands)

    Kappers, I.F.; Dicke, M.; Bouwmeester, H.J.

    2008-01-01

    Terpenoids constitute the largest class of secondary metabolites in the plant kingdom. Because of their immense structural diversity and the resulting diversity in physiochemical properties, these molecules are particularly important for plant communication with other organisms. In this article, we

  6. Repurposing of Aspirin and Ibuprofen as Candidate Anti-Cryptococcus Drugs

    Science.gov (United States)

    Ogundeji, Adepemi O.; Pohl, Carolina H.

    2016-01-01

    The usage of fluconazole and amphotericin B in clinical settings is often limited by, among other things, drug resistance development and undesired side effects. Thus, there is a constant need to find new drugs to better manage fungal infections. Toward this end, the study described in this paper considered the repurposing of aspirin (acetylsalicylic acid) and ibuprofen as alternative drugs to control the growth of cryptococcal cells. In vitro susceptibility tests, including a checkerboard assay, were performed to assess the response of Cryptococcus neoformans and Cryptococcus gattii to the above-mentioned anti-inflammatory drugs. Next, the capacity of these two drugs to induce stress as well as their mode of action in the killing of cryptococcal cells was determined. The studied fungal strains revealed a response to both aspirin and ibuprofen that was dose dependent, with ibuprofen exerting greater antimicrobial action. More importantly, the MICs of these drugs did not negatively (i) affect growth or (ii) impair the functioning of macrophages; rather, they enhanced the ability of these immune cells to phagocytose cryptococcal cells. Ibuprofen was also shown to act in synergy with fluconazole and amphotericin B. The treatment of cryptococcal cells with aspirin or ibuprofen led to stress induction via activation of the high-osmolarity glycerol (HOG) pathway, and cell death was eventually achieved through reactive oxygen species (ROS)-mediated membrane damage. The presented data highlight the potential clinical application of aspirin and ibuprofen as candidate anti-Cryptococcus drugs. PMID:27246782

  7. AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders.

    Science.gov (United States)

    Ivachtchenko, Alexandre V; Lavrovsky, Yan; Okun, Ilya

    2016-05-25

    Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.

  8. Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction.

    Science.gov (United States)

    Banks, Matthew L; Hutsell, Blake A; Schwienteck, Kathryn L; Negus, S Stevens

    2015-06-01

    Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940's, and during the last 10-15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d -amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence.

  9. Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates.

    Science.gov (United States)

    Braggio, Simone; Montanari, Dino; Rossi, Tino; Ratti, Emiliangelo

    2010-07-01

    As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the 'optimal' absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.

  10. Detecting peptidic drugs, drug candidates and analogs in sports doping: current status and future directions.

    Science.gov (United States)

    Thevis, Mario; Thomas, Andreas; Schänzer, Wilhelm

    2014-12-01

    With the growing availability of mature systems and strategies in biotechnology and the continuously expanding knowledge of cellular processes and involved biomolecules, human sports drug testing has become a considerably complex field in the arena of analytical chemistry. Proving the exogenous origin of peptidic drugs and respective analogs at lowest concentration levels in biological specimens (commonly blood, serum and urine) of rather limited volume is required to pursue an action against cheating athletes. Therefore, approaches employing chromatographic-mass spectrometric, electrophoretic, immunological and combined test methods have been required and developed. These allow detecting the misuse of peptidic compounds of lower (such as growth hormone-releasing peptides, ARA-290, TB-500, AOD-9604, CJC-1295, desmopressin, luteinizing hormone-releasing hormones, synacthen, etc.), intermediate (e.g., insulins, IGF-1 and analogs, 'full-length' mechano growth factor, growth hormone, chorionic gonadotropin, erythropoietin, etc.) and higher (e.g., stamulumab) molecular mass with desired specificity and sensitivity. A gap between the technically possible detection and the day-to-day analytical practice, however, still needs to be closed.

  11. Preclinical quantitative MicroPET imaging in evaluation of neuroprotective drug candidates

    International Nuclear Information System (INIS)

    Son, Ji Yeon; Kim, Yu Kyeong; Kim, Ji Sun; Lee, Byung Chul; Kim, Kyeong Min; Choi, Tae Hyun; Cheon, Gi Jeong; Lee, Won Woo; Kim, Sang Eun

    2007-01-01

    Using in vivo molecular imaging with microPET/SPECT has been expected to facilitate drug discovery and development. In this study, we applied quantitative microPET to the preclinical evaluation of the effects of two neuroprotective drug candidates to the nigrostriatal dopaminergic neuronal damage. Fifteen SD rats were divided into three groups. The rats of each group were orally administrated one of neuroprotective candidate; NeuProtec (100mg/kg bid) and SureCero (10mg/kg, qd) or normal saline (0.1ml, qd) for 3 weeks. 6-OHDA was sterotactically placed to the right striatum on eighth day after starting while continuing the medication for additional 14 days. [ 124 I]FP-ClT PET scans were obtained using microPET R4 scanner. The behavioral test by amphetamine-induced rotation and the histological examination after thyrosine hydroxylase (TH) immunohistochemical staining were performed. Different uptake in the lesioned striatum among the groups were demonstrated on [ 124 I]FP-CIT PET images. The rats with NeuProtec showed higher binding in the lesion than controls. No differences were observed in SureCere groups. The FP-CIT uptake in the lesioned striatum was well correlated with the % reduction of TH(+) cells (rho =0.73, p=0.025), and also correlated with rotation test (rho =0.79, p=0.001) [ 124 I]FP-CIT animal PET depicted the neuroprotective effects of NeuProtec to the 6-OHDA neurotoxicity in the rat striatum. No demonstrable effect of SureCero might indicate that inadequate dosage was used in this study. MicroPET imaging with small animal could be a great tool in preclinical evaluation of drug efficacy

  12. Flavonoids and terpenoids from Croton muscicarpa (Euphorbiaceae)

    Energy Technology Data Exchange (ETDEWEB)

    Barreto, Milena B.; Gomes, Clerton L.; Freitas, Joao Vito B. de; Pinto, Francisco das Chagas L.; Silveira, Edilberto R.; Gramosa, Nilce V., E-mail: nilce@dqoi.ufc.br [Departamento de Quimica Organica e Inorganica, Centro de Ciencias, Universidade Federal do Ceara, Fortaleza (Brazil); Torres, Daniela S. Carneiro [Departamento de Ciencias Biologicas Jequie, Universidade Estadual do Sudoeste da Bahia, Jequie, BA (Brazil)

    2013-09-01

    A new sesquiterpene and twelve known compounds comprising eight flavonoids and four terpenoids, were isolated from the leaves, stems, roots and exudate of Croton muscicarpa Muell.. Arg.. Their structures were identified as the terpenoids 6{alpha}-methoxy-cyperene, dammaradienol, squalene, acetyl aleuritolic acid and spathulenol, and as the flavonoids retusin, 3,7,4'-trimethoxy kaempferol, ombuine, pachipodol, kaempferol, casticin, 5-hydroxy-3,6,7,4'-tetramethoxyflavone and artemetin. All isolated compounds were characterized based on IR, MS, {sup 1}H and {sup 13}C NMR, including 2D analyses (COSY, HSQC, HMBC, NOESY) and comparison with data from the literature. (author)

  13. Flavonoids and terpenoids from Croton muscicarpa (Euphorbiaceae)

    International Nuclear Information System (INIS)

    Barreto, Milena B.; Gomes, Clêrton L.; Freitas, João Vito B. de; Pinto, Francisco das Chagas L.; Silveira, Edilberto R.; Gramosa, Nilce V.; Torres, Daniela S. Carneiro

    2013-01-01

    A new sesquiterpene and twelve known compounds comprising eight flavonoids and four terpenoids, were isolated from the leaves, stems, roots and exudate of Croton muscicarpa Müll.. Arg.. Their structures were identified as the terpenoids 6α-methoxy-cyperene, dammaradienol, squalene, acetyl aleuritolic acid and spathulenol, and as the flavonoids retusin, 3,7,4’-trimethoxy kaempferol, ombuine, pachipodol, kaempferol, casticin, 5-hydroxy-3,6,7,4’-tetramethoxyflavone and artemetin. All isolated compounds were characterized based on IR, MS, 1 H and 13 C NMR, including 2D analyses (COSY, HSQC, HMBC, NOESY) and comparison with data from the literature. (author)

  14. Flavonoides e terpenoides de Croton muscicarpa (Euphorbiaceae

    Directory of Open Access Journals (Sweden)

    Milena B. Barreto

    2013-01-01

    Full Text Available A new sesquiterpene and twelve known compounds comprising eight flavonoids and four terpenoids, were isolated from the leaves, stems, roots and exudate of Croton muscicarpa Müll. Arg.. Their structures were identified as the terpenoids 6α-methoxy-cyperene, dammaradienol, squalene, acetyl aleuritolic acid and spathulenol, and as the flavonoids retusin, 3,7,4'-trimethoxy kaempferol, ombuine, pachipodol, kaempferol, casticin, 5-hydroxy-3,6,7,4'-tetramethoxyflavone and artemetin. All isolated compounds were characterized based on IR, MS, ¹H and 13C NMR, including 2D analyses (COSY, HSQC, HMBC, NOESY and comparison with data from the literature.

  15. Terpenoids from the Octocoral Sinularia gaweli

    Directory of Open Access Journals (Sweden)

    Wun-Jie Lin

    2015-08-01

    Full Text Available Two eudesmane sesquiterpenoids, verticillatol (1 and 5α-acetoxy-4(14-eudesmene-1β-ol (2 and two cembrane diterpenoids, (–-leptodiol acetate (3 and sinulacembranolide A (4 were isolated from the octocoral Sinularia gaweli and compounds 2–4 are new isolates. The structures of new terpenoids 2–4 were elucidated by spectroscopic methods and by comparison the spectral data with those of known analogues. Terpenoid 4 was found to inhibit the accumulation of the pro-inflammatory inducible nitric oxide synthase (iNOS protein of the lipopolysaccharide (LPS-stimulated RAW264.7 marcophage cells.

  16. Flavonoids and terpenoids from Croton muscicarpa (Euphorbiaceae)

    Energy Technology Data Exchange (ETDEWEB)

    Barreto, Milena B.; Gomes, Clerton L.; Freitas, Joao Vito B. de; Pinto, Francisco das Chagas L.; Silveira, Edilberto R.; Gramosa, Nilce V., E-mail: nilce@dqoi.ufc.br [Departamento de Quimica Organica e Inorganica, Centro de Ciencias, Universidade Federal do Ceara, Fortaleza (Brazil); Torres, Daniela S. Carneiro [Departamento de Ciencias Biologicas Jequie, Universidade Estadual do Sudoeste da Bahia, Jequie, BA (Brazil)

    2013-09-01

    A new sesquiterpene and twelve known compounds comprising eight flavonoids and four terpenoids, were isolated from the leaves, stems, roots and exudate of Croton muscicarpa Muell.. Arg.. Their structures were identified as the terpenoids 6{alpha}-methoxy-cyperene, dammaradienol, squalene, acetyl aleuritolic acid and spathulenol, and as the flavonoids retusin, 3,7,4'-trimethoxy kaempferol, ombuine, pachipodol, kaempferol, casticin, 5-hydroxy-3,6,7,4'-tetramethoxyflavone and artemetin. All isolated compounds were characterized based on IR, MS, {sup 1}H and {sup 13}C NMR, including 2D analyses (COSY, HSQC, HMBC, NOESY) and comparison with data from the literature. (author)

  17. Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.

    Science.gov (United States)

    Aflaki, Elma; Stubblefield, Barbara K; Maniwang, Emerson; Lopez, Grisel; Moaven, Nima; Goldin, Ehud; Marugan, Juan; Patnaik, Samarjit; Dutra, Amalia; Southall, Noel; Zheng, Wei; Tayebi, Nahid; Sidransky, Ellen

    2014-06-11

    Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. Available cell lines modeling Gaucher disease do not demonstrate lysosomal storage of glycolipids; therefore, we set out to develop two macrophage models of Gaucher disease that exhibit appropriate substrate accumulation. We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candidate drugs for its treatment. We generated and characterized monocyte-derived macrophages from 20 patients carrying different Gaucher disease mutations. In addition, we created induced pluripotent stem cell (iPSC)-derived macrophages from five fibroblast lines taken from patients with type 1 or type 2 Gaucher disease. Macrophages derived from patient monocytes or iPSCs showed reduced glucocerebrosidase activity and increased storage of glucocerebroside and glucosylsphingosine in lysosomes. These macrophages showed efficient phagocytosis of bacteria but reduced production of intracellular reactive oxygen species and impaired chemotaxis. The disease phenotype was reversed with a noninhibitory small-molecule chaperone drug that enhanced glucocerebrosidase activity in the macrophages, reduced glycolipid storage, and normalized chemotaxis and production of reactive oxygen species. Macrophages differentiated from patient monocytes or patient-derived iPSCs provide cellular models that can be used to investigate disease pathogenesis and facilitate drug development. Copyright © 2014, American Association for the Advancement of Science.

  18. In vitro resistance profile of the candidate HIV-1 microbicide drug dapivirine.

    Science.gov (United States)

    Schader, Susan M; Oliveira, Maureen; Ibanescu, Ruxandra-Ilinca; Moisi, Daniela; Colby-Germinario, Susan P; Wainberg, Mark A

    2012-02-01

    Antiretroviral-based microbicides may offer a means to reduce the sexual transmission of HIV-1. Suboptimal use of a microbicide may, however, lead to the development of drug resistance in users that are already, or become, infected with HIV-1. In such cases, the efficacy of treatments may be compromised since the same (or similar) antiretrovirals used in treatments are being developed as microbicides. To help predict which drug resistance mutations may develop in the context of suboptimal use, HIV-1 primary isolates of different subtypes and different baseline resistance profiles were used to infect primary cells in vitro in the presence of increasing suboptimal concentrations of the two candidate microbicide antiretrovirals dapivirine (DAP) and tenofovir (TFV) alone or in combination. Infections were ongoing for 25 weeks, after which reverse transcriptase genotypes were determined and scrutinized for the presence of any clinically recognized reverse transcriptase drug resistance mutations. Results indicated that suboptimal concentrations of DAP alone facilitated the emergence of common nonnucleoside reverse transcriptase inhibitor resistance mutations, while suboptimal concentrations of DAP plus TFV gave rise to fewer mutations. Suboptimal concentrations of TFV alone did not frequently result in the development of resistance mutations. Sensitivity evaluations for stavudine (d4T), nevirapine (NVP), and lamivudine (3TC) revealed that the selection of resistance as a consequence of suboptimal concentrations of DAP may compromise the potential for NVP to be used in treatment, a finding of potential relevance in developing countries.

  19. Methods and materials for production of terpenoids

    DEFF Research Database (Denmark)

    2015-01-01

    The invention provide novel methods for production of terpenoids. The methods take advantage of combinations of enzymes, which are not present in nature. Thus the methods involves use of host organisms expressing a diTPS of class II, diTPS of class I, and one or more CYPs....

  20. Proteomic candidate biomarkers of drug-induced nephrotoxicity in the rat.

    Directory of Open Access Journals (Sweden)

    Rodney Rouse

    Full Text Available Improved biomarkers of acute nephrotoxicity are coveted by the drug development industry, regulatory agencies, and clinicians. In an effort to identify such biomarkers, urinary peptide profiles of rats treated with two different nephrotoxins were investigated. 493 marker candidates were defined that showed a significant response to cis-platin comparing a cis-platin treated cohort to controls. Next, urine samples from rats that received three consecutive daily doses of 150 or 300 mg/kg gentamicin were examined. 557 potential biomarkers were initially identified; 108 of these gentamicin-response markers showed a clear temporal response to treatment. 39 of the cisplatin-response markers also displayed a clear response to gentamicin. Of the combined 147 peptides, 101 were similarly regulated by gentamicin or cis-platin and 54 could be identified by tandem mass spectrometry. Most were collagen type I and type III fragments up-regulated in response to gentamicin treatment. Based on these peptides, classification models were generated and validated in a longitudinal study. In agreement with histopathology, the observed changes in classification scores were transient, initiated after the first dose, and generally persistent over a period of 10-20 days before returning to control levels. The data support the hypothesis that gentamicin-induced renal toxicity up-regulates protease activity, resulting in an increase in several specific urinary collagen fragments. Urinary proteomic biomarkers identified here, especially those common to both nephrotoxins, may serve as a valuable tool to investigate potential new drug candidates for the risk of nephrotoxicity.

  1. Medicinal benefits of marine invertebrates: sources for discovering natural drug candidates.

    Science.gov (United States)

    De Zoysa, Mahanama

    2012-01-01

    Marine invertebrates are one of the major groups of organisms, which could be diversified under the major taxonomic groups of Porifera, Cnidaria, Mollusca, Arthropoda, Echinodermata, and many other minor phyla. To date, range of medicinal benefits and a significant number of marine natural products (MNPs) have been discovered from marine invertebrates. Seafood diet from edible marine invertebrates such as mollusks and crustaceans has been linked with various medicinal benefits to improve human health. Among marine invertebrates, spongers from phylum Porifera is the most dominant group responsible for discovering large number of MNPs, which have been used as template to develop therapeutic drugs. MNPs isolated from invertebrates have shown wide range of therapeutic properties including antimicrobial, antioxidant, antihypertensive, anticoagulant, anticancer, anti-inflammatory, wound healing and immune modulator, and other medicinal effects. Therefore, marine invertebrates are rich sources of chemical diversity and health benefits for developing drug candidates, cosmetics, nutritional supplements, and molecular probes that can be supported to increase the healthy life span of human. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept.

    Science.gov (United States)

    Muenster, Uwe; Mueck, Wolfgang; van der Mey, Dorina; Schlemmer, Karl-Heinz; Greschat-Schade, Susanne; Haerter, Michael; Pelzetter, Christian; Pruemper, Christian; Verlage, Joerg; Göller, Andreas H; Ohm, Andreas

    2016-05-01

    The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. In vitro production of huperzine A, a promising drug candidate for Alzheimer's disease.

    Science.gov (United States)

    Ma, Xiaoqiang; Gang, David R

    2008-07-01

    Alzheimer's disease (AD) is growing in impact on human health. With no known cure, AD is one of the most expensive diseases in the world to treat. Huperzine A (HupA), a anti-AD drug candidate from the traditional Chinese medicine Qian Ceng Ta (Huperzia serrata), has been shown to be a powerful and selective inhibitor of acetylcholinesterase and has attracted widespread attention because of its unique pharmacological activities and low toxicity. As a result, HupA is becoming an important lead compound for drugs to treat AD. HupA is obtained naturally from very limited and slowly growing natural resources, members of the Huperziaceae. Unfortunately, the content of HupA is very low in the raw plant material. This has led to strong interest in developing sources of HupA. We have developed a method to propagate in vitro tissues of Phlegmariurus squarrosus, a member of the Huperziaceae, that produce high levels of HupA. The in vitro propagated tissues produce even higher levels of HupA than the natural plant, and may represent an excellent source for HupA.

  4. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening

    Directory of Open Access Journals (Sweden)

    Pothineni VR

    2016-04-01

    Full Text Available Venkata Raveendra Pothineni,1 Dhananjay Wagh,1 Mustafeez Mujtaba Babar,1 Mohammed Inayathullah,1 David Solow-Cordero,2 Kwang-Min Kim,1 Aneesh V Samineni,1 Mansi B Parekh,1 Lobat Tayebi,3 Jayakumar Rajadas1 1Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, 2Chemical & Systems Biology, Stanford University School of Medicine, Stanford, CA, 3Department of Developmental Sciences, Marquette University School of Dentistry, Milwaukee, WI, USA Abstract: Lyme disease is the most common zoonotic bacterial disease in North America. It is estimated that >300,000 cases per annum are reported in USA alone. A total of 10%–20% of patients who have been treated with antibiotic therapy report the recrudescence of symptoms, such as muscle and joint pain, psychosocial and cognitive difficulties, and generalized fatigue. This condition is referred to as posttreatment Lyme disease syndrome. While there is no evidence for the presence of viable infectious organisms in individuals with posttreatment Lyme disease syndrome, some researchers found surviving Borrelia burgdorferi population in rodents and primates even after antibiotic treatment. Although such observations need more ratification, there is unmet need for developing the therapeutic agents that focus on removing the persisting bacterial form of B. burgdorferi in rodent and nonhuman primates. For this purpose, high-throughput screening was done using BacTiter-Glo assay for four compound libraries to identify candidates that stop the growth of B. burgdorferi in vitro. The four chemical libraries containing 4,366 compounds (80% Food and Drug Administration [FDA] approved that were screened are Library of Pharmacologically Active Compounds (LOPAC1280, the National Institutes of Health Clinical Collection, the Microsource Spectrum, and the Biomol FDA. We subsequently identified 150

  5. New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    2018-03-01

    Full Text Available Medullary thyroid cancer (MTC is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1 plays a pivotal role in regulating the proliferation and apoptosis of a variety of tumor cells. Based on the NR4A1 protein structure, 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA was identified from the Specs compounds database using the protein structure-guided virtual screening approach. Computationally-based molecular modeling studies suggested that IMCA has a high affinity for the ligand binding pocket of NR4A1. MTT [3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2-H-tetrazolium bromide] and apoptosis assays demonstrated that IMCA resulted in significant thyroid cancer cell death. Immunofluorescence assays showed that IMCA induced NR4A1 translocation from the nucleus to the cytoplasm in thyroid cancer cell lines, which may be involved in the cell apoptotic process. In this study, the quantitative polymerase chain reaction results showed that the IMCA-induced upregulation of sestrin1 and sestrin2 was dose-dependent in thyroid cancer cell lines. Western blot showed that IMCA increased phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK and decreased phosphorylation of ribosomal protein S6 kinase (p70S6K, which is the key enzyme in the mammalian target of rapamycin (mTOR pathway. The experimental results suggest that IMCA is a drug candidate for MTC therapy and may work by increasing the nuclear export of NR4A1 to the cytoplasm and the tumor protein 53 (p53-sestrins-AMPK-mTOR signaling pathway.

  6. New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy.

    Science.gov (United States)

    Zhang, Lei; Liu, Wen; Wang, Qun; Li, Qinpei; Wang, Huijuan; Wang, Jun; Teng, Tieshan; Chen, Mingliang; Ji, Ailing; Li, Yanzhang

    2018-03-02

    Medullary thyroid cancer (MTC) is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1) plays a pivotal role in regulating the proliferation and apoptosis of a variety of tumor cells. Based on the NR4A1 protein structure, 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) was identified from the Specs compounds database using the protein structure-guided virtual screening approach. Computationally-based molecular modeling studies suggested that IMCA has a high affinity for the ligand binding pocket of NR4A1. MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] and apoptosis assays demonstrated that IMCA resulted in significant thyroid cancer cell death. Immunofluorescence assays showed that IMCA induced NR4A1 translocation from the nucleus to the cytoplasm in thyroid cancer cell lines, which may be involved in the cell apoptotic process. In this study, the quantitative polymerase chain reaction results showed that the IMCA-induced upregulation of sestrin1 and sestrin2 was dose-dependent in thyroid cancer cell lines. Western blot showed that IMCA increased phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and decreased phosphorylation of ribosomal protein S6 kinase (p70S6K), which is the key enzyme in the mammalian target of rapamycin (mTOR) pathway. The experimental results suggest that IMCA is a drug candidate for MTC therapy and may work by increasing the nuclear export of NR4A1 to the cytoplasm and the tumor protein 53 (p53)-sestrins-AMPK-mTOR signaling pathway.

  7. Biochemical Characterization of Glutamate Racemase-A New Candidate Drug Target against Burkholderia cenocepacia Infections.

    Directory of Open Access Journals (Sweden)

    Aygun Israyilova

    Full Text Available The greatest obstacle for the treatment of cystic fibrosis patients infected with the Burkholderia species is their intrinsic antibiotic resistance. For this reason, there is a need to develop new effective compounds. Glutamate racemase, an essential enzyme for the biosynthesis of the bacterial cell wall, is an excellent candidate target for the design of new antibacterial drugs. To this aim, we recombinantly produced and characterized glutamate racemase from Burkholderia cenocepacia J2315. From the screening of an in-house library of compounds, two Zn (II and Mn (III 1,3,5-triazapentadienate complexes were found to efficiently inhibit the glutamate racemase activity with IC50 values of 35.3 and 10.0 μM, respectively. Using multiple biochemical approaches, the metal complexes have been shown to affect the enzyme activity by binding to the enzyme-substrate complex and promoting the formation of an inhibited dimeric form of the enzyme. Our results corroborate the value of glutamate racemase as a good target for the development of novel inhibitors against Burkholderia.

  8. Natural product terpenoids in Eocene and Miocene conifer fossils.

    Science.gov (United States)

    Otto, Angelika; White, James D; Simoneit, Bernd R T

    2002-08-30

    Numerous saturated and aromatic hydrocarbons, but not polar compounds, originating from plants and microorganisms (biomarkers) have been reported in sediments, coals, and petroleum. Here we describe natural product terpenoids found in two fossil conifers, Taxodium balticum (Eocene) and Glyptostrobus oregonensis (Miocene). A similar terpenoid pattern is also observed in extant Taxodium distichum. The preservation of characteristic terpenoids (unaltered natural products) in the fossil conifers supports their systematic assignment to the Cypress family (Cupressaceae sensu lato). The results also show that fossil conifers can contain polar terpenoids, which are valuable markers for (paleo)chemosystematics and phylogeny.

  9. Static magnetic field exposure reproduces cellular effects of the Parkinson's disease drug candidate ZM241385.

    Directory of Open Access Journals (Sweden)

    Zhiyun Wang

    2010-11-01

    Full Text Available This study was inspired by coalescing evidence that magnetic therapy may be a viable treatment option for certain diseases. This premise is based on the ability of moderate strength fields (i.e., 0.1 to 1 Tesla to alter the biophysical properties of lipid bilayers and in turn modulate cellular signaling pathways. In particular, previous results from our laboratory (Wang et al., BMC Genomics, 10, 356 (2009 established that moderate strength static magnetic field (SMF exposure altered cellular endpoints associated with neuronal function and differentiation. Building on this background, the current paper investigated SMF by focusing on the adenosine A(2A receptor (A(2AR in the PC12 rat adrenal pheochromocytoma cell line that displays metabolic features of Parkinson's disease (PD.SMF reproduced several responses elicited by ZM241385, a selective A(2AR antagonist, in PC12 cells including altered calcium flux, increased ATP levels, reduced cAMP levels, reduced nitric oxide production, reduced p44/42 MAPK phosphorylation, inhibited proliferation, and reduced iron uptake. SMF also counteracted several PD-relevant endpoints exacerbated by A(2AR agonist CGS21680 in a manner similar to ZM241385; these include reduction of increased expression of A(2AR, reversal of altered calcium efflux, dampening of increased adenosine production, reduction of enhanced proliferation and associated p44/42 MAPK phosphorylation, and inhibition of neurite outgrowth.When measured against multiple endpoints, SMF elicited qualitatively similar responses as ZM241385, a PD drug candidate. Provided that the in vitro results presented in this paper apply in vivo, SMF holds promise as an intriguing non-invasive approach to treat PD and potentially other neurological disorders.

  10. Static Magnetic Field Exposure Reproduces Cellular Effects of the Parkinson's Disease Drug Candidate ZM241385

    Science.gov (United States)

    Wang, Zhiyun; Che, Pao-Lin; Du, Jian; Ha, Barbara; Yarema, Kevin J.

    2010-01-01

    Background This study was inspired by coalescing evidence that magnetic therapy may be a viable treatment option for certain diseases. This premise is based on the ability of moderate strength fields (i.e., 0.1 to 1 Tesla) to alter the biophysical properties of lipid bilayers and in turn modulate cellular signaling pathways. In particular, previous results from our laboratory (Wang et al., BMC Genomics, 10, 356 (2009)) established that moderate strength static magnetic field (SMF) exposure altered cellular endpoints associated with neuronal function and differentiation. Building on this background, the current paper investigated SMF by focusing on the adenosine A2A receptor (A2AR) in the PC12 rat adrenal pheochromocytoma cell line that displays metabolic features of Parkinson's disease (PD). Methodology and Principal Findings SMF reproduced several responses elicited by ZM241385, a selective A2AR antagonist, in PC12 cells including altered calcium flux, increased ATP levels, reduced cAMP levels, reduced nitric oxide production, reduced p44/42 MAPK phosphorylation, inhibited proliferation, and reduced iron uptake. SMF also counteracted several PD-relevant endpoints exacerbated by A2AR agonist CGS21680 in a manner similar to ZM241385; these include reduction of increased expression of A2AR, reversal of altered calcium efflux, dampening of increased adenosine production, reduction of enhanced proliferation and associated p44/42 MAPK phosphorylation, and inhibition of neurite outgrowth. Conclusions and Significance When measured against multiple endpoints, SMF elicited qualitatively similar responses as ZM241385, a PD drug candidate. Provided that the in vitro results presented in this paper apply in vivo, SMF holds promise as an intriguing non-invasive approach to treat PD and potentially other neurological disorders. PMID:21079735

  11. Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety.

    Science.gov (United States)

    Meanwell, Nicholas A

    2011-09-19

    The development of small molecule drug candidates from the discovery phase to a marketed product continues to be a challenging enterprise with very low success rates that have fostered the perception of poor productivity by the pharmaceutical industry. Although there have been significant advances in preclinical profiling that have improved compound triaging and altered the underlying reasons for compound attrition, the failure rates have not appreciably changed. As part of an effort to more deeply understand the reasons for candidate failure, there has been considerable interest in analyzing the physicochemical properties of marketed drugs for the purpose of comparing with drugs in discovery and development as a means capturing recent trends in drug design. The scenario that has emerged is one in which contemporary drug discovery is thought to be focused too heavily on advancing candidates with profiles that are most easily satisfied by molecules with increased molecular weight and higher overall lipophilicity. The preponderance of molecules expressing these properties is frequently a function of increased aromatic ring count when compared with that of the drugs launched in the latter half of the 20th century and may reflect a preoccupation with maximizing target affinity rather than taking a more holistic approach to drug design. These attributes not only present challenges for formulation and absorption but also may influence the manifestation of toxicity during development. By providing some definition around the optimal physicochemical properties associated with marketed drugs, guidelines for drug design have been developed that are based largely on calculated parameters and which may readily be applied by medicinal chemists as an aid to understanding candidate quality. The physicochemical properties of a molecule that are consistent with the potential for good oral absorption were initially defined by Lipinski, with additional insights allowing further

  12. Improving yeast strains using recyclable integration cassettes, for the production of plant terpenoids

    Directory of Open Access Journals (Sweden)

    Johnson Christopher B

    2011-01-01

    Full Text Available Abstract Background Terpenoids constitute a large family of natural products, attracting commercial interest for a variety of uses as flavours, fragrances, drugs and alternative fuels. Saccharomyces cerevisiae offers a versatile cell factory, as the precursors of terpenoid biosynthesis are naturally synthesized by the sterol biosynthetic pathway. Results S. cerevisiae wild type yeast cells, selected for their capacity to produce high sterol levels were targeted for improvement aiming to increase production. Recyclable integration cassettes were developed which enable the unlimited sequential integration of desirable genetic elements (promoters, genes, termination sequence at any desired locus in the yeast genome. The approach was applied on the yeast sterol biosynthetic pathway genes HMG2, ERG20 and IDI1 resulting in several-fold increase in plant monoterpene and sesquiterpene production. The improved strains were robust and could sustain high terpenoid production levels for an extended period. Simultaneous plasmid-driven co-expression of IDI1 and the HMG2 (K6R variant, in the improved strain background, maximized monoterpene production levels. Expression of two terpene synthase enzymes from the sage species Salvia fruticosa and S. pomifera (SfCinS1, SpP330 in the modified yeast cells identified a range of terpenoids which are also present in the plant essential oils. Co-expression of the putative interacting protein HSP90 with cineole synthase 1 (SfCinS1 also improved production levels, pointing to an additional means to improve production. Conclusions Using the developed molecular tools, new yeast strains were generated with increased capacity to produce plant terpenoids. The approach taken and the durability of the strains allow successive rounds of improvement to maximize yields.

  13. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects

    Science.gov (United States)

    Russo, Ethan B

    2011-01-01

    Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL−1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. LINKED ARTICLES

  14. Terpenoids and norlignans from Metasequoia glyptostroboides.

    Science.gov (United States)

    Dong, Liao-Bin; He, Juan; Wang, Yuan-Yuan; Wu, Xing-De; Deng, Xu; Pan, Zheng-Hong; Xu, Gang; Peng, Li-Yan; Zhao, Yu; Li, Yan; Gong, Xun; Zhao, Qin-Shi

    2011-02-25

    Four new terpenoids, metaseglyptorin A (1), metasequoic acid C (2), 12α-hydroxy-8,15-isopimaradien-18-oic acid (3), and (-)-acora-2,4(14),8-trien-15-oic acid (4), and three new norlignans, metasequirins D-F (5-7), were isolated from Metasequoia glyptostroboides, together with 15 known compounds. Structures of the new compounds were determined by analysis of their spectroscopic data, and the absolute configuration of 7 was established by the modified Mosher method. All of the compounds were evaluated for cytotoxicity against five human tumor cell lines.

  15. Structure-activity relationship analysis of cytotoxic cyanoguanidines: selection of CHS 828 as candidate drug

    Directory of Open Access Journals (Sweden)

    Gullbo Joachim

    2009-06-01

    Full Text Available Abstract Background N-(6-(4-chlorophenoxyhexyl-N'-cyano-N''-4-pyridyl guanidine (CHS 828 is the first candidate drug from a novel group of anti-tumour agents – the pyridyl cyanoguanidines, shown to be potent compounds interfering with cellular metabolism (inhibition of nicotinamide phosphoribosyl transferase and NF-κB signalling. Substituted cyanoguanidines are also found in anti-hypertensive agents such as the potassium channel opener pinacidil (N-cyano-N'-(4-pyridyl-N''-(1,2,2-trimethylpropylguanidine and histamine-II receptor antagonists (e.g. cimetidine, N-cyano-N'-methyl-N''-[2-[[(5-methylimidazol-4-yl]methyl]thio]ethylguanidine. In animal studies, CHS 828 has shown very promising activity, and phase I and II studies resulted in further development of a with a water soluble prodrug. Findings To study the structural requirements for cyanoguanidine cytotoxicity a set of 19 analogues were synthesized. The cytotoxic effects were then studied in ten cell lines selected for different origins and mechanisms of resistance, using the fluorometric microculture cytotoxicity assay (FMCA. The compounds showed varying cytotoxic activity even though the dose-response curves for some analogues were very shallow. Pinacidil and cimetidine were found to be non-toxic in all ten cell lines. Starting with cyanoguanidine as the crucial core it was shown that 4-pyridyl substitution was more efficient than was 3-pyridyl substitution. The 4-pyridyl cyanoguanidine moiety should be linked by an alkyl chain, optimally a hexyl, heptyl or octyl chain, to a bulky end group. The exact composition of this end group did not seem to be of crucial importance; when the end group was a mono-substituted phenyl ring it was shown that the preferred position was 4-substitution, followed by 3- and, finally, 2-substitution as the least active. Whether the substituent was a chloro, nitro or methoxy substituent seemed to be of minor importance. Finally, the activity patterns in the

  16. Volatile science? Metabolic engineering of terpenoids in plants

    NARCIS (Netherlands)

    Aharoni, A.; Jongsma, M.A.; Bouwmeester, H.J.

    2005-01-01

    Terpenoids are important for plant survival and also possess biological properties that are beneficial to humans. Here, we describe the state of the art in terpenoid metabolic engineering, showing that significant progress has been made over the past few years. Subcellular targeting of enzymes has

  17. Terpenoid antifeedants against insects : a behavioural and sensory study

    NARCIS (Netherlands)

    Messchendorp, L.

    1998-01-01

    This thesis describes a study on the behavioural and sensory effects of terpenoid antifeedants on several insect species. The main aim was to elucidate the mechanisms of action of terpenoid antifeedants. From a fundamental point of view, this will yield insight in the role of these

  18. A strategy to find novel candidate anti-Alzheimer's disease drugs by constructing interaction networks between drug targets and natural compounds in medical plants.

    Science.gov (United States)

    Chen, Bi-Wen; Li, Wen-Xing; Wang, Guang-Hui; Li, Gong-Hua; Liu, Jia-Qian; Zheng, Jun-Juan; Wang, Qian; Li, Hui-Juan; Dai, Shao-Xing; Huang, Jing-Fei

    2018-01-01

    Alzheimer' disease (AD) is an ultimately fatal degenerative brain disorder that has an increasingly large burden on health and social care systems. There are only five drugs for AD on the market, and no new effective medicines have been discovered for many years. Chinese medicinal plants have been used to treat diseases for thousands of years, and screening herbal remedies is a way to develop new drugs. We used molecular docking to screen 30,438 compounds from Traditional Chinese Medicine (TCM) against a comprehensive list of AD target proteins. TCM compounds in the top 0.5% of binding affinity scores for each target protein were selected as our research objects. Structural similarities between existing drugs from DrugBank database and selected TCM compounds as well as the druggability of our candidate compounds were studied. Finally, we searched the CNKI database to obtain studies on anti-AD Chinese plants from 2007 to 2017, and only clinical studies were included. A total of 1,476 compounds (top 0.5%) were selected as drug candidates. Most of these compounds are abundantly found in plants used for treating AD in China, especially the plants from two genera Panax and Morus. We classified the compounds by single target and multiple targets and analyzed the interactions between target proteins and compounds. Analysis of structural similarity revealed that 17 candidate anti-AD compounds were structurally identical to 14 existing approved drugs. Most of them have been reported to have a positive effect in AD. After filtering for compound druggability, we identified 11 anti-AD compounds with favorable properties, seven of which are found in anti-AD Chinese plants. Of 11 anti-AD compounds, four compounds 5,862, 5,863, 5,868, 5,869 have anti-inflammatory activity. The compound 28,814 mainly has immunoregulatory activity. The other six compounds have not yet been reported for any biology activity at present. Natural compounds from TCM provide a broad prospect for the

  19. Exoproteome and Secretome Derived Broad Spectrum Novel Drug and Vaccine Candidates in Vibrio cholerae Targeted by Piper betel Derived Compounds

    Science.gov (United States)

    Barh, Debmalya; Barve, Neha; Gupta, Krishnakant; Chandra, Sudha; Jain, Neha; Tiwari, Sandeep; Leon-Sicairos, Nidia; Canizalez-Roman, Adrian; Rodrigues dos Santos, Anderson; Hassan, Syed Shah; Almeida, Síntia; Thiago Jucá Ramos, Rommel; Augusto Carvalho de Abreu, Vinicius; Ribeiro Carneiro, Adriana; de Castro Soares, Siomar; Luiz de Paula Castro, Thiago; Miyoshi, Anderson; Silva, Artur; Kumar, Anil; Narayan Misra, Amarendra; Blum, Kenneth; Braverman, Eric R.; Azevedo, Vasco

    2013-01-01

    Vibrio cholerae is the causal organism of the cholera epidemic, which is mostly prevalent in developing and underdeveloped countries. However, incidences of cholera in developed countries are also alarming. Because of the emergence of new drug-resistant strains, even though several generic drugs and vaccines have been developed over time, Vibrio infections remain a global health problem that appeals for the development of novel drugs and vaccines against the pathogen. Here, applying comparative proteomic and reverse vaccinology approaches to the exoproteome and secretome of the pathogen, we have identified three candidate targets (ompU, uppP and yajC) for most of the pathogenic Vibrio strains. Two targets (uppP and yajC) are novel to Vibrio, and two targets (uppP and ompU) can be used to develop both drugs and vaccines (dual targets) against broad spectrum Vibrio serotypes. Using our novel computational approach, we have identified three peptide vaccine candidates that have high potential to induce both B- and T-cell-mediated immune responses from our identified two dual targets. These two targets were modeled and subjected to virtual screening against natural compounds derived from Piper betel. Seven compounds were identified first time from Piper betel to be highly effective to render the function of these targets to identify them as emerging potential drugs against Vibrio. Our preliminary validation suggests that these identified peptide vaccines and betel compounds are highly effective against Vibrio cholerae. Currently we are exhaustively validating these targets, candidate peptide vaccines, and betel derived lead compounds against a number of Vibrio species. PMID:23382822

  20. Exoproteome and secretome derived broad spectrum novel drug and vaccine candidates in Vibrio cholerae targeted by Piper betel derived compounds.

    Directory of Open Access Journals (Sweden)

    Debmalya Barh

    Full Text Available Vibrio cholerae is the causal organism of the cholera epidemic, which is mostly prevalent in developing and underdeveloped countries. However, incidences of cholera in developed countries are also alarming. Because of the emergence of new drug-resistant strains, even though several generic drugs and vaccines have been developed over time, Vibrio infections remain a global health problem that appeals for the development of novel drugs and vaccines against the pathogen. Here, applying comparative proteomic and reverse vaccinology approaches to the exoproteome and secretome of the pathogen, we have identified three candidate targets (ompU, uppP and yajC for most of the pathogenic Vibrio strains. Two targets (uppP and yajC are novel to Vibrio, and two targets (uppP and ompU can be used to develop both drugs and vaccines (dual targets against broad spectrum Vibrio serotypes. Using our novel computational approach, we have identified three peptide vaccine candidates that have high potential to induce both B- and T-cell-mediated immune responses from our identified two dual targets. These two targets were modeled and subjected to virtual screening against natural compounds derived from Piper betel. Seven compounds were identified first time from Piper betel to be highly effective to render the function of these targets to identify them as emerging potential drugs against Vibrio. Our preliminary validation suggests that these identified peptide vaccines and betel compounds are highly effective against Vibrio cholerae. Currently we are exhaustively validating these targets, candidate peptide vaccines, and betel derived lead compounds against a number of Vibrio species.

  1. Regulation of Floral Terpenoid Emission and Biosynthesis in Sweet Basil (Ocimum basilicum).

    Science.gov (United States)

    Jiang, Yifan; Ye, Jiayan; Li, Shuai; Niinemets, Ülo

    2016-12-01

    Past studies have focused on the composition of essential oil of Ocimum basilicum leaves, but data on composition and regulation of its aerial emissions, especially floral volatile emissions are scarce. We studied the chemical profile, within-flower spatial distribution (sepals, petals, pistils with stamina and pedicels), diurnal emission kinetics and effects of exogenous methyl jasmonate (MeJA) application on the emission of floral volatiles by dynamic headspace collection and identification using gas chromatography-mass spectrometry (GC-MS) and proton transfer reaction mass spectrometry (PTR-MS). We observed more abundant floral emissions from flowers compared with leaves. Sepals were the main emitters of floral volatiles among the flower parts studied. The emissions of lipoxygenase compounds (LOX) and monoterpenoids, but not sesquiterpene emissions, displayed a diurnal variation driven by light. Response to exogenous MeJA treatment of flowers consisted of a rapid stress response and a longer-term acclimation response. The initial response was associated with enhanced emissions of fatty acid derivatives, monoterpenoids, and sesquiterpenoids without variation of the composition of individual compounds. The longer-term response was associated with enhanced monoterpenoid and sesquiterpenoid emissions with profound changes in the emission spectrum. According to correlated patterns of terpenoid emission changes upon stress, highlighted by a hierarchical cluster analysis, candidate terpenoid synthases responsible for observed diversity and complexity of released terpenoid blends were postulated. We conclude that flower volatile emissions differ quantitatively and qualitatively from leaf emissions, and overall contribute importantly to O. basilicum flavor, especially under stress conditions.

  2. Regulation of Floral Terpenoid Emission and Biosynthesis in Sweet Basil (Ocimum basilicum)

    Science.gov (United States)

    Jiang, Yifan; Ye, Jiayan; Li, Shuai; Niinemets, Ülo

    2018-01-01

    Past studies have focused on the composition of essential oil of Ocimum basilicum leaves, but data on composition and regulation of its aerial emissions, especially floral volatile emissions are scarce. We studied the chemical profile, within-flower spatial distribution (sepals, petals, pistils with stamina and pedicels), diurnal emission kinetics and effects of exogenous methyl jasmonate (MeJA) application on the emission of floral volatiles by dynamic headspace collection and identification using gas chromatography-mass spectrometry (GC-MS) and proton transfer reaction mass spectrometry (PTR-MS). We observed more abundant floral emissions from flowers compared with leaves. Sepals were the main emitters of floral volatiles among the flower parts studied. The emissions of lipoxygenase compounds (LOX) and monoterpenoids, but not sesquiterpene emissions, displayed a diurnal variation driven by light. Response to exogenous MeJA treatment of flowers consisted of a rapid stress response and a longer-term acclimation response. The initial response was associated with enhanced emissions of fatty acid derivatives, monoterpenoids, and sesquiterpenoids without variation of the composition of individual compounds. The longer-term response was associated with enhanced monoterpenoid and sesquiterpenoid emissions with profound changes in the emission spectrum. According to correlated patterns of terpenoid emission changes upon stress, highlighted by a hierarchical cluster analysis, candidate terpenoid synthases responsible for observed diversity and complexity of released terpenoid blends were postulated. We conclude that flower volatile emissions differ quantitatively and qualitatively from leaf emissions, and overall contribute importantly to O. basilicum flavor, especially under stress conditions. PMID:29367803

  3. The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

    Energy Technology Data Exchange (ETDEWEB)

    Marks, Louise, E-mail: louise.marks@astrazeneca.com [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Kirk, Sarah [Innovative Medicines, Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Valentin, Jean-Pierre [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom)

    2012-09-01

    Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt{sub max} and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability.

  4. The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

    International Nuclear Information System (INIS)

    Marks, Louise; Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew; Kirk, Sarah; Valentin, Jean-Pierre

    2012-01-01

    Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt max and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability. ► Haemodynamic

  5. Trafficking of drug candidates relevant for sports drug testing: detection of non-approved therapeutics categorized as anabolic and gene doping agents in products distributed via the Internet.

    Science.gov (United States)

    Thevis, Mario; Geyer, Hans; Thomas, Andreas; Schänzer, Wilhelm

    2011-05-01

    Identifying the use of non-approved drugs by cheating athletes has been a great challenge for doping control laboratories. This is due to the additional complexities associated with identifying relatively unknown and uncharacterized compounds and their metabolites as opposed to known and well-studied therapeutics. In 2010, the prohibited drug candidates and gene doping substances AICAR and GW1516, together with the selective androgen receptor modulator (SARM) MK-2866 were obtained by the Cologne Doping Control Laboratory from Internet suppliers and their structure, quantity, and formulation elucidated. All three compounds proved authentic as determined by liquid chromatography-high resolution/high accuracy (tandem) mass spectrometry and comparison to reference material. While AICAR was provided as a colourless powder in 100 mg aliquots, GW1516 was obtained as an orange/yellow suspension in water/glycerol (150 mg/ml), and MK-2866 (25 mg/ml) was shipped dissolved in polyethylene glycol (PEG) 300. In all cases, the quantified amounts were considerably lower than indicated on the label. The substances were delivered via courier, with packaging identifying them as containing 'amino acids' and 'green tea extract', arguably to circumvent customs control. Although all of the substances were declared 'for research only', their potential misuse in illicit performance-enhancement cannot be excluded; moreover sports drug testing authorities should be aware of the facile availability of black market copies of these drug candidates. Copyright © 2011 John Wiley & Sons, Ltd.

  6. Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates

    Directory of Open Access Journals (Sweden)

    Fatma E. El-Khouly

    2017-10-01

    Full Text Available Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG, patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB. We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%—carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole—are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG.

  7. Parenteral formulation of an antileishmanial drug candidate--tackling poor solubility, chemical instability, and polymorphism.

    Science.gov (United States)

    Kupetz, Eva; Preu, Lutz; Kunick, Conrad; Bunjes, Heike

    2013-11-01

    The paullon chalcone derivative KuRei300 is active against Leishmania donovani, the protozoans causing visceral leishmaniasis. The aim of this study was the development of a parenteral formulation of the virtually water insoluble compound in order to enable future studies in mice. Mixed lecithin/bile salt micelles, liposomes, supercooled smectic cholesterol myristate nanoparticles, cubic phase nanoparticles and a triglyceride emulsion were screened for their solubilizing properties. Due to the limited available amount of KuRei300 a passive loading approach with pre-formulated carriers that were incubated with drug substance deposited onto the walls of glass vials was used. The loading capacities of the nanocarriers, the influence of the solid state properties of the drug and its deposits on the loading results and chemical stability aspects of KuRei300 were investigated. Employed methods included HPLC, UV spectroscopy, (1)H NMR, XRPD, and DSC. All nanocarriers substantially improved the solubility of KuRei300; the mixed micelles exhibited the highest drug load. Related to the lipid matrix, however, the smectic nanoparticles solubilized the significantly highest amount of drug. Loading from physically altered drug deposits improved the obtainable concentration to the threefold compared with untreated drug powder. Formulations with KuRei300 must be stored excluded from light under a nitrogen atmosphere as the substance is susceptible to photoisomerization and decomposition. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Polymeric nanoparticles affect the intracellular delivery, antiretroviral activity and cytotoxicity of the microbicide drug candidate dapivirine.

    Science.gov (United States)

    das Neves, José; Michiels, Johan; Ariën, Kevin K; Vanham, Guido; Amiji, Mansoor; Bahia, Maria Fernanda; Sarmento, Bruno

    2012-06-01

    To assess the intracellular delivery, antiretroviral activity and cytotoxicity of poly(ε-caprolactone) (PCL) nanoparticles containing the antiretroviral drug dapivirine. Dapivirine-loaded nanoparticles with different surface properties were produced using three surface modifiers: poloxamer 338 NF (PEO), sodium lauryl sulfate (SLS) and cetyl trimethylammonium bromide (CTAB). The ability of nanoparticles to promote intracellular drug delivery was assessed in different cell types relevant for vaginal HIV transmission/microbicide development. Also, antiretroviral activity of nanoparticles was determined in different cell models, as well as their cytotoxicity. Dapivirine-loaded nanoparticles were readily taken up by different cells, with particular kinetics depending on the cell type and nanoparticles, resulting in enhanced intracellular drug delivery in phagocytic cells. Different nanoparticles showed similar or improved antiviral activity compared to free drug. There was a correlation between increased antiviral activity and increased intracellular drug delivery, particularly when cell models were submitted to a single initial short-course treatment. PEO-PCL and SLS-PCL nanoparticles consistently showed higher selectivity index values than free drug, contrasting with high cytotoxicity of CTAB-PCL. These results provide evidence on the potential of PCL nanoparticles to affect in vitro toxicity and activity of dapivirine, depending on surface engineering. Thus, this formulation approach may be a promising strategy for the development of next generation microbicides.

  9. Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates.

    Science.gov (United States)

    Lauschke, Volker M; Hendriks, Delilah F G; Bell, Catherine C; Andersson, Tommy B; Ingelman-Sundberg, Magnus

    2016-12-19

    The liver is an organ with critical importance for drug treatment as the disposition and response to a given drug is often determined by its hepatic metabolism. Patient-specific factors can entail increased susceptibility to drug-induced liver injury, which constitutes a major risk for drug development programs causing attrition of promising drug candidates or costly withdrawals in postmarketing stages. Hitherto, mainly animal studies and 2D hepatocyte systems have been used for the examination of human drug metabolism and toxicity. Yet, these models are far from satisfactory due to extensive species differences and because hepatocytes in 2D cultures rapidly dedifferentiate resulting in the loss of their hepatic phenotype and functionality. With the increasing comprehension that 3D cell culture systems more accurately reflect in vivo physiology, in the recent decade more and more research has focused on the development and optimization of various 3D culture strategies in an attempt to preserve liver properties in vitro. In this contribution, we critically review these developments, which have resulted in an arsenal of different static and perfused 3D models. These systems include sandwich-cultured hepatocytes, spheroid culture platforms, and various microfluidic liver or multiorgan biochips. Importantly, in many of these models hepatocytes maintain their phenotype for prolonged times, which allows probing the potential of newly developed chemical entities to cause chronic hepatotoxicity. Moreover, some platforms permit the investigation of drug action in specific genetic backgrounds or diseased hepatocytes, thereby significantly expanding the repertoire of tools to detect drug-induced liver injuries. It is concluded that the development of 3D liver models has hitherto been fruitful and that systems are now at hand whose sensitivity and specificity in detecting hepatotoxicity are superior to those of classical 2D culture systems. For the future, we highlight the

  10. Glutamic acid and its derivatives: candidates for rational design of anticancer drugs.

    Science.gov (United States)

    Ali, Imran; Wani, Waseem A; Haque, Ashanul; Saleem, Kishwar

    2013-05-01

    Throughout the history of human civilizations, cancer has been a major health problem. Its treatment has been interesting but challenging to scientists. Glutamic acid and its derivative glutamine are known to play interesting roles in cancer genesis, hence, it was realized that structurally variant glutamic acid derivatives may be designed and developed and, might be having antagonistic effects on cancer. The present article describes the state-of-art of glutamic acid and its derivatives as anticancer agents. Attempts have been made to explore the effectivity of drug-delivery systems based on glutamic acid for the delivery of anticancer drugs. Moreover, efforts have also been made to discuss the mechanism of action of glutamic acid derivatives as anticancer agents, clinical applications of glutamic acid derivatives, as well as recent developments and future perspectives of glutamic acid drug development have also been discussed.

  11. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort.

    Science.gov (United States)

    Church, Rachel J; Kullak-Ublick, Gerd A; Aubrecht, Jiri; Bonkovsky, Herbert L; Chalasani, Naga; Fontana, Robert J; Goepfert, Jens C; Hackman, Frances; King, Nicholas M P; Kirby, Simon; Kirby, Patrick; Marcinak, John; Ormarsdottir, Sif; Schomaker, Shelli J; Schuppe-Koistinen, Ina; Wolenski, Francis; Arber, Nadir; Merz, Michael; Sauer, John-Michael; Andrade, Raul J; van Bömmel, Florian; Poynard, Thierry; Watkins, Paul B

    2018-01-22

    Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of fourteen promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n=192 and =81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n=55 and =92) and DILI patients (n=98, =28, and =143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total keratin 18 (K18), caspase cleaved K18 (ccK18), glutathione S-transferase alpha (GSTα), alpha fetoprotein (AFP), arginase-1 (ARG1), osteopontin (OPN), sorbitol dehydrogenase (SDH), fatty acid binding protein (FABP1), cadherin-5 (CDH5), macrophage colony stimulating factor receptor (MCSFR), paraoxonase 1 (PON1, normalized to prothrombin protein), and leucocyte cell-derived chemotaxin-2 (LECT2). Most candidate biomarkers were significantly altered in DILI cases compared to healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase (ALT) than miR-122 and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among the healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplant within 6 months of DILI-onset. Prediction of prognosis among DILI patients using Model for End-stage Liver Disease (MELD) was improved by incorporation of K18 and MCSFR levels. GLDH appears to be more useful than miR-122 in identifying DILI patients. K18, OPN and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

  12. Yeast metabolic engineering--targeting sterol metabolism and terpenoid formation.

    Science.gov (United States)

    Wriessnegger, Tamara; Pichler, Harald

    2013-07-01

    Terpenoids comprise various structures conferring versatile functions to eukaryotes, for example in the form of prenyl-anchors they attach proteins to membranes. The physiology of eukaryotic membranes is fine-tuned by another terpenoid class, namely sterols. Evidence is accumulating that numerous membrane proteins require specific sterol structural features for function. Moreover, sterols are intermediates in the synthesis of steroids serving as hormones in higher eukaryotes. Like steroids many compounds of the terpenoid family do not contribute to membrane architecture, but serve as signalling, protective or attractant/repellent molecules. Particularly plants have developed a plenitude of terpenoid biosynthetic routes branching off early in the sterol biosynthesis pathway and, thereby, forming one of the largest groups of naturally occurring organic compounds. Many of these aromatic and volatile molecules are interesting for industrial application ranging from foods to pharmaceuticals. Combining the fortunate situation that sterol biosynthesis is highly conserved in eukaryotes with the amenability of yeasts to genetic and metabolic engineering, basically all naturally occurring terpenoids might be produced involving yeasts. Such engineered yeasts are useful for the study of biological functions and molecular interactions of terpenoids as well as for the large-scale production of high-value compounds, which are unavailable in sufficient amounts from natural sources due to their low abundance. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

    NARCIS (Netherlands)

    Mesens, N.; Crawfordb, A.D.; Menke, A.; Hung, P.D.; Goethem, F. van; Nuyts, R.; Hansen, E.; Wolterbeek, A.; Gompel, J. van; Witte, P. de; Esguerra, C.V.

    2015-01-01

    Drug-induced liver injury (DILI) is poorly predicted by single-cell-based assays, probably because of the lack of physiological interactions with other cells within the liver. An intact whole liver system such as one present in zebrafish larvae could provide added value in a screening strategy for

  14. Novel candidate metastasis genes as putative drug targets for breast cancer

    NARCIS (Netherlands)

    Roosmalen, Wilhelmina Paulina Elisabeth van

    2012-01-01

    Despite extensive studies to unravel molecular mechanisms underlying breast cancer metastasis, still 3500 women die of the results of this disease in the Netherlands each year. Improving our understanding of metastasis formation remains a challenge for further drug development. The scope of this

  15. Potential candidate genomic biomarkers of drug induced vascular injury in the rat

    International Nuclear Information System (INIS)

    Dalmas, Deidre A.; Scicchitano, Marshall S.; Mullins, David; Hughes-Earle, Angela; Tatsuoka, Kay; Magid-Slav, Michal; Frazier, Kendall S.; Thomas, Heath C.

    2011-01-01

    Drug-induced vascular injury is frequently observed in rats but the relevance and translation to humans present a hurdle for drug development. Numerous structurally diverse pharmacologic agents have been shown to induce mesenteric arterial medial necrosis in rats, but no consistent biomarkers have been identified. To address this need, a novel strategy was developed in rats to identify genes associated with the development of drug-induced mesenteric arterial medial necrosis. Separate groups (n = 6/group) of male rats were given 28 different toxicants (30 different treatments) for 1 or 4 days with each toxicant given at 3 different doses (low, mid and high) plus corresponding vehicle (912 total rats). Mesentery was collected, frozen and endothelial and vascular smooth muscle cells were microdissected from each artery. RNA was isolated, amplified and Affymetrix GeneChip® analysis was performed on selectively enriched samples and a novel panel of genes representing those which showed a dose responsive pattern for all treatments in which mesenteric arterial medial necrosis was histologically observed, was developed and verified in individual endothelial cell- and vascular smooth muscle cell-enriched samples. Data were confirmed in samples containing mesentery using quantitative real-time RT-PCR (TaqMan™) gene expression profiling. In addition, the performance of the panel was also confirmed using similarly collected samples obtained from a timecourse study in rats given a well established vascular toxicant (Fenoldopam). Although further validation is still required, a novel gene panel has been developed that represents a strategic opportunity that can potentially be used to help predict the occurrence of drug-induced mesenteric arterial medial necrosis in rats at an early stage in drug development. -- Highlights: ► A gene panel was developed to help predict rat drug-induced mesenteric MAN. ► A gene panel was identified following treatment of rats with 28

  16. Organotin(IV) Carboxylates as Promising Potential Drug Candidates in the Field of Cancer Chemotherapy.

    Science.gov (United States)

    Sirajuddin, Muhammad; Ali, Saqib

    2016-01-01

    Medicinal inorganic chemistry plays an important role in exploring the properties of metal ions for the designing of new drugs. The field has been stimulated by the success of cis-platin, the world best selling anticancer drug and platinum complexes with reduced toxicity, oral activity and activity against resistant tumors are currently on clinical trial. The use of cis-platin is, however, severely limited by its toxic side-effects. This has stimulated chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. The discovery of new non-covalent interactions with the classical target, DNA, was the first developing step in the treatment of cancer. The use of organometallic compounds as a medicine is very common now a days because it offers potential advantages over the more common organic-based drugs. In this article we have highlighted the anticancer activity of the organotin(IV) carboxylates published in the last few years (from 2008 to 2016). In most cases they present lower IC50 values than those of cisplatin, which indicates their high activity against the cancer cell lines. The summarized data reveal that every year new organotin(IV) carboxylate complexes are synthesized with the aim of new anticancer agent with much better results than the than the corresponding activity of cis-platin or other clinically approved drugs. In addition to the advantages of high activity, compared to the platinum compound, tin complexes are much cheaper. Thus by using organotin carboxylate for clinical medicine, cost reduction, dosage reduction and effect enhancement will be reached. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Novel Tacrine-Hydroxyphenylbenzimidazole hybrids as potential multitarget drug candidates for Alzheimer's disease.

    Science.gov (United States)

    Hiremathad, Asha; Keri, Rangappa S; Esteves, A Raquel; Cardoso, Sandra M; Chaves, Sílvia; Santos, M Amélia

    2018-03-25

    Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting millions of people, with no cure so far. The current treatments only achieve some temporary amelioration of the cognition symptoms. The main characteristics of the patient brains include the accumulation of amyloid plaques and neurofibrillary tangles (outside and inside the neurons) but also cholinergic deficit, increased oxidative stress and dyshomeostasis of transition metal ions. Considering the multi-factorial nature of AD, we report herein the development of a novel series of potential multi-target directed drugs which, besides the capacity to recover the cholinergic neurons, can also target other AD hallmarks. The novel series of tacrine-hydroxyphenylbenzimidazole (TAC-BIM) hybrid molecules has been designed, synthesized and studied for their multiple biological activities. These agents showed improved AChE inhibitory activity (IC 50 in nanomolar range), as compared with the single drug tacrine (TAC), and also a high inhibition of self-induced- and Cu-induced-Aβ aggregation (up to 75%). They also present moderate radical scavenging activity and metal chelating ability. In addition, neuroprotective studies revealed that all these tested compounds are able to inhibit the neurotoxicity induced by Aβ and Fe/AscH(-) in neuronal cells. Hence, for this set of hybrids, structure-activity relationships are discussed and finally it is highlighted their real promising interest as potential anti-AD drugs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  18. Plant lectins as carriers for oral drugs: Is wheat germ agglutinin a suitable candidate?

    International Nuclear Information System (INIS)

    Dalla Pellegrina, Chiara; Rizzi, Corrado; Mosconi, Silvia; Zoccatelli, Gianni; Peruffo, Angelo; Chignola, Roberto

    2005-01-01

    Wheat germ agglutinin (WGA) is a plant protein that binds specifically to sugars expressed also by gastrointestinal epithelial cells. WGA is currently investigated as an anti-tumor drug and as a carrier for oral drugs. Information on whether it can cross the gastrointestinal epithelium and on its possible effects on the integrity of the epithelial layer is however scanty or lacking, and herein we address these issues. Differentiated Caco2 cells have been used as a model of polarized intestinal epithelium. WGA concentration at both the apical and the basolateral side of the epithelium has been quantified using a sensitive ELISA assay (sensitivity threshold 0.84 nM). Trans epithelial electrical resistance (TEER) has been measured to evaluate the integrity of the epithelium upon treatments with WGA. 3 H-Mannitol (182.2 Da) and FITC-dextran (3000 Da) have been used to measure the permeability of the epithelium. Cell viability has been measured by the MTT, by 7-AAD uptake, and Annexin-V binding assays. Up to a concentration of 5.6 μM, ∼0.1% of intact WGA molecules only could cross the epithelial layer. WGA perturbed the integrity of the epithelium and increased the permeability of the tissue in a dose- and time-dependent manner. WGA did not induce cell death but increased the permeability of individual cells to 7-AAD which is normally not uptaken by viable cells. These data allowed us to define a toxicity threshold for WGA on epithelial cells. WGA suitability as a carrier for oral drugs can therefore be evaluated on a rational basis

  19. Natural products as promising drug candidates for the treatment of Alzheimer's disease: molecular mechanism aspect.

    Science.gov (United States)

    Ansari, Niloufar; Khodagholi, Fariba

    2013-07-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder to date, with no curative or preventive therapy. Histopathological hallmarks of AD include deposition of β-amyloid plaques and formation of neurofibrillary tangles. Extent studies on pathology of the disease have made important discoveries regarding mechanism of disease and potential therapeutic targets. Many cellular changes including oxidative stress, disruption of Ca2+ homeostasis, inflammation, metabolic disturbances, and accumulation of unfolded/misfolded proteins can lead to programmed cell death in AD. Despite intensive research, only five approved drugs are available for the management of AD. Hence, there is a need to look at alternative therapies. Use of natural products and culinary herbs in medicine has gained popularity in recent years. Several natural substances with neuroprotective effects have been widely studied. Most of these compounds have remarkable antioxidant properties and act mainly by scavenging free radical species. Some of them increase cell survival and improve cognition by directly affecting amyloidogenesis and programmed cell death pathways. Further studies on these natural products and their mechanism of action, parallel with the use of novel pharmaceutical drug design and delivery techniques, enable us to offer an addition to conventional medicine. This review discussed some natural products with potential neuroprotective properties against Aβ with respect to their mechanism of action.

  20. Salt formation improved the properties of a candidate drug during early formulation development.

    Science.gov (United States)

    Sigfridsson, Kalle; Ahlqvist, Matti; Lindsjö, Martin; Paulsson, Stefan

    2018-07-30

    The purpose of this study was to investigate if AZD5329, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development as an oral immediate release (IR) solid dosage form as a final product. The neutral form of AZD5329 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Crystalline material of a maleic acid salt and a fumaric acid salt of AZD5329 were obtained. X-ray powder diffractiometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the two salts. The fumarate salt of AZD5329 is anhydrous, the crystallization is reproducible and the hygroscopicity is acceptable. Early polymorphism assessment work using slurry technique did not reveal any better crystal modification or crystallinity for the fumarate salt. For the maleate salt, the form isolated originally was found to be a solvate, but an anhydrous form was found in later experiments; by suspension in water or acetone, by drying of the solvate to 100-120 °C or by subjecting the solvate form to conditions of 40 °C/75%RH for 3 months. The dissolution behavior and the chemical stability (in aqueous solutions, formulations and solid-state) of both salts were also studied and found to be satisfactory. The compound displays sensitivity to low pH, and the salt of the maleic acid, which is the stronger acid, shows more degradation during stability studies, in line with this observation. The presented data indicate that the substance fulfils basic requirements for further development of an IR dosage form, based on the characterization on crystalline salts of AZD5329. Copyright © 2018 Elsevier B.V. All rights reserved.

  1. Viral induced oxidative and inflammatory response in Alzheimer's disease pathogenesis with identification of potential drug candidates: A systematic review using systems biology approach.

    Science.gov (United States)

    Talwar, Puneet; Gupta, Renu; Kushwaha, Suman; Agarwal, Rachna; Saso, Luciano; Kukreti, Shrikant; Kukreti, Ritushree

    2018-04-19

    Alzheimer's disease (AD) is genetically complex with multifactorial etiology. Here, we aim to identify the potential viral pathogens leading to aberrant inflammatory and oxidative stress response in AD along with potential drug candidates using systems biology approach. We retrieved protein interactions of amyloid precursor protein (APP) and tau protein (MAPT) from NCBI and genes for oxidative stress from NetAge, for inflammation from NetAge and InnateDB databases. Genes implicated in aging were retrieved from GenAge database and two GEO expression datasets. These genes were individually used to create protein-protein interaction network using STRING database (score≥0.7). The interactions of candidate genes with known viruses were mapped using virhostnet v2.0 database. Drug molecules targeting candidate genes were retrieved using the Drug-Gene Interaction Database (DGIdb). Data mining resulted in 2095 APP, 116 MAPT, 214 oxidative stress, 1269 inflammatory genes. After STRING PPIN analysis, 404 APP, 109 MAPT, 204 oxidative stress and 1014 inflammation related high confidence proteins were identified. The overlap among all datasets yielded eight common markers (AKT1, GSK3B, APP, APOE, EGFR, PIN1, CASP8 and SNCA). These genes showed association with hepatitis C virus (HCV), Epstein-Barr virus (EBV), human herpes virus 8 and Human papillomavirus (HPV). Further, screening of drugs targeting candidate genes, and possessing anti-inflammatory property, antiviral activity along with suggested role in AD pathophysiology yielded 12 potential drug candidates. Our study demonstrated the role of viral etiology in AD pathogenesis by elucidating interaction of oxidative stress and inflammation causing candidate genes with common viruses along with the identification of potential AD drug candidates. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates.

    Science.gov (United States)

    Balganesh, Meenakshi; Dinesh, Neela; Sharma, Sreevalli; Kuruppath, Sanjana; Nair, Anju V; Sharma, Umender

    2012-05-01

    Active efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. To understand these efflux mechanisms in Mycobacterium tuberculosis, we generated knockout (KO) mutants of four efflux pumps of the pathogen belonging to different classes. We measured the MICs and kill values of two different compound classes on the wild type (WT) and the efflux pump (EP) KO mutants in the presence and absence of the efflux inhibitors verapamil and l-phenylalanyl-l-arginyl-β-naphthylamide (PAβN). Among the pumps studied, the efflux pumps belonging to the ABC (ATP-binding cassette) class, encoded by Rv1218c, and the SMR (small multidrug resistance) class, encoded by Rv3065, appear to play important roles in mediating the efflux of different chemical classes and antibiotics. Efflux pumps encoded by Rv0849 and Rv1258c also mediate the efflux of these compounds, but to a lesser extent. Increased killing is observed in WT M. tuberculosis cells by these compounds in the presence of either verapamil or PAβN. The efflux pump KO mutants were more susceptible to these compounds in the presence of efflux inhibitors. We have shown that these four efflux pumps of M. tuberculosis play a vital role in mediating efflux of different chemical scaffolds. Inhibitors of one or several of these efflux pumps could have a significant impact in the treatment of tuberculosis. The identification and characterization of Rv0849, a new efflux pump belonging to the MFS (major facilitator superfamily) class, are reported.

  3. Discovery and characterization of antibody variants using mass spectrometry-based comparative analysis for biosimilar candidates of monoclonal antibody drugs.

    Science.gov (United States)

    Li, Wenhua; Yang, Bin; Zhou, Dongmei; Xu, Jun; Ke, Zhi; Suen, Wen-Chen

    2016-07-01

    Liquid chromatography mass spectrometry (LC-MS) is the most commonly used technique for the characterization of antibody variants. MAb-X and mAb-Y are two approved IgG1 subtype monoclonal antibody drugs recombinantly produced in Chinese hamster ovary (CHO) cells. We report here that two unexpected and rare antibody variants have been discovered during cell culture process development of biosimilars for these two approved drugs through intact mass analysis. We then used comprehensive mass spectrometry-based comparative analysis including reduced light, heavy chains, and domain-specific mass as well as peptide mapping analysis to fully characterize the observed antibody variants. The "middle-up" mass comparative analysis demonstrated that the antibody variant from mAb-X biosimilar candidate was caused by mass variation of antibody crystalline fragment (Fc), whereas a different variant with mass variation in antibody antigen-binding fragment (Fab) from mAb-Y biosimilar candidate was identified. Endoproteinase Lys-C digested peptide mapping and tandem mass spectrometry analysis further revealed that a leucine to glutamine change in N-terminal 402 site of heavy chain was responsible for the generation of mAb-X antibody variant. Lys-C and trypsin coupled non-reduced and reduced peptide mapping comparative analysis showed that the formation of the light-heavy interchain trisulfide bond resulted in the mAb-Y antibody variant. These two cases confirmed that mass spectrometry-based comparative analysis plays a critical role for the characterization of monoclonal antibody variants, and biosimilar developers should start with a comprehensive structural assessment and comparative analysis to decrease the risk of the process development for biosimilars. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Microbial production strategies and applications of lycopene and other terpenoids.

    Science.gov (United States)

    Ma, Tian; Deng, Zixin; Liu, Tiangang

    2016-01-01

    Terpenoids are a large class of compounds that have far-reaching applications and economic value, particularly those most commonly found in plants; however, the extraction and synthesis of these compounds is often expensive and technically challenging. Recent advances in microbial metabolic engineering comprise a breakthrough that may enable the efficient, cost-effective production of these limited natural resources. Via the engineering of safe, industrial microorganisms that encode product-specific enzymes, and even entire metabolic pathways of interest, microbial-derived semisynthetic terpenoids may soon replace plant-derived terpenoids as the primary source of these valuable compounds. Indeed, the recent metabolic engineering of an Escherichia coli strain that produces the precursor to lycopene, a commercially and medically important compound, with higher yields than those in tomato plants serves as a successful example. Here, we review the recent developments in the metabolic engineering of microbes for the production of certain terpenoid compounds, particularly lycopene, which has been increasingly used in pharmaceuticals, nutritional supplements, and cosmetics. Furthermore, we summarize the metabolic engineering strategies used to achieve successful microbial production of some similar compounds. Based on this overview, there is a reason to believe that metabolic engineering comprises an optimal approach for increasing the production of lycopene and other terpenoids.

  5. To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling.

    Science.gov (United States)

    Chew, Wee Siong; Wang, Wei; Herr, Deron R

    2016-11-01

    Sphingosine 1-phosphate (S1P) is an extracellular lipid signaling molecule that acts as a selective, high-affinity ligand for a family of five G protein-coupled receptors. This signaling system was first identified twenty years ago, and has since been shown to regulate a diverse range of physiological processes and disease states, such as cardiovascular development, immune function, hypoxic responses, and cancer. The therapeutic potential of targeting this system took center stage when it was demonstrated that the immune modulator, fingolimod (FTY720/Gilenya), exerts it lymphopenic effect by acting on S1P receptors, primarily on S1P receptor 1 (S1P 1 ). In 2010, fingolimod became the first oral medication approved for the treatment of multiple sclerosis (MS). Since then, second-generation S1P receptor modulators have been under development in an effort to provide improved safety and efficacy profiles for MS, and to broaden their use to other autoimmune indications. Beyond the development of S1P 1 -modulators, there has been considerable effort in targeting other components of the S1P signaling pathway for the treatment of other diseases, such as cardiovascular disease, sepsis, and cancer. This manuscript provides an overview of the clinical and preclinical development of drugs targeting S1P signaling. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. BIOPHARMACEUTICAL SUBSTANTIATION OF THE SOLVENT IN THE COMPOSITION OF THE IMMUNOBIOLOGICAL DRUG FOR PREVENTION AND TREATMENT OF CANDIDAL INFECTION

    Directory of Open Access Journals (Sweden)

    Rybalkin М. V

    2014-10-01

    Full Text Available Today diseases caused by potentially pathogenic microorganisms become increasingly important. This phenomenon is connected with increase of power of influence of the environment: chemical pollution, radiation, irrational use of antibiotics and hormone therapy; it leads to decrease of the immune response and human nonspecific resistance. For the last years one of the indicators of failure of the human body immune protection is chronic and local candidiases caused by potentially pathogenic fungi of Candida genus. Prevalence and risk of candidal infections determine the need for searching new medicines with a high efficiency and safety for human. Development of a vaccine for prevention and treatment of candidal infection is being actively conducted in many countries of the world. It should be noted that currently no domestic vaccine is produced in Ukraine and no candidiasis vaccines have been registered. Therefore, development of such vaccine is the topical issue of modern pharmacy and medicine. In our previous studies it was found that the immunobiological drug based on the antigens of fungi of C. albicans with the protein concentration of 3 mg/ml and C. tropicalis with the protein concentration of 5 mg/ml in the ratio of 1:1 possesses the protective and therapeutic effect. At the current stage of research it is necessary to substantiate the solvent in the composition of the immunobiological drug. The aim of this work is the experimental substantiation of the solvent in the composition of the immunobiological drug based on the antigens of C. albicans and C. tropicalis fungi. Materials and Methods. The immunobiological drug with the protein concentration of 4 mg/ml was investigated using various solvents. The following solvents was studied: water for injections, 0.9 % isotonic saline solution, phosphate buffer solution. To determine the protective and therapeutic activity of the immunobiological drug based on the antigens of C. albicans and C

  7. Evaluation of Pterin, a Promising Drug Candidate from Cyanide Degrading Bacteria.

    Science.gov (United States)

    Mahendran, Ramasamy; Thandeeswaran, Murugesan; Kiran, Gopikrishnan; Arulkumar, Mani; Ayub Nawaz, K A; Jabastin, Jayamanoharan; Janani, Balraj; Anto Thomas, Thomas; Angayarkanni, Jayaraman

    2018-06-01

    Pterin is a member of the compounds known as pteridines. They have the same nucleus of 2-amino-4-hydroxypteridine (pterin); however, the side-chain is different at the position 6, and the state of oxidation of the ring may exist in different form viz. tetrahydro, dihydro, or a fully oxidized form. In the present study, the microorganisms able to utilize cyanide, and heavy metals have been tested for the efficient production of pterin compound. The soil samples contaminated with cyanide and heavy metals were collected from Salem steel industries, Tamil Nadu, India. Out of 77 isolated strains, 40 isolates were found to utilize sodium cyanate as nitrogen source at different concentrations. However, only 13 isolates were able to tolerate maximum concentration (60 mM) of sodium cyanate and were screened for pterin production. Among the 13 isolates, only 1 organism showed maximum production of pterin, and the same was identified as Bacillus pumilus SVD06. The compound was extracted and purified by preparative high-performance liquid chromatography and analyzed by UV/visible, FTIR, and fluorescent spectrum. The antioxidant property of the purified pterin compound was determined by cyclic voltammetry. In addition, antimicrobial activity of pterin was also studied which was substantiated by antagonistic activity against Escherichia coli, and Pseudomonas aeruginosa. Besides that the pterin compound was proved to inhibit the formation of biofilm. The extracted pterin compounds could be proposed further not only for antioxidant and antimicrobial but also for its potency to aid as anticancer and psychotic drugs in future.

  8. Identification of new candidate drugs for lung cancer using chemical-chemical interactions, chemical-protein interactions and a K-means clustering algorithm.

    Science.gov (United States)

    Lu, Jing; Chen, Lei; Yin, Jun; Huang, Tao; Bi, Yi; Kong, Xiangyin; Zheng, Mingyue; Cai, Yu-Dong

    2016-01-01

    Lung cancer, characterized by uncontrolled cell growth in the lung tissue, is the leading cause of global cancer deaths. Until now, effective treatment of this disease is limited. Many synthetic compounds have emerged with the advancement of combinatorial chemistry. Identification of effective lung cancer candidate drug compounds among them is a great challenge. Thus, it is necessary to build effective computational methods that can assist us in selecting for potential lung cancer drug compounds. In this study, a computational method was proposed to tackle this problem. The chemical-chemical interactions and chemical-protein interactions were utilized to select candidate drug compounds that have close associations with approved lung cancer drugs and lung cancer-related genes. A permutation test and K-means clustering algorithm were employed to exclude candidate drugs with low possibilities to treat lung cancer. The final analysis suggests that the remaining drug compounds have potential anti-lung cancer activities and most of them have structural dissimilarity with approved drugs for lung cancer.

  9. Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness.

    Directory of Open Access Journals (Sweden)

    Els Torreele

    2010-12-01

    , 30% in rats, and 10% in dogs. Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a C(max of 500, 14171 and 13651 ng/mL respectively, and an AUC₀₋₂₄ of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats.The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.

  10. MRJP1-containing glycoproteins isolated from honey, a novel antibacterial drug candidate with broad spectrum activity against multi-drug resistant clinical isolates

    Directory of Open Access Journals (Sweden)

    Katrina eBrudzynski

    2015-07-01

    Full Text Available The emergence of extended- spectrum β-lactamase (ESBL is the underlying cause of growing antibiotic resistance among Gram-negative bacteria to β-lactam antibiotics. We recently reported the discovery of honey glycoproteins (glps that exhibited a rapid, concentration-dependent antibacterial activity against both Gram-positive Bacillus subtilis and Gram-negative Escherichia coli that resembled action of cell wall-active β-lactam drugs. Glps showed sequence identity with the Major Royal Jelly Protein 1 (MRJP1 precursor that harbors three antimicrobial peptides: Jelleins 1, 2 and 4. Here, we used semi-quantitative radial diffusion assay and broth microdilution assay to evaluate susceptibility of a number of multi-drug resistant (MDR clinical isolates to the MRJP1-contaning honey glycoproteins. The MDR bacterial strains comprised 3 MRSA, 4 Pseudomonas aeruginosa, 2 Klebsiella pneumoniae, 2 VRE and 5 Extended-spectrum beta-lactamase (ESBL identified as 1 Proteus mirabilis, 3 Escherichia coli and 1 Escherichia coli NDM. Their resistance to different classes of antibiotics was confirmed using automated system Vitek 2. MDR isolates differred in their susceptibility to glps with MIC90 values ranging from 4.8μg/ml against B. subtilis to 14.4μg/ml against ESBL K. pneumoniae, Klebsiella spp ESBL and E. coli and up to 33μg/ml against highly resistant strains of P. aeruginosa. Glps isolated from different honeys showed a similar ability to overcome bacterial resistance to β-lactams suggesting that (a their mode of action is distinct from other classes of β-lactams and that (b the common glps structure was the lead structure responsible for the activity. The results of the current study together with our previous evidence of a rapid bactericidal activity of glps demonstrate that glps possess suitable characteristics to be considered a novel antibacterial drug candidate.

  11. Ebselen, a useful tool for understanding cellular redox biology and a promising drug candidate for use in human diseases.

    Science.gov (United States)

    Noguchi, Noriko

    2016-04-01

    Ebselen is an organoselenium compound with glutathione peroxidase (GPx)-like hydroperoxide reducing activity. Moreover, ebselen has its own unique reactivity, with functions that GPx does not have, since it reacts with many kinds of thiols other than glutathione. Ebselen may affect the thioredoxin systems, through which it may contribute to regulation of cell function. With high reactivity toward thiols, hydroperoxides, and peroxynitrite, ebselen has been used as a useful tool in research on cellular redox mechanisms. Unlike α-tocopherol, ebselen does not scavenge lipid peroxyl radicals, which is another advantage of ebselen for use as a research tool in comparison with radical scavenging antioxidants. Selenium is not released from the ebselen molecule, which explains the low toxicity of ebselen. To further understand the mechanism of cellular redox biology, it should be interesting to compare the effects of ebselen with that of selenoprotein P, which supplies selenium to GPx. New medical applications of ebselen as a drug candidate for human diseases such as cancer and diabetes mellitus as well as brain stroke and ischemia will be expected. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Anticancer Activity of Linalool Terpenoid: Apoptosis Induction and ...

    African Journals Online (AJOL)

    Anticancer Activity of Linalool Terpenoid: Apoptosis Induction and Cell Cycle Arrest in ... of linalool on cell morphology and apoptotic body formation in DU145 cells ... It was observed that 4.36, 11.54, 21.88 and 15.54 % of the cells underwent ...

  13. Terpenoid composition and class of Tertiary resins from India

    Energy Technology Data Exchange (ETDEWEB)

    Dutta, Suryendu; Mallick, Monalisa; Mathews, Runcie Paul [Department of Earth Sciences, Indian Institute of Technology Bombay, Powai, Mumbai-400076 (India); Bertram, Norbert [LTA-Labor fuer Toxikologie und Analytik, Friedrichshoeher Str. 28, D-53639 Koenigswinter (Germany); Greenwood, Paul F. [John De Laeter Mass Spectrometry and WA Biogeochemitry Centres (M090), The University of Western Australia, 35 Stirling Hwy, Crawley, WA, 6009 (Australia); WA - Organic and Isotope Geochemistry Centre, Curtin University of Technology, Kent St., Bentley 6102 (Australia)

    2009-10-01

    The terpenoid composition and class of Tertiary resins preserved within lignites of Cambay, Kutch and Cauvery Basins of India have been characterized using Pyrolysis-Gas Chromatography-Mass Spectrometry (Py-GC-MS) and Fourier Transform Infrared (FTIR) Spectroscopy. Major pyrolysis products include cadalene-based C{sub 15}-bicyclic sesquiterpenoids with some C{sub 30} and C{sub 31} bicadinanes and bicadinenes typical of Class II or dammar resin. The occurrence of these terpenoids in Early Eocene sediments may extend the first appearance of Dipterocarpaceae angiosperms, the predominant source of this resin class, back to the Early Eocene epoch in India. The same terpenoid biomarkers have been detected in many SE Asian oils reflecting a close source relationship with these resins. Strong CH{sub 3} (1377 cm{sup -} {sup 1}) and other CH{sub x} (3000-2800 and 1460-1450 cm{sup -} {sup 1}) aliphatic absorptions of much larger intensity than the aromatic C = C (1560-1650 cm{sup -} {sup 1}) absorption were detected in the Indian resins by FTIR Spectroscopy, confirming the quantitative significance of the terpenoid pyrolysates. (author)

  14. Identification of novel anticancer terpenoids from Prosopis juliflora ...

    African Journals Online (AJOL)

    Purpose: To identify a novel source of terpenoid anticancer compounds from P. juliflora (Sw.) DC. (Leguminosae) pods as a medicinal substitute for cancer medicines. Methods: The pods were collected, dried and pulverized. The ethanol extract was prepared by maceration. Various phyto-constituents were detected in the ...

  15. Iodine, a Mild Reagent for the Aromatization of Terpenoids.

    Science.gov (United States)

    Domingo, Victoriano; Prieto, Consuelo; Silva, Lucia; Rodilla, Jesús M L; Quílez del Moral, José F; Barrero, Alejandro F

    2016-04-22

    Efficient procedures based on the use of iodine for the aromatization of a series of terpenoids possessing diene and homoallylic or allylic alcohol functionalities are described. Different examples are reported as a proof-of-concept study. Furthermore, iodine also proved to mediate the dehydrogenation of testosterone.

  16. Open-source approaches for the repurposing of existing or failed candidate drugs: learning from and applying the lessons across diseases.

    Science.gov (United States)

    Allarakhia, Minna

    2013-01-01

    Repurposing has the objective of targeting existing drugs and failed, abandoned, or yet-to-be-pursued clinical candidates to new disease areas. The open-source model permits for the sharing of data, resources, compounds, clinical molecules, small libraries, and screening platforms to cost-effectively advance old drugs and/or candidates into clinical re-development. Clearly, at the core of drug-repurposing activities is collaboration, in many cases progressing beyond the open sharing of resources, technology, and intellectual property, to the sharing of facilities and joint program development to foster drug-repurposing human-capacity development. A variety of initiatives under way for drug repurposing, including those targeting rare and neglected diseases, are discussed in this review and provide insight into the stakeholders engaged in drug-repurposing discovery, the models of collaboration used, the intellectual property-management policies crafted, and human capacity developed. In the case of neglected tropical diseases, it is suggested that the development of human capital be a central aspect of drug-repurposing programs. Open-source models can support human-capital development through collaborative data generation, open compound access, open and collaborative screening, preclinical and possibly clinical studies. Given the urgency of drug development for neglected tropical diseases, the review suggests elements from current repurposing programs be extended to the neglected tropical diseases arena.

  17. Comparative genomics study for the identification of drug and vaccine targets in Staphylococcus aureus: MurA ligase enzyme as a proposed candidate.

    Science.gov (United States)

    Ghosh, Soma; Prava, Jyoti; Samal, Himanshu Bhusan; Suar, Mrutyunjay; Mahapatra, Rajani Kanta

    2014-06-01

    Now-a-days increasing emergence of antibiotic-resistant pathogenic microorganisms is one of the biggest challenges for management of disease. In the present study comparative genomics, metabolic pathways analysis and additional parameters were defined for the identification of 94 non-homologous essential proteins in Staphylococcus aureus genome. Further study prioritized 19 proteins as vaccine candidates where as druggability study reports 34 proteins suitable as drug targets. Enzymes from peptidoglycan biosynthesis, folate biosynthesis were identified as candidates for drug development. Furthermore, bacterial secretory proteins and few hypothetical proteins identified in our analysis fulfill the criteria of vaccine candidates. As a case study, we built a homology model of one of the potential drug target, MurA ligase, using MODELLER (9v12) software. The model has been further selected for in silico docking study with inhibitors from the DrugBank database. Results from this study could facilitate selection of proteins for entry into drug design and vaccine production pipelines. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Microbial Cell Factories for the Production of Terpenoid Flavor and Fragrance Compounds.

    Science.gov (United States)

    Schempp, Florence M; Drummond, Laura; Buchhaupt, Markus; Schrader, Jens

    2018-03-14

    Terpenoid flavor and fragrance compounds are of high interest to the aroma industry. Microbial production offers an alternative sustainable access to the desired terpenoids independent of natural sources. Genetically engineered microorganisms can be used to synthesize terpenoids from cheap and renewable resources. Due to its modular architecture, terpenoid biosynthesis is especially well suited for the microbial cell factory concept: a platform host engineered for a high flux toward the central C 5 prenyl diphosphate precursors enables the production of a broad range of target terpenoids just by varying the pathway modules converting the C 5 intermediates to the product of interest. In this review typical terpenoid flavor and fragrance compounds marketed or under development by biotech and aroma companies are given, and the specificities of the aroma market are discussed. The main part of this work focuses on key strategies and recent advances to engineer microbes to become efficient terpenoid producers.

  19. Ursolic Acid and Oleanolic Acid: Pentacyclic Terpenoids with Promising Anti-Inflammatory Activities.

    Science.gov (United States)

    Kashyap, Dharambir; Sharma, Ajay; Tuli, Hardeep S; Punia, Sandeep; Sharma, Anil K

    2016-01-01

    Plant derived products are not only served as dietary components but also used to treat and prevent the inflammatory associated diseases like cancer. Among the natural products pentacyclic terpenoids including ursolic acid and oleanolic acid are considered as the promising anti-inflammatory therapeutic agents. The current review extensively discusses the anti-inflammatory therapeutic potential of these pentacyclic moieties along with their proposed mechanisms of action. Furthermore, the relevant patents have also been listed to present the health benefits of these promising therapeutic agents to pin down the inflammatory diseases. Expert opinion: Pentacyclic terpenoids are known to negatively down-regulate a variety of extracellular and intracellular molecular targets associated with disease progression. The major anti-inflammatory effects of these molecules have been found to be mediated via inactivation of NFkB, STAT3/6, Akt/mTOR pathways. A number of patents on UA & OA based moieties have been reported between 2010 and 2016. Still there have been only a few compounds which meet the need of sufficient hydro solubility and bioavailability along with higher anti-inflammatory activities. Thus, it is essential to develop novel derivatives of terpenpoids which may not only overcome the solubility issues but also may improve their therapeutic effects. In addition, scientific community may utilize nanotechnology based drug delivery systems so as to increase the bio-availability, selectivity and dosages related problems.

  20. Fruit-Derived Polysaccharides and Terpenoids: Recent Update on the Gastroprotective Effects and Mechanisms

    Directory of Open Access Journals (Sweden)

    Mohammed Safwan Ali Khan

    2018-06-01

    Full Text Available Ulceration in the stomach develops in peptic ulcer disease when there is a loss of protective mucosal layers, particularly in Helicobacter pylori infection. Antibiotic therapy has failed to eradicate and impede the colonization of H. pylori. Despite given treatment, recurrent bleeding can occur and lead to death in the affected individual. The disease progression is also related to the non-steroidal inflammatory drug and stress. There are extensive research efforts to identify the gastroprotective property from various alkaloids, flavonoids, and tannins compounds from plants and marine. These natural products are believed to be safe for consumption. However, not much attention was given to summarize the carbohydrate and terpenoidal anti-ulcer compounds. Hence, this review will cover the possible mechanisms and information about acidic hydroxylans, arabinogalactan and rhamnogalacturon; and limonene, pinene, lupeol, citral, ursolic acid and nomilin to exemplify on the gastroprotective properties of polysaccharides and terpenoid, respectively, obtained from fruits. These compounds could act as a prebiotic to prevent the inhabitation of H. pylori, modulate the inflammation, suppress gastric cancer growth, and capable of stimulating the reparative mechanisms on the affected regions. Finally, this review provides the future research prospects of these natural compounds in an effort to develop new therapy for gastrointestinal tissue healing.

  1. In silico discovery of terpenoid metabolism in Cannabis sativa [version 1; referees: 2 approved, 1 approved with reservations

    Directory of Open Access Journals (Sweden)

    Luca Massimino

    2017-02-01

    Full Text Available Due to their efficacy, cannabis based therapies are currently being prescribed for the treatment of many different medical conditions. Interestingly, treatments based on the use of cannabis flowers or their derivatives have been shown to be very effective, while therapies based on drugs containing THC alone lack therapeutic value and lead to increased side effects, likely resulting from the absence of other pivotal entourage compounds found in the Phyto-complex. Among these compounds are terpenoids, which are not produced exclusively by cannabis plants, so other plant species must share many of the enzymes involved in their metabolism. In the present work, 23,630 transcripts from the canSat3 reference transcriptome were scanned for evolutionarily conserved protein domains and annotated in accordance with their predicted molecular functions. A total of 215 evolutionarily conserved genes encoding enzymes presumably involved in terpenoid metabolism are described, together with their expression profiles in different cannabis plant tissues at different developmental stages. The resource presented here will aid future investigations on terpenoid metabolism in Cannabis sativa.

  2. Enhanced biotransformation of TCE using plant terpenoids in contaminated groundwater.

    Science.gov (United States)

    Brown, J R-M; Thompson, I P; Paton, G I; Singer, A C

    2009-12-01

    To examine plant terpenoids as inducers of TCE (trichloroethylene) biotransformation by an indigenous microbial community originating from a plume of TCE-contaminated groundwater. One-litre microcosms of groundwater were spiked with 100 micromol 1(-1) of TCE and amended weekly for 16 weeks with 20 microl 1(-1) of the following plant monoterpenes: linalool, pulegone, R-(+) carvone, S-(-) carvone, farnesol, cumene. Yeast extract-amended and unamended control treatments were also prepared. The addition of R-carvone and S-carvone, linalool and cumene resulted in the biotransformation of upwards of 88% of the TCE, significantly more than the unamendment control (61%). The aforementioned group of terpenes also significantly (P TCE to be degraded than the remaining two terpenes (farnesol and pulegone), and the yeast extract treatment which biotransformed 74-75% of the TCE. The microbial community profile was monitored by denaturing gradient gel electrophoresis and demonstrated much greater similarities between the microbial communities in terpene-amended treatments than in the yeast extract or unamended controls. TCE biotransformation can be significantly enhanced through the addition of selected plant terpenoids. Plant terpenoid and nutrient supplementation to groundwater might provide an environmentally benign means of enhancing the rate of in situ TCE bioremediation.

  3. Engineering yeast metabolism for production of terpenoids for use as perfume ingredients, pharmaceuticals and biofuels.

    Science.gov (United States)

    Zhang, Yueping; Nielsen, Jens; Liu, Zihe

    2017-12-01

    Terpenoids represent a large class of natural products with significant commercial applications. These chemicals are currently mainly obtained through extraction from plants and microbes or through chemical synthesis. However, these sources often face challenges of unsustainability and low productivity. In order to address these issues, Escherichia coli and yeast have been metabolic engineered to produce non-native terpenoids. With recent reports of engineering yeast metabolism to produce several terpenoids at high yields, it has become possible to establish commercial yeast production of terpenoids that find applications as perfume ingredients, pharmaceuticals and advanced biofuels. In this review, we describe the strategies to rewire the yeast pathway for terpenoid biosynthesis. Recent advances will be discussed together with challenges and perspectives of yeast as a cell factory to produce different terpenoids. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Mutagenic potential of Cordia ecalyculata alone and in association with Spirulina maxima for their evaluation as candidate anti-obesity drugs.

    Science.gov (United States)

    Araldi, R P; Rechiutti, B M; Mendes, T B; Ito, E T; Souza, E B

    2014-07-07

    Obesity is one of the most important nutritional disorders, and can be currently considered as an epidemic. Although there are few weight reduction drugs available on the market, some new drug candidates have been proposed, including Cordia ecalyculata, a Brazilian plant with anorectic properties, and Spirulina maxima, a cyanobacterium with antioxidant and anti-genotoxic activity. In this study, we evaluated the mutagenic potential of C. ecalyculata at doses of 150, 300, and 500 mg/kg alone and in association with S. maxima at doses of 75, 150, and 250 mg/kg, respectively, through an in vivo micronucleus test, using mice of both sexes, and an in vitro micronucleus test and comet assay, using human peripheral blood. For all tests, cyclophosphamide was used as a positive control. The results showed that treatment of 300 mg/kg C. ecalyculata and the combination treatment of 500 mg/kg C. ecalyculata with 250 mg/kg S. maxima resulted in anorectic effects. The mutagenic tests did not reveal any clastogenic or genotoxic activity for any treatment, indicating that these candidates could be marketed as weight-reduction drugs. Moreover, the drugs contain chemo-preventive substances that can protect against tumorigenesis, which has been associated with obesity.

  5. Terpenoids in Buddleja: relevance to chemosystematics, chemical ecology and biological activity.

    Science.gov (United States)

    Houghton, Peter J; Mensah, Abraham Y; Iessa, Noha; Hong, Liao Yong

    2003-09-01

    The terpenoids reported from Buddleja species are described. The antifungal activity of chloroform extracts of B. cordata and B. davidii stembark against the soil fungi Fusarium culmorum and Sordari fimicola is reported, with buddledin A shown to be the major compound responsible. The terpenoids present support the view that the Buddlejaceae should be classified in a taxon with Scrophulariaceae rather than Loganiaceae. Ecological aspects of the terpenoids are considered in relation to insects and soil fungi and the role of terpenoids in the chemical basis of the use of Buddleja in traditional medicine is also discussed, especially with regard to their anti-inflammatory properties.

  6. Critical analysis of 3-D organoid in vitro cell culture models for high-throughput drug candidate toxicity assessments.

    Science.gov (United States)

    Astashkina, Anna; Grainger, David W

    2014-04-01

    Drug failure due to toxicity indicators remains among the primary reasons for staggering drug attrition rates during clinical studies and post-marketing surveillance. Broader validation and use of next-generation 3-D improved cell culture models are expected to improve predictive power and effectiveness of drug toxicological predictions. However, after decades of promising research significant gaps remain in our collective ability to extract quality human toxicity information from in vitro data using 3-D cell and tissue models. Issues, challenges and future directions for the field to improve drug assay predictive power and reliability of 3-D models are reviewed. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

    DEFF Research Database (Denmark)

    Kopec, Wojciech; Khandelia, Himanshu

    2014-01-01

    Thioridazine is a well-known dopamine-antagonist drug with a wide range of pharmacological properties ranging from neuroleptic to antimicrobial and even anticancer activity. Thioridazine is a critical component of a promising multi-drug therapy against M. tuberculosis. Amongst the various propose......-membrane interactions, and reinforce the wider, emerging view of action of many small, bioactive compounds....... mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations...

  8. Recent advances in candidate-gene and whole-genome approaches to the discovery of anthelmintic resistance markers and the description of drug/receptor interactions

    Directory of Open Access Journals (Sweden)

    Andrew C. Kotze

    2014-12-01

    Full Text Available Anthelmintic resistance has a great impact on livestock production systems worldwide, is an emerging concern in companion animal medicine, and represents a threat to our ongoing ability to control human soil-transmitted helminths. The Consortium for Anthelmintic Resistance and Susceptibility (CARS provides a forum for scientists to meet and discuss the latest developments in the search for molecular markers of anthelmintic resistance. Such markers are important for detecting drug resistant worm populations, and indicating the likely impact of the resistance on drug efficacy. The molecular basis of resistance is also important for understanding how anthelmintics work, and how drug resistant populations arise. Changes to target receptors, drug efflux and other biological processes can be involved. This paper reports on the CARS group meeting held in August 2013 in Perth, Australia. The latest knowledge on the development of molecular markers for resistance to each of the principal classes of anthelmintics is reviewed. The molecular basis of resistance is best understood for the benzimidazole group of compounds, and we examine recent work to translate this knowledge into useful diagnostics for field use. We examine recent candidate-gene and whole-genome approaches to understanding anthelmintic resistance and identify markers. We also look at drug transporters in terms of providing both useful markers for resistance, as well as opportunities to overcome resistance through the targeting of the transporters themselves with inhibitors. Finally, we describe the tools available for the application of the newest high-throughput sequencing technologies to the study of anthelmintic resistance.

  9. Engineering yeast metabolism for production of terpenoids for use as perfume ingredients, pharmaceuticals and biofuels

    DEFF Research Database (Denmark)

    Zhang, Yueping; Nielsen, Jens; Liu, Zihe

    2017-01-01

    of terpenoids that find applications as perfume ingredients, pharmaceuticals and advanced biofuels. In this review, we describe the strategies to rewire the yeast pathway for terpenoid biosynthesis. Recent advances will be discussed together with challenges and perspectives of yeast as a cell factory to produce...

  10. Volatile terpenoids: multiple functions, biosynthesis, modulation and manipulation by genetic engineering.

    Science.gov (United States)

    Abbas, Farhat; Ke, Yanguo; Yu, Rangcai; Yue, Yuechong; Amanullah, Sikandar; Jahangir, Muhammad Muzammil; Fan, Yanping

    2017-11-01

    Terpenoids play several physiological and ecological functions in plant life through direct and indirect plant defenses and also in human society because of their enormous applications in the pharmaceutical, food and cosmetics industries. Through the aid of genetic engineering its role can by magnified to broad spectrum by improving genetic ability of crop plants, enhancing the aroma quality of fruits and flowers and the production of pharmaceutical terpenoids contents in medicinal plants. Terpenoids are structurally diverse and the most abundant plant secondary metabolites, playing an important role in plant life through direct and indirect plant defenses, by attracting pollinators and through different interactions between the plants and their environment. Terpenoids are also significant because of their enormous applications in the pharmaceutical, food and cosmetics industries. Due to their broad distribution and functional versatility, efforts are being made to decode the biosynthetic pathways and comprehend the regulatory mechanisms of terpenoids. This review summarizes the recent advances in biosynthetic pathways, including the spatiotemporal, transcriptional and post-transcriptional regulatory mechanisms. Moreover, we discuss the multiple functions of the terpene synthase genes (TPS), their interaction with the surrounding environment and the use of genetic engineering for terpenoid production in model plants. Here, we also provide an overview of the significance of terpenoid metabolic engineering in crop protection, plant reproduction and plant metabolic engineering approaches for pharmaceutical terpenoids production and future scenarios in agriculture, which call for sustainable production platforms by improving different plant traits.

  11. Molecular interaction study of commercial cyclic peptides and MERS-COV papain-like protease as novel drug candidate for MERS-COV

    Science.gov (United States)

    Nasution, M. A. F.; Azzuhdi, M. G.; Tambunan, U. S. F.

    2017-07-01

    Middle-east respiratory syndrome coronavirus (MERS-CoV) has become the current outbreak, MERS-CoV infection results in illness at the respiratory system, digestive, and even lead to death with an average mortality caused by MERS-CoV infection reaches 50 %. Until now, there is not any effective vaccine or drug to ward off MERS-CoV infection. Papain-like protease (PLpro) is responsible for cleavage of a nonstructural protein that is essential for viral maturation. Inhibition of PLpro with a ligand will block the cleavage process of nonstructural protein, thus reduce the infection of MERS-CoV. Through of bioinformatics study with molecular docking and binding interaction analysis of commercial cyclic peptides, aldosterone secretion inhibiting factor (1-35) (bovine) was obtained as an inhibitor for PLpro. Thus, aldosterone secretion inhibiting factor (1-35) (bovine) has a potential as a novel candidate drug for treating MERS-CoV.

  12. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    International Nuclear Information System (INIS)

    Tamura, Akitoshi; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-01-01

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  13. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    Energy Technology Data Exchange (ETDEWEB)

    Tamura, Akitoshi, E-mail: akitoshi-tamura@ds-pharma.co.jp; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-08-15

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  14. Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

    Science.gov (United States)

    Kamimura, Hidetaka; Ito, Satoshi

    2016-01-01

    1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

  15. Terpenoid emissions from fully grown east Siberian Larix cajanderi trees

    Directory of Open Access Journals (Sweden)

    M. K. Kajos

    2013-07-01

    Full Text Available While emissions of many biogenic volatile organic compounds (BVOCs, such as terpenoids, have been studied quite intensively in North American and Scandinavian boreal forests, the vast Siberian boreal forests have remained largely unexplored by experimental emission studies. In this study the shoot-scale terpenoid emission rates from two mature Larix cajanderi trees growing in their natural habitat in eastern Siberia were measured at the Spasskaya Pad flux measurement site (62°15´18.4" N, 129°37´07.9" E located on the western bank of the Lena river. The measurements were conducted during three campaigns: 3–24 June, 8–26 July, and 14–30 August, in the summer of 2009. A dynamic flow-through enclosure technique was applied for adsorbent sampling, and the samples were analysed offline with a gas chromatograph. Between 29 and 45 samples were taken from each shoot during all three campaigns. Seven different monoterpenes, six different sesquiterpenes, linalool isoprene, and 2-methyl-3-buten-2-ol (MBO were identified. The monthly median value of the total terpenoid emissions varied between 0.006 and 10.6 μg gdw−1 h−1. The emissions were dominated by monoterpenes, which constituted between 61 and 92% of the total emissions. About half of the monoterpene emissions were comprised of Δ 3-carene; α- and β-pinene had significant emissions as well. Linalool emissions were also substantial, comprising 3–37% of the total emissions, especially in June. Sesquiterpenes accounted for less than 3% and isoprene less than 1% of the total emissions. Based on the measured emission rates, the relative atmospheric concentration of each compound was estimated. Monoterpenes were the species with the highest relative concentration, while linalool and sesquiterpenes had a notably smaller contribution to the estimated atmospheric concentration than to the emission rates. A temperature-dependent pool algorithm with a constant β (0.09 °C−1 for monoterpenes

  16. Analysis of the transcriptome of Isodon rubescens and key enzymes involved in terpenoid biosynthesis

    Directory of Open Access Journals (Sweden)

    Xiuhong Su

    2016-05-01

    Full Text Available Isodon rubescens is an important medicinal plant in China that has been shown to reduce tumour growth due to the presence of the compound oridonin. In an effort to facilitate molecular research on oridonin biosynthesis, we reported the use of next generation massively parallel sequencing technologies and de novo transcriptome assembly to gain a comprehensive overview of I. rubescens transcriptome. In our study, a total of 50,934,276 clean reads, 101,640 transcripts and 44,626 unigenes were generated through de novo transcriptome assembly. A number of unigenes – 23,987, 10,263, 7359, 18,245, 17,683, 19,485, 9361 – were annotated in the National Center for Biotechnology Information (NCBI non-redundant protein (Nr, NCBI nucleotide sequences (Nt, Kyoto Encyclopedia of Genes and Genomes (KEGG Orthology (KO, Swiss-Prot, protein family (Pfam, gene ontology (GO, eukaryotic ortholog groups (KOG databases, respectively. Furthermore, the annotated unigenes were functionally classified according to the GO, KOG and KEGG. Based on these results, candidate genes encoding enzymes involved in terpenoids backbone biosynthesis were detected. Our data provided the most comprehensive sequence resource available for the study on I. rubescens, as well as demonstrated the effective use of Illumina sequencing and de novo transcriptome assembly on a species lacking genomic information.

  17. Model based on GRID-derived descriptors for estimating CYP3A4 enzyme stability of potential drug candidates

    Science.gov (United States)

    Crivori, Patrizia; Zamora, Ismael; Speed, Bill; Orrenius, Christian; Poggesi, Italo

    2004-03-01

    A number of computational approaches are being proposed for an early optimization of ADME (absorption, distribution, metabolism and excretion) properties to increase the success rate in drug discovery. The present study describes the development of an in silico model able to estimate, from the three-dimensional structure of a molecule, the stability of a compound with respect to the human cytochrome P450 (CYP) 3A4 enzyme activity. Stability data were obtained by measuring the amount of unchanged compound remaining after a standardized incubation with human cDNA-expressed CYP3A4. The computational method transforms the three-dimensional molecular interaction fields (MIFs) generated from the molecular structure into descriptors (VolSurf and Almond procedures). The descriptors were correlated to the experimental metabolic stability classes by a partial least squares discriminant procedure. The model was trained using a set of 1800 compounds from the Pharmacia collection and was validated using two test sets: the first one including 825 compounds from the Pharmacia collection and the second one consisting of 20 known drugs. This model correctly predicted 75% of the first and 85% of the second test set and showed a precision above 86% to correctly select metabolically stable compounds. The model appears a valuable tool in the design of virtual libraries to bias the selection toward more stable compounds. Abbreviations: ADME - absorption, distribution, metabolism and excretion; CYP - cytochrome P450; MIFs - molecular interaction fields; HTS - high throughput screening; DDI - drug-drug interactions; 3D - three-dimensional; PCA - principal components analysis; CPCA - consensus principal components analysis; PLS - partial least squares; PLSD - partial least squares discriminant; GRIND - grid independent descriptors; GRID - software originally created and developed by Professor Peter Goodford.

  18. Development of a Terpenoid-Production Platform in Streptomyces reveromyceticus SN-593.

    Science.gov (United States)

    Khalid, Ammara; Takagi, Hiroshi; Panthee, Suresh; Muroi, Makoto; Chappell, Joe; Osada, Hiroyuki; Takahashi, Shunji

    2017-12-15

    Terpenoids represent the largest class of natural products, some of which are resources for pharmaceuticals, fragrances, and fuels. Generally, mass production of valuable terpenoid compounds is hampered by their low production levels in organisms and difficulty of chemical synthesis. Therefore, the development of microbial biosynthetic platforms represents an alternative approach. Although microbial terpenoid-production platforms have been established in Escherichia coli and yeast, an optimal platform has not been developed for Streptomyces species, despite the large capacity to produce secondary metabolites, such as polyketide compounds. To explore this potential, we constructed a terpenoid-biosynthetic platform in Streptomyces reveromyceticus SN-593. This strain is unique in that it harbors the mevalonate gene cluster enabling the production of furaquinocin, which can be controlled by the pathway specific regulator Fur22. We simultaneously expressed the mevalonate gene cluster and subsequent terpenoid-biosynthetic genes under the control of Fur22. To achieve improved fur22 gene expression, we screened promoters from S. reveromyceticus SN-593. Our results showed that the promoter associated with rvr2030 gene enabled production of 212 ± 20 mg/L botryococcene to levels comparable to those previously reported for other microbial hosts. Given that the rvr2030 gene encodes for an enzyme involved in the primary metabolism, these results suggest that optimized expression of terpenoid-biosynthetic genes with primary and secondary metabolism might be as important for high yields of terpenoid compounds as is the absolute expression level of a target gene(s).

  19. [Diversity of Plants Belonging to the Genus Ligularia (Asteraceae) Based on Terpenoids and Synthetic Studies on Some Terpenoids].

    Science.gov (United States)

    Tori, Motoo

    2016-01-01

    The terpenoid constituents of Ligularia virgaurea (30 samples), Ligularia pleurocaulis (8 samples), Ligularia dictyoneura (8 samples), Ligularia brassicoides (5 samples), Ligularia lingiana (1 sample), and Ligularia liatroides (1 sample)(all belonging to section Senecillis of Ligularia, Asteraceae and collected in Yunnan, Sichuan, Qinghai, and Gansu provinces, China), from which 220 compounds were isolated, including 113 novel ones, are reviewed. Five chemotypes were identified in L. virgaurea based on their chemical constituents, while three clades were detected from the base sequences. Although intra-specific diversity was found in L. virgaurea, more samples were needed of other species in order to reach a definite conclusion. Inter-specific diversity was also examined in section Senecillis but was restricted due to the scarcity of samples. Synthetic studies on chiral natural products to determine their absolute configurations, especially those of riccardiphenols A and B as well as crispatanolide, which were all isolated from the liverwort, are briefly reviewed.

  20. Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial.

    Science.gov (United States)

    Christoph, Annette; Eerdekens, Marie-Henriette; Kok, Maurits; Volkers, Gisela; Freynhagen, Rainer

    2017-09-01

    Chronic low back pain (LBP) is a common condition, usually with the involvement of nociceptive and neuropathic pain components, high economic burden and impact on quality of life. Cebranopadol is a potent, first-in-class drug candidate with a novel mechanistic approach, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. We conducted the first phase II, randomized, double-blind, placebo- and active-controlled trial, evaluating the analgesic efficacy, safety, and tolerability of cebranopadol in patients with moderate-to-severe chronic LBP with and without neuropathic pain component. Patients were treated for 14 weeks with cebranopadol 200, 400, or 600 μg once daily, tapentadol 200 mg twice daily, or placebo. The primary efficacy endpoints were the change from baseline pain to the weekly average 24-hour pain during the entire 12 weeks and during week 12 of the maintenance phase. Cebranopadol demonstrated analgesic efficacy, with statistically significant and clinically relevant improvements over placebo for all doses as did tapentadol. The responder analysis (≥30% or ≥50% pain reduction) confirmed these results. Cebranopadol and tapentadol displayed beneficial effects on sleep and functionality. Cebranopadol treatment was safe, with higher doses leading to higher treatment discontinuations because of treatment-emergent adverse events occurring mostly during titration. Those patients reaching the target doses had an acceptable tolerability profile. The incidence rate of most frequently reported treatment-emergent adverse events during maintenance phase was ≤10%. Although further optimizing the titration scheme to the optimal dose for individual patients is essential, cebranopadol is a new drug candidate with a novel mechanistic approach for potential chronic LBP treatment.

  1. Alpha-glucosidase inhibitory and antiplasmodial properties of terpenoids from the leaves of Buddleja saligna Willd

    Czech Academy of Sciences Publication Activity Database

    Chukwujekwu, J. C.; Rengasamy, K.R.R.; de Kock, C. A.; Smith, P. J.; Poštová Slavětínská, Lenka; van Staden, J.

    2016-01-01

    Roč. 31, č. 1 (2016), s. 63-66 ISSN 1475-6366 Institutional support: RVO:61388963 Keywords : alpha-glucosidase * antidiabetic * antiplasmodial * Buddleja saligna * terpenoids Subject RIV: CC - Organic Chemistry Impact factor: 4.293, year: 2016

  2. Heterologous stable expression of terpenoid biosynthetic genes using the moss Physcomitrella patens

    DEFF Research Database (Denmark)

    Bach, Søren Spanner; King, Brian Christopher; Zhan, Xin

    2014-01-01

    Heterologous and stable expression of genes encoding terpenoid biosynthetic enzymes in planta is an important tool for functional characterization and is an attractive alternative to expression in microbial hosts for biotechnological production. Despite improvements to the procedure, such as stre...

  3. Styrene-maleic acid-copolymer conjugated zinc protoporphyrin as a candidate drug for tumor-targeted therapy and imaging.

    Science.gov (United States)

    Fang, Jun; Tsukigawa, Kenji; Liao, Long; Yin, Hongzhuan; Eguchi, Kanami; Maeda, Hiroshi

    2016-01-01

    Previous studies indicated the potential of zinc protoporphyrin (ZnPP) as an antitumor agent targeting to the tumor survival factor heme oxygenase-1, and/or for photodynamic therapy (PDT). In this study, to achieve tumor-targeted delivery, styrene-maleic acid-copolymer conjugated ZnPP (SMA-ZnPP) was synthesized via amide bond, which showed good water solubility, having ZnPP loading of 15%. More importantly, it forms micelles in aqueous solution with a mean particle size of 111.6 nm, whereas it has an apparent Mw of 65 kDa. This micelle formation was not detracted by serum albumin, suggesting it is stable in circulation. Further SMA-ZnPP conjugate will behave as an albumin complex in blood with much larger size (235 kDa) by virtue of the albumin binding property of SMA. Consequently, SMA-ZnPP conjugate exhibited prolonged circulating retention and preferential tumor accumulation by taking advantage of enhanced permeability and retention (EPR) effect. Clear tumor imaging was thus achieved by detecting the fluorescence of ZnPP. In addition, the cytotoxicity and PDT effect of SMA-ZnPP conjugate was confirmed in human cervical cancer HeLa cells. Light irradiation remarkably increased the cytotoxicity (IC50, from 33 to 5 μM). These findings may provide new options and knowledge for developing ZnPP based anticancer theranostic drugs.

  4. Drug-induced hypotension SEP test and acetazolamide test using sup 133 Xe SPECT in patients with occlusive carotid disease; Selection of candidates for extracranial-intracranial bypass

    Energy Technology Data Exchange (ETDEWEB)

    Kuroda, Satoshi; Kamiyama, Hiroyasu; Abe, Hiroshi; Takigawa, Shugo [Hokkaido Univ., Sapporo (Japan). School of Medicine; Mitsumori, Kenji; Nomura, Mikio; Saitoh, Hisatoshi

    1991-01-01

    The correlation between the drug-induced hypotension somatosensory evoked potential (SEP) test and regional cerebral blood flow changes after acetazolamide administration was studied. Fourteen patients presenting with transient ischemic attack, reversible ischemic neurological deficits, or minor completed stroke were evaluated. All patients had no or only localized low-density areas on computed tomographic scans, and unilateral occlusion or severe stenosis of the internal carotid or middle cerebral artery on cerebral angiograms. The Diamox asymmetry enhancement (DAE) was studied to detect reduced cerebral perfusion reserve in the affected hemispheres. The DAE was 7.9+-5.8% in seven patients positive in the SEP test, significantly higher than -1.5+-2.9% in patients negative in the SEP test. Postoperative SEP tests were negative in all five patients who underwent extracranial-intracranial (EC-IC) bypass surgery, suggesting that the EC-IC bypass improved the cerebral perfusion reserve in the affected hemispheres. The DAE decreased significantly in four of these patients. This study disclosed a significant correlation between the drug-induced hypotension SEP test and DAE. These parameters are considered important for evaluating patients with hemodynamic compromise and/or suitable candidates for EC-IC bypass. (author).

  5. Synthesis and characterisation of zinc oxide nanoparticles using terpenoid fractions of Andrographis paniculata leaves

    Science.gov (United States)

    Kavitha, S.; Dhamodaran, M.; Prasad, Rajendra; Ganesan, M.

    2017-04-01

    Zinc oxide (ZnO) nanoparticles have been widely employed for various pharmacological applications. Several approaches were tried to synthesize ZnO nanoparticles. In this study, ZnO nanoparticles were biosynthesized using terpenoid (TAP) fractions isolated from Andrographis paniculata leaves. Subsequently, the ZnNO3 (0.1 N) is treated with the isolated TAP fractions to biosynthesize zinc oxide nanoparticles (Zn-TAP NPs). This nanoparticle preparation has been confirmed by the colour change from green to cloudy-white and the peak at 300 nm by UV-Visible spectra. FTIR analysis of Zn-TAP NPs showed the presence of functional group (i.e.) C=O which has further been confirmed by H1-NMR studies. From SEM and XRD analysis, it has been found that the hexagonal nanorod particle is 20.23 nm in size and +17.6 mV of zeta potential. Hence, it can be easily absorbed by negatively charged cellular membrane to contribute for efficient intracellular distribution. Therefore, it is suggested that the synthesised Zn-TAP NPs are more suitable in drug delivery processes.

  6. Phenolics and Terpenoids; the Promising New Search for Anthelmintics: A Critical Review.

    Science.gov (United States)

    Mukherjee, Niladri; Mukherjee, Suprabhat; Saini, Prasanta; Roy, Priya; Babu, Santi P Sinha

    2016-01-01

    Ailments caused by helminth parasites are global causing different types of clinical complications with permanent and long term morbidity in humans. Although huge advances have been made in medical sciences the effectiveness of available anthelmintics are still quite limited. Starting from the 50's, most importance was given to synthetic compounds for developing remedies from them, however, the traditional knowledge of medicine of different countries continued to provide us clues against this widespread health problem. Natural products or structural analogs with diverse structures are always been the major sources for discovering new therapeutics and in recent past different active compounds have also been identified form these plant sources having anthelmintic properties. Although compounds of diverse chemical nature and classes were identified, most active ones belong to either phenol or terpene in broad chemical nature. The mechanism of action of these phytotherapeutics is usually multi-targeted and can act against the helminth parasites through diverse spectrum of activities. In this review we summarized the effective anthelmintics belong to either phenolics or terpenoids and highlighted the major way of their effectiveness. This also highlights the recent development of new therapeutic strategies against helminth parasites in the light of recent advances of knowledge. In addition, developing efficient strategies to promote apoptosis and disturbing redox status in them by natural products can provide us a clue in antifilarial drug developmental research and crucial unmet medical need.

  7. The EndoC-βH1 cell line is a valid model of human beta cells and applicable for screenings to identify novel drug target candidates.

    Science.gov (United States)

    Tsonkova, Violeta Georgieva; Sand, Fredrik Wolfhagen; Wolf, Xenia Asbæk; Grunnet, Lars Groth; Kirstine Ringgaard, Anna; Ingvorsen, Camilla; Winkel, Louise; Kalisz, Mark; Dalgaard, Kevin; Bruun, Christine; Fels, Johannes Josef; Helgstrand, Charlotte; Hastrup, Sven; Öberg, Fredrik Kryh; Vernet, Erik; Sandrini, Michael Paolo Bastner; Shaw, Allan Christian; Jessen, Carsten; Grønborg, Mads; Hald, Jacob; Willenbrock, Hanni; Madsen, Dennis; Wernersson, Rasmus; Hansson, Lena; Jensen, Jan Nygaard; Plesner, Annette; Alanentalo, Tomas; Petersen, Maja Borup Kjær; Grapin-Botton, Anne; Honoré, Christian; Ahnfelt-Rønne, Jonas; Hecksher-Sørensen, Jacob; Ravassard, Philippe; Madsen, Ole D; Rescan, Claude; Frogne, Thomas

    2018-02-01

    To characterize the EndoC-βH1 cell line as a model for human beta cells and evaluate its beta cell functionality, focusing on insulin secretion, proliferation, apoptosis and ER stress, with the objective to assess its potential as a screening platform for identification of novel anti-diabetic drug candidates. EndoC-βH1 was transplanted into mice for validation of in vivo functionality. Insulin secretion was evaluated in cells cultured as monolayer and as pseudoislets, as well as in diabetic mice. Cytokine induced apoptosis, glucolipotoxicity, and ER stress responses were assessed. Beta cell relevant mRNA and protein expression were investigated by qPCR and antibody staining. Hundreds of proteins or peptides were tested for their effect on insulin secretion and proliferation. Transplantation of EndoC-βH1 cells restored normoglycemia in streptozotocin induced diabetic mice. Both in vitro and in vivo, we observed a clear insulin response to glucose, and, in vitro, we found a significant increase in insulin secretion from EndoC-βH1 pseudoislets compared to monolayer cultures for both glucose and incretins. Apoptosis and ER stress were inducible in the cells and caspase 3/7 activity was elevated in response to cytokines, but not affected by the saturated fatty acid palmitate. By screening of various proteins and peptides, we found Bombesin (BB) receptor agonists and Pituitary Adenylate Cyclase-Activating Polypeptides (PACAP) to significantly induce insulin secretion and the proteins SerpinA6, STC1, and APOH to significantly stimulate proliferation. ER stress was readily induced by Tunicamycin and resulted in a reduction of insulin mRNA. Somatostatin (SST) was found to be expressed by 1% of the cells and manipulation of the SST receptors was found to significantly affect insulin secretion. Overall, the EndoC-βH1 cells strongly resemble human islet beta cells in terms of glucose and incretin stimulated insulin secretion capabilities. The cell line has an active

  8. The EndoC-βH1 cell line is a valid model of human beta cells and applicable for screenings to identify novel drug target candidates

    Directory of Open Access Journals (Sweden)

    Violeta Georgieva Tsonkova

    2018-02-01

    Full Text Available Objective: To characterize the EndoC-βH1 cell line as a model for human beta cells and evaluate its beta cell functionality, focusing on insulin secretion, proliferation, apoptosis and ER stress, with the objective to assess its potential as a screening platform for identification of novel anti-diabetic drug candidates. Methods: EndoC-βH1 was transplanted into mice for validation of in vivo functionality. Insulin secretion was evaluated in cells cultured as monolayer and as pseudoislets, as well as in diabetic mice. Cytokine induced apoptosis, glucolipotoxicity, and ER stress responses were assessed. Beta cell relevant mRNA and protein expression were investigated by qPCR and antibody staining. Hundreds of proteins or peptides were tested for their effect on insulin secretion and proliferation. Results: Transplantation of EndoC-βH1 cells restored normoglycemia in streptozotocin induced diabetic mice. Both in vitro and in vivo, we observed a clear insulin response to glucose, and, in vitro, we found a significant increase in insulin secretion from EndoC-βH1 pseudoislets compared to monolayer cultures for both glucose and incretins.Apoptosis and ER stress were inducible in the cells and caspase 3/7 activity was elevated in response to cytokines, but not affected by the saturated fatty acid palmitate.By screening of various proteins and peptides, we found Bombesin (BB receptor agonists and Pituitary Adenylate Cyclase-Activating Polypeptides (PACAP to significantly induce insulin secretion and the proteins SerpinA6, STC1, and APOH to significantly stimulate proliferation.ER stress was readily induced by Tunicamycin and resulted in a reduction of insulin mRNA. Somatostatin (SST was found to be expressed by 1% of the cells and manipulation of the SST receptors was found to significantly affect insulin secretion. Conclusions: Overall, the EndoC-βH1 cells strongly resemble human islet beta cells in terms of glucose and incretin stimulated

  9. Prediction of overall in vitro microsomal stability of drug candidates based on molecular modeling and support vector machines. Case study of novel arylpiperazines derivatives.

    Directory of Open Access Journals (Sweden)

    Szymon Ulenberg

    Full Text Available Other than efficacy of interaction with the molecular target, metabolic stability is the primary factor responsible for the failure or success of a compound in the drug development pipeline. The ideal drug candidate should be stable enough to reach its therapeutic site of action. Despite many recent excellent achievements in the field of computational methods supporting drug metabolism studies, a well-recognized procedure to model and predict metabolic stability quantitatively is still lacking. This study proposes a workflow for developing quantitative metabolic stability-structure relationships, taking a set of 30 arylpiperazine derivatives as an example. The metabolic stability of the compounds was assessed in in vitro incubations in the presence of human liver microsomes and NADPH and subsequently quantified by liquid chromatography-mass spectrometry (LC-MS. Density functional theory (DFT calculations were used to obtain 30 models of the molecules, and Dragon software served as a source of structure-based molecular descriptors. For modeling structure-metabolic stability relationships, Support Vector Machines (SVM, a non-linear machine learning technique, were found to be more effective than a regression technique, based on the validation parameters obtained. Moreover, for the first time, general sites of metabolism for arylpiperazines bearing the 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione system were defined by analysis of Q-TOF-MS/MS spectra. The results indicated that the application of one of the most advanced chemometric techniques combined with a simple and quick in vitro procedure and LC-MS analysis provides a novel and valuable tool for predicting metabolic half-life values. Given the reduced time and simplicity of analysis, together with the accuracy of the predictions obtained, this is a valid approach for predicting metabolic stability using structural data. The approach presented provides a novel, comprehensive and reliable tool

  10. High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain.

    Science.gov (United States)

    Zhou, Ting; Tan, Lei; Cederquist, Gustav Y; Fan, Yujie; Hartley, Brigham J; Mukherjee, Suranjit; Tomishima, Mark; Brennand, Kristen J; Zhang, Qisheng; Schwartz, Robert E; Evans, Todd; Studer, Lorenz; Chen, Shuibing

    2017-08-03

    Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke.

    Science.gov (United States)

    Van Kanegan, Michael J; Dunn, Denise E; Kaltenbach, Linda S; Shah, Bijal; He, Dong Ning; McCoy, Daniel D; Yang, Peiying; Peng, Jiangnan; Shen, Li; Du, Lin; Cichewicz, Robert H; Newman, Robert A; Lo, Donald C

    2016-05-12

    We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0-4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0-4 provides broad neuroprotection in organotypic brain slice models for neurodegeneration driven by amyloid precursor protein (APP) and tau implicated in Alzheimer's disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD.

  12. Eudragit ® FS 30 D polymeric films containing chondroitin sulfate as candidates for use in coating seeking modified delivery of drugs

    Directory of Open Access Journals (Sweden)

    Camila Borges dos Reis

    Full Text Available ABSTRACT Polymeric films associating different concentrations of Eudragit(r FS 30 D (EFS and chondroitin sulfate (CS were produced by casting for the development of a new target-specific site material. Formed films kept a final polymer mass of 4% (w/v in the following proportions: EFS 100:00 CS (control, EFS 95:05 CS, EFS 90:10 CS and EFS 80:20 CS. They were analyzed for physical and chemical characteristics using Fourier transform infrared spectroscopy (FTIR, scanning electron microscopy (SEM and Raman spectroscopy. Furthermore, they were characterized by their water vapor permeability and degree of hydration at different conditions simulating the gastrointestinal tract. No chemical interactions were observed between CS and EFS, suggesting only a physical interaction between them in the different combinations tested. The results suggest that EFS and CS, when combined, may form films that are candidates for coating processes seeking a modified drug delivery, especially due to the synergism between pH dependency and specific biodegradability properties by the colonic microbiota. EFS 90:10 CS proved to be the most suitable for this purpose considering hydration and permeability characteristics of different associations analyzed.

  13. Phytochemical studies on the terpenoids of medicinally important plant Aerva lanata L. using HPTLC

    Institute of Scientific and Technical Information of China (English)

    Yamunadevi M; Wesely EG; Johnson M

    2011-01-01

    Objective:To elucidate the terpenoids profile of Aerva lanata (A. lanata) using high performance thin layer chromatography (HPTLC). Methods: Preliminary phytochemical screening was done and HPTLC studies were carried out. The n-hexane:ethyl acetate (7.2: 2.8) was employed as mobile phase for terpenoids. Results: The desired aim was achieved using n-hexane-ethyl acetate (7.2: 2.8) as the mobile phase. The methanolic extract of stem, leaves, root, flower and seeds of A. lanata showed the presence of 27 different types of terpenoids with 27 different Rf values in the range of 0.06 to 0.97. The developed HPTLC method for terpenoid profile is simple, precise and accurate and can be used for the identification and commercial application. Conclusions:HPTLC profile of terpenoids has been chosen here to reveal the diversity existing at biochemical level in A. lanata. Such finger printing is useful in differentiating the species from the adulterant and act as a biochemical marker for this medicinally important plant in the pharmaceutical industry and plant systematic studies.

  14. Applications of plant terpenoids in the synthesis of colloidal silver nanoparticles.

    Science.gov (United States)

    Mashwani, Zia-Ur-Rehman; Khan, Mubarak Ali; Khan, Tariq; Nadhman, Akhtar

    2016-08-01

    Green chemistry is the design of chemical products and processes that reduce or eliminate the generation of hazardous substances. Since the last few years, natural products especially plant secondary metabolites have been extensively explored for their potency to synthesize silver nanoparticles (AgNPs). The plant-based AgNPs are safer, energy efficient, eco-friendly, and less toxic than chemically synthesized counterparts. The secondary metabolites, ubiquitously found in plants especially the terpenoid-rich essential oils, have a significant role in AgNPs synthesis. Terpenoids belong to the largest family of natural products and are found in all kinds of organisms. Their involvement in the synthesis of plant-based AgNPs has got much attention in the recent years. The current article is not meant to provide an exhaustive overview of green synthesis of nanoparticles, but to present the pertinent role of plant terpenoids in the biosynthesis of AgNPs, as capping and reducing agents for development of uniform size and shape AgNPs. An emphasis on the important role of FTIR in the identification and elucidation of major functional groups in terpenoids for AgNPs synthesis has also been reviewed in this manuscript. It was found that no such article is available that has discussed the role of plant terpenoids in the green synthesis of AgNPs. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Drought effects on root and needle terpenoid content of a coastal and an interior Douglas fir provenance.

    Science.gov (United States)

    Kleiber, Anita; Duan, Qiuxiao; Jansen, Kirstin; Verena Junker, Laura; Kammerer, Bernd; Rennenberg, Heinz; Ensminger, Ingo; Gessler, Arthur; Kreuzwieser, Jürgen

    2017-12-01

    Douglas fir (Pseudotsuga menziesii) is a conifer species that stores large amounts of terpenoids, mainly monoterpenoids in resin ducts of various tissues. The effects of drought on stored leaf terpenoid concentrations in trees are scarcely studied and published data are partially controversial, since reduced, unaffected or elevated terpenoid contents due to drought have been reported. Even less is known on the effect of drought on root terpenoids. In the present work, we investigated the effect of reduced water availability on the terpenoid content in roots and needles of Douglas fir seedlings. Two contrasting Douglas fir provenances were studied: an interior provenance (var. glauca) with assumed higher drought resistance, and a coastal provenance (var. menziesii) with assumed lower drought resistance. We tested the hypothesis that both provenances show specific patterns of stored terpenoids and that the patterns will change in response to drought in both, needles and roots. We further expected stronger changes in the less drought tolerant coastal provenance. For this purpose, we performed an experiment under controlled conditions, in which the trees were exposed to moderate and severe drought stress. According to our expectations, the study revealed clear provenance-specific terpenoid patterns in needles. However, such patterns were not detected in the roots. Drought slightly increased the needle terpenoid contents of the coastal but not of the interior provenance. We also observed increased terpenoid abundance mainly in roots of the moderately stressed coastal provenance. Overall, from the observed provenance-specific reactions with increased terpenoid levels in trees of the coastal origin in response to drought, we conclude on functions of terpenoids for abiotic stress tolerance that might be fulfilled by other, constitutively expressed mechanisms in drought-adapted interior provenances. © The Author 2017. Published by Oxford University Press. All rights

  16. In Silico Identification and In Vitro and In Vivo Validation of Anti-Psychotic Drug Fluspirilene as a Potential CDK2 Inhibitor and a Candidate Anti-Cancer Drug.

    Directory of Open Access Journals (Sweden)

    Xi-Nan Shi

    Full Text Available Hepatocellular carcinoma (HCC is one of the leading causes of cancer-related deaths worldwide. Surgical resection and conventional chemotherapy and radiotherapy ultimately fail due to tumor recurrence and HCC's resistance. The development of novel therapies against HCC is thus urgently required. The cyclin-dependent kinase (CDK pathways are important and well-established targets for cancer treatment. In particular, CDK2 is a key factor regulating the cell cycle G1 to S transition and a hallmark for cancers. In this study, we utilized our free and open-source protein-ligand docking software, idock, prospectively to identify potential CDK2 inhibitors from 4,311 FDA-approved small molecule drugs using a repurposing strategy and an ensemble docking methodology. Sorted by average idock score, nine compounds were purchased and tested in vitro. Among them, the anti-psychotic drug fluspirilene exhibited the highest anti-proliferative effect in human hepatocellular carcinoma HepG2 and Huh7 cells. We demonstrated for the first time that fluspirilene treatment significantly increased the percentage of cells in G1 phase, and decreased the expressions of CDK2, cyclin E and Rb, as well as the phosphorylations of CDK2 on Thr160 and Rb on Ser795. We also examined the anti-cancer effect of fluspirilene in vivo in BALB/C nude mice subcutaneously xenografted with human hepatocellular carcinoma Huh7 cells. Our results showed that oral fluspirilene treatment significantly inhibited tumor growth. Fluspirilene (15 mg/kg exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil (10 mg/kg. Moreover, the cocktail treatment with fluspirilene and 5-fluorouracil exhibited the highest therapeutic effect. These results suggested for the first time that fluspirilene is a potential CDK2 inhibitor and a candidate anti-cancer drug for the treatment of human hepatocellular carcinoma. In view of the fact that fluspirilene has a long history

  17. P-glycoprotein mediated efflux limits the transport of the novel anti-Parkinson's disease candidate drug FLZ across the physiological and PD pathological in vitro BBB models.

    Directory of Open Access Journals (Sweden)

    Qian Liu

    Full Text Available FLZ, a novel anti-Parkinson's disease (PD candidate drug, has shown poor blood-brain barrier (BBB penetration based on the pharmacokinetic study using rat brain. P-glycoprotein (P-gp and breast cancer resistance protein (BCRP are two important transporters obstructing substrates entry into the CNS as well as in relation to PD neuropathology. However, it is unclear whether P-gp and BCRP are involved in low BBB permeability of FLZ and what the differences of FLZ brain penetration are between normal and Parkinson's conditions. For this purpose, in vitro BBB models mimicking physiological and PD pathological-related BBB properties were constructed by C6 astroglial cells co-cultured with primary normal or PD rat cerebral microvessel endothelial cells (rCMECs and in vitro permeability experiments of FLZ were carried out. High transepithelial electrical resistance (TEER and low permeability for sodium fluorescein (NaF confirmed the BBB functionality of the two models. Significantly greater expressions of P-gp and BCRP were detected in PD rCMECs associated with the lower in vitro BBB permeability of FLZ in pathological BBB model compared with physiological model. In transport studies only P-gp blocker effectively inhibited the efflux of FLZ, which was consistent with the in vivo permeability data. This result was also confirmed by ATPase assays, suggesting FLZ is a substrate for P-gp but not BCRP. The present study first established in vitro BBB models reproducing PD-related changes of BBB functions in vivo and demonstrated that poor brain penetration of FLZ and low BBB permeability were due to the P-gp transport.

  18. A Novel Orally Available Asthma Drug Candidate That Reduces Smooth Muscle Constriction and Inflammation by Targeting GABAA Receptors in the Lung.

    Science.gov (United States)

    Forkuo, Gloria S; Nieman, Amanda N; Kodali, Revathi; Zahn, Nicolas M; Li, Guanguan; Rashid Roni, M S; Stephen, Michael Rajesh; Harris, Ted W; Jahan, Rajwana; Guthrie, Margaret L; Yu, Olivia B; Fisher, Janet L; Yocum, Gene T; Emala, Charles W; Steeber, Douglas A; Stafford, Douglas C; Cook, James M; Arnold, Leggy A

    2018-05-07

    We describe lead compound MIDD0301 for the oral treatment of asthma based on previously developed positive allosteric α 5 β 3 γ 2 selective GABA A receptor (GABA A R) ligands. MIDD0301 relaxed airway smooth muscle at single micromolar concentrations as demonstrated with ex vivo guinea pig tracheal rings. MIDD0301 also attenuated airway hyperresponsiveness (AHR) in an ovalbumin murine model of asthma by oral administration. Reduced numbers of eosinophils and macrophages were observed in mouse bronchoalveolar lavage fluid without changing mucous metaplasia. Importantly, lung cytokine expression of IL-17A, IL-4, and TNF-α were reduced for MIDD0301-treated mice without changing antiinflammatory cytokine IL-10 levels. Automated patch clamp confirmed amplification of GABA induced current mediated by α 1-3,5 β 3 γ 2 GABA A Rs in the presence of MIDD0301. Pharmacodynamically, transmembrane currents of ex vivo CD4 + T cells from asthmatic mice were potentiated by MIDD0301 in the presence of GABA. The number of CD4 + T cells observed in the lung of MIDD0301-treated mice were reduced by an oral treatment of 20 mg/kg b.i.d. for 5 days. A half-life of almost 14 h was demonstrated by pharmacokinetic studies (PK) with no adverse CNS effects when treated mice were subjected to sensorimotor studies using the rotarod. PK studies also confirmed very low brain distribution. In conclusion, MIDD0301 represents a safe and improved oral asthma drug candidate that relaxes airway smooth muscle and attenuates inflammation in the lung leading to a reduction of AHR at a dosage lower than earlier reported GABA A R ligands.

  19. Analysis of several irdoid and indole precursors of terpenoid indole alkaloids with a single HPLC run

    DEFF Research Database (Denmark)

    Dagnino, Denise; Schripsema, Jan; Verpoorte, Robert

    1996-01-01

    An isocratic HPLC system is described which allows the separation of the iridoid and indole precursors of terpenoid indole alkaloids, which are present in a single crude extract. The system consists of a column of LiChrospher 60 RP select B 5 my, 250x4 mm (Merck) with an eluent of 1 % formic acid...

  20. Identification of Terpenoid Chemotypes Among High (-)-trans-Δ9- Tetrahydrocannabinol-Producing Cannabis sativa L. Cultivars.

    Science.gov (United States)

    Fischedick, Justin T

    2017-01-01

    Introduction: With laws changing around the world regarding the legal status of Cannabis sativa (cannabis) it is important to develop objective classification systems that help explain the chemical variation found among various cultivars. Currently cannabis cultivars are named using obscure and inconsistent nomenclature. Terpenoids, responsible for the aroma of cannabis, are a useful group of compounds for distinguishing cannabis cultivars with similar cannabinoid content. Methods: In this study we analyzed terpenoid content of cannabis samples obtained from a single medical cannabis dispensary in California over the course of a year. Terpenoids were quantified by gas chromatography with flame ionization detection and peak identification was confirmed with gas chromatography mass spectrometry. Quantitative data from 16 major terpenoids were analyzed using hierarchical clustering analysis (HCA), principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA). Results: A total of 233 samples representing 30 cultivars were used to develop a classification scheme based on quantitative data, HCA, PCA, and OPLS-DA. Initially cultivars were divided into five major groups, which were subdivided into 13 classes based on differences in terpenoid profile. Different classification models were compared with PLS-DA and found to perform best when many representative samples of a particular class were included. Conclusion: A hierarchy of terpenoid chemotypes was observed in the data set. Some cultivars fit into distinct chemotypes, whereas others seemed to represent a continuum of chemotypes. This study has demonstrated an approach to classifying cannabis cultivars based on terpenoid profile.

  1. Proteomic Insights on the Metabolism of Penicillium janczewskii during the Biotransformation of the Plant Terpenoid Labdanolic Acid

    Directory of Open Access Journals (Sweden)

    Isabel Martins

    2017-07-01

    Full Text Available Plant terpenoids compose a natural source of chemodiversity of exceptional value. Many of these compounds own biological/pharmacological activity, others are regarded as unique chemical skeletons for the synthesis of derivatives with improved properties. Functional chemical modification of terpenoids through biotransformation frequently relies on the use of Ascomycota strains, but information on major cellular responses is still largely lacking. Penicillium janczewskii mediates a stereo-selective hydroxylation of labdanolic acid (LA—terpenoid found abundantly in Cistus ladanifer—producing 3β-hydroxy-labdanolic acid with yields >90%. Herein, combined analyses of mycelial and extracellular differential proteomes demonstrated that the plant terpenoid increased stress responses, especially against oxidative stress (e.g., accumulation of superoxide dismutase and apparently altered mitochondria functioning. One putative cytochrome P450 monooxygenase differentially accumulated in the secretome and the terpenoid bioconversion was inhibited in vivo in the presence of a P450 inhibitor. The stereo-selective hydroxylation of the plant terpenoid is likely mediated by P450 enzymes, yet its unequivocal identity remains unclear. To the best of our knowledge, this is the first time that proteomics was used to investigate how a plant terpenoid impacts the metabolism of a filamentous fungus during its efficiently biotransformation. Our findings may encourage the development of new strategies for the valorization of plant natural resources through biotechnology.

  2. A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

    NARCIS (Netherlands)

    Kaeaeb, Stefan; Crawford, Dana C.; Sinner, Moritz F.; Behr, Elijah R.; Kannankeril, Prince J.; Wilde, Arthur A. M.; Bezzina, Connie R.; Schulze-Bahr, Eric; Guicheney, Pascale; Bishopric, Nanette H.; Myerburg, Robert J.; Schott, Jean-Jacques; Pfeufer, Arne; Beckmann, Britt-Maria; Martens, Eimo; Zhang, Taifang; Stallmeyer, Birgit; Zumhagen, Sven; Denjoy, Isabelle; Bardai, Abdennasser; Van Gelder, Isabelle C.; Jamshidi, Yalda; Dalageorgou, Chrysoula; Marshall, Vanessa; Jeffery, Steve; Shakir, Saad; Camm, A. John; Steinbeck, Gerhard; Perz, Siegfried; Lichtner, Peter; Meitinger, Thomas; Peters, Annette; Wichmann, H. -Erich; Ingram, Christiana; Bradford, Yuki; Carter, Shannon; Norris, Kris; Ritchie, Marylyn D.; George, Alfred L.; Roden, Dan M.

    Background-Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results-In a

  3. A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

    NARCIS (Netherlands)

    Kääb, Stefan; Crawford, Dana C.; Sinner, Moritz F.; Behr, Elijah R.; Kannankeril, Prince J.; Wilde, Arthur A. M.; Bezzina, Connie R.; Schulze-Bahr, Eric; Guicheney, Pascale; Bishopric, Nanette H.; Myerburg, Robert J.; Schott, Jean-Jacques; Pfeufer, Arne; Beckmann, Britt-Maria; Martens, Eimo; Zhang, Taifang; Stallmeyer, Birgit; Zumhagen, Sven; Denjoy, Isabelle; Bardai, Abdennasser; van Gelder, Isabelle C.; Jamshidi, Yalda; Dalageorgou, Chrysoula; Marshall, Vanessa; Jeffery, Steve; Shakir, Saad; Camm, A. John; Steinbeck, Gerhard; Perz, Siegfried; Lichtner, Peter; Meitinger, Thomas; Peters, Annette; Wichmann, H.-Erich; Ingram, Christiana; Bradford, Yuki; Carter, Shannon; Norris, Kris; Ritchie, Marylyn D.; George, Alfred L.; Roden, Dan M.

    2012-01-01

    Background-Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results-In a

  4. In-silico Leishmania Target Selectivity of Antiparasitic Terpenoids

    Directory of Open Access Journals (Sweden)

    Ifedayo Victor Ogungbe

    2013-07-01

    Full Text Available Neglected Tropical Diseases (NTDs, like leishmaniasis, are major causes of mortality in resource-limited countries. The mortality associated with these diseases is largely due to fragile healthcare systems, lack of access to medicines, and resistance by the parasites to the few available drugs. Many antiparasitic plant-derived isoprenoids have been reported, and many of them have good in vitro activity against various forms of Leishmania spp. In this work, potential Leishmania biochemical targets of antiparasitic isoprenoids were studied in silico. Antiparasitic monoterpenoids selectively docked to L. infantum nicotinamidase, L. major uridine diphosphate-glucose pyrophosphorylase and methionyl t-RNA synthetase. The two protein targets selectively targeted by germacranolide sesquiterpenoids were L. major methionyl t-RNA synthetase and dihydroorotate dehydrogenase. Diterpenoids generally favored docking to L. mexicana glycerol-3-phosphate dehydrogenase. Limonoids also showed some selectivity for L. mexicana glycerol-3-phosphate dehydrogenase and L. major dihydroorotate dehydrogenase while withanolides docked more selectively with L. major uridine diphosphate-glucose pyrophosphorylase. The selectivity of the different classes of antiparasitic compounds for the protein targets considered in this work can be explored in fragment- and/or structure-based drug design towards the development of leads for new antileishmanial drugs.

  5. Overexpression and RNA interference of TwDXR regulate the accumulation of terpenoid active ingredients in Tripterygium wilfordii.

    Science.gov (United States)

    Zhang, Yifeng; Zhao, Yujun; Wang, Jiadian; Hu, Tianyuan; Tong, Yuru; Zhou, Jiawei; Song, Yadi; Gao, Wei; Huang, Luqi

    2018-02-01

    To examine the putative regulatory role of TwDXR in terpenoid biosynthesis and terpenoid biosynthetic pathway-related gene expression, through overexpression and RNA interference with TwDXR. We obtained 1410 and 454 bp TwDXR-specific fragments to construct overexpression and RNAi vectors. qRT-PCR was used to detect the expression of TwDXR and terpenoid biosynthesis pathway-related genes. The overexpression of TwDXR led to a 285% upregulation and the TwDXR RNAi led to a reduction to 26% of the control (empty vector-transformed cells) levels. However, pathway-related genes displayed different trends. When TwDXR was overexpressed, TwDXS expression decreased by 31% but increased to 198% when TwDXR expression was inhibited. The accumulation of terpenoids was also assayed. In the overexpression group, differences were not significant whereas the contents of triptolide and celastrol in the TwDXR RNAi samples were diminished by 27.3 and 24.0%, respectively. The feedback regulation of gene transcription and the accumulation of terpenoids in terpenoid biosynthesis in Tripterygium wilfordii were verified by TwDXR overexpression and RNAi experiments.

  6. Liquid chromatographic separation of terpenoid pigments in foods and food products.

    Science.gov (United States)

    Cserháti, T; Forgács, E

    2001-11-30

    The newest achievements in the use of various liquid chromatographic techniques such as adsorption and reversed-phase thin-layer chromatography and HPLC employed for the separation and quantitative determination of terpenoid-based color substances in foods and food products are reviewed. The techniques applied for the analysis of individual pigments and pigments classes are surveyed and critically evaluated. Future trends in the separation and identification of pigments in foods and food products are delineated.

  7. Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.

    Science.gov (United States)

    Bezençon, Olivier; Heidmann, Bibia; Siegrist, Romain; Stamm, Simon; Richard, Sylvia; Pozzi, Davide; Corminboeuf, Olivier; Roch, Catherine; Kessler, Melanie; Ertel, Eric A; Reymond, Isabelle; Pfeifer, Thomas; de Kanter, Ruben; Toeroek-Schafroth, Michael; Moccia, Luca G; Mawet, Jacques; Moon, Richard; Rey, Markus; Capeleto, Bruno; Fournier, Elvire

    2017-12-14

    We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.

  8. Determination of Terpenoid Content in Pine by Organic Solvent Extraction and Fast-GC Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Harman-Ware, Anne E., E-mail: anne.ware@nrel.gov; Sykes, Robert [National Bioenergy Center, National Renewable Energy Laboratory, Golden, CO (United States); Peter, Gary F. [School of Forest Resources and Conservation, University of Florida, Gainesville, FL (United States); Davis, Mark [National Bioenergy Center, National Renewable Energy Laboratory, Golden, CO (United States)

    2016-01-25

    Terpenoids, naturally occurring compounds derived from isoprene units present in pine oleoresin, are a valuable source of chemicals used in solvents, fragrances, flavors, and have shown potential use as a biofuel. This paper describes a method to extract and analyze the terpenoids present in loblolly pine saplings and pine lighter wood. Various extraction solvents were tested over different times and temperatures. Samples were analyzed by pyrolysis-molecular beam mass spectrometry before and after extractions to monitor the extraction efficiency. The pyrolysis studies indicated that the optimal extraction method used a 1:1 hexane/acetone solvent system at 22°C for 1 h. Extracts from the hexane/acetone experiments were analyzed using a low thermal mass modular accelerated column heater for fast-GC/FID analysis. The most abundant terpenoids from the pine samples were quantified, using standard curves, and included the monoterpenes, α- and β-pinene, camphene, and δ-carene. Sesquiterpenes analyzed included caryophyllene, humulene, and α-bisabolene. Diterpenoid resin acids were quantified in derivatized extractions, including pimaric, isopimaric, levopimaric, palustric, dehydroabietic, abietic, and neoabietic acids.

  9. A new method for microwave assisted ethanolic extraction of Mentha rotundifolia bioactive terpenoids.

    Science.gov (United States)

    García-Sarrió, María Jesús; Sanz, María Luz; Sanz, Jesús; González-Coloma, Azucena; Cristina Soria, Ana

    2018-04-14

    A new microwave-assisted extraction (MAE) method using ethanol as solvent has been optimized by means of a Box-Behnken experimental design for the enhanced extraction of bioactive terpenoids from Mentha rotundifolia leaves; 100°C, 5 min, 1.125 g dry sample: 10 mL solvent and a single extraction cycle were selected as optimal conditions. Improved performance of MAE method in terms of extraction yield and/or reproducibility over conventional solid-liquid extraction and ultrasound assisted extraction was also previously assessed. A comprehensive characterization of MAE extracts was carried out by GC-MS. A total of 46 compounds, mostly terpenoids, were identified; piperitenone oxide and piperitenone were the major compounds determined. Several neophytadiene isomers were also detected for the first time in MAE extracts. Different procedures (solid-phase extraction and activated charcoal (AC) treatment) were also evaluated for clean-up of MAE extracts, with AC providing the highest enrichment in bioactive terpenoids. Finally, the MAE method here developed is shown as a green, fast, efficient and reproducible liquid extraction methodology to obtain M. rotundifolia bioactive extracts for further application, among others, as food preservatives. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Determination of Terpenoid Content in Pine by Organic Solvent Extraction and Fast-GC Analysis

    International Nuclear Information System (INIS)

    Harman-Ware, Anne E.; Sykes, Robert; Peter, Gary F.; Davis, Mark

    2016-01-01

    Terpenoids, naturally occurring compounds derived from isoprene units present in pine oleoresin, are a valuable source of chemicals used in solvents, fragrances, flavors, and have shown potential use as a biofuel. This paper describes a method to extract and analyze the terpenoids present in loblolly pine saplings and pine lighter wood. Various extraction solvents were tested over different times and temperatures. Samples were analyzed by pyrolysis-molecular beam mass spectrometry before and after extractions to monitor the extraction efficiency. The pyrolysis studies indicated that the optimal extraction method used a 1:1 hexane/acetone solvent system at 22°C for 1 h. Extracts from the hexane/acetone experiments were analyzed using a low thermal mass modular accelerated column heater for fast-GC/FID analysis. The most abundant terpenoids from the pine samples were quantified, using standard curves, and included the monoterpenes, α- and β-pinene, camphene, and δ-carene. Sesquiterpenes analyzed included caryophyllene, humulene, and α-bisabolene. Diterpenoid resin acids were quantified in derivatized extractions, including pimaric, isopimaric, levopimaric, palustric, dehydroabietic, abietic, and neoabietic acids.

  11. Metabolic fingerprinting of Cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes.

    Science.gov (United States)

    Fischedick, Justin Thomas; Hazekamp, Arno; Erkelens, Tjalling; Choi, Young Hae; Verpoorte, Rob

    2010-12-01

    Cannabis sativa L. is an important medicinal plant. In order to develop cannabis plant material as a medicinal product quality control and clear chemotaxonomic discrimination between varieties is a necessity. Therefore in this study 11 cannabis varieties were grown under the same environmental conditions. Chemical analysis of cannabis plant material used a gas chromatography flame ionization detection method that was validated for quantitative analysis of cannabis monoterpenoids, sesquiterpenoids, and cannabinoids. Quantitative data was analyzed using principal component analysis to determine which compounds are most important in discriminating cannabis varieties. In total 36 compounds were identified and quantified in the 11 varieties. Using principal component analysis each cannabis variety could be chemically discriminated. This methodology is useful for both chemotaxonomic discrimination of cannabis varieties and quality control of plant material. Copyright © 2010 Elsevier Ltd. All rights reserved.

  12. Expression of MEP Pathway Genes and Non-volatile Sequestration Are Associated with Circadian Rhythm of Dominant Terpenoids Emission in Osmanthus fragrans Lour. Flowers

    Directory of Open Access Journals (Sweden)

    Riru Zheng

    2017-10-01

    Full Text Available Osmanthus fragrans Lour. is one of the top 10 traditional ornamental flowers in China famous for its unique fragrance. Preliminary study proved that the terpenoids including ionone, linalool, and ocimene and their derivatives are the dominant aroma-active compounds that contribute greatly to the scent bouquet. Pollination observation implies the emission of aromatic terpenoids may follow a circadian rhythm. In this study, we investigated the variation of volatile terpenoids and its potential regulators. The results showed that both volatile and non-volatile terpenoids presented circadian oscillation with high emission or accumulation during the day and low emission or accumulation during the night. The volatile terpenoids always increased to reach their maximum values at 12:00 h, while free and glycosylated compounds continued increasing throughout the day. The depletion of non-volatile pool might provide the substrates for volatile emission at 0:00–6:00, suggesting the sequestration of non-volatile compounds acted like a buffer regulating emission of terpenoids. Further detection of MEP pathway genes demonstrated that their expressions increased significantly in parallel with the evident increase of both volatile and non-volatile terpenoids during the day, indicating that the gene expressions were also closely associated with terpenoid formation. Thus, the expression of MEP pathway genes and internal sequestration both played crucial roles in modulating circadian rhythm of terpenoid emission in O. fragrans.

  13. Genes, enzymes and chemicals of terpenoid diversity in the constitutive and induced defence of conifers against insects and pathogens.

    Science.gov (United States)

    Keeling, Christopher I; Bohlmann, Jörg

    2006-01-01

    Insects select their hosts, but trees cannot select which herbivores will feed upon them. Thus, as long-lived stationary organisms, conifers must resist the onslaught of varying and multiple attackers over their lifetime. Arguably, the greatest threats to conifers are herbivorous insects and their associated pathogens. Insects such as bark beetles, stem- and wood-boring insects, shoot-feeding weevils, and foliage-feeding budworms and sawflies are among the most devastating pests of conifer forests. Conifer trees produce a great diversity of compounds, such as an enormous array of terpenoids and phenolics, that may impart resistance to a variety of herbivores and microorganisms. Insects have evolved to specialize in resistance to these chemicals -- choosing, feeding upon, and colonizing hosts they perceive to be best suited to reproduction. This review focuses on the plant-insect interactions mediated by conifer-produced terpenoids. To understand the role of terpenoids in conifer-insect interactions, we must understand how conifers produce the wide diversity of terpenoids, as well as understand how these specific compounds affect insect behaviour and physiology. This review examines what chemicals are produced, the genes and proteins involved in their biosynthesis, how they work, and how they are regulated. It also examines how insects and their associated pathogens interact with, elicit, and are affected by conifer-produced terpenoids.

  14. The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates.

    Science.gov (United States)

    Buccafusco, Jerry J; Terry, Alvin V; Webster, Scott J; Martin, Daniel; Hohnadel, Elizabeth J; Bouchard, Kristy A; Warner, Samantha E

    2008-08-01

    The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents. The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS). The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 microg/kg in the DMTS task. The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.

  15. Computational design of drug candidates for influenza A virus subtype H1N1 by inhibiting the viral neuraminidase-1 enzyme

    Directory of Open Access Journals (Sweden)

    Tambunan Usman Sumo Friend

    2014-06-01

    Full Text Available It is critical to seek potential alternative treatments for H1N1 infections by inhibiting neuraminidase-1 enzyme. One of the viable options for inhibiting the activity of neuraminidase- 1 is peptide drug design. In order to increase peptide stability, cyclization is necessary to prevent its digestion by protease enzyme. Cyclization of peptide ligands by formation of disulfide bridges is preferable for designing inhibitors of neuraminidase-1 because of their high activity and specificity. Here we designed ligands by using molecular docking, drug scan and dynamics computational methods. Based on our docking results, short polypeptides of cystein-arginine-methionine-tyrosine- -proline-cysteine (CRMYPC and cysteine-arginine-aspargine- phenylalanine-proline-cysteine (CRNFPC have good residual interactions with the target and the binding energy ΔGbinding of -31.7402 and -31.0144 kcal mol-1, respectively. These values are much lower than those of the standards, and it means that both ligands are more accessible to ligand-receptor binding. Based on drug scan results, both of these ligands are neither mutagenic nor carcinogenic. They also show good oral bioavailability. Moreover, both ligands show relatively stable molecular dynamics progression of RMSD vs. time plot. However, based on our metods, the CRMYPC ligand has sufficient hydrogen bonding interactions with residues of the active side of neuraminidase-1 and can be therefore proposed as a potential inhibitor of neuraminidase-1

  16. Candidate DNA Barcode Tags Combined With High Resolution Melting (Bar-HRM Curve Analysis for Authentication of Senna alexandrina Mill. With Validation in Crude Drugs

    Directory of Open Access Journals (Sweden)

    Priyanka Mishra

    2018-03-01

    Full Text Available Senna alexandrina (Fabaceae is a globally recognized medicinal plant for its laxative properties as well as the only source of sennosides, and is highly exported bulk herb from India. Its major procurement is exclusively from limited cultivation, which leads to risks of deliberate or unintended adulteration. The market raw materials are in powdered or finished product form, which lead to difficulties in authentication. Here, DNA barcode tags based on chloroplast genes (rbcL and matK and intergenic spacers (psbA-trnH and ITS were developed for S. alexandrina along with the allied species. The ability and performance of the ITS1 region to discriminate among the Senna species resulted in the present proposal of the ITS1 tags as successful barcode. Further, these tags were coupled with high-resolution melting (HRM curve analysis in a real-time PCR genotyping method to derive Bar-HRM (Barcoding-HRM assays. Suitable HRM primer sets were designed through SNP detection and mutation scanning in genomic signatures of Senna species. The melting profiles of S. alexandrina and S. italica subsp. micrantha were almost identical and the remaining five species were clearly separated so that they can be differentiated by HRM method. The sensitivity of the method was utilized to authenticate market samples [Herbal Sample Assays (HSAs]. HSA01 (S. alexandrina crude drug sample from Bangalore and HSA06 (S. alexandrina crude drug sample from Tuticorin, Tamil Nadu, India were found to be highly contaminated with S. italica subsp. micrantha. Species admixture samples mixed in varying percentage was identified sensitively with detection of contamination as low as 1%. The melting profiles of PCR amplicons are clearly distinct, which enables the authentic differentiation of species by the HRM method. This study reveals that DNA barcoding coupled with HRM is an efficient molecular tool to authenticate Senna herbal products in the market for quality control in the drug

  17. Candidate DNA Barcode Tags Combined With High Resolution Melting (Bar-HRM) Curve Analysis for Authentication of Senna alexandrina Mill. With Validation in Crude Drugs.

    Science.gov (United States)

    Mishra, Priyanka; Shukla, Ashutosh K; Sundaresan, Velusamy

    2018-01-01

    Senna alexandrina (Fabaceae) is a globally recognized medicinal plant for its laxative properties as well as the only source of sennosides, and is highly exported bulk herb from India. Its major procurement is exclusively from limited cultivation, which leads to risks of deliberate or unintended adulteration. The market raw materials are in powdered or finished product form, which lead to difficulties in authentication. Here, DNA barcode tags based on chloroplast genes ( rbcL and matK ) and intergenic spacers ( psbA-trnH and ITS ) were developed for S. alexandrina along with the allied species. The ability and performance of the ITS1 region to discriminate among the Senna species resulted in the present proposal of the ITS1 tags as successful barcode. Further, these tags were coupled with high-resolution melting (HRM) curve analysis in a real-time PCR genotyping method to derive Bar-HRM (Barcoding-HRM) assays. Suitable HRM primer sets were designed through SNP detection and mutation scanning in genomic signatures of Senna species. The melting profiles of S. alexandrina and S . italica subsp. micrantha were almost identical and the remaining five species were clearly separated so that they can be differentiated by HRM method. The sensitivity of the method was utilized to authenticate market samples [Herbal Sample Assays (HSAs)]. HSA01 ( S. alexandrina crude drug sample from Bangalore) and HSA06 ( S. alexandrina crude drug sample from Tuticorin, Tamil Nadu, India) were found to be highly contaminated with S . italica subsp. micrantha . Species admixture samples mixed in varying percentage was identified sensitively with detection of contamination as low as 1%. The melting profiles of PCR amplicons are clearly distinct, which enables the authentic differentiation of species by the HRM method. This study reveals that DNA barcoding coupled with HRM is an efficient molecular tool to authenticate Senna herbal products in the market for quality control in the drug supply

  18. Topical delivery of low-cost protein drug candidates made in chloroplasts for biofilm disruption and uptake by oral epithelial cells.

    Science.gov (United States)

    Liu, Yuan; Kamesh, Aditya C; Xiao, Yuhong; Sun, Victor; Hayes, Michael; Daniell, Henry; Koo, Hyun

    2016-10-01

    Protein drugs (PD) are minimally utilized in dental medicine due to high cost and invasive surgical delivery. There is limited clinical advancement in disrupting virulent oral biofilms, despite their high prevalence in causing dental caries. Poor efficacy of antimicrobials following topical treatments or to penetrate and disrupt formed biofilms is a major challenge. We report an exciting low-cost approach using plant-made antimicrobial peptides (PMAMPs) retrocyclin or protegrin with complex secondary structures (cyclic/hairpin) for topical use to control biofilms. The PMAMPs rapidly killed the pathogen Streptococcus mutans and impaired biofilm formation following a single topical application of tooth-mimetic surface. Furthermore, we developed a synergistic approach using PMAMPs combined with matrix-degrading enzymes to facilitate their access into biofilms and kill the embedded bacteria. In addition, we identified a novel role for PMAMPs in delivering drugs to periodontal and gingival cells, 13-48 folds more efficiently than any other tested cell penetrating peptides. Therefore, PDs fused with protegrin expressed in plant cells could potentially play a dual role in delivering therapeutic proteins to gum tissues while killing pathogenic bacteria when delivered as topical oral formulations or in chewing gums. Recent FDA approval of plant-produced PDs augurs well for clinical advancement of this novel concept. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. Oligo-Carrageenan Kappa-Induced Reducing Redox Status and Increase in TRR/TRX Activities Promote Activation and Reprogramming of Terpenoid Metabolism in Eucalyptus Trees

    Directory of Open Access Journals (Sweden)

    Alberto González

    2014-06-01

    Full Text Available In order to analyze whether the reducing redox status and activation of thioredoxin reductase (TRR/thioredoxin(TRX system induced by oligo-carrageenan (OC kappa in Eucalyptus globulus activate secondary metabolism increasing terpenoid synthesis, trees were sprayed on the leaves with water, with OC kappa, or with inhibitors of NAD(PH, ascorbate (ASC and (GSH synthesis and TRR activity, CHS-828, lycorine, buthionine sulfoximine (BSO and auranofine, respectively, and with OC kappa and cultivated for four months. The main terpenoids in control Eucalyptus trees were eucalyptol (76%, α-pinene (7.4%, aromadendrene (3.6%, silvestrene (2.8%, sabinene (2% and α-terpineol (0.9%. Treated trees showed a 22% increase in total essential oils as well as a decrease in eucalyptol (65% and sabinene (0.8% and an increase in aromadendrene (5%, silvestrene (7.8% and other ten terpenoids. In addition, treated Eucalyptus showed seven de novo synthesized terpenoids corresponding to carene, α-terpinene, α-fenchene, γ-maaliene, spathulenol and α-camphenolic aldehyde. Most increased and de novo synthesized terpenoids have potential insecticidal and antimicrobial activities. Trees treated with CHS-828, lycorine, BSO and auranofine and with OC kappa showed an inhibition of increased and de novo synthesized terpenoids. Thus, OC kappa-induced reducing redox status and activation of TRR/TRX system enhance secondary metabolism increasing the synthesis of terpenoids and reprogramming of terpenoid metabolism in Eucalyptus trees.

  20. Oligo-carrageenan kappa-induced reducing redox status and increase in TRR/TRX activities promote activation and reprogramming of terpenoid metabolism in Eucalyptus trees.

    Science.gov (United States)

    González, Alberto; Gutiérrez-Cutiño, Marlen; Moenne, Alejandra

    2014-06-05

    In order to analyze whether the reducing redox status and activation of thioredoxin reductase (TRR)/thioredoxin(TRX) system induced by oligo-carrageenan (OC) kappa in Eucalyptus globulus activate secondary metabolism increasing terpenoid synthesis, trees were sprayed on the leaves with water, with OC kappa, or with inhibitors of NAD(P)H, ascorbate (ASC) and (GSH) synthesis and TRR activity, CHS-828, lycorine, buthionine sulfoximine (BSO) and auranofine, respectively, and with OC kappa and cultivated for four months. The main terpenoids in control Eucalyptus trees were eucalyptol (76%), α-pinene (7.4%), aromadendrene (3.6%), silvestrene (2.8%), sabinene (2%) and α-terpineol (0.9%). Treated trees showed a 22% increase in total essential oils as well as a decrease in eucalyptol (65%) and sabinene (0.8%) and an increase in aromadendrene (5%), silvestrene (7.8%) and other ten terpenoids. In addition, treated Eucalyptus showed seven de novo synthesized terpenoids corresponding to carene, α-terpinene, α-fenchene, γ-maaliene, spathulenol and α-camphenolic aldehyde. Most increased and de novo synthesized terpenoids have potential insecticidal and antimicrobial activities. Trees treated with CHS-828, lycorine, BSO and auranofine and with OC kappa showed an inhibition of increased and de novo synthesized terpenoids. Thus, OC kappa-induced reducing redox status and activation of TRR/TRX system enhance secondary metabolism increasing the synthesis of terpenoids and reprogramming of terpenoid metabolism in Eucalyptus trees.

  1. "Heart-cut" bidimensional achiral-chiral liquid chromatography applied to the evaluation of stereoselective metabolism, in vivo biological activity and brain response to chiral drug candidates targeting the central nervous system.

    Science.gov (United States)

    Battisti, Umberto M; Citti, Cinzia; Larini, Martina; Ciccarella, Giuseppe; Stasiak, Natalia; Troisi, Luigino; Braghiroli, Daniela; Parenti, Carlo; Zoli, Michele; Cannazza, Giuseppe

    2016-04-22

    A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug

  2. Suites of Terpene Synthases Explain Differential Terpenoid Production in Ginger and Turmeric Tissues

    Science.gov (United States)

    Koo, Hyun Jo; Gang, David R.

    2012-01-01

    The essential oils of ginger (Zingiber officinale) and turmeric (Curcuma longa) contain a large variety of terpenoids, some of which possess anticancer, antiulcer, and antioxidant properties. Despite their importance, only four terpene synthases have been identified from the Zingiberaceae family: (+)-germacrene D synthase and (S)-β-bisabolene synthase from ginger rhizome, and α-humulene synthase and β-eudesmol synthase from shampoo ginger (Zingiber zerumbet) rhizome. We report the identification of 25 mono- and 18 sesquiterpene synthases from ginger and turmeric, with 13 and 11, respectively, being functionally characterized. Novel terpene synthases, (−)-caryolan-1-ol synthase and α-zingiberene/β-sesquiphellandrene synthase, which is responsible for formation of the major sesquiterpenoids in ginger and turmeric rhizomes, were also discovered. These suites of enzymes are responsible for formation of the majority of the terpenoids present in these two plants. Structures of several were modeled, and a comparison of sets of paralogs suggests how the terpene synthases in ginger and turmeric evolved. The most abundant and most important sesquiterpenoids in turmeric rhizomes, (+)-α-turmerone and (+)-β-turmerone, are produced from (−)-α-zingiberene and (−)-β-sesquiphellandrene, respectively, via α-zingiberene/β-sesquiphellandrene oxidase and a still unidentified dehydrogenase. PMID:23272109

  3. Characterization of Terpenoids from the Root of Ceriops tagal with Antifouling Activity

    Science.gov (United States)

    Chen, Jun-De; Yi, Rui-Zao; Lin, Yi-Ming; Feng, Dan-Qing; Zhou, Hai-Chao; Wang, Zhan-Chang

    2011-01-01

    One new dimeric diterpenoid, 8(14)-enyl-pimar-2′(3′)-en-4′(18′)-en-15′(16′)-endolabr- 16,15,2′,3′-oxoan-16-one (1) and five known terpenoids: Tagalsin C (2), Tagalsin I (3), lup-20(29)-ene-3β,28-diol (4), 3-oxolup-20(29)-en-28-oic acid (5) and 28-hydroxylup- 20(29)-en-3-one (6) were isolated from the roots of the mangrove plant Ceriops tagal. Their structures and relative stereochemistry were elucidated by means of extensive NMR, IR and MS analysis. The antifouling activity against larval settlement of the barnacle Balanus albicostatus were evaluated using capsaicin as a positive control. All these terpenoids exhibited antifouling activity against cyprid larvae of the barnacle without significant toxicity. The structure-activity relationship results demonstrated that the order of antifouling activity was diterpenoid (Compound 2) > triterpenoid (Compounds 4, 5 and 6) > dimeric diterpenoid (Compounds 1 and 3). The functional groups on the C-28 position of lupane triterpenoid significantly affect the antifouling activity. The diterpenoid dimmer with two identical diterpenoid subunits might display more potent antifouling activity than one with two different diterpenoid subunits. The stability test showed that Compounds 2, 4, 5 and 6 remained stable over 2-month exposure under filtered seawater. PMID:22072902

  4. Suites of terpene synthases explain differential terpenoid production in ginger and turmeric tissues.

    Directory of Open Access Journals (Sweden)

    Hyun Jo Koo

    Full Text Available The essential oils of ginger (Zingiber officinale and turmeric (Curcuma longa contain a large variety of terpenoids, some of which possess anticancer, antiulcer, and antioxidant properties. Despite their importance, only four terpene synthases have been identified from the Zingiberaceae family: (+-germacrene D synthase and (S-β-bisabolene synthase from ginger rhizome, and α-humulene synthase and β-eudesmol synthase from shampoo ginger (Zingiber zerumbet rhizome. We report the identification of 25 mono- and 18 sesquiterpene synthases from ginger and turmeric, with 13 and 11, respectively, being functionally characterized. Novel terpene synthases, (--caryolan-1-ol synthase and α-zingiberene/β-sesquiphellandrene synthase, which is responsible for formation of the major sesquiterpenoids in ginger and turmeric rhizomes, were also discovered. These suites of enzymes are responsible for formation of the majority of the terpenoids present in these two plants. Structures of several were modeled, and a comparison of sets of paralogs suggests how the terpene synthases in ginger and turmeric evolved. The most abundant and most important sesquiterpenoids in turmeric rhizomes, (+-α-turmerone and (+-β-turmerone, are produced from (--α-zingiberene and (--β-sesquiphellandrene, respectively, via α-zingiberene/β-sesquiphellandrene oxidase and a still unidentified dehydrogenase.

  5. Expression of Terpenoid Biosynthetic Genes and Accumulation of Chemical Constituents in Valeriana fauriei

    Directory of Open Access Journals (Sweden)

    Yun Ji Park

    2016-05-01

    Full Text Available Valeriana fauriei (V. fauriei, which emits a characteristic and unpleasant odor, is important in traditional medicine. In this study, the expression of terpenoid biosynthetic genes was investigated in different organs that were also screened for volatile compounds including valerenic acid and its derivatives. Specific expression patterns from different parts of V. fauriei were observed using quantitative real-time PCR (qRT-PCR. The highest transcript levels of biosynthetic genes involved in mevalonic acid (MVA and methylerythritol phosphate (MEP production were found in the stem. Although the amounts of volatile compounds were varied by organ, most of the volatile terpenoids were accumulated in the root. Gas chromatography mass spectrometry (GC-MS analysis identified 128 volatile compounds, which represented 65.33% to 95.66% of total volatiles. Certain compounds were only found in specific organs. For example, isovalerenic acid and valerenic acid and its derivatives were restricted to the root. Organs with high transcript levels did not necessarily have high levels of the corresponding chemical constituents. According to these results, we hypothesize that translocation may occur between different organs in V. fauriei.

  6. Absolute Configurations and NO Inhibitory Activities of Terpenoids from Curcuma longa.

    Science.gov (United States)

    Xu, Jing; Ji, Feifei; Kang, Jing; Wang, Hao; Li, Shen; Jin, Da-Qing; Zhang, Qiang; Sun, Hongwei; Guo, Yuanqiang

    2015-06-24

    Curcuma longa L., belonging to the Zingiberaceae family, is a perennial herb and has been used as a spice and a pigment in the food industry. In the ongoing search for inhibitory reagents of NO production and survey of the chemical composition of natural vegetable foods, the chemical constituents of C. longa used as spice were investigated. This investigation resulted in the isolation of 2 new terpenoids and 14 known analogues. Their structures were established on the basis of the extensive analyses of 1D and 2D NMR spectroscopic data, and the absolute configurations of 1-4 were elucidated by comparison of the calculated and experimental ECD spectra. Among them, compound 1 is a rare norditerpene with an ent-labdane skeleton, and 2 is a skeletally novel sesquiterpene having an eight-membered ring. All of the compounds were found to possess NO inhibitory activities in murine microglial BV-2 cells. The discovery of two new compounds in this chemical investigation further disclosed the chemical composition of C. longa used a food spice, and the bioassay implied that the natural food spice C. longa, containing terpenoids with NO inhibitory activities, may be potentially promotive to human health.

  7. Formulation, evaluation and bioactive potential of Xylaria primorskensis terpenoid nanoparticles from its major compound xylaranic acid.

    Science.gov (United States)

    Adnan, Mohd; Patel, Mitesh; Reddy, Mandadi Narsimha; Alshammari, Eyad

    2018-01-29

    In recent years, fungi have been shown to produce a plethora of new bioactive secondary metabolites of interest, as new lead structures for medicinal and other pharmacological applications. The present investigation was carried out to study the pharmacological properties of a potent and major bioactive compound: xylaranic acid, which was obtained from Xylaria primorskensis (X. primorskensis) terpenoids in terms of antibacterial activity, antioxidant potential against DPPH & H 2 O 2 radicals and anticancer activity against human lung cancer cells. Due to terpenoid nature, low water solubility and wretched bioavailability, its pharmacological use is limited. To overcome these drawbacks, a novel xylaranic acid silver nanoparticle system (AgNPs) is developed. In addition to improving its solubility and bioavailability, other advantageous pharmacological properties has been evaluated. Furthermore, enhanced anticancer activity of xylaranic acid and its AgNPs due to induced apoptosis were also confirmed by determining the expression levels of apoptosis regulatory genes p53, bcl-2 and caspase-3 via qRT PCR method. This is the first study developing the novel xylaranic acid silver nanoparticle system and enlightening its therapeutic significance with its improved physico-chemical properties and augmented bioactive potential.

  8. Exotic multifaceted medicinal plants of drugs and pharmaceutical ...

    African Journals Online (AJOL)

    They are sources of drugs and are used in herbal medicine to treat measles, malaria, asthma, eczema, cough, hepatitis, ringworm, ulcer and scabies. These plants are continuously screened and evaluated for their pharmacological properties. Bioactive compounds comprising flavanoids, alkaloids, steroids, terpenoids and ...

  9. Post-mortem analysis of suicide victims shows ABCB1 haplotype 1236T-2677T-3435T as a candidate predisposing factor behind adverse drug reactions in females.

    Science.gov (United States)

    Rahikainen, Anna-Liina; Palo, Jukka U; Haukka, Jari; Sajantila, Antti

    2018-04-01

    Genetic variation in efflux transporter, permeability glycoprotein (P-gp), has recently been associated with completed violent suicides and also violent suicide attempts. As depression is known to be a risk factor for suicide and many antidepressants are P-gp substrates, it has been speculated that inadequate antidepressant treatment response or adverse side effects could be involved. The aim of this study was to investigate whether there is an association between the P-gp coding ABCB1 gene and completed suicides in citalopram users. Also, the effect of sex and suicide method used (violent vs. non-violent) was evaluated. All cases included in the study population, 349 completed suicide victims and 284 controls, were shown to be positive for antidepressant citalopram in a post-mortem toxicological drug screen. ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms were determined by TaqMan genotyping assays. Haplotypes were constructed from genotype data using the PHASE software. The association between the manner of death and the ABCB1 haplotype was tested with logistic regression analysis. No statistically significant differences were observed in the ABCB1 allele or genotype frequencies between the suicide and control groups. However, the ABCB1 1236T-2677T-3435T haplotype was associated with completed suicides of female citalopram users (odds ratio: 2.23; 95% confidence interval: 1.22-4.07; P=0.009). After stratification by the method used for suicide, the association emerged in fatal intoxications (odds ratio: 2.51; 95% confidence interval: 1.29-4.87; P=0.007). In other groups, no statistically significant associations were observed. Our results suggest that female citalopram users with ABCB1 1236T-2677T-3435T are more vulnerable to adverse effects of the drugs as this haplotype was enriched in non-violent suicides of female citalopram users. Even though the biological mechanism behind this observation is unknown, the results provide another example of the importance

  10. Long-term measurement of terpenoid flux above a Larix kaempferi forest using a relaxed eddy accumulation method

    Science.gov (United States)

    Mochizuki, Tomoki; Tani, Akira; Takahashi, Yoshiyuki; Saigusa, Nobuko; Ueyama, Masahito

    2014-02-01

    Terpenoids emitted from forests contribute to the formation of secondary organic aerosols and affect the carbon budgets of forest ecosystems. To investigate seasonal variation in terpenoid flux involved in the aerosol formation and carbon budget, we measured the terpenoid flux of a Larix kaempferi forest between May 2011 and May 2012 by using a relaxed eddy accumulation method. Isoprene was emitted from a fern plant species Dryopteris crassirhizoma on the forest floor and monoterpenes from the L. kaempferi. α-Pinene was the dominant compound, but seasonal variation of the monoterpene composition was observed. High isoprene and monoterpene fluxes were observed in July and August. The total monoterpene flux was dependent on temperature, but several unusual high positive fluxes were observed after rain fall events. We found a good correlation between total monoterpene flux and volumetric soil water content (r = 0.88), and used this correlation to estimate monoterpene flux after rain events and calculate annual terpenoid emissions. Annual carbon emission in the form of total monoterpenes plus isoprene was determined to be 0.93% of the net ecosystem exchange. If we do not consider the effect of rain fall, carbon emissions may be underestimated by about 50%. Our results suggest that moisture conditions in the forest soil is a key factor controlling the monoterpene emissions from the forest ecosystem.

  11. Needle terpenoid composition of Pinus halepensis (Mill.) Trees infested by the scale insect Marchalina hellenica (Genn.) in Greece

    Science.gov (United States)

    Athanassios Gallis; Carlos Arrabal; Aristotle C. Papageorgiou; Maria C. Garcia-Vallejo

    2012-01-01

    Needle terpenoid composition was determined by using GLC-MS in Pinus halepensis (Mill.) trees that were infested and not infested by the scale insect Marchalina hellenica. The study area was within the Forest National Park of the Cape Sounion, southern Attica region, Greece. A total of 43 compounds, 32 of which were identified...

  12. Genomic and transcriptomic analyses reveal differential regulation of diverse terpenoid and polyketides secondary metabolites in Hericium erinaceus.

    Science.gov (United States)

    Chen, Juan; Zeng, Xu; Yang, Yan Long; Xing, Yong Mei; Zhang, Qi; Li, Jia Mei; Ma, Ke; Liu, Hong Wei; Guo, Shun Xing

    2017-08-31

    The lion's mane mushroom Hericium erinaceus is a famous traditional medicinal fungus credited with anti-dementia activity and a producer of cyathane diterpenoid natural products (erinacines) useful against nervous system diseases. To date, few studies have explored the biosynthesis of these compounds, although their chemical synthesis is known. Here, we report the first genome and tanscriptome sequence of the medicinal fungus H. erinaceus. The size of the genome is 39.35 Mb, containing 9895 gene models. The genome of H. erinaceus reveals diverse enzymes and a large family of cytochrome P450 (CYP) proteins involved in the biosynthesis of terpenoid backbones, diterpenoids, sesquiterpenes and polyketides. Three gene clusters related to terpene biosynthesis and one gene cluster for polyketides biosynthesis (PKS) were predicted. Genes involved in terpenoid biosynthesis were generally upregulated in mycelia, while the PKS gene was upregulated in the fruiting body. Comparative genome analysis of 42 fungal species of Basidiomycota revealed that most edible and medicinal mushroom show many more gene clusters involved in terpenoid and polyketide biosynthesis compared to the pathogenic fungi. None of the gene clusters for terpenoid or polyketide biosynthesis were predicted in the poisonous mushroom Amanita muscaria. Our findings may facilitate future discovery and biosynthesis of bioactive secondary metabolites from H. erinaceus and provide fundamental information for exploring the secondary metabolites in other Basidiomycetes.

  13. Mass spectrometric characterization of the hypoxia-inducible factor (HIF) stabilizer drug candidate BAY 85-3934 (molidustat) and its glucuronidated metabolite BAY-348, and their implementation into routine doping controls.

    Science.gov (United States)

    Dib, Josef; Mongongu, Cynthia; Buisson, Corinne; Molina, Adeline; Schänzer, Wilhelm; Thuss, Uwe; Thevis, Mario

    2017-01-01

    The development of new therapeutics potentially exhibiting performance-enhancing properties implicates the risk of their misuse by athletes in amateur and elite sports. Such drugs necessitate preventive anti-doping research for consideration in sports drug testing programmes. Hypoxia-inducible factor (HIF) stabilizers represent an emerging class of therapeutics that allows for increasing erythropoiesis in patients. BAY 85-3934 is a novel HIF stabilizer, which is currently undergoing phase-2 clinical trials. Consequently, the comprehensive characterization of BAY 85-3934 and human urinary metabolites as well as the implementation of these analytes into routine doping controls is of great importance. The mass spectrometric behaviour of the HIF stabilizer drug candidate BAY 85-3934 and a glucuronidated metabolite (BAY-348) were characterized by electrospray ionization-(tandem) mass spectrometry (ESI-MS(/MS)) and multiple-stage mass spectrometry (MS n ). Subsequently, two different laboratories established different analytical approaches (one each) enabling urine sample analyses by employing either direct urine injection or solid-phase extraction. The methods were cross-validated for the metabolite BAY-348 that is expected to represent an appropriate target analyte for human urine analysis. Two test methods allowing for the detection of BAY-348 in human urine were applied and cross-validated concerning the validation parameters specificity, linearity, lower limit of detection (LLOD; 1-5 ng/mL), ion suppression/enhancement (up to 78%), intra- and inter-day precision (3-21%), recovery (29-48%), and carryover. By means of ten spiked test urine samples sent blinded to one of the participating laboratories, the fitness-for-purpose of both assays was provided as all specimens were correctly identified applying both testing methods. As no post-administration study samples were available, analyses of authentic urine specimens remain desirable. Copyright © 2016 John Wiley

  14. Tanker milk variability according to farm feeding practices: vitamins A and E, carotenoids, color, and terpenoids.

    Science.gov (United States)

    Agabriel, C; Cornu, A; Journal, C; Sibra, C; Grolier, P; Martin, B

    2007-10-01

    The aim of this work was to study the variability in the composition of bulk milk mixtures of fat-soluble compounds (vitamins A and E, carotenoids, and terpenoids) and assess the links with milk production conditions. Milk from 10 collection trips in the French department of the Haute-Loire (10 to 36 herds per trip) was sampled in the tanker twice during the winter period and 3 times during the grazing season. The collection trips differed in their altitude (440 to 1,150 m) and the forage system (grass or based on corn silage). Vitamins A and E, carotenoids, and terpenoids of the 50 tanker loads of milk were analyzed. Data of milk production conditions in the 204 farms made it possible to constitute indicators for the collection trip and to define 50 mean herds. The relationships between mean herd characteristics (breed, stage of lactation, and feed) and milk characteristics were investigated. The constituents of tanker loads of milk were comparable to those observed in milk produced by groups of animals receiving contrasting diets (rich in concentrate or corn silage vs. pasture). The characteristics of the milk differed according to the period; those produced at grazing were more yellow (1.02 +/- 0.4; mean of difference) and richer in beta-carotene, lutein, vitamin E (2.0 +/- 1.2, 0.23 +/- 0.12, and 6.1 +/- 5.0 mug/g of fat, respectively), and sesquiterpenes (2.7 +/- 2.5) than winter. The variations observed for beta-carotene, lutein, and vitamin E were linked to the proportion of grazed grass or grass silage in the forage (r = 0.66, 0.69, and 0.51, respectively), unlike the vitamin A content. During grazing, 20 of the 32 terpenoids identified were associated with the proportion of permanent grassland available for grazing or cut. These results show that feeding is an effective way to modify the quality of dairy products, even in the case of bulk tank milk mixtures. Dairy plants could market different milks, which would contain specific compositions.

  15. Citizen Candidates Under Uncertainty

    OpenAIRE

    Eguia, Jon X.

    2005-01-01

    In this paper we make two contributions to the growing literature on "citizen-candidate" models of representative democracy. First, we add uncertainty about the total vote count. We show that in a society with a large electorate, where the outcome of the election is uncertain and where winning candidates receive a large reward from holding office, there will be a two-candidate equilibrium and no equilibria with a single candidate. Second, we introduce a new concept of equilibrium, which we te...

  16. Systematic in-vitro evaluation of the NCI/NIH Developmental Therapeutics Program Approved Oncology Drug Set for the identification of a candidate drug repertoire for MLL-rearranged leukemia

    Directory of Open Access Journals (Sweden)

    Hoeksema KA

    2011-09-01

    Full Text Available Kimberley A Hoeksema1, Aarthi Jayanthan1, Todd Cooper2, Lia Gore3, Tanya Trippett4, Jessica Boklan6, Robert J Arceci5, Aru Narendran11Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, AB, Canada; 2Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA; 3Center for Cancer and Blood Disorders, Children's Hospital, University of Colorado Denver, Aurora, CO, USA; 4Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 5Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA; 6Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USAAbstract: Despite significant progress made in the overall cure rate, the prognosis for relapsed and refractory malignancies in children remains extremely poor. Hence, there is an urgent need for studies that enable the timely selection of appropriate agents for Phase I clinical studies. The Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC is systematically evaluating libraries of known and novel compounds for activity against subsets of high-risk pediatric malignancies with defined molecular aberrations for future clinical development. In this report, we describe the in-vitro activity of a diverse panel of approved oncology drugs against MLL-rearranged pediatric leukemia cell lines. Agents in the Approved Oncology Drug Set II (National Cancer Institute/National Institutes of Health Developmental Therapeutics Program were evaluated by in-vitro cytotoxicity assays in pediatric acute lymphoblastic leukemia and acute myeloid leukemia cell lines with MLL gene rearrangements. Validation studies were carried out with patient leukemia cells in culture. Comparative analysis for toxicity against nonmalignant cells was evaluated in normal bone marrow stromal cells and normal human lymphocytes. Results from this study show that 42 of the 89 agents tested have

  17. Plant nutraceuticals as antimicrobial agents in food preservation: terpenoids, polyphenols and thiols.

    Science.gov (United States)

    Gutiérrez-Del-Río, Ignacio; Fernández, Javier; Lombó, Felipe

    2018-05-16

    Synthetic food additives generate a negative perception in consumers. Therefore, food manufacturers search for safer natural alternatives as those involving phytochemicals and plant essential oils. These bioactives have antimicrobial activities widely proved in in vitro tests. Foodborne diseases cause thousands of deaths and millions of infections every year, mainly due to pathogenic bacteria as Salmonella spp., Campylobacter spp., Escherichia coli, Bacillus cereus, Listeria monocytogenes or Staphylococcus aureus. This review summarizes industrially interesting antimicrobial bioactivities, as well as their mechanisms of action, for three main types of plant nutraceuticals, terpenoids (as carnosic acid), polyphenols (as quercetin) and thiols (as allicin), which are important constituents of plant essential oils with a broad range of antimicrobial effects. These phytochemicals are widely distributed in fruits and vegetables and are really useful in food preservation as they inhibit microbial growth. Copyright © 2018. Published by Elsevier B.V.

  18. Terpenoid composition and botanical affinity of Cretaceous resins from India and Myanmar

    Energy Technology Data Exchange (ETDEWEB)

    Dutta, Suryendu; Mallick, Monalisa [Department of Earth Sciences, Indian Institute of Technology-Bombay (India); Kumar, Kishor [Wadia Institute of Himalayan Geology, Uttarakhand (India); Mann, Ulrich [Forschungzentrum Juelich (Germany). Institut fuer Chemie und Dynamik der Geosphaere; Greenwood, Paul F. [John De Laeter Mass Spectrometry and WA Biogeochemistry Centres (M090), University of Western Australia, Crawley (Australia)

    2011-01-01

    Fossil resins from the Cretaceous sediments of Meghalaya, India and Kachin, Myanmar (Burma) were analysed using Curie point pyrolysis-gas chromatography-mass spectrometry and thermochemolysis gas chromatography-mass spectrometry to help elucidate their botanical source. The major pyrolysis products and methyl-esterified thermochemolysis products of both the resins were abietane and labdane type diterpenoids with minor amount of sesquiterpenoids. The thermochemolysis products also included methyl-16,17-dinor callitrisate, methyl-16,17-dinor dehydroabietate and methyl-8-pimaren-18-oate - the latter two from just the Myanmarese resin. The exclusive presence of both labdane and abietane diterpenoids and the lack of phenolic terpenoids may suggest that the studied Cretaceous resins were derived from Pinaceae (pine family) conifers. (author)

  19. The evolution of plant secretory structures and emergence of terpenoid chemical diversity.

    Science.gov (United States)

    Lange, Bernd Markus

    2015-01-01

    Secretory structures in terrestrial plants appear to have first emerged as intracellular oil bodies in liverworts. In vascular plants, internal secretory structures, such as resin ducts and laticifers, are usually found in conjunction with vascular bundles, whereas subepidermal secretory cavities and epidermal glandular trichomes generally have more complex tissue distribution patterns. The primary function of plant secretory structures is related to defense responses, both constitutive and induced, against herbivores and pathogens. The ability to sequester secondary (or specialized) metabolites and defense proteins in secretory structures was a critical adaptation that shaped plant-herbivore and plant-pathogen interactions. Although this review places particular emphasis on describing the evolution of pathways leading to terpenoids, it also assesses the emergence of other metabolite classes to outline the metabolic capabilities of different plant lineages.

  20. Cleaning Products and Air Fresheners: Emissions and ResultingConcentrations of Glycol Ethers and Terpenoids

    Energy Technology Data Exchange (ETDEWEB)

    Singer, Brett C.; Destaillat, Hugo; Hodgson, Alfred T.; Nazaroff,William W.

    2005-08-01

    Experiments were conducted to quantify emissions and concentrations of glycol ethers and terpenoids from cleaning product and air freshener use in a 50-m{sup 3} room ventilated at {approx}0.5 h{sup -1}. Five cleaning products were applied full-strength (FS); three were additionally used in dilute solution. FS application of pine-oil cleaner (POC) yielded 1-h concentrations of 10-1300 {micro}g m{sup -3} for individual terpenoids, including {alpha}-terpinene (90-120), d-limonene (1000-1100), terpinolene (900-1300), and {alpha}-terpineol (260-700). One-hour concentrations of 2-butoxyethanol and/or dlimonene were 300-6000 {micro}g m{sup -3} after FS use of other products. During FS application including rinsing with sponge and wiping with towels, fractional emissions (mass volatilized/dispensed) of 2-butoxyethanol and d-limonene were 50-100% with towels retained, {approx}25-50% when towels were removed after cleaning. Lower fractions (2-11%) resulted from dilute use. Fractional emissions of terpenes from FS use of POC were {approx}35-70% with towels retained, 20-50% with towels removed. During floor cleaning with dilute solution of POC, 7-12% of dispensed terpenes were emitted. Terpene alcohols were emitted at lower fractions: 7-30% (FS, towels retained), 2-9% (FS, towels removed), and 2-5% (dilute). During air-freshener use, d-limonene, dihydromyrcenol, linalool, linalyl acetate, and {beta}-citronellol were emitted at 35-180 mg d{sup -1} over three days while air concentrations averaged 30-160 {micro}g m{sup -3}.

  1. Coregulation of terpenoid pathway genes and prediction of isoprene production in Bacillus subtilis using transcriptomics

    Energy Technology Data Exchange (ETDEWEB)

    Hess, Becky M.; Xue, Junfeng; Markillie, Lye Meng; Taylor, Ronald C.; Wiley, H. S.; Ahring, Birgitte K.; Linggi, Bryan E.

    2013-06-19

    The isoprenoid pathway converts pyruvate to isoprene and related isoprenoid compounds in plants and some bacteria. Currently, this pathway is of great interest because of the critical role that isoprenoids play in basic cellular processes as well as the industrial value of metabolites such as isoprene. Although the regulation of several pathway genes has been described, there is a paucity of information regarding the system level regulation and control of the pathway. To address this limitation, we examined Bacillus subtilis grown under multiple conditions and then determined the relationship between altered isoprene production and the pattern of gene expression. We found that terpenoid genes appeared to fall into two distinct subsets with opposing correlations with respect to the amount of isoprene produced. The group whose expression levels positively correlated with isoprene production included dxs, the gene responsible for the commitment step in the pathway, as well as ispD, and two genes that participate in the mevalonate pathway, yhfS and pksG. The subset of terpenoid genes that inversely correlated with isoprene production included ispH, ispF, hepS, uppS, ispE, and dxr. A genome wide partial least squares regression model was created to identify other genes or pathways that contribute to isoprene production. This analysis showed that a subset of 213 regulated genes was sufficient to create a predictive model of isoprene production under different conditions and showed correlations at the transcriptional level. We conclude that gene expression levels alone are sufficiently informative about the metabolic state of a cell that produces increased isoprene and can be used to build a model which accurately predicts production of this secondary metabolite across many simulated environmental conditions.

  2. Development of an achiral supercritical fluid chromatography method with ultraviolet absorbance and mass spectrometric detection for impurity profiling of drug candidates. Part II. Selection of an orthogonal set of stationary phases.

    Science.gov (United States)

    Lemasson, Elise; Bertin, Sophie; Hennig, Philippe; Boiteux, Hélène; Lesellier, Eric; West, Caroline

    2015-08-21

    Impurity profiling of organic products that are synthesized as possible drug candidates requires complementary analytical methods to ensure that all impurities are identified. Supercritical fluid chromatography (SFC) is a very useful tool to achieve this objective, as an adequate selection of stationary phases can provide orthogonal separations so as to maximize the chances to see all impurities. In this series of papers, we have developed a method for achiral SFC-MS profiling of drug candidates, based on a selection of 160 analytes issued from Servier Research Laboratories. In the first part of this study, focusing on mobile phase selection, a gradient elution with carbon dioxide and methanol comprising 2% water and 20mM ammonium acetate proved to be the best in terms of chromatographic performance, while also providing good MS response [1]. The objective of this second part was the selection of an orthogonal set of ultra-high performance stationary phases, that was carried out in two steps. Firstly, a reduced set of analytes (20) was used to screen 23 columns. The columns selected were all 1.7-2.5μm fully porous or 2.6-2.7μm superficially porous particles, with a variety of stationary phase chemistries. Derringer desirability functions were used to rank the columns according to retention window, column efficiency evaluated with peak width of selected analytes, and the proportion of analytes successfully eluted with good peak shapes. The columns providing the worst performances were thus eliminated and a shorter selection of columns (11) was obtained. Secondly, based on 160 tested analytes, the 11 columns were ranked again. The retention data obtained on these columns were then compared to define a reduced set of the best columns providing the greatest orthogonality, to maximize the chances to see all impurities within a limited number of runs. Two high-performance columns were thus selected: ACQUITY UPC(2) HSS C18 SB and Nucleoshell HILIC. Copyright © 2015

  3. Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity

    Energy Technology Data Exchange (ETDEWEB)

    Hargrove, Tatiana Y.; Garvey, Edward P.; Hoekstra, William J.; Yates, Christopher M.; Wawrzak, Zdzislaw; Rachakonda, Girish; Villalta, Fernando; Lepesheva, Galina I.

    2017-05-01

    ABSTRACT

    Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungusAspergillus fumigatus. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 ± 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatusCYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis ofA. fumigatusCYP51/voriconazole andCandida albicansCYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using twoA. fumigatusstrains (strains 32820 and 1022) displayed a direct

  4. Hairy root biotechnology of Rauwolfia serpentina: a potent approach for the production of pharmaceutically important terpenoid indole alkaloids.

    Science.gov (United States)

    Mehrotra, Shakti; Goel, Manoj K; Srivastava, Vikas; Rahman, Laiq Ur

    2015-02-01

    Hairy root cultures of Rauwolfia serpentina induced by Agrobacterium rhizogenes have been investigated extensively for the production of terpenoid indole alkaloids. Various biotechnological developments, such as scaling up in bioreactors, pathway engineering etc., have been explored to improve their metabolite production potential. These hairy roots are competent for regenerating into complete plants and show survival and unaltered biosynthetic potential during storage at low temperature. This review provides a comprehensive account of the hairy root cultures of R. serpentina, their biosynthetic potential and various biotechnological methods used to explore the production of pharmaceutically important terpenoid indole alkaloids. The review also indicates how biotechnological endeavors might improve the future progress of research for production of alkaloids using Rauwolfia hairy roots.

  5. Cleaning products and air fresheners: emissions and resulting concentrations of glycol ethers and terpenoids.

    Science.gov (United States)

    Singer, B C; Destaillats, H; Hodgson, A T; Nazaroff, W W

    2006-06-01

    Experiments were conducted to quantify emissions and concentrations of glycol ethers and terpenoids from cleaning product and air freshener use in a 50-m3 room ventilated at approximately 0.5/h. Five cleaning products were applied full-strength (FS); three were additionally used in dilute solution. FS application of pine-oil cleaner (POC) yielded 1-h concentrations of 10-1300 microg/m3 for individual terpenoids, including alpha-terpinene (90-120), d-limonene (1000-1100), terpinolene (900-1300), and alpha-terpineol (260-700). One-hour concentrations of 2-butoxyethanol and/or d-limonene were 300-6000 microg/m3 after FS use of other products. During FS application including rinsing with sponge and wiping with towels, fractional emissions (mass volatilized/dispensed) of 2-butoxyethanol and d-limonene were 50-100% with towels retained, and approximately 25-50% when towels were removed after cleaning. Lower fractions (2-11%) resulted from dilute use. Fractional emissions of terpenes from FS use of POC were approximately 35-70% with towels retained, and 20-50% with towels removed. During floor cleaning with dilute solution of POC, 7-12% of dispensed terpenes were emitted. Terpene alcohols were emitted at lower fractions: 7-30% (FS, towels retained), 2-9% (FS, towels removed), and 2-5% (dilute). During air-freshener use, d-limonene, dihydromyrcenol, linalool, linalyl acetate, and beta-citronellol) were emitted at 35-180 mg/day over 3 days while air concentrations averaged 30-160 microg/m3. While effective cleaning can improve the healthfulness of indoor environments, this work shows that use of some consumer cleaning agents can yield high levels of volatile organic compounds, including glycol ethers--which are regulated toxic air contaminants--and terpenes that can react with ozone to form a variety of secondary pollutants including formaldehyde and ultrafine particles. Persons involved in cleaning, especially those who clean occupationally or often, might encounter

  6. De novo assembly and analysis of the Artemisia argyi transcriptome and identification of genes involved in terpenoid biosynthesis.

    Science.gov (United States)

    Liu, Miaomiao; Zhu, Jinhang; Wu, Shengbing; Wang, Chenkai; Guo, Xingyi; Wu, Jiawen; Zhou, Meiqi

    2018-04-11

    Artemisia argyi Lev. et Vant. (A. argyi) is widely utilized for moxibustion in Chinese medicine, and the mechanism underlying terpenoid biosynthesis in its leaves is suggested to play an important role in its medicinal use. However, the A. argyi transcriptome has not been sequenced. Herein, we performed RNA sequencing for A. argyi leaf, root and stem tissues to identify as many as possible of the transcribed genes. In total, 99,807 unigenes were assembled by analysing the expression profiles generated from the three tissue types, and 67,446 of those unigenes were annotated in public databases. We further performed differential gene expression analysis to compare leaf tissue with the other two tissue types and identified numerous genes that were specifically expressed or up-regulated in leaf tissue. Specifically, we identified multiple genes encoding significant enzymes or transcription factors related to terpenoid synthesis. This study serves as a valuable resource for transcriptome information, as many transcribed genes related to terpenoid biosynthesis were identified in the A. argyi transcriptome, providing a functional genomic basis for additional studies on molecular mechanisms underlying the medicinal use of A. argyi.

  7. De novo assembly of Eugenia uniflora L. transcriptome and identification of genes from the terpenoid biosynthesis pathway.

    Science.gov (United States)

    Guzman, Frank; Kulcheski, Franceli Rodrigues; Turchetto-Zolet, Andreia Carina; Margis, Rogerio

    2014-12-01

    Pitanga (Eugenia uniflora L.) is a member of the Myrtaceae family and is of particular interest due to its medicinal properties that are attributed to specialized metabolites with known biological activities. Among these molecules, terpenoids are the most abundant in essential oils that are found in the leaves and represent compounds with potential pharmacological benefits. The terpene diversity observed in Myrtaceae is determined by the activity of different members of the terpene synthase and oxidosqualene cyclase families. Therefore, the aim of this study was to perform a de novo assembly of transcripts from E. uniflora leaves and to annotation to identify the genes potentially involved in the terpenoid biosynthesis pathway and terpene diversity. In total, 72,742 unigenes with a mean length of 1048bp were identified. Of these, 43,631 and 36,289 were annotated with the NCBI non-redundant protein and Swiss-Prot databases, respectively. The gene ontology categorized the sequences into 53 functional groups. A metabolic pathway analysis with KEGG revealed 8,625 unigenes assigned to 141 metabolic pathways and 40 unigenes predicted to be associated with the biosynthesis of terpenoids. Furthermore, we identified four putative full-length terpene synthase genes involved in sesquiterpenes and monoterpenes biosynthesis, and three putative full-length oxidosqualene cyclase genes involved in the triterpenes biosynthesis. The expression of these genes was validated in different E. uniflora tissues. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. In vitro evaluation of potential bitterness-masking terpenoids from the Canada goldenrod (Solidago canadensis).

    Science.gov (United States)

    Li, Jie; Pan, Li; Fletcher, Joshua N; Lv, Wei; Deng, Ye; Vincent, Michael A; Slack, Jay P; McCluskey, T Scott; Jia, Zhonghua; Cushman, Mark; Kinghorn, A Douglas

    2014-07-25

    In a screening of extracts of selected plants native to Ohio against the human bitterness receptor hTAS2R31, a chloroform-soluble extract of the aerial parts of Solidago canadensis (Canada goldenrod) was determined to have hTAS2R31 antagonistic activity and, thus, was fractionated for isolation of potential bitterness-masking agents. One new labdane diterpenoid, solidagol (1), and six known terpenoids, including two labdane diterpenoids (2 and 3), three clerodane diterpenoids (6β-angeloyloxykolavenic acid, 6β-tigloyloxykolavenic acid, and crotonic acid), and a triterpenoid (longispinogenin), were isolated. Among these compounds, 3β-acetoxycopalic acid (2) was found to be the first member of the labdane diterpene class shown to have inhibitory activity against hTAS2R31 activation (IC50 8 μM). A homology model of hTAS2R31 was constructed, and the molecular docking of 2 to this model indicated that this diterpenoid binds well to the active site of hTAS2R31, whereas this was not the case for the closely structurally related compound 3 (sempervirenic acid). The content of 2 in the chloroform-soluble portion of the methanolic extract of S. canadensis was up to 2.24 g/100 g dry weight, as determined by HPLC.

  9. Terpenoid Compositions and Botanical Origins of Late Cretaceous and Miocene Amber from China

    Science.gov (United States)

    Shi, Gongle; Dutta, Suryendu; Paul, Swagata; Wang, Bo; Jacques, Frédéric M. B.

    2014-01-01

    The terpenoid compositions of the Late Cretaceous Xixia amber from Central China and the middle Miocene Zhangpu amber from Southeast China were analyzed by gas chromatography-mass spectrometry (GC-MS) to elucidate their botanical origins. The Xixia amber is characterized by sesquiterpenoids, abietane and phyllocladane type diterpenoids, but lacks phenolic abietanes and labdane derivatives. The molecular compositions indicate that the Xixia amber is most likely contributed by the conifer family Araucariaceae, which is today distributed primarily in the Southern Hemisphere, but widely occurred in the Northern Hemisphere during the Mesozoic according to paleobotanical evidence. The middle Miocene Zhangpu amber is characterized by amyrin and amyrone-based triterpenoids and cadalene-based sesquiterpenoids. It is considered derived from the tropical angiosperm family Dipterocarpaceae based on these compounds and the co-occurring fossil winged fruits of the family in Zhangpu. This provides new evidence for the occurrence of a dipterocarp forest in the middle Miocene of Southeast China. It is the first detailed biomarker study for amber from East Asia. PMID:25354364

  10. Terpenoids from Curcuma wenyujin increased glucose consumption on HepG2 cells.

    Science.gov (United States)

    Zhou, Chang-Xin; Zhang, Li-Sha; Chen, Fei-Fei; Wu, Hao-Shu; Mo, Jian-Xia; Gan, Li-She

    2017-09-01

    Thirty four terpenoids, including two new cadinane-type sesquiterpenoids containing conjugated aromatic-ketone moieties, curcujinone A (1) and curcujinone B (2), were isolated from 95% ethanol extract of the root tubers of Curcuma wenyujin. Their structures were determined by spectroscopic methods, especially 2D NMR and HRMS techniques. The relative and absolute configurations of 1 and 2 were identified by quantum chemical DFT and TDDFT calculations of the 13 C NMR chemical shifts, ECD spectra, and specific optical rotations. All compounds and extracts were evaluated for their anti-diabetic activities with a glucose consumption model on HepG2 Cells. The petroleum fraction CWP (10μg/mL) and compounds curcumenol (4), 7α,11α-epoxy-5β-hydroxy-9-guaiaen-8-one (5), curdione (17), (1S, 4S, 5S 10S)-germacrone (18), zederone (20), a mixture of curcumanolide A (25) and curcumanolide B (26), gajutsulactone B (27), and wenyujinin C (30) showed promising activities with over 45% increasing of glucose consumption at 10μM. Copyright © 2017. Published by Elsevier B.V.

  11. Alpha-glucosidase inhibitory and antiplasmodial properties of terpenoids from the leaves of Buddleja saligna Willd.

    Science.gov (United States)

    Chukwujekwu, Jude C; Rengasamy, Kannan R R; de Kock, Carmen A; Smith, Peter J; Slavětínská, Lenka Poštová; van Staden, Johannes

    2016-01-01

    In our continuing search for biologically active natural product(s) of plant origin, Buddleja saligna, a South African medicinal plant, was screened in line with its traditional use for antidiabetic (yeast alpha glucosidase inhibitory) and antiplasmodial (against a chloroquine sensitive strain of Plasmodium falciparum (NF54)) activities. The hexane fraction showed the most promising activity with regards to its antidiabetic (IC(50) = 260 ± 0.112 µg/ml) and antiplasmodial (IC(50) = 8.5 ± 1.6 µg/ml) activities. Using activity guided fractionation three known terpenoids (betulonic acid, betulone and spinasterol) were isolated from this species for the first time. The compounds displayed varying levels of biological activities (antidiabetic: 27.31 µg/ml ≥ IC(50) ≥ 5.6 µg/ml; antiplasmodial: 14 µg/ml ≥ IC(50) ≥ 2 µg/ml) with very minimal toxicity.

  12. The genus Scrophularia: a source of iridoids and terpenoids with a diverse biological activity.

    Science.gov (United States)

    Pasdaran, Ardalan; Hamedi, Azadeh

    2017-12-01

    Scrophularia genus (Scrophulariaceae) includes about 350 species commonly known as figwort. Many species of this genus grow wild in nature and have not been cultivated yet. However, some species are in danger of extinction. This paper reviews the chemical compounds, biological activities and the ethnopharmacology of some Scrophularia species. All information was obtained through reported data on bibliographic database such as Scopus, United States National Agricultural Library, Biological Abstracts, EMBASE, PubMed, MedlinePlus, PubChem and Springer Link (1934-2017). The information in different Pharmacopoeias on this genus was also gathered from 1957 to 2007. The structures of 204 compounds and their biological activity were presented in the manuscript: glycoside esters, iridoid glycosides and triterpenoids are the most common compounds in this genus. Among them, scropolioside like iridoids have shown potential for anti-inflammatory, hepatoprotective and wound healing activity. Among the less frequently isolated compounds, resin glycosides such as crypthophilic acids have shown potent antiprotozoal and antimicrobial activities. The Scrophularia genus seems to be a rich source of iridoids and terpenoids, but isolation and identification of its alkaloids have been a neglected area of scientific study. The diverse chemical compounds and biological activities of this genus will motivate further investigation on Scrophularia genus as a source of new therapeutic medications.

  13. Transcriptional regulation of genes involved in terpenoid índole alkaloid production in Catharanthus roseus seedlings

    Directory of Open Access Journals (Sweden)

    Pedro J. Rocha

    2002-07-01

    Full Text Available Catharanthus roseus (L. G Don is a medicinal plant that produces a variety of terpenoid indole alkaloids (TIAs, some of which display pharmacological activity. C. roseus plants and cell cultures have been used to elucidate the TIAs biosynthetic pathway. A considerable number or enzymes have also been characterised, and their respective genes cloned. TIAs production in C. roseus plant and cell cultures is highly regulated at transcriptional-, develop-mental-, and environmental-level. Studies into TIAs biosynthetic gene regulation have been carried out using cell cultures. However, regulation in plants is almost unknown. Here, biosynthetic genes idc, strl, d4h and dat expres-sion levels are qualitatively examined in a developmental series of C. roseus seedlings. The effect of water- and light-stress and methyl jasmonate (MeJa and acetyl salicylic acid (ASA elicitation is also examined. Comparison between seedlings and cell cultures strongly suggests that TIAs biosynthetic gene transcriptional regulation is different in C.roseus plants and cell cultures.

  14. Design and synthesis of new esters of terpenoid alcohols as 15-lipoxygenase inhibitors

    Directory of Open Access Journals (Sweden)

    Hamid Sadeghian

    2018-07-01

    Full Text Available Objective(s: 15-Lipoxygenases are one of the iron-containing proteins capable of performing peroxidation of unsaturated fatty acids in animals and plants. The critical role of enzymes in the formation of inflammations, sensitivities, and some cancers has been demonstrated in mammals. The importance of enzymes has led to the development of mechanistic studies, product analysis, and synthesis of inhibitors. Materials and Methods: The inhibitory activity of all synthetic compounds against SLO (soybean 15-lipoxygenase: L1; EC 1,13,11,12 was determined using the peroxide formation method. In this method, the basis of evaluation of lipoxygenase activity is measuring the concentration of fatty acid peroxide. All measurements were compared with  4-​methyl-​2-​(4-​methylpiperazinylpyrimido[4,​5-​b]benzothiazine (4-MMPB as one of the known lipoxygenase inhibitors. The radical scavenging ability of all synthetic compounds using stable free radicals (DPPH: 2,2-diphenyl-1-picrylhydrazyl was measured for further investigation.Results: In this study, a series of esters from phenolic acids with terpenoid alcohols was synthesized and their inhibitory potency against soybean 15-lipoxygenase and their free radical scavenging properties were determined. Among the synthetic compounds, adamantyl protocatetuate 2j and bornyl protocatetuate 2o showed the most potent inhibitory activity with IC50 values of 0.95 and 0.78 μm, respectively.Conclusion: By changing the alcohol and acyl portions of stylosin, it was found that electronic properties play main role in lipoxygenase inhibition potency in contrast with steric features. Insertion of more reductive phenolic moiety such as catechuate and gallate lead to more lipoxygenase inhibition potency of the esters as observed in their radical scavenging activity.

  15. Terpenoid variations within and among half-sibling avocado trees, Persea americana Mill. (Lauraceae.

    Directory of Open Access Journals (Sweden)

    Jerome Niogret

    Full Text Available Chemical analyses were conducted to determine the qualitative and quantitative differences in monoterpenes and sesquiterpenes in plant material from avocado trees, Persea americana Mill. (Lauraceae. The initial study analyzed plant material sampled from the trunk to the leaves through different branch diameters to quantify proximo-distal spatial differences within a tree. All trees were seedlings initiated from a single maternal tree. Two-way analysis of variance was conducted on 34 chemicals that comprised at least 3% of the total chemical content of at least one tree and/or location within a tree. There were significant interactions between genotype and location sampled for most chemicals. Parentage analysis using microsatellite molecular markers (SSR's determined that the four trees had three fathers and that they represented two full-siblings and two half-sibling trees. Descriptive discriminant analysis found that both genotype and location within a tree could be separated based on chemical content, and that the chemical content from full-siblings tended to be more similar than chemical content from half-siblings. To further explore the relationship between genetic background and chemical content, samples were analyzed from leaf material from 20 trees that included two sets of full-sibling seedling trees, the maternal tree and the surviving paternal tree. Descriptive discriminant analysis found good separation between the two full-sibling groups, and that the separation was associated with chemistry of the parental trees. Six groups of chemicals were identified that explained the variation among the trees. We discuss the results in relation to the discrimination process used by wood-boring insects for site-selection on host trees, for tree selection among potential host trees, and the potential use of terpenoid chemical content in chemotaxonomy of avocado trees.

  16. Terpenoid variations within and among half-sibling avocado trees, Persea americana Mill. (Lauraceae).

    Science.gov (United States)

    Niogret, Jerome; Epsky, Nancy D; Schnell, Raymond J; Boza, Edward J; Kendra, Paul E; Heath, Robert R

    2013-01-01

    Chemical analyses were conducted to determine the qualitative and quantitative differences in monoterpenes and sesquiterpenes in plant material from avocado trees, Persea americana Mill. (Lauraceae). The initial study analyzed plant material sampled from the trunk to the leaves through different branch diameters to quantify proximo-distal spatial differences within a tree. All trees were seedlings initiated from a single maternal tree. Two-way analysis of variance was conducted on 34 chemicals that comprised at least 3% of the total chemical content of at least one tree and/or location within a tree. There were significant interactions between genotype and location sampled for most chemicals. Parentage analysis using microsatellite molecular markers (SSR's) determined that the four trees had three fathers and that they represented two full-siblings and two half-sibling trees. Descriptive discriminant analysis found that both genotype and location within a tree could be separated based on chemical content, and that the chemical content from full-siblings tended to be more similar than chemical content from half-siblings. To further explore the relationship between genetic background and chemical content, samples were analyzed from leaf material from 20 trees that included two sets of full-sibling seedling trees, the maternal tree and the surviving paternal tree. Descriptive discriminant analysis found good separation between the two full-sibling groups, and that the separation was associated with chemistry of the parental trees. Six groups of chemicals were identified that explained the variation among the trees. We discuss the results in relation to the discrimination process used by wood-boring insects for site-selection on host trees, for tree selection among potential host trees, and the potential use of terpenoid chemical content in chemotaxonomy of avocado trees.

  17. Spatiotemporal variability of biogenic terpenoid emissions in Pearl River Delta, China, with high-resolution land-cover and meteorological data

    Science.gov (United States)

    Wang, Xuemei; Situ, Shuping; Guenther, Alex; Chen, Fei; Wu, Zhiyong; Xia, Beicheng; Wang, Tijian

    2011-04-01

    This study intended to provide 4-km gridded, hourly, year-long, regional estimates of terpenoid emissions in the Pearl River Delta (PRD), China. It combined Thematic Mapper images and local-survey data to characterize plant functional types, and used observed emission potential of biogenic volatile organic compounds (BVOC) from local plant species and high-resolution meteorological outputs from the MM5 model to constrain the MEGAN BVOC-emission model. The estimated annual emissions for isoprene, monoterpene and sesquiterpene are 95.55 × 106 kg C, 117.35 × 106 kg C and 9.77 × 106 kg C, respectively. The results show strong variabilities of terpenoid emissions spanning diurnal and seasonal time scales, which are mainly distributed in the remote areas (with more vegetation and less economic development) in PRD. Using MODIS PFTs data reduced terpenoid emissions by 27% in remote areas. Using MEGAN-model default emission factors led to a 24% increase in BVOC emission. The model errors of temperature and radiation in MM5 output were used to assess impacts of uncertainties in meteorological forcing on emissions: increasing (decreasing) temperature and downward shortwave radiation produces more (less) terpenoid emissions for July and January. Strong temporal variability of terpenoid emissions leads to enhanced ozone formation during midday in rural areas where the anthropogenic VOC emissions are limited.

  18. Chemosystematics and diagenesis of terpenoids in fossil conifer species and sediment from the Eocene Zeitz formation, Saxony, Germany

    Science.gov (United States)

    Otto, Angelika; Simoneit, Bernd R. T.

    2001-10-01

    The biomarker contents of three fossil conifer species (Athrotaxis couttsiae, Taxodium balticum, Pinus palaeostrobus) and the clay sediment from the Eocene Zeitz formation, Germany, have been analyzed by gas chromatography-mass spectrometry. Triterpenoids of the oleanane, ursane and lupane series and aliphatic wax lipids are the major compounds in the total extracts of the sediment indicating a major angiosperm input. In contrast, diterpenoids (abietanes, phenolic abietanes, pimaranes, isopimaranes, kauranes, phyllocladanes, totaranes) and lignin degradation products are predominant in the conifer fossil extracts. Polar diterpenoids (ferruginol and derivatives, dehydroabietic acid) are preserved as major compounds in the conifers, accompained by saturated and aromatic diterpenoid products. The extracts of the fossil conifer species show characteristic biomarker patterns and contain terpenoids of chemosystematic value. The terpenoid composition of the fossil conifers is similar to that of related modern species. Phenolic abietanes (ferruginol, 6,7-dehydroferruginol, hydroxyferruginols, sugiol) which are known from modern species of the Cupressaceae and Podocarpaceae are the major terpenoids in shoots of Athrotaxis couttsiae and a cone of Taxodium balticum (both Cupressaceae). Sesquiterpenoids characteristic for Cupressaceae (cuparene, α-cedrene) are also present in Athrotaxis. Abietane-type acids (dehydroabietic acid, abietic acid) and saturated abietanes [fichtelite, 13α(H)-fichtelite] predominate in the extracts of a Pinus palaeostrobus cone and phenolic abietanes are not detectable. A diagenetic pathway for the degradation of abietic acid is proposed based on the presence of abietane-type acids and a series of their presumed degradation products in the Pinus cone. The formation of diagenetic products from the phenolic abietanes is also discussed.

  19. Genomics-Based Discovery of Plant Genes for Synthetic Biology of Terpenoid Fragrances: A Case Study in Sandalwood oil Biosynthesis.

    Science.gov (United States)

    Celedon, J M; Bohlmann, J

    2016-01-01

    Terpenoid fragrances are powerful mediators of ecological interactions in nature and have a long history of traditional and modern industrial applications. Plants produce a great diversity of fragrant terpenoid metabolites, which make them a superb source of biosynthetic genes and enzymes. Advances in fragrance gene discovery have enabled new approaches in synthetic biology of high-value speciality molecules toward applications in the fragrance and flavor, food and beverage, cosmetics, and other industries. Rapid developments in transcriptome and genome sequencing of nonmodel plant species have accelerated the discovery of fragrance biosynthetic pathways. In parallel, advances in metabolic engineering of microbial and plant systems have established platforms for synthetic biology applications of some of the thousands of plant genes that underlie fragrance diversity. While many fragrance molecules (eg, simple monoterpenes) are abundant in readily renewable plant materials, some highly valuable fragrant terpenoids (eg, santalols, ambroxides) are rare in nature and interesting targets for synthetic biology. As a representative example for genomics/transcriptomics enabled gene and enzyme discovery, we describe a strategy used successfully for elucidation of a complete fragrance biosynthetic pathway in sandalwood (Santalum album) and its reconstruction in yeast (Saccharomyces cerevisiae). We address questions related to the discovery of specific genes within large gene families and recovery of rare gene transcripts that are selectively expressed in recalcitrant tissues. To substantiate the validity of the approaches, we describe the combination of methods used in the gene and enzyme discovery of a cytochrome P450 in the fragrant heartwood of tropical sandalwood, responsible for the fragrance defining, final step in the biosynthesis of (Z)-santalols. © 2016 Elsevier Inc. All rights reserved.

  20. North American Lauraceae: terpenoid emissions, relative attraction and boring preferences of redbay ambrosia beetle, Xyleborus glabratus (coleoptera: curculionidae: scolytinae.

    Directory of Open Access Journals (Sweden)

    Paul E Kendra

    Full Text Available The invasive redbay ambrosia beetle, Xyleborus glabratus, is the primary vector of Raffaelea lauricola, a symbiotic fungus and the etiologic agent of laurel wilt. This lethal disease has caused severe mortality of redbay (Persea borbonia and swampbay (P. palustris trees in the southeastern USA, threatens avocado (P. americana production in Florida, and has potential to impact additional New World species. To date, all North American hosts of X. glabratus and suscepts of laurel wilt are members of the family Lauraceae. This comparative study combined field tests and laboratory bioassays to evaluate attraction and boring preferences of female X. glabratus using freshly-cut bolts from nine species of Lauraceae: avocado (one cultivar of each botanical race, redbay, swampbay, silkbay (Persea humilis, California bay laurel (Umbellularia californica, sassafras (Sassafras albidum, northern spicebush (Lindera benzoin, camphor tree (Cinnamomum camphora, and lancewood (Nectandra coriacea. In addition, volatile collections and gas chromatography-mass spectroscopy (GC-MS were conducted to quantify terpenoid emissions from test bolts, and electroantennography (EAG was performed to measure olfactory responses of X. glabratus to terpenoids identified by GC-MS. Significant differences were observed among treatments in both field and laboratory tests. Silkbay and camphor tree attracted the highest numbers of the beetle in the field, and lancewood and spicebush the lowest, whereas boring activity was greatest on silkbay, bay laurel, swampbay, and redbay, and lowest on lancewood, spicebush, and camphor tree. The Guatemalan cultivar of avocado was more attractive than those of the other races, but boring response among the three was equivalent. The results suggest that camphor tree may contain a chemical deterrent to boring, and that different cues are associated with host location and host acceptance. Emissions of α-cubebene, α-copaene, α-humulene, and

  1. North American Lauraceae: terpenoid emissions, relative attraction and boring preferences of redbay ambrosia beetle, Xyleborus glabratus (coleoptera: curculionidae: scolytinae).

    Science.gov (United States)

    Kendra, Paul E; Montgomery, Wayne S; Niogret, Jerome; Pruett, Grechen E; Mayfield, Albert E; MacKenzie, Martin; Deyrup, Mark A; Bauchan, Gary R; Ploetz, Randy C; Epsky, Nancy D

    2014-01-01

    The invasive redbay ambrosia beetle, Xyleborus glabratus, is the primary vector of Raffaelea lauricola, a symbiotic fungus and the etiologic agent of laurel wilt. This lethal disease has caused severe mortality of redbay (Persea borbonia) and swampbay (P. palustris) trees in the southeastern USA, threatens avocado (P. americana) production in Florida, and has potential to impact additional New World species. To date, all North American hosts of X. glabratus and suscepts of laurel wilt are members of the family Lauraceae. This comparative study combined field tests and laboratory bioassays to evaluate attraction and boring preferences of female X. glabratus using freshly-cut bolts from nine species of Lauraceae: avocado (one cultivar of each botanical race), redbay, swampbay, silkbay (Persea humilis), California bay laurel (Umbellularia californica), sassafras (Sassafras albidum), northern spicebush (Lindera benzoin), camphor tree (Cinnamomum camphora), and lancewood (Nectandra coriacea). In addition, volatile collections and gas chromatography-mass spectroscopy (GC-MS) were conducted to quantify terpenoid emissions from test bolts, and electroantennography (EAG) was performed to measure olfactory responses of X. glabratus to terpenoids identified by GC-MS. Significant differences were observed among treatments in both field and laboratory tests. Silkbay and camphor tree attracted the highest numbers of the beetle in the field, and lancewood and spicebush the lowest, whereas boring activity was greatest on silkbay, bay laurel, swampbay, and redbay, and lowest on lancewood, spicebush, and camphor tree. The Guatemalan cultivar of avocado was more attractive than those of the other races, but boring response among the three was equivalent. The results suggest that camphor tree may contain a chemical deterrent to boring, and that different cues are associated with host location and host acceptance. Emissions of α-cubebene, α-copaene, α-humulene, and calamenene were

  2. Elucidation of the regio- and chemoselectivity of enzymatic allylic oxidations with Pleurotus sapidus – conversion of selected spirocyclic terpenoids and computational analysis

    Directory of Open Access Journals (Sweden)

    Verena Weidmann

    2013-10-01

    Full Text Available Allylic oxidations of olefins to enones allow the efficient synthesis of value-added products from simple olefinic precursors like terpenes or terpenoids. Biocatalytic variants have a large potential for industrial applications, particularly in the pharmaceutical and food industry. Herein we report efficient biocatalytic allylic oxidations of spirocyclic terpenoids by a lyophilisate of the edible fungus Pleurotus sapidus. This ‘’mushroom catalysis’’ is operationally simple and allows the conversion of various unsaturated spirocyclic terpenoids. A number of new spirocyclic enones have thus been obtained with good regio- and chemoselectivity and chiral separation protocols for enantiomeric mixtures have been developed. The oxidations follow a radical mechanism and the regioselectivity of the reaction is mainly determined by bond-dissociation energies of the available allylic CH-bonds and steric accessibility of the oxidation site.

  3. De Novo Transcriptome Assembly (NGS) of Curcuma longa L. Rhizome Reveals Novel Transcripts Related to Anticancer and Antimalarial Terpenoids

    Science.gov (United States)

    Jayakumar, Vasanthan; Damodaran, Anand C.; Rao, Sudha Narayana; Katta, Mohan A. V. S. K.; Gopinathan, Sreeja; Sarma, Santosh Prasad; Senthilkumar, Vanitha; Niranjan, Vidya; Gopinath, Ashok; Mugasimangalam, Raja C.

    2013-01-01

    Herbal remedies are increasingly being recognised in recent years as alternative medicine for a number of diseases including cancer. Curcuma longa L., commonly known as turmeric is used as a culinary spice in India and in many Asian countries has been attributed to lower incidences of gastrointestinal cancers. Curcumin, a secondary metabolite isolated from the rhizomes of this plant has been shown to have significant anticancer properties, in addition to antimalarial and antioxidant effects. We sequenced the transcriptome of the rhizome of the 3 varieties of Curcuma longa L. using Illumina reversible dye terminator sequencing followed by de novo transcriptome assembly. Multiple databases were used to obtain a comprehensive annotation and the transcripts were functionally classified using GO, KOG and PlantCyc. Special emphasis was given for annotating the secondary metabolite pathways and terpenoid biosynthesis pathways. We report for the first time, the presence of transcripts related to biosynthetic pathways of several anti-cancer compounds like taxol, curcumin, and vinblastine in addition to anti-malarial compounds like artemisinin and acridone alkaloids, emphasizing turmeric's importance as a highly potent phytochemical. Our data not only provides molecular signatures for several terpenoids but also a comprehensive molecular resource for facilitating deeper insights into the transcriptome of C. longa. PMID:23468859

  4. Use of chemometric and quantum-mechanical methods in the analysis of bioactive terpenoids and phenylpropanoids against the Aedes aegypti

    Directory of Open Access Journals (Sweden)

    Reginaldo Bezerra dos Santos

    2010-01-01

    Full Text Available Dengue fever is one of the main public health problems in the world. Many mosquitoes have developed resistance to the conventional insecticides used. Thus, the search for vegetable extracts and natural substances as alternative insecticides has increased. In this study, chemometric methods were employed to classify a group of terpenoid and phenylpropanoid compounds with biological activity against the larval of the A. aegypti mosquitoes. The AM1 (Austin Model 1 method was used to calculate a set of molecular descriptors (properties for the studied compounds. Then, the descriptors were analyzed using the following methods of pattern recognition: Principal Component Analysis (PCA and Hierarchical Clustering Analysis (HCA. The PCA and HCA methods have shown to be very effective for the classification of the study compounds in two groups (active and inactive. The electronic variables EHOMO-1, EHOMO-2, ELUMO, ELUMO+2, and the structural LogP were used to classify as active and inactive compounds. In most studied compounds, the variables responsible for separating active from inactive compounds were electronic descriptors. Thus, it can be concluded that electronic effects play a fundamental role in the interaction between biological receptor and terpenoid and phenylpropanoid compounds with activity against larval A. aegypti mosquitoes.

  5. Anti-proliferation activity of terpenoids isolated from Euphorbia kansui in human cancer cells and their structure-activity relationship.

    Science.gov (United States)

    Hou, Jin-Jun; Shen, Yao; Yang, Zhou; Fang, Lin; Cai, Lu-Ying; Yao, Shuai; Long, Hua-Li; Wu, Wan-Ying; Guo, De-An

    2017-10-01

    Euphorbia kansui is a commonly used traditional Chinese medicine for the treatment of edema, pleural effusion, and asthma, etc. According to the previous researches, terpenoids in E. kansui possess various biological activities, e.g., anti-virus, anti-allergy, antitumor effects. In this work, twenty five terpenoids were isolated from E. kansui, including thirteen ingenane- and eight jatrophane-type diterpenoids (with two new compounds, kansuinin P and Q) and four triterpenoids. Eighteen of them were analyzed by MTS assay for in vitro anticancer activity in five human cancer cell lines. Structure-activity relationship for 12 ingenane-type diterpenoids in colorectal cancer Colo205 cells were preliminary studied. Significant anti-proliferation activities were observed in human melanoma cells breast cancer MDA-MB-435 cells and Colo205 cells. More than half of the isolated ingenane-type diterpenoids showed inhibitory activities in MDA-MB-435 cells. Eight ingenane- and one jatrophane-type diterpenoids possessed much lower IC 50 values in MDA-MB-435 cells than positive control staurosporine. Preliminary structure-activity relationship analysis showed that substituent on position 20 was important for the activity of ingenane-type diterpenoids in Colo205 cells and substituent on position 3 contributed more significant biological activity of the compounds than that on position 5 in both MDA-MB-435 and Colo205 cells. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  6. De Novo transcriptome assembly (NGS of Curcuma longa L. rhizome reveals novel transcripts related to anticancer and antimalarial terpenoids.

    Directory of Open Access Journals (Sweden)

    Ramasamy S Annadurai

    Full Text Available Herbal remedies are increasingly being recognised in recent years as alternative medicine for a number of diseases including cancer. Curcuma longa L., commonly known as turmeric is used as a culinary spice in India and in many Asian countries has been attributed to lower incidences of gastrointestinal cancers. Curcumin, a secondary metabolite isolated from the rhizomes of this plant has been shown to have significant anticancer properties, in addition to antimalarial and antioxidant effects. We sequenced the transcriptome of the rhizome of the 3 varieties of Curcuma longa L. using Illumina reversible dye terminator sequencing followed by de novo transcriptome assembly. Multiple databases were used to obtain a comprehensive annotation and the transcripts were functionally classified using GO, KOG and PlantCyc. Special emphasis was given for annotating the secondary metabolite pathways and terpenoid biosynthesis pathways. We report for the first time, the presence of transcripts related to biosynthetic pathways of several anti-cancer compounds like taxol, curcumin, and vinblastine in addition to anti-malarial compounds like artemisinin and acridone alkaloids, emphasizing turmeric's importance as a highly potent phytochemical. Our data not only provides molecular signatures for several terpenoids but also a comprehensive molecular resource for facilitating deeper insights into the transcriptome of C. longa.

  7. De Novo transcriptome assembly (NGS) of Curcuma longa L. rhizome reveals novel transcripts related to anticancer and antimalarial terpenoids.

    Science.gov (United States)

    Annadurai, Ramasamy S; Neethiraj, Ramprasad; Jayakumar, Vasanthan; Damodaran, Anand C; Rao, Sudha Narayana; Katta, Mohan A V S K; Gopinathan, Sreeja; Sarma, Santosh Prasad; Senthilkumar, Vanitha; Niranjan, Vidya; Gopinath, Ashok; Mugasimangalam, Raja C

    2013-01-01

    Herbal remedies are increasingly being recognised in recent years as alternative medicine for a number of diseases including cancer. Curcuma longa L., commonly known as turmeric is used as a culinary spice in India and in many Asian countries has been attributed to lower incidences of gastrointestinal cancers. Curcumin, a secondary metabolite isolated from the rhizomes of this plant has been shown to have significant anticancer properties, in addition to antimalarial and antioxidant effects. We sequenced the transcriptome of the rhizome of the 3 varieties of Curcuma longa L. using Illumina reversible dye terminator sequencing followed by de novo transcriptome assembly. Multiple databases were used to obtain a comprehensive annotation and the transcripts were functionally classified using GO, KOG and PlantCyc. Special emphasis was given for annotating the secondary metabolite pathways and terpenoid biosynthesis pathways. We report for the first time, the presence of transcripts related to biosynthetic pathways of several anti-cancer compounds like taxol, curcumin, and vinblastine in addition to anti-malarial compounds like artemisinin and acridone alkaloids, emphasizing turmeric's importance as a highly potent phytochemical. Our data not only provides molecular signatures for several terpenoids but also a comprehensive molecular resource for facilitating deeper insights into the transcriptome of C. longa.

  8. Diversity of ABBA Prenyltransferases in Marine Streptomyces sp. CNQ-509: Promiscuous Enzymes for the Biosynthesis of Mixed Terpenoid Compounds.

    Directory of Open Access Journals (Sweden)

    Franziska Leipoldt

    Full Text Available Terpenoids are arguably the largest and most diverse family of natural products, featuring prominently in e.g. signalling, self-defence, UV-protection and electron transfer. Prenyltransferases are essential players in terpenoid and hybrid isoprenoid biosynthesis that install isoprene units on target molecules and thereby often modulate their bioactivity. In our search for new prenyltransferase biocatalysts we focused on the marine-derived Streptomyces sp. CNQ-509, a particularly rich source of meroterpenoid chemistry. Sequencing and analysis of the genome of Streptomyces sp. CNQ-509 revealed seven putative phenol/phenazine-specific ABBA prenyltransferases, and one putative indole-specific ABBA prenyltransferase. To elucidate the substrate specificity of the ABBA prenyltransferases and to learn about their role in secondary metabolism, CnqP1 -CnqP8 were produced in Escherichia coli and incubated with various aromatic and isoprenoid substrates. Five of the eight prenyltransferases displayed enzymatic activity. The efficient conversion of dihydroxynaphthalene derivatives by CnqP3 (encoded by AA958_24325 and the co-location of AA958_24325 with genes characteristic for the biosynthesis of THN (tetrahydroxynaphthalene-derived natural products indicates that the enzyme is involved in the formation of debromomarinone or other naphthoquinone-derived meroterpenoids. Moreover, CnqP3 showed high flexibility towards a range of aromatic and isoprenoid substrates and thus represents an interesting new tool for biocatalytic applications.

  9. Dark matter candidates

    International Nuclear Information System (INIS)

    Turner, M.S.

    1989-01-01

    One of the simplest, yet most profound, questions we can ask about the Universe is, how much stuff is in it, and further what is that stuff composed of? Needless to say, the answer to this question has very important implications for the evolution of the Universe, determining both the ultimate fate and the course of structure formation. Remarkably, at this late date in the history of the Universe we still do not have a definitive answer to this simplest of questions---although we have some very intriguing clues. It is known with certainty that most of the material in the Universe is dark, and we have the strong suspicion that the dominant component of material in the Cosmos is not baryons, but rather is exotic relic elementary particles left over from the earliest, very hot epoch of the Universe. If true, the Dark Matter question is a most fundamental one facing both particle physics and cosmology. The leading particle dark matter candidates are: the axion, the neutralino, and a light neutrino species. All three candidates are accessible to experimental tests, and experiments are now in progress. In addition, there are several dark horse, long shot, candidates, including the superheavy magnetic monopole and soliton stars. 13 refs

  10. Terpenoids Isolated From the Shoot of Plectranthus hadiensis Induces Apoptosis in Human Colon Cancer Cells Via the Mitochondria-Dependent Pathway.

    Science.gov (United States)

    Menon, Darsan B; Gopalakrishnan, V K

    2015-01-01

    The plant Plectranthus hadiensis is a rich source of many bioactive phytochemicals, especially terpenoids. The terpenoid fraction was isolated and phytochemical characterization was done using GC-MS. The aim of the present study was to find out the antiproliferative activity and the mechanism of cell death induction by the terpenoid fraction on human colon cancer cells (HCT-15). MTT assay was performed with different concentrations of the fraction (10, 20, and 50 µg/mL) to obtain IC50 value for 24 h to induce cell death. The induction of apoptosis were studied by Hoechst staining, acridine orange/ethidium bromide staining, Comet assay, DNA fragmentation, and caspase-3 activity assays. The mechanism of apoptosis induction was studied by expression analysis of antiapoptotic Bcl-2 and proapoptotic Bax using RT-PCR and also by Western blot analysis of proteins involved in the apoptotic pathway. The terpenoid fraction induced significant morphological changes and DNA fragmentation in the cells. Positive Hoechst staining and acridine orange/ethidium bromide staining indicated apoptosis induction by the fraction. DNA fragmentation, which is a characteristic feature of apoptosis, was also observed. Upregulation of caspase-3 activity and proapoptotic Bax, and the downregulation of antiapoptotic Bcl-2 and COX-2 confirmed that the apoptosis induction was via the mitochondria-dependent pathway.

  11. Evaluation of tobacco (Nicotiana tabacum L. cv. Petit Havana SR1) hairy roots for the production of geraniol, the first committed step in terpenoid indole alkaloid pathway

    NARCIS (Netherlands)

    Ritala, A.; Dong, L.; Imseng, N.; Seppanen-Laakso, T.; Vasilev, N.; Krol, van der A.R.; Rischer, H.; Maaheimo, H.; Virkki, A.; Brandli, J.; Schillberg, S.; Eibl, R.; Bouwmeester, H.J.; Oksman-Caldentey, K.M.

    2014-01-01

    The terpenoid indole alkaloids are one of the major classes of plant-derived natural products and are well known for their many applications in the pharmaceutical, fragrance and cosmetics industries. Hairy root cultures are useful for the production of plant secondary metabolites because of their

  12. Terpenoids from Zingiber officinale (Ginger induce apoptosis in endometrial cancer cells through the activation of p53.

    Directory of Open Access Journals (Sweden)

    Yang Liu

    Full Text Available Novel strategies are necessary to improve chemotherapy response in advanced and recurrent endometrial cancer. Here, we demonstrate that terpenoids present in the Steam Distilled Extract of Ginger (SDGE are potent inhibitors of proliferation of endometrial cancer cells. SDGE, isolated from six different batches of ginger rhizomes, consistently inhibited proliferation of the endometrial cancer cell lines Ishikawa and ECC-1 at IC(50 of 1.25 µg/ml. SDGE also enhanced the anti-proliferative effect of radiation and cisplatin. Decreased proliferation of Ishikawa and ECC-1 cells was a direct result of SDGE-induced apoptosis as demonstrated by FITC-Annexin V staining and expression of cleaved caspase 3. GC/MS analysis identified a total of 22 different terpenoid compounds in SDGE, with the isomers neral and geranial constituting 30-40%. Citral, a mixture of neral and geranial inhibited the proliferation of Ishikawa and ECC-1 cells at an IC(50 10 µM (2.3 µg/ml. Phenolic compounds such as gingerol and shogaol were not detected in SDGE and 6-gingerol was a weaker inhibitor of the proliferation of the endometrial cancer cells. SDGE was more effective in inducing cancer cell death than citral, suggesting that other terpenes present in SDGE were also contributing to endometrial cancer cell death. SDGE treatment resulted in a rapid and strong increase in intracellular calcium and a 20-40% decrease in the mitochondrial membrane potential. Ser-15 of p53 was phosphorylated after 15 min treatment of the cancer cells with SDGE. This increase in p53 was associated with 90% decrease in Bcl2 whereas no effect was observed on Bax. Inhibitor of p53, pifithrin-α, attenuated the anti-cancer effects of SDGE and apoptosis was also not observed in the p53(neg SKOV-3 cells. Our studies demonstrate that terpenoids from SDGE mediate apoptosis by activating p53 and should be therefore be investigated as agents for the treatment of endometrial cancer.

  13. Highly efficient conversion of terpenoid biomass to jet-fuel range cycloalkanes in a biphasic tandem catalytic process

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaokun [Univ. of Nevada, Reno, NV (United States); Li, Teng [Washington State Univ., Pullman, WA (United States); Tang, Kan [Washington State Univ., Pullman, WA (United States); Zhou, Xinpei [Univ. of Nevada, Reno, NV (United States); Lu, Mi [Univ. of Nevada, Reno, NV (United States); Ounkham, Whalmany L. [Univ. of Nevada, Reno, NV (United States); Spain, Stephen M. [Univ. of Nevada, Reno, NV (United States); Frost, Brian J. [Univ. of Nevada, Reno, NV (United States); Lin, Hongfei [Washington State Univ., Pullman, WA (United States)

    2017-06-12

    The demand for bio-jet fuels to reduce carbon emissions is increasing substantially in the aviation sector, while the scarcity of high-density jet fuel components limits the use of bio-jet fuels in high-performance aircrafts compared with conventional jet fuels. In this paper, we report a novel biphasic tandem catalytic process (biTCP) for synthesizing cycloalkanes from renewable terpenoid biomass, such as 1,8-cineole. Multistep tandem reactions, including C–O ring opening by hydrolysis, dehydration, and hydrogenation, were carried out in the “one-pot” biTCP. 1,8-Cineole was efficiently converted to p-menthane at high yields (>99%) in the biTCP under mild reaction conditions. Finally, the catalytic reaction mechanism is discussed.

  14. Optimized candidal biofilm microtiter assay

    NARCIS (Netherlands)

    Krom, Bastiaan P.; Cohen, Jesse B.; Feser, Gail E. McElhaney; Cihlar, Ronald L.

    Microtiter based candidal biofilm formation is commonly being used. Here we describe the analysis of factors influencing the development of candidal biofilms such as the coating with serum, growth medium and pH. The data reported here show that optimal candidal biofilm formation is obtained when

  15. Produtos naturais como candidatos a fármacos úteis no tratamento do Mal de Alzheimer Natural products as candidates for useful drugs in the treatment of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Cláudio Viegas Junior

    2004-08-01

    Full Text Available Alzheimer's disease (AD is a progressive neurodegenerative pathology with severe economic and social impact. There is currently no cure, although cholinesterase inhibitors provide effective temporary relief of symptoms in some patients. Nowadays drug research and development are based on the cholinergic hypothesis that supports the cognition improvement by regulation of the synthesis and release of acetylcholine in the brain. There are only four commercial medicines approved for treatment of AD and natural products have played an important role in the research for new acetylcholinesterase inhibitors.

  16. Differential microRNA Analysis of Glandular Trichomes and Young Leaves in Xanthium strumarium L. Reveals Their Putative Roles in Regulating Terpenoid Biosynthesis.

    Science.gov (United States)

    Fan, Rongyan; Li, Yuanjun; Li, Changfu; Zhang, Yansheng

    2015-01-01

    The medicinal plant Xanthium strumarium L. (X. strumarium) is covered with glandular trichomes, which are the sites for synthesizing pharmacologically active terpenoids such as xanthatin. MicroRNAs (miRNAs) are a class of 21-24 nucleotide (nt) non-coding RNAs, most of which are identified as regulators of plant growth development. Identification of miRNAs involved in the biosynthesis of plant secondary metabolites remains limited. In this study, high-throughput Illumina sequencing, combined with target gene prediction, was performed to discover novel and conserved miRNAs with potential roles in regulating terpenoid biosynthesis in X. strumarium glandular trichomes. Two small RNA libraries from leaves and glandular trichomes of X. strumarium were established. In total, 1,185 conserved miRNAs and 37 novel miRNAs were identified, with 494 conserved miRNAs and 18 novel miRNAs being differentially expressed between the two tissue sources. Based on the X. strumarium transcriptome data that we recently constructed, 3,307 annotated mRNA transcripts were identified as putative targets of the differentially expressed miRNAs. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis suggested that some of the differentially expressed miRNAs, including miR6435, miR5021 and miR1134, might be involved in terpenoid biosynthesis in the X. strumarium glandular trichomes. This study provides the first comprehensive analysis of miRNAs in X. strumarium, which forms the basis for further understanding of miRNA-based regulation on terpenoid biosynthesis.

  17. Differential microRNA Analysis of Glandular Trichomes and Young Leaves in Xanthium strumarium L. Reveals Their Putative Roles in Regulating Terpenoid Biosynthesis

    OpenAIRE

    Fan, Rongyan; Li, Yuanjun; Li, Changfu; Zhang, Yansheng

    2015-01-01

    The medicinal plant Xanthium strumarium L. (X. strumarium) is covered with glandular trichomes, which are the sites for synthesizing pharmacologically active terpenoids such as xanthatin. MicroRNAs (miRNAs) are a class of 21-24 nucleotide (nt) non-coding RNAs, most of which are identified as regulators of plant growth development. Identification of miRNAs involved in the biosynthesis of plant secondary metabolites remains limited. In this study, high-throughput Illumina sequencing, combined w...

  18. Differential microRNA Analysis of Glandular Trichomes and Young Leaves in Xanthium strumarium L. Reveals Their Putative Roles in Regulating Terpenoid Biosynthesis.

    Directory of Open Access Journals (Sweden)

    Rongyan Fan

    Full Text Available The medicinal plant Xanthium strumarium L. (X. strumarium is covered with glandular trichomes, which are the sites for synthesizing pharmacologically active terpenoids such as xanthatin. MicroRNAs (miRNAs are a class of 21-24 nucleotide (nt non-coding RNAs, most of which are identified as regulators of plant growth development. Identification of miRNAs involved in the biosynthesis of plant secondary metabolites remains limited. In this study, high-throughput Illumina sequencing, combined with target gene prediction, was performed to discover novel and conserved miRNAs with potential roles in regulating terpenoid biosynthesis in X. strumarium glandular trichomes. Two small RNA libraries from leaves and glandular trichomes of X. strumarium were established. In total, 1,185 conserved miRNAs and 37 novel miRNAs were identified, with 494 conserved miRNAs and 18 novel miRNAs being differentially expressed between the two tissue sources. Based on the X. strumarium transcriptome data that we recently constructed, 3,307 annotated mRNA transcripts were identified as putative targets of the differentially expressed miRNAs. KEGG (Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that some of the differentially expressed miRNAs, including miR6435, miR5021 and miR1134, might be involved in terpenoid biosynthesis in the X. strumarium glandular trichomes. This study provides the first comprehensive analysis of miRNAs in X. strumarium, which forms the basis for further understanding of miRNA-based regulation on terpenoid biosynthesis.

  19. Volatile composition and enantioselective analysis of chiral terpenoids of nine fruit and vegetable fibres resulting from juice industry by-products

    OpenAIRE

    Marsol i Vall, Alexis; Sgorbini, Barbara; Cagliero, Cecilia; Bicchi, Carlo; Eras i Joli, Jordi; Balcells Fluvià, Mercè

    2017-01-01

    Fruit and vegetable fibres resulting as by-products of the fruit juice industry have won popularity because they can be valorised as food ingredients. In this regard, bioactive compounds have already been studied but little attention has been paid to their remaining volatiles. Considering all the samples, 57 volatiles were identified. Composition greatly differed between citrus and noncitrus fibres. The former presented over 90% of terpenoids, with limonene being the most abundant and ranging...

  20. Effect of Cytokinin and Auxin Treatments on Morphogenesis, Terpenoid Biosynthesis, Photosystem Structural Organization, and Endogenous Isoprenoid Cytokinin Profile in Artemisia alba Turra In Vitro

    Czech Academy of Sciences Publication Activity Database

    Danova, K.; Motyka, Václav; Todorova, M.; Trendafilova, A.; Krumova, S.; Dobrev, Petre; Andreeva, T.; Oreshkova, T.; Taneva, S.; Evstatieva, L.

    2018-01-01

    Roč. 37, č. 2 (2018), s. 403-418 ISSN 0721-7595 R&D Projects: GA ČR(CZ) GA16-14649S Institutional support: RVO:61389030 Keywords : Artemisia alba Turra in vitro * Cis- and trans-zeatin * Endogenous cytokinins * Photosystem II and thylakoid morphology * Plant growth regulators * Terpenoid profile of the essential oil Subject RIV: EF - Botanics OBOR OECD: Plant sciences, botany Impact factor: 2.073, year: 2016

  1. Volatile Composition and Enantioselective Analysis of Chiral Terpenoids of Nine Fruit and Vegetable Fibres Resulting from Juice Industry By-Products

    Directory of Open Access Journals (Sweden)

    Alexis Marsol-Vall

    2017-01-01

    Full Text Available Fruit and vegetable fibres resulting as by-products of the fruit juice industry have won popularity because they can be valorised as food ingredients. In this regard, bioactive compounds have already been studied but little attention has been paid to their remaining volatiles. Considering all the samples, 57 volatiles were identified. Composition greatly differed between citrus and noncitrus fibres. The former presented over 90% of terpenoids, with limonene being the most abundant and ranging from 52.7% in lemon to 94.0% in tangerine flesh. Noncitrus fibres showed more variable compositions, with the predominant classes being aldehydes in apple (57.5% and peach (69.7%, esters (54.0% in pear, and terpenoids (35.3% in carrot fibres. In addition, enantioselective analysis of some of the chiral terpenoids present in the fibre revealed that the enantiomeric ratio for selected compounds was similar to the corresponding volatile composition of raw fruits and vegetables and some derivatives, with the exception of terpinen-4-ol and α-terpineol, which showed variation, probably due to the drying process. The processing to which fruit residues were submitted produced fibres with low volatile content for noncitrus products. Otherwise, citrus fibres analysed still presented a high volatile composition when compared with noncitrus ones.

  2. Development of a Matrix Solid-Phase Dispersion Extraction Combined with UPLC/Q-TOF-MS for Determination of Phenolics and Terpenoids from the Euphorbia fischeriana.

    Science.gov (United States)

    Li, Wenjing; Lin, Yu; Wang, Yuchun; Hong, Bo

    2017-09-11

    A method based on a simplified extraction by matrix solid phase dispersion (MSPD) followed by ultra-performance liquid chromatography coupled with the quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS) determination is validated for analysis of two phenolics and three terpenoids in Euphorbia fischeriana . The optimized experimental parameters of MSPD including dispersing sorbent (silica gel), ratio of sample to dispersing sorbent (1:2), elution solvent (water-ethanol: 30-70) and volume of the elution solvent (10 mL) were examined and set down. The highest extraction yields of chromatogram information and the five compounds were obtained under the optimized conditions. A total of 25 constituents have been identified and five components have been quantified from Euphorbia fischeriana . A linear relationship (r² ≥ 0.9964) between the concentrations and the peak areas of the mixed standard substances were revealed. The average recovery was between 92.4% and 103.2% with RSD values less than 3.45% ( n = 5). The extraction yields of two phenolics and three terpenoids obtained by the MSPD were higher than those of traditional reflux and sonication extraction with reduced requirement on sample, solvent and time. In addition, the optimized method will be applied for analyzing terpenoids in other Chinese herbal medicine samples.

  3. Elucidation of terpenoid metabolism in Scoparia dulcis by RNA-seq analysis.

    Science.gov (United States)

    Yamamura, Yoshimi; Kurosaki, Fumiya; Lee, Jung-Bum

    2017-03-07

    Scoparia dulcis biosynthesize bioactive diterpenes, such as scopadulcic acid B (SDB), which are known for their unique molecular skeleton. Although the biosynthesis of bioactive diterpenes is catalyzed by a sequence of class II and class I diterpene synthases (diTPSs), the mechanisms underlying this process are yet to be fully identified. To elucidate these biosynthetic machinery, we performed a high-throughput RNA-seq analysis, and de novo assembly of clean reads revealed 46,332 unique transcripts and 40,503 two unigenes. We found diTPSs genes including a putative syn-copalyl diphosphate synthase (SdCPS2) and two kaurene synthase-like (SdKSLs) genes. Besides them, total 79 full-length of cytochrome P450 (CYP450) genes were also discovered. The expression analyses showed selected CYP450s associated with their expression pattern of SdCPS2 and SdKSL1, suggesting that CYP450 candidates involved diterpene modification. SdCPS2 represents the first predicted gene to produce syn-copalyl diphosphate in dicots. In addition, SdKSL1 potentially contributes to the SDB biosynthetic pathway. Therefore, these identified genes associated with diterpene biosynthesis lead to the development of genetic engineering focus on diterpene metabolism in S. dulcis.

  4. Investigation of polycyclic aromatic hydrocarbons (PAHs) and cyclic terpenoid biomarkers in the sediments of fishing harbors in Taiwan

    International Nuclear Information System (INIS)

    Kao, Nien-Hsin; Su, Ming-Chien; Fan, Jheng-Rong; Yen, Chih-Chun

    2015-01-01

    Highlights: • Biomarkers in three fishing harbors were investigated and identified. • 17 terpanes, 10 steranes and 10 bicyclic sesquiterpanes were quantified. • Marine diesel and the three kinds of lubricants were studied. • The study can be applied to other harbors to identify oil products in sediments. - Abstract: Three fishing harbors were investigated to study the polycyclic aromatic hydrocarbons in the sediments and trace possible anthropogenic sources by identification of cyclic terpenoid biomarkers. Seventeen terpanes, 10 steranes and 10 bicyclic sesquiterpanes in the marine diesel and the three kinds of lubricants that are mainly used by fishing boats were identified and quantified. Eighteen biomarker diagnostic ratios are suggested and the correlation coefficients among the lubricants and sediment samples have the R 2 value greater than 0.73. Analyzed 16 PAHs in the sediment shows non-normal distributions and the Kruskal Wallis Test shows the significant differences (p value smaller than 0.05) with the greatest variability in benzo[g,h,i]perylene which more than 84% of the effective size (E.S.) is accounted. X-ray Photoelectron Spectroscopy (XPS) analysis was applied and the Kruskal Wallis Test shows a significant difference (p value smaller than 0.05) among certain atoms with the effective size greater than 60%

  5. Silencing the Transcriptional Repressor, ZCT1, Illustrates the Tight Regulation of Terpenoid Indole Alkaloid Biosynthesis in Catharanthus roseus Hairy Roots.

    Directory of Open Access Journals (Sweden)

    Noreen F Rizvi

    Full Text Available The Catharanthus roseus plant is the source of many valuable terpenoid indole alkaloids (TIAs, including the anticancer compounds vinblastine and vincristine. Transcription factors (TFs are promising metabolic engineering targets due to their ability to regulate multiple biosynthetic pathway genes. To increase TIA biosynthesis, we elicited the TIA transcriptional activators (ORCAs and other unidentified TFs with the plant hormone, methyl jasmonate (MJ, while simultaneously silencing the expression of the transcriptional repressor ZCT1. To silence ZCT1, we developed transgenic hairy root cultures of C. roseus that expressed an estrogen-inducible Zct1 hairpin for activating RNA interference. The presence of 17β-estradiol (5μM effectively depleted Zct1 in hairy root cultures elicited with MJ dosages that either optimize or inhibit TIA production (250 or 1000μM. However, silencing Zct1 was not sufficient to increase TIA production or the expression of the TIA biosynthetic genes (G10h, Tdc, and Str, illustrating the tight regulation of TIA biosynthesis. The repression of the TIA biosynthetic genes at the inhibitory MJ dosage does not appear to be solely regulated by ZCT1. For instance, while Zct1 and Zct2 levels decreased through activating the Zct1 hairpin, Zct3 levels remained elevated. Since ZCT repressors have redundant yet distinct functions, silencing all three ZCTs may be necessary to relieve their repression of alkaloid biosynthesis.

  6. Evaluation of the intestinal permeability of rosemary (Rosmarinus officinalis L. extract polyphenols and terpenoids in Caco-2 cell monolayers.

    Directory of Open Access Journals (Sweden)

    Almudena Pérez-Sánchez

    Full Text Available Rosemary (Rosmarinus officinalis is grown throughout the world and is widely used as a medicinal herb and to season and preserve food. Rosemary polyphenols and terpenoids have attracted great interest due to their potential health benefits. However, complete information regarding their absorption and bioavailability in Caco-2 cell model is scarce. The permeation properties of the bioactive compounds (flavonoids, diterpenes, triterpenes and phenylpropanoids of a rosemary extract (RE, obtained by supercritical fluid extraction, was studied in Caco-2 cell monolayer model, both in a free form or liposomed. Compounds were identified and quantitated by liquid chromatography coupled to quadrupole time-of-flight with electrospray ionization mass spectrometry analysis (HPLC-ESI-QTOF-MS, and the apparent permeability values (Papp were determined, for the first time in the extract, for 24 compounds in both directions across cell monolayer. For some compounds, such as triterpenoids and some flavonoids, Papp values found were reported for the first time in Caco-2 cells.Our results indicate that most compounds are scarcely absorbed, and passive diffusion is suggested to be the primary mechanism of absorption. The use of liposomes to vehiculize the extract resulted in reduced permeability for most compounds. Finally, the biopharmaceutical classification (BCS of all the compounds was achieved according to their permeability and solubility data for bioequivalence purposes. BCS study reveal that most of the RE compounds could be classified as classes III and IV (low permeability; therefore, RE itself should also be classified into this category.

  7. Evaluation of the intestinal permeability of rosemary (Rosmarinus officinalis L.) extract polyphenols and terpenoids in Caco-2 cell monolayers

    Science.gov (United States)

    Arráez-Román, David; González-Álvarez, Isabel; Ibáñez, Elena; Segura-Carretero, Antonio; Bermejo, Marival; Micol, Vicente

    2017-01-01

    Rosemary (Rosmarinus officinalis) is grown throughout the world and is widely used as a medicinal herb and to season and preserve food. Rosemary polyphenols and terpenoids have attracted great interest due to their potential health benefits. However, complete information regarding their absorption and bioavailability in Caco-2 cell model is scarce. The permeation properties of the bioactive compounds (flavonoids, diterpenes, triterpenes and phenylpropanoids) of a rosemary extract (RE), obtained by supercritical fluid extraction, was studied in Caco-2 cell monolayer model, both in a free form or liposomed. Compounds were identified and quantitated by liquid chromatography coupled to quadrupole time-of-flight with electrospray ionization mass spectrometry analysis (HPLC-ESI-QTOF-MS), and the apparent permeability values (Papp) were determined, for the first time in the extract, for 24 compounds in both directions across cell monolayer. For some compounds, such as triterpenoids and some flavonoids, Papp values found were reported for the first time in Caco-2 cells.Our results indicate that most compounds are scarcely absorbed, and passive diffusion is suggested to be the primary mechanism of absorption. The use of liposomes to vehiculize the extract resulted in reduced permeability for most compounds. Finally, the biopharmaceutical classification (BCS) of all the compounds was achieved according to their permeability and solubility data for bioequivalence purposes. BCS study reveal that most of the RE compounds could be classified as classes III and IV (low permeability); therefore, RE itself should also be classified into this category. PMID:28234919

  8. Analysis of iridoids content and expression studies of genes encoding early enzymes in the indol terpenoid biosynthesis pathway in Catharanthus roseus Análisis de iridoides y expresión de genes que codifican enzimas tempranas en la síntesis de alcaloides indol terpenoicos en Catharanthus roseus

    OpenAIRE

    Leech Mark; Palacios-Rojas Natalia

    2004-01-01

    Terpenoid indole alkaloids (TIA) are of pharmaceutical importance, however the industrial use of these compouds is very limited because its accumulation is very low in plant tissues. TIA are derived f rom the shikimate and terpenoid pathways, which supply secologanin and tryptamine, the indole and iridoid moieties, respectively. Secololganin is a terpenoid which is belived to be synthesised the MEP pathway rather than by the acetate/mevalonic acid pathway. Secologanin is thought to be a limit...

  9. Antiproliferative terpenoids from almond hulls (Prunus dulcis): identification and structure-activity relationships.

    Science.gov (United States)

    Amico, Vincenzo; Barresi, Vincenza; Condorelli, Daniele; Spatafora, Carmela; Tringali, Corrado

    2006-02-08

    Bioassay-guided fractionation of the EtOAc crude extract from Sicilian almond hulls, a waste material from Prunus dulcis crop, allowed identification of 10 constituents, isolated as pure compounds (1-5, 7, and 10) or unseparable mixtures (5 + 6 and 8 + 9). All compounds were subjected to spectroscopic analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide bioassay on MCF-7 human breast cancer cells. In addition to the main components oleanolic (1), ursolic (2), and betulinic (3) acids, the 2-hydroxy analogues alphitolic (4), corosolic (5), and maslinic (6) acids, as well as the related aldehydes, namely, betulinic (7), oleanolic (8), and ursolic (9), were identified. From a more polar fraction, the beta-sitosterol 3-O-glucoside (10) was also identified. A sample of commercially available betulin (11) was also included in bioassays as further support to a structure-activity relationship study. Betulinic acid showed antiproliferative activity toward MCF-7 cells (GI50 = 0.27 microM), higher than the anticancer drug 5-fluorouracil.

  10. Biotransformation of terpenoids by mammals, microorganisms, and plant-cultured cells.

    Science.gov (United States)

    Ishida, Takashi

    2005-05-01

    This review article summarizes our knowledge of the metabolism of mono- and sesquiterpenoids in mammals, microorganisms, cloned-insect enzymes, and plant-cultured cells. A number of unusual enzymatic reactions and products are reported such as the stereoselective formation of primary alcohols from sterically congested Me2C groups. Such enzymatic processes, including unknown chemical transformations under abiotic conditions, could lead to the discovery of new chemical reactions and might be helpful in the design of new drugs. The transformations of the following mono- and sesquiterpenoids (in alphabetical order) are discussed: (+)-(1R)-aromadendrene (61), (-)-allo-aromadendrene (62), (+/-)-camphene (21), (-)-cis-carane (20), (+)-3-carene (17), (+/-)-carvone (27), (-)-beta-caryophyllene (43), (+)-cedrol (35), cuminaldehyde (25), (+)-curdione (69), (-)-cyclocolorenone (60), (-)-elemol (51), (2E,6E)-farnesol (31), germacrone (67), ginsenol (40), (-)-globulol (63), isoprobotryan-9alpha-ol (82a), juvenile hormone III (33), (+)-ledol (65), (+)-longifolene (46), myrcene (3), (-)-myrtenal (23), (+)-nootkatone (48), patchouli alcohol (37), (-)-perillaldehyde (24), (-)-alpha- and beta-pinene (8 and 9), alpha-santalol (28), (-)-6beta-santonin (83a), 6beta-tetrahydrosantonin (83b), beta-selinene (57), alpha-thujone (26a), beta-thujone (26b), T-2 toxin (87), and valerianol (53).

  11. Generating Genome-Scale Candidate Gene Lists for Pharmacogenomics

    DEFF Research Database (Denmark)

    Hansen, Niclas Tue; Brunak, Søren; Altman, R. B.

    2009-01-01

    A critical task in pharmacogenomics is identifying genes that may be important modulators of drug response. High-throughput experimental methods are often plagued by false positives and do not take advantage of existing knowledge. Candidate gene lists can usefully summarize existing knowledge...

  12. Drug resistance of yeasts isolated from oropharyngeal candidiasis in aids patients Resistência à drogas de leveduras isoladas de candidíase orofaríngea em pacientes com Aids

    Directory of Open Access Journals (Sweden)

    Maria do Rosário Rodrigues Silva

    1998-10-01

    Full Text Available Candida spp was isolated from 59 (68.60% out of eighty six samples of oral mucosa of AIDS patients. The identification, based or the production of a germ tube and chlamydospores, and on the assimilation and fermentation of carbohydrates, revealed 52 strains (88.13% of C. albicans, 4 (6.77% of C. tropicalis and 3 (5.08% of C. krusei. The susceptibility of these strains to amphotericin B, flucytosine, itraconazole, fluconazole and ketoconazole was determined using the agar dilution method. Comparing the minimum inhibitory concentration values found in the susceptibility test with the serum levels achieved by these drugs, only 8.47% and 5.08% of the yeasts strains proved to be resistant to amphotericin B and flucitosyne, respectively. A high frequency of strains resistant to azole derivatives (25.42%, to itraconazole, 45.76%, to ketoconazole and 66.10% to fluconazole was observed.Entre oitenta e seis amostras da mucosa oral de pacientes com AIDS, 59 (68,60% foram positivas para leveduras do gênero Candida. A identificação, feita pela produção de tubo germinativo e clamidósporos e através de assimilação e fermentação de hidratos de carbono, revelou 52 cepas (88,13% de C.albicans, 4 (6,77% de C. tropicalis e 3 (5,08% de C.krusei. Avaliação destas leveduras para susceptibilidade in vitro frente a anfotericina B, flucitosina, itraconazol, fluconazol e cetoconazol, foi realizada pelo método de diluição em ágar. Comparando-se os valores de concentração inibitória mínima encontrados com os níveis séricos alcançados por estes antifúngicos verificou-se que apenas 8,47% e 5,08% das 59 leveduras foram resistentes a anfotericina B e flucitosina, respectivamente. Foi registrada uma percentagem de cepas resistentes aos derivados azólicos, sendo 25,42% ao itraconazol, 45,76% ao cetoconazol e 66,10% ao fluconazol.

  13. Satisfaction and convenience of using terpenoid-impregnated eyelid wipes and teaching method in people without blepharitis.

    Science.gov (United States)

    Qiu, Tian Yu; Yeo, Sharon; Tong, Louis

    2018-01-01

    Demodex infestations cause blepharitis and are difficult to treat. Recently, a new type of eyelid wipes with terpenoids has been found effective. We aim to evaluate patient satisfaction after short-term use and compare two teaching modalities on the techniques of use. Eligible participants were taught to use eyelid wipes (Cliradex ® ) by either live or online video demonstration based on random allocation. Participants used the wipes twice daily for a week. All participants had prior evaluation of socioeconomic status, dry eye symptoms, and meibomian gland features. After 1 week, competence of use was assessed by participants showing their technique to the investigator, and a questionnaire on comfort, ease, and convenience of use was administered. Higher scores indicate greater satisfaction, and these levels are compared among the two teaching modalities using chi square. A total of 50 participants were recruited, with a mean age of 42±16 years, and 88% of the participants were females. Overall, median comfort level was 4.0 (range: 1-6), ease level was 5.0 (3-6), and convenience level was 5.0 (2-6). Median stinging was 2.0 (1-4), which corresponded to some but mild stinging. The median competence level was 4.0 (2-4), which corresponded to excellent competence. These satisfactory levels (ease, comfort, and convenience) experienced were not significantly associated with different socioeconomic indicators, that is, housing type, income, highest education level, and were not different between teaching methods ( p >0.05). Short-term use of Cliradex eyelid wipes seems to be acceptable to most people. The teaching instructions before using these wipes were equally effective - whether live or online video demonstration was used.

  14. Terpenoid biosynthesis in Arabidopsis attacked by caterpillars and aphids: effects of aphid density on the attraction of a caterpillar parasitoid.

    Science.gov (United States)

    Kroes, Anneke; Weldegergis, Berhane T; Cappai, Francesco; Dicke, Marcel; van Loon, Joop J A

    2017-12-01

    One of the responses of plants to insect attack is the production of volatile organic compounds that mediate indirect defence of plants by attracting natural enemies of the attacking herbivores. Herbivore-induced plant volatiles (HIPVs) include terpenoids that play key roles in the attraction of natural enemies. Crosstalk between phytohormonal signalling pathways is well known to affect the regulation of plant defences, including the emission of HIPVs. Thus, simultaneous feeding on the same plant by caterpillars and aphids, can affect the attraction of parasitoids by the plant compared to single insect attack. The role of aphid density in the regulation of HIPV emission by plants under dual attack has not been studied previously. Here, we investigated the attraction of Diadegma semiclausum, a parasitoid of the Diamondback moth Plutella xylostella, to volatiles emitted by Arabidopsis thaliana plants, simultaneously attacked by host caterpillars, and by the non-host aphid Brevicoryne brassicae. Our study shows that the effect of aphid infestation on parasitoid attraction is influenced by the density of the aphids. Biosynthesis and emission of (E,E)-α-farnesene could be linked to the observed preference of D. semiclausum parasitoids for the HIPV blend emitted by plants dually infested by caterpillars and aphids at a high density compared to dually infested plants with a low aphid density. Parasitoids such as D. semiclausum are important enemies of herbivorous insects and a better understanding of how plants express indirect defence mechanisms in response to multiple insect attack will provide important knowledge on plant-herbivore-parasitoid interactions under multiple stress conditions.

  15. Rapid Induction of Multiple Terpenoid Groups by Ponderosa Pine in Response to Bark Beetle-Associated Fungi.

    Science.gov (United States)

    Keefover-Ring, Ken; Trowbridge, Amy; Mason, Charles J; Raffa, Kenneth F

    2016-01-01

    Ponderosa pine (Pinus ponderosa) is a major and widely distributed component of conifer biomes in western North America and provides substantial ecological and economic benefits. This tree is exposed to several tree-killing bark beetle-microbial complexes, including the mountain pine beetle (Dendroctonus ponderosae) and the phytopathogenic fungus Grosmannia clavigera that it vectors, which are among the most important. Induced responses play a crucial role in conifer defenses, yet these have not been reported in ponderosa pine. We compared concentrations of terpenes and a phenylpropanoid, two phytochemical classes with strong effects against bark beetles and their symbionts, in constitutive phloem tissue and in tissue following mechanical wounding or simulated D. ponderosae attack (mechanical wounding plus inoculation with G. clavigera). We also tested whether potential induced responses were localized or systemic. Ponderosa pines showed pronounced induced defenses to inoculation, increasing their total phloem concentrations of monoterpenes 22.3-fold, sesquiterpenes 56.7-fold, and diterpenes 34.8-fold within 17 days. In contrast, responses to mechanical wounding alone were only 5.2, 11.3, and 7.7-fold, respectively. Likewise, the phenylpropanoid estragole (4-allyanisole) rose to 19.1-fold constitutive levels after simulated attack but only 4.4-fold after mechanical wounding. Overall, we found no evidence of systemic induction after 17 days, which spans most of this herbivore's narrow peak attack period, as significant quantitative and compositional changes within and between terpenoid groups were localized to the wound site. Implications to the less frequent exploitation of ponderosa than lodgepole pine by D. ponderosae, and potential advantages of rapid localized over long-term systemic responses in this system, are discussed.

  16. Observations and models of emissions of volatile terpenoid compounds from needles of ponderosa pine trees growing in situ: control by light, temperature and stomatal conductance.

    Science.gov (United States)

    Harley, Peter; Eller, Allyson; Guenther, Alex; Monson, Russell K

    2014-09-01

    Terpenoid emissions from ponderosa pine (Pinus ponderosa subsp. scopulorum) were measured in Colorado, USA over two growing seasons to evaluate the role of incident light, needle temperature, and stomatal conductance in controlling emissions of 2-methyl-3-buten-2-ol (MBO) and several monoterpenes. MBO was the dominant daylight terpenoid emission, comprising on average 87% of the total flux, and diurnal variations were largely determined by light and temperature. During daytime, oxygenated monoterpenes (especially linalool) comprised up to 75% of the total monoterpenoid flux from needles. A significant fraction of monoterpenoid emissions was dependent on light and 13CO2 labeling studies confirmed de novo production. Thus, modeling of monoterpenoid emissions required a hybrid model in which a significant fraction of emissions was dependent on both light and temperature, while the remainder was dependent on temperature alone. Experiments in which stomata were forced to close using abscisic acid demonstrated that MBO and a large fraction of the monoterpene flux, presumably linalool, could be limited at the scale of seconds to minutes by stomatal conductance. Using a previously published model of terpenoid emissions, which explicitly accounts for the physicochemical properties of emitted compounds, we were able to simulate these observed stomatal effects, whether induced experimentally or arising under naturally fluctuation conditions of temperature and light. This study shows unequivocally that, under naturally occurring field conditions, de novo light-dependent monoterpenes comprise a significant fraction of emissions in ponderosa pine. Differences between the monoterpene composition of ambient air and needle emissions imply a significant non-needle emission source enriched in Δ-3-carene.

  17. Observations and models of emissions of volatile terpenoid compounds from needles of ponderosa pine trees growing in situ: control by light, temperature and stomatal conductance

    Energy Technology Data Exchange (ETDEWEB)

    Harley, Peter; Eller, Allyson; Guenther, Alex; Monson, Russell K.

    2014-07-12

    Terpenoid emissions from ponderosa pine (Pinus ponderosa subsp. scopulorum) were measured in Colorado, USA over two growing seasons to evaluate the role of incident light, needle temperature and stomatal conductance in controlling emissions of 2-methyl-3-buten-2-ol (MBO) and several monoterpenes. MBO was the dominant daylight terpenoid emission, comprising on average 87% of the total flux, and diurnal variations were largely determined by light and temperature. During daytime, oxygenated monoterpenes (especially linalool) comprised up to 75% of the total monoterpenoid flux from needles. A significant fraction of monoterpenoid emissions was light dependent and 13CO2 labeling studies confirmed de novo production. Thus, modeling of monoterpenoid emissions required a hybrid model in which a significant fraction of emissions was dependent on both light and temperature, while the remainder was dependent on temperature alone. Experiments in which stomata were forced to close using abscisic acid demonstrated that MBO and a large fraction of the monoterpene flux, presumably linalool, could be limited at the scale of seconds to minutes by stomatal conductance. Using a previously published model of terpenoid emissions which explicitly accounts for the physico-chemical properties of emitted compounds, we are able to simulate these observed stomatal effects, whether induced through experimentation or arising under naturally fluctuation conditions of temperature and light. This study shows unequivocally that, under naturally occurring field conditions, de novo light dependent monoterpenes can comprise a large fraction of emissions. Differences between the monoterpene composition of ambient air and needle emissions imply a significant non-needle emission source enriched in Δ-3-carene.

  18. Attractiveness of Host Plant Volatile Extracts to the Asian Citrus Psyllid, Diaphorina citri, is Reduced by Terpenoids from the Non-Host Cashew.

    Science.gov (United States)

    Fancelli, Marilene; Borges, Miguel; Laumann, Raul A; Pickett, John A; Birkett, Michael A; Blassioli-Moraes, Maria C

    2018-04-01

    Diaphorina citri is a vector of the bacterial causative agent of Huanglongbing (HLB = Citrus greening), a severe disease affecting citrus crops. As there is no known control for HLB, manipulating insect behaviour through deployment of semiochemicals offers a promising opportunity for protecting citrus crops. The behavioural responses of D. citri to plant volatiles, and the identity of these plant volatiles were investigated. Volatiles were collected from host plants Murraya paniculata, Citrus sinensis, C. reshni, C. limettioides, Poncirus trifoliata, and from non-host plants Psidium guajava, Mangifera indica, Anacardium occidentale. In behavioural assays, female D. citri spent more time in the arms containing volatiles from either M. paniculata or C. sinensis compared to the control arms. When D. citri was exposed to volatiles collected from A. occidentale, they preferred the control arm. Volatiles emitted from the other studied plants did not influence the foraging behaviour of D. citri. Chemical analyses of volatile extracts from C. sinensis, M. paniculata, and A. occidentale revealed the presence of the terpenoids (E)-4,8-dimethylnona-1,3,7-triene (DMNT) and (E,E)-4,8,12-trimethyltrideca-1,3,7,11-tetraene (TMTT) in higher amounts in A. occidentale. In further behavioural bioassays, female D. citri spent less time in arms containing a synthetic blend of DMNT and TMTT compared to the control arms. Female D. citri also spent less time in arms containing the synthetic blend in combination with volatile extracts from either M. paniculata or C. sinensis compared to the control arms. Results suggest that higher release of the two terpenoids by A. occidentale make this species unattractive to D. citri, and that the terpenoids could be used in reducing colonisation of citrus plants and therefore HLB infection.

  19. A comparison of accelerated solvent extraction, Soxhlet extraction, and ultrasonic-assisted extraction for analysis of terpenoids and sterols in tobacco.

    Science.gov (United States)

    Shen, Jinchao; Shao, Xueguang

    2005-11-01

    The performance of accelerated solvent extraction in the analysis of terpenoids and sterols in tobacco samples was investigated and compared with those of Soxhlet extraction and ultrasonically assisted extraction with respect to yield, extraction time, reproducibility and solvent consumption. The results indicate that although the highest yield was achieved by Soxhlet extraction, ASE appears to be a promising alternative to classical methods since it is faster and uses less solvent, especially when applied to the investigation of large batch tobacco samples. However, Soxhlet extraction is still the preferred method for analyzing sterols since it gives a higher extraction efficiency than other methods.

  20. Enhancement of anti-candidal activity of endophytic fungus Phomopsis sp. ED2, isolated from Orthosiphon stamineus Benth, by incorporation of host plant extract in culture medium.

    Science.gov (United States)

    Yenn, Tong Woei; Lee, Chong Chai; Ibrahim, Darah; Zakaria, Latiffah

    2012-08-01

    This study examined the effect of host extract in the culture medium on anti-candidal activity of Phomopsis sp. ED2, previously isolated from the medicinal herb Orthosiphon stamineus Benth. Interestingly, upon addition of aqueous host extract to the culture medium, the ethyl acetate extract prepared from fermentative broth exhibited moderate anti-candidal activity in a disc diffusion assay. The minimal inhibitory concentration of this extract was 62.5 μg/ml and it only exhibited fungistatic activity against C. albicans. In the time-kill study, a 50% growth reduction of C. albicans was observed at 31.4 h for extract from the culture incorporating host extract. In the bioautography assay, only one single spot (Rf 0.59) developed from the extract exhibited anti-candidal activity. A spot with the a similar Rf was not detected for the crude extract from YES broth without host extract. This indicated that the terpenoid anti-candidal compound was only produced when the host extract was introduced into the medium. The study concluded that the incorporation of aqueous extract of the host plant into the culture medium significantly enhanced the anti-candidal activity of Phomopsis sp. ED2.

  1. Teacher Candidate Selection and Evaluation.

    Science.gov (United States)

    Collins, Mary Lynn; And Others

    Summaries are presented of three papers presented at a summer workshop on Quality Assurance in Teacher Education conducted by the Association of Teacher Educators. The general topic covered by these presentations was teacher candidate selection and evaluation. Papers focused upon the following questions: (1) What entry level criteria should be…

  2. Candidate Prediction Models and Methods

    DEFF Research Database (Denmark)

    Nielsen, Henrik Aalborg; Nielsen, Torben Skov; Madsen, Henrik

    2005-01-01

    This document lists candidate prediction models for Work Package 3 (WP3) of the PSO-project called ``Intelligent wind power prediction systems'' (FU4101). The main focus is on the models transforming numerical weather predictions into predictions of power production. The document also outlines...... the possibilities w.r.t. different numerical weather predictions actually available to the project....

  3. Candidate cave entrances on Mars

    Science.gov (United States)

    Cushing, Glen E.

    2012-01-01

    This paper presents newly discovered candidate cave entrances into Martian near-surface lava tubes, volcano-tectonic fracture systems, and pit craters and describes their characteristics and exploration possibilities. These candidates are all collapse features that occur either intermittently along laterally continuous trench-like depressions or in the floors of sheer-walled atypical pit craters. As viewed from orbit, locations of most candidates are visibly consistent with known terrestrial features such as tube-fed lava flows, volcano-tectonic fractures, and pit craters, each of which forms by mechanisms that can produce caves. Although we cannot determine subsurface extents of the Martian features discussed here, some may continue unimpeded for many kilometers if terrestrial examples are indeed analogous. The features presented here were identified in images acquired by the Mars Odyssey's Thermal Emission Imaging System visible-wavelength camera, and by the Mars Reconnaissance Orbiter's Context Camera. Select candidates have since been targeted by the High-Resolution Imaging Science Experiment. Martian caves are promising potential sites for future human habitation and astrobiology investigations; understanding their characteristics is critical for long-term mission planning and for developing the necessary exploration technologies.

  4. Predicting drug?drug interactions through drug structural similarities and interaction networks incorporating pharmacokinetics and pharmacodynamics knowledge

    OpenAIRE

    Takeda, Takako; Hao, Ming; Cheng, Tiejun; Bryant, Stephen H.; Wang, Yanli

    2017-01-01

    Drug?drug interactions (DDIs) may lead to adverse effects and potentially result in drug withdrawal from the market. Predicting DDIs during drug development would help reduce development costs and time by rigorous evaluation of drug candidates. The primary mechanisms of DDIs are based on pharmacokinetics (PK) and pharmacodynamics (PD). This study examines the effects of 2D structural similarities of drugs on DDI prediction through interaction networks including both PD and PK knowledge. Our a...

  5. Drug Facts

    Medline Plus

    Full Text Available ... Why Is It So Hard to Quit Drugs? Effects of Drugs Drug Use and Other People Drug ... Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug ...

  6. Evaluation of Candidate Anti-Aids Drugs In Vitro

    Science.gov (United States)

    1991-05-31

    numba by 50% (ED5) was calulatad using a regression aa-ysis program for semi-log curve fit’tig and was exnpresed a* ."g/Tn- The eapic index ,) wa dvte b y...czztairng 1.25 pg of poly (rA). p(c!T)12.11, 200 pM d= (400 kLCi of •’H,’•nle of ’- dT’P). 1mM S apo-rne•’ý • ol, 120 mM KCI, 0.6 mM MnC½, 0. 10 mM EDTA...Appendix B). The Mrst aýtive compounds (i.e. confirrnme activity with Selectivity Index (SI) of >10) are listed in Table !. During our overall experience

  7. Novel and Efficient Synthesis of the Promising Drug Candidate Discodermolide

    Science.gov (United States)

    2010-02-01

    of its production may require its wide use as a livestock antibiotic , a market that seems to have disappeared. Therefore, as a purely practical...building block 9. Thus, chiral syn, anti stereotriad building blocks, useful for the preparation of polypropionate antibiotics , may be efficiently accessed... antibiotics that are used in human and veterinary medicine. In this paper, we illustrate the potential of a deconstruction-reconstruction strategy for the

  8. Green synthesis and antibacterial effects of aqueous colloidal solutions of silver nanoparticles using camomile terpenoids as a combined reducing and capping agent.

    Science.gov (United States)

    Parlinska-Wojtan, Magdalena; Kus-Liskiewicz, Małgorzata; Depciuch, Joanna; Sadik, Omowunmi

    2016-08-01

    Green synthesis method using camomile extract was applied to synthesize silver nanoparticles to tune their antibacterial properties merging the synergistic effect of camomile and Ag. Scanning transmission electron microscopy revealed that camomile extract (CE) consisted of porous globular nanometer sized structures, which were a perfect support for Ag nanoparticles. The Ag nanoparticles synthesized with the camomile extract (AgNPs/CE) of 7 nm average sizes, were uniformly distributed on the CE support, contrary to the pure Ag nanoparticles synthesized with glucose (AgNPs/G), which were over 50 nm in diameter and strongly agglomerated. The energy dispersive X-ray spectroscopy chemical analysis showed that camomile terpenoids act as a capping and reducing agent being adsorbed on the surface of AgNPs/CE enabling their reduction from Ag(+) and preventing them from agglomeration. Fourier transform infrared and ultraviolet-visible spectroscopy measurements confirmed these findings, as the spectra of AgNPs/CE, compared to pure CE, did not contain the 1109 cm(-1) band, corresponding to -C-O groups of terpenoids and the peaks at 280 and 320 nm, respectively. Antibacterial tests using four bacteria strains showed that the AgNPs/CE performed five times better compared to CE AgNPs/G samples, reducing totally all the bacteria in 2 h.

  9. Natural Flavonoids as Promising Analgesic Candidates: A Systematic Review.

    Science.gov (United States)

    Xiao, Xiao; Wang, Xiaoyu; Gui, Xuan; Chen, Lu; Huang, Baokang

    2016-11-01

    Due to the chemical structural diversity and various analgesic mechanisms, an increasing number of studies indicated that some flavonoids from medicinal plants could be promising candidates for new natural analgesic drugs, which attract high interests of advanced users and academic researchers. The aim of this systematic review is to report flavonoids and its derivatives as new analgesic candidates based on the pharmacological evidences. Sixty-four papers were found concerning the potential analgesic activity of 46 flavonoids. In this case, the evidence for analgesic activity of flavonoids and total flavonoids was investigated. Meanwhile, the corresponding analgesic mechanism of flavonoids was discussed by generalizing and analyzing the current publications. Based on this review, the conclusion can be drawn that some flavonoids are promising candidates for painful conditions and deserve particular attention in further research and development. © 2016 Wiley-VHCA AG, Zurich, Switzerland.

  10. Candidate genes in panic disorder

    DEFF Research Database (Denmark)

    Howe, A. S.; Buttenschön, Henriette N; Bani-Fatemi, A.

    2016-01-01

    The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered...... association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed......-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed...

  11. The prediction of candidate genes for cervix related cancer through gene ontology and graph theoretical approach.

    Science.gov (United States)

    Hindumathi, V; Kranthi, T; Rao, S B; Manimaran, P

    2014-06-01

    With rapidly changing technology, prediction of candidate genes has become an indispensable task in recent years mainly in the field of biological research. The empirical methods for candidate gene prioritization that succors to explore the potential pathway between genetic determinants and complex diseases are highly cumbersome and labor intensive. In such a scenario predicting potential targets for a disease state through in silico approaches are of researcher's interest. The prodigious availability of protein interaction data coupled with gene annotation renders an ease in the accurate determination of disease specific candidate genes. In our work we have prioritized the cervix related cancer candidate genes by employing Csaba Ortutay and his co-workers approach of identifying the candidate genes through graph theoretical centrality measures and gene ontology. With the advantage of the human protein interaction data, cervical cancer gene sets and the ontological terms, we were able to predict 15 novel candidates for cervical carcinogenesis. The disease relevance of the anticipated candidate genes was corroborated through a literature survey. Also the presence of the drugs for these candidates was detected through Therapeutic Target Database (TTD) and DrugMap Central (DMC) which affirms that they may be endowed as potential drug targets for cervical cancer.

  12. Drug Facts

    Medline Plus

    Full Text Available ... Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use and Other People Drug Use and Families Drug Use and Kids Drug Use and Unborn ...

  13. Drug Facts

    Medline Plus

    Full Text Available ... Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, ... Drugs? Effects of Drugs Drug Use and Other People Drug Use and Families Drug Use and Kids ...

  14. Drug Facts

    Medline Plus

    Full Text Available ... People Drug Use and Families Drug Use and Kids Drug Use and Unborn Children Drug Use and ... Children and Teens Stay Drug-Free Talking to Kids About Drugs: What to Say if You Used ...

  15. Volatile compounds in the perirenal fat from calves finished on semiextensive or intensive systems with special emphasis on terpenoids

    Directory of Open Access Journals (Sweden)

    Soto, S.

    2015-12-01

    ; n=8. Los compuestos volátiles de grasa perirrenal fueron analizados utilizando un método de extracción-destilación simultánea seguido por cromatografía de gases acoplada a un detector de espectro de masas (CG/EM, operando en modo de barrido completo. Por otra parte, se determinaron de forma específica los terpenoides utilizando la técnica de microextracción en fase solida seguida por CG/EM, operando en modo de barrido selectivo de iones. La grasa del sistema SE mostró menores niveles de octanal, 2-octenal y 2,4-decadienal y mayores niveles de 2,3-octanodiona y escatol que el sistema I. Además, los niveles de α-pineno, aromadendreno, α-felandreno, eucaliptol, α-gurjuneno fueron más altos en el sistema SE. La presencia de fencheno, eucaliptol y α-gurjuneno no ha sido descrita en estudios previos en compuestos volátiles en carne o grasa de bovino. Este estudio muestra la posibilidad de utilizar varios terpenos presentes la grasa perirrenal como indicadores de alimentación en pastoreo en terneros Tudancos.

  16. Alternative dark matter candidates. Axions

    International Nuclear Information System (INIS)

    Ringwald, Andreas

    2017-01-01

    The axion is arguably one of the best motivated candidates for dark matter. For a decay constant >or similar 10 9 GeV, axions are dominantly produced non-thermally in the early universe and hence are ''cold'', their velocity dispersion being small enough to fit to large scale structure. Moreover, such a large decay constant ensures the stability at cosmological time scales and its behaviour as a collisionless fluid at cosmological length scales. Here, we review the state of the art of axion dark matter predictions and of experimental efforts to search for axion dark matter in laboratory experiments.

  17. Alternative dark matter candidates. Axions

    Energy Technology Data Exchange (ETDEWEB)

    Ringwald, Andreas

    2017-01-15

    The axion is arguably one of the best motivated candidates for dark matter. For a decay constant >or similar 10{sup 9} GeV, axions are dominantly produced non-thermally in the early universe and hence are ''cold'', their velocity dispersion being small enough to fit to large scale structure. Moreover, such a large decay constant ensures the stability at cosmological time scales and its behaviour as a collisionless fluid at cosmological length scales. Here, we review the state of the art of axion dark matter predictions and of experimental efforts to search for axion dark matter in laboratory experiments.

  18. Improved anti-inflammatory activity of three new terpenoids derived, by systematic chemical modifications, from the abundant triterpenes of the flowery plant Calendula officinalis.

    Science.gov (United States)

    Neukirch, Hannes; D'Ambrosio, Michele; Sosa, Silvio; Altinier, Gianmario; Della Loggia, Roberto; Guerriero, Antonio

    2005-05-01

    Rings A, D and E of faradiol (1), and ring E of both arnidiol (10) and calenduladiol (4) have been subjected to various selective chemical manipulations to modify polarity, water affinity, H-bonding, sterics, and number of aromatic groups of these anti-inflammatory natural compounds. A total of 15 new and four known pentacyclic triterpenoids have been obtained in this way. Some 13 terpenoids were evaluated for their topical anti-inflammatory activities with respect to inhibition of croton oil induced ear oedema in mouse. Three derivatives of 1, the C(16) benzyl ether 15, the C(30) aldehyde 24, and the C(30) primary alcohol 25 showed significantly improved anti-inflammatory potencies, which is relevant for (future) structure-activity-relationship (SAR) studies.

  19. Cloning and expression analysis of JcAACT, jcMDC and JcFPS, involved in terpenoid biosynthesis in jatropha curcas l

    International Nuclear Information System (INIS)

    Huang, Y.; Wen, J.

    2018-01-01

    To better understand the functions of key genes involved in terpenoid biosynthesis in Jatropha curcas, we cloned and characterized three genes, namely acetyl CoA acyltransferase (JcAACT), diphosphate mevalonate decarboxylase (JcMDC) and farnesyl pyrophosphate synthase (JcFPS). The opening reading frames (ORFs) of JcAACT, JcMDC and JcFPS were 1239 bp,1248 bp and 1029 bp, respectively, encoding a 412-amino acid, 415-amino acid and 342-amino acid polypeptide, respectively. Results of homology analysis showed that JcAACT, JcMDC and JcFPS encoded proteins that all had the highest identity and closest relationship with the corresponding genes in Hevea brasiliensis, with identities of 89%, 92% and 93%, respectively. JcAACT, JcMDC and JcFPS were expressed in all organs tested of J. curcas; the highest expression level for each gene occurred in seeds. In the early growth stage of seeds, the expression level of each of these three genes increased with time, with JcAACT and JcMDC expression level reaching a peak at the late stage of seed development (50 d), while JcFPS expression level reached a peak at the mid-late stage (40 d). Following the peak, the expression of each gene then declined. The expression level of JcAACT was the highest of the three genes, regardless of the organ or the stage of seed growth, indicating its important role in J. curcas. This study lays the foundation for a better understanding of the important role of the JcAACT, JcMDC and JcFPS genes in the terpenoid biosynthesis pathway of J. curcas. (author)

  20. 11 CFR 100.154 - Candidate debates.

    Science.gov (United States)

    2010-01-01

    ... 11 Federal Elections 1 2010-01-01 2010-01-01 false Candidate debates. 100.154 Section 100.154 Federal Elections FEDERAL ELECTION COMMISSION GENERAL SCOPE AND DEFINITIONS (2 U.S.C. 431) Exceptions to Expenditures § 100.154 Candidate debates. Funds used to defray costs incurred in staging candidate debates in...

  1. 11 CFR 100.92 - Candidate debates.

    Science.gov (United States)

    2010-01-01

    ... 11 Federal Elections 1 2010-01-01 2010-01-01 false Candidate debates. 100.92 Section 100.92 Federal Elections FEDERAL ELECTION COMMISSION GENERAL SCOPE AND DEFINITIONS (2 U.S.C. 431) Exceptions to Contributions § 100.92 Candidate debates. Funds provided to defray costs incurred in staging candidate debates...

  2. Drug Facts

    Medline Plus

    Full Text Available ... Treatment and Recovery Resources? Prevention Help Children and Teens Stay Drug-Free Talking to Kids About Drugs: What to Say if You Used Drugs in the Past Drug Use ... Videos Information About Drugs Alcohol ...

  3. Drug Allergy

    Science.gov (United States)

    ... Loss of consciousness Other conditions resulting from drug allergy Less common drug allergy reactions occur days or ... you take the drug. Drugs commonly linked to allergies Although any drug can cause an allergic reaction, ...

  4. [Obesity studies in candidate genes].

    Science.gov (United States)

    Ochoa, María del Carmen; Martí, Amelia; Martínez, J Alfredo

    2004-04-17

    There are more than 430 chromosomic regions with gene variants involved in body weight regulation and obesity development. Polymorphisms in genes related to energy expenditure--uncoupling proteins (UCPs), related to adipogenesis and insulin resistance--hormone-sensitive lipase (HLS), peroxisome proliferator-activated receptor gamma (PPAR gamma), beta adrenergic receptors (ADRB2,3), and alfa tumor necrosis factor (TNF-alpha), and related to food intake--ghrelin (GHRL)--appear to be associated with obesity phenotypes. Obesity risk depends on two factors: a) genetic variants in candidate genes, and b) biographical exposure to environmental risk factors. It is necessary to perform new studies, with appropriate control groups and designs, in order to reach relevant conclusions with regard to gene/environmental (diet, lifestyle) interactions.

  5. BEEF CATTLE MUSCULARITY CANDIDATE GENES

    Directory of Open Access Journals (Sweden)

    Irida Novianti

    2010-04-01

    Full Text Available Muscularity is a potential indicator for the selection of more productive cattle. Mapping quantitative trait loci (QTL for traits related to muscularity is useful to identify the genomic regions where the genes affecting muscularity reside. QTL analysis from a Limousin-Jersey double backcross herd was conducted using QTL Express software with cohort and breed as the fixed effects. Nine QTL suggested to have an association with muscularity were identified on cattle chromosomes BTA 1, 2, 3, 4, 5, 8, 12, 14 and 17. The myostatin gene is located at the centromeric end of chromosome 2 and not surprisingly, the Limousin myostatin F94L variant accounted for the QTL on BTA2. However, when the myostatin F94L genotype was included as an additional fixed effect, the QTL on BTA17 was also no longer significant. This result suggests that there may be gene(s that have epistatic effects with myostatin located on cattle chromosome 17. Based on the position of the QTL in base pairs, all the genes that reside in the region were determined using the Ensembl data base (www.ensembl.org. There were two potential candidate genes residing within these QTL regions were selected. They were Smad nuclear interacting protein 1 (SNIP1 and similar to follistatin-like 5 (FSTL5. (JIIPB 2010 Vol 20 No 1: 1-10

  6. Microfluidics Enables Small-Scale Tissue-Based Drug Metabolism Studies With Scarce Human Tissue

    NARCIS (Netherlands)

    van Midwoud, Paul M.; Verpoorte, Elisabeth; Groothuis, Geny M. M.; Merema, M.T.

    2011-01-01

    Early information on the metabolism and toxicity properties of new drug candidates is crucial for selecting the right candidates for further development. Preclinical trials rely on cell-based in vitro tests and animal studies to characterize the in vivo behavior of drug candidates, although neither

  7. Drug Safety

    Science.gov (United States)

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  8. Drug Abuse

    Science.gov (United States)

    ... Cocaine Heroin Inhalants Marijuana Prescription drugs, including opioids Drug abuse also plays a role in many major social problems, such as drugged driving, violence, stress, and child abuse. Drug abuse can lead to ...

  9. Drug Facts

    Medline Plus

    Full Text Available ... Use and Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug ...

  10. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use and Kids Drug Use and Unborn Children Drug Use and Your Health Other Effects on ... Someone Find Treatment and Recovery Resources? Prevention Help Children and Teens Stay Drug-Free Talking to Kids ...

  11. Club Drugs

    Science.gov (United States)

    ... uses. Other uses of these drugs are abuse. Club drugs are also sometimes used as "date rape" drugs, to make someone unable to say no to or fight back against sexual assault. Abusing these drugs can ...

  12. Change in the terpenoid profile and secondary growth in declining stands of Pinus sylvestris L. under mediterranean influence as a response to local factors

    Directory of Open Access Journals (Sweden)

    Sanz, M. A.

    2014-12-01

    Full Text Available The terpenoid profile could give information about the water status in Scots pine, especially for trees growing in the same geographical area but under contrasting local environmental conditions. Terpenes were analyzed by gas chromatography-mass spectrometry in needles, twigs and wood of ten affected and ten unaffected Scots pines in the southern “Sistema Ibérico” range (Teruel, Spain, where forest decline has been recently reported. Soil depth and secondary growth was also studied in both types of trees. Needles and twigs total resin acids were significantly higher in affected trees. The pimarane type resin acids were also higher in the twigs of affected trees. Secondary growth was lower in affected trees and it showed higher climate sensitivity. The use of the terpenoid profile may be used as an additional tool for the estimation of the water status, especially for situations inducing moderate but relatively prolonged stress conditions.El perfil terpénico podría dar información sobre el estado hídrico en el pino albar, especialmente cuando se comparen especímenes de una zona geográfica concreta afectados por factores ambientales locales. Los terpenos de acículas, brotes del año y madera fueron analizados en diez ejemplares afectados y otros tantos no afectados por el decaimiento mediante cromatografía de masas acoplada a espectrometría de masas. La serie de crecimiento secundario en ambos tipos de ejemplares fue también estudiada. La concentración total de ácidos resínicos aumentó de modo significativo en los árboles afectados tanto en brotes del año como en acículas. La cantidad de ácidos de tipo pimarano también aumentó en los brotes de los árboles afectados. La profundidad del suelo y el crecimiento secundario era menor en este tipo de ejemplares, que muestran una mayor sensibilidad en términos dendrocronológicos. El perfíl terpénico podría utilizarse como una herramienta adicional a la estimación del estado

  13. Emissions of terpenoids, benzenoids, and other biogenic gas-phase organic compounds from agricultural crops and their potential implications for air quality

    Science.gov (United States)

    Gentner, D. R.; Ormeño, E.; Fares, S.; Ford, T. B.; Weber, R.; Park, J.-H.; Brioude, J.; Angevine, W. M.; Karlik, J. F.; Goldstein, A. H.

    2014-06-01

    Agriculture comprises a substantial, and increasing, fraction of land use in many regions of the world. Emissions from agricultural vegetation and other biogenic and anthropogenic sources react in the atmosphere to produce ozone and secondary organic aerosol, which comprises a substantial fraction of particulate matter (PM2.5). Using data from three measurement campaigns, we examine the magnitude and composition of reactive gas-phase organic carbon emissions from agricultural crops and their potential to impact regional air quality relative to anthropogenic emissions from motor vehicles in California's San Joaquin Valley, which is out of compliance with state and federal standards for tropospheric ozone PM2.5. Emission rates for a suite of terpenoid compounds were measured in a greenhouse for 25 representative crops from California in 2008. Ambient measurements of terpenoids and other biogenic compounds in the volatile and intermediate-volatility organic compound ranges were made in the urban area of Bakersfield and over an orange orchard in a rural area of the San Joaquin Valley during two 2010 seasons: summer and spring flowering. We combined measurements from the orchard site with ozone modeling methods to assess the net effect of the orange trees on regional ozone. When accounting for both emissions of reactive precursors and the deposition of ozone to the orchard, the orange trees are a net source of ozone in the springtime during flowering, and relatively neutral for most of the summer until the fall, when it becomes a sink. Flowering was a major emission event and caused a large increase in emissions including a suite of compounds that had not been measured in the atmosphere before. Such biogenic emission events need to be better parameterized in models as they have significant potential to impact regional air quality since emissions increase by several factors to over an order of magnitude. In regions like the San Joaquin Valley, the mass of biogenic

  14. 11 CFR 110.13 - Candidate debates.

    Science.gov (United States)

    2010-01-01

    ... debates include at least two candidates; and (2) The staging organization(s) does not structure the... PROHIBITIONS § 110.13 Candidate debates. (a) Staging organizations. (1) Nonprofit organizations described in 26..., subparts D and E. (b) Debate structure. The structure of debates staged in accordance with this section and...

  15. A possible candidate for cold dark matter

    Indian Academy of Sciences (India)

    This additional scalar can be a viable candidate of cold dark matter (CDM) since the stability of is achieved by the application of Z 2 symmetry on . Considering as a possible candidate of CDM, Boltzmann's equation is solved to find the freeze-out temperature and relic density of for Higgs mass 120 GeV in the scalar ...

  16. 76 FR 36130 - Call for Candidates

    Science.gov (United States)

    2011-06-21

    ... financial information in decision-making. The Board meets in Washington, DC, for two days every other month... FEDERAL ACCOUNTING STANDARDS ADVISORY BOARD Call for Candidates AGENCY: Federal Accounting... candidates. Any applicant who provided the Federal Accounting Standards Advisory Board (FASAB or the Board...

  17. Evaluating historical candidate genes for schizophrenia

    DEFF Research Database (Denmark)

    Farrell, M S; Werge, T; Sklar, P

    2015-01-01

    Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of thes...

  18. 11 CFR 9003.2 - Candidate certifications.

    Science.gov (United States)

    2010-01-01

    ... funds under 11 CFR 9003.2(c)(3) shall not count against such candidate's $50,000 expenditure limitation... expenditures. (8) Expenditures made using a credit card for which the candidate is jointly or solely liable will count against the limits of this section to the extent that the full amount due, including any...

  19. Transforming fragments into candidates: small becomes big in medicinal chemistry.

    Science.gov (United States)

    de Kloe, Gerdien E; Bailey, David; Leurs, Rob; de Esch, Iwan J P

    2009-07-01

    Fragment-based drug discovery (FBDD) represents a logical and efficient approach to lead discovery and optimisation. It can draw on structural, biophysical and biochemical data, incorporating a wide range of inputs, from precise mode-of-binding information on specific fragments to wider ranging pharmacophoric screening surveys using traditional HTS approaches. It is truly an enabling technology for the imaginative medicinal chemist. In this review, we analyse a representative set of 23 published FBDD studies that describe how low molecular weight fragments are being identified and efficiently transformed into higher molecular weight drug candidates. FBDD is now becoming warmly endorsed by industry as well as academia and the focus on small interacting molecules is making a big scientific impact.

  20. Candidate genes for COPD: current evidence and research

    Directory of Open Access Journals (Sweden)

    Kim WJ

    2015-10-01

    Full Text Available Woo Jin Kim,1 Sang Do Lee2 1Department of Internal Medicine and Environmental Health Center, Kangwon National University, Chuncheon, 2Department of Pulmonary and Critical Care Medicine, Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea Abstract: COPD is a common complex disease characterized by progressive airflow limitation. Several genome-wide association studies (GWASs have discovered genes that are associated with COPD. Recently, candidate genes for COPD identified by GWASs include CHRNA3/5 (cholinergic nicotine receptor alpha 3/5, IREB2 (iron regulatory binding protein 2, HHIP (hedgehog-interacting protein, FAM13A (family with sequence similarity 13, member A, and AGER (advanced glycosylation end product–specific receptor. Their association with COPD susceptibility has been replicated in multiple populations. Since these candidate genes have not been considered in COPD, their pathological roles are still largely unknown. Herein, we review some evidences that they can be effective drug targets or serve as biomarkers for diagnosis or subtyping. However, more study is required to understand the functional roles of these candidate genes. Future research is needed to characterize the effect of genetic variants, validate gene function in humans and model systems, and elucidate the genes’ transcriptional and posttranscriptional regulatory mechanisms. Keywords: chronic obstructive pulmonary disease, genetics, genome-wide association study

  1. Extensively Drug-Resistant TB

    Centers for Disease Control (CDC) Podcasts

    2016-12-16

    Dr. Charlotte Kvasnovsky, a surgery resident and Ph.D. candidate in biostatistics, discusses various types of drug resistance in TB patients in South Africa.  Created: 12/16/2016 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 12/16/2016.

  2. Assessing pharmacologic and nonpharmacologic risks in candidates for kidney transplantation.

    Science.gov (United States)

    Maldonado, Angela Q; Tichy, Eric M; Rogers, Christin C; Campara, Maya; Ensor, Christopher; Doligalski, Christina T; Gabardi, Steven; Descourouez, Jillian L; Doyle, Ian C; Trofe-Clark, Jennifer

    2015-05-15

    Pharmacotherapy concerns and other factors with a bearing on patient selection for kidney transplantation are discussed. The process of selecting appropriate candidates for kidney transplantation involves multidisciplinary assessment to evaluate a patient's mental, social, physical, financial, and medical readiness for successful surgery and good posttransplantation outcomes. Transplantation pharmacists can play important roles in the recognition and stratification of pharmacologic and nonpharmacologic risks in prospective kidney transplant recipients and the identification of issues that require a mitigation strategy. Key pharmacotherapy-related issues and considerations during the risk assessment process include (1) anticoagulation concerns, (2) cytochrome P-450 isoenzyme-mediated drug interactions, (3) mental health-related medication use, (4) chronic pain-related medication use, (5) medication allergies, (6) use of hormonal contraception and replacement therapy, (7) prior or current use of immunosuppressants, (8) issues with drug absorption, (9) alcohol use, (10) tobacco use, (11) active use of illicit substances, and (12) use of herbal supplements. Important areas of nonpharmacologic risk include vaccine delivery, infection prophylaxis and treatment, and socially related factors such as nonadherent behavior, communication barriers, and financial, insurance, or transportation challenges that can compromise posttransplantation outcomes. Consensus opinions of practitioners in transplantation pharmacy regarding the pharmacologic and nonpharmacologic factors that should be considered in assessing candidates for kidney transplantation are presented. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  3. Safety Lead Optimization and Candidate Identification: Integrating New Technologies into Decision-Making.

    Science.gov (United States)

    Dambach, Donna M; Misner, Dinah; Brock, Mathew; Fullerton, Aaron; Proctor, William; Maher, Jonathan; Lee, Dong; Ford, Kevin; Diaz, Dolores

    2016-04-18

    Discovery toxicology focuses on the identification of the most promising drug candidates through the development and implementation of lead optimization strategies and hypothesis-driven investigation of issues that enable rational and informed decision-making. The major goals are to [a] identify and progress the drug candidate with the best overall drug safety profile for a therapeutic area, [b] remove the most toxic drugs from the portfolio prior to entry into humans to reduce clinical attrition due to toxicity, and [c] establish a well-characterized hazard and translational risk profile to enable clinical trial designs. This is accomplished through a framework that balances the multiple considerations to identify a drug candidate with the overall best drug characteristics and provides a cogent understanding of mechanisms of toxicity. The framework components include establishing a target candidate profile for each program that defines the qualities of a successful candidate based on the intended therapeutic area, including the risk tolerance for liabilities; evaluating potential liabilities that may result from engaging the therapeutic target (pharmacology-mediated or on-target) and that are chemical structure-mediated (off-target); and characterizing identified liabilities. Lead optimization and investigation relies upon the integrated use of a variety of technologies and models (in silico, in vitro, and in vivo) that have achieved a sufficient level of qualification or validation to provide confidence in their use. We describe the strategic applications of various nonclinical models (established and new) for a holistic and integrated risk assessment that is used for rational decision-making. While this review focuses on strategies for small molecules, the overall concepts, approaches, and technologies are generally applicable to biotherapeutics.

  4. Quantitative decisions in drug development

    CERN Document Server

    Chuang-Stein, Christy

    2017-01-01

    This book offers a high-level treatise of evidence-based decisions in drug development. Because of the inseparable relationship between designs and decisions, a good portion of this book is devoted to the design of clinical trials. The book begins with an overview of product development and regulatory approval pathways. It then discusses how to incorporate prior knowledge into study design and decision making at different stages of drug development. The latter include selecting appropriate metrics to formulate decisions criteria, determining go/no-go decisions for progressing a drug candidate to the next stage and predicting the effectiveness of a product. Lastly, it points out common mistakes made by drug developers under the current drug-development paradigm. The book offers useful insights to statisticians, clinicians, regulatory affairs managers and decision-makers in the pharmaceutical industry who have a basic understanding of the drug-development process and the clinical trials conducted to support dru...

  5. New Zealand’s Drug Development Industry

    Directory of Open Access Journals (Sweden)

    Christopher Carswell

    2013-09-01

    Full Text Available The pharmaceutical industry’s profitability depends on identifying and successfully developing new drug candidates while trying to contain the increasing costs of drug development. It is actively searching for new sources of innovative compounds and for mechanisms to reduce the enormous costs of developing new drug candidates. There is an opportunity for academia to further develop as a source of drug discovery. The rising levels of industry outsourcing also provide prospects for organisations that can reduce the costs of drug development. We explored the potential returns to New Zealand (NZ from its drug discovery expertise by assuming a drug development candidate is out-licensed without clinical data and has anticipated peak global sales of $350 million. We also estimated the revenue from NZ’s clinical research industry based on a standard per participant payment to study sites and the number of industry-sponsored clinical trials approved each year. Our analyses found that NZ’s clinical research industry has generated increasing foreign revenue and appropriate policy support could ensure that this continues to grow. In addition the probability-based revenue from the out-licensing of a drug development candidate could be important for NZ if provided with appropriate policy and financial support.

  6. Drug allergies

    Science.gov (United States)

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The first time ...

  7. Study Drugs

    Science.gov (United States)

    ... to quit, they may have withdrawal symptoms like depression, thoughts of suicide, intense drug cravings, sleep problems, and fatigue. The health risks aren't the only downside to study drugs. Students caught with illegal prescription drugs may get suspended ...

  8. Drug Facts

    Medline Plus

    Full Text Available ... symptoms of someone with a drug use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to ...

  9. Drug Facts

    Medline Plus

    Full Text Available ... Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen ... to prescription drugs. The addiction slowly took over his life. I need different people around me. To ...

  10. Drug Reactions

    Science.gov (United States)

    ... problem is interactions, which may occur between Two drugs, such as aspirin and blood thinners Drugs and food, such as statins and grapefruit Drugs and supplements, such as ginkgo and blood thinners ...

  11. Drug Facts

    Science.gov (United States)

    ... Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol ...

  12. Seasonal variation of gastroprotective terpenoids in Maytenus robusta (Celastraceae) quantified by gas chromatography-flame ionization detection (GC-FID).

    Science.gov (United States)

    Zermiani, Tailyn; Junior, Antonio A S; Ferreira, Renê A; Wagner, Theodoro M; Machado, Marina S; Cechinel-Filho, Valdir; Niero, Rivaldo

    2016-11-01

    The triterpenes friedelin (1), β-friedelinol (2) and 3,15-dioxo-21α-hydroxyfriedelane (3) in the aerial parts of Maytenus robusta, a Brazilian medicinal plant with antiulcer potential, were seasonally quantified by gas chromatography flame-ionization detection (GC-FID) using an external standard. The method was found to be linear, precise and sensitive. Compounds 1 and 2 were found in M. robusta leaves and branches, with highest concentrations in the leaves collected in autumn, i.e. 3.21 ± 0.16 and 12.60 ± 1.49 mg g-1 dry weight of 1 and 2, respectively. On the other hand, compound 3 was found only in the branches, with the highest concentrations in winter and autumn (0.21 ± 0.01 and 0.20 ± 0.02 mg g-1). The results allow to define the optimal season and plant parts for the collection of M. robusta as a phytotherapeutic drug.

  13. 76 FR 4896 - Call for Candidates

    Science.gov (United States)

    2011-01-27

    ... designated to establish generally accepted accounting principles for federal government entities. Generally, non-federal Board members are selected from the general financial community, the accounting and... FEDERAL ACCOUNTING STANDARDS ADVISORY BOARD Call for Candidates AGENCY: Federal Accounting...

  14. Updated candidate list for engineered barrier materials

    International Nuclear Information System (INIS)

    McCright, R.D.

    1995-10-01

    This report describes candidate materials to be evaluated over the next several years during advanced design phases for the waste package to be used for the underground disposal of high-level radioactive wastes at the Yucca Mountain facility

  15. Characterization of nanoparticles as candidate reference materials

    International Nuclear Information System (INIS)

    Martins Ferreira, E.H.; Robertis, E. de; Landi, S.M.; Gouvea, C.P.; Archanjo, B.S.; Almeida, C.A.; Araujo, J.R. de; Kuznetsov, O.; Achete, C.A.

    2013-01-01

    We report the characterization of three different nanoparticles (silica, silver and multi-walled carbon nanotubes) as candidate reference material. We focus our analysis on the size distribution of those particles as measured by different microscopy techniques. (author)

  16. Indico CONFERENCE: Candidate participant's registration/application

    CERN Multimedia

    CERN. Geneva; Ferreira, Pedro

    2017-01-01

    In this tutorial you are going to learn how to apply as a candidate participant (if the event requires approval from the event manager) or to register (if participation to the event doesn't require approval from an event manager) to the conference using the registration form for the event. You are also going to learn how to approve a candidate participant's application as an event manager.

  17. Do People 'Like' Candidates on Facebook?

    DEFF Research Database (Denmark)

    Nielsen, Rasmus Kleis

    The online popularity of a few exceptional candidates has led many to suggest that social media have given politicians powerful ways of communicating directly with voters. In this paper, we examine whether this is happening on a significant scale and show, based on analysis of 224 candidates....... We therefore suggest that the political implications of social media are generally better understood in terms of facilitating indirect communication and institutional change than in terms of direct communication....

  18. Amorphous drugs and dosage forms

    DEFF Research Database (Denmark)

    Grohganz, Holger; Löbmann, K.; Priemel, P.

    2013-01-01

    The transformation to an amorphous form is one of the most promising approaches to address the low solubility of drug compounds, the latter being an increasing challenge in the development of new drug candidates. However, amorphous forms are high energy solids and tend to recry stallize. New...... formulation principles are needed to ensure the stability of amorphous drug forms. The formation of solid dispersions is still the most investigated approach, but additional approaches are desirable to overcome the shortcomings of solid dispersions. Spatial separation by either coating or the use of micro-containers...... before single molecules are available for the formation of crystal nuclei, thus stabilizing the amorphous form....

  19. A New Way to Confirm Planet Candidates

    Science.gov (United States)

    Kohler, Susanna

    2016-05-01

    What was the big deal behind the Kepler news conference yesterday? Its not just that the number of confirmed planets found by Kepler has more than doubled (though thats certainly exciting news!). Whats especially interesting is the way in which these new planets were confirmed.Number of planet discoveries by year since 1995, including previous non-Kepler discoveries (blue), previous Kepler discoveries (light blue) and the newly validated Kepler planets (orange). [NASA Ames/W. Stenzel; Princeton University/T. Morton]No Need for Follow-UpBefore Kepler, the way we confirmed planet candidates was with follow-up observations. The candidate could be validated either by directly imaging (which is rare) or obtaining a large number radial-velocity measurements of the wobble of the planets host star due to the planets orbit. But once Kepler started producing planet candidates, these approaches to validation became less feasible. A lot of Kepler candidates are small and orbit faint stars, making follow-up observations difficult or impossible.This problem is what inspired the development of whats known as probabilistic validation, an analysis technique that involves assessing the likelihood that the candidates signal is caused by various false-positive scenarios. Using this technique allows astronomers to estimate the likelihood of a candidate signal being a true planet detection; if that likelihood is high enough, the planet candidate can be confirmed without the need for follow-up observations.A breakdown of the catalog of Kepler Objects of Interest. Just over half had previously been identified as false positives or confirmed as candidates. 1284 are newly validated, and another 455 have FPP of1090%. [Morton et al. 2016]Probabilistic validation has been used in the past to confirm individual planet candidates in Kepler data, but now Timothy Morton (Princeton University) and collaborators have taken this to a new level: they developed the first code thats designed to do fully

  20. Transcriptome sequence analysis of an ornamental plant, Ananas comosus var. bracteatus, revealed the potential unigenes involved in terpenoid and phenylpropanoid biosynthesis.

    Science.gov (United States)

    Ma, Jun; Kanakala, S; He, Yehua; Zhang, Junli; Zhong, Xiaolan

    2015-01-01

    Ananas comosus var. bracteatus (Red Pineapple) is an important ornamental plant for its colorful leaves and decorative red fruits. Because of its complex genome, it is difficult to understand the molecular mechanisms involved in the growth and development. Thus high-throughput transcriptome sequencing of Ananas comosus var. bracteatus is necessary to generate large quantities of transcript sequences for the purpose of gene discovery and functional genomic studies. The Ananas comosus var. bracteatus transcriptome was sequenced by the Illumina paired-end sequencing technology. We obtained a total of 23.5 million high quality sequencing reads, 1,555,808 contigs and 41,052 unigenes. In total 41,052 unigenes of Ananas comosus var. bracteatus, 23,275 unigenes were annotated in the NCBI non-redundant protein database and 23,134 unigenes were annotated in the Swiss-Port database. Out of these, 17,748 and 8,505 unigenes were assigned to gene ontology categories and clusters of orthologous groups, respectively. Functional annotation against Kyoto Encyclopedia of Genes and Genomes Pathway database identified 5,825 unigenes which were mapped to 117 pathways. The assembly predicted many unigenes that were previously unknown. The annotated unigenes were compared against pineapple, rice, maize, Arabidopsis, and sorghum. Unigenes that did not match any of those five sequence datasets are considered to be Ananas comosus var. bracteatus unique. We predicted unigenes encoding enzymes involved in terpenoid and phenylpropanoid biosynthesis. The sequence data provide the most comprehensive transcriptomic resource currently available for Ananas comosus var. bracteatus. To our knowledge; this is the first report on the de novo transcriptome sequencing of the Ananas comosus var. bracteatus. Unigenes obtained in this study, may help improve future gene expression, genetic and genomics studies in Ananas comosus var. bracteatus.

  1. Transcriptome sequence analysis of an ornamental plant, Ananas comosus var. bracteatus, revealed the potential unigenes involved in terpenoid and phenylpropanoid biosynthesis.

    Directory of Open Access Journals (Sweden)

    Jun Ma

    Full Text Available Ananas comosus var. bracteatus (Red Pineapple is an important ornamental plant for its colorful leaves and decorative red fruits. Because of its complex genome, it is difficult to understand the molecular mechanisms involved in the growth and development. Thus high-throughput transcriptome sequencing of Ananas comosus var. bracteatus is necessary to generate large quantities of transcript sequences for the purpose of gene discovery and functional genomic studies.The Ananas comosus var. bracteatus transcriptome was sequenced by the Illumina paired-end sequencing technology. We obtained a total of 23.5 million high quality sequencing reads, 1,555,808 contigs and 41,052 unigenes. In total 41,052 unigenes of Ananas comosus var. bracteatus, 23,275 unigenes were annotated in the NCBI non-redundant protein database and 23,134 unigenes were annotated in the Swiss-Port database. Out of these, 17,748 and 8,505 unigenes were assigned to gene ontology categories and clusters of orthologous groups, respectively. Functional annotation against Kyoto Encyclopedia of Genes and Genomes Pathway database identified 5,825 unigenes which were mapped to 117 pathways. The assembly predicted many unigenes that were previously unknown. The annotated unigenes were compared against pineapple, rice, maize, Arabidopsis, and sorghum. Unigenes that did not match any of those five sequence datasets are considered to be Ananas comosus var. bracteatus unique. We predicted unigenes encoding enzymes involved in terpenoid and phenylpropanoid biosynthesis.The sequence data provide the most comprehensive transcriptomic resource currently available for Ananas comosus var. bracteatus. To our knowledge; this is the first report on the de novo transcriptome sequencing of the Ananas comosus var. bracteatus. Unigenes obtained in this study, may help improve future gene expression, genetic and genomics studies in Ananas comosus var. bracteatus.

  2. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug Treatment Work? What Are the Treatment Options? What Is Recovery? ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... 4357) at any time to find drug treatment centers near you. I want my daughter to avoid drugs. "Debbie" has been drug-free for years. She wants her daughter to stay away from drugs. But she's afraid ...

  4. Nanosuspension Technology for Solubilizing Poorly Soluble Drugs

    OpenAIRE

    Deoli Mukesh

    2012-01-01

    Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. It is estimated that around 40% of drugs in the pipeline cannot be delivered through the preferred route or in some cases, at all owing to poor water solubility. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor1 EL). To date, nanoscale systems f...

  5. An invertebrate model for CNS drug discovery

    DEFF Research Database (Denmark)

    Al-Qadi, Sonia; Schiøtt, Morten; Hansen, Steen Honoré

    2015-01-01

    BACKGROUND: ABC efflux transporters at the blood brain barrier (BBB), namely the P-glycoprotein (P-gp), restrain the development of central nervous system (CNS) drugs. Consequently, early screening of CNS drug candidates is pivotal to identify those affected by efflux activity. Therefore, simple,...... barriers. CONCLUSION: Findings suggest a conserved mechanism of brain efflux activity between insects and vertebrates, confirming that this model holds promise for inexpensive and high-throughput screening relative to in vivo models, for CNS drug discovery....

  6. Nanoformulations and Clinical Trial Candidates as Probably ...

    African Journals Online (AJOL)

    Encapsulation of existing anti-TB drugs into nano-delivery systems and introduction of new drugs in combination treatment for all forms of tuberculosis have resulted in novel treatments with more effectiveness and reduced side effects. Keywords: Tuberculosis, Nanotechnology, Anti-tuberculosis drugs, Nano carriers, ...

  7. JELLYFISH GALAXY CANDIDATES AT LOW REDSHIFT

    Energy Technology Data Exchange (ETDEWEB)

    Poggianti, B. M.; Fasano, G.; Omizzolo, A.; Gullieuszik, M.; Bettoni, D.; Paccagnella, A. [INAF-Astronomical Observatory of Padova (Italy); Moretti, A.; D’Onofrio, M. [Physics and Astronomy Department, University of Padova (Italy); Jaffé, Y. L. [Department of Astronomy, Universidad de Concepción, Concepción (Chile); Vulcani, B. [Kavli Institute for the Physics and Mathematics of the universe (WPI), The University of Tokyo Institutes for Advanced Study (UTIAS), the University of Tokyo, Kashiwa, 277-8582 (Japan); Fritz, J. [Centro de Radioastronomía y Astrofísica, CRyA, UNAM, Michoacán (Mexico); Couch, W. [Australian Astronomical Observatory, North Ryde, NSW 1670 (Australia)

    2016-03-15

    Galaxies that are being stripped of their gas can sometimes be recognized from their optical appearance. Extreme examples of stripped galaxies are the so-called “jellyfish galaxies” that exhibit tentacles of debris material with a characteristic jellyfish morphology. We have conducted the first systematic search for galaxies that are being stripped of their gas at low-z (z = 0.04−0.07) in different environments, selecting galaxies with varying degrees of morphological evidence for stripping. We have visually inspected B- and V-band images and identified 344 candidates in 71 galaxy clusters of the OMEGAWINGS+WINGS sample and 75 candidates in groups and lower mass structures in the PM2GC sample. We present the atlas of stripping candidates and a first analysis of their environment and their basic properties, such as morphologies, star formation rates and galaxy stellar masses. Candidates are found in all clusters and at all clustercentric radii, and their number does not correlate with the cluster velocity dispersion σ or X-ray luminosity L{sub X}. Interestingly, convincing cases of candidates are also found in groups and lower mass halos (10{sup 11}−10{sup 14}M{sub ⊙}), although the physical mechanism at work needs to be securely identified. All the candidates are disky, have stellar masses ranging from log M/M{sub ⊙} < 9 to > 11.5 and the majority of them form stars at a rate that is on average a factor of 2 higher (2.5σ) compared to non-stripped galaxies of similar mass. The few post-starburst and passive candidates have weak stripping evidence. We conclude that disturbed morphologies suggestive of stripping phenomena are ubiquitous in clusters and could be present even in groups and low mass halos. Further studies will reveal the physics of the gas stripping and clarify the mechanisms at work.

  8. Scalar tetraquark candidates on the lattice

    International Nuclear Information System (INIS)

    Berlin, Joshua

    2017-01-01

    The topic of this thesis is the investigation of scalar tetraquark candidates from lattice QCD. It is motivated by a previous study originating in the twisted mass collaboration. The initial tetraquark candidate of choice is the a 0 (980), an isovector in the nonet of light scalars (J P =0 + ). This channel is still poorly understood. It displays an inverted mass hierarchy to what is expected from the conventional quark model and the a 0 (980) and f 0 (980) feature a surprising mass degeneracy. For this reasons the a 0 (980) is a long assumed tetraquark candidate in the literature. We follow a methodological approach by studying the sensitivity of the scalar spectrum with fully dynamical quarks to a large basis of two-quark and four-quark creation operators. Ultimately, the candidate has to be identified in the direct vicinity of two two-particles states, which is understandably inevitable for a tetraquark candidate. To succeed in this difficult task two-meson creation operators are essential to employ in this channel. By localized four-quark operators we intend to probe the Hamiltonian on eigenstates with a closely bound four-quark structure.

  9. Scalar tetraquark candidates on the lattice

    Energy Technology Data Exchange (ETDEWEB)

    Berlin, Joshua

    2017-07-01

    The topic of this thesis is the investigation of scalar tetraquark candidates from lattice QCD. It is motivated by a previous study originating in the twisted mass collaboration. The initial tetraquark candidate of choice is the a{sub 0}(980), an isovector in the nonet of light scalars (J{sup P}=0{sup +}). This channel is still poorly understood. It displays an inverted mass hierarchy to what is expected from the conventional quark model and the a{sub 0}(980) and f{sub 0}(980) feature a surprising mass degeneracy. For this reasons the a{sub 0}(980) is a long assumed tetraquark candidate in the literature. We follow a methodological approach by studying the sensitivity of the scalar spectrum with fully dynamical quarks to a large basis of two-quark and four-quark creation operators. Ultimately, the candidate has to be identified in the direct vicinity of two two-particles states, which is understandably inevitable for a tetraquark candidate. To succeed in this difficult task two-meson creation operators are essential to employ in this channel. By localized four-quark operators we intend to probe the Hamiltonian on eigenstates with a closely bound four-quark structure.

  10. Probing cardiac repolarization reserve in drug safety assessment

    NARCIS (Netherlands)

    Nalos, L.

    2011-01-01

    Excessive prolongation of cardiac repolarization, manifested as QT prolongation on ECG, is common unwanted side effect of many drugs and drug candidates. Prolongation of QT interval may lead to life threatening cardiac arrhythmia – Torsade de Point (TdP). Number of drugs was withdrawn from the

  11. Developing Potential Candidates of Preclinical Preeclampsia

    Directory of Open Access Journals (Sweden)

    Sandra Founds

    2015-11-01

    Full Text Available The potential for developing molecules of interest in preclinical preeclampsia from candidate genes that were discovered on gene expression microarray analysis has been challenged by limited access to additional first trimester trophoblast and decidual tissues. The question of whether these candidates encode secreted proteins that may be detected in maternal circulation early in pregnancy has been investigated using various proteomic methods. Pilot studies utilizing mass spectrometry based proteomic assays, along with enzyme linked immunosorbent assays (ELISAs, and Western immunoblotting in first trimester samples are reported. The novel targeted mass spectrometry methods led to robust multiple reaction monitoring assays. Despite detection of several candidates in early gestation, challenges persist. Future antibody-based studies may lead to a novel multiplex protein panel for screening or detection to prevent or mitigate preeclampsia.

  12. Substance use - prescription drugs

    Science.gov (United States)

    Substance use disorder - prescription drugs; Substance abuse - prescription drugs; Drug abuse - prescription drugs; Drug use - prescription drugs; Narcotics - substance use; Opioid - substance use; Sedative - substance ...

  13. Issue-Advocacy versus Candidate Advertising: Effects on Candidate Preferences and Democratic Process.

    Science.gov (United States)

    Pfau, Michael; Holbert, R. Lance; Szabo, Erin Alison; Kaminski, Kelly

    2002-01-01

    Examines the influence of soft-money-sponsored issue-advocacy advertising in U.S. House and Senate campaigns, comparing its effects against candidate-sponsored positive advertising and contrast advertising on viewers' candidate preferences and on their attitude that reflect democratic values. Reveals no main effects for advertising approach on…

  14. Curcumin, a potential therapeutic candidate for retinal diseases.

    Science.gov (United States)

    Wang, Lei-Lei; Sun, Yue; Huang, Kun; Zheng, Ling

    2013-09-01

    Curcumin, the major extraction of turmeric, has been widely used in many countries for centuries both as a spice and as a medicine. In the last decade, researchers have found the beneficial effects of curcumin on multiple disorders are due to its antioxidative, anti-inflammatory, and antiproliferative properties, as well as its novel function as an inhibitor of histone aectyltransferases. In this review, we summarize the recent progress made on studying the beneficial effects of curcumin on multiple retinal diseases, including diabetic retinopathy, glaucoma, and age-related macular degeneration. Recent clinical trials on the effectiveness of phosphatidylcholine formulated curcumin in treating eye diseases have also shown promising results, making curcumin a potent therapeutic drug candidate for inflammatory and degenerative retinal and eye diseases. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Identifying candidate driver genes by integrative ovarian cancer genomics data

    Science.gov (United States)

    Lu, Xinguo; Lu, Jibo

    2017-08-01

    Integrative analysis of molecular mechanics underlying cancer can distinguish interactions that cannot be revealed based on one kind of data for the appropriate diagnosis and treatment of cancer patients. Tumor samples exhibit heterogeneity in omics data, such as somatic mutations, Copy Number Variations CNVs), gene expression profiles and so on. In this paper we combined gene co-expression modules and mutation modulators separately in tumor patients to obtain the candidate driver genes for resistant and sensitive tumor from the heterogeneous data. The final list of modulators identified are well known in biological processes associated with ovarian cancer, such as CCL17, CACTIN, CCL16, CCL22, APOB, KDF1, CCL11, HNF1B, LRG1, MED1 and so on, which can help to facilitate the discovery of biomarkers, molecular diagnostics, and drug discovery.

  16. Drug Facts

    Medline Plus

    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can ...

  17. Prescription Drugs

    Science.gov (United States)

    ... different competition is going on: the National Football League (NFL) vs. drug use. Read More » 92 Comments ... Future survey highlights drug use trends among the Nation’s youth for marijuana, alcohol, cigarettes, e-cigarettes (e- ...

  18. Drug Facts

    Medline Plus

    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth ... 662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter ...

  19. Drug Facts

    Medline Plus

    Full Text Available ... form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts ... addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain ...

  20. Drug Facts

    Medline Plus

    Full Text Available ... Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs of ... Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call 1- ...

  1. Drug Control

    Science.gov (United States)

    Leviton, Harvey S.

    1975-01-01

    This article attempts to assemble pertinent information about the drug problem, particularily marihuana. It also focuses on the need for an educational program for drug control with the public schools as the main arena. (Author/HMV)

  2. Drug Facts

    Medline Plus

    Full Text Available ... Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs ... Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... Nicotine Facts Other Drugs of Abuse What is Addiction? What are some signs and symptoms of someone ... use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely to Get Addicted ...

  4. Drug Facts

    Medline Plus

    Full Text Available ... Numbers and Websites Search Share Listen English Español Information about this page Click on the button that ... about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana ...

  5. Drug Facts

    Medline Plus

    Full Text Available ... Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) ... treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice ( ...

  6. Drug Facts

    Medline Plus

    Full Text Available ... call 1-800-662-HELP (4357) at any time to find drug treatment centers near you. I ... The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , the ...

  7. Small Molecule Screen for Candidate Antimalarials Targeting Plasmodium Kinesin-5*

    Science.gov (United States)

    Liu, Liqiong; Richard, Jessica; Kim, Sunyoung; Wojcik, Edward J.

    2014-01-01

    Plasmodium falciparum and vivax are responsible for the majority of malaria infections worldwide, resulting in over a million deaths annually. Malaria parasites now show measured resistance to all currently utilized drugs. Novel antimalarial drugs are urgently needed. The Plasmodium Kinesin-5 mechanoenzyme is a suitable “next generation” target. Discovered via small molecule screen experiments, the human Kinesin-5 has multiple allosteric sites that are “druggable.” One site in particular, unique in its sequence divergence across all homologs in the superfamily and even within the same family, exhibits exquisite drug specificity. We propose that Plasmodium Kinesin-5 shares this allosteric site and likewise can be targeted to uncover inhibitors with high specificity. To test this idea, we performed a screen for inhibitors selective for Plasmodium Kinesin-5 ATPase activity in parallel with human Kinesin-5. Our screen of nearly 2000 compounds successfully identified compounds that selectively inhibit both P. vivax and falciparum Kinesin-5 motor domains but, as anticipated, do not impact human Kinesin-5 activity. Of note is a candidate drug that did not biochemically compete with the ATP substrate for the conserved active site or disrupt the microtubule-binding site. Together, our experiments identified MMV666693 as a selective allosteric inhibitor of Plasmodium Kinesin-5; this is the first identified protein target for the Medicines of Malaria Venture validated collection of parasite proliferation inhibitors. This work demonstrates that chemical screens against human kinesins are adaptable to homologs in disease organisms and, as such, extendable to strategies to combat infectious disease. PMID:24737313

  8. Optical observations of southern planetary nebula candidates

    NARCIS (Netherlands)

    VandeSteene, GC; Sahu, KC; Pottasch, [No Value

    1996-01-01

    We present H alpha+[NII] images and low resolution spectra of 16 IRAS-selected, southern planetary nebula candidates previously detected in the radio continuum. The H alpha+[NII] images are presented as finding charts. Contour plots are shown for the resolved planetary nebulae. From these images

  9. 47 CFR 73.1942 - Candidate rates.

    Science.gov (United States)

    2010-10-01

    ... Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) BROADCAST RADIO SERVICES RADIO BROADCAST SERVICES Rules Applicable to All Broadcast Stations § 73.1942 Candidate rates. (a) Charges for use of stations... periods. Any station practices offered to commercial advertisers that enhance the value of advertising...

  10. Candidate genes in ocular dominance plasticity

    NARCIS (Netherlands)

    Rietman, M.L.; Sommeijer, J.-P.; Levelt, C.N.; Heimel, J.A.; Brussaard, A.B.; Borst, J.G.G.; Elgersma, Y.; Galjart, N.; van der Horst, G.T.; Pennartz, C.M.; Smit, A.B.; Spruijt, B.M.; Verhage, M.; de Zeeuw, C.I.

    2012-01-01

    Many studies have been devoted to the identification of genes involved in experience-dependent plasticity in the visual cortex. To discover new candidate genes, we have reexamined data from one such study on ocular dominance (OD) plasticity in recombinant inbred BXD mouse strains. We have correlated

  11. Fuzzy Treatment of Candidate Outliers in Measurements

    Directory of Open Access Journals (Sweden)

    Giampaolo E. D'Errico

    2012-01-01

    Full Text Available Robustness against the possible occurrence of outlying observations is critical to the performance of a measurement process. Open questions relevant to statistical testing for candidate outliers are reviewed. A novel fuzzy logic approach is developed and exemplified in a metrology context. A simulation procedure is presented and discussed by comparing fuzzy versus probabilistic models.

  12. Gallium-67 imaging in candidal esophagitis

    International Nuclear Information System (INIS)

    Rundback, J.H.; Goldfarb, C.R.; Ongseng, F.

    1990-01-01

    Ga-67 scanning has been used to evaluate esophageal carcinoma. It has demonstrated candidal infection in other body sites and, in one previous case, in the esophagus. The authors present a case of diffuse esophageal uptake of Ga-67 in esophageal candidiasis

  13. Gallium-67 imaging in candidal esophagitis

    Energy Technology Data Exchange (ETDEWEB)

    Rundback, J.H.; Goldfarb, C.R.; Ongseng, F. (Beth Israel Medical Center, New York, NY (USA))

    1990-01-01

    Ga-67 scanning has been used to evaluate esophageal carcinoma. It has demonstrated candidal infection in other body sites and, in one previous case, in the esophagus. The authors present a case of diffuse esophageal uptake of Ga-67 in esophageal candidiasis.

  14. Towards Treating Chemistry Teacher Candidates as Human

    Science.gov (United States)

    Lewthwaite, Brian Ellis

    2008-01-01

    This research inquiry investigates the factors influencing chemistry teacher candidates' development during their extended practica in the second and final year of an After-Degree Bachelor of Education at a university in central Canada. A variety of data sources are used to identify the risk and protective factors impeding and contributing to the…

  15. Promoting Team Leadership Skills in Doctoral Candidates

    Science.gov (United States)

    Suleiman, Mahmoud; Whetton, Danny

    2014-01-01

    Doctoral programs can serve as an optimal opportunity for candidates to engage in tasks and activities to transform them and their schools. The paradigm shifts in such preparation involve moving from sitting and getting to making and taking. Most importantly, it requires building leadership skills and styles necessary to bring about desired change…

  16. Query by image example: The CANDID approach

    Energy Technology Data Exchange (ETDEWEB)

    Kelly, P.M.; Cannon, M. [Los Alamos National Lab., NM (United States). Computer Research and Applications Group; Hush, D.R. [Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Electrical and Computer Engineering

    1995-02-01

    CANDID (Comparison Algorithm for Navigating Digital Image Databases) was developed to enable content-based retrieval of digital imagery from large databases using a query-by-example methodology. A user provides an example image to the system, and images in the database that are similar to that example are retrieved. The development of CANDID was inspired by the N-gram approach to document fingerprinting, where a ``global signature`` is computed for every document in a database and these signatures are compared to one another to determine the similarity between any two documents. CANDID computes a global signature for every image in a database, where the signature is derived from various image features such as localized texture, shape, or color information. A distance between probability density functions of feature vectors is then used to compare signatures. In this paper, the authors present CANDID and highlight two results from their current research: subtracting a ``background`` signature from every signature in a database in an attempt to improve system performance when using inner-product similarity measures, and visualizing the contribution of individual pixels in the matching process. These ideas are applicable to any histogram-based comparison technique.

  17. Waiting narratives of lung transplant candidates.

    Science.gov (United States)

    Yelle, Maria T; Stevens, Patricia E; Lanuza, Dorothy M

    2013-01-01

    Before 2005, time accrued on the lung transplant waiting list counted towards who was next in line for a donor lung. Then in 2005 the lung allocation scoring system was implemented, which meant the higher the illness severity scores, the higher the priority on the transplant list. Little is known of the lung transplant candidates who were listed before 2005 and were caught in the transition when the lung allocation scoring system was implemented. A narrative analysis was conducted to explore the illness narratives of seven lung transplant candidates between 2006 and 2007. Arthur Kleinman's concept of illness narratives was used as a conceptual framework for this study to give voice to the illness narratives of lung transplant candidates. Results of this study illustrate that lung transplant candidates expressed a need to tell their personal story of waiting and to be heard. Recommendation from this study calls for healthcare providers to create the time to enable illness narratives of the suffering of waiting to be told. Narrative skills of listening to stories of emotional suffering would enhance how healthcare providers could attend to patients' stories and hear what is most meaningful in their lives.

  18. Waiting Narratives of Lung Transplant Candidates

    Directory of Open Access Journals (Sweden)

    Maria T. Yelle

    2013-01-01

    Full Text Available Before 2005, time accrued on the lung transplant waiting list counted towards who was next in line for a donor lung. Then in 2005 the lung allocation scoring system was implemented, which meant the higher the illness severity scores, the higher the priority on the transplant list. Little is known of the lung transplant candidates who were listed before 2005 and were caught in the transition when the lung allocation scoring system was implemented. A narrative analysis was conducted to explore the illness narratives of seven lung transplant candidates between 2006 and 2007. Arthur Kleinman’s concept of illness narratives was used as a conceptual framework for this study to give voice to the illness narratives of lung transplant candidates. Results of this study illustrate that lung transplant candidates expressed a need to tell their personal story of waiting and to be heard. Recommendation from this study calls for healthcare providers to create the time to enable illness narratives of the suffering of waiting to be told. Narrative skills of listening to stories of emotional suffering would enhance how healthcare providers could attend to patients’ stories and hear what is most meaningful in their lives.

  19. Orphan drugs

    OpenAIRE

    Goločorbin-Kon, Svetlana; Vojinović, Aleksandra; Lalić-Popović, Mladena; Pavlović, Nebojša; Mikov, Momir

    2013-01-01

    Introduction. Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in ”adopting” them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of ...

  20. Drug Testing

    Science.gov (United States)

    ... testing, substance abuse testing, toxicology screen, tox screen, sports doping tests What is it used for? Drug screening is used to find out whether or not a person has taken a certain drug or drugs. It ... Sports organizations. Professional and collegiate athletes usually need to ...

  1. Drug Facts

    Medline Plus

    Full Text Available ... to main content Easy-to-Read Drug Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts ... Past Drug Use Prevention Phone Numbers and Websites Search Share Listen English Español Information about this page ...

  2. Drug Facts

    Medline Plus

    Full Text Available ... can call 1-800-662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter to avoid drugs. "Debbie" has been drug-free for years. She wants her daughter to stay away from ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... the computer will read the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos ... I want my daughter to avoid drugs. "Debbie" has been drug-free for years. She wants her daughter to stay away from ...

  4. Drug Facts

    Medline Plus

    Full Text Available ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs ... adicción. English Español About the National Institute on Drug Abuse (NIDA) | About This Website Tools and Resources | Contact ...

  5. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug Treatment Work? What Are the Treatment Options? What Is Recovery? ...

  6. Drug Facts

    Medline Plus

    Full Text Available ... Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol ...

  7. Use of [2-14C]mevalonate and saponin-bound [14C]-3-hydroxy-3-methylglutaric acid for the biosynthesis of terpenoids in leaves of Dioscorea deltoidea

    International Nuclear Information System (INIS)

    Gurielidze, K.G.; Paseshnichenko, V.A.; Vasil'eva, I.S.

    1986-01-01

    After the introduction of [2- 14 C]acetate into leaves of Dioscorea deltoidea, a radioactive furonanalog of deltafolin - protodeltofolin, containing two-thirds of the label in the 3-hydroxy-3-methylglutaryl portion - was isolated from them. Radioactive β-careotene and sterols were isolated from cut young leaves of Dioscorea 24 h after the introduction of [ 14 C] protodeltofolin into them, using chromatography on a column of silica gel and precipitation of sterols in the form of digitonins for this purpose. The incorporation of radioactivity from [ 14 C]-3-hydroxy-3-methyl-glutaric acid, bound in the form of a saponin, and β-carotene came to 0.18-0.80%, while incorporation into sterols came to 0.07-2.86% of the radioactivity of the alcohol extract. Thereby it was shown that 3-hydroxyl-3-methylglutaric acid, bound in the form of the saponin, can be used to form terpenoids in Dioscorea leaves. It was suggested that the binding of hydroxymethylglutaric acid to saponin represents one of the mechanisms of regulation of the rate of terpenoid biosynthesis in Dioscorea leaves

  8. Pharmacodynamics and common drug-drug interactions of the third-generation antiepileptic drugs.

    Science.gov (United States)

    Stefanović, Srđan; Janković, Slobodan M; Novaković, Milan; Milosavljević, Marko; Folić, Marko

    2018-02-01

    Anticonvulsants that belong to the third generation are considered as 'newer' antiepileptic drugs, including: eslicarbazepine acetate, lacosamide, perampanel, brivaracetam, rufinamide and stiripentol. Areas covered: This article reviews pharmacodynamics (i.e. mechanisms of action) and clinically relevant drug-drug interactions of the third-generation antiepileptic drugs. Expert opinion: Newer antiepileptic drugs have mechanisms of action which are not shared with the first and the second generation anticonvulsants, like inhibition of neurotransmitters release, blocking receptors for excitatory amino acids and new ways of sodium channel inactivation. New mechanisms of action increase chances of controlling forms of epilepsy resistant to older anticonvulsants. Important advantage of the third-generation anticonvulsants could be their little propensity for interactions with both antiepileptic and other drugs observed until now, making prescribing much easier and safer. However, this may change with new studies specifically designed to discover drug-drug interactions. Although the third-generation antiepileptic drugs enlarged therapeutic palette against epilepsy, 20-30% of patients with epilepsy is still treatment-resistant and need new pharmacological approach. There is great need to explore all molecular targets that may directly or indirectly be involved in generation of seizures, so a number of candidate compounds for even newer anticonvulsants could be generated.

  9. Electoral Competition when Candidates are Better Informed than Voters

    DEFF Research Database (Denmark)

    Jensen, Thomas

    candidates are both completely office-motivated but differ in state-dependent quality. Voters have some information about the state but candidates are better informed. If voters' information is unknown to the candidates when they take positions and sufficiently accurate then candidates will, in refined...

  10. WAr on DrugS

    African Journals Online (AJOL)

    2009-04-12

    Apr 12, 2009 ... ABStrAct. Since drugs became both a public and social issue in Nigeria, fear about both the real and .... drugs as being morally reprehensible, and ..... tice system (see for instance, Shaw, 1995; ..... A cut throat business:.

  11. Candidate marketing takes the guessing game out of choosing employers.

    Science.gov (United States)

    Russell, Judith; Havel, Stacey

    2010-01-01

    Candidate marketing builds a foundation for relationships between employers and potential employees. Additionally, candidate marketing differentiates organizations in the marketplace. Organizations using candidate marketing to communicate the employer brand can expect a higher quality of candidates, and new employees are better prepared for the work environment and culture. Today, organizations can use a variety of integrated tools and techniques to communicate and build relationships with candidates. Candidate marketing demonstrates an organization's willingness towards transparency, and ability to invite open conversations between candidates and members of the organizations.

  12. SHORT COMMUNICATION TERPENOIDS OF BOSWELLIA ...

    African Journals Online (AJOL)

    CH3CO. Glc. 1'. 2'. 3'. 4'. 5'. 6'. 36.2. 24.8. 75.6. 44.0. 50.4. 18.3. 34.0. 41.9. 58.0. 35.0. 205.3. 132.7. 165.5. 44.3. 30.7. 26.6. 34.4. 56.5. 40.0. 43.0. 26.9. 36.9. 24.1. 182.1. 16.0. 17.2. 20.3. 68.8. 16.9. 28.8. 169.8. 20.5. 37.1. 27.7. 70.1. 43.0. 48.0. 20.0. 33.5. 39.4. 47.9. 36.9. 72.1. 122.5. 141.4. 42.1. 29.5. 25.5. 33.8. 55.7. 38.0.

  13. Terpenoid Metabolism in Plastids 1

    Science.gov (United States)

    Camara, Bilal; Bardat, Françoise; Seye, Ababacar; D'Harlingue, Alain; Monéger, René

    1982-01-01

    The synthesis of α-tocopherol from 2,3-dimethylphytylquinol and S-adenosyl-l-methionine was achieved using Capsicum annuum fruit chromoplasts. The enzymes involved in the cyclization (2,3-dimethyl-phytylquinol cyclase) and methylation (S-adenosyl methionine:γ-tocopherol methyl-transferase) are both localized in the chromoplast membrane fraction (envelopes and/or a-chlorophyll lamellae), in contrast to the stroma fraction. PMID:16662717

  14. Terpenoids from Tripterygium doianum (Celastraceae).

    Science.gov (United States)

    Tanaka, Naonobu; Duan, Hongquan; Takaishi, Yoshihisa; Kawazoe, Kazuyoshi; Goto, Satoru

    2002-09-01

    The extract of Tripterygium doianum (Celastraceae) afforded three triterpenoids [3beta-acetoxy-11-ursen-13alpha,30-olide, 25-chloro-24-hydroxytirucall-7-en-3-one and tirucall-7-en-3,24-dione], two sesquiterpenoids [5alpha-acetoxy-1beta,8alpha-bis-cinnamoyl-4alpha-hydroxydihydroagarofuran and 5alpha-acetoxy-1beta-benzoyl-8alpha-cinnamoyl-4alpha-hydroxydihydroagarofuran] and nine known triterpenoids. Their structures were established based on spectroscopic studies. Copyright 2002 Elsevier Science Ltd.

  15. Albumin-based drug delivery

    DEFF Research Database (Denmark)

    Larsen, Maja Thim; Kuhlmann, Matthias; Hvam, Michael Lykke

    2016-01-01

    The effectiveness of a drug is dependent on accumulation at the site of action at therapeutic levels, however, challenges such as rapid renal clearance, degradation or non-specific accumulation requires drug delivery enabling technologies. Albumin is a natural transport protein with multiple ligand...... binding sites, cellular receptor engagement, and a long circulatory half-life due to interaction with the recycling neonatal Fc receptor. Exploitation of these properties promotes albumin as an attractive candidate for half-life extension and targeted intracellular delivery of drugs attached by covalent...... conjugation, genetic fusions, association or ligand-mediated association. This review will give an overview of albumin-based products with focus on the natural biological properties and molecular interactions that can be harnessed for the design of a next-generation drug delivery platform....

  16. In Silico Predictions of hERG Channel Blockers in Drug Discovery

    DEFF Research Database (Denmark)

    Taboureau, Olivier; Sørensen, Flemming Steen

    2011-01-01

    The risk for cardiotoxic side effects represents a major problem in clinical studies of drug candidates and regulatory agencies have explicitly recommended that all new drug candidates should be tested for blockage of the human Ether-a-go-go Related-Gene (hERG) potassium channel. Indeed, several ...

  17. Spectroscopic follow up of Kepler planet candidates

    DEFF Research Database (Denmark)

    Latham..[], D. W.; Cochran, W. D.; Marcy, G.W.

    2010-01-01

    Spectroscopic follow-up observations play a crucial role in the confirmation and characterization of transiting planet candidates identified by Kepler. The most challenging part of this work is the determination of radial velocities with a precision approaching 1 m/s in order to derive masses from...... spectroscopic orbits. The most precious resource for this work is HIRES on Keck I, to be joined by HARPS-North on the William Herschel Telescope when that new spectrometer comes on line in two years. Because a large fraction of the planet candidates are in fact stellar systems involving eclipsing stars...... and not planets, our strategy is to start with reconnaissance spectroscopy using smaller telescopes, to sort out and reject as many of the false positives as possible before going to Keck. During the first Kepler observing season in 2009, more than 100 nights of telescope time were allocated for this work, using...

  18. Discriminating dark matter candidates using direct detection

    International Nuclear Information System (INIS)

    Belanger, G.; Nezri, E.; Pukhov, A.

    2009-01-01

    We examine the predictions for both the spin-dependent and spin-independent direct detection rates in a variety of new particle physics models with dark matter candidates. We show that a determination of both spin-independent and spin-dependent amplitudes on protons and neutrons can in principle discriminate different candidates of dark matter up to a few ambiguities. We emphasize the importance of making measurements with different spin-dependent sensitive detector materials and the need for significant improvement of the detector sensitivities. Scenarios where exchange of new colored particles contributes significantly to the elastic scattering cross sections are often the most difficult to identify, the LHC should give an indication whether such scenarios are relevant for direct detection.

  19. Warm Debris Disk Candidates from WISE

    Science.gov (United States)

    Padgett, Deborah; Stapelfeldt, Karl; Liu, Wilson; Leisawitz, David

    2011-01-01

    The Wide Field Infrared Survey Explorer (WISE) has just completed a sensitive all-sky survey in photometric bands at 3.4, 4.6, 12, and 22 microns. We report on a preliminary investigation of main sequence Hipparcos and Tycho catalog stars with 22 micron emission in excess of photospheric levels. This warm excess emission traces material in the circumstellar region likely to host terrestrial planets and is preferentially found in young systems with ages warm debris disk candidates are detected among FGK stars and 150 A stars within 120 pc. We are in the process of obtaining spectra to determine spectral types and activity level of these stars and are using HST, Herschel and Keck to characterize the dust, multiplicity, and substellar companions of these systems. In this contribution, we will discuss source selection methods and individual examples from among the WISE debris disk candidates.

  20. Candidates for non-baryonic dark matter

    International Nuclear Information System (INIS)

    Fornengo, Nicolao

    2002-01-01

    This report is a brief review of the efforts to explain the nature of non-baryonic dark matter and of the studies devoted to the search for relic particles. Among the different dark matter candidates, special attention is devoted to relic neutralinos, by giving an overview of the recent calculations of its relic abundance and detection rates in a wide variety of supersymmetric schemes

  1. Candidates for non-baryonic dark matter

    OpenAIRE

    Fornengo, Nicolao

    2002-01-01

    This report is a brief review of the efforts to explain the nature of non-baryonic dark matter and of the studies devoted to the search for relic particles. Among the different dark matter candidates, special attention is devoted to relic neutralinos, by giving an overview of the recent calculations of its relic abundance and detection rates in a wide variety of supersymmetric schemes.

  2. Educational intervention for liver transplantation candidates

    OpenAIRE

    Mendes,Karina Dal Sasso; Silva Junior,Orlando de Castro e; Ziviani,Luciana da Costa; Rossin,Fabiana Murad; Zago,Márcia Maria Fontão; Galvão,Cristina Maria

    2013-01-01

    OBJECTIVE: The objective in this study was to analyze candidates' knowledge on the liver transplantation process before and after putting in practice an educational intervention. METHOD: A quasi-experimental, one-group pretest-posttest research design was adopted. The final sample included 15 subjects. Research data were collected between January and March 2010 in three phases, which were: pretest, implementation of the educational intervention (two meetings) and posttest. RESULTS: The result...

  3. Energy Beverage Consumption Among Naval Aviation Candidates.

    Science.gov (United States)

    Sather, Thomas E; Delorey, Donald R

    2016-06-01

    Since the debut of energy beverages, the consumption of energy beverages has been immensely popular with young adults. Research regarding energy beverage consumption has included college students, European Union residents, and U.S. Army military personnel. However, energy beverage consumption among naval aviation candidates in the United States has yet to be examined. The purpose of this study was to assess energy beverage consumption patterns (frequency and volume) among naval aviation candidates, including attitudes and perceptions regarding the benefits and safety of energy beverage consumption. A 44-item survey was used to assess energy beverage consumption patterns of 302 students enrolled in the Aviation Preflight Indoctrination Course at Naval Air Station Pensacola, FL. Results indicated that 79% of participants (N = 239) reported consuming energy beverages within the last year. However, of those who reported consuming energy beverages within the last year, only 36% (N = 85) reported consuming energy beverages within the last 30 d. Additionally, 51% (N = 153) of participants reported no regular energy beverages consumption. The majority of participants consumed energy beverages for mental alertness (67%), mental endurance (37%), and physical endurance (12%). The most reported side effects among participants included increased mental alertness (67%), increased heart rate (53%), and restlessness (41%). Naval aviation candidates appear to use energy drinks as frequently as a college student population, but less frequently than expected for an active duty military population. The findings of this study indicate that naval aviation candidates rarely use energy beverages (less than once per month), but when consumed, they use it for fatigue management.

  4. Reducing stigma and discrimination: Candidate interventions

    OpenAIRE

    Thornicroft, Graham; Brohan, Elaine; Kassam, Aliya; Lewis-Holmes, Elanor

    2008-01-01

    Abstract This paper proposes that stigma in relation to people with mental illness can be understood as a combination of problems of knowledge (ignorance), attitudes (prejudice) and behaviour (discrimination). From a literature review, a series of candidate interventions are identified which may be effective in reducing stigmatisation and discrimination at the following levels: individuals with mental illness and their family members; the workplace; and local, national and international. The ...

  5. Various Approaches for Targeting Quasar Candidates

    Science.gov (United States)

    Zhang, Y.; Zhao, Y.

    2015-09-01

    With the establishment and development of space-based and ground-based observational facilities, the improvement of scientific output of high-cost facilities is still a hot issue for astronomers. The discovery of new and rare quasars attracts much attention. Different methods to select quasar candidates are in bloom. Among them, some are based on color cuts, some are from multiwavelength data, some rely on variability of quasars, some are based on data mining, and some depend on ensemble methods.

  6. Caffeine Consumption Among Naval Aviation Candidates.

    Science.gov (United States)

    Sather, Thomas E; Williams, Ronald D; Delorey, Donald R; Woolsey, Conrad L

    2017-04-01

    Education frequently dictates students need to study for prolonged periods of time to adequately prepare for examinations. This is especially true with aviation preflight indoctrination (API) candidates who have to assimilate large volumes of information in a limited amount of time during API training. The purpose of this study was to assess caffeine consumption patterns (frequency, type, and volume) among naval aviation candidates attending API to determine the most frequently consumed caffeinated beverage and to examine if the consumption of a nonenergy drink caffeinated beverage was related to energy drink consumption. Data were collected by means of an anonymous 44-item survey administered and completed by 302 students enrolled in API at Naval Air Station Pensacola, FL. Results indicated the most frequently consumed caffeinated beverage consumed by API students was coffee (86.4%), with daily coffee consumption being approximately 28% and the most frequent pattern of consumption being 2 cups per day (85%). The least frequently consumed caffeinated beverages reported were energy drinks (52%) and energy shots (29.1%). The present study also found that the consumption patterns (weekly and daily) of caffeinated beverages (coffee and cola) were positively correlated to energy drink consumption patterns. Naval aviation candidates' consumption of caffeinated beverages is comparable to other college and high school cohorts. This study found that coffee and colas were the beverages of choice, with energy drinks and energy shots being the least frequently reported caffeinated beverages used. Additionally, a relationship between the consumption of caffeinated beverages and energy drinks was identified.Sather TE, Williams RD, Delorey DR, Woolsey CL. Caffeine consumption among naval aviation candidates. Aerosp Med Hum Perform. 2017; 88(4):399-405.

  7. Upper gastrointestinal alterations in kidney transplant candidates.

    Science.gov (United States)

    Homse Netto, João Pedro; Pinheiro, João Pedro Sant'Anna; Ferrari, Mariana Lopes; Soares, Mirella Tizziani; Silveira, Rogério Augusto Gomes; Maioli, Mariana Espiga; Delfino, Vinicius Daher Alvares

    2018-05-14

    The incidence of gastrointestinal disorders among patients with chronic kidney disease (CKD) is high, despite the lack of a good correlation between endoscopic findings and symptoms. Many services thus perform upper gastrointestinal (UGI) endoscopy on kidney transplant candidates. This study aims to describe the alterations seen on the upper endoscopies of 96 kidney-transplant candidates seen from 2014 to 2015. Ninety-six CKD patients underwent upper endoscopic examination as part of the preparation to receive kidney grafts. The data collected from the patients' medical records were charted on Microsoft Office Excel 2016 and presented descriptively. Mean values, medians, interquartile ranges and 95% confidence intervals of the clinic and epidemiological variables were calculated. Possible associations between endoscopic findings and infection by H. pylori were studied. Males accounted for 54.17% of the 96 patients included in the study. Median age and time on dialysis were 50 years and 50 months, respectively. The most frequent upper endoscopy finding was enanthematous pangastritis (57.30%), followed by erosive esophagitis (30.20%). Gastric intestinal metaplasia and peptic ulcer were found in 8.33% and 7.30% of the patients, respectively. H. pylori tests were positive in 49 patients, and H. pylori infection was correlated only with non-erosive esophagitis (P = 0.046). Abnormal upper endoscopy findings were detected in all studied patients. This study suggested that upper endoscopy is a valid procedure for kidney transplant candidates. However, prospective studies are needed to shed more light on this matter.

  8. Pulmonary rehabilitation in lung transplant candidates.

    Science.gov (United States)

    Li, Melinda; Mathur, Sunita; Chowdhury, Noori A; Helm, Denise; Singer, Lianne G

    2013-06-01

    While awaiting lung transplantation, candidates may participate in pulmonary rehabilitation to improve their fitness for surgery. However, pulmonary rehabilitation outcomes have not been systematically evaluated in lung transplant candidates. This investigation was a retrospective cohort study of 345 pre-transplant pulmonary rehabilitation participants who received a lung transplant between January 2004 and June 2009 and had available pre-transplant exercise data. Data extracted included: 6-minute walk tests at standard intervals; exercise training details; health-related quality-of-life (HRQL) measures; and early post-transplant outcomes. Paired t-tests were used to examine changes in the 6MW distance (6MWD), exercise training volume and HRQL during the pre-transplant period. We evaluated the association between pre-transplant 6MWD and transplant hospitalization outcomes. The final 6MWD prior to transplantation was only 15 m less than the listing 6MWD (n = 200; p = 0.002). Exercise training volumes increased slightly from the start of the pulmonary rehabilitation program until transplant: treadmill, increase 0.69 ml/kg/min (n = 238; p volumes are well preserved among lung transplant candidates participating in pulmonary rehabilitation, even in the setting of severe, progressive lung disease. Participants with greater exercise capacity prior to transplantation have more favorable early post-transplant outcomes. Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  9. Nuclear safety in EU candidate countries

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2000-10-01

    Nuclear safety in the candidate countries to the European Union is a major issue that needs to be addressed in the framework of the enlargement process. Therefore WENRA members considered it was their duty to offer their technical assistance to their Governments and the European Union Institutions. They decided to express their collective opinion on nuclear safety in those candidate countries having at least one nuclear power plant: Bulgaria, the Czech Republic, Hungary, Lithuania, Romania, Slovakia and Slovenia. The report is structured as follows: A foreword including background information, structure of the report and the methodology used, General conclusions of WENRA members reflecting their collective opinion, For each candidate country, an executive summary, a chapter on the status of the regulatory regime and regulatory body, and a chapter on the nuclear power plant safety status. Two annexes are added to address the generic safety characteristics and safety issues for RBMK and VVER plants. The report does not cover radiation protection and decommissioning issues, while safety aspects of spent fuel and radioactive waste management are only covered as regards on-site provisions. In order to produce this report, WENRA used different means: For the chapters on the regulatory regimes and regulatory bodies, experts from WENRA did the work. For the chapters on nuclear power plant safety status, experts from WENRA and from French and German technical support organisations did the work. Taking into account the contents of these chapters, WENRA has formulated its general conclusions in this report.

  10. Molecular candidates of MTV in air

    Science.gov (United States)

    Dam, Nico; Mirzaei, Mehrnoosh; van de Water, Willem

    2011-11-01

    In molecular tagging velocimetry (MTV), the molecules of a gas are used as flow tracers. These tracers can be produced at will by illumination with a laser which promotes molecules to a long- lived excited state, fuses N2 and N2 to NO, or makes molecules phosphoresce. A while later these tagged molecules can be visualized by laser-induced fluorescence, or by just watching them while they phosphoresce. Candidates for MTV in turbulence research must be arranged in structures narrower than the Kolmogorov scale, which remain narrow as time progresses, and must live longer than the Kolmogorov time. These requirements invalidate many candidates, candidates once deemed successful. They do so in various surprising manners that involve a combination of fluid flow and molecular dynamics. Rather than velocimetry in turbulence, MTV techniques offer a unique view on basic dispersion processes at the smallest scales of turbulence. In this way we have measured the spreading of clouds whose size is a few times the Kolmogorov length and the Batchelor dispersion of objects whose size is inside the inertial range.

  11. Nuclear safety in EU candidate countries

    International Nuclear Information System (INIS)

    2000-10-01

    Nuclear safety in the candidate countries to the European Union is a major issue that needs to be addressed in the framework of the enlargement process. Therefore WENRA members considered it was their duty to offer their technical assistance to their Governments and the European Union Institutions. They decided to express their collective opinion on nuclear safety in those candidate countries having at least one nuclear power plant: Bulgaria, the Czech Republic, Hungary, Lithuania, Romania, Slovakia and Slovenia. The report is structured as follows: A foreword including background information, structure of the report and the methodology used, General conclusions of WENRA members reflecting their collective opinion, For each candidate country, an executive summary, a chapter on the status of the regulatory regime and regulatory body, and a chapter on the nuclear power plant safety status. Two annexes are added to address the generic safety characteristics and safety issues for RBMK and VVER plants. The report does not cover radiation protection and decommissioning issues, while safety aspects of spent fuel and radioactive waste management are only covered as regards on-site provisions. In order to produce this report, WENRA used different means: For the chapters on the regulatory regimes and regulatory bodies, experts from WENRA did the work. For the chapters on nuclear power plant safety status, experts from WENRA and from French and German technical support organisations did the work. Taking into account the contents of these chapters, WENRA has formulated its general conclusions in this report

  12. 6-mercaptopurine and daunorubicin double drug liposomes-preparation, drug-drug interaction and characterization.

    Science.gov (United States)

    Agrawal, Vineet; Paul, Manash K; Mukhopadhyay, Anup K

    2005-01-01

    This article addresses and investigates the dual incorporation of daunorubicin (DR) and 6-mercaptopurine (6-MP) in liposomes for better chemotherapy. These drugs are potential candidates for interaction due to the quinone (H acceptor) and hydroxyl (H donor) groups on DR and 6-MP, respectively. Interactions between the two drugs in solution were monitored by UV/Vis and fluorescence spectroscopy. Interaction between the two drugs inside the liposomes was evaluated by HPLC (for 6-MP) and by fluorescence spectroscopy (for daunorubicin) after phospholipase-mediated liposome lysis. Our results provide evidence for the lack of interaction between the two drugs in solution and in liposomes. The entrapment efficiencies of 6-MP in the neutral Phosphatidyl choline (PC):Cholesterol (Chol):: 2:1 and anionic PC:Chol:Cardiolipin (CL) :: 4:5:1 single and double drug liposomes were found to be 0.4% and 1.5% (on average), respectively. The entrapment efficiencies of DR in the neutral and anionic double drug liposomes were found to be 55% and 31%, respectively. The corresponding entrapment of daunorubicin in the single drug liposomes was found to be 62% on average. Our thin layer chromatography (TLC) and transmission electron microscopy (TEM) results suggest stability of lipid and liposomes, thus pointing plausible existence of double drug liposomes. Cytotoxicity experiments were performed by using both single drug and double drug liposomes. By comparing the results of phase contrast and fluorescence microscopy, it was observed that the double drug liposomes were internalized in the jurkat and Hut78 (highly resistant cell line) leukemia cells as viewed by the fluorescence of daunorubicin. The cytotoxicity was dose dependent and had shown a synergistic effect when double drug liposome was used.

  13. COPD - control drugs

    Science.gov (United States)

    Chronic obstructive pulmonary disease - control drugs; Bronchodilators - COPD - control drugs; Beta agonist inhaler - COPD - control drugs; Anticholinergic inhaler - COPD - control drugs; Long-acting inhaler - COPD - control drugs; ...

  14. [Orphan drugs].

    Science.gov (United States)

    Golocorbin Kon, Svetlana; Vojinović, Aleksandra; Lalić-Popović, Mladena; Pavlović, Nebojsa; Mikov, Momir

    2013-01-01

    Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in "adopting" them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of drugs meant to treat diseases whose pathogenesis has not yet been clarified in majority of cases. The aim of this paper is to present previous and present status of orphan drugs in Serbia and other countries. THE BEGINNING OF ORPHAN DRUGS DEVELOPMENT: This problem was first recognized by Congress of the United States of America in January 1983, and when the "Orphan Drug Act" was passed, it was a turning point in the development of orphan drugs. This law provides pharmaceutical companies with a series of reliefs, both financial ones that allow them to regain funds invested into the research and development and regulatory ones. Seven years of marketing exclusivity, as a type of patent monopoly, is the most important relief that enables companies to make large profits. There are no sufficient funds and institutions to give financial support to the patients. It is therefore necessary to make health professionals much more aware of rare diseases in order to avoid time loss in making the right diagnosis and thus to gain more time to treat rare diseases. The importance of discovery, development and production of orphan drugs lies in the number of patients whose life quality can be improved significantly by administration of these drugs as well as in the number of potential survivals resulting from the treatment with these drugs.

  15. Nanoformulations and Clinical Trial Candidates as Probably ...

    African Journals Online (AJOL)

    Review Article ... Tuberculosis (TB) is the main infectious disease causing 1.8 million deaths worldwide every ... Encapsulation of existing anti-TB drugs into nano-delivery systems and introduction .... MTB heat shock protein 65 (HSP 65), IL-12,.

  16. Nanoformulations and Clinical Trial Candidates as Probably ...

    African Journals Online (AJOL)

    Nanotechnology-based rational targeting may improve ... Encapsulation of existing anti-TB drugs into nano-delivery systems and introduction ... Despite the accessibility to cost saving and ..... nanoparticles with elevated antimicrobial activity.

  17. An automated synthesis-purification-sample-management platform for the accelerated generation of pharmaceutical candidates.

    Science.gov (United States)

    Sutherland, J David; Tu, Noah P; Nemcek, Thomas A; Searle, Philip A; Hochlowski, Jill E; Djuric, Stevan W; Pan, Jeffrey Y

    2014-04-01

    A flexible and integrated flow-chemistry-synthesis-purification compound-generation and sample-management platform has been developed to accelerate the production of small-molecule organic-compound drug candidates in pharmaceutical research. Central to the integrated system is a Mitsubishi robot, which hands off samples throughout the process to the next station, including synthesis and purification, sample dispensing for purity and quantification analysis, dry-down, and aliquot generation.

  18. AIDSinfo Drug Database

    Science.gov (United States)

    ... AIDS Drugs Clinical Trials Apps skip to content Drugs Home Drugs Find information on FDA-approved HIV/ ... infection drugs and investigational HIV/AIDS drugs. Search Drugs Search drug Search Icon What's this? Close Popup ...

  19. Ranking candidate disease genes from gene expression and protein interaction: a Katz-centrality based approach.

    Directory of Open Access Journals (Sweden)

    Jing Zhao

    Full Text Available Many diseases have complex genetic causes, where a set of alleles can affect the propensity of getting the disease. The identification of such disease genes is important to understand the mechanistic and evolutionary aspects of pathogenesis, improve diagnosis and treatment of the disease, and aid in drug discovery. Current genetic studies typically identify chromosomal regions associated specific diseases. But picking out an unknown disease gene from hundreds of candidates located on the same genomic interval is still challenging. In this study, we propose an approach to prioritize candidate genes by integrating data of gene expression level, protein-protein interaction strength and known disease genes. Our method is based only on two, simple, biologically motivated assumptions--that a gene is a good disease-gene candidate if it is differentially expressed in cases and controls, or that it is close to other disease-gene candidates in its protein interaction network. We tested our method on 40 diseases in 58 gene expression datasets of the NCBI Gene Expression Omnibus database. On these datasets our method is able to predict unknown disease genes as well as identifying pleiotropic genes involved in the physiological cellular processes of many diseases. Our study not only provides an effective algorithm for prioritizing candidate disease genes but is also a way to discover phenotypic interdependency, cooccurrence and shared pathophysiology between different disorders.

  20. Drug Repositioning for Effective Prostate Cancer Treatment.

    Science.gov (United States)

    Turanli, Beste; Grøtli, Morten; Boren, Jan; Nielsen, Jens; Uhlen, Mathias; Arga, Kazim Y; Mardinoglu, Adil

    2018-01-01

    Drug repositioning has gained attention from both academia and pharmaceutical companies as an auxiliary process to conventional drug discovery. Chemotherapeutic agents have notorious adverse effects that drastically reduce the life quality of cancer patients so drug repositioning is a promising strategy to identify non-cancer drugs which have anti-cancer activity as well as tolerable adverse effects for human health. There are various strategies for discovery and validation of repurposed drugs. In this review, 25 repurposed drug candidates are presented as result of different strategies, 15 of which are already under clinical investigation for treatment of prostate cancer (PCa). To date, zoledronic acid is the only repurposed, clinically used, and approved non-cancer drug for PCa. Anti-cancer activities of existing drugs presented in this review cover diverse and also known mechanisms such as inhibition of mTOR and VEGFR2 signaling, inhibition of PI3K/Akt signaling, COX and selective COX-2 inhibition, NF-κB inhibition, Wnt/β-Catenin pathway inhibition, DNMT1 inhibition, and GSK-3β inhibition. In addition to monotherapy option, combination therapy with current anti-cancer drugs may also increase drug efficacy and reduce adverse effects. Thus, drug repositioning may become a key approach for drug discovery in terms of time- and cost-efficiency comparing to conventional drug discovery and development process.

  1. Drug Facts

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    Full Text Available ... Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs of Abuse What ... Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call 1-800- ...

  2. Drug Facts

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    Full Text Available ... Oxy, Vike) Facts Spice (K2) Facts Tobacco and Nicotine Facts Other Drugs of Abuse What is Addiction? ... Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call 1-800-662- ...

  3. Antineoplastic Drugs

    Science.gov (United States)

    Sadée, Wolfgang; El Sayed, Yousry Mahmoud

    The limited scope of therapeutic drug-level monitoring in cancer chemotherapy results from the often complex biochemical mechanisms that contribute to antineoplastic activity and obscure the relationships among drug serum levels and therapeutic benefits. Moreover, new agents for cancer chemotherapy are being introduced at a more rapid rate than for the treatment of other diseases, although the successful application of therapeutic drug-level monitoring may require several years of intensive study of the significance of serum drug levels. However, drug level monitoring can be of considerable value during phase I clinical trials of new antineoplastic agents in order to assess drug metabolism, bioavailability, and intersubject variability; these are important parameters in the interpretation of clinical studies, but have no immediate benefit to the patient. High performance liquid chromatography (HPLC) probably represents the most versatile and easily adaptable analytical technique for drug metabolite screening (1). HPLC may therefore now be the method of choice during phase I clinical trials of antineoplastic drugs. For example, within a single week we developed an HPLC assay—using a C18 reverse-phase column, UV detection, and direct serum injection after protein precipitation—for the new radiosensitizer, misonidazole (2).

  4. Drugged Driving

    Science.gov (United States)

    ... Survey Results Synthetic Cannabinoids (K2/Spice) Unpredictable Danger Drug and Alcohol Use in College-Age Adults in 2016 Monitoring the Future 2016 Survey Results Drug and Alcohol Use in College-Age Adults in 2015 View All NIDA Home ...

  5. Reducing stigma and discrimination: Candidate interventions

    Directory of Open Access Journals (Sweden)

    Kassam Aliya

    2008-04-01

    Full Text Available Abstract This paper proposes that stigma in relation to people with mental illness can be understood as a combination of problems of knowledge (ignorance, attitudes (prejudice and behaviour (discrimination. From a literature review, a series of candidate interventions are identified which may be effective in reducing stigmatisation and discrimination at the following levels: individuals with mental illness and their family members; the workplace; and local, national and international. The strongest evidence for effective interventions at present is for (i direct social contact with people with mental illness at the individual level, and (ii social marketing at the population level.

  6. Processability analysis of candidate waste forms

    International Nuclear Information System (INIS)

    Gould, T.H. Jr.; Dunson, J.B. Jr.; Eisenberg, A.M.; Haight, H.G. Jr.; Mello, V.E.; Schuyler, R.L. III.

    1982-01-01

    A quantitative merit evaluation, or processability analysis, was performed to assess the relative difficulty of remote processing of Savannah River Plant high-level wastes for seven alternative waste form candidates. The reference borosilicate glass process was rated as the simplest, followed by FUETAP concrete, glass marbles in a lead matrix, high-silica glass, crystalline ceramics (SYNROC-D and tailored ceramics), and coated ceramic particles. Cost estimates for the borosilicate glass, high-silica glass, and ceramic waste form processing facilities are also reported

  7. Blend Analysis of HATNet Transit Candidates

    Directory of Open Access Journals (Sweden)

    Bakos G.Á.

    2011-02-01

    Full Text Available Candidate transiting planet systems discovered by wide-field groundbased surveys must go through an intensive follow-up procedure to distinguish the true transiting planets from the much more common false positives. Especially pernicious are configurations of three or more stars which produce radial velocity and light curves that are similar to those of single stars transited by a planet. In this contribution we describe the methods used by the HATNet team to reject these blends, giving a few illustrative examples.

  8. Reducing stigma and discrimination: Candidate interventions.

    Science.gov (United States)

    Thornicroft, Graham; Brohan, Elaine; Kassam, Aliya; Lewis-Holmes, Elanor

    2008-04-13

    This paper proposes that stigma in relation to people with mental illness can be understood as a combination of problems of knowledge (ignorance), attitudes (prejudice) and behaviour (discrimination). From a literature review, a series of candidate interventions are identified which may be effective in reducing stigmatisation and discrimination at the following levels: individuals with mental illness and their family members; the workplace; and local, national and international. The strongest evidence for effective interventions at present is for (i) direct social contact with people with mental illness at the individual level, and (ii) social marketing at the population level.

  9. Geoscience Training for NASA Astronaut Candidates

    Science.gov (United States)

    Young, K. E.; Evans, C. A.; Bleacher, J. E.; Graff, T. G.; Zeigler, R.

    2017-01-01

    After being selected to the astronaut office, crewmembers go through an initial two year training flow, astronaut candidacy, where they learn the basic skills necessary for spaceflight. While the bulk of astronaut candidate training currently centers on the multiple subjects required for ISS operations (EVA skills, Russian language, ISS systems, etc.), training also includes geoscience training designed to train crewmembers in Earth observations, teach astronauts about other planetary systems, and provide field training designed to investigate field operations and boost team skills. This training goes back to Apollo training and has evolved to support ISS operations and future exploration missions.

  10. Drug repurposing based on drug-drug interaction.

    Science.gov (United States)

    Zhou, Bin; Wang, Rong; Wu, Ping; Kong, De-Xin

    2015-02-01

    Given the high risk and lengthy procedure of traditional drug development, drug repurposing is gaining more and more attention. Although many types of drug information have been used to repurpose drugs, drug-drug interaction data, which imply possible physiological effects or targets of drugs, remain unexploited. In this work, similarity of drug interaction was employed to infer similarity of the physiological effects or targets for the drugs. We collected 10,835 drug-drug interactions concerning 1074 drugs, and for 700 of them, drug similarity scores based on drug interaction profiles were computed and rendered using a drug association network with 589 nodes (drugs) and 2375 edges (drug similarity scores). The 589 drugs were clustered into 98 groups with Markov Clustering Algorithm, most of which were significantly correlated with certain drug functions. This indicates that the network can be used to infer the physiological effects of drugs. Furthermore, we evaluated the ability of this drug association network to predict drug targets. The results show that the method is effective for 317 of 561 drugs that have known targets. Comparison of this method with the structure-based approach shows that they are complementary. In summary, this study demonstrates the feasibility of drug repurposing based on drug-drug interaction data. © 2014 John Wiley & Sons A/S.

  11. Semantic Web Ontology and Data Integration: a Case Study in Aiding Psychiatric Drug Repurposing.

    Science.gov (United States)

    Liang, Chen; Sun, Jingchun; Tao, Cui

    2015-01-01

    There remain significant difficulties selecting probable candidate drugs from existing databases. We describe an ontology-oriented approach to represent the nexus between genes, drugs, phenotypes, symptoms, and diseases from multiple information sources. We also report a case study in which we attempted to explore candidate drugs effective for bipolar disorder and epilepsy. We constructed an ontology incorporating knowledge between the two diseases and performed semantic reasoning tasks with the ontology. The results suggested 48 candidate drugs that hold promise for further breakthrough. The evaluation demonstrated the validity our approach. Our approach prioritizes the candidate drugs that have potential associations among genes, phenotypes and symptoms, and thus facilitates the data integration and drug repurposing in psychiatric disorders.

  12. [Club drugs].

    Science.gov (United States)

    Guerreiro, Diogo Frasquilho; Carmo, Ana Lisa; da Silva, Joaquim Alves; Navarro, Rita; Góis, Carlos

    2011-01-01

    Club drugs are the following substances: Methylenedioxymethamphetamine (MDMA); Methamphetamine; Lysergic Acid Diethylamide (LSD); Ketamine; Gamma-hydroxybutyrate (GHB) and Flunitrazepam. These substances are mainly used by adolescents and young adults, mostly in recreational settings like dance clubs and rave parties. These drugs have diverse psychotropic effects, are associated with several degrees of toxicity, dependence and long term adverse effects. Some have been used for several decades, while others are relatively recent substances of abuse. They have distinct pharmacodynamic and pharmacokinetic properties, are not easy to detect and, many times, the use of club drugs is under diagnosed. Although the use of these drugs is increasingly common, few health professionals feel comfortable with the diagnosis and treatment. The authors performed a systematic literature review, with the goal of synthesising the existing knowledge about club drugs, namely epidemiology, mechanism of action, detection, adverse reactions and treatment. The purpose of this article is creating in Portuguese language a knowledge data base on club drugs, that health professionals of various specialties can use as a reference when dealing with individual with this kind of drug abuse.

  13. Study on the Application of Chinese Patent Drug and Chinese Formula of Rabdosia Rubescens

    Science.gov (United States)

    Peng, Mengfan; Liu, Baosong; Mao, Mingsan

    2018-01-01

    Rabdosia rubescens contais many active ingredients such as terpenoids, flavonoids, polysaccharides and organic acids. Modern research has proved that Rabdosia rubescens has the effect of heat-clearing and detoxicating, antibacterial and anticancer, promoting blood circulation to arrest pain and anti-tumor. It is used in the treatment of sore throat, rheumatoid arthritis and various kinds of cancer. The clinical application of Rabdosia rubescens is restricted in the fat-soluble components, and the solubility of water solubility is ignored. The application of prescriptions, Chinese patent drug and food therapy of Rabdosia rubescens are less and fragmented. This paper inquires relevant literature, the application of Rabdosia rubescens in prescription, Chinese patent medicine and food therapy was reviewed, in order to make Rabdosiae rubescens play a greater role in the relevant area. On the basis of make the best use of everything, to promote the innovation and development of Chinese medicine and services to the people in our country.

  14. Criteria for candidate species for aquaculture

    Energy Technology Data Exchange (ETDEWEB)

    Webber, H H; Riordan, P F

    1976-01-01

    The nature of the animal taxa that are the most probable candidates for an intensive, commercial aquatic animal husbandry industry is considered. A characterization is presented of those biological criteria that lend the species the necessary physiological and genetic malleability to be adapted and molded into a domesticated race. The animal cultivated must be amenable to intensive management in high-density confinements such as those now being engineered for high-yield aquaculture. Attributes considered are discussed in the context of the various aquacultural ecosystems in which the specific biotype is expected to achieve satisfactory growth and survival. Correlative with bionomic criteria, economic requirements are posed and evaluated in an effort to define a socially and financially profitable agribusiness system. Investment requirements and operating costs are considered in terms of expected returns. However, since production alone is insufficient to sustain an enterprise - i.e., the product must be sold - production costs must be judged against market values. Therefore, ultimate use or consumer acceptance criteria are incorporated into the list of essential requirements for a candidate species for aquafarming.

  15. Elemental abundances of solar sibling candidates

    International Nuclear Information System (INIS)

    Ramírez, I.; Lambert, D. L.; Endl, M.; Cochran, W. D.; MacQueen, P. J.; Bajkova, A. T.; Bobylev, V. V.; Roederer, I. U.; Wittenmyer, R. A.

    2014-01-01

    Dynamical information along with survey data on metallicity and in some cases age have been used recently by some authors to search for candidates of stars that were born in the cluster where the Sun formed. We have acquired high-resolution, high signal-to-noise ratio spectra for 30 of these objects to determine, using detailed elemental abundance analysis, if they could be true solar siblings. Only two of the candidates are found to have solar chemical composition. Updated modeling of the stars' past orbits in a realistic Galactic potential reveals that one of them, HD 162826, satisfies both chemical and dynamical conditions for being a sibling of the Sun. Measurements of rare-element abundances for this star further confirm its solar composition, with the only possible exception of Sm. Analysis of long-term high-precision radial velocity data rules out the presence of hot Jupiters and confirms that this star is not in a binary system. We find that chemical tagging does not necessarily benefit from studying as many elements as possible but instead from identifying and carefully measuring the abundances of those elements that show large star-to-star scatter at a given metallicity. Future searches employing data products from ongoing massive astrometric and spectroscopic surveys can be optimized by acknowledging this fact.

  16. Advanced Vaccine Candidates for Lassa Fever

    Directory of Open Access Journals (Sweden)

    Igor S. Lukashevich

    2012-10-01

    Full Text Available Lassa virus (LASV is the most prominent human pathogen of the Arenaviridae. The virus is transmitted to humans by a rodent reservoir, Mastomys natalensis, and is capable of causing lethal Lassa Fever (LF. LASV has the highest human impact of any of the viral hemorrhagic fevers (with the exception of Dengue Fever with an estimated several hundred thousand infections annually, resulting in thousands of deaths in Western Africa. The sizeable disease burden, numerous imported cases of LF in non-endemic countries, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. Presently there is no licensed vaccine against LF or approved treatment. Recently, several promising vaccine candidates have been developed which can potentially target different groups at risk. The purpose of this manuscript is to review the LASV pathogenesis and immune mechanisms involved in protection. The current status of pre-clinical development of the advanced vaccine candidates that have been tested in non-human primates will be discussed. Major scientific, manufacturing, and regulatory challenges will also be considered.

  17. Political Candidate Campaign Advertising: A Selected Review of the Literature.

    Science.gov (United States)

    Hellweg, Susan A.

    This paper provides a selected review of political candidate campaign advertising studies from the political science, mass communication, advertising, and political communication literature. The paper examines the literature in terms of research pertaining to (1) candidate advertising content (commercials for male versus female candidates and for…

  18. Evaluation of candidate geomagnetic field models for IGRF-11

    DEFF Research Database (Denmark)

    Finlay, Chris; Maus, S.; Beggan, C. D.

    2010-01-01

    variations between candidates originate. A retrospective analysis of IGRF-10 main field candidates for epoch 2005.0 and predictive secular variation candidates for 2005.0–2010.0 using the new IGRF-11 models as a reference is also reported. The high quality and consistency of main field models derived using...

  19. Views on Values Education: From Teacher Candidates to Experienced Teachers

    Science.gov (United States)

    Iscan, Canay Demirhan

    2015-01-01

    This study aimed to identify the views of experienced class teachers and class teacher candidates on values education. It conducted standard open-ended interviews with experienced class teachers and teacher candidates. The study group comprised 9 experienced class teachers from different socio-economic levels and 9 teacher candidates with…

  20. Opinions of the Geography Teacher Candidates toward Mind Maps

    Science.gov (United States)

    Seyihoglu, Aysegul

    2013-01-01

    The purpose of this study is to reveal the opinions of the teacher candidates about mind mapping technique used in Geography education of undergraduate program. In this study, the qualitative research techniques were used. The study group consists of 55 teacher candidates. The teacher candidates have been asked for their opinions about the process…

  1. Cognitive Styles in Admission Procedures for Assessing Candidates of Architecture

    Science.gov (United States)

    Casakin, Hernan; Gigi, Ariela

    2016-01-01

    Cognitive style has a strong predictive power in academic and professional success. This study investigated the cognitive profile of candidates studying architecture. Specifically, it explored the relation between visual and verbal cognitive styles, and the performance of candidates in admission procedures. The cognitive styles of candidates who…

  2. Changing Perceptions of Teacher Candidates in High-Needs Schools

    Science.gov (United States)

    DeJarnette, Nancy K.

    2016-01-01

    Candidates enter teacher education programs with established beliefs about diversity and urban education. These belief systems impact decisions that teacher candidates make both now and in the future. Providing opportunities for candidates to spend quality time in an urban Professional Development School (PDS) setting with the support and guidance…

  3. Preclinical experimental models of drug metabolism and disposition in drug discovery and development

    Directory of Open Access Journals (Sweden)

    Donglu Zhang

    2012-12-01

    Full Text Available Drug discovery and development involve the utilization of in vitro and in vivo experimental models. Different models, ranging from test tube experiments to cell cultures, animals, healthy human subjects, and even small numbers of patients that are involved in clinical trials, are used at different stages of drug discovery and development for determination of efficacy and safety. The proper selection and applications of correct models, as well as appropriate data interpretation, are critically important in decision making and successful advancement of drug candidates. In this review, we discuss strategies in the applications of both in vitro and in vivo experimental models of drug metabolism and disposition.

  4. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

    Science.gov (United States)

    Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Conery, Annie L; Kim, Wooseong; Jayamani, Elamparithi; Kwon, Bumsup; Ausubel, Frederick M; Mylonakis, Eleftherios

    2015-01-01

    Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

  5. Microreactor for electrochemical conversion: in drug screening and proteomics

    NARCIS (Netherlands)

    van den Brink, Floris Teunis Gerardus

    2016-01-01

    The majority of marketed drugs are metabolized through oxidation by enzymes of the cytochrome P450 family, thereby producing phase I metabolites. For pharmaceutical companies it is essential to thoroughly screen candidate drugs for potentially toxic metabolites, in order to avoid high costs

  6. A multi-infrastructure gateway for virtual drug screening

    NARCIS (Netherlands)

    Jaghoori, Mohammad Mahdi; van Altena, Allard J.; Bleijlevens, Boris; Ramezani, Sara; Font, Juan Luis; Olabarriaga, Silvia D.

    2015-01-01

    In computer-aided drug design, software tools are used to narrow down possible drug candidates, thereby reducing the amount of expensive in vitro research, by a process called virtual screening. This process includes large computations that require advanced computing infrastructure; however, using

  7. Drug Facts

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    Full Text Available ... MDMA (Ecstasy, Molly) Facts Meth (Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco ... Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You ...

  8. Drug Facts

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  9. Drug Facts

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    Full Text Available ... Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth ( ... Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine ...

  10. Drug Facts

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  11. Drug Metabolism

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 19; Issue 3. Drug Metabolism: A Fascinating Link Between Chemistry and Biology. Nikhil Taxak Prasad V Bharatam. General Article Volume 19 Issue 3 March 2014 pp 259-282 ...

  12. Drugged Driving

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  13. Club Drugs

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  14. Drug Metabolism

    Indian Academy of Sciences (India)

    IAS Admin

    behind metabolic reactions, importance, and consequences with several ... required for drug action. ... lism, which is catalyzed by enzymes present in the above-men- ... catalyze the transfer of one atom of oxygen to a substrate produc-.

  15. Drug Facts

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  16. Drug Facts

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    Full Text Available ... 800-662-HELP (4357) at any time to find drug treatment centers near you. I want my ... is making positive changes in her life. She finds support from family and friends who don't ...

  17. Drug Facts

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  18. Drug Facts

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    Full Text Available ... Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? ... of Health (NIH) , the principal biomedical and behavioral research agency of the United States Government. NIH is ...

  19. Drug Reactions

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    ... Kids and Teens Pregnancy and Childbirth Women Men Seniors Your Health Resources Healthcare Management End-of-Life Issues Insurance & Bills Self Care Working With Your Doctor Drugs, Procedures & Devices Over-the- ...

  20. Drug Facts

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    Full Text Available ... prescription drugs. The addiction slowly took over his life. I need different people around me. To stop ... marijuana, "Cristina" is making positive changes in her life. She finds support from family and friends who ...

  1. Drug Resistance

    Science.gov (United States)

    ... Drug-resistance testing is also recommended for all pregnant women with HIV before starting HIV medicines and also in some pregnant women already taking HIV medicines. Pregnant women will work with their health ...

  2. Drug Facts

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    Full Text Available ... Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth (Crank, ... Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine ...

  3. Drug Addiction

    Science.gov (United States)

    ... as hearing colors Impulsive behavior Rapid shifts in emotions Permanent mental changes in perception Rapid heart rate ... Drug use can negatively affect academic performance and motivation to excel in school. Legal issues. Legal problems ...

  4. Drug Facts

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    Full Text Available ... That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana ( ... Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) ...

  5. Relationship between candidate communication ability and oral certification examination scores.

    Science.gov (United States)

    Lunz, Mary E; Bashook, Philip G

    2008-12-01

    Structured case-based oral examinations are widely used in medical certifying examinations in the USA. These orals assess the candidate's decision-making skills using real or realistic patient cases. Frequently mentioned but not empirically evaluated is the potential bias introduced by the candidate's communication ability. This study aimed to assess the relationship between candidate communication ability and medical certification oral examination scores. Non-doctor communication observers rated a random sample of 90 candidates on communication ability during a medical oral certification examination. The multi-facet Rasch model was used to analyse the communication survey and the oral examination data. The multi-facet model accounts for observer and examiner severity bias. anova was used to measure differences in communication ability between passing and failing candidates and candidates grouped by level of communication ability. Pearson's correlations were used to compare candidate communication ability and oral certification examination performance. Candidate separation reliability values for the communication survey and the oral examination were 0.85 and 0.97, respectively, suggesting accurate candidate measurement. The correlation between communication scores and oral examination scores was 0.10. No significant difference was found between passing and failing candidates for measured communication ability. When candidates were grouped by high, moderate and low communication ability, there was no significant difference in their oral certification examination performance. Candidates' communication ability has little relationship to candidate performance on high-stakes, case-based oral examinations. Examiners for this certifying examination focused on assessing candidate decision-making ability and were not influenced by candidate communication ability.

  6. What Do Teacher Candidates Think about the Teaching Education? The Example of Social Studies Teacher Candidates

    Science.gov (United States)

    Tonga, Deniz

    2016-01-01

    In this research, it is aimed to reveal the opinions and observations of social studies teacher candidate about the courses they have taken during their 4-year university education. The focus group interview was used as the data collecting tool, and the content analyses were performed on the data obtained. The criterion sampling approach was used…

  7. MXene: a potential candidate for yarn supercapacitors.

    Science.gov (United States)

    Zhang, Jizhen; Seyedin, Shayan; Gu, Zhoujie; Yang, Wenrong; Wang, Xungai; Razal, Joselito M

    2017-12-07

    The increasing developments in wearable electronics demand compatible power sources such as yarn supercapacitors (YSCs) that can effectively perform in a limited footprint. MXene nanosheets, which have been recently shown in the literature to possess ultra-high volumetric capacitance, were used in this study for the fabrication of YSCs in order to identify their potential merit and performance in YSCs. With the aid of a conductive binder (PEDOT-PSS), YSCs with high mass loading of MXene are demonstrated. These MXene-based YSCs exhibit excellent device performance and stability even under bending and twisting. This study demonstrates that MXene is a promising candidate for YSCs and its further development can lead to flexible power sources with sufficient performance for powering miniaturized and/or wearable electronics.

  8. Ailing voters advance attractive congressional candidates.

    Science.gov (United States)

    Zebrowitz, Leslie A; Franklin, Robert G; Palumbo, Rocco

    2015-01-06

    Among many benefits of facial attractiveness, there is evidence that more attractive politicians are more likely to be elected. Recent research found this effect to be most pronounced in congressional districts with high disease threat-a result attributed to an adaptive disease avoidance mechanism, whereby the association of low attractiveness with poor health is particularly worrisome to voters who feel vulnerable to disease. We provided a more direct test of this explanation by examining the effects of individuals' own health and age. Supporting a disease avoidance mechanism, less healthy participants showed a stronger preference for more attractive contenders in U.S. Senate races than their healthier peers, and this effect was stronger for older participants, who were generally less healthy than younger participants. Stronger effects of health for older participants partly reflected the absence of positive bias toward attractive candidates among the healthiest, suggesting that healthy older adults may be unconcerned about disease threat or sufficiently wise to ignore attractiveness.

  9. ELECTIONS PENSION FUND 3rd candidate

    CERN Multimedia

    2001-01-01

    ORGANISATION EUROPEENNE POUR LA RECHERCHE NUCLEAIRE CERN EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH CAISSE DE PENSIONS / PENSION FUND Caisse de Pensions - ELECTIONS - Pension Fund This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund. Candidate : Name : Hauviller First Name : Claude Dear colleague of CERN and ESO, For the first time, I am standing and requesting your support to become a member of the Governing Board of our Pension Fund. CERN staff member since 1974, I have already carried elective mandates: I have been Delegate to the Staff Council and Member of the Senior Staff Consultative Committee (the Nine). For the majority of us, our Pension Fund is our only social provident scheme and source of retirement income; I believe I can usefully contribute to its successful management and help ensure its balance. Our Fund reaches its majority: soon, there will be more beneficiaries tha...

  10. ELECTIONS PENSION FUND CANDIDATE NR 3

    CERN Multimedia

    2001-01-01

    ORGANISATION EUROPEENNE POUR LA RECHERCHE NUCLEAIRE CERN EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH CAISSE DE PENSIONS / PENSION FUND Caisse de Pensions - ELECTIONS - Pension Fund This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund. Candidate : Name : HAUVILLER First Name : Claude Dear colleague of CERN and ESO, For the first time, I am standing and requesting your support to become a member of the Governing Board of our Pension Fund. CERN staff member since 1974, I have already carried elective mandates: I have been Delegate to the Staff Council and Member of the Senior Staff Consultative Committee (the Nine). For the majority of us, our Pension Fund is our only social provident scheme and source of retirement income; I believe I can usefully contribute to its successful management and help ensure its balance. Our Fund reaches its majority: soon, there will be more beneficiaries tha...

  11. ELECTIONS PENSION FUND 4th candidate

    CERN Multimedia

    2001-01-01

    ORGANISATION EUROPEENNE POUR LA RECHERCHE NUCLEAIRE CERN EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH CAISSE DE PENSIONS / PENSION FUND Caisse de Pensions - ELECTIONS - Pension Fund This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund. Candidate : Name : MYERS First Name : Stephen I have been at CERN since 1972, and was elected member of the Governing Board for the first time in 1998. The Governing Board then nominated me to the Investments Committee where I have been a member since the beginning of 1999. Since then I have actively participated in redefining and transforming the investment portfolio in order to improve the overall return and where possible reduce the risk. The portfolio has recently been greatly improved and now allows much simpler more transparent monitoring of our investment. I have also actively participated and hopefully made useful contributions in discussions conc...

  12. ELECTIONS PENSION FUND CANDIDATE NR 4

    CERN Multimedia

    2001-01-01

    ORGANISATION EUROPEENNE POUR LA RECHERCHE NUCLEAIRE CERN EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH CAISSE DE PENSIONS / PENSION FUND Caisse de Pensions - ELECTIONS - Pension Fund This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund. Candidate : Name : MYERS First Name : Stephen I have been at CERN since 1972, and was elected member of the Governing Board for the first time in 1998. The Governing Board then nominated me to the Investments Committee where I have been a member since the beginning of 1999. Since then I have actively participated in redefining and transforming the investment portfolio in order to improve the overall return and where possible reduce the risk. The portfolio has recently been greatly improved and now allows much simpler more transparent monitoring of our investment. I have also actively participated and hopefully made useful contributions in discussions conc...

  13. Halopentacenes: Promising Candidates for Organic Semiconductors

    International Nuclear Information System (INIS)

    Gong-He, Du; Zhao-Yu, Ren; Ji-Ming, Zheng; Ping, Guo

    2009-01-01

    We introduce polar substituents such as F, Cl, Br into pentacene to enhance the dissolubility in common organic solvents while retaining the high charge-carrier mobilities of pentacene. Geometric structures, dipole moments, frontier molecule orbits, ionization potentials and electron affinities, as well as reorganization energies of those molecules, and of pentacene for comparison, are successively calculated by density functional theory. The results indicate that halopentacenes have rather small reorganization energies (< 0.2 eV), and when the substituents are in position 2 or positions 2 and 9, they are polarity molecules. Thus we conjecture that they can easily be dissolved in common organic solvents, and are promising candidates for organic semiconductors. (condensed matter: electronicstructure, electrical, magnetic, and opticalproperties)

  14. [Identification of candidate genes and expression profiles, as doping biomarkers].

    Science.gov (United States)

    Paparini, A; Impagnatiello, F; Pistilli, A; Rinaldi, M; Gianfranceschi, G; Signori, E; Stabile, A M; Fazio, V; Rende, M; Romano Spica, V

    2007-01-01

    Administration of prohibited substances to enhance athletic performance represents an emerging medical, social, ethical and legal issue. Traditional controls are based on direct detection of substances or their catabolites. However out-of-competition doping may not be easily revealed by standard analytical methods. Alternative indirect control strategies are based on the evaluation of mid- and long-term effects of doping in tissues. Drug-induced long-lasting changes of gene expression may be taken as effective indicators of doping exposure. To validate this approach, we used real-time PCR to monitor the expression pattern of selected genes in human haematopoietic cells exposed to nandrolone, insulin-like growth factor I (IGF-I) or growth hormone (GH). Some candidate genes were found significantly and consistently modulated by treatments. Nandrolone up-regulated AR, ESR2 and PGR in K562 cells, and SRD5A1, PPARA and JAK2 in Jurkat cells; IGF-I up-regulated EPOR and PGR in HL60 cells, and SRD5A1 in Jurkat; GH up-regulated SRD5A1 and GHR in K562. GATA1 expression was down-regulated in IGF-1-treated HL60, ESR2 was down-regulated in nandrolone-treated Jurkat, and AR and PGR were down-regulated in GH-treated Jurkat. This pilot study shows the potential of molecular biology-based strategies in anti-doping controls.

  15. Buckyballs meet Viral Nanoparticles – Candidates for Biomedicine

    Science.gov (United States)

    Steinmetz, Nicole F.; Hong, Vu; Spoerke, Erik D.; Lu, Ping; Breitenkamp, Kurt; Finn, M.G.; Manchester, Marianne

    2009-01-01

    Fullerenes such as C60 show promise as functional components in several emerging technologies. For biomedical applications, C60 has been used in gene- and drug-delivery vectors, as imaging agents, and as photosensitizers in cancer therapy. A major drawback of C60 for bioapplications is its insolubility in water. To overcome this limitation, we covalently attached C60 derivatives to Cowpea mosaic virus and bacteriophage Qβ virus-like particles, as examples of naturally occurring viral nanoparticle (VNP) structures that have been shown to be promising candidates for biomedicine. Two different labeling strategies were employed, giving rise to water-soluble and stable VNP-C60 and VNP-PEG-C60 conjugates. Samples were characterized using a combination of transmission electron microscopy, scanning transmission electron microscopy (STEM), gel electrophoresis, size-exclusion chromatography, dynamic light scattering, and western blotting. “Click” chemistry bioconjugation using a PEG-modified propargyl-O-PEG-C60 derivative gave rise to high loadings of fullerene on the VNP surface, indicated by the imaging of individual C60 units by STEM. The cellular uptake of dye-labeled VNP-PEG-C60 complexes in a human cancer cell line was found by confocal microscopy to be robust, showing that cell internalization was not inhibited by the attached C60 units. These results open the door for the development of novel therapeutic devices with potential applications in photo-activated tumor therapy. PMID:19904938

  16. Mining biological databases for candidate disease genes

    Science.gov (United States)

    Braun, Terry A.; Scheetz, Todd; Webster, Gregg L.; Casavant, Thomas L.

    2001-07-01

    The publicly-funded effort to sequence the complete nucleotide sequence of the human genome, the Human Genome Project (HGP), has currently produced more than 93% of the 3 billion nucleotides of the human genome into a preliminary `draft' format. In addition, several valuable sources of information have been developed as direct and indirect results of the HGP. These include the sequencing of model organisms (rat, mouse, fly, and others), gene discovery projects (ESTs and full-length), and new technologies such as expression analysis and resources (micro-arrays or gene chips). These resources are invaluable for the researchers identifying the functional genes of the genome that transcribe and translate into the transcriptome and proteome, both of which potentially contain orders of magnitude more complexity than the genome itself. Preliminary analyses of this data identified approximately 30,000 - 40,000 human `genes.' However, the bulk of the effort still remains -- to identify the functional and structural elements contained within the transcriptome and proteome, and to associate function in the transcriptome and proteome to genes. A fortuitous consequence of the HGP is the existence of hundreds of databases containing biological information that may contain relevant data pertaining to the identification of disease-causing genes. The task of mining these databases for information on candidate genes is a commercial application of enormous potential. We are developing a system to acquire and mine data from specific databases to aid our efforts to identify disease genes. A high speed cluster of Linux of workstations is used to analyze sequence and perform distributed sequence alignments as part of our data mining and processing. This system has been used to mine GeneMap99 sequences within specific genomic intervals to identify potential candidate disease genes associated with Bardet-Biedle Syndrome (BBS).

  17. Quantitation of small intestinal permeability during normal human drug absorption

    OpenAIRE

    Levitt, David G

    2013-01-01

    Background Understanding the quantitative relationship between a drug?s physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations. Methods Given the blood concentration following an oral and intravenous dose, the time course of intestinal absorpti...

  18. Target Essentiality and Centrality Characterize Drug Side Effects

    OpenAIRE

    Wang, Xiujuan; Thijssen, Bram; Yu, Haiyuan

    2013-01-01

    Author Summary The ultimate goal of medical research is to develop effective treatments for disease with minimal side effects. Currently, about 20% of drug candidates failed at clinical trial phases II and III due to safety issues. Therefore, understanding the determining factors of drug side effects is of paramount importance to human health and the pharmaceutical industry. Here, we present the first systematic study to uncover key factors leading to drug side effects within the framework of...

  19. Legal Drugs Are Good Drugs and Illegal Drugs Are Bad Drugs

    OpenAIRE

    Indrati, Dina; Prasetyo, Herry

    2011-01-01

    ABSTRACT : Labelling drugs are important issue nowadays in a modern society. Although it is generally believed that legal drugs are good drugs and illegal drugs are bad drugs, it is evident that some people do not aware about the side effects of drugs used. Therefore, a key contention of this philosophical essay is that explores harms minimisation policy, discuss whether legal drugs are good drugs and illegal drugs are bad drugs and explores relation of drugs misuse in a psychiatric nursing s...

  20. A high content screening assay to predict human drug-induced liver injury during drug discovery.

    Science.gov (United States)

    Persson, Mikael; Løye, Anni F; Mow, Tomas; Hornberg, Jorrit J

    2013-01-01

    Adverse drug reactions are a major cause for failures of drug development programs, drug withdrawals and use restrictions. Early hazard identification and diligent risk avoidance strategies are therefore essential. For drug-induced liver injury (DILI), this is difficult using conventional safety testing. To reduce the risk for DILI, drug candidates with a high risk need to be identified and deselected. And, to produce drug candidates without that risk associated, risk factors need to be assessed early during drug discovery, such that lead series can be optimized on safety parameters. This requires methods that allow for medium-to-high throughput compound profiling and that generate quantitative results suitable to establish structure-activity-relationships during lead optimization programs. We present the validation of such a method, a novel high content screening assay based on six parameters (nuclei counts, nuclear area, plasma membrane integrity, lysosomal activity, mitochondrial membrane potential (MMP), and mitochondrial area) using ~100 drugs of which the clinical hepatotoxicity profile is known. We find that a 100-fold TI between the lowest toxic concentration and the therapeutic Cmax is optimal to classify compounds as hepatotoxic or non-hepatotoxic, based on the individual parameters. Most parameters have ~50% sensitivity and ~90% specificity. Drugs hitting ≥2 parameters at a concentration below 100-fold their Cmax are typically hepatotoxic, whereas non-hepatotoxic drugs typically hit based on nuclei count, MMP and human Cmax, we identified an area without a single false positive, while maintaining 45% sensitivity. Hierarchical clustering using the multi-parametric dataset roughly separates toxic from non-toxic compounds. We employ the assay in discovery projects to prioritize novel compound series during hit-to-lead, to steer away from a DILI risk during lead optimization, for risk assessment towards candidate selection and to provide guidance of safe

  1. Drugs@FDA: FDA Approved Drug Products

    Science.gov (United States)

    ... Cosmetics Tobacco Products Home Drug Databases Drugs@FDA Drugs@FDA: FDA Approved Drug Products Share Tweet Linkedin Pin it More sharing ... Download Drugs@FDA Express for free Search by Drug Name, Active Ingredient, or Application Number Enter at ...

  2. Study Drugs

    OpenAIRE

    Lam, Stephanie Phuong; Roosta, Natalie; Nielsen, Mikkel Fuhr; Meyer, Maria Holmgaard; Friis, Katrine Birk

    2016-01-01

    In recent years, students around the world, started to use preparations as Ritalin and Modafinil,also known as study drugs, to improve their cognitive abilities1. It is a common use among thestudents in United States of America, but it is a new tendency in Denmark. Our main focus is tolocate whether study drugs needs to be legalized in Denmark or not. To investigate this ourstarting point is to understand central ethical arguments in the debate. We have chosen twoarguments from Nick Bostrom a...

  3. Candidate Quality Measures for Hand Surgery.

    Science.gov (United States)

    2017-11-01

    Quality measures are tools used by physicians, health care systems, and payers to evaluate performance, monitor the outcomes of interventions, and inform quality improvement efforts. A paucity of quality measures exist that address hand surgery care. We completed a RAND/UCLA (University of California Los Angeles) Delphi Appropriateness process with the goal of developing and evaluating candidate hand surgery quality measures to be used for national quality measure development efforts. A consortium of 9 academic upper limb surgeons completed a RAND/UCLA Delphi Appropriateness process to evaluate the importance, scientific acceptability, usability, and feasibility of 44 candidate quality measures. These addressed hand problems the panelists felt were most appropriate for quality measure development. Panelists rated the measures on an ordinal scale between 1 (definitely not valid) and 9 (definitely valid) in 2 rounds (preliminary round and final round) with an intervening face-to-face discussion. Ratings from 1 to 3 were considered not valid, 4 to 6 as equivocal or uncertain, and 7 to 9 as valid. If no more than 2 of the 9 ratings were outside the 3-point range that included the median (1-3, 4-6, or 7-9), the panelists were considered to be in agreement. If 3 or more of the panelists' ratings of a measure were within the 1 to 3 range and 3 or more ratings were in the 7 to 9 range, the panelists were considered to be in disagreement. There was agreement on 43% (19) of the measures as important, 27% (12) as scientifically sound, 48% (21) as usable, and 59% (26) as feasible to complete. Ten measures met all 4 of these criteria and were, therefore, considered valid measurements of quality. Quality measures that were developed address outcomes (patient-reported outcomes for assessment and improvement of function) and processes of care (utilization rates of imaging, antibiotics, occupational therapy, ultrasound, and operative treatment). The consortium developed 10

  4. Recent advances in targeted drug therapy for hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    FAN Yongqiang

    2018-02-01

    Full Text Available More and more clinical trials have proved the efficacy of targeted drugs in the treatment of hepatocellular carcinoma (HCC. With the development of science and technology, more and more targeted drugs have appeared. In recent years, targeted drugs such as regorafenib and ramucirumab have shown great potential in related clinical trials. In addition, there are ongoing clinical trials for second-line candidate drugs, such as c-Met inhibitors tivantinib and cabozantinib and a VEGFR-2 inhibitor ramucirumab. This article summarizes the advances in targeted drug therapy for HCC and related trial data, which provides a reference for further clinical trials and treatment.

  5. Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma.

    Science.gov (United States)

    Bosse, Kristopher R; Raman, Pichai; Zhu, Zhongyu; Lane, Maria; Martinez, Daniel; Heitzeneder, Sabine; Rathi, Komal S; Kendsersky, Nathan M; Randall, Michael; Donovan, Laura; Morrissy, Sorana; Sussman, Robyn T; Zhelev, Doncho V; Feng, Yang; Wang, Yanping; Hwang, Jennifer; Lopez, Gonzalo; Harenza, Jo Lynne; Wei, Jun S; Pawel, Bruce; Bhatti, Tricia; Santi, Mariarita; Ganguly, Arupa; Khan, Javed; Marra, Marco A; Taylor, Michael D; Dimitrov, Dimiter S; Mackall, Crystal L; Maris, John M

    2017-09-11

    We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues. In addition, we demonstrate that GPC2 is required for neuroblastoma proliferation. Finally, we develop a GPC2-directed antibody-drug conjugate that is potently cytotoxic to GPC2-expressing neuroblastoma cells. Collectively, these findings validate GPC2 as a non-mutated neuroblastoma oncoprotein and candidate immunotherapeutic target. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Loading of microcontainers for oral drug delivery

    DEFF Research Database (Denmark)

    Marizza, Paolo

    The pharmaceutical research is facing several obstacles in the development of drug products for the oral delivery. The main problem deals with the intrinsic chemical nature of the new drug candidates, which are often poorly soluble and barely absorbed in the gastro-intestinal tract. Furthermore......, they are usually degraded before they are absorbed. These combined factors considerably reduce the bioavailability of many active ingredients. Several strategies have been developed to overcome these challenges. One of them are microfabricated drug delivery devices. Microreservoir based-systems are characterized...... of UV photolithography was developed. The fabrication of polymer patterns was optimized and loading with both small hydrophobic drugs and proteins was demonstrated. Finally, structural properties of hydrogels were elucidated by rheology and NMR with the perspective of controlling the drug release...

  7. Permeation enhancer strategies in transdermal drug delivery.

    Science.gov (United States)

    Marwah, Harneet; Garg, Tarun; Goyal, Amit K; Rath, Goutam

    2016-01-01

    Today, ∼74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system.

  8. Photon defects in noncommutative standard model candidates

    International Nuclear Information System (INIS)

    Abel, S.A.; Khoze, V.V.

    2006-06-01

    Restrictions imposed by gauge invariance in noncommutative spaces together with the effects of ultraviolet/infrared mixing lead to strong constraints on possible candidates for a noncommutative extension of the Standard Model. We study a general class of noncommutative models consistent with these restrictions. Specifically we consider models based upon a gauge theory with the gauge group U(N 1 ) x U(N 2 ) x.. x U(N m ) coupled to matter fields transforming in the (anti)-fundamental, bi-fundamental and adjoint representations. We pay particular attention to overall trace-U(1) factors of the gauge group which are affected by the ultraviolet/infrared mixing. Typically, these trace-U(1) gauge fields do not decouple sufficiently fast in the infrared, and lead to sizable Lorentz symmetry violating effects in the low-energy effective theory. In a 4-dimensional theory on a continuous space-time making these effects unobservable would require making the effects of noncommutativity tiny, M NC >> M P . This severely limits the phenomenological prospects of such models. However, adding additional universal extra dimensions the trace-U(1) factors decouple with a power law and the constraint on the noncommutativity scale is weakened considerably. Finally, we briefly mention some interesting properties of the photon that could arise if the noncommutative theory is modified at a high energy scale. (Orig.)

  9. ELECTIONS PENSION FUND CANDIDATE NR 5

    CERN Multimedia

    2001-01-01

    ORGANISATION EUROPEENNE POUR LA RECHERCHE NUCLEAIRE CERN EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH CAISSE DE PENSIONS / PENSION FUND Caisse de Pensions - ELECTIONS - Pension Fund This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund. Candidate :  Name : Sonnemann  First Name : Florian Since my arrival at CERN in 1997 I have worked in the accelerator and administrative sectors. I have recently been elected as member of the Staff Council and of the Executive Committee of the Staff Association in which I am actively following matters concerning the Pension Fund. My candidature for the Governing Board of the CERN Pension Fund is mainly motivated to add my part in ensuring a solid financial situation of the Pension Fund. The Pension Fund is our only social security system. I wish to play a role in ensuring that the pensions will remain a secure revenue for all staff membe...

  10. ELECTIONS PENSION FUND 5th candidate

    CERN Multimedia

    2001-01-01

    ORGANISATION EUROPEENNE POUR LA RECHERCHE NUCLEAIRE CERN EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH CAISSE DE PENSIONS / PENSION FUND Caisse de Pensions - ELECTIONS - Pension Fund This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund. Candidate :  Name : Sonnemann  First Name : Florian Since my arrival at CERN in 1997 I have worked in the accelerator and administrative sectors. I have recently been elected as member of the Staff Council and of the Executive Committee of the Staff Association in which I am actively following matters concerning the Pension Fund. My candidature for the Governing Board of the CERN Pension Fund is mainly motivated to add my part in ensuring a solid financial situation of the Pension Fund. The Pension Fund is our only social security system. I wish to play a role in ensuring that the pensions will remain a secure revenue for all staff membe...

  11. Face time: educating face transplant candidates.

    Science.gov (United States)

    Lamparello, Brooke M; Bueno, Ericka M; Diaz-Siso, Jesus Rodrigo; Sisk, Geoffroy C; Pomahac, Bohdan

    2013-01-01

    Face transplantation is the innovative application of microsurgery and immunology to restore appearance and function to those with severe facial disfigurements. Our group aims to establish a multidisciplinary education program that can facilitate informed consent and build a strong knowledge base in patients to enhance adherence to medication regimes, recovery, and quality of life. We analyzed handbooks from our institution's solid organ transplant programs to identify topics applicable to face transplant patients. The team identified unique features of face transplantation that warrant comprehensive patient education. We created a 181-page handbook to provide subjects interested in pursuing transplantation with a written source of information on the process and team members and to address concerns they may have. While the handbook covers a wide range of topics, it is easy to understand and visually appealing. Face transplantation has many unique aspects that must be relayed to the patients pursuing this novel therapy. Since candidates lack third-party support groups and programs, the transplant team must provide an extensive educational component to enhance this complex process. As face transplantation continues to develop, programs must create sound education programs that address patients' needs and concerns to facilitate optimal care.

  12. Virus-like particles as nanovaccine candidates

    International Nuclear Information System (INIS)

    Guillen, G; Aguilar, J C; Dueñas, S; Hermida, L; Iglesias, E; Penton, E; Lobaina, Y; Lopez, M; Mussachio, A; Falcon, V; Alvarez, L; Martinez, G; Gil, L; Valdes, I; Izquierdo, A; Lazo, L; Marcos, E; Guzman, G; Muzio, V; Herrera, L

    2013-01-01

    The existing vaccines are mainly limited to the microorganisms we are able to culture and produce and/or to those whose killing is mediated by humoral response (antibody mediated). It has been more difficult to develop vaccines capable of inducing a functional cellular response needed to prevent or cure chronic diseases. New strategies should be taken into account in the improvement of cell-based immune responses in order to prevent and control the infections and eventually clear the virus. Preclinical and clinical results with vaccine candidates developed as a vaccine platform based on virus-like particles (VLPs) evidenced their ability to stimulate mucosal as well as systemic immunity. Particles based on envelope, membrane or nucleocapsid microbial proteins induce a strong immune response after nasal or parenteral administration in mice, non-human primates and humans. In addition, the immune response obtained was modulated in a Th1 sense. The VLPs were also able to immunoenhance the humoral and cellular immune responses against several viral pathogens. Studies in animals and humans with nasal and systemic formulations evidenced that it is possible to induce functional immune response against HBV, HCV, HIV and dengue virus. (paper)

  13. ELECTIONS PENSION FUND CANDIDATE NR 1

    CERN Multimedia

    2001-01-01

    ORGANISATION EUROPEENNE POUR LA RECHERCHE NUCLEAIRE CERN EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH CAISSE DE PENSIONS / PENSION FUND Caisse de Pensions - ELECTIONS - Pension Fund This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund. Candidate : Name : CHIAVERI First Name : Enrico I have been a CERN staff member since 1973 and have always been interested in our working conditions. As a member of the Executive Committee of the Staff Association I participated from 1980 to 1984 in the Working Group on Pensions mandated by the CERN Council. This commitment led to my becoming a member of the Governing Board of the Pension Fund in 1983, since when I have taken an active part in various commissions and working groups (Real Estate Asset Management Committee, Working Group on Actuarial Matters etc.); in so doing I have gained a thorough knowledge of different areas of the Pension Fund. Since ...

  14. ELECTIONS PENSION FUND CANDIDATE NO 1

    CERN Multimedia

    2000-01-01

    This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund. Candidate : Name: MAURINFirst Name:Guy I have been a member of the personnel since 1967 and as early as 1972 I was involved, in my capacity as President of the Staff Association, in the improvement of the Pension Fund benefits. As for most of us the Pension Fund is the only social provident scheme to which we belong, it is important to ensure that it is well managed and in balance. As a member of the Governing Board since 1974 and Vice-Chairman of this Board since 1977, I have continued to pursue these objectives.One of the main responsibilities of the Governing Board is our asset investment policy. The Investment Committee, of which I am Chairman, must have an overall view of the management of our 4 billion Swiss francs and seek the best yield with minimum risk. The investment structure must continuously be adapted...

  15. ELECTIONS PENSION FUND CANDIDATE NR 2

    CERN Multimedia

    2001-01-01

    ORGANISATION EUROPEENNE POUR LA RECHERCHE NUCLEAIRE CERN EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH CAISSE DE PENSIONS / PENSION FUND Caisse de Pensions - ELECTIONS - Pension Fund This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund. Candidate : Name : FRANDSEN First Name : Poul Kjaer  I have been member of the staff since 1974, and member of staff council for more than 12 years, and my main motivation has been to work for improving the social conditions of the CERN staff. A very important pillar of this is a sound and healthy pension fund. A capitalised scheme has been and still is the best choice for assuring the benefits for the CERN staff, present and future, this social system being part of the whole necessary to attract the best staff to the future High Energy Physics in Europe. However, even the hypothetic close down of the Organisation should allow the benefits to exi...

  16. ELECTIONS PENSION FUND 2nd candidate

    CERN Multimedia

    2001-01-01

    ORGANISATION EUROPEENNE POUR LA RECHERCHE NUCLEAIRE CERN EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH CAISSE DE PENSIONS / PENSION FUND Caisse de Pensions - ELECTIONS - Pension Fund This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund. Candidate : Name : FRANDSEN First Name : Poul Kjaer  I have been member of the staff since 1974, and member of staff council for more than 12 years, and my main motivation has been to work for improving the social conditions of the CERN staff. A very important pillar of this is a sound and healthy pension fund. A capitalised scheme has been and still is the best choice for assuring the benefits for the CERN staff, present and future, this social system being part of the whole necessary to attract the best staff to the future High Energy Physics in Europe. However, even the hypothetic close down of the Organisation should allow the benefits to exi...

  17. Characterisation of a candidate dual AGN

    Science.gov (United States)

    Lena, D.; Panizo-Espinar, G.; Jonker, P. G.; Torres, M.; Heida, M.

    2018-05-01

    We present Chandra and optical observations of a candidate dual AGN discovered serendipitously while searching for recoiling black holes via a cross-correlation between the serendipitous XMM source catalog (2XMMi) and SDSS-DR7 galaxies with a separation no larger than ten times the sum of their Petrosian radii. The system has a stellar mass ratio M1/M2 ≈ 0.7. One of the galaxies (Source 1) shows clear evidence for AGN activity in the form of hard X-ray emission and optical emission-line diagnostics typical of AGN ionisation. The nucleus of the other galaxy (Source 2) has a soft X-ray spectrum, bluer colours, and optical emission line ratios dominated by stellar photoionisation with a "composite" signature, which might indicate the presence of a weak AGN. When plotted on a diagram with X-ray luminosity vs [OIII] luminosity both nuclei fall within the locus defined by local Seyfert galaxies. From the optical spectrum we estimate the electron densities finding n1 active nature of Source 1 can be established with confidence, whether the nucleus of Source 2 is active remains a matter of debate. Evidence that a faint AGN might reside in its nucleus is, however, tantalising.

  18. ELECTIONS PENSION FUND CANDIDATE NO 2

    CERN Multimedia

    2000-01-01

    This candidature has been duly registered and is hereby presented in accordance with paragraph 6.h of the Regulations for Elections to the Governing Board of the Pension Fund.   Candidate: Name: RANJARDFirst Name: Florence Having been a member of the Governing Board of the Pension Fund since 1983 as Guy Maurin’s alternate, I am standing for a further 3-year term of office. Over the past few years work has concentrated essentially on following items: Monitoring of the work of the fund managers and their performances. The three-yearly study of the Fund’s actuarial situation. The pension guarantees ­ second phase. The Fund is approaching its maturity: the level of benefits exceeds contributions. In this context it has to strike a suitable balance between management of the risk from a dynamic investment policy, while a prudent policy avoiding any significant loss of its capital. These will be my concerns within the Governing Board of the Pension Fund if you...

  19. Drug Facts

    Medline Plus

    Full Text Available ... Phone Numbers and Websites Search Share Listen English Español Information about this page Click on the button ... sobre el abuso de drogas, y adicción. English Español About the National Institute on Drug Abuse (NIDA) | ...

  20. Drugs reviews

    African Journals Online (AJOL)

    Angel_D

    tests (LFTs) to monitor hepatotoxicity (liver [hepatic] damage) is uncommon in many resource-poor ... cholesterol ester storage disease. ... The problem with many patients is that they are taking several drugs often ... Urine, saliva and other body fluids may be coloured orange-red: this can be very alarming to patients.

  1. Drug resistance

    NARCIS (Netherlands)

    Gorter, J.A.; Potschka, H.; Noebels, J.L.; Avoli, M.; Rogawski, M.A.; Olsen, R.W.; Delgado-Escueta, A.V.

    2012-01-01

    Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure

  2. Capping Drugs

    Indian Academy of Sciences (India)

    preventing disease in human beings or in animals. In the process ... of requirement. In the process, they may cause toxic side effects. .... the liver to release the physiologically active drug. Similarly ... patients addicted to alcohol. However, it is a ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... Prevention Phone Numbers and Websites Search Share Listen English Español Information about this page Click on the ... información sobre el abuso de drogas, y adicción. English Español About the National Institute on Drug Abuse ( ...

  4. Physical attractiveness, issue agreement, and assimilation effects in candidate appraisal.

    Science.gov (United States)

    Schubert, James N; Curran, Margaret Ann; Strungaru, Carmen

    2011-01-01

    This study examines the cognitive and affective factors of candidate appraisal by manipulating candidate attractiveness and levels of issue agreement with voters. Drawing upon research in evolutionary psychology and cognitive neuroscience, this analysis proposes that automatic processing of physical appearance predisposes affective disposition toward more attractive candidates, thereby influencing cognitive processing of issue information. An experimental design presented attractive and unattractive candidates who were either liberal or conservative in a mock primary election. The data show strong partial effects for appearance on vote intention, an interaction between appearance and issue agreement, and a tendency for voters to assimilate the dissimilar views of attractive candidates. We argue that physical appearance is important in primary elections when the differences in issue positions and ideology between candidates is small.

  5. Lost in translation? Role of metabolomics in solving translational problems in drug discovery and development

    NARCIS (Netherlands)

    Greef, J. van der; Adourian, A.; Muntendam, P.; McBurney, R.N.

    2006-01-01

    Too few drug discovery projects generate a marketed drug product, often because preclinical studies fail to predict the clinical experience with a drug candidate. Improving the success of preclinical-to-clinical translation is of paramount importance in optimizing the pharmaceutical value chain.

  6. Leveraging 3D chemical similarity, target and phenotypic data in the identification of drug-protein and drug-adverse effect associations.

    Science.gov (United States)

    Vilar, Santiago; Hripcsak, George

    2016-01-01

    Drug-target identification is crucial to discover novel applications for existing drugs and provide more insights about mechanisms of biological actions, such as adverse drug effects (ADEs). Computational methods along with the integration of current big data sources provide a useful framework for drug-target and drug-adverse effect discovery. In this article, we propose a method based on the integration of 3D chemical similarity, target and adverse effect data to generate a drug-target-adverse effect predictor along with a simple leveraging system to improve identification of drug-targets and drug-adverse effects. In the first step, we generated a system for multiple drug-target identification based on the application of 3D drug similarity into a large target dataset extracted from the ChEMBL. Next, we developed a target-adverse effect predictor combining targets from ChEMBL with phenotypic information provided by SIDER data source. Both modules were linked to generate a final predictor that establishes hypothesis about new drug-target-adverse effect candidates. Additionally, we showed that leveraging drug-target candidates with phenotypic data is very useful to improve the identification of drug-targets. The integration of phenotypic data into drug-target candidates yielded up to twofold precision improvement. In the opposite direction, leveraging drug-phenotype candidates with target data also yielded a significant enhancement in the performance. The modeling described in the current study is simple and efficient and has applications at large scale in drug repurposing and drug safety through the identification of mechanism of action of biological effects.

  7. Drug abuse first aid

    Science.gov (United States)

    ... use of these drugs is a form of drug abuse. Medicines that are for treating a health problem ... about local resources. Alternative Names Overdose from drugs; Drug abuse first aid References Myck MB. Hallucinogens and drugs ...

  8. Physical education candidate teachers' beliefs about vocational self-esteem

    OpenAIRE

    OZSAKER, Murat; CANPOLAT, A. Meliha

    2014-01-01

    The purpose of this study was to determine epistemological belief and vocational self-esteem physical education candidate teachers of Physical Education and Sports Department in 3 different universities, and also to examine effect of epistemological beliefs on vocational self-esteem. A total of 346 candidate teacher respondents (137 female and 209 male) participated in the study. Epistemological Beliefs and Vocational Self-Esteem Scale were used to determine candidate teachers’ epistemologica...

  9. Selection of radio pulsar candidates using artificial neural networks

    OpenAIRE

    Eatough, R. P.; Molkenthin, N.; Kramer, M.; Noutsos, A.; Keith, M. J.; Stappers, B. W.; Lyne, A. G.

    2010-01-01

    Radio pulsar surveys are producing many more pulsar candidates than can be inspected by human experts in a practical length of time. Here we present a technique to automatically identify credible pulsar candidates from pulsar surveys using an artificial neural network. The technique has been applied to candidates from a recent re-analysis of the Parkes multi-beam pulsar survey resulting in the discovery of a previously unidentified pulsar.

  10. Identification Of Protein Vaccine Candidates Using Comprehensive Proteomic Analysis Strategies

    National Research Council Canada - National Science Library

    Rohrbough, James G

    2007-01-01

    Presented in this dissertation are proteomic analysis studies focused on identifying proteins to be used as vaccine candidates against Coccidioidomycosis, a potentially fatal human pulmonary disease...

  11. Drug Safety: Managing Multiple Drugs

    Science.gov (United States)

    ... This series is produced by Consumers Union and Consumer Reports Best Buy Drugs , a public information project sup- ported by grants from the Engelberg Foundation and the National Library of Medicine of ... Consumer and Prescriber Education Grant Program which is funded ...

  12. Legal Drugs Are Good Drugs And Illegal Drugs Are Bad Drugs

    Directory of Open Access Journals (Sweden)

    Dina Indrati

    2011-07-01

    Full Text Available ABSTRACT : Labelling drugs are important issue nowadays in a modern society. Although it is generally believed that legal drugs are good drugs and illegal drugs are bad drugs, it is evident that some people do not aware about the side effects of drugs used. Therefore, a key contention of this philosophical essay is that explores harms minimisation policy, discuss whether legal drugs are good drugs and illegal drugs are bad drugs and explores relation of drugs misuse in a psychiatric nursing setting and dual diagnosis.Key words: Legal, good drugs, illegal, bad drugs.

  13. Chemical Genomics and Emerging DNA Technologies in the Identification of Drug Mechanisms and Drug Targets

    DEFF Research Database (Denmark)

    Olsen, Louise Cathrine Braun; Færgeman, Nils J.

    2012-01-01

    and validate therapeutic targets and to discover drug candidates for rapidly and effectively generating new interventions for human diseases. The recent emergence of genomic technologies and their application on genetically tractable model organisms like Drosophila melanogaster,Caenorhabditis elegans...... critical roles in the genomic age of biological research and drug discovery. In the present review we discuss how simple biological model organisms can be used as screening platforms in combination with emerging genomic technologies to advance the identification of potential drugs and their molecular...

  14. Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans.

    Science.gov (United States)

    Fujiwara, Ryoichi; Yoda, Emiko; Tukey, Robert H

    2018-02-01

    More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  15. HOT HIGH-MASS ACCRETION DISK CANDIDATES

    International Nuclear Information System (INIS)

    Beuther, H.; Walsh, A. J.; Longmore, S. N.

    2009-01-01

    To better understand the physical properties of accretion disks in high-mass star formation, we present a study of a dozen high-mass accretion disk candidates observed at high spatial resolution with the Australia Telescope Compact Array (ATCA) in the high-excitation (4,4) and (5,5) lines of NH 3 . All of our originally selected sources were detected in both NH 3 transitions, directly associated with CH 3 OH Class II maser emission and implying that high-excitation NH 3 lines are good tracers of the dense gas components in hot-core-type targets. Only the one source that did not satisfy the initial selection criteria remained undetected. From the 11 mapped sources, six show clear signatures of rotation and/or infall motions. These signatures vary from velocity gradients perpendicular to the outflows, to infall signatures in absorption against ultracompact H II regions, to more spherical infall signatures in emission. Although our spatial resolution is ∼1000 AU, we do not find clear Keplerian signatures in any of the sources. Furthermore, we also do not find flattened structures. In contrast to this, in several of the sources with rotational signatures, the spatial structure is approximately spherical with sizes exceeding 10 4 AU, showing considerable clumpy sub-structure at even smaller scales. This implies that on average typical Keplerian accretion disks-if they exist as expected-should be confined to regions usually smaller than 1000 AU. It is likely that these disks are fed by the larger-scale rotating envelope structure we observe here. Furthermore, we do detect 1.25 cm continuum emission in most fields of view. While in some cases weak cm continuum emission is associated with our targets, more typically larger-scale H II regions are seen offset more than 10'' from our sources. While these H II regions are unlikely to be directly related to the target regions, this spatial association nevertheless additionally stresses that high-mass star formation rarely

  16. Academic Dishonesty Tendencies and Values of Teacher Candidates

    Directory of Open Access Journals (Sweden)

    Ayşegül KADI

    2016-12-01

    Full Text Available The purpose of this study was to examine the values and academic dishonesty tendencies of teacher candidates. The population of this study included teacher candidates who received pedagogic formation education during 2013-2014 academic semester at the Faculty of Education at Ege University. The study was conducted with 244 teacher candidates, who were chosen through convenient sampling method. Academic Dishonesty Tendency Scale and Portrait Values Questionnaire were used to collect data. It was a correlational study due to the investigation of the relationship between values and academic dishonesty tendencies of teacher candidates. It was also a survey study since the academic dishonesty tendencies and values of teacher candidates were examined in relation to demographic variables. The results suggested that there wass a significant difference between the values and academic dishonesty tendencies of teacher candidates for gender variable. The values and academic dishonesty tendencies of teacher candidates did not differ for different fields of study. There was not a significant relationship between the academic dishonesty tendencies and values of teacher candidates.

  17. University Offer Rates for Candidates from Different Ethnic Categories

    Science.gov (United States)

    Noden, Philip; Shiner, Michael; Modood, Tariq

    2014-01-01

    Previous research suggested that candidates from some black and minority ethnic groups were less likely to receive an offer of a place from an "old" university. These findings were disputed in a re-analysis carried out for HEFCE which found that only Pakistani candidates were significantly less likely to receive offers (from both…

  18. MAT@USC Candidates and Latino English Language Learners

    Science.gov (United States)

    Lomeli, Cynthia Leticia

    2012-01-01

    The purpose of this study was to further understand the perceptions of MAT@USC teacher candidates and how their perceptions and previous experiences affect the educational experiences of Latino English language learners. Three questions were developed to guide this study: (1) What are the perceptions of MAT@USC candidates in selected courses…

  19. Measuring College Success for International Baccalaureate Diploma and Certificate Candidates

    Science.gov (United States)

    Hill, Jennifer Coles

    2018-01-01

    This quantitative study was conducted at a private international high school. The study purpose was to investigate United States college trends comparing International Baccalaureate Diploma Program candidates and International Baccalaureate Non-Diploma Program candidates from the same school in Asia. Data was collected for the Classes of 2007-2012…

  20. Assessing Student Teaching Experiences: Teacher Candidates' Perceptions of Preparedness

    Science.gov (United States)

    Lee, Joohi; Tice, Kathleen; Collins, Denise; Brown, Amber; Smith, Cleta; Fox, Jill

    2012-01-01

    The purpose of this study is to investigate the effectiveness of student teaching experiences by measuring teacher candidates' perceptions of their preparedness. The participants were 130 teacher candidates who had completed their student teaching as part of a program preparing them to teach children in pre-K through grade 4. Teacher candidates…

  1. Undergraduate Teacher Candidate Perceptions Integrating Technology in Classroom Instruction

    Science.gov (United States)

    Anderson, Charlise Askew

    2016-01-01

    The purpose of this study was to analyze undergraduate teacher candidates' perceptions on integrating technology in the classroom. The study was embedded in the "Technology Pedagogical Content Knowledge" theoretical model. A sample of 143 undergraduate teacher candidates participated in the study. They were asked to address items on a…

  2. Elections, Information, and State-Dependent Candidate Quality

    DEFF Research Database (Denmark)

    Jensen, Thomas

    voters are uncertain about the state. Candidates are fully informed and completely office-motivated. With a reasonable restriction on voters' beliefs, an equilibrium where candidates' positions reveal the true state does not exist. Non-revealing equilibria always exist. Some main findings...

  3. Five kepler target stars that show multiple transiting exoplanet candidates

    DEFF Research Database (Denmark)

    Steffen..[], Jason H.; Batalha, N. M.; Broucki, W J.

    2010-01-01

    We present and discuss five candidate exoplanetary systems identified with the Kepler spacecraft. These five systems show transits from multiple exoplanet candidates. Should these objects prove to be planetary in nature, then these five systems open new opportunities for the field of exoplanets a...

  4. Teacher Candidate Mental Health and Mental Health Literacy

    Science.gov (United States)

    Dods, Jennifer

    2016-01-01

    Providing teacher candidates with a strong foundation in mental health literacy during their teacher education program is crucial in ensuring novice teachers are prepared to support the mental health needs of their students. In addition to responding to students, teacher candidates are typically at an age when mental health disorders are common…

  5. 14 CFR 91.321 - Carriage of candidates in elections.

    Science.gov (United States)

    2010-01-01

    ... carrier or commercial operator; (2) You carry the candidate, agent, or person traveling on behalf of a... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Carriage of candidates in elections. 91.321 Section 91.321 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION...

  6. Metaphors of Social Studies Teacher Candidates on Democracy

    Science.gov (United States)

    Tural, Aysegül

    2018-01-01

    Democracy is a form of government in which principle of equality is based, human rights and freedoms are protected. In this research, it is aimed to reveal democracy perceptions of social science teacher candidates through metaphors. Towards this aim, 105 social science teacher candidates are consulted about their democracy opinions. Study is a…

  7. Elementary School Teacher Candidates' Perceptions of Good Problems

    Science.gov (United States)

    Lee, Ji-Eun; Kim, Kyoung-Tae

    2005-01-01

    This study describes a classroom action research activity regarding a group of elementary school teacher candidates' perceptions of good mathematics problems. A questionnaire containing 20 problems was given, and the candidates were asked to rate the quality of each problem on a 5-point scale. The results revealed that the majority of the teacher…

  8. Fostering the Development of Chemistry Teacher Candidates: A Bioecological Approach

    Science.gov (United States)

    Lewthwaite, Brian; Wiebe, Rick

    2012-01-01

    This ongoing research inquiry investigates through the analysis of teacher candidate experiences the factors influencing two groups of chemistry teacher candidates' development during their extended practica in their second and final year of an after-degree bachelor of education at a university in central Canada. The tenets of Bronfenbrenner's…

  9. Web tools for the prioritization of candidate disease genes.

    NARCIS (Netherlands)

    Oti, M.O.; Ballouz, S.; Wouters, M.A.

    2011-01-01

    Despite increasing sequencing capacity, genetic disease investigation still frequently results in the identification of loci containing multiple candidate disease genes that need to be tested for involvement in the disease. This process can be expedited by prioritizing the candidates prior to

  10. Class Teacher Candidates' Opinions on Genetically Modified Organisms (GMO)

    Science.gov (United States)

    Ural Keles, Pinar; Aydin, Suleyman

    2017-01-01

    This study was conducted to determine the Class teacher candidates' opinions on Genetically Modified Organisms. The study was carried out with 101 teacher candidates who were studying in the 3rd grade of Agri Ibrahim Çeçen University Classroom Teacher Department in 2016-2017 academic year. Of the students who participated in the survey, 56 were…

  11. t Leave Before You Understand': Supporting Masters Candidates in ...

    African Journals Online (AJOL)

    example, due to increased enrolments and the 'pile up' effect, South African academics are increasingly burdened with ... postgraduate level. This research study is part of a larger study on candidates' experiences of postgraduate business studies, with the aim of enhancing supervision practices for the benefit of candidates.

  12. Psychometric Personality Differences Between Candidates in Astronaut Selection.

    Science.gov (United States)

    Mittelstädt, Justin M; Pecena, Yvonne; Oubaid, Viktor; Maschke, Peter

    This paper investigates personality traits as potential factors for success in an astronaut selection by comparing personality profiles of unsuccessful and successful astronaut candidates in different phases of the ESA selection procedure. It is further addressed whether personality traits could predict an overall assessment rating at the end of the selection. In 2008/2009, ESA performed an astronaut selection with 902 candidates who were either psychologically recommended for mission training (N = 46) or failed in basic aptitude (N = 710) or Assessment Center and interview testing (N = 146). Candidates completed the Temperament Structure Scales (TSS) and the NEO Personality Inventory Revised (NEO-PI-R). Those candidates who failed in basic aptitude testing showed higher levels of Neuroticism (M = 49.8) than the candidates who passed that phase (M = 45.4 and M = 41.6). Additionally, candidates who failed in basic testing had lower levels of Agreeableness (M = 132.9) than recommended candidates (M = 138.1). TSS scales for Achievement (r = 0.19) and Vitality (r = 0.18) showed a significant correlation with the overall assessment rating given by a panel board after a final interview. Results indicate that a personality profile similar to Helmreich's "Right Stuff" is beneficial in astronaut selection. Influences of test anxiety on performance are discussed. Mittelstädt JM, Pecena Y, Oubaid V, Maschke P. Psychometric personality differences between candidates in astronaut selection. Aerosp Med Hum Perform. 2016; 87(11):933-939.

  13. Social Studies Teacher Candidates' Views on Historical Thinking Skills

    Science.gov (United States)

    Ozmen, Cengiz

    2015-01-01

    Current study aimed to present Social Studies teacher candidates' views on historical thinking skills. Study was conducted using qualitative design and working group was composed of a total of 121 teacher candidates (62 females and 59 males) attending Social Studies Teaching Department of Karadeniz Technical University and Adiyaman University…

  14. Candidate Political Philosophy: Revelations in the 1960 and 1976 Debates.

    Science.gov (United States)

    Meadow, Robert G.; Jackson-Beeck, Marilyn

    Since voters rarely have access to a candidate's unexpurgated statements, they rely on political advertising, film footage, and media interpretations. Thus, their expectations of candidates generally reflect selective reporting and self-aggrandizement. A framework for researching the degree of understanding reached between politicians and the…

  15. Teacher Candidate Technology Integration: For Student Learning or Instruction?

    Science.gov (United States)

    Clark, Cynthia; Zhang, Shaoan; Strudler, Neal

    2015-01-01

    Transfer of instructional technology knowledge for student-centered learning by teacher candidates is investigated in this study. Using the transfer of learning theoretical framework, a mixed methods research design was employed to investigate whether secondary teacher candidates were able to transfer the instructional technology knowledge for…

  16. Holmes versus Traditional Teacher Candidates: Labor Market Receptivity.

    Science.gov (United States)

    Young, I. Phillip; And Others

    1997-01-01

    "Typical" paper credentials were used to create 12 hypothetical teacher candidates. Credential contents were varied to reflect all combinations of college preparatory institutions (Holmes vs. traditional), education degree types, and chronological ages. Randomly selected high school principals then evaluated candidates. Holmes-prepared…

  17. Candidate gene studies and the quest for the entrepreneurial gene

    NARCIS (Netherlands)

    M.J.H.M. van der Loos (Matthijs); Ph.D. Koellinger (Philipp); P.J.F. Groenen (Patrick); C.A. Rietveld (Niels); F. Rivadeneira Ramirez (Fernando); F.J.A. van Rooij (Frank); A.G. Uitterlinden (André); A. Hofman (Albert); A.R. Thurik (Roy)

    2011-01-01

    textabstractCandidate gene studies of human behavior are gaining interest in economics and entrepreneurship research. Performing and interpreting these studies is not straightforward because the selection of candidates influences the interpretation of the results. As an example, Nicolaou et al.

  18. Integrated Metabolo-Transcriptomics Reveals Fusarium Head Blight Candidate Resistance Genes in Wheat QTL-Fhb2.

    Directory of Open Access Journals (Sweden)

    Dhananjay Dhokane

    Full Text Available Fusarium head blight (FHB caused by Fusarium graminearum not only causes severe losses in yield, but also reduces quality of wheat grain by accumulating mycotoxins. Breeding for host plant resistance is considered as the best strategy to manage FHB. Resistance in wheat to FHB is quantitative in nature, involving cumulative effects of many genes governing resistance. The poor understanding of genetics and lack of precise phenotyping has hindered the development of FHB resistant cultivars. Though more than 100 QTLs imparting FHB resistance have been reported, none discovered the specific genes localized within the QTL region, nor the underlying mechanisms of resistance.In our study recombinant inbred lines (RILs carrying resistant (R-RIL and susceptible (S-RIL alleles of QTL-Fhb2 were subjected to metabolome and transcriptome profiling to discover the candidate genes. Metabolome profiling detected a higher abundance of metabolites belonging to phenylpropanoid, lignin, glycerophospholipid, flavonoid, fatty acid, and terpenoid biosynthetic pathways in R-RIL than in S-RIL. Transcriptome analysis revealed up-regulation of several receptor kinases, transcription factors, signaling, mycotoxin detoxification and resistance related genes. The dissection of QTL-Fhb2 using flanking marker sequences, integrating metabolomic and transcriptomic datasets, identified 4-Coumarate: CoA ligase (4CL, callose synthase (CS, basic Helix Loop Helix (bHLH041 transcription factor, glutathione S-transferase (GST, ABC transporter-4 (ABC4 and cinnamyl alcohol dehydrogenase (CAD as putative resistance genes localized within the QTL-Fhb2 region.Some of the identified genes within the QTL region are associated with structural resistance through cell wall reinforcement, reducing the spread of pathogen through rachis within a spike and few other genes that detoxify DON, the virulence factor, thus eventually reducing disease severity. In conclusion, we report that the wheat

  19. Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery

    Directory of Open Access Journals (Sweden)

    Nicholas Ekow Thomford

    2018-05-01

    Full Text Available The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification of one or two active compounds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of “active compound” has made the compound ineffective. Drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of ‘organ-on chip’ and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compounds whilst allowing novel ways of drug design and synthesis based on natural compounds. Recent advances in analytical and computational techniques have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs. Indeed, we are in the era of computational molecular design, as applied to natural products. Predictive computational softwares have contributed to the discovery of molecular targets of natural products and their derivatives. In future the use of quantum computing, computational softwares and databases in modelling molecular interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false positive leads in drug

  20. Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery.

    Science.gov (United States)

    Thomford, Nicholas Ekow; Senthebane, Dimakatso Alice; Rowe, Arielle; Munro, Daniella; Seele, Palesa; Maroyi, Alfred; Dzobo, Kevin

    2018-05-25

    The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification of one or two active compounds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of "active compound" has made the compound ineffective. Drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of 'organ-on chip' and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compounds whilst allowing novel ways of drug design and synthesis based on natural compounds. Recent advances in analytical and computational techniques have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs. Indeed, we are in the era of computational molecular design, as applied to natural products. Predictive computational softwares have contributed to the discovery of molecular targets of natural products and their derivatives. In future the use of quantum computing, computational softwares and databases in modelling molecular interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false positive leads in drug development. This review