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Sample records for synthetic analogues inhibit

  1. Eugenol and its synthetic analogues inhibit cell growth of human cancer cells (Part I)

    Energy Technology Data Exchange (ETDEWEB)

    Carrasco A, H.; Cardona, W. [Universidad Andres Bello, Vina del Mar (Chile). Dept. de Ciencias Quimicas]. E-mail: hcarrasco@unab.cl; Espinoza C, L.; Gallardo, C.; Catalan M, K. [Universidad Tecnica Federico Santa Maria, Valparaiso (Chile). Dept. de Quimica; Cardile, V.; Lombardo, L. [University of Catania (Italy). Dept. of Physiological Sciences; Cuellar F, M. [Universidad de Valparaiso (Chile). Facultad de Farmacia; Russo, A. [University of Catania (Italy). Dept. of Biological Chemistry, Medical Chemistry and Molecular Biology

    2008-07-01

    Eugenol (4-allyl-2-methoxyphenol) (1) has been reported to possess antioxidant and anticancer properties. In an attempt to enhance intrinsic activity of this natural compound, some derivatives were synthesized. Eugenol was extracted from cloves oil and further, the eugenol analogues (2-6) were obtained through acetylation and nitration reactions. Eugenol (1) and its analogues (2-6) were examined by in vitro model of cancer using two human cancer cell lines: DU-145 (androgeninsensitive prostate cancer cells) and KB (oral squamous carcinoma cells). Cell viability, by tetrazolium salts assay, was measured. Lactic dehydrogenase (LDH) release was also investigated to evaluate the presence of cell toxicity as a result of cell disruption, subsequent to membrane rupture. In the examined cancer cells, all compounds showed cell-growth inhibition activity. The obtained results demonstrate that the compounds 5-allyl-3-nitrobenzene-1,2-diol (3) and 4-allyl- 2-methoxy-5-nitrophenyl acetate (5) were significantly (p < 0,001) more active than eugenol, with IC{sub 50} values in DU-145 cells of 19.02 x 10{sup -6} and 21.5 x 10{sup -6} mol L{sup -1}, respectively, and in KB cells of 18.11 x 10{sup -6} and 21.26 x 10{sup -6} mol L{sup -1}, respectively, suggesting that the presence of nitro and hydroxyl groups could be important in the activity of these compounds. In addition, our results seem to indicate that apoptotic cell demise appears to be induced in KB and DU-145 cells. In fact, in our experimental conditions, no statistically significant increase in LDH release was observed in cancer cells treated with eugenol and its analogues. (author)

  2. Inhibition of topoisomerase II α activity and induction of apoptosis in mammalian cells by semi-synthetic andrographolide analogues.

    Science.gov (United States)

    Nateewattana, Jintapat; Saeeng, Rungnapha; Kasemsook, Sakkasem; Suksen, Kanoknetr; Dutta, Suman; Jariyawat, Surawat; Chairoungdua, Arthit; Suksamrarn, Apichart; Piyachaturawat, Pawinee

    2013-04-01

    Topoisomerase II α enzyme plays a critical role in DNA replication process. It controls the topologic states of DNA during transcription and is essential for cell proliferation. Human DNA topoisomerase II α (hTopo II α) is a promising chemotherapeutic target for anticancer agents against a variety of cancer types. In the present study, andrographolide and its structurally modified analogues were investigated for their inhibitory activities on hTopo II α enzyme. Five out of nine andrographolide analogues potently reduced hTopo II α activity and inhibited cell proliferation in four mammalian cell lines (Hela, CHO, BCA-1 and HepG2 cells). IC50 values for cytotoxicity of analogues 3A.1, 3A.2, 3A.3, 1B and 2C were 4 to 7 μM. Structure-activity relationship studies revealed that both core structure of andrographolide and silicon based molecule of functional group were important for the inhibition of hTopo II α activity whereas position C-19 of analogues was required for anti-proliferation. In addition, the analogue 2C at 10 μM concentration inhibited hTopo II α, and induced apoptosis with nuclear fragmentation and formation of apoptotic bodies in HepG2 cells. The analogue 2C may, therefore, have a therapeutic potential as effective anticancer agent targeting the hTopo II α functions.

  3. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis

    Science.gov (United States)

    Jameson, Bradford A.; McDonnell, James M.; Marini, Joseph C.; Korngold, Robert

    1994-04-01

    EXPERIMENTAL allergic encephalomyelitis (EAE) is an acute inflammatory autoimmune disease of the central nervous system that can be elicited in rodents and is the major animal model for the study of multiple sclerosis (MS)1,2. The pathogenesis of both EAE and MS directly involves the CD4+ helper T-cell subset3-5. Anti-CD4 monoclonal antibodies inhibit the development of EAE in rodents6-9, and are currently being used in human clinical trials for MS. We report here that similar therapeutic effects can be achieved in mice using a small (rationally designed) synthetic analogue of the CD4 protein surface. It greatly inhibits both clinical incidence and severity of EAE with a single injection, but does so without depletion of the CD4+ subset and without the inherent immunogenicity of an antibody. Furthermore, this analogue is capable of exerting its effects on disease even after the onset of symptoms.

  4. Migrastatin analogues inhibit canine mammary cancer cell migration and invasion.

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    Kinga Majchrzak

    Full Text Available BACKGROUND: Cancer spread to other organs is the main cause of death of oncological patients. Migration of cancer cells from a primary tumour is the crucial step in the complex process of metastasis, therefore blocking this process is currently the main treatment strategy. Metastasis inhibitors derived from natural products, such as, migrastatin, are very promising anticancer agents. Thus, the aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6 on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Canine mammary tumours constitute a valuable tool for studying multiple aspect of human cancer. RESULTS: OUR RESULTS SHOWED THAT TWO OF SIX FULLY SYNTHETIC ANALOGUES OF MIGRASTATIN: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. These data were obtained using the wound healing test, as well as trans-well migration and invasion assays. Furthermore, the treatment of cancer cells with the most effective compound (MGSTA-6 disturbed binding between filamentous F-actin and fascin1. Confocal microscopy analyses revealed that treatment with MGSTA-6 increased the presence of unbound fascin1 and reduced co-localization of F-actin and fascin1 in canine cancer cells. Most likely, actin filaments were not cross-linked by fascin1 and did not generate the typical filopodial architecture of actin filaments in response to the activity of MGSTA-6. Thus, administration of MGSTA-6 results in decreased formation of filopodia protrusions and stress fibres in canine mammary cancer cells, causing inhibition of cancer migration and invasion. CONCLUSION: Two synthetic migrastatin analogues (MGSTA-5 and MGSTA-6 were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs

  5. Synthetic analogues of natural semiochemicals as promising insect control agents

    International Nuclear Information System (INIS)

    Ujvary, Istvan; Toth, Miklos; Guerin, Patrick

    2000-01-01

    After decades of research and development, insect pheromones and other semiochemicals became indispensable tools of ecologically based agricultural pest and disease vector management programmes with main uses as: 1) detection and population monitoring of emerging and migrating insects, 2) mass trapping of insects, 3) combined formulation of semiochemicals and insecticides ('lure-and-kill'), and 4) mating disruption with specially formulated pheromone components. In spite of their demonstrated safety and biodegradability, the direct application of these semiochemicals for pest control has not fulfilled initial expectations. Nonetheless considerable field experience has been accumulated (Carde and Minks 1995). Evidently, two important factors limit the practical potential of these substances: 1) inherent in their particular mode of action, semiochemicals, especially pheromones, are effectively cleared by specific enzymes in the insect antennae, and 2) some of these compounds contain labile functional moieties that are prone to degradation (oxidation, isomerisation and polymerisation) under field conditions. Appropriate chemical modifications of these natural compounds, however, can circumvent these problems by providing synthetic analogues (sometimes also called parapheromones or antipheromones; for early studies, see Roelofs and Comeau 1971, Payne et al. 1973) which in ideal cases are not only more potent and environmentally acceptable but more economical as well. It should also be mentioned that many effective attractants have been discovered through the empirical screening of synthetic chemicals, some of which have actually turned out to be structural relatives of natural semiochemicals of the particular insect. In this paper, selected case studies of analogues of sex pheromones and kairomones will be presented. The examples from our work include nitrile bioisosteres of labile aldehyde pheromone components of the cranberry girdler moth, Chrysoteuchia topiaria

  6. Insecticidal action of synthetic girgensohnine analogues and essential oils on Rhodnius prolixus (Hemiptera: Reduviidae

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    Juliana Cuadros

    2017-03-01

    Conclusion: Synthetic girgensohnine analogues, and C. flexuosus and C. sinensis essential oils showed insecticidal activity in R. prolixus. Analogue 3 showed the greatest insecticidal activity among all molecules and oils evaluated under our laboratory conditions.

  7. Chemoprevention of colon cancer by minor dietary constituents and their synthetic analogues.

    Science.gov (United States)

    Reddy, B S

    1996-01-01

    Large bowel cancer is one of the leading causes of cancer deaths in the United States and other Western countries. Based on epidemiologic and mechanistic studies, preclinical studies were designed to evaluate the chemopreventive efficacy of several nonsteroidal antiinflammatory drugs (NSAIDs) and phytochemicals and their synthetic analogues in colon carcinogenesis. These studies demonstrated that NSAIDs such as piroxicam, ibuprofen, aspirin and sulindac, D,L-alpha-difluoromethylornithine, oltipraz, anethole trithione, and diallyl disulfide inhibited colon adenocarcinomas. These results provide compelling rationale to pursue clinical trials in humans.

  8. Antifouling activity of bromotyrosine-derived sponge metabolites and synthetic analogues.

    Science.gov (United States)

    Ortlepp, Sofia; Sjögren, Martin; Dahlström, Mia; Weber, Horst; Ebel, Rainer; Edrada, RuAngelie; Thoms, Carsten; Schupp, Peter; Bohlin, Lars; Proksch, Peter

    2007-01-01

    Eighteen brominated sponge-derived metabolites and synthetic analogues were analyzed for antilarval settlement of Balanus improvisus. Only compounds exhibiting oxime substituents including bastadin-3 (4), -4 (1), -9 (2), and -16 (3), hemibastadin-1 (6), aplysamine-2 (5), and psammaplin A (10) turned out to inhibit larval settling at 1 to 10 microM. Analogues of hemibastadin-1 (6) were synthesized and tested for structure activity studies. Debromohemibastadin-1 (8) inhibited settling of B. improvisus, albeit at lower concentrations than hemibastadin-1 (6). Both 6 and 8 also induced cyprid mortality. 5,5'-dibromohemibastadin-1 (7) proved to be nontoxic, but settlement inhibition was observed at 10 microM. Tyrosinyltyramine (9), lacking the oxime function, was not antifouling active and was non-toxic at 100 microM. Hemibastadin-1 (6) and the synthetic products showed no general toxicity when tested against brine shrimp larvae. In contrast to the lipophilic psammaplin A (10), the hydrophilic sulfated psammaplin A derivative (11) showed no antifouling activity even though it contains an oxime group. We therefore hypothesize that the compound needs to cross membranes (probably by diffusion) and that the target for psammaplin A lies intracellularly.

  9. Synthetic Strigolactone Analogues Reveal Anti-Cancer Activities on Hepatocellular Carcinoma Cells

    KAUST Repository

    Hasan, Mohammed Nihal

    2018-02-09

    Hepatocellular carcinoma (HCC) remains one of the leading causes of death worldwide. The complex etiology is attributed to many factors like heredity, cirrhosis, hepatitis infections or the dysregulation of the different molecular pathways. Nevertheless, the current treatment regimens have either severe side effects or tumors gradually acquire resistance upon prolonged use. Thus, developing a new selective treatment for HCC is the need of the hour. Many anticancer agents derived from plants have been evaluated for their cytotoxicity towards many human cancer cell lines. Strigolactones (SLs)-a newly discovered class of phytohormones, play a crucial role in the development of plant-root and shoot. Recently, many synthetic analogues of SLs have demonstrated pro-apoptotic effects on different cancer cell lines like prostate, breast, colon and lung. In this study, we tested synthetic SLs analogues on HCC cell line-HepG2 and evaluated their capability to induce cell proliferation inhibition and apoptosis. Primary WST-1 assays, followed by annexin-V/7AAD staining, demonstrated the anti-proliferative effects. The SLs analogues TIT3 and TIT7 were found to significantly reduce HepG2 cell viability in a dose- and time-dependent manner and induce apoptosis. Interestingly, though TIT3 and TIT7 strongly affected cancer cell proliferation, both compounds showed moderate anti-proliferative effect on normal cells. Further, migration of cancer cells was suppressed upon treatment with TIT3 and TIT7 in a wound healing assay. In summary, these findings suggest that two SLs analogues TIT3 and TIT7 exert selective inhibitory effects on cancer cells most likely through targeting microtubules. SLs analogues could be used in future as potential anti-cancer candidates in chemotherapy.

  10. Nontoxic piperamides and their synthetic analogues as novel antifouling reagents

    KAUST Repository

    Huang, Xiang-Zhong

    2014-03-25

    Bioassay-guided isolation of an acetone extract from a terrestrial plant Piper betle produced four known piperamides with potent antifouling (AF) activities, as evidenced by inhibition of settlement of barnacle cypris larvae. The AF activities of the four piperamides and 15 synthesized analogues were compared and their structure-activity relationships were probed. Among the compounds, piperoleine B and 1-[1-oxo-7-(3′,4′-methylenedioxyphenyl)-6E-heptenyl]-piperidine (MPHP) showed strong activity against settlement of cyprids of the barnacle Balanus amphitrite, having EC50 values of 1.1 ± 0.3 and 0.5 ± 0.2 μg ml-1, respectively. No toxicity against zebra fish was observed following incubation with these two compounds. Besides being non-toxic, 91% of piperoleine B-treated cyprids and 84% of MPHP-treated cyprids at a concentration of 100 μM completed normal metamorphosis in recovery bioassays, indicating that the anti-settlement effect of these two compounds was reversible. Hydrolysis and photolysis experiments indicated that MPHP could be decomposed in the marine environment. It is concluded that piperamides are promising compounds for use in marine AF coatings. © 2014 © 2014 Taylor & Francis.

  11. Physical Characterization of Synthetic Phosphatidylinositol Dimannosides and Analogues in Binary Systems with Phosphatidylcholine

    DEFF Research Database (Denmark)

    Hubert, Madlen; Larsen, David S; Hayman, Colin M

    2014-01-01

    Native phosphatidylinositol mannosides (PIMs) from the cell wall of Mycobacterium bovis (M. bovis) and synthetic analogues have been identified to exert immunostimulatory activities. These activities have been investigated using particulate delivery systems containing native mannosylated lipids o...

  12. Binding of lysozyme to synthetic monosaccharide lipid A analogue, GLA60.

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    Tanida, N; Onho, N; Adachi, Y; Matsuura, M; Nakano, M; Kiso, M; Hasegawa, A; Yadomae, T

    1993-03-01

    Recent studies by our group suggested that lysozyme (LZM) has a high affinity for bacterial lipopolysaccharide (LPS) of both the smooth and rough forms, and inhibits various immunomodulatory activities of LPS. GLA60 is a synthetic monosaccharide analogue of bacterial lipid A, well-known as sharing large part of lipid A activities but with very low toxicity. In this study, we characterized the interaction of LZM with GLA60 in comparison to that with E. coli 0111 LPS (smooth form), taking a physicochemical approach. Using a dansylated lysozyme probe (DNS-LZM), LZM was found to bind to GLA60 in all 3 of its forms, free acid, triethylamine (TEA) salt and bovine serum albumin (BSA) complex of GLA60, as well as natural LPS. Compared with LPS, the complex formation of the TEA salt was weakly dependent on temperature and incubation time. LZM also bound to biologically inactive GLA analogues, GLA 64 and GLA69, at a high affinity, as well as to GLA 60. By using chemically modified LZM, it was found that the ionic as well as hydrophobic interactions are important for the complex formation.

  13. Modification of immunopharmacological activities of synthetic monosaccharide lipid A analogue, GLA60, by lysozyme.

    Science.gov (United States)

    Tanida, N; Ohno, N; Adachi, Y; Matsuura, M; Nakano, M; Kiso, M; Hasegawa, A; Yadomae, T

    1992-11-01

    Recent studies by our group suggested that lysozyme has a high affinity for bacterial lipopolysaccharide (LPS) of both the smooth and rough forms, and inhibits various immunomodulatory activities of LPS. GLA60 is a synthetic monosaccharide analogue of bacterial lipid A well known as having most of the activities of lipid A with very low toxicity. In this study, we characterized the interaction of lysozyme with GLA60 in comparison to that with Escherichia coli 0111 LPS (smooth form) by means of an immunopharmacological approach. Using dansylated lysozyme (DNS-LZM) as a probe, LZM was found to bind to GLA60. The mitogenic and polyclonal B-cell activating activities were significantly reduced by complex formation. However, there was no inhibitory effect on GLA60 induced production of IL-1 and TNF of macrophages. Interestingly, the activities of macrophages induced by the complex were found to be significantly higher than those induced by GLA60 itself. In contrast, the activities of 0111 LPS were significantly inhibited by LZM. Since the GLA60-LZM complex produced a turbid suspension but the 0111 LPS-LZM complex remained soluble, we consider that the activities of GLA60 alone were mediated by the common functional LPS receptor for dispersed form in both macrophages and B-lymphocytes, but activation of macrophages by the complex was mediated either by another LPS receptor not present in B-lymphocytes or through the phagocytic function of macrophages.

  14. Synthetic Nucleic Acid Analogues in Gene Therapy: An Update for Peptide–Oligonucleotide Conjugates

    DEFF Research Database (Denmark)

    Taskova, Maria; Mantsiou, Anna; Astakhova, Kira

    2017-01-01

    The main objective of this work is to provide an update on synthetic nucleic acid analogues and nanoassemblies as tools in gene therapy. In particular, the synthesis and properties of peptide–oligonucleotide conjugates (POCs), which have high potential in research and as therapeutics, are described...

  15. Synthetic Nucleic Acid Analogues in Gene Therapy: An Update for Peptide-Oligonucleotide Conjugates.

    Science.gov (United States)

    Taskova, Maria; Mantsiou, Anna; Astakhova, Kira

    2017-09-05

    The main objective of this work is to provide an update on synthetic nucleic acid analogues and nanoassemblies as tools in gene therapy. In particular, the synthesis and properties of peptide-oligonucleotide conjugates (POCs), which have high potential in research and as therapeutics, are described in detail. The exploration of POCs has already led to fruitful results in the treatment of neurological diseases, lung disorders, cancer, leukemia, viral, and bacterial infections. However, delivery and in vivo stability are the major barriers to the clinical application of POCs and other analogues that still have to be overcome. This review summarizes recent achievements in the delivery and in vivo administration of synthetic nucleic acid analogues, focusing on POCs, and compares their efficiency. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. MODULATING LPS SIGNAL TRANSDUCTION AT THE LPS RECEPTOR COMPLEX WITH SYNTHETIC LIPID A ANALOGUES

    Science.gov (United States)

    White, Aileen F. B.; Demchenko, Alexei V.

    2015-01-01

    Sepsis, defined as a clinical syndrome brought about by an amplified and dysregulated inflammatory response to infections, is one of the leading causes of death worldwide. Despite persistent attempts to develop treatment strategies to manage sepsis in the clinical setting, the basic elements of treatment have not changed since the 1960s. As such, the development of effective therapies for reducing inflammatory reactions and end-organ dysfunction in critically ill patients with sepsis remains a global priority. Advances in understanding of the immune response to sepsis provide the opportunity to develop more effective pharmaceuticals. This article details current information on the modulation of the lipopolysaccharide (LPS) receptor complex with synthetic Lipid A mimetics. As the initial and most critical event in sepsis pathophysiology, the LPS receptor provides an attractive target for antisepsis agents. One of the well-studied approaches to sepsis therapy involves the use of derivatives of Lipid A, the membrane-anchor portion of an LPS, which is largely responsible for its endotoxic activity. This article describes the structural and conformational requirements influencing the ability of Lipid A analogues to compete with LPS for binding to the LPS receptor complex and to inhibit the induction of the signal transduction pathway by impairing LPS-initiated receptor dimerization. PMID:25480508

  17. Sensory responses of human skin to synthetic histamine analogues and histamine.

    OpenAIRE

    Davies, M G; Greaves, M W

    1980-01-01

    The potential for itch production in human skin of the synthetic analogues of histamine, 2-methyl histamine (an H1-receptor agonist) and 4-methyl histamine and dimaprit (H2-receptor agonists) has been studied in vivo and compared with histamine. Itch thresholds for 2-methyl histamine were consistently much higher than for histamine (P < 0.001). The H1-receptor antagonist chlorpheniramine raised the itch thresholds to 2-methyl histamine and histamine significantly (P < 0.001). Pruritus was not...

  18. The resveratrol analogue trimethoxystilbene inhibits cancer cell growth by inducing multipolar cell mitosis.

    Science.gov (United States)

    Traversi, Gianandrea; Fiore, Mario; Percario, Zulema; Degrassi, Francesca; Cozzi, Renata

    2017-03-01

    Natural compounds are extensively studied for their potential use in traditional and non-traditional medicine. Several natural and synthetic Resveratrol analogues have shown interesting biological activities in the field of cancer chemoprevention. In the present study, we have focused on the ability of Resveratrol and two methoxylated derivatives (Trimethoxystilbene and Pterostilbene) to inhibit human cancer cell growth particularly analyzing their ability to interfere with tubulin dynamics at mitosis. We show that Trimethoxystilbene, differently from Resveratrol and Pterostilbene, alters microtubule polymerization dynamics in HeLa cells specifically inducing multipolar spindles and mitotic arrest coupled to a reduction of cell growth and an increase in apoptotic death by mitotic catastrophe. This work demonstrates that the structural modification of Rsv causes substantial changes in the mechanism of action of the derivatives. The presence of three extra methyl groups renders Trimethoxy very efficient in impairing cell proliferation by inducing mitotic catastrophe in cancer cells. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Synthetic analogues of the natural compound cryphonectric acid interfere with photosynthetic machinery through two different mechanisms.

    Science.gov (United States)

    Teixeira, Róbson Ricardo; Pereira, Wagner Luiz; Tomaz, Deborah Campos; de Oliveira, Fabrício Marques; Giberti, Samuele; Forlani, Giuseppe

    2013-06-12

    A series of isobenzofuran-1(3H)-ones (phthalides), analogues of the naturally occurring phytotoxin cryphonectric acid, were designed, synthesized, and fully characterized by NMR, IR, and MS analyses. Their synthesis was achieved via condensation, aromatization, and acetylation reactions. The measurement of the electron transport chain in spinach chloroplasts showed that several derivatives are capable of interfering with the photosynthetic apparatus. Few of them were found to inhibit the basal rate, but a significant inhibition was brought about only at concentrations exceeding 50 μM. Some other analogues acted as uncouplers or energy transfer inhibitors, with a remarkably higher effectiveness. Isobenzofuranone addition to the culture medium inhibited the growth of the cyanobacterium Synechococcus elongatus , with patterns consistent with the effects measured in vitro upon isolated chloroplasts. The most active derivatives, being able to completely suppress algal growth at 20 μM, may represent structures to be exploited for the design of new active ingredients for weed control.

  20. Toxicity Assessments of Chalcone and Some Synthetic Chalcone Analogues in a Zebrafish Model

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    Ya-Ting Lee

    2014-01-01

    Full Text Available The aim of this study was to investigate the in vivo toxicities of some novel synthetic chalcones. Chalcone and four chalcone analogues 1a–d were evaluated using zebrafish embryos following antibody staining to visualize their morphological changes and muscle fiber alignment. Results showed that embryos treated with 3'-hydroxychalcone (compound 1b displayed a high percentage of muscle defects (96.6%, especially myofibril misalignment. Ultrastructural analysis revealed that compound 1b-treated embryos displayed many muscle defect phenotypes, including breakage and collapse of myofibrils, reduced cell numbers, and disorganized thick (myosin and thin (actin filaments. Taken together, our results provide in vivo evidence of the myotoxic effects of the synthesized chalcone analogues on developing zebrafish embryos.

  1. Biological armors under impact—effect of keratin coating, and synthetic bio-inspired analogues

    International Nuclear Information System (INIS)

    Achrai, B; Wagner, H D; Bar-On, B

    2015-01-01

    A number of biological armors, such as turtle shells, consist of a strong exoskeleton covered with a thin keratin coating. The mechanical role upon impact of this keratin coating has surprisingly not been investigated thus far. Low-velocity impact tests on the turtle shell reveal a unique toughening phenomenon attributed to the thin covering keratin layer, the presence of which noticeably improves the fracture energy and shell integrity. Synthetic substrate/coating analogues were subsequently prepared and exhibit an impact behavior similar to the biological ones. The results of the present study may improve our understanding, and even future designs, of impact-tolerant structures. (paper)

  2. Biomechanical Comparison of Cadaveric and Commercially Available Synthetic Osteoporotic Bone Analogues in a Locked Plate Fracture Model Under Torsional Loading.

    Science.gov (United States)

    Becker, Edward H; Kim, Hyunchul; Shorofsky, Michael; Hsieh, Adam H; Watson, Jeffrey D; OʼToole, Robert V

    2017-05-01

    Biomechanical studies of osteoporotic bone have used synthetic models rather than cadaveric samples because of decreased variability, increased availability, and overall ease of the use of synthetic models. We compared the torsional mechanical properties of cadaveric osteoporotic bone with those of currently available synthetic osteoporotic bone analogues. We tested 12 osteoporotic cadaveric humeri and 6 specimens each of 6 types of synthetic analogues. A 5-mm fracture gap model and posterior plating technique with 4.5-mm narrow 10-hole locking compression plate were used. Torque was applied to a peak of ±10 N·m for 1000 cycles at 0.3 Hz. Data were continuously collected during cyclical and ramped loading with a servohydraulic materials testing system. Cadaveric bone had a 17% failure rate before completing 1000 cycles. Three osteoporotic bone models had 100% failure (P Osteoporotic bone analogues had torsional mechanical properties different from those of osteoporotic cadaveric specimens. The differences between osteoporotic cadaveric humeri and synthetic osteoporotic bone analogues ranged from profound with complete catastrophic failure after a few cycles to subtler differences in stiffness and strain hardening. These findings suggest that different bone analogue models vary substantially in their torsional mechanical properties and might not be appropriate substitutes for cadaveric bone in biomechanical studies of osteoporotic bone.

  3. A Modular Synthetic Approach to Isosteric Sulfonic Acid Analogues of the Anticoagulant Pentasaccharide Idraparinux

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    Erika Mező

    2016-11-01

    Full Text Available Heparin-based anticoagulants are drugs of choice in the therapy and prophylaxis of thromboembolic diseases. Idraparinux is a synthetic anticoagulant pentasaccharide based on the heparin antithrombin-binding domain. In the frame of our ongoing research aimed at the synthesis of sulfonic acid-containing heparinoid anticoagulants, we elaborated a modular pathway to obtain a series of idraparinux-analogue pentasaccharides bearing one or two primary sulfonic acid moieties. Five protected pentasaccharides with different C-sulfonation patterns were prepared by two subsequent glycosylation reactions, respectively, using two monosaccharide and four disaccharide building blocks. Transformation of the protected derivatives into the fully O-sulfated, O-methylated sulfonic acid end-products was also studied.

  4. Synthetic Rock Analogue for Permeability Studies of Rock Salt with Mudstone

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    Hongwu Yin

    2017-09-01

    Full Text Available Knowledge about the permeability of surrounding rock (salt rock and mudstone interlayer is an important topic, which acts as a key parameter to characterize the tightness of gas storage. The goal of experiments that test the permeability of gas storage facilities in rock salt is to develop a synthetic analogue to use as a permeability model. To address the permeability of a mudstone/salt layered and mixed rock mass in Jintan, Jiangsu Province, synthetic mixed and layered specimens using the mudstone and the salt were fabricated for permeability testing. Because of the gas “slippage effect”, test results are corrected by the Klinkenberg method, and the permeability of specimens is obtained by regression fitting. The results show that the permeability of synthetic pure rock salt is 6.9 × 10−20 m2, and its porosity is 3.8%. The permeability of synthetic mudstone rock is 2.97 × 10−18 m2, with a porosity 17.8%. These results are close to those obtained from intact natural specimens. We also find that with the same mudstone content, the permeability of mixed specimens is about 40% higher than for the layered specimens, and with an increase in the mudstone content, the Klinkenberg permeability increases for both types of specimens. The permeability and mudstone content have a strong exponential relationship. When the mudstone content is below 40%, the permeability increases only slightly with mudstone content, whereas above this threshold, the permeability increases rapidly with mudstone content. The results of the study are of use in the assessment of the tightness of natural gas storage facilities in mudstone-rich rock salt formations in China.

  5. Synthesis and characterization of folate decorated albumin bio-conjugate nanoparticles loaded with a synthetic curcumin difluorinated analogue.

    Science.gov (United States)

    Gawde, Kaustubh A; Kesharwani, Prashant; Sau, Samaresh; Sarkar, Fazlul H; Padhye, Subhash; Kashaw, Sushil K; Iyer, Arun K

    2017-06-15

    Albumin-bound paclitaxel colloidal nanoparticle (Abraxane®) is an FDA approved anticancer formulation available in the market. It is a suspension which is currently used therapeutically for treating cancers of the breast, lung, and pancreas among others. CDF is a novel new and potent synthetic curcumin analogue that is widely used for breast and ovarian cancer. The aim of this study was to use biocompatible albumin as well as folate decorated albumin to formulate colloidal nanoparticles encapsulating curcumin difluorinated (CDF). CDF has demonstrated a 16-fold improvement in stability and remarkable anticancer potency compared to its natural derivative, curcumin. CDF showed marked inhibition of cancer cell growth through down-regulation of multiple miRNAs, up-regulation of phosphatase and tensin homolog (PTEN), and attenuation of histone methyl transferase EZH2. However, CDF is highly hydrophobic and photodegradable with sparing aqueous solubility. In this study, we have formulated albumin nanoparticle using a modified desolvation method, which yielded high CDF loading in a nanoformulation. The physicochemical properties of CDF loaded albumin and folate-decorated albumin nanosuspensions were assessed for particle size, morphology, zeta potential, drug encapsulation efficiency/loading, solubility and drug release. Importantly, the folate ligand decorated albumin nanoparticles were formulated in principle to passively and actively target folate-overexpressing-cancers. In this study, the synthesis and optimization of BSA and folate decorated BSA conjugated CDF nanoparticles are assessed in detail that will be useful for its future clinical translation. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Sorption of 60Co on a synthetic titanosilicate analogue of the mineral penkvilksite-2O and antimonysilicate

    International Nuclear Information System (INIS)

    Koudsi, Y.; Dyer, A.

    2001-01-01

    The ability of two different types of synthetic inorganic ion-exchangers to sorb radioactive cobalt-60 using a batch-type method was studied. The two materials examined were the analogue of the natural titanosilicate penkvilksite-2O (AM-3) and a synthetic antimonysilicate. Ion-exchange experiments were performed with solutions labelled with radioactive cobalt ( 60 Co). The sorption of 60 Co onto the two samples materials were compared in terms of distribution coefficient (K d ), sorption percentage and cobalt quantity removed in mg per gram weight of the material. Several parameters were investigated viz. contact time, cobalt concentration, and sorbent concentration. It was found that the batch factor and cobalt concentration had a significant influence on the sorption of cobalt onto both of the materials. This was associated with the difference in pH generated by suspensions of the materials in water which was alkaline for the penkvilksite-2O analogue, and acid for the synthetic antimonysilicate. (author)

  7. Effect of polyamines and synthetic polyamine-analogues on the expression of antizyme (AtoC and its regulatory genes

    Directory of Open Access Journals (Sweden)

    Garnelis Thomas

    2007-01-01

    Full Text Available Abstract Background In bacteria, the biosynthesis of polyamines is modulated at the level of transcription as well as post-translationally. Antizyme (Az has long been identified as a non-competitive protein inhibitor of polyamine biosynthesis in E. coli. Az was also revealed to be the product of the atoC gene. AtoC is the response regulator of the AtoS-AtoC two-component system and it functions as the positive transcriptional regulator of the atoDAEB operon genes, encoding enzymes involved in short chain fatty acid metabolism. The antizyme is referred to as AtoC/Az, to indicate its dual function as both a transcriptional and post-translational regulator. Results The roles of polyamines on the transcription of atoS and atoC genes as well as that of atoDAEB(ato operon were studied. Polyamine-mediated induction was tested both in atoSC positive and negative E. coli backgrounds by using β-galactosidase reporter constructs carrying the appropriate promoters patoDAEB, patoS, patoC. In addition, a selection of synthetic polyamine analogues have been synthesized and tested for their effectiveness in inducing the expression of atoC/Az, the product of which plays a pivotal role in the feedback inhibition of putrescine biosynthesis and the transcriptional regulation of the ato operon. The effects of these compounds were also determined on the ato operon expression. The polyamine analogues were also tested for their effect on the activity of ornithine decarboxylase (ODC, the key enzyme of polyamine biosynthesis and on the growth of polyamine-deficient E. coli. Conclusion Polyamines, which have been reported to induce the protein levels of AtoC/Az in E. coli, act at the transcriptional level, since they cause activation of the atoC transcription. In addition, a series of polyamine analogues were studied on the transcription of atoC gene and ODC activity.

  8. The monoamine oxidase inhibition properties of selected structural analogues of methylene blue.

    Science.gov (United States)

    Delport, Anzelle; Harvey, Brian H; Petzer, Anél; Petzer, Jacobus P

    2017-06-15

    The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, the present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC 50 =0.0037μM), Nile blue (IC 50 =0.0077μM) and 1,9-dimethyl methylene blue (IC 50 =0.018μM) exhibiting higher potency inhibition compared to MB (IC 50 =0.07μM). Nile blue also represents a potent MAO-B inhibitor with an IC 50 value of 0.012μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Response of wild and weedy broomrapes to synthetic strigolactone analogue GR24

    Directory of Open Access Journals (Sweden)

    Radoslava Matusova

    2014-12-01

    Full Text Available Parasitic plants of genera Orobanche and Phelipanche germinate after exposition to chemical signals exuded by roots of the host plants. The most studied germination stimulants belong to strigolactones (SLs, the newly discovered plant hormones which are stimulating hyphal branching of arbuscular mycorrhizal fungi and are involved in regulation of shoot and root architecture of plants. However, little is known about the effect of strigolactones on germination of non-weedy broomrapes. The objective of our study was to investigate the sensitivity of seeds of non-weedy broomrapes to synthetic analogue of SLs, GR24. The seeds of non-weedy broomrapes Orobanche alba, O. alsatica, O. caryophyllacea, O. elatior, O. flava, O. lutea, O. pallidiflora, O. reticulata, Phelipanche arenaria, P. purpurea and weedy species P. ramosa were collected in natural and cropland plant communities in Slovakia. Seeds of P. ramosa and P. purpurea were highly sensitive to GR24. On the other hand, effectivity of GR24 in inducing germination of several wild species, O. alba, O. caryophyllacea and P. arenaria was low, while the stimulant shown to be completely not effective on other non-weedy species O. alsatica, O. elatior, O. flava, O. lutea, O. pallidiflora, and O. reticulata. The results point out there are differences in the requirement for germination signals that possibly depend on the host.

  10. Induction of apoptosis in cholangiocarcinoma by an andrographolide analogue is mediated through topoisomerase II alpha inhibition.

    Science.gov (United States)

    Nateewattana, Jintapat; Dutta, Suman; Reabroi, Somrudee; Saeeng, Rungnapha; Kasemsook, Sakkasem; Chairoungdua, Arthit; Weerachayaphorn, Jittima; Wongkham, Sopit; Piyachaturawat, Pawinee

    2014-01-15

    Cholangiocarcinoma (CCA), the common primary malignant tumor of bile duct epithelial cells, is unresponsive to most chemotherapeutic drugs. Diagnosis with CCA has a poor prognosis, and therefore urgently requires effective therapeutic agents. In the present study we investigated anti-cancer effects of andrographolide analogue 3A.1 (19-tert-butyldiphenylsilyl-8, 17-epoxy andrographolide) and its mechanism in human CCA cell line KKU-M213 derived from a Thai CCA patient. By 24h after exposure, the analogue 3A.1 exhibited a potent cytotoxic effect on KKU-M213 cells with an inhibition concentration 50 (IC50) of approximately 8.0µM. Analogue 3A.1 suppressed DNA topoisomerase II α (Topo II α) protein expression, arrested the cell cycle at sub G0/G1 phase, induced cleavage of DNA repair protein poly (ADP-ribose) polymerases-1 (PARP-1), and enhanced expression of tumor suppressor protein p53 and pro-apoptotic protein Bax. In addition, analogue 3A.1 induced caspase 3 activity and inhibited cyclin D1, CDK6, and COX-2 protein expression. These results suggest that andrographolide analogue 3A.1, a novel topo II inhibitor, has significant potential to be developed as a new anticancer agent for the treatment of CCA. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Adjuvants based on synthetic mycobacterial cord factor analogues: Biophysical properties of neat glycolipids and nano-self-assemblies with DDA

    DEFF Research Database (Denmark)

    Kallerup, Rie Selchau; Franzyk, Henrik; Schiøth, Mikkel Lohmann

    2017-01-01

    Synthetic mycobacterial cord factor analogues, e.g., trehalose 6,6'-dibehenate (TDB), are highly promising adjuvants due to their strong immunopotentiating capabilities, but their biophysical properties have remained poorly characterized. Here, we report the synthesis of an array of synthetic TDB...... and the acyl chains (PEG-TDS). All dispersions were liposomes, but in contrast to the colloidally stable and highly cationic TDX-containing liposomes, the zeta-potential was significantly reduced for DDA/TMX and DDA/PEG-TDS liposomes, suggesting a charge-shielding effect, which compromises the colloidal...... stability. An increased d-spacing was observed for the lamellar phase of neat TDB analogues in excess buffer (TDShighly cooperative...

  12. Opposite responses of rabbit and human globin mRNAs to translational inhibition by cap analogues

    International Nuclear Information System (INIS)

    Shakin, S.H.; Liebhaber, S.A.

    1987-01-01

    The translational efficiency of an mRNA may be determined at the step of translational initiation by the efficiency of its interaction with the cap binding protein complex. To further investigate the role of these interactions in translational control, the authors compare in vitro the relative sensitivities of rabbit and human α- and β-globin mRNAs to translational inhibition by cap analogues. They find that rabbit β-globin mRNA is more resistant to translational inhibition by cap analogues than rabbit α-globin mRNA, while in contrast, human β-globin mRNA is more sensitive to cap analogue inhibition than human α- and β-globin mRNAs is unexpected as direct in vivo and in vitro comparisons of polysome profiles reveal parallel translational handling of the α- and β-globin mRNAs from these two species. This discordance between the relative translational sensitivities of these mRNAs to cap analogues and their relative ribosome loading activities suggests that cap-dependent events may not be rate limiting in steady-state globin translation

  13. Adjuvants Based on Synthetic Mycobacterial Cord Factor Analogues: Biophysical Properties of Neat Glycolipids and Nanoself-Assemblies with DDA.

    Science.gov (United States)

    Kallerup, Rie S; Franzyk, Henrik; Schiøth, Mikkel L; Justesen, Sarah; Martin-Bertelsen, Birte; Rose, Fabrice; Madsen, Cecilie M; Christensen, Dennis; Korsholm, Karen S; Yaghmur, Anan; Foged, Camilla

    2017-07-03

    Synthetic mycobacterial cord factor analogues, e.g., trehalose 6,6'-dibehenate (TDB), are highly promising adjuvants due to their strong immunopotentiating capabilities, but their biophysical properties have remained poorly characterized. Here, we report the synthesis of an array of synthetic TDB analogues varying in acyl chain length, degree of acylation, and headgroup display, which was subjected to biophysical characterization of neat nondispersed self-assembled nanostructures in excess buffer and as aqueous dispersions with cationic dimethyldioctadecylammonium (DDA) bromide. The array comprised trehalose mono- (TMX) and diester (TDX) analogues with symmetrically shortened acyl chains [denoted by X: arachidate (A), stearate (S), palmitate (P), myristate (Myr), and laurate (L)] and an analogue with a short hydrophilic polyethylene glycol (PEG) linker inserted between the trehalose headgroup of TDS and the acyl chains (PEG-TDS). All dispersions were liposomes, but in contrast to the colloidally stable and highly cationic TDX-containing liposomes, the zeta-potential was significantly reduced for DDA/TMX and DDA/PEG-TDS liposomes, suggesting a charge-shielding effect, which compromises the colloidal stability. An increased d-spacing was observed for the lamellar phase of neat TDB analogues in excess buffer (TDS < TMS < PEG-TDS), confirming that the charge shielding is caused by an extended molecular configuration of the more flexible headgroup. Differential scanning calorimetry showed highly cooperative phase transitions for all tested dispersions albeit the monoesters destabilized the lipid bilayers. Langmuir experiments demonstrated that incorporation of TDXs and PEG-TDS stabilized DDA monolayers due to improved hydrogen bonding and reduced intermolecular repulsions. In conclusion, data suggest that the DDA/TDS dispersions exhibit favorable physicochemical properties rendering these DDA/TDS liposomes an attractive vaccine adjuvant, and they emphasize that not only

  14. Inhibition of LPS and Plasmodium falciparum induced cytokine secretion by pentoxifylline and two analogues

    DEFF Research Database (Denmark)

    Jakobsen, P H; Koch, C; Bendtzen, K

    1997-01-01

    Pentoxifylline and the two analogues HWA138 and HWA448, at concentrations exceeding 60 micrograms/ml, inhibited malaria antigen or lipopolysaccharide (LPS) induced TNF-alpha and IL-1 alpha secretion, but not IL-6 secretion, from human peripheral blood mononuclear cells in vitro. HWA448 had lower...... inhibitory activity in vitro than pentoxifylline and HWA138. A small enhancement of cytokine secretion was induced by pentoxifylline and the two analogues at low concentrations. The drugs did not affect cell viability. Pentoxifylline, HWA138 and HWA448 also inhibited LPS induced TNF production in vivo...... in female CF1xBalb/c mice. The drugs were inhibitory at 0.5-1 mg per mouse when mixed with LPS, and 1 mg per mouse of the drugs was inhibitory when injected 1 h before LPS challenge. HWA448 had similar inhibitory activities in vivo compared to pentoxifylline and HWA138, possibly because of the longer serum...

  15. Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues.

    Science.gov (United States)

    Petrelli, Riccardo; Sham, Yuk Yin; Chen, Liqiang; Felczak, Krzysztof; Bennett, Eric; Wilson, Daniel; Aldrich, Courtney; Yu, Jose S; Cappellacci, Loredana; Franchetti, Palmarisa; Grifantini, Mario; Mazzola, Francesca; Di Stefano, Michele; Magni, Giulio; Pankiewicz, Krzysztof W

    2009-08-01

    Diadenosine disulfide (5) was reported to inhibit NAD kinase from Listeria monocytogenes and the crystal structure of the enzyme-inhibitor complex has been solved. We have synthesized tiazofurin adenosine disulfide (4) and the disulfide 5, and found that these compounds were moderate inhibitors of human NAD kinase (IC(50)=110 microM and IC(50)=87 microM, respectively) and Mycobacterium tuberculosis NAD kinase (IC(50)=80 microM and IC(50)=45 microM, respectively). We also found that NAD mimics with a short disulfide (-S-S-) moiety were able to bind in the folded (compact) conformation but not in the common extended conformation, which requires the presence of a longer pyrophosphate (-O-P-O-P-O-) linkage. Since majority of NAD-dependent enzymes bind NAD in the extended conformation, selective inhibition of NAD kinases by disulfide analogues has been observed. Introduction of bromine at the C8 of the adenine ring restricted the adenosine moiety of diadenosine disulfides to the syn conformation making it even more compact. The 8-bromoadenosine adenosine disulfide (14) and its di(8-bromoadenosine) analogue (15) were found to be the most potent inhibitors of human (IC(50)=6 microM) and mycobacterium NAD kinase (IC(50)=14-19 microM reported so far. None of the disulfide analogues showed inhibition of lactate-, and inosine monophosphate-dehydrogenase (IMPDH), enzymes that bind NAD in the extended conformation.

  16. Photochemistry of free and bound Zn-chlorophyll analogues to synthetic peptides depend on the quinone and pH.

    Science.gov (United States)

    Razeghifard, Reza

    2015-11-01

    A synthetic peptide was used as a scaffold to bind Zn-Chlorophyll (ZnChl) analogues through histidine ligation to study their photochemistry in the presence of different type of quinones. The Chl analogues were chlorin e6 (Ce6), chlorin e6 trimethyl ester, pyropheophorbide a, and pheophorbide a while the quinones were PPBQ, DMBQ, NPHQ, DBTQ, DCBQ and PBQ. The binding of each ZnChl analogue to the peptide was verified by native gel electrophoresis. First the photo-stability of the ZnChl analogues were tested under continuous light. The ZnCe6 and ZnCe6TM analogues showed the least stability judged by the loss of optical signal intensity at their Qy band. The photoactivity of each ZnChl analogue was measured in the presence of each of the six quinones using time-resolved EPR spectroscopy. DMBQ was found to be the most efficient electron acceptor when all four ZnChl analogues were compared. The light-induced electron transfer between the ZnChl analogues complexed with the peptide and DMBQ were also measured using time-resolved EPR spectroscopy. The ZnCe6-peptide complex exhibited the highest photoactivity. The electron transfer in the complex was faster and the photoactivity yield was higher than those values obtained for free ZnCe6 and DMBQ. The fast phase of kinetics can be attributed to intra-protein electron transfer in the complex since it was not observed in the presence of DMBQ-glutathione adduct. Unlike free ZnCe6, the ZnCe6-peptide complex was robust and demonstrated very similar photoactivity efficiency in pH values 10, 8.0 and 5.0. The electron transfer kinetics were pH dependent and appeared to be modulated by the peptide charge and possibly fold. The charge recombination rate was slowed by an order of magnitude when the pH value was changed from 10.0 to 5.0. The implications of constructing the photoactive peptide complexes in terms of artificial photosynthesis are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. A novel peptide sansalvamide analogue inhibits pancreatic cancer cell growth through G0/G1 cell-cycle arrest

    International Nuclear Information System (INIS)

    Ujiki, Michael B.; Milam, Ben; Ding Xianzhong; Roginsky, Alexandra B.; Salabat, M. Reza; Talamonti, Mark S.; Bell, Richard H.; Gu Wenxin; Silverman, Richard B.; Adrian, Thomas E.

    2006-01-01

    Patients with pancreatic cancer have little hope for cure because no effective therapies are available. Sansalvamide A is a cyclic depsipeptide produced by a marine fungus. We investigated the effect of a novel sansalvamide A analogue on growth, cell-cycle phases, and induction of apoptosis in human pancreatic cancer cells in vitro. The sansalvamide analogue caused marked time- and concentration-dependent inhibition of DNA synthesis and cell proliferation of two human pancreatic cancer cell lines (AsPC-1 and S2-013). The analogue induced G0/G1 phase cell-cycle arrest and morphological changes suggesting induction of apoptosis. Apoptosis was confirmed by annexin V binding. This novel sansalvamide analogue inhibits growth of pancreatic cancer cells through G0/G1 arrest and induces apoptosis. Sansalvamide analogues may be valuable for the treatment of pancreatic cancer

  18. The effect of synthetic ceramide analogues on gastritis and esophagitis in rats.

    Science.gov (United States)

    Kim, Sung Hyo; Um, Seung In; Nam, Yoonjin; Park, Sun Young; Dong, Je Hyun; Ko, Sung Kwon; Sohn, Uy Dong; Lee, Sang Joon

    2016-09-01

    The effects of ceremide analogues on esophagitis and gastritis in rats were examined. Gastritis induced by indomethacin was significantly reduced after CY3325 and CY3723 treatment, whereas other analogues had no effect. The amount of malondialdehyde in gastritis was significantly reduced by CY3325 or CY 3723. CY3325 or CY 3723 decreased the glutathione levels in gastritis. The myeloperoxidase level in gastritis is increased, and its increment was decreased by CY3325 and CY3723. In reflux esophagitis, the ulceration was decreased by CY3325, CY3723. The gastric volume and acid output are reduced, whereas the pH value is increased by CY3325 or CY3723 after esophagitis. These results suggest that ceramide analogues, CY3325 and CY3723, can prevent the development of gastritis and reflux esophagitis in rats.

  19. Cytostatic versus cytocidal activities of chloroquine analogues and inhibition of hemozoin crystal growth.

    Science.gov (United States)

    Gorka, Alexander P; Alumasa, John N; Sherlach, Katy S; Jacobs, Lauren M; Nickley, Katherine B; Brower, Jonathan P; de Dios, Angel C; Roepe, Paul D

    2013-01-01

    We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365-374, 2013).

  20. Inhibition of platelet aggregation by tartrazine and a pyrazolone analogue in normal and allergic individuals.

    Science.gov (United States)

    Gallagher, J S; Splansky, G L; Bernstein, I L

    1980-11-01

    The effect of tartrazine (T) (yellow dye No. 5) and one of its metabolites an aminopyrazolone analogue (1-sulphophenyl-3-carboxy-5-hydroxypyrazole, SCHP) upon collagen-induced platelet aggregation (C-PA) was investigated in fourteen atopic patients and fourteen normal subjects. Both T and SCHP inhibited C-PA in atopic patients at significantly lower doses than in normal volunteers. The mean inhibitory concentrations of SCHP were similar to aspirin in both atopic and normal individuals. Although the precise mechanism by which these chemicals block C-PA has not been elucidated, this in vitro system may be a useful method of assessing non-immune mechanisms involved in reactions to tartrazine.

  1. Synthetic analogues of bovine bactenecin dodecapeptide reduce herpes simplex virus type 2 infectivity in mice

    DEFF Research Database (Denmark)

    Jenssen, Håvard; Shestakov, Andrey; Hancock, Robert E. W

    2013-01-01

    We have evaluated the potential of four synthetic peptides (denoted HH-2, 1002, 1006, 1018) with a distant relationship to the host defense peptide bovine bactenecin dodecapeptide for their ability to prevent genital infections with herpes simplex virus type 2 (HSV-2) in mice. All four peptides...... was introduced in human semen. Two of the peptides proved especially effective in reducing HSV-2 infection also in vivo. When admixed with virus prior to inoculation, both HH-2 and 1018 reduced viral replication and disease development in a genital model of HSV-2 infection in mice, and also when using very high...

  2. Inhibition of Dengue Virus 3 in Mammalian Cell Culture by Synthetic ...

    African Journals Online (AJOL)

    HP

    Purpose: To evaluate the inhibition of Dengue virus 3 by synthetic siRNAs targeting the untranslated regions UTR and structural regions of DENV3 genome in Vero-81 cell line. Methods: Vero-81 cells transfected with synthetic siRNAs were challenged by DENV3. The effectiveness of siRNAs was confirmed by four ...

  3. Inhibition of dengue virus 3 in mammalian cell culture by synthetic ...

    African Journals Online (AJOL)

    Purpose: To evaluate the inhibition of Dengue virus 3 by synthetic siRNAs targeting the untranslated regions UTR and structural regions of DENV3 genome in Vero-81 cell line. Methods: Vero-81 cells transfected with synthetic siRNAs were challenged by DENV3. The effectiveness of siRNAs was confirmed by four ...

  4. Prevention of Marine Biofouling Using the Natural Allelopathic Compound Batatasin-III and Synthetic Analogues.

    Science.gov (United States)

    Moodie, Lindon W K; Trepos, Rozenn; Cervin, Gunnar; Bråthen, Kari Anne; Lindgård, Bente; Reiersen, Rigmor; Cahill, Patrick; Pavia, Henrik; Hellio, Claire; Svenson, Johan

    2017-07-28

    The current study reports the first comprehensive evaluation of a class of allelopathic terrestrial natural products as antifoulants in a marine setting. To investigate the antifouling potential of the natural dihydrostilbene scaffold, a library of 22 synthetic dihydrostilbenes with varying substitution patterns, many of which occur naturally in terrestrial plants, were prepared and assessed for their antifouling capacity. The compounds were evaluated in an extensive screen against 16 fouling marine organisms. The dihydrostilbene scaffold was shown to possess powerful general antifouling effects against both marine microfoulers and macrofoulers with inhibitory activities at low concentrations. The species of microalgae examined displayed a particular sensitivity toward the evaluated compounds at low ng/mL concentrations. It was shown that several of the natural and synthetic compounds exerted their repelling activities via nontoxic and reversible mechanisms. The activities of the most active compounds such as 3,5-dimethoxybibenzyl (5), 3,4-dimethoxybibenzyl (9), and 3-hydroxy-3',4,5'-trimethoxybibenzyl (20) were comparable to the commercial antifouling booster biocide Sea-nine, which was employed as a positive control. The investigation of terrestrial allelopathic natural products to counter marine fouling represents a novel strategy for the design of "green" antifouling technologies, and these compounds offer a potential alternative to traditional biocidal antifoulants.

  5. Synthesis, anticancer activity, and inhibition of tubulin polymerization by conformationally restricted analogues of lavendustin A.

    Science.gov (United States)

    Mu, Fanrong; Hamel, Ernest; Lee, Debbie J; Pryor, Donald E; Cushman, Mark

    2003-04-24

    Compounds in the lavendustin A series have been shown to inhibit both protein-tyrosine kinases (PTKs) and tubulin polymerization. Since certain lavendustin A derivatives can exist in conformations that resemble both the trans-stilbene structure of the PTK inhibitor piceatannol and the cis-stilbene structure of the tubulin polymerization inhibitor combretastatin A-4, the possibility exists that the ratio of the two types of activities of the lavendustins could be influenced through the synthesis of conformationally restricted analogues. Accordingly, the benzylaniline structure of a series of pharmacologically active lavendustin A fragments was replaced by either their cis- or their trans-stilbene relatives, and effects on both inhibition of tubulin polymerization and cytotoxicity in cancer cell cultures were monitored. Both dihydrostilbene and 1,2-diphenylalkyne congeners were also prepared and evaluated biologically. Surprisingly, conformational restriction of the bridge between the two aromatic rings of the lavendustins had no significant effect on biological activity. On the other hand, conversion of the three phenolic hydroxyl groups of the lavendustin A derivatives to their corresponding methyl ethers consistently abolished their ability to inhibit tubulin polymerization and usually decreased cytotoxicity in cancer cell cultures as well, indicating the importance of at least one of the phenolic hydroxyl groups. Further investigation suggested that the phenolic hydroxyl group in the salicylamide ring was required for activity, while the two phenol moieties in the hydroquinone ring could be methylated with retention of activity. Two of the lavendustin A derivatives displayed IC(50) values of 1.4 microM for inhibition of tubulin polymerization, which ranks them among the most potent of the known tubulin polymerization inhibitors.

  6. Tyrosol and Its Analogues Inhibit Alpha-Melanocyte-Stimulating Hormone Induced Melanogenesis

    Directory of Open Access Journals (Sweden)

    Kuo-Ching Wen

    2013-11-01

    Full Text Available Melanin is responsible for skin color and plays a major role in defending against harmful external factors such as ultraviolet (UV irradiation. Tyrosinase is responsible for the critical steps of melanogenesis, including the rate-limiting step of tyrosine hydroxylation. The mechanisms of action of skin hypopigmenting agents are thought to be based on the ability of a given agent to inhibit the activity of tyrosinase and, hence, down regulate melanin synthesis. Tyrosol and its glycoside, salidroside, are active components of Rhodiola rosea, and in our preliminary study we found that Rhodiola rosea extract inhibited melanogenesis. In this study, we examined the effects of tyrosol and its analogues on melanin synthesis. We found that treatment of B16F0 cells to tyrosol (1, 4-hydroxyphenylacetic acid (5, 3-hydroxyphenylacetic acid (6, 2-hydroxyphenylacetic acid (7, or salidroside (11 resulted in a reduction in melanin content and inhibition of tyrosinase activity as well as its expression. Tyrosol (1, 4-hydroxyphenylacetic acid (5 and 2-hydroxyphenylacetic acid (7 suppressed MC1R expression. Tyrosol (1, 4-hydroxyphenylacetic acid (5, 3-hydroxyphenylacetic acid (6, and 2-hydroxyphenylacetic acid (7 inhibited α-MSH induced TRP-1 expression, but salidroside (11 did not. All the compounds did not affect MITF and TRP-2 expression. Furthermore, we found that the cell viability of tyrosol (1, 4-hydroxyphenylacetic acid (5, 3-hydroxyphenylacetic acid (6, and 2-hydroxyphenylacetic acid (7 at concentrations below 4 mM and salidroside (11 at concentrations below 0.5 mM were higher than 90%. The compounds exhibited metal-coordinating interactions with copper ion in molecular docking with tyrosinase. Our results suggest that tyrosol, 4-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 2-hydroxyphenylacetic acid, and salidroside are potential hypopigmenting agents.

  7. A bifunctional curcumin analogue for two-photon imaging and inhibiting crosslinking of amyloid beta in Alzheimer's disease.

    Science.gov (United States)

    Zhang, Xueli; Tian, Yanli; Yuan, Peng; Li, Yuyan; Yaseen, Mohammad A; Grutzendler, Jaime; Moore, Anna; Ran, Chongzhao

    2014-10-09

    In this report, we designed a highly bright bifunctional curcumin analogue CRANAD-28. In vivo two-photon imaging suggested that CRANAD-28 could penetrate the blood brain barrier (BBB) and label plaques and cerebral amyloid angiopathies (CAAs). We also demonstrated that this imaging probe could inhibit the crosslinking of amyloid beta induced either by copper or by natural conditions.

  8. Plumbagin, a vitamin K3 analogue ameliorate malaria pathogenesis by inhibiting oxidative stress and inflammation.

    Science.gov (United States)

    Gupta, Amit Chand; Mohanty, Shilpa; Saxena, Archana; Maurya, Anil Kumar; Bawankule, Dnyaneshwar U

    2018-03-22

    Plumbagin, a vitamin K3 analogue is the major active constituent in several plants including root of Plumbago indica Linn. This compound has been shown to exhibit a wide spectrum of pharmacological activities. The present investigation was to evaluate the ameliorative effects of plumbagin (PL) against severe malaria pathogenesis due to involvement of oxidative stress and inflammatory response in Plasmodium berghei infected malaria in mice. Malaria pathogenesis was induced by intra-peritoneal injection of P. berghei infected red blood cells into the Swiss albino mice. PL was administered orally at doses of 3, 10 and 30 mg/kg/day following Peter's 4 day suppression test. Oral administration of PL showed significant reduction of parasitaemia and increase in mean survival time. PL treatment is also attributed to significant increase in the blood glucose and haemoglobin level when compared with vehicle-treated infected mice. Significant inhibition in level of oxidative stress and pro-inflammation related markers were observed in PL treated group. The trend of inhibition in oxidative stress markers level after oral treatment of PL was MPO > LPO > ROS in organ injury in P. berghei infected mice. This study showed that plumbagin is able to ameliorate malaria pathogenesis by augmenting anti-oxidative and anti-inflammatory mechanism apart from its effect on reducing parasitaemia and increasing mean survival time of malaria-induced mice.

  9. New castanospermine glycoside analogues inhibit breast cancer cell proliferation and induce apoptosis without affecting normal cells.

    Directory of Open Access Journals (Sweden)

    Ghada Allan

    Full Text Available sp²-Iminosugar-type castanospermine analogues have been shown to exhibit anti-tumor activity. However, their effects on cell proliferation and apoptosis and the molecular mechanism at play are not fully understood. Here, we investigated the effect of two representatives, namely the pseudo-S- and C-octyl glycoside 2-oxa-3-oxocastanospermine derivatives SO-OCS and CO-OCS, on MCF-7 and MDA-MB-231 breast cancer and MCF-10A mammary normal cell lines. We found that SO-OCS and CO-OCS inhibited breast cancer cell viability in a concentration- and time-dependent manner. This effect is specific to breast cancer cells as both molecules had no impact on normal MCF-10A cell proliferation. Both drugs induced a cell cycle arrest. CO-OCS arrested cell cycle at G1 and G2/M in MCF-7 and MDA-MB-231 cells respectively. In MCF-7 cells, the G1 arrest is associated with a reduction of CDK4 (cyclin-dependent kinase 4, cyclin D1 and cyclin E expression, pRb phosphorylation, and an overexpression of p21(Waf1/Cip1. In MDA-MB-231 cells, CO-OCS reduced CDK1 but not cyclin B1 expression. SO-OCS accumulated cells in G2/M in both cell lines and this blockade was accompanied by a decrease of CDK1, but not cyclin B1 expression. Furthermore, both drugs induced apoptosis as demonstrated by the increased percentage of annexin V positive cells and Bax/Bcl-2 ratio. Interestingly, in normal MCF-10A cells the two drugs failed to modify cell proliferation, cell cycle progression, cyclins, or CDKs expression. These results demonstrate that the effect of CO-OCS and SO-OCS is triggered by both cell cycle arrest and apoptosis, suggesting that these castanospermine analogues may constitute potential anti-cancer agents against breast cancer.

  10. Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue.

    Science.gov (United States)

    Chène, Patrick; Rudloff, Joëlle; Schoepfer, Joseph; Furet, Pascal; Meier, Peter; Qian, Zhiyan; Schlaeppi, Jean-Marc; Schmitz, Rita; Radimerski, Thomas

    2009-01-07

    Topoisomerase II poisons are in clinical use as anti-cancer therapy for decades and work by stabilizing the enzyme-induced DNA breaks. In contrast, catalytic inhibitors block the enzyme before DNA scission. Although several catalytic inhibitors of topoisomerase II have been described, preclinical concepts for exploiting their anti-proliferative activity based on molecular characteristics of the tumor cell have only recently started to emerge. Topoisomerase II is an ATPase and uses the energy derived from ATP hydrolysis to orchestrate the movement of the DNA double strands along the enzyme. Thus, interfering with ATPase function with low molecular weight inhibitors that target the nucleotide binding pocket should profoundly affect cells that are committed to undergo mitosis. Here we describe the discovery and characterization of a novel purine diamine analogue as a potent ATP-competitive catalytic inhibitor of topoisomerase II. Quinoline aminopurine compound 1 (QAP 1) inhibited topoisomerase II ATPase activity and decatenation reaction at sub-micromolar concentrations, targeted both topoisomerase II alpha and beta in cell free assays and, using a quantitative cell-based assay and a chromosome segregation assay, displayed catalytic enzyme inhibition in cells. In agreement with recent hypothesis, we show that BRCA1 mutant breast cancer cells have increased sensitivity to QAP 1. The results obtained with QAP 1 demonstrate that potent and selective catalytic inhibition of human topoisomerase II function with an ATP-competitive inhibitor is feasible. Our data suggest that further drug discovery efforts on ATP-competitive catalytic inhibitors are warranted and that such drugs could potentially be developed as anti-cancer therapy for tumors that bear the appropriate combination of molecular alterations.

  11. Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue

    Directory of Open Access Journals (Sweden)

    Schlaeppi Jean-Marc

    2009-01-01

    Full Text Available Abstract Background Topoisomerase II poisons are in clinical use as anti-cancer therapy for decades and work by stabilizing the enzyme-induced DNA breaks. In contrast, catalytic inhibitors block the enzyme before DNA scission. Although several catalytic inhibitors of topoisomerase II have been described, preclinical concepts for exploiting their anti-proliferative activity based on molecular characteristics of the tumor cell have only recently started to emerge. Topoisomerase II is an ATPase and uses the energy derived from ATP hydrolysis to orchestrate the movement of the DNA double strands along the enzyme. Thus, interfering with ATPase function with low molecular weight inhibitors that target the nucleotide binding pocket should profoundly affect cells that are committed to undergo mitosis. Results Here we describe the discovery and characterization of a novel purine diamine analogue as a potent ATP-competitive catalytic inhibitor of topoisomerase II. Quinoline aminopurine compound 1 (QAP 1 inhibited topoisomerase II ATPase activity and decatenation reaction at sub-micromolar concentrations, targeted both topoisomerase II alpha and beta in cell free assays and, using a quantitative cell-based assay and a chromosome segregation assay, displayed catalytic enzyme inhibition in cells. In agreement with recent hypothesis, we show that BRCA1 mutant breast cancer cells have increased sensitivity to QAP 1. Conclusion The results obtained with QAP 1 demonstrate that potent and selective catalytic inhibition of human topoisomerase II function with an ATP-competitive inhibitor is feasible. Our data suggest that further drug discovery efforts on ATP-competitive catalytic inhibitors are warranted and that such drugs could potentially be developed as anti-cancer therapy for tumors that bear the appropriate combination of molecular alterations.

  12. The role of inhibition by phosphocitrate and its analogue in chondrocyte differentiation and subchondral bone advance in Hartley guinea pigs.

    Science.gov (United States)

    Sun, Yubo; Kiraly, Alex J; Cox, Michael; Mauerhan, David R; Hanley, Edward N

    2018-04-01

    Phosphocitrate (PC) and its analogue, PC-β ethyl ester, inhibit articular cartilage degeneration in Hartley guinea pigs. However, the underlying molecular mechanisms remain unclear. The present study aimed to investigate the hypothesis that PC exerted its disease-modifying effect on osteoarthritis (OA), in part, by inhibiting a molecular program similar to that in the endochondral pathway of ossification. The results demonstrated that severe proteoglycan loss occurred in the superficial and middle zones, as well as in the calcified zone of articular cartilage in the Hartley guinea pigs. Subchondral bone advance was greater in the control Hartley guinea pigs compared with PC- or PC analogue-treated guinea pigs. Resorption of cartilage bars or islands and vascular invasion in the growth plate were also greater in the control guinea pigs compared with the PC- or PC analogue-treated guinea pigs. The levels of matrix metalloproteinase-13 and type X collagen within the articular cartilage and growth plate were significantly increased in the control guinea pigs compared with PC-treated guinea pigs (Pguinea pigs exhibited a hypertrophic phenotype and recapitulated a developmental molecular program similar to the endochondral pathway of ossification. Activation of this molecular program resulted in resorption of calcified articular cartilage and subchondral bone advance. This suggests that PC and PC analogues exerted their OA disease-modifying activity, in part, by inhibiting this molecular program.

  13. Cell motility is inhibited by the antiepileptic compound, valproic acid and its teratogenic analogues

    DEFF Research Database (Denmark)

    Walmod, P S; Foley, A; Berezin, A

    1998-01-01

    Valproic acid (VPA) is an established human teratogen that causes neural tube defects in 1-2% of human foetuses exposed to the drug during early pregnancy. In this study, individual cell motility was evaluated using short- and long-term time-lapse video-recording and computer assisted image analy......-actin and of a series of focal adhesion proteins, indicating that the effect of VPA on cell motility may be causally related to increased cell-substratum interactions or to alterations in the organisation or dynamics of the actin cytoskeleton.......Valproic acid (VPA) is an established human teratogen that causes neural tube defects in 1-2% of human foetuses exposed to the drug during early pregnancy. In this study, individual cell motility was evaluated using short- and long-term time-lapse video-recording and computer assisted image...... analysis, and it was found that VPA and selected VPA-analogues inhibited individual cell motility of L-cells in a dose-dependent manner. The compounds caused a decrease in the root-mean-square speed, S, and in the rate of diffusion, R, but an increase in the time of persistence in direction, P. Using short...

  14. 1082-39, an analogue of sorafenib, inhibited human cancer cell growth more potently than sorafenib.

    Science.gov (United States)

    Chu, Jia-Hui; Zhao, Cui-Rong; Song, Zhi-Yu; Wang, Rui-Qi; Qin, Yi-Zhuo; Li, Wen-Bao; Qu, Xian-Jun

    2014-04-01

    1082-39, an analogue of sorafenib, is a derivative of indazole diarylurea. We evaluated the activity of 1082-39 against human cancer cell growth. Its effects and mechanisms of action were then compared with those of sorafenib. The experiments were performed in human melanoma M21 cells. Cell viability was estimated by using the colorimetric assay. Annexin V-FITC/PI staining assay was used to recognize the apoptotic cells. Further analysis of the mitochondria membrane potential (MMP) was performed by the JC-1 fluorescence probe staining. The levels of apoptotic proteins and kinases related to cancer proliferation were determined by western blotting assay. 1082-39 possessed the activity against cancer cell proliferation with time- and dose-dependent manner. 1082-39 induced M21 cell to apoptosis, showing the increase of annexin V-FITC/PI staining cells, the MMP collapse and releasing cytochrome c from mitochondria. Western blotting analysis showed the activation of the mitochondria-mediated intrinsic pathway, showing the increase of cleaved caspase-9, cleaved caspase-3 and cleaved PARP. Statistical analysis suggested that 1082-39 possessed greater activities than sorafenib in the inhibition of M21 proliferation and induction of apoptosis. These effects of 1082-39 might arise from its activity of regulation the PI3K/Akt and Wnt/β-catenin signaling pathways. 1082-39 is a promising candidate compound which could develop as a potent anticancer agent. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  15. Mechanism of inhibition of Shiga-toxigenicEscherichia coliSubAB cytotoxicity by steroids and diacylglycerol analogues.

    Science.gov (United States)

    Yahiro, Kinnosuke; Nagasawa, Sayaka; Ichimura, Kimitoshi; Takeuchi, Hiroki; Ogura, Kohei; Tsutsuki, Hiroyasu; Shimizu, Takeshi; Iyoda, Sunao; Ohnishi, Makoto; Iwase, Hirotaro; Moss, Joel; Noda, Masatoshi

    2018-12-01

    Shiga toxigenic Escherichia coli (STEC) are responsible for a worldwide foodborne disease, which is characterized by severe bloody diarrhea and hemolytic uremic syndrome (HUS). Subtilase cytotoxin (SubAB) is a novel AB 5 toxin, which is produced by Locus for Enterocyte Effacement (LEE)-negative STEC. Cleavage of the BiP protein by SubAB induces endoplasmic reticulum (ER) stress, followed by induction of cytotoxicity in vitro or lethal severe hemorrhagic inflammation in mice. Here we found that steroids and diacylglycerol (DAG) analogues (e.g., bryostatin 1, Ingenol-3-angelate) inhibited SubAB cytotoxicity. In addition, steroid-induced Bcl-xL expression was a key step in the inhibition of SubAB cytotoxicity. Bcl-xL knockdown increased SubAB-induced apoptosis in steroid-treated HeLa cells, whereas SubAB-induced cytotoxicity was suppressed in Bcl-xL overexpressing cells. In contrast, DAG analogues suppressed SubAB activity independent of Bcl-xL expression at early time points. Addition of Shiga toxin 2 (Stx2) with SubAB to cells enhanced cytotoxicity even in the presence of steroids. In contrast, DAG analogues suppressed cytotoxicity seen in the presence of both toxins. Here, we show the mechanism by which steroids and DAG analogues protect cells against SubAB toxin produced by LEE-negative STEC.

  16. Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones.

    Science.gov (United States)

    Malik, Minnie; Britten, Joy; Cox, Jeris; Patel, Amrita; Catherino, William H

    2016-01-01

    To determine the effect of GnRH analogues (GnRH-a) leuprolide acetate (LA) and cetrorelix acetate on gonadal hormone-regulated expression of extracellular matrix in uterine leiomyoma three-dimensional (3D) cultures. Laboratory study. University research laboratory. Women undergoing hysterectomy for symptomatic leiomyomas. The 3D cell cultures, protein analysis, Western blot, immunohistochemistry. Expression of extracellular matrix proteins, collagen 1, fibronectin, and versican in leiomyoma cells 3D cultures exposed to E2, P, LA, cetrorelix acetate, and combinations for 24- and 72-hour time points. The 3D leiomyoma cultures exposed to E2 for 24 hours demonstrated an increased expression of collagen-1 and fibronectin, which was maintained for up to 72 hours, a time point at which versican was up-regulated significantly. Although P up-regulated collagen-1 protein (1.29 ± 0.04) within 24 hours of exposure, significant increase in all extracellular matrix (ECM) proteins was observed when the gonadal hormones were used concomitantly. Significant decrease in the amount of ECM proteins was observed on use of GnRH-a, LA and cetrorelix, with 24-hour exposure. Both the compounds also significantly decreased ECM protein concentration despite the presence of E2 or both gonadal hormones. This study demonstrates that GnRH-a directly affect the gonadal hormone-regulated collagen-1, fibronectin, and versican production in their presence. These findings suggest that localized therapy with GnRH-a may inhibit leiomyoma growth even in the presence of endogenous gonadal hormone exposure, thereby providing a mechanism to eliminate the hypoestrogenic side effects associated with GnRH-a therapy. Published by Elsevier Inc.

  17. Synthetic surfactant based on analogues of SP-B and SP-C is superior to single-peptide surfactants in ventilated premature rabbits.

    Science.gov (United States)

    Almlén, Andreas; Walther, Frans J; Waring, Alan J; Robertson, Bengt; Johansson, Jan; Curstedt, Tore

    2010-06-01

    Respiratory distress syndrome (RDS) is currently treated with surfactant preparations obtained from natural sources and attempts to develop equally active synthetic surfactants have been unsuccessful. One difference in composition is that naturally derived surfactants contain the two hydrophobic proteins SP-B and SP-C while synthetic preparations contain analogues of either SP-B or SP-C. It was recently shown that both SP-B and SP-C (or SP-C33, an SP-C analogue) are necessary to establish alveolar stability at end-expiration in a rabbit RDS model, as reflected by high lung gas volumes without application of positive end-expiratory pressure. To study the efficacy of fully synthetic surfactants containing analogues of both SP-B and SP-C compared to surfactants with only one protein analogue. Premature newborn rabbits, treated with synthetic surfactants, were ventilated for 30 min without positive end-expiratory pressure. Tidal volumes as well as lung gas volumes at end-expiration were determined. Treatment with 2% Mini-B (a short-cut version of SP-B) and 2% SP-C33, or its C-terminally truncated form SP-C30, in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, 68:31 (w/w) resulted in median lung gas volumes of 8-9 ml/kg body weight, while animals treated with 2% Mini-B surfactant or 2% SP-C33/SP-C30 surfactant had lung gas volumes of 3-4 ml/kg, and those treated with Curosurf, a porcine surfactant, 15-17 ml/kg. In contrast, mixing SP-C33 with peptides with different distributions of positively charged and hydrophobic residues did not improve lung gas volumes. The data indicate that synthetic surfactants containing analogues of both SP-B and SP-C might be superior to single-peptide surfactants in the treatment of RDS.

  18. Isomer-specific comparisons of the hydrolysis of synthetic pyrethroids and their fluorogenic analogues by esterases from the cotton bollworm Helicoverpa armigera.

    Science.gov (United States)

    Yuan, G; Li, Y; Farnsworth, C A; Coppin, C W; Devonshire, A L; Scott, C; Russell, R J; Wu, Y; Oakeshott, J G

    2015-06-01

    The low aqueous solubility and chiral complexity of synthetic pyrethroids, together with large differences between isomers in their insecticidal potency, have hindered the development of meaningful assays of their metabolism and metabolic resistance to them. To overcome these problems, Shan and Hammock (2001) [7] therefore developed fluorogenic and more water-soluble analogues of all the individual isomers of the commonly used Type 2 pyrethroids, cypermethrin and fenvalerate. The analogues have now been used in several studies of esterase-based metabolism and metabolic resistance. Here we test the validity of these analogues by quantitatively comparing their hydrolysis by a battery of 22 heterologously expressed insect esterases with the hydrolysis of the corresponding pyrethroid isomers by these esterases in an HPLC assay recently developed by Teese et al. (2013) [14]. We find a strong, albeit not complete, correlation (r = 0.7) between rates for the two sets of substrates. The three most potent isomers tested were all relatively slowly degraded in both sets of data but three esterases previously associated with pyrethroid resistance in Helicoverpa armigera did not show higher activities for these isomers than did allelic enzymes derived from susceptible H. armigera. Given their amenability to continuous assays at low substrate concentrations in microplate format, and ready detection of product, we endorse the ongoing utility of the analogues in many metabolic studies of pyrethroids. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Epoxyeicosatrienoic acid analogue lowers blood pressure through vasodilation and sodium channel inhibition

    Czech Academy of Sciences Publication Activity Database

    Khan, M. A. H.; Pavlov, T. S.; Christain, S. V.; Neckář, Jan; Staruschenko, A.; Gauthier, K. M.; Capdevila, J. H.; Falck, J. R.; Campbell, W. B.; Imig, J. D.

    2014-01-01

    Roč. 127, č. 7 (2014), s. 463-474 ISSN 0143-5221 Institutional support: RVO:67985823 Keywords : angiotensin II * epithelial sodium channel (ENaC) * epoxyeicosatrienoic acid analogue * hypertension Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 5.598, year: 2014

  20. Uses of Nucleic Acid Analogues in the Inhibition of Nucleic Acid Amplification

    DEFF Research Database (Denmark)

    1999-01-01

    The present invention relates to the use of nucleic acid analogues in blocking nucleic acid ampli?cation procedures and to diagnostic and analytical techniques based thereon. Also included are kits for use in the conduct of nucleic acid ampli?cation reactions....

  1. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells.

    Science.gov (United States)

    Dyari, Herryawan Ryadi Eziwar; Rawling, Tristan; Chen, Yongjuan; Sudarmana, William; Bourget, Kirsi; Dwyer, Julie M; Allison, Sarah E; Murray, Michael

    2017-12-01

    A saturated analog of the cytochrome P450-mediated ω-3-17,18-epoxide of ω-3-eicosapentaenoic acid (C20E) activated apoptosis in human triple-negative MDA-MB-231 breast cancer cells. This study evaluated the apoptotic mechanism of C20E. Increased cytosolic cytochrome c expression and altered expression of pro- and antiapoptotic B-cell lymphoma-2 proteins indicated activation of the mitochondrial pathway. Caspase-3 activation by C20E was prevented by pharmacological inhibition and silencing of the JNK and p38 MAP kinases (MAPK), upstream MAPK kinases MKK4 and MKK7, and the upstream MAPK kinase kinase apoptosis signal-regulating kinase 1 (ASK1). Silencing of the death receptor TNF receptor 1 (TNFR1), but not Fas, DR4, or DR5, and the adapters TRADD and TNF receptor-associated factor 2, but not Fas-associated death domain, prevented C20E-mediated apoptosis. B-cell lymphoma-2 homology 3-interacting domain death agonist (Bid) cleavage by JNK/p38 MAPK linked the extrinsic and mitochondrial pathways of apoptosis. In further studies, an antibody against the extracellular domain of TNFR1 prevented apoptosis by TNF-α but not C20E. These findings suggest that C20E acts intracellularly at TNFR1 to activate ASK1-MKK4/7-JNK/p38 MAPK signaling and to promote Bid-dependent mitochondrial disruption and apoptosis. In in vivo studies, tumors isolated from C20E-treated nu/nu mice carrying MDA-MB-231 xenografts showed increased TUNEL staining and decreased Ki67 staining, reflecting increased apoptosis and decreased proliferation, respectively. ω-3-Epoxy fatty acids like C20E could be incorporated into treatments for triple-negative breast cancers.-Dyari, H. R. E., Rawling, T., Chen, Y., Sudarmana, W., Bourget, K., Dwyer, J. M., Allison, S. E., Murray, M. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells. © FASEB.

  2. Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

    Science.gov (United States)

    Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

    2004-01-01

    Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (PPiracetam and TRH have no direct effects on net glucose transport, but competitively antagonise hypnotic drug inhibition of glucose transport. Other nootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis. PMID:15148255

  3. Infrared study of synthetic peptide analogues of the calcium-binding site III of troponin C: The role of helix F of an EF-hand motif.

    Science.gov (United States)

    Nara, Masayuki; Morii, Hisayuki; Tanokura, Masaru

    2013-05-01

    The EF-hand motif (helix-loop-helix) is a Ca(2+)-binding domain that is common among many intracellular Ca(2+)-binding proteins. We applied Fourier-transform infrared spectroscopy to study the synthetic peptide analogues of site III of rabbit skeletal muscle troponin C (helix E-loop-helix F). The 17-residue peptides corresponding to loop-helix F (DRDADGYIDAEELAEIF), where one residue is substituted by the D-type amino acid, were investigated to disturb the α-helical conformation of helix F systematically. These D-type-substituted peptides showed no band at about 1555 cm(-1) even in the Ca(2+)-loaded state although the native peptide (L-type only) showed a band at about 1555 cm(-1) in the Ca(2+)-loaded state, which is assigned to the side-chain COO(-) group of Glu at the 12th position, serving as the ligand for Ca(2+) in the bidentate coordination mode. Therefore, helix F is vital to the interaction between the Ca(2+) and the side-chain COO(-) group of Glu at the 12th position. Implications of the COO(-) antisymmetric stretch and the amide-I' of the synthetic peptide analogues of the Ca(2+)-binding sites are discussed. Copyright © 2012 Wiley Periodicals, Inc.

  4. Inhibition of emetic and superantigenic activities of staphylococcal enterotoxin A by synthetic peptides.

    Science.gov (United States)

    Maina, Edward K; Hu, Dong-Liang; Asano, Krisana; Nakane, Akio

    2012-11-01

    Staphylococcus aureus is a major human pathogen producing different types of toxins. Enterotoxin A (SEA) is the most common type among clinical and food-related strains. The aim of the present study was to estimate functional regions of SEA that are responsible for emetic and superantigenic activities using synthetic peptides. A series of 13 synthetic peptides corresponding to specific regions of SEA were synthesized, and the effect of these peptides on superantigenic activity of SEA including interferon γ (IFN-γ) production in mouse spleen cells, SEA-induced lethal shock in mice, spleen cell proliferation in house musk shrew, and emetic activity in shrews were assessed. Pre-treatment of spleen cells with synthetic peptides corresponding to the regions 21-40, 35-50, 81-100, or 161-180 of SEA significantly inhibited SEA-induced IFN-γ production and cell proliferation. These peptides also inhibited SEA-induced lethal shock. Interestingly, peptides corresponding to regions 21-40, 35-50 and 81-100 significantly inhibited SEA-induced emesis in house musk shrews, but region 161-180 did not. These findings indicated that regions 21-50 and 81-100 of SEA are important for both superantigenic and emetic activities of SEA molecule while region 161-180 is involved in superantigenic activity but not emetic activity of SEA. These regions could be important targets for therapeutic intervention against SEA exposure. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport.

    Science.gov (United States)

    Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

    2004-06-01

    1 Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. 2 The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (Paniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. 4 There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. 5 Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis.

  6. Biophysical inhibition of synthetic vs. naturally-derived pulmonary surfactant preparations by polymeric nanoparticles.

    Science.gov (United States)

    Beck-Broichsitter, Moritz; Ruppert, Clemens; Schmehl, Thomas; Günther, Andreas; Seeger, Werner

    2014-01-01

    Reasonable suspicion has accumulated that inhaled nano-scale particulate matter influences the biophysical function of the pulmonary surfactant system. Hence, it is evident to provide novel insights into the extent and mechanisms of nanoparticle-surfactant interactions in order to facilitate the fabrication of safe nanomedicines suitable for pulmonary applications. Negatively- and positively-charged poly(styrene) nanoparticles (diameters of ~100nm) served as model carriers. Nanoparticles were incubated with several synthetic and naturally-derived pulmonary surfactants to characterize the sensitivity of each preparation to biophysical inactivation. Changes in surface properties (i.e. adsorption and dynamic surface tension behavior) were monitored in a pulsating bubble surfactometer. Both nanoparticle formulations revealed a dose-dependent influence on the biophysical behavior of all investigated pulmonary surfactants. However, the surfactant sensitivity towards inhibition depended on both the carrier type, where negatively-charged nanoparticles showed increased inactivation potency compared to their positively-charged counterparts, and surfactant composition. Among the surfactants tested, synthetic mixtures (i.e. phospholipids, phospholipids supplemented with surfactant protein B, and Venticute®) were more susceptible to surface-activity inhibition as the more complex naturally-derived preparations (i.e. Alveofact® and large surfactant aggregates isolated from rabbit bronchoalveolar lavage fluid). Overall, nanoparticle characteristics and surfactant constitution both influence the extent of biophysical inhibition of pulmonary surfactants. © 2013.

  7. The use of a-methyl-D-glucoside, a synthetic analogue of maltose, as inducer of amylase by Aspergillus sp in solid-state and submerged fermentations

    Directory of Open Access Journals (Sweden)

    Moreira Fabiana G.

    2001-01-01

    Full Text Available The use of a methyl-D-glucoside (alphaMG, a synthetic analogue of maltose, as carbon source and inducer of amylase synthesis to several species of Aspergillus was studied in submerged and solid-state fermentations. Among a group of ten species, A. tamarii, A. fumigatus and A. flavus were able to produce biomass and high specific amylolytic activity in submerged cultures containing alphaMG as the only carbon source. In solid state fermentation, the enrichment of basal wheat bran or corn cob medium with alphaMG increased up to 3 times the production of amylases. In both submerged and solid state fermentations, alphaMG was more effective inducer of amylases than maltose and starch.

  8. The use of alpha-methyl-D-glucoside, a synthetic analogue of maltose, as inducer of amylase by Aspergillus sp in solid-state and submerged fermentations

    Directory of Open Access Journals (Sweden)

    Fabiana G. Moreira

    2001-03-01

    Full Text Available The use of a methyl-D-glucoside (alphaMG, a synthetic analogue of maltose, as carbon source and inducer of amylase synthesis to several species of Aspergillus was studied in submerged and solid-state fermentations. Among a group of ten species, A. tamarii, A. fumigatus and A. flavus were able to produce biomass and high specific amylolytic activity in submerged cultures containing alphaMG as the only carbon source. In solid state fermentation, the enrichment of basal wheat bran or corn cob medium with alphaMG increased up to 3 times the production of amylases. In both submerged and solid state fermentations, alphaMG was more effective inducer of amylases than maltose and starch.

  9. Synthetic Peptides Analogue to Enamel Proteins Promote Osteogenic Differentiation of MC3T3-E1 and Mesenchymal Stem Cells

    Czech Academy of Sciences Publication Activity Database

    Rubert, M.; Ramis, J. M.; Vondrášek, Jiří; Gaya, A.; Lyngstadaas, S. P.; Monjo, M.

    2011-01-01

    Roč. 1, č. 2 (2011), s. 198-209 ISSN 2157-9083 Grant - others:GA ČR(CZ) GAP302/10/0427 Institutional research plan: CEZ:AV0Z40550506 Keywords : proline-rich regions * synthetic peptides * bone formation * mineralization * In Vitro Subject RIV: EI - Biotechnology ; Bionics

  10. Characterization of the LM5 pectic galactan epitope with synthetic analogues of β-1,4-d-galactotetraose

    DEFF Research Database (Denmark)

    Andersen, Mathias Christian Franch; Boos, Irene; Marcus, Susan E.

    2016-01-01

    .g. Immunofluorescent microscopy. Here, we describe the detailed epitope mapping of the mab LM5 that is shown to bind to a minimum of three sugar residues at the non-reducing end of linear beta-1,4-linked galactan. The study uses de novo synthetic analogs of galactans combined with carbohydrate microarray...

  11. Inhibition of c-Kit, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930.

    Science.gov (United States)

    Patel, Jay P; Kuang, Ye-Hong; Chen, Zhe-Sheng; Korlipara, Vijaya L

    2011-11-01

    The quinoline domain of OSI-930, a dual inhibitor of receptor tyrosine kinases (RTKs) c-Kit and KDR, was modified in an effort to further understand the SAR of OSI-930, and the binding site characteristics of c-Kit and KDR. A series of 16 compounds with heteroatom substituted pyridyl and phenyl ring systems was synthesized and evaluated against a panel of kinases including c-Kit and KDR. Aminopyridyl derivative 6 was found to be the most active member of the series with 91% and 57% inhibition of c-Kit at 10μM and 1μM, respectively and 88% and 50% inhibition of KDR at 10μM and 1μM, respectively. The target compounds were also tested for their ability to inhibit efflux of mitoxantrone through inhibition of ATP dependent ABCG2 pump. Nitropyridyl derivative 5 and o-nitrophenyl derivative 7 exhibited complete inhibition of the ABCG2 pump with IC(50) values of 13.67μM and 16.67μM, respectively. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. Solubility enhancement and in vitro evaluation of PEG-b-PLA micelles as nanocarrier of semi-synthetic andrographolide analogue for cholangiocarcinoma chemotherapy.

    Science.gov (United States)

    Puntawee, Sujittra; Theerasilp, Man; Reabroi, Somrudee; Saeeng, Rungnapha; Piyachaturawat, Pawinee; Chairoungdua, Arthit; Nasongkla, Norased

    2016-01-01

    Semi-synthetic andrographolide analogue (19-triphenylmethyl ether andrographolide, AG 050) is a C-19 substituted andrographolide which is the major constituent from Andrographis Paniculata Nees (Acanthaceae). The analogue has previously been reported to be highly cytotoxic against several cancer cell lines. Nevertheless, its poor water solubility limits clinical applications of this compound. To improve the aqueous solubility and bioavailability of AG 050 by protonation and encapsulation in poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-b-PLA) polymeric micelles. PEG-b-PLA micelle was employed as a nanocarrier for AG 050. The physicochemical properties and in vitro cytotoxicity against cholangiocarcinoma (CCA) (KKU-M213) cell line were done in this study. Hydrochloride salt of AG 050 (AG 050-P) greatly enhanced the solubility of this compound (15-fold). PEG-b-PLA was able to encapsulate AG 050-P in hydrophobic core with a significant increase in the amount of AG 050-P in aqueous solution (280-fold). Film sonication method provided greater results in drug-loading study as compared to micelles via solvent evaporation. In addition, the encapsulated AG 050-P exhibited sustained release pattern and excellent cytotoxicity activity against KKU-M213 with IC50 of 3.33 µM. Nanoencapsulation of AG 050-P implicated its potential development for clinical use in CCA treatment.

  13. Inhibition of larval development of the marine copepod Acartia tonsa by four synthetic musk substances

    DEFF Research Database (Denmark)

    Wollenberger, Leah; Breitholtz, M.; Kusk, Kresten Ole

    2003-01-01

    A nitro musk (musk ketone). and three polycyclic musks (Tonalide(TM), Galaxolide(TM) and Celestolide(TM)) were tested for acute and subchronic effects on a marine crustacean, the calanoid copepod Acartia tonsa. Sublethal effects on A. tonsa larvae were investigated with a rapid and cost effective...... ketone) and 2.5 mg/l (Tonalide(TM)). Since, the synthetic musks strongly inhibited larval development in A. tonsa at low nominal concentrations, they should be considered as very toxic. The larval development test with A. tonsa is able to provide important aquatic toxicity data for the evaluation...

  14. Development and characterization of a synthetic PVC/DEHP myocardial tissue analogue material for CT imaging applications.

    Science.gov (United States)

    Ramadan, Sherif; Paul, Narinder; Naguib, Hani E

    2018-04-01

    A simple myocardial analogue material has great potential to help researchers in the creation of medical CT Imaging phantoms. This work aims to outline a Bis(2-ethylhexyl) phthalate (DEHP) plasticizer/PVC material to achieve this. DEHP-PVC was manufactured in three ratios, 75, 80, and 85% DEHP by heating at 110 °C for 10 min to promote DEHP-PVC binding followed by heating at 150 °C to melt the blend. The material was then tested utilizing FTIR, tensile testing, dynamic mechanical analysis and imaged with computed tomography. The FTIR testing finds the presence of C-CL and carbonyl bonds that demonstrate the binding required in this plasticized material. The tensile testing finds a modulus of 180-20 kPa that increases with the proportion of plasticizer. The dynamic mechanical analysis finds a linear increase in viscoelastic properties with a storage/loss modulus of 6/.5-120/18 kPa. Finally, the CT number of the material increases with higher PVC content from 55 to 144HU. The 80% DEHP-PVC ratio meets the mechanical and CT properties necessary to function as a myocardial tissue analogue.

  15. Inhibition of PrPSc formation by synthetic O-sulfated glycopyranosides and their polymers.

    Science.gov (United States)

    Yamaguchi, Satoko; Nishida, Yoshihiro; Sasaki, Kenji; Kambara, Mikie; Kim, Chan-Lan; Ishiguro, Naotaka; Nagatsuka, Takehiro; Uzawa, Hirotaka; Horiuchi, Motohiro

    2006-10-20

    Sulfated glycosaminoglycans (GAGs) and sulfated glycans inhibit formation of the abnormal isoform of prion protein (PrPSc) in prion-infected cells and prolong the incubation time of scrapie-infected animals. Sulfation of GAGs is not tightly regulated and possible sites of sulfation are randomly modified, which complicates elucidation of the fundamental structures of GAGs that mediate the inhibition of PrPSc formation. To address the structure-activity relationship of GAGs in the inhibition of PrPSc formation, we screened the ability of various regioselectively O-sulfated glycopyranosides to inhibit PrPSc formation in prion-infected cells. Among the glycopyranosides and their polymers examined, monomeric 4-sulfo-N-acetyl-glucosamine (4SGN), and two glycopolymers, poly-4SGN and poly-6-sulfo-N-acetyl-glucosamine (poly-6SGN), inhibited PrPSc formation with 50% effective doses below 20 microg/ml, and their inhibitory effect became more evident with consecutive treatments. Structural comparisons suggested that a combination of an N-acetyl group at C-2 and an O-sulfate group at either O-4 or O-6 on glucopyranoside might be involved in the inhibition of PrPSc formation. Furthermore, polymeric but not monomeric 6SGN inhibited PrPSc formation, suggesting the importance of a polyvalent configuration in its effect. These results indicate that the synthetic sulfated glycosides are useful not only for the analysis of structure-activity relationship of GAGs but also for the development of therapeutics for prion diseases.

  16. Purine nucleoside analogues inhibit the repair of radiation-induced potentially lethal damage in mammalian cells in culture

    International Nuclear Information System (INIS)

    Nakatsugawa, S.; Kumar, A.

    1982-01-01

    Three purine nucleoside analogues were found to be much more effective than pyrimidine nucleoside analogues in the screening of PLD repair inhibitors using X-irradiated Chinese hamster HA-1 cells. Among the three purine nucleoside analogues, 3'-dG was the most effective at a non-toxic concentration. (author)

  17. Inhibition of lipid peroxidation by IRFI 042, a vitamin E analogue, decreases monensin cardiotoxicity in chicks

    International Nuclear Information System (INIS)

    Calo, Margherita; Altavilla, Domenica; Seminara, Paolo; Marini, Herbert; Minutoli, Letteria; Bitto, Alessandra; Naccari, Francesco; Squadrito, Francesco

    2005-01-01

    Monensin, a well-known ionophore antibiotic, may cause severe damage in myocardial cells. We investigated whether IRFI 042, a new analogue of vitamin E, may block lipid peroxidation in myocardial cells and in turn protect against monensin toxicity. Monensin toxicity was induced by repeated daily administration of the ionophore antibiotic (150 mg/kg/day for 7 days). Sham animals received by oral gavages only a saline solution and were used as controls. All animals were randomized to receive concomitantly by oral gavages IRFI 042 (20 mg/kg) or its vehicle. The experiment lasted 8 days. Survival rate, heart lipid peroxidation, studied by means of thiobarbituric acid-reactive substances (TBARs) levels, cardiac expression of endothelial nitric oxide (e-NOS) and histological analysis of the heart were performed. Monensin administration caused a decrease in survival rate. Mortality appeared following the second monensin injection and at day 7 caused a survival rate of 20%. Thereafter, no further mortality was observed. IRFI 042 administration improved survival rate. Injection of the ionophore antibiotic resulted in a marked cardiac lipid peroxidation and in a significant reduction in cardiac e-NOS message and protein expression. IRFI 042 decreased heart TBARs levels (Monensin + vehicle = 6.5 ± 0.8 nmol/mg; Monensin + IRFI 042 = 3.2 ± 1.1 nmol/mg; P < 0.001) and increased e-NOS message and protein expression. Histological analysis showed that IRFI 042 improved myocardial cells damage and enhanced the depressed e-NOS expression in chick heart samples following monensin administration. Our data suggest that IRFI 042 is a promising drug to reduce monensin cardio-toxicity in chicks

  18. Antimicrobial peptide inhibition of Porphyromonas gingivalis 381-induced hemagglutination is improved with a synthetic decapeptide.

    Science.gov (United States)

    Dixon, Douglas R; Jeffrey, Nicole R; Dubey, Vinod S; Leung, Kai P

    2009-12-01

    The effects of various antimicrobial peptides (AMPs) on disrupting the hemagglutinating ability of cellular components of the putative oral pathogen Porphyromonas gingivalis were examined. AMP inhibition of P. gingivalis 381-induced hemagglutination using vesicles (VES) or outer membrane (OM) preparations was determined within standardized hemagglutination assays using various mammalian erythrocytes. A synthetic decapeptide (KSL-W) and its truncated peptide analogs were evaluated and compared with selected classes of AMPs derived from naturally occurring innate defense peptides. All tested AMPs were effective in disrupting P. gingivalis-induced hemagglutination among tested erythrocytes, with the exception of magainin I and the truncated KSL-W analogs. LL-37 was generally the most potent followed by histatin 5. The synthetic decapeptide (KSL-W) was found to be similar to the histatin 8 peptide in terms of inhibitory effect. In addition, co-application assays (with selected oral-related AMPs+/-KSL-W) were employed to determine if co-application procedures would improve hemagglutination abrogation above that of oral-related AMPs alone. These experiments revealed that the KSL-W peptide improved hemagglutination inhibition above that of each of the oral-related peptides (histatin 5 and 8, LL-37) alone. Among mammalian erythrocytes, significant peptide-induced hemagglutination was observed for the cathelicidin class AMPs, LL-37 and indolicidin (>or=25 and >or=100 microM respectively). In contrast, KSL-W did not induce erythrocyte agglutination throughout any concentration range tested (0.1-1000 microM). Our results suggest that several AMPs are effective in disrupting P. gingivalis 381-induced hemagglutination and that the co-application of a small, synthetically derived peptide may serve to augment the role of local host AMPs engaged in innate defense.

  19. Synthetic

    Directory of Open Access Journals (Sweden)

    Anna Maria Manferdini

    2010-06-01

    Full Text Available Traditionally materials have been associated with a series of physical properties that can be used as inputs to production and manufacturing. Recently we witnessed an interest in materials considered not only as ‘true matter’, but also as new breeds where geometry, texture, tooling and finish are able to provoke new sensations when they are applied to a substance. These artificial materials can be described as synthetic because they are the outcome of various qualities that are not necessarily true to the original matter, but they are the combination of two or more parts, whether by design or by natural processes. The aim of this paper is to investigate the potential of architectural surfaces to produce effects through the invention of new breeds of artificial matter, using micro-scale details derived from Nature as an inspiration.

  20. Azure B and a synthetic structural analogue of methylene blue, ethylthioninium chloride, present with antidepressant-like properties.

    Science.gov (United States)

    Delport, Anzelle; Harvey, Brian H; Petzer, Anél; Petzer, Jacobus P

    2014-11-11

    The phenothiazinium compound, methylene blue (MB), possesses diverse pharmacological actions and is attracting attention for the treatment of bipolar disorder and Alzheimer's disease. MB acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and possesses antidepressant activity in rodents. The goal of this study was to synthesise a structural analogue of MB, ethylthioninium chloride (ETC), and to evaluate the effects of the structural changes on the MAO inhibitory and antidepressant properties of MB. This study also investigated the antidepressant properties of azure B, the major metabolite of MB, versus MB and imipramine as active comparators. ETC and azure B were firstly evaluated as inhibitors of human MAO, and secondly for antidepressant-like activity in the acute forced swim test (FST) in rats, and compared to saline, imipramine and MB. The results document that ETC is a reversible inhibitor of MAO-A and MAO-B with IC50 values of 0.510 μM and 0.592 μM, respectively, and that it is a weaker MAO-A inhibitor than MB and azure B. ETC and azure B were more effective than imipramine and MB in reversing immobility in the FST without inducing locomotor effects, with evidence supporting a serotonergic action. Of interest is the finding that ETC is more toxic for cultured cells than MB. Azure B may therefore be a contributor to the antidepressant effect of MB. Small structural changes made to MB retain its antidepressant effect, even though the resulting phenothiazinium compound possesses reduced MAO-A inhibitory potency.

  1. Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits myeloperoxidase activity in inflammatory cells.

    Science.gov (United States)

    Mishra, Om P; Popov, Anatoliy V; Pietrofesa, Ralph A; Nakamaru-Ogiso, Eiko; Andrake, Mark; Christofidou-Solomidou, Melpo

    2018-03-07

    Myeloperoxidase (MPO) generates hypochlorous acid (HOCl) during inflammation and infection. We showed that secoisolariciresinol diglucoside (SDG) scavenges radiation-induced HOCl in physiological solutions. However, the action of SDG and its synthetic version, LGM2605, on MPO-catalyzed generation of HOCl is unknown. The present study evaluated the effect of LGM2605 on human MPO, and murine MPO from macrophages and neutrophils. MPO activity was determined fluorometrically using hypochlorite-specific 3'-(p-aminophenyl) fluorescein (APF). The effect of LGM2605 on (a) the peroxidase cycle of MPO was determined using Amplex Red while the effect on (b) the chlorination cycle was determined using a taurine chloramine assay. Using electron paramagnetic resonance (EPR) spectroscopy we determined the effect of LGM2605 on the EPR signals of MPO. Finally, computational docking of SDG was used to identify energetically favorable docking poses to enzyme's active site. LGM2605 inhibited human and murine MPO activity. MPO inhibition was observed in the absence and presence of Cl - . EPR confirmed that LGM2605 suppressed the formation of Compound I, an oxoiron (IV) intermediate [Fe(IV)O] containing a porphyrin π-radical of MPO's catalytic cycle. Computational docking revealed that SDG can act as an inhibitor by binding to the enzyme's active site. We conclude that LGM2605 inhibits MPO activity by suppressing both the peroxidase and chlorination cycles. EPR analysis demonstrated that LGM2605 inhibits MPO by decreasing the formation of the highly oxidative Compound I. This study identifies a novel mechanism of LGM2605 action as an inhibitor of MPO and indicates that LGM2605 may be a promising attenuator of oxidant-dependent inflammatory tissue damage. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. S-Adenosyl-L-Homocysteine Hydrolase Inhibition by a Synthetic Nicotinamide Cofactor Biomimetic

    Directory of Open Access Journals (Sweden)

    Lyn L. Kailing

    2018-03-01

    Full Text Available S-adenosyl-L-homocysteine (SAH hydrolases (SAHases are involved in the regulation of methylation reactions in many organisms and are thus crucial for numerous cellular functions. Consequently, their dysregulation is associated with severe health problems. The SAHase-catalyzed reaction is reversible and both directions depend on the redox activity of nicotinamide adenine dinucleotide (NAD+ as a cofactor. Therefore, nicotinamide cofactor biomimetics (NCB are a promising tool to modulate SAHase activity. In the present in vitro study, we investigated 10 synthetic truncated NAD+ analogs against a SAHase from the root-nodulating bacterium Bradyrhizobium elkanii. Among this set of analogs, one was identified to inhibit the SAHase in both directions. Isothermal titration calorimetry (ITC and crystallography experiments suggest that the inhibitory effect is not mediated by a direct interaction with the protein. Neither the apo-enzyme (i.e., deprived of the natural cofactor, nor the holo-enzyme (i.e., in the NAD+-bound state were found to bind the inhibitor. Yet, enzyme kinetics point to a non-competitive inhibition mechanism, where the inhibitor acts on both, the enzyme and enzyme-SAH complex. Based on our experimental results, we hypothesize that the NCB inhibits the enzyme via oxidation of the enzyme-bound NADH, which may be accessible through an open molecular gate, leaving the enzyme stalled in a configuration with oxidized cofactor, where the reaction intermediate can be neither converted nor released. Since the reaction mechanism of SAHase is quite uncommon, this kind of inhibition could be a viable pharmacological route, with a low risk of off-target effects. The NCB presented in this work could be used as a template for the development of more potent SAHase inhibitors.

  3. [Growth-regulating activity of N-benzyl- and O-benzyl-containing compounds belonging to a new group of synthetic analogues of natural auxins].

    Science.gov (United States)

    Gafurov, R G; Makhmutova, A A

    2005-01-01

    We studied the effect of benzylamine, benzyl alcohol, and their derivatives (constituting a new group of synthetic analogues of natural auxins) on rooting of leaf and stem cuttings, rhizogenesis and growth of barley plantlets and tomato seedlings, and tomato plant productivity. These compounds promoted rooting of leaf and stem bean cuttings, increased rhizogenic activity, and stimulated the development of root systems in barley and tomato seeds. The activity of the compounds studied was similar to that of standard substances (3-indoleacetic acid potassium salt and 2-naphthylacetic acid). The benzyl group attached to the oxygen or nitrogen atom was shown to be the smallest molecular structure which provided auxin activity of the compounds. Derivatives of benzyl alcohol containing the quaternary ammonium fragment possessed auxin and anti-gibberellin (retardant) properties. They were selected by chemical synthesis of low-molecular-weight bioregulators with desired properties (a combination of chemical fragments with complementary physiological activity in the molecule). Auxin and anti-gibberellin (retardant) activities produced a synergistic effect. Germination of seeds treated with these compounds was accompanied by a more significant increase in the weight and length of roots (compared to standard auxins). The rate of seedling establishment reached 100%. The development of fruits and accumulation of reserve nutrient substances were synchronized and accelerated after spraying vegetating plants with solutions of studied compounds. The synergistic effect underlay a significant increase in the amount and quality of the crop (e.g., tomatoes).

  4. A synthetic peptide blocking TRPV1 activation inhibits UV-induced skin responses.

    Science.gov (United States)

    Kang, So Min; Han, Sangbum; Oh, Jang-Hee; Lee, Young Mee; Park, Chi-Hyun; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

    2017-10-01

    Transient receptor potential type 1 (TRPV1) can be activated by ultraviolet (UV) irradiation, and mediates UV-induced matrix metalloproteinase (MMP)-1 and proinflammatory cytokines in keratinocytes. Various chemicals and compounds targeting TRPV1 activation have been developed, but are not in clinical use mostly due to their safety issues. We aimed to develop a novel TRPV1-targeting peptide to inhibit UV-induced responses in human skin. We designed and generated a novel TRPV1 inhibitory peptide (TIP) which mimics the specific site in TRPV1 (aa 701-709: Gln-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr, QRAITILDT), Thr 705 , and tested its efficacy of blocking UV-induced responses in HaCaT, mouse, and human skin. TIP effectively inhibited capsaicin-induced calcium influx and TRPV1 activation. Treatment of HaCaT with TIP prevented UV-induced increases of MMP-1 and pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α. In mouse skin in vivo, TIP inhibited UV-induced skin thickening and prevented UV-induced expression of MMP-13 and MMP-9. Moreover, TIP attenuated UV-induced erythema and the expression of MMP-1, MMP-2, IL-6, and IL-8 in human skin in vivo. The novel synthetic peptide targeting TRPV1 can ameliorate UV-induced skin responses in vitro and in vivo, providing a promising therapeutic approach against UV-induced inflammation and photoaging. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

  5. Identification of the primary peptide contaminant that inhibits fibrillation and toxicity in synthetic amyloid-β42.

    Science.gov (United States)

    Adams, Daniel J; Nemkov, Travis G; Mayer, John P; Old, William M; Stowell, Michael H B

    2017-01-01

    Understanding the pathophysiology of Alzheimer disease has relied upon the use of amyloid peptides from a variety of sources, but most predominantly synthetic peptides produced using t-butyloxycarbonyl (Boc) or 9-fluorenylmethoxycarbonyl (Fmoc) chemistry. These synthetic methods can lead to minor impurities which can have profound effects on the biological activity of amyloid peptides. Here we used a combination of cytotoxicity assays, fibrillation assays and high resolution mass spectrometry (MS) to identify impurities in synthetic amyloid preparations that inhibit both cytotoxicity and aggregation. We identify the Aβ42Δ39 species as the major peptide contaminant responsible for limiting both cytotoxicity and fibrillation of the amyloid peptide. In addition, we demonstrate that the presence of this minor impurity inhibits the formation of a stable Aβ42 dimer observable by MS in very pure peptide samples. These results highlight the critical importance of purity and provenance of amyloid peptides in Alzheimer's research in particular, and biological research in general.

  6. The pattern recognition molecule deleted in malignant brain tumors 1 (DMBT1) and synthetic mimics inhibit liposomal nucleic acid delivery

    DEFF Research Database (Denmark)

    Lund Hansen, Pernille; Blaich, Stephanie; End, Caroline

    2011-01-01

    Liposomal nucleic acid delivery is a preferred option for therapeutic settings. The cellular pattern recognition molecule DMBT1, secreted at high levels in various diseases, and synthetic mimics efficiently inhibit liposomal nucleic acid delivery to human cells. These findings may have relevance ...

  7. Exposure to synthetic gray water inhibits amoeba encystation and alters expression of Legionella pneumophila virulence genes.

    Science.gov (United States)

    Buse, Helen Y; Lu, Jingrang; Ashbolt, Nicholas J

    2015-01-01

    Water conservation efforts have focused on gray water (GW) usage, especially for applications that do not require potable water quality. However, there is a need to better understand environmental pathogens and their free-living amoeba (FLA) hosts within GW, given their growth potential in stored gray water. Using synthetic gray water (sGW) we examined three strains of the water-based pathogen Legionella pneumophila and its FLA hosts Acanthamoeba polyphaga, A. castellanii, and Vermamoeba vermiformis. Exposure to sGW for 72 h resulted in significant inhibition (P vermiformis (1 versus 92%), suggesting sGW induced maintenance of the actively feeding trophozoite form. During sGW exposure, L. pneumophila culturability decreased as early as 5 h (1.3 to 2.9 log10 CFU, P < 0.001) compared to controls (Δ0 to 0.1 log10 CFU) with flow cytometric analysis revealing immediate changes in membrane permeability. Furthermore, reverse transcription-quantitative PCR was performed on total RNA isolated from L. pneumophila cells at 0 to 48 h after sGW incubation, and genes associated with virulence (gacA, lirR, csrA, pla, and sidF), the type IV secretion system (lvrB and lvrE), and metabolism (ccmF and lolA) were all shown to be differentially expressed. These results suggest that conditions within GW may promote interactions between water-based pathogens and FLA hosts, through amoebal encystment inhibition and alteration of bacterial gene expression, thus warranting further exploration into FLA and L. pneumophila behavior in GW systems. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  8. Synthetic anti-endotoxin peptides inhibit cytoplasmic LPS-mediated responses.

    Science.gov (United States)

    Pfalzgraff, Anja; Heinbockel, Lena; Su, Qi; Brandenburg, Klaus; Weindl, Günther

    2017-09-15

    Toll-like receptor (TLR) 4-independent recognition of lipopolysaccharide (LPS) in the cytosol by inflammatory caspases leads to non-canonical inflammasome activation and induction of IL-1 secretion and pyroptosis. The discovery of this novel mechanism has potential implications for the development of effective drugs to treat sepsis since LPS-mediated hyperactivation of caspases is critically involved in endotoxic shock. Previously, we demonstrated that Pep19-2.5, a synthetic anti-endotoxin peptide, efficiently neutralises pathogenicity factors of Gram-negative and Gram-positive bacteria and protects against sepsis in vivo. Here, we report that Pep19-2.5 inhibits the effects of cytoplasmic LPS in human myeloid cells and keratinocytes. In THP-1 monocytes and macrophages, the peptide strongly reduced secretion of IL-1β and LDH induced by intracellular LPS. In contrast, the TLR4 signaling inhibitor TAK-242 abrogates LPS-induced TNF and IL-1β secretion, but not pyroptotic cell death. Furthermore, Pep19-2.5 suppressed LPS-induced HMGB-1 production and caspase-1 activation in THP-1 monocytes. Consistent with this observation, we found impaired IL-1β and IL-1α release in LPS-stimulated primary monocytes in the presence of Pep19-2.5 and reduced LDH release and IL-1B and IL-1A expression in LPS-transfected HaCaT keratinocytes. Additionally, Pep19-2.5 completely abolished IL-1β release induced by LPS/ATP in macrophages via canonical inflammasome activation. In conclusion, we provide evidence that anti-endotoxin peptides inhibit the inflammasome/IL-1 axis induced by cytoplasmic LPS sensing in myeloid cells and keratinocytes and activation of the classical inflammasome by LPS/ATP which may contribute to the protection against bacterial sepsis and skin infections with intracellular Gram-negative bacteria. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Triterpene Acids from Frankincense and Semi-Synthetic Derivatives That Inhibit 5-Lipoxygenase and Cathepsin G

    Directory of Open Access Journals (Sweden)

    Andreas Koeberle

    2018-02-01

    Full Text Available Age-related diseases, such as osteoarthritis, Alzheimer’s disease, diabetes, and cardiovascular disease, are often associated with chronic unresolved inflammation. Neutrophils play central roles in this process by releasing tissue-degenerative proteases, such as cathepsin G, as well as pro-inflammatory leukotrienes produced by the 5-lipoxygenase (5-LO pathway. Boswellic acids (BAs are pentacyclic triterpene acids contained in the gum resin of the anti-inflammatory remedy frankincense that target cathepsin G and 5-LO in neutrophils, and might thus represent suitable leads for intervention with age-associated diseases that have a chronic inflammatory component. Here, we investigated whether, in addition to BAs, other triterpene acids from frankincense interfere with 5-LO and cathepsin G. We provide a comprehensive analysis of 17 natural tetra- or pentacyclic triterpene acids for suppression of 5-LO product synthesis in human neutrophils. These triterpene acids were also investigated for their direct interference with 5-LO and cathepsin G in cell-free assays. Furthermore, our studies were expanded to 10 semi-synthetic BA derivatives. Our data reveal that besides BAs, several tetra- and pentacyclic triterpene acids are effective or even superior inhibitors of 5-LO product formation in human neutrophils, and in parallel, inhibit cathepsin G. Their beneficial target profile may qualify triterpene acids as anti-inflammatory natural products and pharmacological leads for intervention with diseases related to aging.

  10. Triterpene Acids from Frankincense and Semi-Synthetic Derivatives That Inhibit 5-Lipoxygenase and Cathepsin G.

    Science.gov (United States)

    Koeberle, Andreas; Henkel, Arne; Verhoff, Moritz; Tausch, Lars; König, Stefanie; Fischer, Dagmar; Kather, Nicole; Seitz, Stefanie; Paul, Michael; Jauch, Johann; Werz, Oliver

    2018-02-24

    Age-related diseases, such as osteoarthritis, Alzheimer's disease, diabetes, and cardiovascular disease, are often associated with chronic unresolved inflammation. Neutrophils play central roles in this process by releasing tissue-degenerative proteases, such as cathepsin G, as well as pro-inflammatory leukotrienes produced by the 5-lipoxygenase (5-LO) pathway. Boswellic acids (BAs) are pentacyclic triterpene acids contained in the gum resin of the anti-inflammatory remedy frankincense that target cathepsin G and 5-LO in neutrophils, and might thus represent suitable leads for intervention with age-associated diseases that have a chronic inflammatory component. Here, we investigated whether, in addition to BAs, other triterpene acids from frankincense interfere with 5-LO and cathepsin G. We provide a comprehensive analysis of 17 natural tetra- or pentacyclic triterpene acids for suppression of 5-LO product synthesis in human neutrophils. These triterpene acids were also investigated for their direct interference with 5-LO and cathepsin G in cell-free assays. Furthermore, our studies were expanded to 10 semi-synthetic BA derivatives. Our data reveal that besides BAs, several tetra- and pentacyclic triterpene acids are effective or even superior inhibitors of 5-LO product formation in human neutrophils, and in parallel, inhibit cathepsin G. Their beneficial target profile may qualify triterpene acids as anti-inflammatory natural products and pharmacological leads for intervention with diseases related to aging.

  11. [Hemodynamic effects of the synthetic analogue of endogenous nitric oxide (II) donors a dinitrosyl iron complex in hypertensive patients with uncomplicated hypertensive crisis].

    Science.gov (United States)

    Gosteev, A Iu; Zorin, A V; Rodnenkov, O V; Dragnev, A G; Chazov, E I

    2014-01-01

    To examine the antihypertensive effect of the synthetic analogue of the endogenous nitric oxide donors in patients with grades 2-3 hypertension and uncomplicated hypertensive crisis (HC). The study included 30 male patients aged 35 to 73 years (mean age 55.5 ± 10.8 years). All the patients had grades 2-3 essential or secondary hypertension. Thirteen (43.3%) patients were observed to have signs of HC; 17 (56.7%) patients had persistent blood pressure (BP) elevation. A dinitrosyl iron complex was injected in a dose of 1.5 or 3 mg per kg of body weight. The purpose of its administration was to lower BP by at least 20% of its baseline level. No significant side effects associated with the administration of the test drug were recorded when the clinical trial protocol was implemented. All the patients reported fever and facial hyperemia during and 10-20 minutes after injection. They all (100%) showed efficient blood pressure reduction of at least 20% of the baseline level. Blood pressure changes were similar when the agent was administered in doses of 1.5 or 3 mg/kg. At 6-8 minutes after the drug was injected, there was a maximal decrease in blood pressure, then its gradual rise and stabilization at a lower level than the baseline one within the following 8 hours. There were no significant differences in the magnitude of a blood pressure reduction after administration of 1.5 and 3 mg/kg. The findings suggest that the dinitrosyl iron complex is highly effective in treating uncomplicated HC. The antihypertensive effect of the drug persists for 8 hours after its injection, which is very important during prehospital therapy. The drug is well tolerated by patients and causes an insignificant number of side effects.

  12. Inhibition of S-adenosylmethionine decarboxylase and diamine oxidase activities by analogues of methylglyoxal bis(guanylhydrazone) and their cellular uptake during lymphocyte activation.

    Science.gov (United States)

    Jänne, J; Morris, D R

    1984-03-15

    Several congeners of methylglyoxal bis(guanylhydrazone) were tested for their ability to inhibit eukaryotic putrescine-activated S-adenosylmethionine decarboxylase (EC 4.1.1.50) and intestinal diamine oxidase (EC 1.4.3.6). All the compounds tested, namely methylglyoxal bis(guanylhydrazone), ethylglyoxal bis(guanylhydrazone), dimethylglyoxal bis(guanylhydrazone) and the di-N"-methyl derivative of methylglyoxal bis(guanylhydrazone), were strong inhibitors of both yeast and mouse liver adenosylmethionine decarboxylase activity in vitro. The enzyme from both sources was most powerfully inhibited by ethylglyoxal bis(guanylhydrazone). All the diguanidines likewise inhibited diamine oxidase activity in vitro. The maximum intracellular concentrations of the ethyl and dimethylated analogues achieved in activated lymphocytes were only about one-fifth of that of the parent compound. However, both derivatives appeared to utilize the polyamine-carrier system, as indicated by competition experiments with spermidine.

  13. A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments

    Science.gov (United States)

    Mohni, Kareem N.; Thompson, Petria S.; Luzwick, Jessica W.; Glick, Gloria G.; Pendleton, Christopher S.; Lehmann, Brian D.; Pietenpol, Jennifer A.; Cortez, David

    2015-01-01

    The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic. PMID:25965342

  14. Activation dependence and kinetics of force and stiffness inhibition by aluminiofluoride, a slowly dissociating analogue of inorganic phosphate, in chemically skinned fibres from rabbit psoas muscle.

    Science.gov (United States)

    Chase, P B; Martyn, D A; Hannon, J D

    1994-04-01

    To examine the mechanism by which aluminiofluoride, a tightly binding analogue of inorganic phosphate, inhibits force in single, chemically skinned fibres from rabbit psoas muscle, we measured the Ca(2+)-dependence of the kinetics of inhibitor dissociation and the kinetics of actomyosin interactions when aluminiofluoride was bound to the crossbridges. The relation between stiffness and the speed of stretch during small amplitude ramp stretches (strength (pCa 4.0, 0.2 M gamma/2), stiffness exhibited a steep dependence on the rate of stretch; aluminiofluoride inhibition at pCa 4.0 (0.2 M gamma/2) resulted in an overall decrease in stiffness, with stiffness at high rates of stretch (10(3)-10(4) nm per h.s. per s) being disproportionately reduced. Thus the slope of the stiffness-speed relation was reduced during aluminiofluoride inhibition of activated fibres. Relaxation of inhibited fibres (pCa 9.2, 0.2 M gamma/2) resulted in aluminiofluoride being 'trapped' and was accompanied by a further decrease in stiffness at all rates of stretch which was comparable to that found in control relaxed fibres. In relaxed, low ionic strength conditions (pCa 9.2, 0.02 M gamma/2) which promote weak crossbridge binding, stiffness at all rates of stretch was significantly inhibited by aluminiofluoride 'trapped' in the fibre. To determine the Ca(2+)-dependence of inhibitor dissociation, force was regulated independent of Ca2+ using an activating troponin C (aTnC). Results obtained with a TnC-activated fibres confirmed that there is no absolute requirement for Ca2+ for recovery from force inhibition by inorganic phosphate analogues in skinned fibres; the only requirement is thin filament activation which enables active crossbridge cycling. These results indicate that aluminiofluoride preferentially inhibits rapid equilibrium or weak crossbridge attachment to actin, that aluminiofluoride-bound crossbridges attach tightly to the activated thin filament, and that, at maximal (or near

  15. Synthesis, Characterization and In Vitro Anticancer Activity of C-5 Curcumin Analogues with Potential to Inhibit TNF-α-Induced NF-κB Activation

    Directory of Open Access Journals (Sweden)

    Amit Anthwal

    2014-01-01

    Full Text Available In a search of new compounds active against cancer, synthesis of a series of C-5 curcumin analogues was carried out. The new compounds demonstrated good cytotoxicity against chronic myeloid leukemia (KBM5 and colon cancer (HCT116 cell lines. Further, these compounds were found to have better potential to inhibit TNF-α-induced NF-κB activation in comparison to curcumin, which show their potential to act as anti-inflammatory agents. Some compounds were found to show higher cytotoxicity against cancer cell lines in comparison to curcumin used as standard.

  16. A CD36 synthetic peptide inhibits silica-induced lung fibrosis in the mice.

    Science.gov (United States)

    Wang, Xin; Lv, Lina; Chen, Ying; Chen, Jie

    2010-02-01

    Silicosis is a kind of pneumoconiosis caused by inhalation of silica dust, which is characterized by lung fibrosis. The biologically active form of transforming growth factor-beta1 (TGF-beta1) plays a key role in the development of lung fibrosis. CD36 is involved in the transformation of latent TGF-beta1 (L-TGF-beta1) to active TGF-beta1. The antagonistic effect of the synthetic peptide was analyzed by the administration of CD36 (93-110) synthetic peptide to the silicosis model of mice. The hydroxyproline content of the silica + CD36 (93-110) synthetic peptide group was significantly lower than that of the other experimental groups [silica and silica + CD36 (208-225) synthetic peptide groups] (p synthetic peptide group were less than those of the other experimental groups. The expressions of collagen I and III of the silica + CD36 (93-110) synthetic peptide group were significantly lower than those of the other experimental groups (p synthetic peptide reduced the tissue fibrotic pathologies and collagen accumulation in the silicosis model of mice, resulting in the decreased severity of silica-induced lung fibrosis.

  17. [The inhibition of Mycoplasma pneumoniae adhesion in a fetuin test system by synthetic analogs and polymeric forms of neuraminic acid].

    Science.gov (United States)

    Tokovenko, I P; Skripal', I G; Malinovskaia, L P; Baĭramova, N E; Mochalova, L V; Tuzikov, A B; Bovin, N V

    1994-01-01

    Eight glycosides and structural analogues of neuraminic acid as well as eight polymeric forms of N-acetyl neuraminic acid have been studied for their inhibitory effect on adhesion of Mycoplasma pneumoniae. Maximum inhibiting effect among low-molecular compounds was manifested by 2-->3 sialyllactose which, being used in concentrations 5.0 and 10.0 micrograms/ml, inhibited adhesion of mycoplasmas by 76 and 87%, respectively. These indices for other derivatives in the above mentioned concentrations were as follows (%): 2-->6 sialyllactose, 31 and 74%; alpha-Me-glycoside NeuAc, 75 and 85%; alpha-Bn-glycoside-N-trifluoruracetyl NeuAc, 30 and 63%; alpha-Bn-glycoside NeuAc, 32 and 59%; alpha-Bn-glycoside-4-epi-NeuAc, 20 and 27%; beta-Bn-glycoside NeuAc, 2-4%; beta-me-glycoside NeuAc, 4-5%. The maximum inhibiting effect (50% inhibition at concentration 2.5 mumol) among polymeric forms was exerted by the conjugate alpha-benzeneglycoside with polyacrylic acid containing 12 mol% of NeuAc. Conjugates with 8, 16 and 20 mol% of NeuAc possessed a bit less activity. The 50% concentration for them was 5.3, 3.1 and 8.3 mumol, respectively. Polymeric forms on the basis of polyacrylamide proved less active.

  18. Reaction Characteristics of Andrographolide and its Analogue AL-1 with GSH, as a Simple Chemical Simulation of NF-κB Inhibition

    Directory of Open Access Journals (Sweden)

    Yuqiang Wang

    2012-01-01

    Full Text Available 14-α-Lipoic acid-3,19-dihydroxyandrographolide (AL-1, 2 is an analogue of andrographolide (Andro, 1 coupled to α-lipoic acid (LA, 4. AL-1 was at least 10-fold more potent than the natural parent compound Andro in inhibiting nuclear factor (NF-κB activation in RIN-m cells. In the present study, glutathione (GSH, 3 was used as a simple chemical model molecule of NF-κB with cysteine 62. The characteristics of the reaction between AL-1 or Andro and GSH were investigated to trace some possible elucidation for the inhibitive mechanism and stronger inhibition of AL-1 to NF-κB activation. The results showed that the main reaction products of AL-1 and Andro were identical, sulfhydryl adduct and amino adduct. AL-1 reacted much faster than Andro with GSH. The product yield of AL-1 was much higher than that of Andro. It was speculated that AL-1 might inhibit NF-κB by the same mechanism as Andro. And the faster reaction rate and higher yield may account for the stronger NF-κB inhibition of AL-1 when compared with Andro.

  19. Activity and biophysical inhibition resistance of a novel synthetic lung surfactant containing Super-Mini-B DATK peptide

    Directory of Open Access Journals (Sweden)

    Robert H. Notter

    2016-01-01

    Full Text Available Background/objectives. This study examines the surface activity, resistance to biophysical inhibition, and pulmonary efficacy of a synthetic lung surfactant containing glycerophospholipids combined with Super Mini-B (S-MB DATK, a novel and stable molecular mimic of lung surfactant protein (SP-B. The objective of the work is to test whether S-MB DATK synthetic surfactant has favorable biophysical and physiological activity for future use in treating surfactant deficiency or dysfunction in lung disease or injury.Methods. The structure of S-MB DATK peptide was analyzed by homology modeling and by FTIR spectroscopy. The in vitro surface activity and inhibition resistance of synthetic S-MB DATK surfactant was assessed in the presence and absence of albumin, lysophosphatidylcholine (lyso-PC, and free fatty acids (palmitoleic and oleic acid. Adsorption and dynamic surface tension lowering were measured with a stirred subphase dish apparatus and a pulsating bubble surfactometer (20 cycles/min, 50% area compression, 37 °C. In vivo pulmonary activity of S-MB DATK surfactant was measured in ventilated rabbits with surfactant deficiency/dysfunction induced by repeated lung lavages that resulted in arterial PO2 values <100 mmHg.Results. S-MB DATK surfactant had very high surface activity in all assessments. The preparation adsorbed rapidly to surface pressures of 46–48 mN/m at 37 °C (low equilibrium surface tensions of 22–24 mN/m, and reduced surface tension to <1 mN/m under dynamic compression on the pulsating bubble surfactometer. S-MB DATK surfactant showed a significant ability to resist inhibition by serum albumin, C16:0 lyso-PC, and free fatty acids, but surfactant inhibition was mitigated by increasing surfactant concentration. S-MB DATK synthetic surfactant quickly improved arterial oxygenation and lung compliance after intratracheal instillation to ventilated rabbits with severe surfactant deficiency.Conclusions. S-MB DATK is an active mimic

  20. Vanillin Analogues o-Vanillin and 2,4,6-Trihydroxybenzaldehyde Inhibit NFĸB Activation and Suppress Growth of A375 Human Melanoma.

    Science.gov (United States)

    Marton, Annamária; Kúsz, Erzsébet; Kolozsi, Csongor; Tubak, Vilmos; Zagotto, Giuseppe; Buzás, Krisztina; Quintieri, Luigi; Vizler, Csaba

    2016-11-01

    Constitutive activation of nuclear factor kappa-B (NFĸB) is a hallmark of various cancer types, including melanoma. Chemotherapy may further increase tumour NFĸB activity, a phenomenon that, in turn, exacerbates drug resistance. This study aimed at preliminary screening of a panel of aromatic aldehydes, including vanillin, for cytotoxicity and suppression of tumour cell NFĸB activity. The cytotoxic and NFĸB-inhibitory effects of 10 aromatic aldehydes, including vanillin, were investigated in cultured A375 human melanoma cells. Each compound was assayed alone and in combination with the model NFĸB-activating drug doxorubicin. The most promising analogues were then tested alone and in combination with 4-hydroperoxycyclophosphamide in vitro, and with cyclophosphamide in mice bearing A375 xenografts. The vanillin analogues o-vanillin and 2,4,6-trihydroxybenzaldehyde exhibited cytotoxicity against cultured A375 cells, and inhibited doxorubicin- and 4-hydroperoxycyclophosphamide-induced NFĸB activation. They also suppressed A375 cell growth in mice. o-vanillin and 2,4,6-trihydroxybenzaldehyde deserve further evaluation as potential anticancer drugs. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  1. ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin.

    Science.gov (United States)

    Li, Ke; Yan, Huaying; Guo, Wenhao; Tang, Mei; Zhao, Xinyu; Tong, Aiping; Peng, Yong; Li, Qintong; Yuan, Zhu

    2018-05-01

    PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects. We found that KU-60019 preferentially sensitizes PTEN-deficient MDA-MB-468 breast cancer cells to cisplatin, though it also slightly enhances sensitivity of PTEN wild-type breast cancer cells. The increased cytotoxic sensitivity is associated with apoptosis, as evidenced by flow cytometry and PARP cleavage. Additionally, the increase of DNA damage accumulation due to the decreased capability of DNA repair, as indicated by γ-H2AX and Rad51 foci, also contributed to this selective cytotoxicity. Mechanistically, compared with PTEN wild-type MDA-MB-231 cells, PTEN-deficient MDA-MB-468 cells have lower level of Rad51, higher ATM kinase activity, and display the elevated level of DNA damage. Moreover, these differences could be further enlarged by cisplatin. Our findings suggest that ATM is a promising target for PTEN-defective breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Identification of Electronic and Structural Descriptors of Adenosine Analogues Related to Inhibition of Leishmanial Glyceraldehyde-3-Phosphate Dehydrogenase

    Directory of Open Access Journals (Sweden)

    Norka B. H. Lozano

    2013-04-01

    Full Text Available Quantitative structure–activity relationship (QSAR studies were performed in order to identify molecular features responsible for the antileishmanial activity of 61 adenosine analogues acting as inhibitors of the enzyme glyceraldehyde 3-phosphate dehydrogenase of Leishmania mexicana (LmGAPDH. Density functional theory (DFT was employed to calculate quantum-chemical descriptors, while several structural descriptors were generated with Dragon 5.4. Variable selection was undertaken with the ordered predictor selection (OPS algorithm, which provided a set with the most relevant descriptors to perform PLS, PCR and MLR regressions. Reliable and predictive models were obtained, as attested by their high correlation coefficients, as well as the agreement between predicted and experimental values for an external test set. Additional validation procedures were carried out, demonstrating that robust models were developed, providing helpful tools for the optimization of the antileishmanial activity of adenosine compounds.

  3. Efficient inhibition of tumor angiogenesis and growth by a synthetic peptide blocking S100A4-methionine aminopeptidase 2 interaction

    Directory of Open Access Journals (Sweden)

    Takahiro Ochiya

    Full Text Available The prometastatic calcium-binding protein, S100A4, is expressed in endothelial cells, and its downregulation markedly suppresses tumor angiogenesis in a xenograft cancer model. Given that endothelial S100A4 can be a molecular target for inhibiting tumor angiogenesis, we addressed here whether synthetic peptide capable of blocking S100A4-effector protein interaction could be a novel antiangiogenic agent. To examine this hypothesis, we focused on the S100A4-binding domain of methionine aminopeptidase 2, an effector protein, which plays a role in endothelial cell growth. Overexpression of the domain in mouse endothelial MSS31 cells reduced DNA synthesis, and the corresponding synthetic peptide (named NBD indeed interacted with S100A4 and inhibited capillary formation in vitro and new blood vessel formation in vivo. Intriguingly, a single intra-tumor administration of the NBD peptide in human prostate cancer xenografts significantly reduced vascularity, resulting in tumor regression. Mechanistically, the NBD peptide enhanced assembly of nonmuscle myosin IIA filaments along with Ser1943 phosphorylation, stimulated formation of focal adhesions without phosphorylation of focal adhesion kinase, and provoked G1/S arrest of the cell cycle. Altogether, the NBD peptide is a potent inhibitor for tumor angiogenesis, and is the first example of an anticancer peptide drug developed on the basis of an endothelial S100A4-targeted strategy.

  4. Efficient inhibition of tumor angiogenesis and growth by a synthetic peptide blocking S100A4-methionine aminopeptidase 2 interaction.

    Science.gov (United States)

    Ochiya, Takahiro; Takenaga, Keizo; Asagiri, Masataka; Nakano, Kazumi; Satoh, Hitoshi; Watanabe, Toshiki; Imajoh-Ohmi, Shinobu; Endo, Hideya

    2015-01-01

    The prometastatic calcium-binding protein, S100A4, is expressed in endothelial cells, and its downregulation markedly suppresses tumor angiogenesis in a xenograft cancer model. Given that endothelial S100A4 can be a molecular target for inhibiting tumor angiogenesis, we addressed here whether synthetic peptide capable of blocking S100A4-effector protein interaction could be a novel antiangiogenic agent. To examine this hypothesis, we focused on the S100A4-binding domain of methionine aminopeptidase 2, an effector protein, which plays a role in endothelial cell growth. Overexpression of the domain in mouse endothelial MSS31 cells reduced DNA synthesis, and the corresponding synthetic peptide (named NBD) indeed interacted with S100A4 and inhibited capillary formation in vitro and new blood vessel formation in vivo. Intriguingly, a single intra-tumor administration of the NBD peptide in human prostate cancer xenografts significantly reduced vascularity, resulting in tumor regression. Mechanistically, the NBD peptide enhanced assembly of nonmuscle myosin IIA filaments along with Ser1943 phosphorylation, stimulated formation of focal adhesions without phosphorylation of focal adhesion kinase, and provoked G1/S arrest of the cell cycle. Altogether, the NBD peptide is a potent inhibitor for tumor angiogenesis, and is the first example of an anticancer peptide drug developed on the basis of an endothelial S100A4-targeted strategy.

  5. Analogue Gravity

    Directory of Open Access Journals (Sweden)

    Barceló Carlos

    2005-12-01

    Full Text Available Analogue models of (and for gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity.

  6. Inhibition of adjuvant-induced arthritis by nasal administration of novel synthetic peptides from heat shock protein 65.

    Science.gov (United States)

    Shi, Xiao-Lian; Wang, Li-Ping; Feng, Xuan; Fan, Dan-Dan; Zang, Wei-Jin; Wang, Bing; Zhou, Jun

    2014-07-25

    Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mediated by T cells. The aim of the present study was to investigate the therapeutic efficacy of synthetic peptides (HP-R1, HP-R2 and HP-R3), derived from the sequence of 65-kD mycobacterial heat shock protein (HSP), in the treatment of RA using adjuvant-induced arthritis (AA) animal model. AA was induced by a single intradermal injection Freund's complete adjuvant in male Lewis rats. At the first clinical sign of disease, rats were administered nasally by micropipette of peptides or phosphate buffer saline (PBS). Disease progression was monitored by measurement of body weight, arthritis score and paw swelling. The changes of histopathology were assessed by hematoxylin eosin staining. The serum levels of tumor necrosis factor (TNF) - alpha and interleukin (IL)-4 were measured by enzyme-linked immunosorbent assay (ELISA). The peptides efficiently inhibited the footpad swelling and arthritic symptoms in AA rats. The synthetic peptides displayed significantly less inflammatory cellular infiltration and synovium hyperplasia than model controls. This effect was associated with a suppression of pro-inflammatory cytokine TNF-alpha production and an increase of anti-inflammatory cytokine IL-4 production after peptides treatment. These results suggest that the synthetic peptides derived from HSP65 induce highly effective protection against AA, which is mediated in part by down-regulation of inflammatory cytokines, and support the view that the synthetic peptides is a potential therapy for RA that may help to diminish both joint inflammation and destruction.

  7. Analysis of HIV-1 fusion peptide inhibition by synthetic peptides from E1 protein of GB virus C.

    Science.gov (United States)

    Sánchez-Martín, Maria Jesús; Hristova, Kalina; Pujol, Montserrat; Gómara, Maria J; Haro, Isabel; Alsina, M Asunción; Busquets, M Antònia

    2011-08-01

    The aim of this study was to identify proteins that could inhibit the activity of the peptide sequence representing the N-terminal of the surface protein gp41 of HIV, corresponding to the fusion peptide of the virus (HIV-1 FP). To do this we synthesized and studied 58 peptides corresponding to the envelope protein E1 of the hepatitis G virus (GBV-C). Five of the E1 synthetic peptides: NCCAPEDIGFCLEGGCLV (P7), APEDIGFCLEGGCLVALG (P8), FCLEGGCLVALGCTICTD (P10), QAGLAVRPGKSAAQLVGE (P18) and AQLVGELGSLYGPLSVSA (P22) were capable of inhibiting the leakage of vesicular contents caused by HIV-1 FP. A series of experiments were carried out to determine how these E1 peptides interact with HIV-1 FP. Our studies analyzed the interactions with and without the presence of lipid membranes. Isothermal titration calorimetry revealed that the binding of P7, P18 and P22 peptides to HIV-1 FP is strongly endothermic, and that binding is entropy-driven. Gibbs energy for the process indicates a spontaneous binding between E1 peptides and HIV-1 FP. Moreover, confocal microscopy of Giant Unilamellar Vesicles revealed that the disruption of the lipid bilayer by HIV-1 FP alone was inhibited by the presence of any of the five selected peptides. Our results highlight that these E1 synthetic peptides could be involved in preventing the entry of HIV-1 by binding to the HIV-1 FP. Therefore, the continued study into the interaction between GBV-C peptides and HIV-1 FP could lead to the development of new therapeutic agents for the treatment of AIDS. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Inhibition of microbial β-N-acetylhexosaminidases by 4-deoxy- and galacto-analogues of NAG-thiazoline

    Czech Academy of Sciences Publication Activity Database

    Krejzová, Jana; Ježová-Kalachová, Lubica; Šimon, Petr; Pelantová, Helena; Slámová, Kristýna; Křen, Vladimír

    2014-01-01

    Roč. 24, č. 22 (2014), s. 5321-5323 ISSN 0960-894X R&D Projects: GA ČR(CZ) GAP207/11/0629; GA MŠk(CZ) 7E11011 Institutional support: RVO:61388971 Keywords : NAG-thiazoline * enzyme inhibition Subject RIV: CE - Biochemistry Impact factor: 2.420, year: 2014

  9. Systematic Exploration of Natural and Synthetic Flavonoids for the Inhibition of Staphylococcus aureus Biofilms

    Science.gov (United States)

    Manner, Suvi; Skogman, Malena; Goeres, Darla; Vuorela, Pia; Fallarero, Adyary

    2013-01-01

    When single-cell (or suspended) bacteria switch into the biofilm lifestyle, they become less susceptible to antimicrobials, imposing the need for anti-biofilms research. Flavonoids are among the most extensively studied natural compounds with an unprecedented amount of bioactivity claims. Most studies focus on the antibacterial effects against suspended cells; fewer reports have researched their anti-biofilm properties. Here, a high throughput phenotypic platform was utilized to screen for the inhibitory activity of 500 flavonoids, including natural and synthetic derivatives, against Staphylococcus aureus biofilms. Since discrepancies among results from earlier antibacterial studies on flavonoids had been noted, the current study aimed to minimize sources of variations. After the first screen, flavonoids were classified as inactive (443), moderately active (47) or highly active (10). Further, exclusion criteria combining bioactivity and selectivity identified two synthetic flavans as the most promising. The body of data reported here serves three main purposes. First, it offers an improved methodological workflow for anti-biofilm screens of chemical libraries taking into account the (many times ignored) connections between anti-biofilm and antibacterial properties. This is particularly relevant for the study of flavonoids and other natural products. Second, it provides a large and freely available anti-biofilm bioactivity dataset that expands the knowledge on flavonoids and paves the way for future structure-activity relationship studies and structural optimizations. Finally, it identifies two new flavans that can successfully act on biofilms, as well as on suspended bacteria and represent more feasible antibacterial candidates. PMID:24071942

  10. Analogue Gravity

    Directory of Open Access Journals (Sweden)

    Carlos Barceló

    2011-05-01

    Full Text Available Analogue gravity is a research programme which investigates analogues of general relativistic gravitational fields within other physical systems, typically but not exclusively condensed matter systems, with the aim of gaining new insights into their corresponding problems. Analogue models of (and for gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity.

  11. A Dual Non-ATP Analogue Inhibitor of Aurora Kinases A and B, Derived from Resorcinol with a Mixed Mode of Inhibition.

    Science.gov (United States)

    Karthigeyan, Dhanasekaran; Surabhi, Sudhevan; Mizar, Pushpak; Soumik, Siddhanta; Banerjee, Amrita; Sinha, Sarmistha Halder; Dasgupta, Dipak; Narayana, Chandrabhas; Kundu, Tapas K

    2016-06-01

    Aurora kinases are the most commonly targeted mitotic kinases in the intervention of cancer progression. Here, we report a resorcinol derivative, 5-methyl-4-(2-thiazolylazo) resorcinol (PTK66), a dual inhibitor of Aurora A and Aurora B kinases. PTK66 is a surface binding non-ATP analogue inhibitor that shows a mixed pattern of inhibition against both of Aurora A and B kinases. The in vitro IC50 is approximately 47 and 40 μm for Aurora A and Aurora B kinases, respectively. In cellular systems, PTK66 exhibits a substantially low cytotoxicity at micromolar concentrations but it can induce aneuploidy under similar dosages as a consequence of Aurora kinase inhibition. This result was corroborated by a drop in the histone H3 (S10) phosphorylation level detected via Western blot analysis using three different cell types. Altogether, our findings indicate that the ligand containing resorcinol backbone is one of the novel scaffolds targeting the Aurora family of kinases, which could be a target for antineoplastic drug development. © 2016 John Wiley & Sons A/S.

  12. Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

    OpenAIRE

    Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

    2004-01-01

    Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide...

  13. Chloroquine inhibits accessory cell presentation of soluble natural and synthetic protein antigens

    DEFF Research Database (Denmark)

    Buus, S; Werdelin, O

    1984-01-01

    We have studied the in vitro effect of the lysosomotrophic agent, chloroquine, on the presentation of soluble protein antigens by guinea pig accessory cells. Chloroquine inhibited the capacity of antigen-pulsed accessory cells to stimulate proliferation in appropriately primed T cells. The effect...... was time- and dose-dependent. A brief treatment solely of the accessory cells with the drug compromised their ability to stimulate primed T cells in a subsequent culture provided the accessory cells were treated with chloroquine before their exposure to the antigen. These results suggest that chloroquine...... acts on an early event in the antigen handling by accessory cells. Chloroquine is a well known inhibitor of lysosomal proteolysis, and it is likely that its effect on antigen presentation is caused by an inhibition of antigen degradation....

  14. Inhibition of dengue virus entry into target cells using synthetic antiviral peptides.

    Science.gov (United States)

    Alhoot, Mohammed Abdelfatah; Rathinam, Alwin Kumar; Wang, Seok Mui; Manikam, Rishya; Sekaran, Shamala Devi

    2013-01-01

    Despite the importance of DENV as a human pathogen, there is no specific treatment or protective vaccine. Successful entry into the host cells is necessary for establishing the infection. Recently, the virus entry step has become an attractive therapeutic strategy because it represents a barrier to suppress the onset of the infection. Four putative antiviral peptides were designed to target domain III of DENV-2 E protein using BioMoDroid algorithm. Two peptides showed significant inhibition of DENV when simultaneously incubated as shown by plaque formation assay, RT-qPCR, and Western blot analysis. Both DET4 and DET2 showed significant inhibition of virus entry (84.6% and 40.6% respectively) using micromolar concentrations. Furthermore, the TEM images showed that the inhibitory peptides caused structural abnormalities and alteration of the arrangement of the viral E protein, which interferes with virus binding and entry. Inhibition of DENV entry during the initial stages of infection can potentially reduce the viremia in infected humans resulting in prevention of the progression of dengue fever to the severe life-threatening infection, reduce the infected vector numbers, and thus break the transmission cycle. Moreover these peptides though designed against the conserved region in DENV-2 would have the potential to be active against all the serotypes of dengue and might be considered as Hits to begin designing and developing of more potent analogous peptides that could constitute as promising therapeutic agents for attenuating dengue infection.

  15. Feleucin-BO1: a novel antimicrobial non-apeptide amide from the skin secretion of the toad, Bombina orientalis, and design of a potent broad-spectrum synthetic analogue, feleucin-K3.

    Science.gov (United States)

    Hou, Xiaojuan; Du, Qiang; Li, Renjie; Zhou, Mei; Wang, Hui; Wang, Lei; Guo, Can; Chen, Tianbao; Shaw, Chris

    2015-03-01

    Feleucins-BV1 and -BV2 are recently described prototypes of a novel antimicrobial non-apeptide (AMP) family identified in the skin secretion of the bombinid toad, Bombina variegata. They are encoded on different precursors that also encode a novel bombinin. Here we describe the identification of feleucin-BO1 (FLGLLGSLLamide) which is co-encoded with a different novel bombinin, named feleucin precursor-associated bombinin (FPA-bombinin-BO), from the skin secretion of Bombina orientalis. Synthetic feleucin-BO1 displayed activity against a reference Gram-positive bacterium. Staphylococcus aureus (MIC 34 μm) but was inactive (> 250 μm) against the Gram-negative bacterium, Escherichia coli, and the yeast, Candida albicans. This pattern of activity was similar to that of the prototypes. Design and synthesis of a cationicity-enhanced analogue, feleucin-K3 (F-K3), in which the amino acid residues at positions 3 (G), 6 (G) and 7 (S) of feleucin-BO1 were substituted with Lys (K) residues, resulted in a peptide with significantly enhanced potency and spectrum of activity. The MICs of F-K3 against the reference micro-organisms were 7 μm (S. aureus), 14 μm (E. coli) and 7 μm (C. albicans). These data indicate that the skin secretions of amphibians can continue to provide novel peptide templates for the rational design of analogues with possible therapeutic utility. © 2014 John Wiley & Sons A/S.

  16. Inhibition of core gene of HCV 3a genotype using synthetic and vector derived siRNAs.

    Science.gov (United States)

    Khaliq, Saba; Jahan, Shah; Ijaz, Bushra; Ahmad, Waqar; Asad, Sultan; Pervaiz, Asim; Samreen, Baila; Khan, Mahwish; Hassan, Sajida

    2010-11-13

    Hepatitis C virus (HCV) is a major causative agent of liver associated diseases throughout the world, with genotype 3a responsible for most of the cases in Pakistan. Due to the limited efficiency of current therapy, RNA interference (RNAi) a novel regulatory and powerful silencing approach for molecular therapeutics through a sequence-specific RNA degradation process represents an alternative option. The current study was purposed to assess and explore the possibility of RNAi to silence the HCV-3a Core gene expression, which play complex role in regulation of cell growth and host genes expression essential for infectivity and disease progression. To identify the potent siRNA target sites, 5 small interfering RNAs (siRNAs) against Core gene were designed and in vitro transcribed after consensus sequence analysis of different HCV-3a isolates. Antiviral effects of siRNAs showed upto 80% inhibition of Core gene expression by different siRNAs into Huh-7 cells as compared with Mock transfected and control siRNAs treated cells. For long lasting effect of siRNAs, vector based short hairpin siRNAs (shRNAs) were designed and tested against HCV-3a Core which resulted in a similar pattern of inhibition on RNA and protein expression of HCV Core as synthetic siRNAs. Furthermore, the efficacy of cell culture tested siRNA and shRNA, were evaluated for inhibition of HCV replication in HCV infected serum inoculated Huh-7 cells and a significant decrease in HCV viral copy number was observed. Our results support the possibility of using consensus siRNA and shRNA-based molecular therapy as a promising strategy in effective inhibition of HCV-3a genotype.

  17. 2-Substituted benzoxazinone analogues as anti-human coronavirus (anti-HCoV) and ICAM-1 expression inhibition agents.

    Science.gov (United States)

    Hsieh, Pei-Wen; Chang, Fang-Rong; Chang, Cheng-Hsien; Cheng, Pei-Wen; Chiang, Lien-Chai; Zeng, Fu-Long; Lin, Kuei-Hsiang; Wu, Yang-Chang

    2004-09-20

    A series of 2-substituted benzoxazinones were synthesized and subjected to anti-human coronavirus and ICAM-1 expression inhibition assays. Among them, compounds 1, 3, 4, 5, 6, and 7 exhibited significant anti-HCoV activities, and the IC(50) value of these compounds are 6.08, 5.06, 6.83, 1.92, 7.59, and 5.79 microg/mL, respectively. Furthermore, compounds 1 and 6 showed significant inhibitory effect on ICAM-1 expression, the ED(50) values of 1 and 6 are 1.00 and 0.50 microg/mL, respectively.

  18. Resveratrol analogue 3,4,4′,5-tetramethoxystilbene inhibits growth, arrests cell cycle and induces apoptosis in ovarian SKOV‐3 and A-2780 cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Piotrowska, Hanna; Myszkowski, Krzysztof; Ziółkowska, Alicja [Department of Toxicology, Poznan University of Medical Sciences, Poznan (Poland); Kulcenty, Katarzyna [Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan (Poland); Wierzchowski, Marcin [Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Poznan (Poland); Kaczmarek, Mariusz [Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan (Poland); Murias, Marek [Department of Toxicology, Poznan University of Medical Sciences, Poznan (Poland); Kwiatkowska-Borowczyk, Eliza [Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan (Poland); Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, Poznan (Poland); Jodynis-Liebert, Jadwiga, E-mail: liebert@ump.edu.pl [Department of Toxicology, Poznan University of Medical Sciences, Poznan (Poland)

    2012-08-15

    In the screening studies, cytotoxicity of 12 methylated resveratrol analogues on 11 human cancer cell lines was examined. The most active compound 3,4,4′5-tetramethoxystilbene (DMU-212) and two ovarian cancer cell lines A-2780 (IC{sub 50} = 0.71 μM) and SKOV-3 (IC{sub 50} = 11.51 μM) were selected for further investigation. To determine the mechanism of DMU-212 cytotoxicity, its ability to induce apoptosis was examined. DMU-212 arrested cell cycle in the G2/M or G0/G1 phase which resulted in apoptosis of both cell lines. The expression level of 84 apoptosis-related genes was investigated. In SKOV-3 cells DMU-212 caused up-regulation of pro-apoptotic Bax, Apaf-1 and p53 genes, specific to intrinsic pathway of apoptosis, and a decrease in Bcl-2 and Bcl 2110 mRNA expressions. Conversely, in A-2780 cells an increased expression of pro-apoptotic genes Fas, FasL, TNF, TNFRSF10A, TNFRSF21, TNFRSF16 specific to extracellular mechanism of apoptosis was observed. There are no data published so far regarding the receptor mediated apoptosis induced by DMU-212. The activation of caspase-3/7 was correlated with decreased TRAF-1 and BIRC-2 expression level in A-2780 cells exposed to DMU-212. DMU-212 caused a decrease in CYP1A1 and CYP1B1 mRNA levels in A-2780 by 50% and 75%, and in SKOV-3 cells by 15% and 45%, respectively. The protein expression was also reduced in both cell lines. It is noteworthy that the expression of CYP1B1 protein was entirely inhibited in A-2780 cells treated with DMU-212. It can be suggested that different CYP1B1 expression patterns in either ovarian cell line may affect their sensitivity to cytotoxic activity of DMU-212. -- Highlights: ► DMU-212 was the most cytotoxic among 12 O-methylated resveratrol analogues. ► DMU-212 arrested cell cycle at G2/M and G0/G1phase ► DMU-212 triggered mitochondria- and receptor‐mediated apoptosis. ► DMU-212 entirely inhibited CYP1B1 protein expression in A-2780 cells.

  19. Inhibition of HIV-1 infection by synthetic peptides derived CCR5 fragments

    International Nuclear Information System (INIS)

    Imai, Masaki; Baranyi, Lajos; Okada, Noriko; Okada, Hidechika

    2007-01-01

    HIV-1 infection requires interaction of viral envelope protein gp160 with CD4 and a chemokine receptor, CCR5 or CXCR4 as entry coreceptor. We designed HIV-inhibitory peptides targeted to CCR5 using a novel computer program (ANTIS), which searched all possible sense-antisense amino acid pairs between proteins. Seven AHBs were found in CCR5 receptor. All AHB peptides were synthesized and tested for their ability to prevent HIV-1 infection to human T cells. A peptide fragment (LC5) which is a part of the CCR5 receptor corresponding to the loop between the fifth and sixth transmembrane regions (amino acids 222-240) proved to inhibit HIV-1 IIIB infection of MT-4 cells. Interaction of these antisense peptides could be involved in sustaining HIV-1 infectivity. LC5 effectively indicated dose-dependent manner, and the suppression was enhanced additively by T20 peptide, which inhibits infection in vitro by disrupting the gp41 conformational changes necessary for membrane fusion. Thus, these results indicate that CCR5-derived AHB peptides could provide a useful tool to define the mechanism(s) of HIV infection, and may provide insight which will contribute to the development of an anti-HIV-1 reagent

  20. Amino acid containing thapsigargin analogues deplete androgen receptor protein via synthesis inhibition and induce the death of prostate cancer cells

    DEFF Research Database (Denmark)

    Griend, Donald J Vander; Antony, Lizamma; Dalrymple, Susan L

    2009-01-01

    There are quantitative and/or qualitative mechanisms allowing androgen receptor (AR) growth signaling in androgen ablation refractory prostate cancer cells. Regardless of the mechanism, agents that deplete AR protein expression prevent such AR growth signaling. Thapsigargin (TG) is a highly cell......-penetrant sequiterpene-lactone that once inside cells inhibits (IC(50), approximately 10 nmol/L) critically important housekeeping SERCA 2b calcium pumps in the endoplasmic reticulum. Using a series of five genetically diverse androgen ablation refractory human prostate cancer lines (LNCaP, LAPC-4, VCaP, MDA-PCa-2b......-specific proteases, such as prostate-specific antigen and prostate-specific membrane antigen, or cancer-specific proteases, such as fibroblast activation protein, so that toxicity of these prodrugs is selectively targeted to metastatic sites of prostate cancer. Based on these results, these prodrugs are undergoing...

  1. Application of feces extracts and synthetic analogues of the host marking pheromone of Anastrepha ludens significantly reduces fruit infestation by A. obliqua in tropical plum and mango backyard orchards.

    Science.gov (United States)

    Aluja, Martín; Díaz-Fleischer, F; Boller, E F; Hurter, J; Edmunds, A J F; Hagmann, L; Patrian, B; Reyes, J

    2009-12-01

    We determined the efficacy of three potential oviposition deterrents in reducing fruit infestation by Anastrepha obliqua in tropical plum and mango orchards. These were: (1) Extracts of feces of Mexican fruit fly, Anastrepha ludens, known to contain the A. ludens host marking pheromone (HMP) and (2) two fully synthetic simplified analogues of the naturally occurring compound, which we have named desmethyl A. ludens HMP (DM-HMP) and Anastrephamide. Two applications of feces extracts 2 or 3 wk before fruit color break reduced A. obliqua infestation in plums by 94.1, 75.9, and 72% when measured 8, 14, and 25 d, respectively, after application. The natural A. ludens-HMP containing extract retained its effectiveness despite considerable rainfall (112.5 mm) and high A. obliqua populations. The synthetic desmethyl HMP derivative (DM-HMP) also reduced infestation in plums by 53.3 and 58.7% when measured, 18 and 26 d, respectively, after application. Finally, applications of Anastrephamide resulted in fruit loss cut by half and an 80% reduction in numbers of fly larvae per fruit. Our results confirm previous findings indicating that there is interspecific cross-recognition of the HMP in two of the most pestiferous Anastrepha species and open the door for the development of a highly selective, biorational Anastrepha management scheme.

  2. Andrographolide Analogue Induces Apoptosis and Autophagy Mediated Cell Death in U937 Cells by Inhibition of PI3K/Akt/mTOR Pathway.

    Directory of Open Access Journals (Sweden)

    Deepak Kumar

    Full Text Available Current chemotherapeutic agents based on apoptosis induction are lacking in desired efficacy. Therefore, there is continuous effort to bring about new dimension in control and gradual eradication of cancer by means of ever evolving therapeutic strategies. Various forms of PCD are being increasingly implicated in anti-cancer therapy and the complex interplay among them is vital for the ultimate fate of proliferating cells. We elaborated and illustrated the underlying mechanism of the most potent Andrographolide analogue (AG-4 mediated action that involved the induction of dual modes of cell death-apoptosis and autophagy in human leukemic U937 cells.AG-4 induced cytotoxicity was associated with redox imbalance and apoptosis which involved mitochondrial depolarisation, altered apoptotic protein expressions, activation of the caspase cascade leading to cell cycle arrest. Incubation with caspase inhibitor Z-VAD-fmk or Bax siRNA decreased cytotoxic efficacy of AG-4 emphasising critical roles of caspase and Bax. In addition, AG-4 induced autophagy as evident from LC3-II accumulation, increased Atg protein expressions and autophagosome formation. Pre-treatment with 3-MA or Atg 5 siRNA suppressed the cytotoxic effect of AG-4 implying the pro-death role of autophagy. Furthermore, incubation with Z-VAD-fmk or Bax siRNA subdued AG-4 induced autophagy and pre-treatment with 3-MA or Atg 5 siRNA curbed AG-4 induced apoptosis-implying that apoptosis and autophagy acted as partners in the context of AG-4 mediated action. AG-4 also inhibited PI3K/Akt/mTOR pathway. Inhibition of mTOR or Akt augmented AG-4 induced apoptosis and autophagy signifying its crucial role in its mechanism of action.Thus, these findings prove the dual ability of AG-4 to induce apoptosis and autophagy which provide a new perspective to it as a potential molecule targeting PCD for future cancer therapeutics.

  3. Andrographolide Analogue Induces Apoptosis and Autophagy Mediated Cell Death in U937 Cells by Inhibition of PI3K/Akt/mTOR Pathway.

    Science.gov (United States)

    Kumar, Deepak; Das, Bimolendu; Sen, Rupashree; Kundu, Priyanka; Manna, Alak; Sarkar, Avijit; Chowdhury, Chinmay; Chatterjee, Mitali; Das, Padma

    2015-01-01

    Current chemotherapeutic agents based on apoptosis induction are lacking in desired efficacy. Therefore, there is continuous effort to bring about new dimension in control and gradual eradication of cancer by means of ever evolving therapeutic strategies. Various forms of PCD are being increasingly implicated in anti-cancer therapy and the complex interplay among them is vital for the ultimate fate of proliferating cells. We elaborated and illustrated the underlying mechanism of the most potent Andrographolide analogue (AG-4) mediated action that involved the induction of dual modes of cell death-apoptosis and autophagy in human leukemic U937 cells. AG-4 induced cytotoxicity was associated with redox imbalance and apoptosis which involved mitochondrial depolarisation, altered apoptotic protein expressions, activation of the caspase cascade leading to cell cycle arrest. Incubation with caspase inhibitor Z-VAD-fmk or Bax siRNA decreased cytotoxic efficacy of AG-4 emphasising critical roles of caspase and Bax. In addition, AG-4 induced autophagy as evident from LC3-II accumulation, increased Atg protein expressions and autophagosome formation. Pre-treatment with 3-MA or Atg 5 siRNA suppressed the cytotoxic effect of AG-4 implying the pro-death role of autophagy. Furthermore, incubation with Z-VAD-fmk or Bax siRNA subdued AG-4 induced autophagy and pre-treatment with 3-MA or Atg 5 siRNA curbed AG-4 induced apoptosis-implying that apoptosis and autophagy acted as partners in the context of AG-4 mediated action. AG-4 also inhibited PI3K/Akt/mTOR pathway. Inhibition of mTOR or Akt augmented AG-4 induced apoptosis and autophagy signifying its crucial role in its mechanism of action. Thus, these findings prove the dual ability of AG-4 to induce apoptosis and autophagy which provide a new perspective to it as a potential molecule targeting PCD for future cancer therapeutics.

  4. Crystal structure of mineral grechishchevite synthetic analogue and Hg-X (X=S, Se, Te) bonds topology in structures of mercury chalcogenhalides

    International Nuclear Information System (INIS)

    Pervukhina, N.V.; Borisov, S.V.; Magarill, S.A.; Naumov, D.Yu.; Vasil'ev, V.I.; Nenashev, B.G.

    2004-01-01

    Structural studies of synthetic analog of mineral grechishchevite Hg 3 S 2 Br 1.00 Cl 0.50 I 0.50 were conducted, the mineral crystal structure was refined, the results of the studies being analyzed. For chalcogenhalides Hg 3 X 2 Hal 2 (X=S, Se, Te; Hal=Cl, Br, I) inventory was taken of intergrowing isolated and infinite, i.e. continuous, layered and carcass, covalently bonded Hg-X-radicals into pseudocubical matrix from halide ions [ru

  5. Fluorescence properties of the anti-tumour alkaloid luotonin A and new synthetic analogues: pH modulation as an approach to their fluorimetric quantitation in biological samples

    Energy Technology Data Exchange (ETDEWEB)

    Gonzalez-Ruiz, Victor; Gonzalez-Cuevas, Yamisley; Arunachalam, Sankaralingam [S. D. Quimica Analitica, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid (Spain); Martin, M. Antonia, E-mail: mantonia@farm.ucm.es [S. D. Quimica Analitica, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid (Spain); Olives, Ana I. [S. D. Quimica Analitica, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid (Spain); Ribelles, Pascual; Ramos, M. Teresa; Menendez, J. Carlos [D. Quimica Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid (Spain)

    2012-09-15

    Luotonin A is an alkaloid structurally related to the natural anti-tumour agent camptothecin. The fluorescence behaviour of luotonin A and a series of six analogues is described in the present work. The influence of solvent polarity and pH on the native fluorescence properties of these alkaloids was studied, finding that in organic solvents or in aqueous solutions (pH 5.5-7.2) the neutral form of the luotonin derivatives emit in the region of 410-450 nm but, in both media, acidification to pH values below 3.0 causes a new emission band to appear at about 500 nm. An ESPT reaction occurs due to the protonation of the basic nitrogen atoms of the pentacyclic ring. Acid-base titrations of luotonin A and its derivatives in aqueous and acetonitrile media were carried out in order to determine their pK{sub a}{sup Low-Asterisk} values which were around 2, showing these compounds to be very weak bases. In aqueous media, the absence of an iso-emissive point in the emission spectra suggests the existence of more than two species in the proton transfer equilibria. The basicity of the luotonin A derivatives is increased in organic media, and a good correlation between the pK{sub a}{sup Low-Asterisk} values and the chemical structure was found. The protonation of luotonin A was also studied by {sup 1}H-NMR and {sup 13}C-NMR experiments, which proved the protonation of the nitrogen atoms at the positions 5 and 6 of the pentacyclic ring. The fluorescence quantum yields were determined in ethanol and in aqueous solutions under neutral and acidic conditions. The fluorescence quantum yields were higher in water for the case of the more polar compounds, and the opposite result was obtained for the more hydrophobic ones. The remarkable and interesting fluorescence properties of luotonin A prompted the development of its fluorimetric analytical quantitation, obtaining very good analytical features. - Highlights: Black-Right-Pointing-Pointer This is the first study on the fluorescence

  6. Fluorescence properties of the anti-tumour alkaloid luotonin A and new synthetic analogues: pH modulation as an approach to their fluorimetric quantitation in biological samples

    International Nuclear Information System (INIS)

    González-Ruiz, Víctor; González-Cuevas, Yamisley; Arunachalam, Sankaralingam; Martín, M. Antonia; Olives, Ana I.; Ribelles, Pascual; Ramos, M. Teresa; Menéndez, J. Carlos

    2012-01-01

    Luotonin A is an alkaloid structurally related to the natural anti-tumour agent camptothecin. The fluorescence behaviour of luotonin A and a series of six analogues is described in the present work. The influence of solvent polarity and pH on the native fluorescence properties of these alkaloids was studied, finding that in organic solvents or in aqueous solutions (pH 5.5–7.2) the neutral form of the luotonin derivatives emit in the region of 410–450 nm but, in both media, acidification to pH values below 3.0 causes a new emission band to appear at about 500 nm. An ESPT reaction occurs due to the protonation of the basic nitrogen atoms of the pentacyclic ring. Acid-base titrations of luotonin A and its derivatives in aqueous and acetonitrile media were carried out in order to determine their pK a ⁎ values which were around 2, showing these compounds to be very weak bases. In aqueous media, the absence of an iso-emissive point in the emission spectra suggests the existence of more than two species in the proton transfer equilibria. The basicity of the luotonin A derivatives is increased in organic media, and a good correlation between the pK a ⁎ values and the chemical structure was found. The protonation of luotonin A was also studied by 1 H-NMR and 13 C-NMR experiments, which proved the protonation of the nitrogen atoms at the positions 5 and 6 of the pentacyclic ring. The fluorescence quantum yields were determined in ethanol and in aqueous solutions under neutral and acidic conditions. The fluorescence quantum yields were higher in water for the case of the more polar compounds, and the opposite result was obtained for the more hydrophobic ones. The remarkable and interesting fluorescence properties of luotonin A prompted the development of its fluorimetric analytical quantitation, obtaining very good analytical features. - Highlights: ► This is the first study on the fluorescence properties of luotonin A analogues. ► Fluorescence and NMR experiments

  7. A new class of synthetic anti-lipopolysaccharide peptides inhibits influenza A virus replication by blocking cellular attachment.

    Science.gov (United States)

    Hoffmann, Julia; Schneider, Carola; Heinbockel, Lena; Brandenburg, Klaus; Reimer, Rudolph; Gabriel, Gülsah

    2014-04-01

    Influenza A viruses are a continuous threat to human health as illustrated by the 2009 H1N1 pandemic. Since circulating influenza virus strains become increasingly resistant against currently available drugs, the development of novel antivirals is urgently needed. Here, we have evaluated a recently described new class of broad-spectrum antiviral peptides (synthetic anti-lipopolysaccharide peptides; SALPs) for their potential to inhibit influenza virus replication in vitro and in vivo. We found that particularly SALP PEP 19-2.5 shows high binding affinities for the influenza virus receptor molecule, N-Acetylneuraminic acid, leading to impaired viral attachment and cellular entry. As a result, replication of several influenza virus subtypes (H7N7, H3N2 and 2009 pandemic H1N1) was strongly reduced. Furthermore, mice co-treated with PEP 19-2.5 were protected against an otherwise 100% lethal H7N7 influenza virus infection. These findings show that SALPs exhibit antiviral activity against influenza viruses by blocking virus attachment and entry into host cells. Thus, SALPs present a new class of broad-spectrum antiviral peptides for further development for influenza virus therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. BALANOL ANALOGUES

    DEFF Research Database (Denmark)

    1997-01-01

    The present invention relates to a solid phase methodology for the preparation of a combinatorial library of structural analogues of the natural product balanol (ophiocordin, azepinostatin), which is a protein kinase C (PKC) and protein kinase A (PKA) inhibitor. The method comprises solid...

  9. Pharmacology of Cumyl-Carboxamide Synthetic Cannabinoid New Psychoactive Substances (NPS) CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-5F-PINACA, and Their Analogues.

    Science.gov (United States)

    Longworth, Mitchell; Banister, Samuel D; Boyd, Rochelle; Kevin, Richard C; Connor, Mark; McGregor, Iain S; Kassiou, Michael

    2017-10-18

    Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues. All cumyl-derived SCs were potent, efficacious agonists at CB 1 (EC 50 = 0.43-12.3 nM) and CB 2 (EC 50 = 11.3-122 nM) receptors in a fluorometric assay of membrane potential, with selectivity for CB 1 activation (3.1-53 times over CB 2 ). CUMYL-PICA and CUMYL-5F-PICA were evaluated in rats using biotelemetry, and induced hypothermia and bradycardia at doses of 1 mg/kg. Hypothermia was reversed by pretreatment with a CB 1 , but not CB 2 , antagonist, confirming that cumyl-derived SCs are cannabimimetic in vivo.

  10. Laboratory Measurements of Synthetic Pyroxenes and their Mixtures with Iron Sulfides as Inorganic Refractory Analogues for Rosetta/VIRTIS' Surface Composition Analysis of 67P/CG

    Science.gov (United States)

    Markus, Kathrin; Arnold, Gabriele; Moroz, Ljuba; Henckel, Daniela; Kappel, David; Capaccioni, Fabrizio; Filacchione, Gianrico; Schmitt, Bernard; Tosi, Federico; Érard, Stéphane; Bockelee-Morvan, Dominique; Leyrat, Cedric; VIRTIS Team

    2016-10-01

    The Visible and InfraRed Thermal Imaging Spectrometer VIRTIS on board Rosetta provided 0.25-5.1 µm spectra of 67P/CG's surface (Capaccioni et al., 2015). Thermally corrected reflectance spectra display a low albedo of 0.06 at 0.65 µm, different red VIS and IR spectral slopes, and a broad 3.2 µm band. This absorption feature is due to refractory surface constituents attributed to organic components, but other refractory constituents influence albedo and spectral slopes. Possible contributions of inorganic components to spectral characteristics and spectral variations across the surface should be understood based on laboratory studies and spectral modeling. Although a wide range of silicate compositions was found in "cometary" anhydrous IDPs and cometary dust, Mg-rich crystalline mafic minerals are dominant silicate components. A large fraction of silicate grains are Fe-free enstatites and forsterites that are not found in terrestrial rocks but can be synthesized in order to provide a basis for laboratory studies and comparison with VIRTIS data. We report the results of the synthesis, analyses, and spectral reflectance measurements of Fe-free low-Ca pyroxenes (ortho- and clinoenstatites). These minerals are generally very bright and almost spectrally featureless. However, even trace amounts of Fe-ions produce a significant decrease in the near-UV reflectance and hence can contribute to slope variations. Iron sulfides (troilite, pyrrhotite) are among the most plausible phases responsible for the low reflectance of 67P's surface from the VIS to the NIR. The darkening efficiency of these opaque phases is strongly particle-size dependent. Here we present a series of reflectance spectra of fine-grained synthetic enstatite powders mixed in various proportions with iron sulfide powders. The influence of dark sulfides on reflectance in the near-UV to near-IR spectral ranges is investigated. This study can contribute to understand the shape of reflectance spectra of 67P

  11. Synthesis and structural investigation of 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid containing a peptide analogue of the amyloidogenic AS(6-7) sequence: inhibition of fibril formation.

    Science.gov (United States)

    Paikar, Arpita; Debnath, Mintu; Podder, Debasish; Sasmal, Supriya; Haldar, Debasish

    2017-05-16

    The incorporation of a single β-amino acid moiety in a highly amyloidogenic peptide sequence resulted in the complete inhibition of amyloid fibril formation. The Boc-l-Phe-l-Leu-OMe sequence 1, which has sequence identity with the N-terminal AS(6-7) of the non-immunoglobulin amyloid fibril protein AS, which is responsible for rheumatoid arthritis, self-associates to produce fibrils. The d-Phe analogue peptide 2 shows an elongated ribbon-like morphology. However, the 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid containing analogue peptide 3 exhibits a polydisperse microsphere morphology. Moreover, fibrils from peptides 1 and 2 exhibit typical green-gold birefringence upon Congo red (CR) staining and show an amyloid-like morphological resemblance. However, the 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid modified peptide 3 does not respond to the Congo red assay. From X-ray crystallography, peptide 1 with the l-Phe residue adopts an extended structure, whereas the d-Phe analogue 2 adopts a kink-like structure. Both peptides 1 and 2 show twisted anti-parallel sheet-like structures at higher order assembly. However, peptide 3 adopts a nine-membered hydrogen bonded δ-turn-like structure in the solid state and self-associates to form a loop-like supramolecular structure through multiple intermolecular hydrogen bonds. The structural analysis presented herein may foster new studies for de novo design and therapeutics.

  12. Synthetic peptides from heat-shock protein 65 inhibit proinflammatory cytokine secretion by peripheral blood mononuclear cells from rheumatoid arthritis patients.

    Science.gov (United States)

    Zhou, Jun; Wang, Li-Ping; Feng, Xuan; Fan, Dan-Dan; Zang, Wei-Jin; Wang, Bing

    2014-01-01

    1. Rheumatoid arthritis (RA) is a systemic autoimmune disease mediated by T cells. Proinflammatory cytokines plays a critical role in the pathogenesis of RA. The aim of the present study was to investigate the effects of synthetic peptides (HP-R1, HP-R2 and HP-R3), derived from the sequence of 65 kDa mycobacterial heat shock protein (HSP), on the proliferation of and cytokine secretion by peripheral blood mononuclear cells (PBMC) from RA patients. 2. The PBMC were obtained from RA patients and collected by Ficoll-Hypaque density centrifugation. Peripheral blood mononuclear cells were treated with one of the three synthetic peptides for 4 h, after which time proliferation and cytokine production were determined. The effects of the three peptides on the proliferation of PBMC were analysed by the colorimetric cell proliferation (CCK-8) assay. Cytokine production was measured in culture supernatants using specific ELISAs. 3. None of the three peptides had any significant effect on the proliferation of PBMC from healthy controls. However, the proliferation of PBMC from RA patients was inhibited by all three peptides. The production of tumour necrosis factor-α from RA patients was significantly inhibited by all three peptides. The secretion of interferon-γ was significantly suppressed by HP-R1 and HP-R2. Unlike the other two peptides, HP-R2 increased the secretion of interleukin (IL)-4. None of the peptides had any significant effect on the production of IL-10. 4. The results of the present study suggest that the synthetic peptides derived from HSP65 exhibit antiproliferative and anti-inflammatory activity, and support the potential use of synthetic peptides as therapeutic drugs in RA patients. © 2013 Wiley Publishing Asia Pty Ltd.

  13. Synthetic antifreeze peptide

    OpenAIRE

    1991-01-01

    A synthetic antifreeze peptide and a synthetic gene coding for the antifreeze peptide have been produced. The antifreeze peptide has a greater number of repeating amino acid sequences than is present in the native antifreeze peptides from winter flounder upon which the synthetic antifreeze peptide was modeled. Each repeating amino acid sequence has two polar amino acid residues which are spaced a controlled distance apart so that the antifreeze peptide may inhibit ice formation. The synthetic...

  14. Salutaxel, a Conjugate of Docetaxel and a Muramyl Dipeptide (MDP) Analogue, Acts as Multifunctional Prodrug That Inhibits Tumor Growth and Metastasis.

    Science.gov (United States)

    Wen, Xiaoming; Zheng, Purong; Ma, Yao; Ou, Yingye; Huang, Weixin; Li, Shuo; Liu, Shoujia; Zhang, Xuan; Wang, Ziyu; Zhang, Qianli; Cheng, Wenming; Lin, Ruwen; Li, Hongzu; Cai, Youyou; Hu, Chunyun; Wu, Ningbin; Wan, Long; Pan, Tingting; Rao, Jinlong; Bei, Xuelu; Wu, Weibin; Jin, Jian; Yan, Jie; Liu, Gang

    2018-02-22

    Salutaxel (3) is a conjugate of docetaxel (7) and a muramyl dipeptide (MDP) analogue. Docetaxel (7) has been recognized as a highly active chemotherapeutic agent against various cancers. MDP and its analogues are powerful potentiators of the antitumor actions of various tumor-necrotizing agents. This article documents the discovery of compound 3 and presents pharmacological proof of its biological function in tumor-bearing mice. Drug candidate 3 was superior to compound 7 in its ability to prevent tumor growth and metastasis. Compound 3 suppressed myeloid-derived suppressor cell (MDSC) accumulation in the spleens of tumor-bearing mice and decreased various serum inflammatory cytokines levels. Furthermore, compound 3 antagonized the nucleotide-binding oligomerization domain-like receptor 1 (NOD1) signaling pathway both in vitro and in vivo.

  15. The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta.

    OpenAIRE

    Colletta, A A; Wakefield, L M; Howell, F V; Danielpour, D; Baum, M; Sporn, M B

    1991-01-01

    Recent experimental work has identified a novel intracellular binding site for the synthetic progestin, Gestodene, that appears to be uniquely expressed in human breast cancer cells. Gestodene is shown here to inhibit the growth of human breast cancer cells in a dose-dependent fashion, but has no effect on endocrine-responsive human endometrial cancer cells. Gestodene induced a 90-fold increase in the secretion of transforming growth factor-beta (TGF-beta) by T47D human breast cancer cells. O...

  16. The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta.

    Science.gov (United States)

    Colletta, A A; Wakefield, L M; Howell, F V; Danielpour, D; Baum, M; Sporn, M B

    1991-01-01

    Recent experimental work has identified a novel intracellular binding site for the synthetic progestin, Gestodene, that appears to be uniquely expressed in human breast cancer cells. Gestodene is shown here to inhibit the growth of human breast cancer cells in a dose-dependent fashion, but has no effect on endocrine-responsive human endometrial cancer cells. Gestodene induced a 90-fold increase in the secretion of transforming growth factor-beta (TGF-beta) by T47D human breast cancer cells. Other synthetic progestins had no effect, indicating that this induction is mediated by the novel Gestodene binding site and not by the conventional progesterone receptor. Furthermore, in four breast cancer cell lines, the extent of induction of TGF-beta correlated with intracellular levels of Gestodene binding site. No induction of TGF-beta was observed with the endometrial cancer line, HECl-B, which lacks the Gestodene binding site, but which expresses high levels of progesterone receptor. The inhibition of growth of T47D cells by Gestodene is partly reversible by a polyclonal antiserum to TGF-beta. These data indicate that the growth-inhibitory action of Gestodene may be mediated in part by an autocrine induction of TGF-beta. Images PMID:1985102

  17. Synthetic matrix metalloproteinase inhibitors inhibit growth of established breast cancer osteolytic lesions and prolong survival in mice

    DEFF Research Database (Denmark)

    Winding, Bent; NicAmhlaoibh, Róisín; Misander, Henriette

    2002-01-01

    Breast cancer frequently leads to incurable bone metastasis. Essential requirements for the development of bone metastasis are cell-cell and cell-matrix interactions, release of bioactive growth factors and cytokines, and removal of large amounts of bone matrix. Matrix metalloproteinases (MMPs) p......) play an important role in all of these processes, but the possibility of using synthetic MMP inhibitors to decrease bone metastasis has received little attention....

  18. Synthetic and Natural Lipase Inhibitors.

    Science.gov (United States)

    Białecka-Florjańczyk, Ewa; Fabiszewska, Agata Urszula; Krzyczkowska, Jolanta; Kuryłowicz, Alina

    2016-06-30

    Lipases are enzymes that catalyse the hydrolysis of ester bonds of triglycerides ranging among biocatalysts of considerable physiological significance and industrial potential. Better understanding of the catalytic functions and achieving the possibility to control the biocatalysis process, in particular exploring some activators and inhibitors of lipases, seems to be crucial in the context of novel applications. The lipase activity is a function of interfacial composition: the enzyme can be there activated as well as denaturated or deactivated and the interface is an appropriate site for modulating lipolysis. Lipase inhibitor, interacts directly with the enzyme and inhibits lipase action. Alternatively, some compounds can postpone the lipolytic reaction via adsorption to the interphase or to the substrate molecules. The aim of this review is to summarise the current knowledge concerning human, animal and microbial lipase inhibitors, which were grouped into two categories: synthetic lipase inhibitors (including phosphonates, boronic acids and fats analogues) and natural compounds (including β-lactones and some botanical foodstuffs - plant extracts and plant metabolites, mainly polyphenols and saponins as well as peptides and some dietary fibers). The topics discussed include also inhibition issues from the viewpoint of obesity treatment. Among natural compounds able to inhibit lipase activity are β-lactones including orlistat. Orlistat is the only registered drug for obesity treatment in many countries, especially pancreatic lipase which is responsible for the hydrolysis of over 80% of total dietary fats. Its effectiveness in obesity treatment was also described.

  19. Synthesis of an Orthogonal Topological Analogue of Helicene

    DEFF Research Database (Denmark)

    Wixe, Torbjörn; Wallentin, Carl‐Johan; Johnson, Magnus T.

    2013-01-01

    The synthesis of an orthogonal topological pentamer analogue of helicene is presented. This analogue forms a tubular structure with its aromatic systems directed parallel to the axis of propagation, which creates a cavity with the potential to function as a host molecule. The synthetic strategy...

  20. Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice

    DEFF Research Database (Denmark)

    Wu, H.; Song, Z.; Hentzer, Morten

    2004-01-01

    lung infection by targeting bacterial quorum-sensing without directly killing bacteria or inhibiting their growth. Methods: Study I. Mice with Escherichia coli MT102 [luxR-PluxI-gfp(ASV)] lung infection were injected intravenously with N-acyl homoserine lactones with or without furanones to test...

  1. Synthetic resveratrol-curcumin hybrid derivative inhibits mitosis progression in estrogen positive MCF-7 breast cancer cells.

    Science.gov (United States)

    de Freitas Silva, Matheus; Coelho, Letícia Ferreira; Guirelli, Isadora Mitestainer; Pereira, Rodrigo Machado; Ferreira-Silva, Guilherme Álvaro; Graravelli, Graciana Y; Horvath, Renato de Oliveira; Caixeta, Ester Siqueira; Ionta, Marisa; Viegas, Claudio

    2018-03-02

    Curcumin (1) and resveratrol (2) are bioactive natural compounds that display wide pharmacological properties, including antitumor activity. However, their clinical application has been limited due to their low solubility and bioavailability. Nevertheless, independent studies have considered these compounds as interesting prototypes for developing new chemical structures useful for anticancer therapy. Here in, we report the synthesis of novel curcumin-like hydrazide analogues (3a and 3b), and a series of curcumin-resveratrol hybrid compounds (4a-f), and the evaluation of their cytotoxic potential on three tumor cell lines MCF-7 (breast), A549 (lung), and HepG2 (liver). Cell viability was significantly reduced in all tested cell lines when compounds 4c-4e were used. The IC 50 values for these compounds on MCF-7 cells were lower than those for curcumin, resveratrol, or curcumin combined with resveratrol. We evidenced that 4c promoted a drastic increase of G2/M population. The accumulation of cells in mitosis onset in treated cultures was due to, at least in part, the ability of 4c to modulate nuclear kinase proteins, which orchestrate important events in mitosis progression. We have also observed significant reduction of the relative RNAm abundance of CCNB1, PLK1, AURKA, AURKB in samples treated with 4c, with concomitant increase of CDKN1A (p21). Thus, compound 4c is a promising multi-target antitumor agent that should be considered for further in vivo studies. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Analogue computing methods

    CERN Document Server

    Welbourne, D

    1965-01-01

    Analogue Computing Methods presents the field of analogue computation and simulation in a compact and convenient form, providing an outline of models and analogues that have been produced to solve physical problems for the engineer and how to use and program the electronic analogue computer. This book consists of six chapters. The first chapter provides an introduction to analogue computation and discusses certain mathematical techniques. The electronic equipment of an analogue computer is covered in Chapter 2, while its use to solve simple problems, including the method of scaling is elaborat

  3. INHIBITION OF THE GROWTH OF TOLERANT YEAST Saccharomyces cerevisiae STRAIN I136 BY A MIXTURE OF SYNTHETIC INHIBITORS

    Directory of Open Access Journals (Sweden)

    Eny Ida Riyanti

    2017-09-01

    Full Text Available Biomass from lignocellulosic wastes is a potential source for biobased products.  However, one of the constraints in utilization of biomass hydrolysate is the presence of inhibitors. Therefore, the use of inhibitor-tolerant microorganisms in the fermentation is required. The study aimed to investigate the effect of a mixture of inhibitors on the growth of Saccharomyces cerevisiae strain I136 grown in medium containing synthetic inhibitors (acetic acid, formic acid, furfural, 5-hydroxymethyl furfural/5-HMF, and levulinic acid in four different concentrations with a mixture of carbon sources, glucose  (50 g.l-1 and xylose (50 g.l-1 at 30oC. The parameters related to growth and fermentation products were observed. Results showed that the strain was able to grow in media containing natural inhibitors (BSL medium with µmax of 0.020/h. Higher level of synthetic inhibitors prolonged the lag phase, decreased the cell biomass and ethanol production, and specific growth rate. The strain could detoxify furfural and 5-HMF and produced the highest ethanol (Y(p/s of 0.32 g.g-1 when grown in BSL. Glucose was utilized as its level decreased in a result of increase in cell biomass, in contrast to xylose which was not consumed. The highest cell biomass was produced in YNB with Y (x/s value of 0.25 g.g-1. The strain produced acetic acid as a dominant side product and could convert furfural into a less toxic compound, hydroxyl furfural. This robust tolerant strain provides basic information on resistance mechanism and would be useful for bio-based cell factory using lignocellulosic materials. 

  4. The synthetic peptide P111-136 derived from the C-terminal domain of heparin affin regulatory peptide inhibits tumour growth of prostate cancer PC-3 cells

    Science.gov (United States)

    2011-01-01

    Background Heparin affin regulatory peptide (HARP), also called pleiotrophin, is a heparin-binding, secreted factor that is overexpressed in several tumours and associated to tumour growth, angiogenesis and metastasis. The C-terminus part of HARP composed of amino acids 111 to 136 is particularly involved in its biological activities and we previously established that a synthetic peptide composed of the same amino acids (P111-136) was capable of inhibiting the biological activities of HARP. Here we evaluate the ability of P111-136 to inhibit in vitro and in vivo the growth of a human tumour cell line PC-3 which possess an HARP autocrine loop. Methods A total lysate of PC-3 cells was incubated with biotinylated P111-136 and pulled down for the presence of the HARP receptors in Western blot. In vitro, the P111-136 effect on HARP autocrine loop in PC-3 cells was determined by colony formation in soft agar. In vivo, PC-3 cells were inoculated in the flank of athymic nude mice. Animals were treated with P111-136 (5 mg/kg/day) for 25 days. Tumour volume was evaluated during the treatment. After the animal sacrifice, the tumour apoptosis and associated angiogenesis were evaluated by immunohistochemistry. In vivo anti-angiogenic effect was confirmed using a mouse Matrigel™ plug assay. Results Using pull down experiments, we identified the HARP receptors RPTPβ/ζ, ALK and nucleolin as P111-136 binding proteins. In vitro, P111-136 inhibits dose-dependently PC-3 cell colony formation. Treatment with P111-136 inhibits significantly the PC-3 tumour growth in the xenograft model as well as tumour angiogenesis. The angiostatic effect of P111-136 on HARP was also confirmed using an in vivo Matrigel™ plug assay in mice Conclusions Our results demonstrate that P111-136 strongly inhibits the mitogenic effect of HARP on in vitro and in vivo growth of PC-3 cells. This inhibition could be linked to a direct or indirect binding of this peptide to the HARP receptors (ALK, RPTP

  5. Synthetic (+)-antroquinonol exhibits dual actions against insulin resistance by triggering AMP kinase and inhibiting dipeptidyl peptidase IV activities.

    Science.gov (United States)

    Hsu, C Y; Sulake, R S; Huang, P-K; Shih, H-Y; Sie, H-W; Lai, Y-K; Chen, C; Weng, C F

    2015-01-01

    The fungal product (+)-antroquinonol activates AMP kinase (AMPK) activity in cancer cell lines. The present study was conducted to examine whether chemically synthesized (+)-antroquinonol exhibited beneficial metabolic effects in insulin-resistant states by activating AMPK and inhibiting dipeptidyl peptidase IV (DPP IV) activity. Effects of (+)-antroquinonol on DPP IV activity were measured with a DPPIV Assay Kit and effects on GLP-1-induced PKA were measured in AR42J cells. Translocation of the glucose transporter 4, GLUT4, induced either by insulin-dependent PI3K/AKT signalling or by insulin-independent AMPK activation, was assayed in differentiated myotubes. Glucose uptake and GLUT4 translocation were assayed in L6 myocytes. Mice with diet-induced obesity were used to assess effects of acute and chronic treatment with (+)-antroquinonol on glycaemic control in vivo. The results showed that of (+)-antroquinonol (100 μM ) inhibited the DPP IV activity as effectively as the clinically used inhibitor, sitagliptin. The phosphorylation of AMPK Thr(172) in differentiated myotubes was significantly increased by (+)-antroquinonol. In cells simultaneously treated with S961 (insulin receptor antagonist), insulin and (+)-antroquinonol, the combination of (+)-antroquinonol plus insulin still increased both GLUT4 translocation and glucose uptake. Further, (+)-antroquinonol and sitagliptin reduced blood glucose, when given acutely or chronically to DIO mice. Chemically synthesized (+)-antroquinonol exhibits dual effects to ameliorate insulin resistance, by increasing AMPK activity and GLUT4 translocation, along with inhibiting DPP IV activity. © 2014 The British Pharmacological Society.

  6. Lack of Constitutively Active DNA Repair Sensitizes Glioblastomas to Akt Inhibition and Induces Synthetic Lethality with Radiation Treatment in a p53-Dependent Manner.

    Science.gov (United States)

    Palanichamy, Kamalakannan; Patel, Disha; Jacob, John R; Litzenberg, Kevin T; Gordon, Nicolaus; Acus, Kirstin; Noda, Shin-Ei; Chakravarti, Arnab

    2018-02-01

    Treatment refractory glioblastoma (GBM) remains a major clinical problem globally, and targeted therapies in GBM have not been promising to date. The Cancer Genome Atlas integrative analysis of GBM reported the striking finding of genetic alterations in the p53 and PI3K pathways in more than 80% of GBMs. Given the role of these pathways in making cell-fate decisions and responding to genotoxic stress, we investigated the reliance of these two pathways in mediating radiation resistance. We selected a panel of GBM cell lines and glioma stem cells (GSC) with wild-type TP53 (p53-wt) and mutant TP53 , mutations known to interfere with p53 functionality (p53-mt). Cell lines were treated with a brain permeable inhibitor of P-Akt (ser473), phosphatidylinositol ether lipid analogue (PIA), with and without radiation treatment. Sensitivity to treatment was measured using Annexin-V/PI flow cytometry and Western blot analysis for the markers of apoptotic signaling, alkaline COMET assay. All results were verified in p53 isogenic cell lines. p53-mt cell lines were selectively radiosensitized by PIA. This radiosensitization effect corresponded with an increase in DNA damage and a decrease in DNA-PKcs levels. TP53 silencing in p53-wt cells showed a similar response as the p53-mt cells. In addition, the radiosensitization effects of Akt inhibition were not observed in normal human astrocytes, suggesting that this treatment strategy could have limited off-target effects. We demonstrate that the inhibition of the PI3K/Akt pathway by PIA radiosensitizes p53-mt cells by antagonizing DNA repair. In principle, this strategy could provide a large therapeutic window for the treatment of TP53 -mutant tumors. Mol Cancer Ther; 17(2); 336-46. ©2017 AACR See all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology." ©2017 American Association for Cancer Research.

  7. Activity and Safety of Synthetic Lectins Based on Benzoboroxole-Functionalized Polymers for Inhibition of HIV Entry

    Science.gov (United States)

    Mahalingam, Alamelu; Geonnotti, Anthony R.; Balzarini, Jan; Kiser, Patrick F.

    2011-01-01

    Lectins derived from plant and microbial sources constitute a vital class of entry inhibitors that target the oligomannose residues on the HIV envelope gp120. Despite their potency and specificity, success of lectin-based entry inhibitors may be impeded by issues in regards to economical production, formulation and potential mitogenicity. Therefore, there exists a gap in the HIV therapeutics pipeline that underscores the need for mass producible, synthetic, broad-spectrum, and biocomptabile inhibitors of HIV entry. Here, we present the development of a polymeric synthetic lectin, based on benzoboroxole (BzB), which exhibits weak affinity (~25 M−1) for non-reducing sugars, similar to those found on the HIV envelope. High molecular weight BzB-functionalized polymers demonstrated antiviral activity that increased with an increase in ligand density and molecular weight of the polymer construct; revealing that polyvalency improves activity. Polymers showed significant increase in activity from 25 to 75 mol% BzB functionalization with EC50 of 15 μM and 15 nM, respectively. A further increase in mole functionalization to 90% resulted in an increase of the EC50 (59 ± 5 nM), likely due to the elongated rigid structure of the polymer chain compelled by electrostatic repulsion between the boronic acid groups. An increase in molecular weight of the polymer at 50 mol% BzB functionalization showed a gradual but significant increase in antiviral activity, with the highest activity seen with the 382 kDa polymer (EC50 of 1.1 ± 0.5 nM in CEM cells and 11 ± 3 nM in TZM-bl cells). Supplementing the polymer backbone with 10 mol% sulfonic acid not only increased the aqueous solubility of the polymers by at least 50-fold, but also demonstrated a synergistic increase in anti-HIV activity (4.0 ± 1.5 nM in TZM-bl cells), possibly due to electrostatic interactions between the negatively charged polymer backbone and the positively charged V3-loop in the gp120. The benzoboroxole

  8. Synthetic cyclohexenyl chalcone natural products possess cytotoxic activities against prostate cancer cells and inhibit cysteine cathepsins in vitro.

    Science.gov (United States)

    Deb Majumdar, Ishita; Devanabanda, Arvind; Fox, Benjamin; Schwartzman, Jacob; Cong, Huan; Porco, John A; Weber, Horst C

    2011-12-16

    A number of cyclohexenyl chalcone Diels-Alder natural products possess promising biological properties including strong cytotoxicity in various human cancer cells. Herein, we show that natural products in this class including panduratin A and nicolaioidesin C inhibit cysteine cathepsins as indicated by protease profiling assays and cell-free cathepsin L enzyme assays. Owing to the critical roles of cathepsins in the biology of human tumor progression, invasion, and metastasis, these findings should pave the way for development of novel antitumor agents for use in clinical settings. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. AWRK6, A Synthetic Cationic Peptide Derived from Antimicrobial Peptide Dybowskin-2CDYa, Inhibits Lipopolysaccharide-Induced Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Qiuyu Wang

    2018-02-01

    Full Text Available Lipopolysaccharides (LPS are major outer membrane components of Gram-negative bacteria and produce strong inflammatory responses in animals. Most antibiotics have shown little clinical anti-endotoxin activity while some antimicrobial peptides have proved to be effective in blocking LPS. Here, the anti-LPS activity of the synthetic peptide AWRK6, which is derived from antimicrobial peptide dybowskin-2CDYa, has been investigated in vitro and in vivo. The positively charged α-helical AWRK6 was found to be effective in blocking the binding of LBP (LPS binding protein with LPS in vitro using ELISA. In a murine endotoxemia model, AWRK6 offered satisfactory protection efficiency against endotoxemia death, and the serum levels of LPS, IL-1β, IL-6, and TNF-α were found to be attenuated using ELISA. Further, histopathological analysis suggested that AWRK6 could improve the healing of liver and lung injury in endotoxemia mice. The results of real-time PCR and Western blotting showed that AWRK6 significantly reversed LPS-induced TLR4 overexpression and IκB depression, as well as the enhanced IκB phosphorylation. Additionally, AWRK6 did not produce any significant toxicity in vivo and in vitro. In summary, AWRK6 showed efficacious protection from LPS challenges in vivo and in vitro, by blocking LPS binding to LBP, without obvious toxicity, providing a promising strategy against LPS-induced inflammatory responses.

  10. Inhibition of neuroinflammation by synthetic androstene derivatives incorporating amino acid methyl esters on activated BV-2 microglia.

    Science.gov (United States)

    Wu, Jing; Du, Juanjuan; Gu, Ruinan; Zhang, Li; Zhen, Xuechu; Li, Yuanchao; Chen, Hongli; Jiang, Biao; Zheng, Longtai

    2015-04-01

    Androstene derivatives incorporating amino acid methyl esters were prepared, and their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Several compounds exhibited dose-dependent inhibition. The most active compound, methyl ((3S,10R,13S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonyl)-L-phenylalaninate (10) significantly suppressed LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Mechanistic studies revealed that compound 10 markedly inhibits phosphorylation of p38 mitogen-activated protein kinases (MAPKs) and subsequent transcription factor (NF-κB) and activator protein-1 (AP-1) activation. Furthermore, compound 10 decreased LPS-activated microglial neurotoxicity in a condition medium/HT-22 neuroblastoma co-culture model. Taken together, these results suggest 10 is a potential lead compound for the development of a novel therapeutic agent for neurodegenerative diseases. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. DYT-40, a novel synthetic 2-styryl-5-nitroimidazole derivative, blocks malignant glioblastoma growth and invasion by inhibiting AEG-1 and NF-κB signaling pathways

    Science.gov (United States)

    Zou, Meijuan; Duan, Yongtao; Wang, Pengfei; Gao, Rui; Chen, Xuguan; Ou, Yingwei; Liang, Mingxing; Wang, Zhongchang; Yuan, Yi; Wang, Li; Zhu, Hailiang

    2016-01-01

    Astrocyte elevated gene-1 (AEG-1) has been explored as a novel target for human glioma therapy, thus reflecting its potential contribution to gliomagenesis. In the present study, we investigated the effect of DYT-40, a novel synthetic 2-styryl-5-nitroimidazole derivative, on cell growth and invasion in glioblastoma (GBM) and uncovered the underlying mechanisms of this molecule. DYT-40 induces the intrinsic mitochondrial pathway of apoptosis and inhibits the epithelial-mesenchymal transition (EMT) and invasion of GBM cell lines. Furthermore, DYT-40 deactivates PI3K/Akt and MAPK pathways, suppresses AEG-1 expression, and inhibits NF-κB nuclear translocation. DYT-40 reduced the tumor volumes in a rat C6 glioma model by apoptotic induction. Moreover, HE staining demonstrated that the glioma rat model treated with DYT-40 exhibited better defined tumor margins and fewer invasive cells to the contralateral striatum compared with the vehicle control and temozolomide-treated rats. Microscopic examination showed a decrease in AEG-1-positive cells in DYT-40-treated rats compared with the untreated controls. DYT-40-treatment increases the in vivo apoptotic response of glioma cells to DYT-40 treatment by TUNEL staining. In conclusion, the inhibitory effects of DYT-40 on growth and invasion in GBM suggest that DYT-40 might be a potential AEG-1 inhibitor to prevent the growth and motility of malignant glioma. PMID:27251589

  12. Speculative synthetic chemistry and the nitrogenase problem

    Science.gov (United States)

    Lee, Sonny C.; Holm, Richard H.

    2003-01-01

    There exist a limited but growing number of biological metal centers whose properties lie conspicuously outside the realm of known inorganic chemistry. The synthetic analogue approach, broadly directed, offers a powerful exploratory tool that can define intrinsic chemical possibilities for these sites while simultaneously expanding the frontiers of fundamental inorganic chemistry. This speculative application of analogue study is exemplified here in the evolution of synthetic efforts inspired by the cluster chemistry of biological nitrogen fixation. PMID:12642670

  13. Inhibition of S-adenosylmethionine decarboxylase and diamine oxidase activities by analogues of methylglyoxal bis(guanylhydrazone) and their cellular uptake during lymphocyte activation.

    OpenAIRE

    Jänne, J; Morris, D R

    1984-01-01

    Several congeners of methylglyoxal bis(guanylhydrazone) were tested for their ability to inhibit eukaryotic putrescine-activated S-adenosylmethionine decarboxylase (EC 4.1.1.50) and intestinal diamine oxidase (EC 1.4.3.6). All the compounds tested, namely methylglyoxal bis(guanylhydrazone), ethylglyoxal bis(guanylhydrazone), dimethylglyoxal bis(guanylhydrazone) and the di-N"-methyl derivative of methylglyoxal bis(guanylhydrazone), were strong inhibitors of both yeast and mouse liver adenosylm...

  14. The chemistry of nicotinamide adenine dinucleotide (NAD) analogues containing C-nucleosides related to nicotinamide riboside.

    Science.gov (United States)

    Pankiewicz, Krzysztof W; Watanabe, Kyoichi A; Lesiak-Watanabe, Krystyna; Goldstein, Barry M; Jayaram, Hiremagalur N

    2002-04-01

    Oncolytic C-nucleosides, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) and benzamide riboside (3-beta-D-ribofuranosylbenzamide) are converted in cell into active metabolites thiazole-4-carboxamide- and benzamide adenine dinucleotide, TAD and BAD, respectively. TAD and BAD as NAD analogues were found to bind at the nicotinamide adenine dinucleotide (cofactor NAD) site of inosine monophosphate dehydrogenase (IMPDH), an important target in cancer treatment. The synthesis and evaluation of anticancer activity of a number of C-nucleosides related to tiazofurin and nicotinamide riboside then followed and are reviewed herein. Interestingly, pyridine C-nucleosides (such as C-nicotinamide riboside) are not metabolized into the corresponding NAD analogues in cell. Their conversion by chemical methods is described. As dinucleotides these compounds show inhibition of IMPDH in low micromolar level. Also, the synthesis of BAD in metabolically stable bis(phosphonate) form is discussed indicating the usefulness of such preformed inhibitors in drug development. Among tiazofurin analogues, Franchetti and Grifantini found, that the replacement of the sulfur by oxygen (as in oxazafurin) but not the removal of nitrogen (tiophenfurin) of the thiazole ring resulted in inactive compounds. The anti cancer activity of their synthetic dinucleotide analogues indicate that inactive compounds are not only poorly metabolized in cell but also are weak inhibitors of IMPDH as dinucleotides.

  15. Analogue MIMO Detection

    Directory of Open Access Journals (Sweden)

    McNamara Darren

    2006-01-01

    Full Text Available In this contribution we propose an analogue receiver that can perform turbo detection in MIMO systems. We present the case for a receiver that is built from nonlinear analogue devices, which perform detection in a "free-flow" network (no notion of iterations. This contribution can be viewed as an extension of analogue turbo decoder concepts to include MIMO detection. These first analogue implementations report reductions of few orders of magnitude in the number of required transistors and in consumed energy, and the same order of improvement in processing speed. It is anticipated that such analogue MIMO decoder could bring about the same advantages, when compared to traditional digital implementations.

  16. Initial-rate kinetics of human NMN-adenylyltransferases: substrate and metal ion specificity, inhibition by products and multisubstrate analogues, and isozyme contributions to NAD+ biosynthesis.

    Science.gov (United States)

    Sorci, Leonardo; Cimadamore, Flavio; Scotti, Stefania; Petrelli, Riccardo; Cappellacci, Loredana; Franchetti, Palmarisa; Orsomando, Giuseppe; Magni, Giulio

    2007-04-24

    Initial-rate and product inhibition studies revealed distinctive ordered ternary complex kinetic mechanisms, substrate specificities, and metal ion preferences for the three isozymes of human nicotinamide mononucleotide adenylyl-transferase (NMNAT, EC 2.7.7.1). ATP binds before NMN with nuclear isozyme NMNAT1 and Golgi apparatus NMNAT2, but the opposite order is observed with the mitochondrial isozyme NMNAT3. Only the latter utilizes ITP efficiently in place of ATP, and while NMNH conversion to NADH by NMNAT1 and NMNAT3 occurs at similar rates, conversion by NMNAT2 is much slower. These isozymes can also be discriminated by their action on tiazofurin monophosphate (TrMP), a metabolite of the antineoplastic prodrug tiazofurin. Our finding that TrMP is only a substrate with NMNAT1 and NMNAT3 reveals for the first time an organelle selectivity in the metabolism of this important drug. In search of additional ways to discriminate these isozymes, we synthesized and tested the P1-(nicotinamide/nicotinate-riboside-5')-Pn-(adenosine-5') dinucleotides Np3AD, Np4AD, and Nap4AD. In addition to being highly effective inhibitors, these multisubstrate geometric inhibitors gave inhibition patterns that are consistent with the aforementioned isozyme differences in substrate binding order. Distinctive differences in their substrate specificity and metal ion selectivity also permitted us to quantify individual isozyme contributions to NAD+ formation in human cell extracts.

  17. Inhibition of transmitter release and attenuation of anti-retroviral-associated and tibial nerve injury-related painful peripheral neuropathy by novel synthetic Ca2+ channel peptides.

    Science.gov (United States)

    Wilson, Sarah M; Schmutzler, Brian S; Brittain, Joel M; Dustrude, Erik T; Ripsch, Matthew S; Pellman, Jessica J; Yeum, Tae-Sung; Hurley, Joyce H; Hingtgen, Cynthia M; White, Fletcher A; Khanna, Rajesh

    2012-10-12

    N-type Ca(2+) channels (CaV2.2) are a nidus for neurotransmitter release and nociceptive transmission. However, the use of CaV2.2 blockers in pain therapeutics is limited by side effects resulting from inhibition of the physiological functions of CaV2.2 within the CNS. We identified an anti-nociceptive peptide (Brittain, J. M., Duarte, D. B., Wilson, S. M., Zhu, W., Ballard, C., Johnson, P. L., Liu, N., Xiong, W., Ripsch, M. S., Wang, Y., Fehrenbacher, J. C., Fitz, S. D., Khanna, M., Park, C. K., Schmutzler, B. S., Cheon, B. M., Due, M. R., Brustovetsky, T., Ashpole, N. M., Hudmon, A., Meroueh, S. O., Hingtgen, C. M., Brustovetsky, N., Ji, R. R., Hurley, J. H., Jin, X., Shekhar, A., Xu, X. M., Oxford, G. S., Vasko, M. R., White, F. A., and Khanna, R. (2011) Suppression of inflammatory and neuropathic pain by uncoupling CRMP2 from the presynaptic Ca(2+) channel complex. Nat. Med. 17, 822-829) derived from the axonal collapsin response mediator protein 2 (CRMP2), a protein known to bind and enhance CaV2.2 activity. Using a peptide tiling array, we identified novel peptides within the first intracellular loop (CaV2.2(388-402), "L1") and the distal C terminus (CaV1.2(2014-2028) "Ct-dis") that bound CRMP2. Microscale thermophoresis demonstrated micromolar and nanomolar binding affinities between recombinant CRMP2 and synthetic L1 and Ct-dis peptides, respectively. Co-immunoprecipitation experiments showed that CRMP2 association with CaV2.2 was inhibited by L1 and Ct-dis peptides. L1 and Ct-dis, rendered cell-penetrant by fusion with the protein transduction domain of the human immunodeficiency virus TAT protein, were tested in in vitro and in vivo experiments. Depolarization-induced calcium influx in dorsal root ganglion (DRG) neurons was inhibited by both peptides. Ct-dis, but not L1, peptide inhibited depolarization-stimulated release of the neuropeptide transmitter calcitonin gene-related peptide in mouse DRG neurons. Similar results were obtained in DRGs from mice

  18. A novel tool for studying auxin-metabolism: the inhibition of grapevine indole-3-acetic acid-amido synthetases by a reaction intermediate analogue.

    Directory of Open Access Journals (Sweden)

    Christine Böttcher

    Full Text Available An important process for the regulation of auxin levels in plants is the inactivation of indole-3-acetic acid (IAA by conjugation to amino acids. The conjugation reaction is catalysed by IAA-amido synthetases belonging to the family of GH3 proteins. Genetic approaches to study the biological significance of these enzymes have been hampered by large gene numbers and a high degree of functional redundancy. To overcome these difficulties a chemical approach based on the reaction mechanism of GH3 proteins was employed to design a small molecule inhibitor of IAA-amido synthetase activity. Adenosine-5'-[2-(1H-indol-3-ylethyl]phosphate (AIEP mimics the adenylated intermediate of the IAA-conjugation reaction and was therefore proposed to compete with the binding of MgATP and IAA in the initial stages of catalysis. Two grapevine IAA-amido synthetases with different catalytic properties were chosen to test the inhibitory effects of AIEP in vitro. GH3-1 has previously been implicated in the grape berry ripening process and is restricted to two amino acid substrates, whereas GH3-6 conjugated IAA to 13 amino acids. AIEP is the most potent inhibitor of GH3 enzymes so far described and was shown to be competitive against MgATP and IAA binding to both enzymes with K(i-values 17-68-fold lower than the respective K(m-values. AIEP also exhibited in vivo activity in an ex planta test system using young grape berries. Exposure to 5-20 µM of the inhibitor led to decreased levels of the common conjugate IAA-Asp and reduced the accumulation of the corresponding Asp-conjugate upon treatment with a synthetic auxin. AIEP therefore represents a novel chemical probe with which to study IAA-amido synthetase function.

  19. Synthetic antifreeze peptide and synthetic gene coding for its production

    OpenAIRE

    1991-01-01

    A synthetic antifreeze peptide and a synthetic gene coding for the antifreeze peptide have been produced. The antifreeze peptide has a greater number of repeating amino acid sequences than is present in the native antifreeze peptides from winter flounder upon which the synthetic antifreeze peptide was modeled. Each repeating amino acid sequence has two polar amino acid residues which are spaced a controlled distance apart so that the antifreeze peptide may inhibit ice formation. The synthetic...

  20. Infectivity inhibition by overlapping synthetic peptides derived from the gH/gL heterodimer of herpes simplex virus type 1.

    Science.gov (United States)

    Franci, Gianluigi; Falanga, Annarita; Zannella, Carla; Folliero, Veronica; Martora, Francesca; Galdiero, Marilena; Galdiero, Stefania; Morelli, Giancarlo; Galdiero, Massimiliano

    2017-04-01

    Herpes simplex virus (HSV) is a human pathogen that infects epithelial cells. The cutaneous lesions, caused by the virus, spread to the nervous system creating several complications. Fusion of host membranes with the viral envelope is mandatory and mediated by a group of glycoproteins conserved in all Herpesviridae subfamilies, such as the glycoproteins B (gB), H (gH), L (gL) and D (gD). We investigated the inhibitory activity mediated by synthetic overlapping peptides spanning the entire ectodomains of gH and gL glycoproteins. We have performed a brute analysis of the complete gH/gL heterodimer in order to explore the inhibitory activity of peptides modelled on these glycoproteins against HSV-1 infection. Twenty-four of the gH peptides at a concentration of 150 μM reached the 50% of inhibition cut-off. Interestingly, they are mainly located in the gH carboxy-terminal domain. None of the gL peptides had a clear inhibiting effect. No peptide toxicity was observed by lactate dehydrogenase assay at the concentrations used in our experimental conditions. HSV-1 therapy is based on acyclovir treatment, but some resistant strains are emerging. In this scenario, innovative approaches for HSV-1 treatment are necessary. Our data support the direct involvement of the described domains in the process of virus penetration; therefore, these results are of relevance to the potential development of novel therapeutic compounds to prevent HSV-1 infections. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

  1. Murine analogues of etanercept and of F8-IL10 inhibit the progression of collagen-induced arthritis in the mouse.

    Science.gov (United States)

    Doll, Fabia; Schwager, Kathrin; Hemmerle, Teresa; Neri, Dario

    2013-09-27

    Etanercept is a fusion protein consisting of the soluble portion of the p75-tumor necrosis factor receptor (TNFR) and the Fc fragment of human IgG1, which is often used for the treatment of patients with rheumatoid arthritis. F8-IL10 is a human immunocytokine based on the F8 antibody and interleukin-10, which is currently being investigated in rheumatoid arthritis with promising clinical results. We have aimed at expressing murine versions of these two fusion proteins, in order to assess their pharmaceutical performance in the collagen-induced model of rheumatoid arthritis in the mouse. Two fusion proteins (termed muTNFR-Fc and F8-muIL10) were cloned, expressed in chinese hamster ovary (CHO) cells, purified and characterized. Biological activity of muTNFR-Fc was assessed by its ability to inhibit TNF-induced killing of mouse fibroblasts, while F8-muIL10 was characterized in terms of muIL10 activity, of binding affinity to the cognate antigen of F8, the alternatively-spliced EDA domain of fibronectin, by quantitative biodistribution analysis and in vivo imaging. The therapeutic activity of both fusion proteins was investigated in a collagen-induced mouse model of arthritis. Mouse plasma was analyzed for anti-drug antibody formation and cytokine levels were determined by bead-based multiplex technology. The association of F8-IL10 proteins with blood cells was studied in a centrifugation assay with radiolabeled protein. Both fusion proteins exhibited excellent purity and full biological activity in vitro. In addition, F8-muIL10 was able to localize on newly-formed blood vessels in vivo. When used in a murine model of arthritis, the two proteins inhibited arthritis progression. The activity of muTNFR-Fc was tested alone and in combination with F8-huIL10. The chimeric version of F8-IL10 was not better then the fully human fusion protein and showed similar generation of mouse anti-fusion protein antibodies. Incubation studies of F8-muIL10 and F8-huIL10 with blood

  2. bba, a synthetic derivative of 23-hydroxybutulinic acid, reverses multidrug resistance by inhibiting the efflux activity of MRP7 (ABCC10.

    Directory of Open Access Journals (Sweden)

    Jun-Jiang Chen

    Full Text Available Natural products are frequently used for adjuvant chemotherapy in cancer treatment. 23-O-(1,4'-bipiperidine-1-carbonyl betulinic acid (BBA is a synthetic derivative of 23-hydroxybutulinic acid (23-HBA, which is a natural pentacyclic triterpene and the major active constituent of the root of Pulsatillachinensis. We previously reported that BBA could reverse P-glycoprotein (P-gp/ABCB1-mediated multidrug resistance (MDR. In the present study, we investigated whether BBA has the potential to reverse multidrug resistance protein 7 (MRP7/ABCC10-mediated MDR. We found that BBA concentration-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine. Accumulation and efflux experiments demonstrated that BBA increased the intracellular accumulation of [(3H]-paclitaxel by inhibiting the efflux of [(3H]-paclitaxel from HEK293/MRP7 cells. In addition, immunoblotting and immunofluorescence analyses indicated no significant alteration of MRP7 protein expression and localization in plasma membranes after treatment with BBA. These results demonstrate that BBA reverses MRP7-mediated MDR through blocking the drug efflux function of MRP7 without affecting the intracellular ATP levels. Our findings suggest that BBA has the potential to be used in combination with conventional chemotherapeutic agents to augment the response to chemotherapy.

  3. A Novel Approach for Overcoming Drug Resistance in Breast Cancer Chemotherapy by Targeting new Synthetic Curcumin Analogues Against Aldehyde Dehydrogenase 1 (ALDH1A1) and Glycogen Synthase Kinase-3 β (GSK-3β).

    Science.gov (United States)

    Kesharwani, Rajesh Kumar; Srivastava, Vandana; Singh, Prabhakar; Rizvi, Syed Ibrahim; Adeppa, Kuruba; Misra, Krishna

    2015-08-01

    Breast cancer stem cells are well known to resist the traditional methods like chemo and radio therapy. Aldehyde dehydrogenase 1 (ALDHIA1) and glycogen synthase kinase-3 β (GSK-3β) are the two selected proteins for study, due to their overexpression and upregulation in breast cancer cells. Curcumin, the yellow pigment of the spice turmeric, is widely reported as an antioxidant and acts as a synergist along with traditional drugs. Under hypoxic conditions, it gets converted to free radical which causes apoptosis. Three naturally occurring curcuminoids, i.e. curcumin, demethoxycurcumin, and bisdemethoxycurcumin along with five derivatives/analogues of curcumin, viz. 4,4'-di-O-(carboxy-methyl)-curcumin, 4-O-(2-hydroxyethyl)curcumin, 4,4'-di-O-allyl-curcumin, 4,4'-di-O-(acetyl)-curcumin, and 3,3'-bisdemethylcurcumin were synthesized and evaluated for their anti-breast cancer potential by docking simulation and assessment of their antioxidant character, studied via 2, 2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(·+)) radical cation scavenging assay, 2,2-diphenyl-1-picrylhydrazyl (DPPH·) radical, and ferric reducing ability potential (FRAP) assay. A co-relation between structure and activity of curcuminoids/its analogues and derivatives has been worked out.

  4. Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer's disease.

    Science.gov (United States)

    Zhang, Xueli; Tian, Yanli; Li, Zeng; Tian, Xiaoyu; Sun, Hongbin; Liu, Hong; Moore, Anna; Ran, Chongzhao

    2013-11-06

    In this article, we first designed and synthesized curcumin-based near-infrared (NIR) fluorescence imaging probes for detecting both soluble and insoluble amyloid beta (Aβ) species and then an inhibitor that could attenuate cross-linking of Aβ induced by copper. According to our previous results and the possible structural stereohindrance compatibility of the Aβ peptide and the hydrophobic/hydrophilic property of the Aβ13-20 (HHQKLVFF) fragment, NIR imaging probe CRANAD-58 was designed and synthesized. As expected CRANAD-58 showed significant fluorescence property changes upon mixing with both soluble and insoluble Aβ species in vitro. In vivo NIR imaging revealed that CRANAD-58 was capable of differentiating transgenic and wild-type mice as young as 4 months old, the age that lacks apparently visible Aβ plaques and Aβ is likely in its soluble forms. According to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the cross-linking of Aβ42 induced by copper. It is well-known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of Aβ peptides could initialize covalent cross-linking of Aβ. In CRANAD-17, a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of Aβ, and imidazole rings were incorporated to compete with H13/H14 for copper binding. The results of SDS-PAGE gel and Western blot indicated that CRANAD-17 was capable of inhibiting Aβ42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy.

  5. Chalcones from Chinese liquorice inhibit proliferation of T cells and production of cytokines

    DEFF Research Database (Denmark)

    Barfod, Lea; Kemp, Kåre; Hansen, Majbritt

    2002-01-01

    Licochalcone A (LicA), an oxygenated chalcone, has been shown to inhibit the growth of both parasites and bacteria. In this study, we investigated the effect of LicA and four synthetic analogues on the activity of human peripheral blood mononuclear cell proliferation and cytokine production. Four...... out of five chalcones tested inhibited the proliferation of lymphocytes measured by thymidine incorporation and by flow cytometry. The production of pro- and anti-inflammatory cytokines from monocytes and T cells was also inhibited by four of five chalcones. Furthermore, intracellular detection...... of cytokines revealed that the chalcones inhibited the production rather than the release of the cytokines. Taken together, these results indicate that LicA and some analogues may have immunomodulatory effects, and may thus be candidates not only as anti-microbial agents, but also for the treatment of other...

  6. Synthesis and Biological Investigation of Δ(12)-Prostaglandin J3 (Δ(12)-PGJ3) Analogues and Related Compounds.

    Science.gov (United States)

    Nicolaou, K C; Pulukuri, Kiran Kumar; Rigol, Stephan; Heretsch, Philipp; Yu, Ruocheng; Grove, Charles I; Hale, Christopher R H; ElMarrouni, Abdelatif; Fetz, Verena; Brönstrup, Mark; Aujay, Monette; Sandoval, Joseph; Gavrilyuk, Julia

    2016-05-25

    A series of Δ(12)-prostaglandin J3 (Δ(12)-PGJ3) analogues and derivatives were synthesized employing an array of synthetic strategies developed specifically to render them readily available for biological investigations. The synthesized compounds were evaluated for their cytotoxicity against a number of cancer cell lines, revealing nanomolar potencies for a number of them against certain cancer cell lines. Four analogues (2, 11, 21, and 27) demonstrated inhibition of nuclear export through a covalent addition at Cys528 of the export receptor Crm1. One of these compounds (i.e., 11) is currently under evaluation as a potential drug candidate for the treatment of certain types of cancer. These studies culminated in useful and path-pointing structure-activity relationships (SARs) that provide guidance for further improvements in the biological/pharmacological profiles of compounds within this class.

  7. Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus

    DEFF Research Database (Denmark)

    Kumar, Ashwani; Khan, Inshad Ali; Koul, Surrinder

    2008-01-01

    effective concentration. Furthermore, these inhibitors also significantly suppressed the in vitro emergence of ciprofloxacin-resistant S. aureus. CONCLUSIONS: A newly identified class of compounds derived from a natural amide, piperine, is more potent than the parent molecule in potentiating the activity......OBJECTIVES: Evaluation of novel synthetic analogues of piperine as inhibitors of multidrug efflux pump NorA of Staphylococcus aureus. METHODS: A library of piperine-derived compounds was evaluated for their potential to inhibit ethidium bromide efflux in NorA-overexpressing S. aureus SA 1199B...... inhibitors of the NorA efflux pump. These inhibitors acted in a synergistic manner with ciprofloxacin, by substantially increasing its activity against both NorA-overexpressing and wild-type S. aureus isolates. These analogues were 2- to 4-fold more potent than piperine at a significantly lower minimal...

  8. 3-alkyl fentanyl analogues: Structure-activity-relationship study

    OpenAIRE

    Vučković, Sonja; Savić-Vujović, Katarina; Srebro, Dragana; Ivanović, Milovan; Došen-Mićović, Ljiljana; Stojanović, Radan; Prostran, Milica

    2012-01-01

    Introduction. Fentanyl belongs to 4-anilidopiperidine class of synthetic opioid analgesics. It is characterized by high potency, rapid onset and short duration of action. A large number of fentanyl analogues have been synthesized so far, both to establish the structure-activity-relationship (SAR) and to find novel, clinically useful analgesic drugs. Objective. In this study, newly synthesized 3-alkyl fentanyl analogues were examined for analgesic activity and compared with fentanyl. Methods. ...

  9. Synthesis of new triazole arotinoids analogues via "Click Chemistry" with potential anticancer activity

    Directory of Open Access Journals (Sweden)

    Mariana A. A. Aleixo

    2012-06-01

    Full Text Available Retinoids are  a  class  of  natural  and  synthetic  vitamin A analogues structurally related to all-trans-retinoic acid (ATRA. This class of compounds can inhibit cell proliferation and induce differentiation and apoptosis of cells, and several are used in cancer therapy. Using the concept of bioisosterism, new triazole analogues were designed from the molecular modification of the potent derivative arotinoid AM580. This compound has an amide grouping which is a bioisostere of 1,2,3-triazole ring. Through "Click Chemistry” approach, triazole analogues were obtained by reaction of Huisgen 1,3-dipolar cycloaddition between aryl azides and terminal acetylene, previously synthesized. The reagents used were CuI, triethylamine and mixture of ethanol:water. The first compound synthesized showed anticancer activity, while the second proved to be inactive. The molecular docking results showed that both compounds have high affinity for the retinoid RARα receptor (related to anticancer activity, but probably the second compound has antagonist activity on this receptor.

  10. Misoprostol inhibits gastric mucosal release of endogenous prostaglandin E2 and thromboxane B2 in healthy volunteers

    DEFF Research Database (Denmark)

    Mertz-Nielsen, A; Eskerod, O; Bukhave, K

    1995-01-01

    antagonists in preventing ulcer relapse. It could be that prostaglandin analogues inhibit gastric mucosal synthesis or release of endogenous eicosanoids, thereby abrogating their own effects. This study, therefore, examined how a single therapeutic dose (200 micrograms) of misoprostol, a synthetic analogue...... blind, cross over design. In each subject misoprostol or placebo was instilled in randomised order into the stomach, which was subsequently perfused with isotonic mannitol. Misoprostol significantly decreased basal as well as acid stimulated output of PGE2 and TXB2, without affecting output of LTB4....... These data show that misoprostol inhibits gastric mucosal synthesis of prostanoids. Decreased concentrations, or even a changed profile, of native eicosanoids modulating the release of inflammatory mediators from immune cells might explain why prostaglandin analogues have a comparatively poor clinical...

  11. Rabbit IgG directed to a synthetic C-terminal peptide of the major grass pollen allergen Lol p I inhibits human basophil histamine release induced by natural Lol p I.

    Science.gov (United States)

    van Ree, R; Aalberse, R C

    1995-03-01

    The potential role of allergen-specific IgG antibodies as 'blocking' antibodies in allergen-induced human basophil histamine release was investigated. This was studied in a model with the major grass pollen allergen Lol p I and polyclonal rabbit antisera directed against this allergen and against a synthetic peptide of its C terminus. When allergen and antibodies were allowed to preincubate, Lol p I induced histamine release was inhibited up to 85% by the antiserum against Lol p I. By omitting preincubation, and thereby more closely mimicking an in vivo situation, up to 55% inhibition was realized. This indicates that allergen-specific IgG can act as 'blocking' antibody without preincubation. Immunization of rabbits with a synthetic C-terminal peptide of Lol p I resulted in antibodies reactive with natural Lol p I. Despite their 100-fold lower avidity for Lol p I (as compared with antinatural Lol p I), these antibodies had the capacity to inhibit Lol p I induced histamine release for > 90% (up to 50% without preincubation). This indicates that it is possible to block histamine release induced by a major allergen with low-avidity IgG antibodies directed against a minor proportion of the allergen (25 amino acids). IgE antibodies from the donors studied were unreactive with this synthetic peptide, indicating that for blocking activity identical epitope specificity of IgE and IgG is not essential. This opens interesting perspectives for application of synthetic peptides in immunotherapy, distinct from their effects on T cell reactivity.

  12. Selective small-molecule inhibition of an RNA structural element

    Energy Technology Data Exchange (ETDEWEB)

    Howe, John A.; Wang, Hao; Fischmann, Thierry O.; Balibar, Carl J.; Xiao, Li; Galgoci, Andrew M.; Malinverni, Juliana C.; Mayhood, Todd; Villafania, Artjohn; Nahvi, Ali; Murgolo, Nicholas; Barbieri, Christopher M.; Mann, Paul A.; Carr, Donna; Xia, Ellen; Zuck, Paul; Riley, Dan; Painter, Ronald E.; Walker, Scott S.; Sherborne, Brad; de Jesus, Reynalda; Pan, Weidong; Plotkin, Michael A.; Wu, Jin; Rindgen, Diane; Cummings, John; Garlisi, Charles G.; Zhang, Rumin; Sheth, Payal R.; Gill, Charles J.; Tang, Haifeng; Roemer , Terry (Merck)

    2015-09-30

    Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.

  13. LmrBPP9: A synthetic bradykinin-potentiating peptide from Lachesis muta rhombeata venom that inhibits the angiotensin-converting enzyme activity in vitro and reduces the blood pressure of hypertensive rats.

    Science.gov (United States)

    Pinheiro-Júnior, Ernesto Lopes; Boldrini-França, Johara; de Campos Araújo, Luciana Mattoso Pires; Santos-Filho, Norival Alves; Bendhack, Lusiane Maria; Cilli, Eduardo Maffud; Arantes, Eliane Candiani

    2018-04-01

    Bradykinin-potentiating peptides (BPPs) are an important group of toxins present in Lachesis muta rhombeata venom. They act directly at renin-angiotensin-aldosterone system, through the inhibition of angiotensin-converting enzyme (ACE). This action may contribute to the hypotensive shock observed during the envenoming by this species. Thus, the main goal of this study was the solid-phase synthesis of a BPP found in L. m. rhombeata venom and its in vitro and in vivo characterization in relation to ACE inhibition and hypotensive activity, respectively. The LmrBPP9 peptide was synthesized using an automated solid-phase peptide synthesizer and purified by reversed-phase fast protein liquid chromatography (FPLC). The in vitro IC50 of the synthetic peptide is 4.25 ± 0.10 μM, showing a great capacity of ACE inhibition. The in vivo studies showed that LmrBPP9 induces blood pressure reduction, both in normotensive and hypertensive rats, being more pronounced in the last ones. These results agree with the in vitro results, showing that the synthetic peptide LmrBPP9 is a potential molecule to the development of a new antihypertensive drug. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. An azumamide C analogue without the zinc-binding functionality

    DEFF Research Database (Denmark)

    Villadsen, Jesper; Kitir, Betül; Wich, Kathrine

    2014-01-01

    + - coordinating moiety. Herein, we describe the synthesis of an azumamide analogue lacking its native Zn 2+ -binding group and evaluation of its inhibitory activity against recombinant human HDAC1 – 11. Furthermore, kinetic investigation of the inhibitory mechanism of both parent natural product and synthetic...

  15. A Short Review on Cardiotonic Steroids and Their Aminoguanidine Analogues

    Directory of Open Access Journals (Sweden)

    Arturo San Feliciano

    2000-01-01

    Full Text Available A short review on cardiotonic steroids and their analogues is presented. The natural, semisynthetic and synthetic derivatives, as well as their mechanism of action and structure-activity relationships are shown, with a special reference to aminoguanidine derivatives.

  16. Induction of avian musculoaponeurotic fibrosarcoma proteins by toxic bile acid inhibits expression of glutathione synthetic enzymes and contributes to cholestatic liver injury in mice.

    Science.gov (United States)

    Yang, Heping; Ko, Kwangsuk; Xia, Meng; Li, Tony W H; Oh, Pilsoo; Li, Jiaping; Lu, Shelly C

    2010-04-01

    We previously showed that hepatic expression of glutathione (GSH) synthetic enzymes and GSH levels fell 2 weeks after bile duct ligation (BDL) in mice. This correlated with a switch in nuclear anti-oxidant response element (ARE) binding activity from nuclear factor erythroid 2-related factor 2 (Nrf2) to c-avian musculoaponeurotic fibrosarcoma (c-Maf)/V-maf musculoaponeurotic fibrosarcoma oncogene homolog G (MafG). Our current aims were to examine whether the switch in ARE binding activity from Nrf2 to Mafs is responsible for decreased expression of GSH synthetic enzymes and the outcome of blocking this switch. Huh7 cells treated with lithocholic acid (LCA) exhibited a similar pattern of change in GSH synthetic enzyme expression as BDL mice. Nuclear protein levels of Nrf2 fell at 20 hours after LCA treatment, whereas c-Maf and MafG remained persistently induced. These changes translated to ARE nuclear binding activity. Knockdown of c-Maf or MafG individually blunted the LCA-induced decrease in Nrf2 ARE binding and increased ARE-dependent promoter activity, whereas combined knockdown was more effective. Knockdown of c-Maf or MafG individually increased the expression of GSH synthetic enzymes and raised GSH levels, and combined knockdown exerted an additive effect. Ursodeoxycholic acid (UDCA) or S-adenosylmethionine (SAMe) prevented the LCA-induced decrease in expression of GSH synthetic enzymes and promoter activity and prevented the increase in MafG and c-Maf levels. In vivo knockdown of the Maf genes protected against the decrease in GSH enzyme expression, GSH level, and liver injury after BDL. Toxic bile acid induces a switch from Nrf2 to c-Maf/MafG ARE nuclear binding, which leads to decreased expression of GSH synthetic enzymes and GSH levels and contributes to liver injury during BDL. UDCA and SAMe treatment targets this switch.

  17. Induction of Maf Proteins by Toxic Bile Acid Inhibits Expression of GSH Synthetic Enzymes and Contributes to Cholestatic Liver Injury in Mice

    Science.gov (United States)

    Yang, Heping; Ko, Kwangsuk; Xia, Meng; Li, Tony W.H.; Oh, Pilsoo; Li, Jiaping; Lu, Shelly C.

    2010-01-01

    Background and rationale We previously showed that hepatic expression of GSH synthetic enzymes and GSH levels fell two weeks after bile duct ligation (BDL) in mice. This correlated with a switch in nuclear anti-oxidant response element (ARE) binding activity from nuclear factor-erythroid 2 related factor 2 (Nrf2) to c-Maf/MafG. Our current aims were to examine whether the switch in ARE binding activity from Nrf2 to Mafs is responsible for decreased expression of GSH synthetic enzymes and the outcome of blocking this switch. Results HuH-7 cells treated with lithocholic acid (LCA) exhibited a similar pattern of change in GSH synthetic enzyme expression as BDL mice. Nuclear protein levels of Nrf2 fell at 20 hours following LCA treatment while c-Maf and MafG remained persistently induced. These changes translated to ARE nuclear binding activity. Knockdown of c-Maf or MafG individually blunted the LCA-induced fall in Nrf2 ARE binding and increased ARE-dependent promoter activity while combined knockdown was more effective. Knockdown of c-Maf or MafG individually increased the expression of GSH synthetic enzymes and raised GSH levels and combined knockdown exerted additive effect. Ursodeoxycholic acid (UDCA) or S-adenosylmethionine (SAMe) prevented the LCA-induced fall in expression of GSH synthetic enzymes and promoter activity and prevented the increase in MafG and c-Maf levels. In vivo knockdown of the Maf genes protected against fall in GSH enzymes expression, GSH level and liver injury following BDL. Conclusions Toxic bile acid induces a switch from Nrf2 to c-Maf/MafG ARE nuclear binding, which leads to decreased expression of GSH synthetic enzymes and GSH levels and contributes to liver injury during BDL. UDCA and SAMe treatment targets this switch. PMID:20146260

  18. UCLA1, a synthetic derivative of a gp120 RNA aptamer, inhibits entry of human immunodeficiency virus type 1 subtype C

    CSIR Research Space (South Africa)

    Mufhandu, Hazel T

    2012-05-01

    Full Text Available aptamers and showed that they neutralized the infectivity of HIV-1. In this study, we assessed the activity of a shortened synthetic derivative of the B40 aptamer, called UCLA1, against a large panel of HIV-1 subtype C viruses. UCLA1 tightly bound to a...

  19. Natural Analogue Synthesis Report

    Energy Technology Data Exchange (ETDEWEB)

    A. M. Simmons

    2002-05-01

    The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the ''Yucca Mountain Site Description'' (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature, along with results of quantitative studies conducted specifically for the Yucca Mountain Site Characterization Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement drift degradation, waste form degradation, waste package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated zone (SZ) transport

  20. NATURAL ANALOGUE SYNTHESIS REPORT

    International Nuclear Information System (INIS)

    Simmons, A.M.

    2004-01-01

    The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the Yucca Mountain Site Description (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature along with results of quantitative studies conducted specifically for the Yucca Mountain Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement-drift degradation, waste-form degradation, waste-package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated-zone (SZ) transport, impact of radionuclide release on the biosphere

  1. Synthetic Cannabinoids

    Directory of Open Access Journals (Sweden)

    Aslihan Okan Ibiloglu

    2017-09-01

    Full Text Available Synthetic cannabinoids which is a subgroup of cannabinoids are commonly used for recreational drug use throughout the whole world. Although both marijuana and synthetic cannabinoids stimulate the same receptors, cannabinoid receptor 1 (CB1 and cannabinoid receptor 2 (CB2, studies have shown that synthetic cannabinoids are much more potent than marijuana. The longer use of synthetic cannabinoids can cause severe physical and psychological symptoms that might even result in death, similar to many known illicit drugs. Main treatment options mostly involve symptom management and supportive care. The aim of this article is to discuss clinical and pharmacological properties of the increasingly used synthetic cannabinoids. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2017; 9(3.000: 317-328

  2. Novel Carbonyl Analogues of Tamoxifen: Design, Synthesis, and Biological Evaluation

    Science.gov (United States)

    Kasiotis, Konstantinos M.; Lambrinidis, George; Fokialakis, Nikolas; Tzanetou, Evangelia N.; Mikros, Emmanuel; Haroutounian, Serkos A.

    2017-09-01

    Aim of this work was to provide tamoxifen analogues with enhanced estrogen receptor binding affinity. Hence, several derivatives were prepared using an efficient triarylethylenes synthetic protocol. The novel compounds bioactivity was evaluated through the determination of their receptor binding affinity and their agonist/antagonist activity against breast cancer tissue using a MCF-7 cell-based assay. Phenyl esters 6a,b and 8a,b exhibited binding affinity to both ERα and ERβ higher than 4-hydroxytamoxifen while compounds 13 and 14 have shown cellular antiestrogenic activity similar to 4-hydroxytamoxifen and the known estrogen receptor inhibitor ICI182,780. Theoretical calculations and molecular modelling were applied to investigate, support and explain the biological profile of the new compounds. The relevant data indicated an agreement between calculations and demonstrated biological activity allowing to extract useful structure-activity relationships. Results herein underline that modifications of tamoxifen structure still provide molecules with substantial activity, as portrayed in the inhibition of MCF-7 cells proliferation.

  3. CEC natural analogue working group

    International Nuclear Information System (INIS)

    Come, B.; Chapman, N.A.

    1986-01-01

    The second meeting of the CEC Natural Analogue Working Group took place on June 17-19, 1986, hosted by the Swiss NAGRA in Interlaken (CH). A review of recent progress in natural analogue programmes was carried out, and complemented by detailed discussions about geomicrobiology, archaeological analogues, natural colloids, and use of analogues to increase confidence in safety assessments for radioactive waste disposal. A statement drafted by the Group, and the presentations made, are put together in this report

  4. Folate analogues altered in the C9-N10 bridge region. 10-Oxafolic acid and 10-oxaaminopterin.

    Science.gov (United States)

    Nair, M G; Campbell, P T

    1976-06-01

    The unambiguous synthesis of two folate analogues, in which the 10-amino group of folic acid was replaced with oxygen, is described. The synthetic sequence employed commercially available methyl p-hydroxybenzoate and n-(2,3-epoxypropyl)phthalimide as starting materials. The use of cesium bicarbonate as a coreactant in the nucleophilic displacement reaction between bromo ketone 3 and the nucleophile 4 was found to be unique in character. The aminoacetonyl oxime 7 obtained by the hydrazinolysis of 6 was used as a common intermediate for the synthesis of both compounds. The generality of the use of the TFA-HCL mixture to deprotect the carbonyl group of both 10 and 12 reductions involving sodium hydrosulfite in aqueous dmf were further substantiated by conversions of 11 and 13 to 14 and 15 quickly and efficiently without employing catalytic hydrogenations. Subsequent cyclizations, oxidations, and hydrolysis of these reduction products to the pteroate analogues 17 and 19 were carried out efficiently as described for the synthesis of the sulfur analogues. Activation of the carboxyl group of 19 by way of the mixed anhydride 22 and subsequent coupling to glutamic acid was carried out using the solid-phase coupling procedure. However, compound 17 required trifluoroacetylation to 20 prior to the coupling reaction due to solubility problems. Both 10-oxafolic acid (1) and 10-oxaaminopterin (2) showed potent antifolate activity when tested against two folate-requiring organisms. Compound 2 was a very powerful inhibitor of DCM-resistant lactobacillus casei dihydrofolate reductase. The activity was comparable to that of methotrexate while the 4-hydroxy analogue did not show inhibition. 7,8-Dihydro-10-oxafolic acid failed to show any substrate activity to this enzyme and did not inhibit the enzymatic reaction when used with an equimolar concentration of the natural substrate.

  5. CEC Natural Analogue Working Group

    International Nuclear Information System (INIS)

    Come, B.; Chapman, N.A.

    1989-01-01

    The central theme for the third meeting of the CEC analogue working group was ''How can analogue data be used for performance assessments, both in support of the results and for presentation to the public''. This report puts together the most recent achievements in this field, together with a review of on-going natural analogue programmes

  6. Synthesis of phosphono analogues of dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.

    Science.gov (United States)

    Page, P; Blonski, C; Périé, J

    1999-07-01

    The present paper describes the synthetic routes of six phosphono analogues of dihydroxyacetone phosphate and five phosphono analogues of glyceraldehyde 3-phosphate through alpha-, beta- and gamma-hydroxyphosphonate esters precursors containing a protected carbonyl group. In some situations, depending on the sequence used for the deprotection of the phosphonate and carbonyl groups, the aldol/ketol rearrangement allowed the synthesis of either dihydroxyacetone phosphate or glyceraldehyde 3-phosphate analogues from the same precursors. All these analogues are of interest both as active-site probes and as potential substrates for glycolytic enzymes such as fructose 1,6-diphosphate aldolases (EC 4.1.2.13).

  7. Peramivir analogues bearing hydrophilic side chains exhibit higher activities against H275Y mutant than wild-type influenza virus.

    Science.gov (United States)

    Chiu, Din-Chi; Lin, Tzu-Chen; Huang, Wen-I; Cheng, Ting-Jen; Tsai, Keng-Chang; Fang, Jim-Min

    2017-11-29

    Peramivir is an effective anti-influenza drug in the clinical treatment of influenza, but its efficacy toward the H275Y mutant is reduced. The previously reported cocrystal structures of inhibitors in the mutant neuraminidase (NA) suggest that the hydrophobic side chain should be at the origin of reduced binding affinity. In contrast, zanamivir having a hydrophilic glycerol side chain still possesses high affinity toward the H275Y NA. We thus designed five peramivir analogues (5-9) carrying hydrophilic glycol or glycerol side chains, and evaluated their roles in anti-influenza activity, especially for the H275Y mutant. The synthetic sequence involves a key step of (3 + 2) cycloaddition reactions between alkenes and nitrile oxides to construct the scaffold of peramivir carrying the desired hydrophilic side chains and other appropriate functional groups. The molecular docking experiments reveal that the hydrophilic side chain can provide extra hydrogen bonding with the translocated Glu-276 residue in the H275Y NA active site. Thus, the H275Y mutant may be even more sensitive than wild-type virus toward the peramivir analogues bearing hydrophilic side chains. Notably, the peramivir analogue bearing a glycerol side chain inhibits the H275Y mutant with an IC 50 value of 35 nM, which is better than the WSN virus by 9 fold.

  8. Natural analogue working group

    International Nuclear Information System (INIS)

    Come, B.; Chapman, N.

    1986-01-01

    A Natural Analogue Working Group was established by the Commission of the European Communities in 1985. The purpose of this group is to bring together modellers with earth scientists and others, so that maximum benefit can be obtained from natural analogue studies with a view to safe geological disposal of radioactive waste. The first meeting of this group was held in Brussels from November 5 to 7, 1985. The discussions mainly concerned the identification of the modellers' needs and of the earth scientists' capacity to provide for them. Following the debates, a written statement was produced by the Group; this document forms the core of the present Report. Notes and outlines of many of the presentations made are grouped in four appendixes. The valuable contribution of all those involved in the meeting is gratefully acknowledged

  9. Synthetic oils

    Science.gov (United States)

    Hatton, R. E.

    1973-01-01

    Synthetic lubricants are discussed by chemical class and their general strengths and weaknesses in terms of lubrication properties are analyzed. Comparative ratings are given for 14 chemical classes and are used as a guide for lubricant selection. The effects of chemical structure on the properties of the lubricant are described with special emphasis on thermal stability. The diversity of synthetic lubricants which is provided by the wide range of properties permits many applications, some of which are reported.

  10. Quantum analogue computing.

    Science.gov (United States)

    Kendon, Vivien M; Nemoto, Kae; Munro, William J

    2010-08-13

    We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

  11. The Palmottu analogue project

    International Nuclear Information System (INIS)

    Ahonen, L.; Blomqvist, R.; Suksi, J.

    1993-01-01

    The report gives a summary of the results of investigations carried out in 1992 at the Palmottu natural analogue study site, which is a small U-Th mineralization in Nummi-Pusula, southwestern Finland. Additionally, the report includes several separate articles dealing with various aspects of the Palmottu Analogue Project: (1) deep groundwater flow, (2) interpretation of hydraulic connections, (3) characterization of groundwater colloids, (4) uranium mineral-groundwater equilibrium, (5) water-rock interaction and (6) modelling of in situ matrix diffusion. The Palmottu Analogue Project aims at a more profound understanding of radionuclide transport processes in fractured crystalline bedrock. The essential factors controlling transport are groundwater flow and interaction between water and rock. Accordingly, the study includes (1) structural interpretations partly based on geophysical measurements, (2) hydrological studies including hydraulic drill-hole measurements, (3) flow modelling, (4) hydrogeochemical characterization of groundwater, uranium chemistry and colloid chemistry, (5) mineralogical studies, (6) geochemical interpretation and modelling, (7) studies of radionuclide mobilization and retardation including matrix diffusion, and (8) modelling of uranium series data. Palaeohydrogeological aspects, due to the anticipated future glaciation of the Fennoscandian Shield, are of special interest. Quaternary sediments are studied to gain information on post-glacial migration in the overburden. (orig.)

  12. A Conserved 19-Amino Acid Synthetic Peptide from the Carboxy Terminus of Phosphoenolpyruvate Carboxylase Inhibits the in Vitro Phosphorylation of the Enzyme by the Calcium-Independent Phosphoenolpyruvate Carboxylase Kinase1

    Science.gov (United States)

    Alvarez, Rosario; García-Mauriño, Sofía; Feria, Ana-Belén; Vidal, Jean; Echevarría, Cristina

    2003-01-01

    Higher plant phosphoenolpyruvate carboxylase (PEPC) is subject to in vivo phosphorylation of a regulatory serine located in the N-terminal domain of the protein. Studies using synthetic peptide substrates and mutated phosphorylation domain photosynthetic PEPC (C4 PEPC) suggested that the interaction of phosphoenolpyruvate carboxylase kinase (PEPCk) with its target was not restricted to this domain. However, no further information was available as to where PEPCk-C4 PEPC interactions take place. In this work, we have studied the possible interaction of the conserved 19-amino acid C-terminal sequence of sorghum (Sorghum vulgare Pers cv Tamaran) C4 PEPC with PEPCk. In reconstituted assays, a C-terminal synthetic peptide containing this sequence (peptide C19) was found to inhibit the phosphorylation reaction by the partially purified Ca2+-independent PEPCk (50% inhibition of initial activity = 230 μm). This effect was highly specific because peptide C19 did not alter C4 PEPC phosphorylation by either a partially purified sorghum leaf Ca2+-dependent protein kinase or the catalytic subunit of mammalian protein kinase A. In addition, the Ca2+-independent PEPCk was partially but significantly retained in affinity chromatography using a peptide C19 agarose column. Because peptide C15 (peptide C19 lacking the last four amino acids, QNTG) also inhibited C4 PEPC phosphorylation, it was concluded that the amino acid sequence downstream from the QNTG motif was responsible for the inhibitory effect. Specific antibodies raised against peptide C19 revealed that native C4 PEPC could be in two different conformational states. The results are discussed in relation with the reported crystal structure of the bacterial (Escherichia coli) and plant (maize [Zea mays]) enzymes. PMID:12805637

  13. Inhibition of Cell-Free Human T-Cell Leukemia Virus Type 1 Infection at a Postbinding Step by the Synthetic Peptide Derived from an Ectodomain of the gp21 Transmembrane Glycoprotein

    Science.gov (United States)

    Jinno, A.; Haraguchi, Y.; Shiraki, H.; Hoshino, H.

    1999-01-01

    To investigate the roles of human T-cell leukemia virus type 1 (HTLV-1) envelope (Env) proteins gp46 and gp21 in the early steps of infection, the effects of the 23 synthetic peptides covering the entire Env proteins on transmission of cell-free HTLV-1 were examined by PCR and by the plaque assay using a pseudotype of vesicular stomatis virus (VSV) bearing the Env of HTLV-1 [VSV(HTLV-1)]. The synthetic peptide corresponding to amino acids 400 to 429 of the gp21 Env protein (gp21 peptide 400-429, Cys-Arg-Phe-Pro-Asn-Ile-Thr-Asn-Ser-His-Val-Pro-Ile-Leu-Gln-Glu-Arg-Pro-Pro-Leu-Glu-Asn-Arg-Val-Leu-Thr-Gly-Trp-Gly-Leu) strongly inhibited infection of cell-free HTLV-1. By using the mutant peptide, Asn407, Ser408, and Leu413, -419, -424, and -429 were confirmed to be important amino acids for neutralizing activity of the gp21 peptide 400-429. Addition of this peptide before or during adsorption of HTLV-1 at 4°C did not affect its entry. However, HTLV-1 infection was inhibited about 60% when the gp21 peptide 400-429 was added even 30 min after adsorption of HTLV-1 to cells, indicating that the amino acid sequence 400 to 429 on the gp21 Env protein plays an important role at the postbinding step of HTLV-1 infection. In contrast, a monoclonal antibody reported to recognize the gp46 191-196 peptide inhibited the infection of HTLV-1 at the binding step. PMID:10516085

  14. Dienogest, a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system.

    Science.gov (United States)

    Shimizu, Yutaka; Mita, Shizuka; Takeuchi, Takashi; Notsu, Tatsuto; Mizuguchi, Kiyoshi; Kyo, Satoru

    2011-01-01

    Prostaglandin E(2) (PGE(2)) is a major mediator in the pathophysiology, and pathogenesis of gynecological diseases associated with abnormal endometrial disease with proliferation and inflammation, such as endometriosis. In this study, we investigated the effect of dienogest, a selective progesterone receptor agonist, on PGE(2) production and the expression of aromatase, an estrogen synthase, in human immortalized endometrial epithelial cells. Compared with monolayer culture, the cells showed enhanced PGE(2) production and expression of the PGE(2) synthases cyclooxygenase-2 (COX-2), and microsomal prostaglandin E(2) synthase-1 (mPGES-1) in a spheroid culture system. Dienogest inhibited PGE(2) production and this effect was reversed by RU486, a progesterone receptor antagonist. Dienogest inhibited the PGE(2) synthases mRNA and protein expression, and the nuclear factor-κB activation. Moreover, the suppressive effect of dienogest on PGE(2) production was sustained 24h after the drug was withdrawn. Dienogest but not COX inhibitors inhibited aromatase expression. These results suggest that progesterone receptor activation reduces the gene expressions of COX-2, mPGES-1, and aromatase. Our findings suggest that the pharmacological mechanism of dienogest includes the direct inhibition of PGE(2) synthase and aromatase expression and may contribute to the therapeutic effect on the progression of endometriosis. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Synthetic environments

    Science.gov (United States)

    Lukes, George E.; Cain, Joel M.

    1996-02-01

    The Advanced Distributed Simulation (ADS) Synthetic Environments Program seeks to create robust virtual worlds from operational terrain and environmental data sources of sufficient fidelity and currency to interact with the real world. While some applications can be met by direct exploitation of standard digital terrain data, more demanding applications -- particularly those support operations 'close to the ground' -- are well-served by emerging capabilities for 'value-adding' by the user working with controlled imagery. For users to rigorously refine and exploit controlled imagery within functionally different workstations they must have a shared framework to allow interoperability within and between these environments in terms of passing image and object coordinates and other information using a variety of validated sensor models. The Synthetic Environments Program is now being expanded to address rapid construction of virtual worlds with research initiatives in digital mapping, softcopy workstations, and cartographic image understanding. The Synthetic Environments Program is also participating in a joint initiative for a sensor model applications programer's interface (API) to ensure that a common controlled imagery exploitation framework is available to all researchers, developers and users. This presentation provides an introduction to ADS and the associated requirements for synthetic environments to support synthetic theaters of war. It provides a technical rationale for exploring applications of image understanding technology to automated cartography in support of ADS and related programs benefitting from automated analysis of mapping, earth resources and reconnaissance imagery. And it provides an overview and status of the joint initiative for a sensor model API.

  16. Iron Sulfur Proteins and their Synthetic Analogues: Structure ...

    Indian Academy of Sciences (India)

    The understanding of structures and functions of iron sulfur proteins is an area ofbio-inorganic chemistry which has developed into a subject of great significance over the last two decades. This group of non-heme iron-sulfur (Fe-S) compounds are involved in electron transfer reactions in biological systems and are thus.

  17. Characterization of Synthetic and Natural Manganese Oxides as Martian Analogues

    Science.gov (United States)

    Fox, V. K.; Arvidson, R. E.; Jolliff, B. L.; Carpenter, P. K.; Catalano, J. G.; Hinkle, M. A. G.; Morris, R. V.

    2015-01-01

    Recent discoveries of highly concentrated manganese oxides in Gale Crater and on the rim of Endeavour Crater by the Mars Science Laboratory Curiosity and Mars Exploration Rover Opportunity, respectively, imply more highly oxidizing aqueous conditions than previously recognized. Manganese oxides are a significant environmental indicator about ancient aqueous conditions, provided the phases can be characterized reliably. Manganese oxides are typically fine-grained and poorly crystalline, making the mineral structures difficult to determine, and they generally have very low visible reflectance with few distinctive spectral features in the visible to near infrared, making them a challenge for interpretation from remote sensing data. Therefore, these recent discoveries motivate better characterization using methods available on Mars, particularly visible to near infrared (VNIR) spectroscopy, X-ray diffractometry (XRD), and compositional measurements. Both rovers have complementary instruments in this regard. Opportunity is equipped with its multispectral visible imager, Pancam, and an Alpha Particle X-ray Spectrometer (APXS), and Curiosity has the multispectral Mastcam, ChemCam (laser-induced breakdown spectroscopy and passive spectroscopy), and APXS for in situ characterization, and ChemMin (XRD) for collected samples.

  18. Iron Sulfur Proteins and their Synthetic Analogues: Structure ...

    Indian Academy of Sciences (India)

    group of non-heme iron-sulfur (Fe-S) compounds are involved in ... The sulfur ligands are arranged tetrahedrally about the iron atoms. The presence of inorganic sulfur is indicated through the release of. H. 2. S gas when these proteins are treated with a ... analysis of this structure and the tri-iron cluster was corrected as.

  19. Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors.

    Science.gov (United States)

    Kalaba, Predrag; Aher, Nilima Y; Ilić, Marija; Dragačević, Vladimir; Wieder, Marcus; Miklosi, Andras G; Zehl, Martin; Wackerlig, Judith; Roller, Alexander; Beryozkina, Tetyana; Radoman, Bojana; Saroja, Sivaprakasam R; Lindner, Wolfgang; Gonzalez, Eduardo Perez; Bakulev, Vasiliy; Leban, Johann Jakob; Sitte, Harald H; Urban, Ernst; Langer, Thierry; Lubec, Gert

    2017-11-22

    Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.

  20. ACTINOMYCIN D ANALOGUES

    DEFF Research Database (Denmark)

    1997-01-01

    acids, $g(b)-amino acids and/or longer chain $g(v)-amino acids, and a difunctional group which preferably is a cyclic entity, in particular, an aromatic or heteroaromatic entity acting as an intercalator group. Specific compounds and a library of such compounds may be prepared using conventional solid......The present invention relates to new compounds being structurally and functionally similar to Actinomycin D and to combinatorial libraries of such compounds. The Actinomycin D analogues according to the present invention comprise two linear or cyclic peptide moieties constituted by $g(a)-amino...

  1. Novel 2-step synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models.

    Science.gov (United States)

    Lee, Ching-Hsiao; Yao, Ching-Fa; Huang, Sin-Ming; Ko, Shengkai; Tan, Yi-Hung; Lee-Chen, Guey-Jen; Wang, Yi-Ching

    2008-08-15

    The clinical responses to chemotherapy in lung cancer patients are unsatisfactory. Thus, the development of more effective anticancer drugs for lung cancer is urgently needed. A 2-step novel synthetic compound, referred to as 1,1,3-tri(3-indolyl)cyclohexane (3-indole), was generated in high purity and yield. 3-Indole was tested for its biologic activity in A549, H1299, H1435, CL1-1, and H1437 lung cancer cells. Animal studies were also performed. The data indicate that 3-indole induced apoptosis in various lung cancer cells. Increased cytochrome-c release from mitochondria to cytosol, decreased expression of antiapoptotic Bcl-2, and increased expression of proapoptotic Bax were observed. In addition, 3-indole stimulated caspases-3, -9, and to a lesser extent caspase-8 activities in cancer cells, suggesting that the intrinsic mitochondria pathway was the potential mechanism involved in 3-indole-induced apoptosis. 3-Indole-induced a concentration-dependent mitochondrial membrane potential dissipation and an increase in reactive oxygen species (ROS) production. Activation of c-Jun N-terminal kinase (JNK) and triggering of DNA damage were also apparent. Note that 3-indole-induced JNK activation and DNA damage can be partially suppressed by an ROS inhibitor. Apoptosis induced by 3-indole could be abrogated by ROS or JNK inhibitors, suggesting the importance of ROS and JNK stress-related pathways in 3-indole-induced apoptosis. Moreover, 3-indole showed in vivo antitumor activities against human xenografts in murine models. On the basis of its potent anticancer activity in cell and animal models, the data suggest that this 2-step synthetic 3-indole compound of high purity and yield is a potential candidate to be tested as a lead pharmaceutical compound for cancer treatment. 2008 American Cancer Society

  2. Cyclobutanone Analogues of β-Lactam Antibiotics: β-Lactamase Inhibitors with Untapped Potential?

    Science.gov (United States)

    Devi, Prarthana; Rutledge, Peter J

    2017-02-16

    β-Lactam antibiotics have been used for many years to treat bacterial infections. However the effective treatment of an increasing range of microbial infections is threatened by bacterial resistance to β-lactams: the prolonged, widespread (and at times reckless) use of these drugs has spawned widespread resistance, which renders them ineffective against many bacterial strains. The cyclobutanone ring system is isosteric with β-lactam: in cyclobutanone analogues, the eponymous cyclic amide is replaced with an all-carbon ring, the amide N is substituted by a tertiary C-H α to a ketone. Cyclobutanone analogues of various β-lactam antibiotics have been investigated over the last 35 years, initially as prospective antibiotics in their own right and inhibitors of the β-lactamase enzymes that impart resistance to β-lactams. More recently they have been tested as inhibitors of other serine proteases and as mechanistic probes of β-lactam biosynthesis. Cyclobutanone analogues of the penam ring system are the first reversible inhibitors with moderate activity against all classes of β-lactamase; other compounds from this family inhibit Streptomyces R61 dd-carboxypeptidase/transpeptidase, human neutrophil elastase and porcine pancreatic elastase. But has their potential as enzyme inhibitors been fully exploited? Challenges in synthesising diversely functionalised cyclobutanone derivatives mean that only a limited number have been made (with limited structural diversity) and evaluated. This review surveys the different synthetic approaches that have been taken to these compounds, the investigations made to evaluate their biological activity and prospects for future developments in this area. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. GEN-27, a Newly Synthetic Isoflavonoid, Inhibits the Proliferation of Colon Cancer Cells in Inflammation Microenvironment by Suppressing NF-κB Pathway

    Directory of Open Access Journals (Sweden)

    Yajing Wang

    2016-01-01

    Full Text Available Nonresolving inflammation is one of the consistent features of the tumor microenvironment in the intestine and plays a critical role in the initiation and development of colon cancer. Here we reported the inhibitory effects of GEN-27, a new derivative of genistein, on the inflammation-related colon cancer cell proliferation and delineated the mechanism of its action. The results indicated that GEN-27 inhibited the proliferation of human colon tumor HCT116 cells stimulated by culture supernatants of LPS-induced human monocytes THP-1 cells and significantly decreased LPS-induced secretion of proinflammatory cytokines interleukin-6 and interleukin-1β in THP-1 cells. The HCT116 cell proliferation elicited by THP-1-conditioned medium could be blocked by the interleukin-1 receptor antagonist (IL-1RA. Further mechanistic study revealed that GEN-27 remarkably inhibited the nuclear translocation of NF-κB and phosphorylation of IκB and IKKα/β in both HCT116 and THP-1 cells. In addition, GEN-27 markedly suppressed the HCT116 cell proliferation stimulated by IL-1β treatment, which was dependent on the inhibition of NF-κB/p65 nuclear localization, as verified by p65 overexpression and BAY 11-7082, an NF-κB inhibitor. Taken together, our findings established that GEN-27 modulated NF-κB signaling pathway involved in inflammation-induced cancer cells proliferation and therefore could be a potential chemopreventive agent against inflammation-associated colon cancer.

  4. GEN-27, a Newly Synthetic Isoflavonoid, Inhibits the Proliferation of Colon Cancer Cells in Inflammation Microenvironment by Suppressing NF-κB Pathway.

    Science.gov (United States)

    Wang, Yajing; Lu, Ping; Zhang, Weifeng; Du, Qianming; Tang, Jingjing; Wang, Hong; Lu, Jinrong; Hu, Rong

    2016-01-01

    Nonresolving inflammation is one of the consistent features of the tumor microenvironment in the intestine and plays a critical role in the initiation and development of colon cancer. Here we reported the inhibitory effects of GEN-27, a new derivative of genistein, on the inflammation-related colon cancer cell proliferation and delineated the mechanism of its action. The results indicated that GEN-27 inhibited the proliferation of human colon tumor HCT116 cells stimulated by culture supernatants of LPS-induced human monocytes THP-1 cells and significantly decreased LPS-induced secretion of proinflammatory cytokines interleukin-6 and interleukin-1β in THP-1 cells. The HCT116 cell proliferation elicited by THP-1-conditioned medium could be blocked by the interleukin-1 receptor antagonist (IL-1RA). Further mechanistic study revealed that GEN-27 remarkably inhibited the nuclear translocation of NF-κB and phosphorylation of IκB and IKKα/β in both HCT116 and THP-1 cells. In addition, GEN-27 markedly suppressed the HCT116 cell proliferation stimulated by IL-1β treatment, which was dependent on the inhibition of NF-κB/p65 nuclear localization, as verified by p65 overexpression and BAY 11-7082, an NF-κB inhibitor. Taken together, our findings established that GEN-27 modulated NF-κB signaling pathway involved in inflammation-induced cancer cells proliferation and therefore could be a potential chemopreventive agent against inflammation-associated colon cancer.

  5. Transaxial analogue tomography

    International Nuclear Information System (INIS)

    Duinker, S.; Geluk, R.J.; Mulder, H.

    1978-01-01

    After an introduction on computerized tomography (CT) scanners summarizing the various generations, the general outline of the concept of a transaxial tomography system is given, which is entirely based on analogue instead of digital techniques (AT system). In particular, the use of X-ray image-intensifier systems as a means of detecting the transmission profiles of the object in a so-called half-field detection method are discussed as well as various possibilities of detector scanning. It is further discussed how in a purely electronic way with the aid of a scan-converter, density profiles representative of parallel beams can be derived from the family of profiles as obtained from the fan-shaped beams in the actual experiment. A practical opto-electronic solution of the analogue spatial filtering problem is described as to how to process, on a real-time basis, parallel density profiles so that after back-projection tomographic images which are free from point-spreading effects will be obtained. Finally, after a brief indication of certain technical details for which corrective measures have to be worked out in the course of practical realization, the main relative advantages of AT scanners in comparison to CT scanners are enumerated. (Auth.)

  6. A novel synthetic derivative of melatonin, 5-hydroxy-2’-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation

    Energy Technology Data Exchange (ETDEWEB)

    Shim, Do-Wan [Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju (Korea, Republic of); Shin, Hee Jae [Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science & Technology, Ansan (Korea, Republic of); Han, Ji-Won; Ji, Young-Eun; Jang, Cheol-Hun; Koppula, Sushruta; Kang, Tae-Bong [Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju (Korea, Republic of); Lee, Kwang-Ho, E-mail: kwangho@kku.ac.kr [Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju (Korea, Republic of)

    2015-04-15

    Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2′-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (ALI) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1β, IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of pro-inflammatory cytokines such as IL-6 and TNF-α in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-β (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1β secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1β, IL-6 and interferon-β production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signaling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases. - Highlights: • Νovel compound, 5-hydroxy-2′-isobutyl-streptochlorin (HIS) was

  7. Synthetic Rutile

    International Nuclear Information System (INIS)

    Burastero, J.

    1975-01-01

    This work is about the laboratory scale investigation of the conditions in the rutile synthetic production from one me nita in Aguas Dulces reservoir. The iron mineral is chlorinated and volatilized selectively leaving a residue enriched in titanium dioxide which can be used as a substitute of rutile mineral

  8. Evaluation of proline analogs as trypanocidal agents through the inhibition of a Trypanosoma cruzi proline transporter.

    Science.gov (United States)

    Sayé, Melisa; Fargnoli, Lucía; Reigada, Chantal; Labadie, Guillermo R; Pereira, Claudio A

    2017-11-01

    Trypanosoma cruzi, the etiological agent of Chagas disease, uses proline as its main carbon source, essential for parasite growth and stage differentiation in epimastigotes and amastigotes. Since proline is involved in many essential biological processes in T. cruzi, its transport and metabolism are interesting drug targets. Four synthetic proline analogues (ITP-1B/1C/1D/1G) were evaluated as inhibitors of proline transport mediated through the T. cruzi proline permease TcAAAP069. The trypanocidal activity of the compounds was also assessed. The compounds ITP-1B and ITP-1G inhibited proline transport mediated through TcAAAP069 permease in a dose-dependent manner. The analogues ITP-1B, -1D and -1G had trypanocidal effect on T. cruzi epimastigotes with IC 50 values between 30 and 40μM. However, only ITP-1G trypanocidal activity was related with its inhibitory effect on TcAAAP069 proline transporter. Furthermore, this analogue strongly inhibited the parasite stage differentiation from epimastigote to metacyclic trypomastigote. Finally, compounds ITP-1B and ITP-1G were also able to inhibit the transport mediated by other permeases from the same amino acid permeases family, TcAAAP. It is possible to design synthetic amino acid analogues with trypanocidal activity. The compound ITP-1G is an interesting starting point for new trypanocidal drug design which is also an inhibitor of transport of amino acids and polyamines mediated by permeases from the TcAAAP family, such as proline transporter TcAAAP069 among others. The Trypanosoma cruzi amino acid transporter family TcAAAP constitutes a multiple and promising therapeutic target for the development of new treatments against Chagas disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Synthesis of Analogues of Thyroid Hormones: Nuclear Receptor Modulators

    Directory of Open Access Journals (Sweden)

    Guilherme Vieira de Castro

    2015-09-01

    Full Text Available Thyroid hormones are essential for the development and differentiation of all cells of the human body. This work reports the synthesis of some synthetic structural analogues of thyroid hormones, which may be modulators of the thyroid hormone receptor. The known compounds GC-1 (Sobetirome and CG-24 were successfully prepared and two novel analogous molecules were also synthesized by a new and efficient synthetic methodology. DOI: http://dx.doi.org/10.17807/orbital.v7i3.739  

  10. Assessment of structurally diverse philanthotoxin analogues for inhibitory activity on ionotropic glutamate receptor subtypes

    DEFF Research Database (Denmark)

    Frølund, Sidsel; Bella, Angelo; Kristensen, Anders Skov

    2010-01-01

    -electrode voltage-clamp electrophysiology employing Xenopus laevis oocytes expressing GluA1(i) AMPA or GluN1/2A NMDA receptors. Several of the analogues showed significantly increased inhibition of the GluN1/2A NMDA receptor. Thus, an analogue containing N-(1-naphtyl)acetyl group showed an IC(50) value of 47 n...

  11. The novel synthetic ether lipid inositol-C2-PAF inhibits phosphorylation of the tyrosine kinases Src and FAK independent of integrin activation in transformed skin cells.

    Science.gov (United States)

    Semini, Geo; Hildmann, Annette; Reissig, Hans-Ulrich; Reutter, Werner; Danker, Kerstin

    2011-04-15

    New alkyl-phospholipids that are structurally derived from platelet-activating factor are promising candidates for anticancer treatment. The mechanism of action of derivatives of the platelet-activating factor is distinctly different from that of known DNA- or tubulin-targeting anticancer agents because they are incorporated into cell membranes, where they accumulate and interfere with a wide variety of key enzymes. We recently presented evidence of a novel group of alkyl-phospholipids, glycosidated phospholipids that efficiently inhibit cell proliferation. One member of this group, inositol-C2-PAF (Ino-C2-PAF), displays high efficacy and low cytotoxicity in HaCaT-cells, an immortalized non-tumorigenic skin keratinocyte cell line. Here, we show that Ino-C2-PAF also inhibits the motility of the skin-derived transformed cell lines HaCaT and squamous cell carcinoma (SCC)-25. This decrease in motility is accompanied by an altered F-actin cytoskeleton, increased clustering of integrins, and increased cell-matrix adhesion. Despite enhanced integrin clustering and matrix adhesion, we observed less phosphorylation of the cytoplasmic tyrosine kinases focal adhesion kinase (FAK) and Src, key regulators of cellular motility, at focal adhesion sites. Transient transfection of constitutively active variants of FAK and Src could at least in part bybass this inhibitory effect of Ino-C2-PAF. This fact indicates that Ino-C2-PAF interferes with the fine-tuned balance between adhesion and migration. Ino-C2-PAF at least partially uncouples integrin-mediated attachment from subsequent integrin-dependent signaling steps, which inhibits migration in transformed keratinocyte cell lines. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Inhibition of lipid oxidation in foods and feeds and hydroxyl radical-treated fish erythrocytes: A comparative study of Ginkgo biloba leaves extracts and synthetic antioxidants

    Directory of Open Access Journals (Sweden)

    Huatao Li

    2016-09-01

    Full Text Available This study explored the effects of butylated hydroxytoluene (BHT and ethoxyquin (EQ and ethyl ether extracts, ethyl acetate extracts (EAE, acetone extracts, ethanol extracts and aqueous extracts of Ginkgo biloba leaves (EGbs on lipid oxidation in a linoleic acid emulsion, fish flesh and fish feed and in hydroxyl radical (·OH-treated carp erythrocytes. The linoleic acid, fish flesh and fish feed were incubated with BHT, EQ and EGbs at 45°C for 8 d, respectively, except for the control group. The lipid oxidation in the linoleic acid emulsion, fish flesh and fish feed was then measured by the ferric thiocyanate method or thiobarbituric acid method. The carp erythrocytes were treated with BHT, EQ or EGbs in the presence of 40 μmol/L FeSO4 and 20 μmol/L H2O2 at 37°C for 6 h, except for the control group. Oxidative stress and apoptosis parameters in carp erythrocytes were then evaluated by the commercial kit. The results showed that BHT, EQ and EGbs inhibited lipid oxidation in the linoleic acid emulsion, fish flesh and fish feed and ·OH-induced phosphatidylserine exposure and DNA fragmentation (the biomarkers of apoptosis in carp erythrocytes. Furthermore, BHT, EQ and EGbs decreased the generation of reactive oxygen species (ROS, inhibited the oxidation of cellular components and restored the activities of enzymatic antioxidants in ·OH-treated carp erythrocytes. Of all examined EGbs, EAE showed the strongest effects. The effects of EAE on lipid oxidation in the linoleic acid emulsion and on superoxide anion and malonaldehyde levels, catalase activity and apoptosis in ·OH-treated carp erythrocytes were equivalent to or stronger than those of BHT. Moreover, these results indicated that the inhibition order of EGbs on the generation of ROS and oxidation of cellular components in fish erythrocytes approximately agreed with that for the food and feed materials tested above. And, the antioxidative and anti-apoptotic effects of EGbs were

  13. New alloferon analogues: synthesis and antiviral properties.

    Science.gov (United States)

    Kuczer, Mariola; Majewska, Anna; Zahorska, Renata

    2013-02-01

    We have extended our study on structure/activity relationship studies of insect peptide alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH) by evaluating the antiviral effects of new alloferon analogues. We synthesized 18 alloferon analogues: 12 peptides with sequences shortened from N- or C-terminus and 6 N-terminally modified analogues H-X(1)-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH, where X(1) = Phe (13), Tyr (14), Trp (15), Phg (16), Phe(p-Cl) (17), and Phe(p-OMe) (18). We found that most of the evaluated peptides inhibit the replication of Human Herpesviruses or Coxsackievirus B2 in Vero, HEp-2 and LLC-MK(2) cells. Our results indicate that the compound [3-13]-alloferon (1) exhibits the strongest antiviral activity (IC(50) = 38 μM) among the analyzed compound. Moreover, no cytotoxic activity against the investigated cell lines was observed for all studied peptides at concentration 165 μM or higher. © 2012 John Wiley & Sons A/S.

  14. Dienogest, a synthetic progestin, inhibits the proliferation of immortalized human endometrial epithelial cells with suppression of cyclin D1 gene expression.

    Science.gov (United States)

    Shimizu, Yutaka; Takeuchi, Takashi; Mita, Shizuka; Mizuguchi, Kiyoshi; Kiyono, Tohru; Inoue, Masaki; Kyo, Satoru

    2009-10-01

    Dienogest is a specific progesterone receptor agonist with potent oral endometrial activity and is used in the treatment of endometriosis. In this study, we examined the direct effects of dienogest on the proliferation of human endometrial epithelial cells using an immortalized cell line. 5-Bromo-2'-deoxyuridine incorporation into the cells was inhibited by dienogest and by progesterone (P(4)) in dose-dependent fashion at concentrations of 10(-8) mol/l or higher. To identify the target genes of dienogest and P(4), we screened the expression of 84 genes related to cell cycle regulation by real-time polymerase chain reaction after 6 h of treatment at a concentration of 10(-7) mol/l. Results showed that only cyclin D1 expression was significantly down-regulated, although expression of the other genes did not significantly change after dienogest or P(4) treatment compared with the control. In a time-course study during the first 24 h after drug treatment, dienogest and P(4) each produced a lasting decrease in the expression of cyclin D1 mRNA, followed by a decrease in cyclin E1 mRNA but not an increase in the expression of cell cycle inhibitor genes (p21, p27 and p53). These findings suggest that dienogest directly inhibits the proliferation of human endometrial epithelial cells with suppression of cyclin D1 gene expression.

  15. In-Vitro Inhibition of Pythium ultimum, Fusarium graminearum, and Rhizoctonia solani by a Stabilized Lactoperoxidase System alone and in Combination with Synthetic Fungicides

    Directory of Open Access Journals (Sweden)

    Zachariah R. Hansen

    2017-11-01

    Full Text Available Advances in enzyme stabilization and immobilization make the use of enzymes for industrial applications increasingly feasible. The lactoperoxidase (LPO system is a naturally occurring enzyme system with known antimicrobial activity. Stabilized LPO and glucose oxidase (GOx enzymes were combined with glucose, potassium iodide, and ammonium thiocyanate to create an anti-fungal formulation, which inhibited in-vitro growth of the plant pathogenic oomycete Pythium ultimum, and the plant pathogenic fungi Fusarium graminearum and Rhizoctonia solani. Pythium ultimum was more sensitive than F. graminearum and R. solani, and was killed at LPO and GOx concentrations of 20 nM and 26 nM, respectively. Rhizoctonia solani and F. graminearum were 70% to 80% inhibited by LPO and GOx concentrations of 242 nM and 315 nM, respectively. The enzyme system was tested for compatibility with five commercial fungicides as co-treatments. The majority of enzyme + fungicide co-treatments resulted in additive activity. Synergism ranging from 7% to 36% above the expected additive activity was observed when P. ultimum was exposed to the enzyme system combined with Daconil® (active ingredient (AI: chlorothalonil 29.6%, GardenTech, Lexington, KY, USA, tea tree oil, and mancozeb at select fungicide concentrations. Antagonism was observed when the enzyme system was combined with Tilt® (AI: propiconazole 41.8%, Syngenta, Basel, Switzerland at one fungicide concentration, resulting in activity 24% below the expected additive activity at that concentration.

  16. Alligator Rivers analogue project

    International Nuclear Information System (INIS)

    Duerden, P.

    1990-01-01

    Australian Nuclear Science and Technology Organization has extensively evaluated uranium ore bodies in the Alligator Rivers Uranium Province in Australia as analogues of radioactive waste repositories. The work was extended for a three-year program as an international project based on the Koongarra uranium deposit and sponsored by the OECD Nuclear Energy Agency. The technical program comprises six major sub-projects involving modelling and experimental work: modelling of radionuclide migration; hydrogeology of the Koongarra uranium deposit; uranium/thorium series disequilibria studies; groundwater and colloid studies; fission product studies; transuranic nuclide studies; an outline of the technical programs and a summary of progress in the technical sub-projects is given. This is followed by a series of technical reports which briefly describe current research tasks, and which have been separately indexed

  17. A Short Term Analogue Memory

    DEFF Research Database (Denmark)

    Shah, Peter Jivan

    1992-01-01

    A short term analogue memory is described. It is based on a well-known sample-hold topology in which leakage currents have been minimized partly by circuit design and partly by layout techniques. Measurements on a test chip implemented in a standard 2.4 micron analogue CMOS process show a droop...

  18. Proteomic characterization of an isolated fraction of synthetic proteasome inhibitor (PSI-induced inclusions in PC12 cells might offer clues to aggresomes as a cellular defensive response against proteasome inhibition by PSI

    Directory of Open Access Journals (Sweden)

    Li Xing'an

    2010-08-01

    Full Text Available Abstract Background Cooperation of constituents of the ubiquitin proteasome system (UPS with chaperone proteins in degrading proteins mediate a wide range of cellular processes, such as synaptic function and neurotransmission, gene transcription, protein trafficking, mitochondrial function and metabolism, antioxidant defence mechanisms, and apoptotic signal transduction. It is supposed that constituents of the UPS and chaperone proteins are recruited into aggresomes where aberrant and potentially cytotoxic proteins may be sequestered in an inactive form. Results To determinate the proteomic pattern of synthetic proteasome inhibitor (PSI-induced inclusions in PC12 cells after proteasome inhibition by PSI, we analyzed a fraction of PSI-induced inclusions. A proteomic feature of the isolated fraction was characterized by identification of fifty six proteins including twenty previously reported protein components of Lewy bodies, twenty eight newly identified proteins and eight unknown proteins. These proteins, most of which were recognized as a profile of proteins within cellular processes mediated by the UPS, a profile of constituents of the UPS and a profile of chaperone proteins, are classed into at least nine accepted categories. In addition, prolyl-4-hydroxylase beta polypeptide, an endoplasmic reticulum member of the protein disulfide isomerase family, was validated in the developmental process of PSI-induced inclusions in the cells. Conclusions It is speculated that proteomic characterization of an isolated fraction of PSI-induced inclusions in PC12 cells might offer clues to appearance of aggresomes serving as a cellular defensive response against proteasome inhibition.

  19. Inhibition of corneal neovascularization with the combination of bevacizumab and plasmid pigment epithelium-derived factor-synthetic amphiphile INTeraction-18 (p-PEDF-SAINT-18) vector in a rat corneal experimental angiogenesis model.

    Science.gov (United States)

    Kuo, Chien-Neng; Chen, Chung-Yi; Chen, San-Ni; Yang, Lin-Cheng; Lai, Li-Ju; Lai, Chien-Hsiung; Chen, Miao-Fen; Hung, Chia-Hui; Chen, Ching-Hsein

    2013-04-16

    Bevacizumab, a 149-kDa protein, is a recombinant humanized monoclonal antibody to VEGF. PEDF, a 50-kDa glycoprotein, has demonstrated anti-vasopermeability properties. In this study, we demonstrated that the combination of bevacizumab and plasmid pigment epithelium-derived factor-synthetic amphiphile INTeraction-18(p-PEDF-SAINT-18) has a favorable antiangiogenic effect on corneal NV. Four groups(Group A: 0 μg + 0 μg, B: 0.1 μg + 0.1 μg, C: 1 μg + 1 μg, and D: 10 μg + 10 μg) of bevacizumab + p-PEDF-SAINT-18 were prepared and implanted into the rat subconjunctival substantia propria 1.5 mm from the limbus on the temporal side. Then, 1 μgof p-bFGF-SAINT-18 was prepared and implanted into the rat corneal stroma 1.5 mm from the limbus on the same side. The inhibition of NV was observed and quantified from days 1 to 60. Biomicroscopic examination, western blot analysis and immunohistochemistry were used to analyze the 18-kDa bFGF, 50-kDa PEDF and VEGF protein expression. No inhibition activity for normal limbal vessels was noted. Subconjunctival injection with the combination of bevacizumab and p-PEDF-SAINT-18 successfully inhibited corneal NV.The bFGF and PEDF genes were successfully expressed as shown by western blot analysis,and a mild immune response to HLA-DR was shown by immunohistochemistry. We concluded that the combination of bevacizumab and p-PEDF-SAINT-18 may have more potent and prolonged antiangiogenic effects, making it possible to reduce the frequency of subconjunctival bevacizumab administration combined with a relatively safe profile and low toxicity.

  20. Inhibition of corneal neovascularization with plasmid pigment epithelium-derived factor (p-PEDF) delivered by synthetic amphiphile INTeraction-18 (SAINT-18) vector in an experimental model of rat corneal angiogenesis.

    Science.gov (United States)

    Kuo, Chien-Neng; Yang, Lin-Cheng; Yang, Cheng-Ta; Lai, Chien-Hsiung; Chen, Miao-Fen; Chen, Chung-Yi; Chen, Chi-Hung; Wu, Pei-Chang; Kou, Hsi-Kung; Chen, Yung-Jen; Hung, Chia-Hui; Tsai, Chong-Bin

    2009-11-01

    The use of Synthetic Amphiphile INTeraction-18 (SAINT-18) carrying plasmid pigment epithelium-derived factor (p-PEDF) as an anti-angiogenesis strategy to treat corneal neovascularization in a rat model was evaluated. Four partially dried forms (Group A: 0 microg, B: 0.1 microg, C: 1 microg, D: 10 microg) of a p-PEDF-SAINT-18 were prepared and implanted into the rat subconjunctival substantia propria 1.5 mm from the limbus at the temporal side. The 1 microg of plasmid-basic fibroblast growth factor--SAINT-18 (p-bFGF-SAINT-18) (1 microg) was prepared and implanted into the rat corneal stroma 1.5 mm from the limbus on the same side. Inhibition of neovascularization was observed and quantified from day 1 to day 60. PEDF (50-kDa) and bFGF (18-kDa) protein expression were analyzed by biomicroscopic examination, Western blot analysis, and immunohistochemistry. Gene expression in corneal and conjunctival tissue was observed as early as 3 days after gene transfer and stably lasted for over 3 months with minimal immune reaction. Subconjunctival injection of a highly efficient p-PEDF-SAINT-18 successfully inhibited corneal neovascularization. Successful gene expression of bFGF, PEDF and a mild immune response of HLA-DR were shown by immunohistochemistry staining. We concluded that SAINT-18 was capable of directly delivering genes to the ocular surface by way of subconjunctival injection, and delivered sustained, high levels of gene expression in vivo to inhibit angiogenesis.

  1. Synthetic peptides derived from the C-terminal 6kDa region of Plasmodium falciparum SERA5 inhibit the enzyme activity and malaria parasite development.

    Science.gov (United States)

    Kanodia, Shivani; Kumar, Gautam; Rizzi, Luca; Pedretti, Alessandro; Hodder, Anthony N; Romeo, Sergio; Malhotra, Pawan

    2014-09-01

    Plasmodium falciparum serine repeat antigen 5 (PfSERA5) is an abundant blood stage protein that plays an essential role in merozoite egress and invasion. The native protein undergoes extensive proteolytic cleavage that appears to be tightly regulated. PfSERA5 N-terminal fragment is being developed as vaccine candidate antigen. Although PfSERA5 belongs to papain-like cysteine protease family, its catalytic domain has a serine in place of cysteine at the active site. In the present study, we synthesized a number of peptides from the N- and C-terminal regions of PfSERA5 active domain and evaluated their inhibitory potential. The final proteolytic step of PfSERA5 involves removal of a C-terminal ~6kDa fragment that results in the generation of a catalytically active ~50kDa enzyme. In the present study, we demonstrate that two of the peptides derived from the C-terminal ~6kDa region inhibit the parasite growth and also cause a delay in the parasite development. These peptides reduced the enzyme activity of the recombinant protein and co-localized with the PfSERA5 protein within the parasite, thereby indicating the specific inhibition of PfSERA5 activity. Molecular docking studies revealed that the inhibitory peptides interact with the active site of the protein. Interestingly, the peptides did not have an effect on the processing of PfSERA5. Our observations indicate the temporal regulation of the final proteolytic cleavage step that occurs just prior to egress. These results reinforce the role of PfSERA5 for the intra-erythrocytic development of malaria parasite and show the role of carboxy terminal ~6kDa fragments in the regulation of PfSERA5 activity. The results also suggest that final cleavage step of PfSERA5 can be targeted for the development of new anti-malarials. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Andrographolide and analogues in cancer prevention.

    Science.gov (United States)

    Mishra, Siddhartha Kumar; Tripathi, Swati; Shukla, Archana; Oh, Seung Hyun; Kim, Hwan Mook

    2015-01-01

    Andrographis paniculata is a medicinal plant traditionally used for treatment of cough and cold, fever, laryngitis, and several infectious diseases. Extracts of A. paniculata have shown versatile potency against various diseases including cancer. The active biomolecules of A. paniculata mainly are lactone and diterpene. Andrographolide and analogues have been widely used for prevention of different diseases. Andrographolides have shown potent antiinflammatory and anticancer activities. It showed potentials as chemopreventive agents by suppressing growth of cancer cells by inhibiting NF-kappaB, PI3K/AKT and other kinase pathways and by inducing apoptosis. Andrographolide induced both intrinsic and extrinsic apoptosis pathway in different cancer cells via expression of different anti-apoptotic protein like Bax, p53, and activated caspases. Andrographolide was successfully used as an antineoplastic drug in cancer chemotherapy. Andrographolide inhibited the growth of human breast, prostate, and hepatoma tumors. Andrographolide and analogues need to be subjected to further clinical and biomedical studies in cancer chemoprevention. Andrographolide could be potent anticancer agent when used in combination with other chemotherapeutic agents.

  3. Methods for preparing synthetic freshwaters.

    Science.gov (United States)

    Smith, E J; Davison, W; Hamilton-Taylor, J

    2002-03-01

    Synthetic solutions that emulate the major ion compositions of natural waters are useful in experiments aimed at understanding biogeochemical processes. Standard recipes exist for preparing synthetic analogues of seawater, with its relatively constant composition, but, due to the diversity of freshwaters, a range of compositions and recipes is required. Generic protocols are developed for preparing synthetic freshwaters of any desired composition. The major problems encountered in preparing hard and soft waters include dissolving sparingly soluble calcium carbonate, ensuring that the ionic components of each concentrated stock solution cannot form an insoluble salt and dealing with the supersaturation of calcium carbonate in many hard waters. For acidic waters the poor solubility of aluminium salts requires attention. These problems are overcome by preparing concentrated stock solutions according to carefully designed reaction paths that were tested using a combination of experiment and equilibrium modeling. These stock solutions must then be added in a prescribed order to prepare a final solution that is brought into equilibrium with the atmosphere. The example calculations for preparing hard, soft and acidic freshwater surrogates with major ion compositions the same as published analyses, are presented in a generalized fashion that should allow preparation of any synthetic freshwater according to its known analysis.

  4. Inhibition of Corneal Neovascularization with the Combination of Bevacizumab and Plasmid Pigment Epithelium-Derived Factor-Synthetic Amphiphile INTeraction-18 (p-PEDF-SAINT-18 Vector in a Rat Corneal Experimental Angiogenesis Model

    Directory of Open Access Journals (Sweden)

    Ching-Hsein Chen

    2013-04-01

    Full Text Available Bevacizumab, a 149-kDa protein, is a recombinant humanized monoclonal antibody to VEGF. PEDF, a 50-kDa glycoprotein, has demonstrated anti-vasopermeability properties. In this study, we demonstrated that the combination of bevacizumab and plasmid pigment epithelium-derived factor-synthetic amphiphile INTeraction-18 (p-PEDF-SAINT-18 has a favorable antiangiogenic effect on corneal NV. Four groups (Group A: 0 μg + 0 μg, B: 0.1 μg + 0.1 μg, C: 1 μg + 1 μg, and D: 10 μg + 10 μg of bevacizumab + p-PEDF-SAINT-18 were prepared and implanted into the rat subconjunctival substantia propria 1.5 mm from the limbus on the temporal side. Then, 1 μg of p-bFGF-SAINT-18 was prepared and implanted into the rat corneal stroma 1.5 mm from the limbus on the same side. The inhibition of NV was observed and quantified from days 1 to 60. Biomicroscopic examination, western blot analysis and immunohistochemistry were used to analyze the 18-kDa bFGF, 50-kDa PEDF and VEGF protein expression. No inhibition activity for normal limbal vessels was noted. Subconjunctival injection with the combination of bevacizumab and p-PEDF-SAINT-18 successfully inhibited corneal NV. The bFGF and PEDF genes were successfully expressed as shown by western blot analysis, and a mild immune response to HLA-DR was shown by immunohistochemistry. We concluded that the combination of bevacizumab and p-PEDF-SAINT-18 may have more potent and prolonged antiangiogenic effects, making it possible to reduce the frequency of subconjunctival.Bevacizumab, a 149-kDa protein, is a recombinant humanized monoclonalantibody to VEGF. PEDF, a 50-kDa glycoprotein, has demonstrated anti-vasopermeabilityproperties. In this study, we demonstrated that the combination of bevacizumaband plasmid pigment epithelium-derived factor-synthetic amphiphile INTeraction-18(p-PEDF-SAINT-18 has a favorable antiangiogenic effect on corneal NV. Four groups(Group A: 0 μg + 0 μg, B: 0.1 μg + 0.1 μg, C: 1 μg + 1 μg, and

  5. Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

    DEFF Research Database (Denmark)

    Rabe, Patrick; Klapschinski, Tim A.; Brock, Nelson L.

    2014-01-01

    aureus and Vibrio anguillarum for a structure-activity relationship (SAR) study, revealing that the sulfur-free analogue of TDA, tropone-2-carboxylic acid, has an antibiotic activity that is even stronger than the bioactivity of the natural product. The synthesis of this compound and of several analogues......Tropodithietic acid (TDA) is a structurally unique sulfur-containing antibiotic from the Roseobacter clade bacterium Phaeobacter inhibens DSM 17395 and a few other related species. We have synthesised several structural analogues of TDA and used them in bioactivity tests against Staphylococcus...... is presented and the bioactivity of the synthetic compounds is discussed....

  6. Comparison of two synthetic methods to obtain [18F] N-(2-aminoethyl)-5-fluoropyridine-2-carboxamide, a potential MAO-B imaging tracer for PET

    International Nuclear Information System (INIS)

    Beer, H.-F.; Haeberli, M.; Ametamey, S.; Schubiger, P.A.

    1995-01-01

    The compound Ro 19-6327, N-(2-aminoethyl)-5-chloropyridine-2-carboxamide, is known to inhibit reversibly and site specifically the enzyme monoamine oxidase B (MAO-B). The 123 I-labelled iodo-analogue N-(2-aminoethyl)-5-iodopyridine-2-carboxamide (Ro 43-0463) was investigated successfully in human volunteers by means of SPET (Single Photon Emission Tomography). We developed therefore the synthesis and radiolabelling of the corresponding fluoro-analogue N-(2-aminoethyl)-5-fluoropyridine-2-carboxamide with 18 F in order to carry out PET (Positron Emission Tomography) investigations of MAO-B related neuropsychiatric diseases. For this purpose two synthetic approaches leading to the electrophilic and the nucleophilic methods of 18 F radiolabelling were undertaken. The nucleophilic approach appeared to be superior when factors such as precursor synthesis, beam time, specific activity and radiochemical purity of the product are considered. (author)

  7. Rheological and physical characteristics of crustal-scaled materials for centrifuge analogue modelling

    Science.gov (United States)

    Waffle, Lindsay; Godin, Laurent; Harris, Lyal B.; Kontopoulou, M.

    2016-05-01

    We characterize a set of analogue materials used for centrifuge analogue modelling simulating deformation at different levels in the crust simultaneously. Specifically, we improve the rheological characterization in the linear viscoelastic region of materials for the lower and middle crust, and cohesive synthetic sands without petroleum-binding agents for the upper crust. Viscoelastic materials used in centrifuge analogue modelling demonstrate complex dynamic behaviour, so viscosity alone is insufficient to determine if a material will be an effective analogue. Two series of experiments were conducted using an oscillating bi-conical plate rheometer to measure the storage and loss moduli and complex viscosities of several modelling clays and silicone putties. Tested materials exhibited viscoelastic and shear-thinning behaviour. The silicone putties and some modelling clays demonstrated viscous-dominant behaviour and reached Newtonian plateaus at strain rates centrifuge test models. These synthetic sands are recommended as analogues for the brittle upper crust. These new results increase the accuracy of scaling analogue models to prototype. Additionally, with the characterization of three new materials, we propose a complete lithospheric profile of analogue materials for centrifuge modelling, allowing future studies to replicate a broader range of crustal deformation behaviours.

  8. Cobalamin analogues in humans

    DEFF Research Database (Denmark)

    Hardlei, Tore Forsingdal; Obeid, Rima; Herrmann, Wolfgang

    2013-01-01

    BACKGROUND: Haptocorrin (HC) carries cobalamin analogues (CorA), but whether CorA are produced in the body is unknown. All cobalamins (Cbl) to the foetus are delivered by the Cbl-specific protein transcobalamin (TC), and therefore analysis of cord serum for CorA may help to clarify the origin...... of CorA. METHODS: HC-CorA were quantified in paired samples of cord serum from newborns and serum from mothers (n = 69). RESULTS: The CorA-concentration was higher in cord serum (median = 380, range: 41-780 pmol/L) than in serum from the mothers (median = 160, range: 64-330 pmol/L), (p...-analysis showed CorA-peaks with retention times of 13.5, 14,5 and 16.5 min in samples from both the mother and cord serum. The peak with retention time 16.5 min constituted 24% (mother) and 45% (cord serum) of the total amount CorA, and eluted as does dicyanocobinamide. CONCLUSION: Our results support that Cor...

  9. Targeted expression of redesigned and codon optimised synthetic gene leads to recrystallisation inhibition and reduced electrolyte leakage in spring wheat at sub-zero temperatures.

    Science.gov (United States)

    Khanna, Harjeet K; Daggard, Grant E

    2006-12-01

    Antifreeze proteins (AFPs) adsorb to ice crystals and inhibit their growth, leading to non-colligative freezing point depression. Crops like spring wheat, that are highly susceptible to frost damage, can potentially be made frost tolerant by expressing AFPs in the cytoplasm and apoplast where ice recrystallisation leads to cellular damage. The protein sequence for HPLC-6 alpha-helical antifreeze protein from winter flounder was rationally redesigned after removing the prosequences in the native protein. Wheat nuclear gene preferred amino acid codons were used to synthesize a recombinant antifreeze gene, rAFPI. Antifreeze protein was targeted to the apoplast using a Murine leader peptide sequence from the mAb24 light chain or retained in the endoplasmic reticulum using C-terminus KDEL sequence. The coding sequences were placed downstream of the rice Actin promoter and Actin-1 intron and upstream of the nopaline synthase terminator in the plant expression vectors. Transgenic wheat lines were generated through micro projectile bombardment of immature embryos of spring wheat cultivar Seri 82. Levels of antifreeze protein in the transgenic lines without any targeting peptide were low (0.06-0.07%). The apoplast-targeted protein reached a level of 1.61% of total soluble protein, 90% of which was present in the apoplast. ER-retained protein accumulated in the cells at levels up to 0.65% of total soluble proteins. Transgenic wheat line T-8 with apoplast-targeted antifreeze protein exhibited the highest levels of antifreeze activity and provided significant freezing protection even at temperatures as low as -7 degrees C.

  10. A novel synthetic Asiatic acid derivative induces apoptosis and inhibits proliferation and mobility of gastric cancer cells by suppressing STAT3 signaling pathway

    Directory of Open Access Journals (Sweden)

    Wang G

    2016-12-01

    Full Text Available Gang Wang,1 Yue Jing,2 Lingsen Cao,3 Changchang Gong,1 Zhunan Gong,1,3 Xiangrong Cao3 1Center for New Drug Research and Development, College of Life Science, Nanjing Normal University, 2Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 3Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, People’s Republic of China Abstract: Activation of the transcription factor, signal transducers and activators of transcription 3 (STAT3, has been linked to the proliferation and migration of a variety of human cancer cells. These actions occur via the upregulation or downregulation of cell survival and tumor suppressor genes, respectively. Importantly, agents that can suppress STAT3 activation have the potential for use in the prevention and treatment of various cancers. In this study, an Asiatic acid (AA derivative, N-(2α,3β,23-acetoxyurs-12-en-28-oyl-L-proline methyl ester (AA-PMe, is reported to dose dependently suppress constitutive STAT3 activation in gastric cancer cells. This inhibition was mediated by blockade of Janus-activated kinase 2. Additionally, AA-PMe regulated the expression of STAT3-modulated gene products, including cyclin D1, Bax, Bcl-2, c-Myc, and matrix metalloproteinase (MMP-2 and MMP-9. Finally, transfection with both a STAT3 mimic and an inhibitor reversed the AA-PMe-driven modulation of STAT3 downstream gene products. Overall, these results suggest that AA-PMe is a novel blocker of STAT3 activation and has the potential for the prevention and treatment of gastric cancer. Keywords: gastric cancer, signal transducer and activator of transcription 3, Asiatic acid derivative, cell cycle, apoptosis, invasion

  11. Synthetic Cannabinoids.

    Science.gov (United States)

    Mills, Brooke; Yepes, Andres; Nugent, Kenneth

    2015-07-01

    Synthetic cannabinoids (SCBs), also known under the brand names of "Spice," "K2," "herbal incense," "Cloud 9," "Mojo" and many others, are becoming a large public health concern due not only to their increasing use but also to their unpredictable toxicity and abuse potential. There are many types of SCBs, each having a unique binding affinity for cannabinoid receptors. Although both Δ-tetrahydrocannabinol (THC) and SCBs stimulate the same receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), studies have shown that SCBs are associated with higher rates of toxicity and hospital admissions than is natural cannabis. This is likely due to SCBs being direct agonists of the cannabinoid receptors, whereas THC is a partial agonist. Furthermore, the different chemical structures of SCBs found in Spice or K2 may interact in unpredictable ways to elicit previously unknown, and the commercial products may have unknown contaminants. The largest group of users is men in their 20s who participate in polydrug use. The most common reported toxicities with SCB use based on studies using Texas Poison Control records are tachycardia, agitation and irritability, drowsiness, hallucinations, delusions, hypertension, nausea, confusion, dizziness, vertigo and chest pain. Acute kidney injury has also been strongly associated with SCB use. Treatment mostly involves symptom management and supportive care. More research is needed to identify which contaminants are typically found in synthetic marijuana and to understand the interactions between different SBCs to better predict adverse health outcomes.

  12. Chemoenzymatic preparation of germacrene analogues.

    Science.gov (United States)

    Cascón, Oscar; Touchet, Sabrina; Miller, David J; Gonzalez, Veronica; Faraldos, Juan A; Allemann, Rudolf K

    2012-10-09

    A small library of novel germacrenes was generated using a combination of two plant enzymes, germacrene A synthase, and D synthase and modified farnesyl diphosphate (FDP) analogues. This chemoenzymatic approach allows the preparation of potentially valuable volatiles for biological studies.

  13. Chemoenzymatic preparation of germacrene analogues

    OpenAIRE

    Cascón, Oscar; Touchet, Sabrina; Miller, David James; Gonzalez, Veronica; Faraldos, Juan A.; Allemann, Rudolf Konrad

    2012-01-01

    A small library of novel germacrenes was generated using a combination of two plant enzymes, germacrene A synthase, and D synthase and modified farnesyl diphosphate (FDP) analogues. This chemoenzymatic approach allows the preparation of potentially valuable volatiles for biological studies.

  14. Synthetic Botany.

    Science.gov (United States)

    Boehm, Christian R; Pollak, Bernardo; Purswani, Nuri; Patron, Nicola; Haseloff, Jim

    2017-07-05

    Plants are attractive platforms for synthetic biology and metabolic engineering. Plants' modular and plastic body plans, capacity for photosynthesis, extensive secondary metabolism, and agronomic systems for large-scale production make them ideal targets for genetic reprogramming. However, efforts in this area have been constrained by slow growth, long life cycles, the requirement for specialized facilities, a paucity of efficient tools for genetic manipulation, and the complexity of multicellularity. There is a need for better experimental and theoretical frameworks to understand the way genetic networks, cellular populations, and tissue-wide physical processes interact at different scales. We highlight new approaches to the DNA-based manipulation of plants and the use of advanced quantitative imaging techniques in simple plant models such as Marchantia polymorpha. These offer the prospects of improved understanding of plant dynamics and new approaches to rational engineering of plant traits. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  15. Synthetic Brainbows

    KAUST Repository

    Wan, Y.

    2013-06-01

    Brainbow is a genetic engineering technique that randomly colorizes cells. Biological samples processed with this technique and imaged with confocal microscopy have distinctive colors for individual cells. Complex cellular structures can then be easily visualized. However, the complexity of the Brainbow technique limits its applications. In practice, most confocal microscopy scans use different florescence staining with typically at most three distinct cellular structures. These structures are often packed and obscure each other in rendered images making analysis difficult. In this paper, we leverage a process known as GPU framebuffer feedback loops to synthesize Brainbow-like images. In addition, we incorporate ID shuffing and Monte-Carlo sampling into our technique, so that it can be applied to single-channel confocal microscopy data. The synthesized Brainbow images are presented to domain experts with positive feedback. A user survey demonstrates that our synthetic Brainbow technique improves visualizations of volume data with complex structures for biologists.

  16. Analogues of neuroactive polyamine wasp toxins that lack inner basic sites exhibit enhanced antagonism toward a muscle-type mammalian nicotinic acetylcholine receptor

    DEFF Research Database (Denmark)

    Stromgaard, K; Brierley, M J; Andersen, K

    1999-01-01

    Philanthotoxin-433 (PhTX-433), a natural polyamine wasp toxin, is a noncompetitive antagonist of certain ionotropic receptors. Six analogues of PhTX-343 (a synthetic analogue of the natural product), in which the secondary amino groups are systematically replaced by oxygen or methylene groups, ha...

  17. Charge isomers of myelin basic protein: structure and interactions with membranes, nucleotide analogues, and calmodulin.

    Directory of Open Access Journals (Sweden)

    Chaozhan Wang

    Full Text Available As an essential structural protein required for tight compaction of the central nervous system myelin sheath, myelin basic protein (MBP is one of the candidate autoantigens of the human inflammatory demyelinating disease multiple sclerosis, which is characterized by the active degradation of the myelin sheath. In this work, recombinant murine analogues of the natural C1 and C8 charge components (rmC1 and rmC8, two isoforms of the classic 18.5-kDa MBP, were used as model proteins to get insights into the structure and function of the charge isomers. Various biochemical and biophysical methods such as size exclusion chromatography, calorimetry, surface plasmon resonance, small angle X-ray and neutron scattering, Raman and fluorescence spectroscopy, and conventional as well as synchrotron radiation circular dichroism were used to investigate differences between these two isoforms, both from the structural point of view, and regarding interactions with ligands, including calmodulin (CaM, various detergents, nucleotide analogues, and lipids. Overall, our results provide further proof that rmC8 is deficient both in structure and especially in function, when compared to rmC1. While the CaM binding properties of the two forms are very similar, their interactions with membrane mimics are different. CaM can be used to remove MBP from immobilized lipid monolayers made of synthetic lipids--a phenomenon, which may be of relevance for MBP function and its regulation. Furthermore, using fluorescently labelled nucleotides, we observed binding of ATP and GTP, but not AMP, by MBP; the binding of nucleoside triphosphates was inhibited by the presence of CaM. Together, our results provide important further data on the interactions between MBP and its ligands, and on the differences in the structure and function between MBP charge isomers.

  18. Synthesis and Neurotrophic Activity Studies of Illicium Sesquiterpene Natural Product Analogues.

    Science.gov (United States)

    Richers, Johannes; Pöthig, Alexander; Herdtweck, Eberhardt; Sippel, Claudia; Hausch, Felix; Tiefenbacher, Konrad

    2017-03-02

    Neurotrophic natural products hold potential as privileged structures for the development of therapeutic agents against neurodegeneration. However, only a few studies have been conducted to investigate a common pharmacophoric motif and structure-activity relationships (SARs). Here, an investigation of structurally more simple analogues of neurotrophic sesquiterpenes of the illicium family is presented. A concise synthetic route enables preparation of the carbon framework of (±)-Merrilactone A and (±)-Anislactone A/B on a gram scale. This has allowed access to a series of structural analogues by modification of the core structure, including variation of oxidation levels and alteration of functional groups. In total, 15 derivatives of the natural products have been synthesized and tested for their neurite outgrowth activities. Our studies indicate that the promising biological activity can be retained by structurally simpler natural product analogues, which are accessible by a straightforward synthetic route. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Synthesis and Biological Evaluation of New (−)‐Englerin Analogues

    Science.gov (United States)

    López‐Suárez, Laura; Riesgo, Lorena; Bravo, Fernando; Ransom, Tanya T.

    2016-01-01

    Abstract We report the synthesis and biological evaluation of a series of (−)‐englerin A analogues obtained along our previously reported synthetic route based on a stereoselective gold(I) cycloaddition process. This synthetic route is a convenient platform to access analogues with broad structural diversity and has led us to the discovery of unprecedented and easier‐to‐synthesize derivatives with an unsaturation in the cyclopentyl ring between C4 and C5. We also introduce novel analogues in which the original isopropyl motif has been substituted with cyclohexyl, phenyl, and cyclopropyl moieties. The high selectivity and growth‐inhibitory activity shown by these new derivatives in renal cancer cell lines opens new ways toward the final goal of finding effective drugs for the treatment of renal cell carcinoma (RCC). PMID:27005578

  20. Introduction to electronic analogue computers

    CERN Document Server

    Wass, C A A

    1965-01-01

    Introduction to Electronic Analogue Computers, Second Revised Edition is based on the ideas and experience of a group of workers at the Royal Aircraft Establishment, Farnborough, Hants. This edition is almost entirely the work of Mr. K. C. Garner, of the College of Aeronautics, Cranfield. As various advances have been made in the technology involving electronic analogue computers, this book presents discussions on the said progress, including some acquaintance with the capabilities of electronic circuits and equipment. This text also provides a mathematical background including simple differen

  1. Fusaric acid and analogues as Gram-negative bacterial quorum sensing inhibitors.

    Science.gov (United States)

    Tung, Truong Thanh; Jakobsen, Tim Holm; Dao, Trong Tuan; Fuglsang, Anja Thoe; Givskov, Michael; Christensen, Søren Brøgger; Nielsen, John

    2017-01-27

    Taking advantage of microwave-assisted synthesis, efficient and expedite procedures for preparation of a library of fusaric acid and 39 analogues are reported. The fusaric acid analogues were tested in cell-based screening assays for inhibition of the las and rhl quorum sensing system in Pseudomonas aeruginosa and the lux quorum sensing system in Vibrio fischeri. Eight of the 40 compounds in the library including fusaric acid inhibited lux quorum sensing and one compound inhibited activity of the las quorum sensing system. To our delight, none of the compounds showed growth inhibitory effects in the tested concentration ranges. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  2. Synthesis of analogues of Congo red and evaluation of their anti-prion activity.

    Science.gov (United States)

    Sellarajah, Shane; Lekishvili, Tamuna; Bowring, Claire; Thompsett, Andrew R; Rudyk, Helene; Birkett, Christopher R; Brown, David R; Gilbert, Ian H

    2004-10-21

    No cure as of yet exists for any of the transmissible spongiform encephalopathies. In this paper, we describe the synthesis of analogues of Congo red and evaluation against a cellular model of infection, the SMB (scrapie mouse brain) persistently infected cell line, for their ability to inhibit the infectivity of the abnormal form of prion protein (PrP-res). The compounds have also been tested for their ability to inhibit the polymerization of PrPC by PrP-res. A number of analogues showed inhibition of PrP-res infectivity at nanomolar concentrations. Several analogues show promise; the most active compound, 2a, inhibits the formation of PrP-res in SMB cells with an EC50 of 25-50 nM.

  3. Superconductive analogue of spin glasses

    International Nuclear Information System (INIS)

    Feigel'man, M.; Ioffe, L.; Vinokur, V.; Larkin, A.

    1987-07-01

    The properties of granular superconductors in magnetic fields, namely the existence of a new superconductive state analogue of the low-temperature superconductive state in spin glasses are discussed in the frame of the infinite-range model and the finite-range models. Experiments for elucidation of spin-glass superconductive state in real systems are suggested. 30 refs

  4. PTH analogues and osteoporotic fractures

    NARCIS (Netherlands)

    Verhaar, H.J.; Lems, W.F.

    2010-01-01

    Importance of the field: At present there are two parathyroid hormone (PTH) analogues (PTH 1 34 and PTH 1 84) registered for the treatment of established osteoporosis in postmenopausal women (PTH 1 34 and PTH 1 84) and in men (PTH 1 34 only) who are at increased risk of having a fracture. Areas

  5. Chemopreventive properties of curcumin analogues ...

    African Journals Online (AJOL)

    Chemopreventive properties of curcumin analogues, hexagamavunone-0 and gamavutone-0, in rat colorectal cancer model. ... Histopathological analysis was performed using H & E staining and immunohistochemistry with antibodies against adenomatous polyposis coli (APC) and cyclooxygenase 2 (COX-2). Results: All ...

  6. Indoleamine 2,3-dioxygenase inhibitors isolated from the sponge Xestospongia vansoesti: structure elucidation, analogue synthesis, and biological activity.

    Science.gov (United States)

    Centko, Ryan M; Steinø, Anne; Rosell, Federico I; Patrick, Brian O; de Voogd, Nicole; Mauk, A Grant; Andersen, Raymond J

    2014-12-19

    Two new IDO inhibitory meroterpenoids, xestolactone A (1) and xestosaprol O (2), have been isolated from the sponge Xestospongia vansoesti. Xestolactone A (1) has an unprecedented degraded meroterpenoid carbon skeleton. A short synthesis of the xestosaprol O (2) analogues 3 and 4 features the application of a rarely used photochemical coupling reaction. Synthetic analogue 3 is ∼40 times more potent than the inspirational natural product 2.

  7. Synthesis and antiangiogenic activity study of new hop chalcone Xanthohumol analogues.

    Science.gov (United States)

    Nuti, Elisa; Bassani, Barbara; Camodeca, Caterina; Rosalia, Lea; Cantelmo, AnnaRita; Gallo, Cristina; Baci, Denisa; Bruno, Antonino; Orlandini, Elisabetta; Nencetti, Susanna; Noonan, Douglas M; Albini, Adriana; Rossello, Armando

    2017-09-29

    Angiogenesis induction is a hallmark of cancer. Antiangiogenic properties of Xanthohumol (XN), a naturally occurring prenylated chalcone from hops, have been widely reported. Here we describe the synthesis and study the antiangiogenic activity in vitro of a series of XN derivatives, where different substituents on the B-ring of the chalcone scaffold were inserted. The new XN derivatives inhibited human umbilical-vein endothelial cell (HUVEC) proliferation, adhesion, migration, invasion and their ability to form capillary-like structures in vitro at 10 μM concentration. The preliminary results indicate that the phenolic OH group in R, present in natural XN, is not necessary for having antiangiogenic activity. In fact, the most effective compound from this series, 13, was characterized by a para-methoxy group in R and a fluorine atom in R 2 on B-ring. This study paves the way for future development of synthetic analogues of XN to be used as cancer angiopreventive and chemopreventive agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. Novel acetylcholine and carbamoylcholine analogues

    DEFF Research Database (Denmark)

    Hansen, Camilla Petrycer; Jensen, Anders Asbjørn; Christensen, Jeppe K.

    2008-01-01

    A series of carbamoylcholine and acetylcholine analogues were synthesized and characterized pharmacologically at neuronal nicotinic acetylcholine receptors (nAChRs). Several of the compounds displayed low nanomolar binding affinities to the alpha 4beta 2 nAChR and pronounced selectivity...... for this subtype over alpha 3beta 4, alpha 4beta 4, and alpha 7 nAChRs. The high nAChR activity of carbamoylcholine analogue 5d was found to reside in its R-enantiomer, a characteristic most likely true for all other compounds in the series. Interestingly, the pronounced alpha 4beta 2 selectivities exhibited...... by some of the compounds in the binding assays translated into functional selectivity. Compound 5a was a fairly potent partial alpha 4beta 2 nAChR agonist with negligible activities at the alpha 3beta 4 and alpha 7 subtypes, thus being one of the few truly functionally selective alpha 4beta 2 nACh...

  9. Substrate analogues for isoprenoid enzymes

    Energy Technology Data Exchange (ETDEWEB)

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  10. Natural and Semisynthetic Analogues of Manadoperoxide B Reveal New Structural Requirements for Trypanocidal Activity

    Directory of Open Access Journals (Sweden)

    Orazio Taglialatela-Scafati

    2013-08-01

    Full Text Available Chemical analysis of the Indonesian sponge Plakortis cfr. lita afforded two new analogues of the potent trypanocidal agent manadoperoxide B (1, namely 12-isomanadoperoxide B (2 and manadoperoxidic acid B (3. These compounds were isolated along with a new short chain dicarboxylate monoester (4, bearing some interesting relationships with the polyketide endoperoxides found in this sponge. Some semi-synthetic analogues of manadoperoxide B (6–8 were prepared and evaluated for antitrypanosomal activity and cytotoxicity. These studies revealed crucial structure–activity relationships that should be taken into account in the design of optimized and simplified endoperoxyketal trypanocidal agents.

  11. Synthesis of furanone-based natural product analogues with quorum sensing antagonist activity

    DEFF Research Database (Denmark)

    Hjelmgaard, Thomas; Persson, T.; Rasmussen, Thomas Bovbjerg

    2003-01-01

    The synthesis of 5- and 3-(1'-hydroxyalkyl)-substituted 5H-furan-2-ones 4a-d and 8a-d as well as 5-alkylidene-5H-furan-2-ones 5a-d is described. A study of the structure-activity relationship of these furanone-based natural product analogues towards two different quorum sensing systems is reporte....... Although the synthesized compounds are not as potent quorum sensing inhibitors as some natural counterparts and a synthetic analogue hereof, interesting structure-activity relationships are seen....

  12. Neurochemical binding profiles of novel indole and benzofuran MDMA analogues.

    Science.gov (United States)

    Shimshoni, Jakob A; Winkler, Ilan; Golan, Ezekiel; Nutt, David

    2017-01-01

    3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT 2 receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT 2a,b,c and NE α2 receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT 2a,b,c receptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT 2c receptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC 50 determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT 2a,c receptors as compared to MDMA.

  13. From boron analogues of amino acids to boronated DNA: potential new pharmaceuticals and neutron capture agents

    International Nuclear Information System (INIS)

    Spielvogel, B.F.; Sood, Anup; Duke Univ., Durham, NC; Shaw, B.R.; Hall, I.H.

    1991-01-01

    Isoelectronic and isostructural boron analogues of the α-amino acids ranging from simple glycine analogues such as H 3 NBH 2 COOH and Me 2 NHBH 2 COOH to alanine analogues have been synthesised. A diverse variety of analogues, including precursors and derivatives (such as peptides) have potent pharmacological activity, including anticancer, antiinflammatory, analgesic, and hypolipidemic activity in animal model studies and in vitro cell cultures. Boronated nucleosides and (oligo)nucleotides, synthetic oligonucleotide analogues of ''antisense'' agents interact with a complementary nucleic acid sequence blocking the biological effect of the target sequence. Nucleosides boronated on the pyrimidine and purine bases have been prepared. It has been established that an entirely new class of nucleic acid derivatives is feasible in which one of the non-bridging oxygens in the internucleotide phosphodiester linkage can be replaced by an isoelectronic analogue, the borane group, (BH 3 ). The boronated oligonucleotides can be viewed as hybrids of the normal oxygen oligonucleotides and the methylphosphonate oligonucleotides. (author)

  14. Plant synthetic biology.

    Science.gov (United States)

    Liu, Wusheng; Stewart, C Neal

    2015-05-01

    Plant synthetic biology is an emerging field that combines engineering principles with plant biology toward the design and production of new devices. This emerging field should play an important role in future agriculture for traditional crop improvement, but also in enabling novel bioproduction in plants. In this review we discuss the design cycles of synthetic biology as well as key engineering principles, genetic parts, and computational tools that can be utilized in plant synthetic biology. Some pioneering examples are offered as a demonstration of how synthetic biology can be used to modify plants for specific purposes. These include synthetic sensors, synthetic metabolic pathways, and synthetic genomes. We also speculate about the future of synthetic biology of plants. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Synthetic and Medicinal Prospective of Structurally Modified Curcumins.

    Science.gov (United States)

    Kumar, Bhupinder; Singh, Virender; Shankar, Ravi; Kumar, Kapil; Rawal, Ravindra K

    2017-01-01

    Curcumin, a natural yellow phenolic compound, is present in various types of herbs, particularly in Turmeric, Curcuma longa Linn. (Zingiberaceae family) rhizomes. Curcumin is a polyphenolic natural compound with diverse and attractive biological activities. In the last decade curcumine and its various synthetic analogues have been prepared and evaluated for various pharmacological activities that prove it as a lead molecule against several biological targets. It is a natural antioxidant and exhibited many pharmacological activities such as anti-inflammatory, anti-microbial, anticancer, anti-Alzheimer in both preclinical and clinical studies. Moreover, Curcumin and its analogues have anti-tubercular, cardioprotective, anti-diabetic, hepatoprotective, neuroprotective, nephroprotective, antirheumatic and anti-viral activities. The substitutions of 1,6-heptadiene linkage moiety via carbonyl group sustituion and addition of heterocyclic linker; isoxazole, 1H-pyrazole, cyclopentanone, piperidin-4-one, N-methylpiperidin-4-one enhance biological activities. The structure activity relationship of various curcumin analogues is studied for medicinal purposes and it reveals that monocarbonyl linkage analogues have anticancer properties. The current review gives an insight of the history, chemistry, analogues and most interesting in vitro and in vivo studies on the biological effects of Curcumin and its analogues.

  16. Inhibition of human arginase I by substrate and product analogues

    Energy Technology Data Exchange (ETDEWEB)

    Di Costanzo, Luigi; Ilies, Monica; Thorn, Katherine J.; Christianson, David W. (UPENN)

    2010-06-21

    Human arginase I is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to generate l-ornithine and urea. We demonstrate that N-hydroxy-l-arginine (NOHA) binds to this enzyme with K{sub d} = 3.6 {micro}M, and nor-N-hydroxy-l-arginine (nor-NOHA) binds with K{sub d} = 517 nM (surface plasmon resonance) or K{sub d} {approx} 50 nM (isothermal titration calorimetry). Crystals of human arginase I complexed with NOHA and nor-NOHA afford 2.04 and 1.55 {angstrom} resolution structures, respectively, which are significantly improved in comparison with previously-determined structures of the corresponding complexes with rat arginase I. Higher resolution structures clarify the binding interactions of the inhibitors. Finally, the crystal structure of the complex with l-lysine (K{sub d} = 13 {micro}M) is reported at 1.90 {angstrom} resolution. This structure confirms the importance of hydrogen bond interactions with inhibitor {alpha}-carboxylate and {alpha}-amino groups as key specificity determinants of amino acid recognition in the arginase active site.

  17. Inhibition of Human Arginase I by Substrate adn Product Analogues

    Energy Technology Data Exchange (ETDEWEB)

    L Di Costanzo; M Ilies; K Thorn; D Christianson

    2011-12-31

    Human arginase I is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine to generate L-ornithine and urea. We demonstrate that N-hydroxy-L-arginine (NOHA) binds to this enzyme with K(d)=3.6 microM, and nor-N-hydroxy-L-arginine (nor-NOHA) binds with K(d)=517 nM (surface plasmon resonance) or K(d) approximately 50 nM (isothermal titration calorimetry). Crystals of human arginase I complexed with NOHA and nor-NOHA afford 2.04 and 1.55 A resolution structures, respectively, which are significantly improved in comparison with previously-determined structures of the corresponding complexes with rat arginase I. Higher resolution structures clarify the binding interactions of the inhibitors. Finally, the crystal structure of the complex with L-lysine (K(d)=13 microM) is reported at 1.90 A resolution. This structure confirms the importance of hydrogen bond interactions with inhibitor alpha-carboxylate and alpha-amino groups as key specificity determinants of amino acid recognition in the arginase active site.

  18. [SYNTHETIC PEPTIDE VACCINES].

    Science.gov (United States)

    Sergeyev, O V; Barinsky, I F

    2016-01-01

    An update on the development and trials of synthetic peptide vaccines is reviewed. The review considers the successful examples of specific protection as a result of immunization with synthetic peptides using various protocols. The importance of conformation for the immunogenicity of the peptide is pointed out. An alternative strategy of the protection of the organism against the infection using synthetic peptides is suggested.

  19. Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability

    DEFF Research Database (Denmark)

    Petersen, Asger Bjørn; Andersen, Nikolaj Sten; Konotop, Gleb

    2017-01-01

    potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve...... the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation...... studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low μM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral...

  20. The Valles natural analogue project

    International Nuclear Information System (INIS)

    Stockman, H.; Krumhansl, J.; Ho, C.; McConnell, V.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and 39 Ar/ 4O isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks

  1. [Exogenous surfactant therapy: new synthetic surfactants].

    Science.gov (United States)

    Lacaze-Masmonteil, Th

    2008-06-01

    There are numerous pulmonary conditions in which qualitative or quantitative anomalies of the surfactant system have been demonstrated. In premature newborns with immature lungs, a functional deficit in surfactant is the main physiopathologic mechanism of the neonatal respiratory distress syndrome (RDS). Since the landmark pilot study of Fujiwara, published more than 20 years ago, the efficacy of exogenous surfactant for the treatment of neonatal RDS has been established by numerous controlled studies and meta-analyses. Enlightened by a growing insight into both the structure and function of the different surfactant components, a new generation of synthetic surfactants has been developed. Various complementary approaches have confirmed the fundamental role of the two hydrophobic proteins, SP-B and SP-C, in the surfactant system, thus opening the way to the design of analogues, either by chemical synthesis or expression in a prokaryotic system. An example of these peptide-containing synthetic surfactant preparations, lucinactant (Surfaxin), has been recently tested in comparison to a synthetic surfactant that does not contain protein as well as to animal derived surfactant preparations. Major clinical outcomes between lucinactant and animal-derived surfactant preparations were fund similar in two randomized controlled trials, opening the way to a new generation of synthetic surfactants in the near future.

  2. In Silico Screening and In Vitro Activity Measurement of Javamide Analogues as Potential p38 MAPK Inhibitors.

    Science.gov (United States)

    Park, Jae B

    2017-12-13

    p38 Mitogen-activated protein kinase (p38 MAPK) is a protein kinase critically involved in the progress of inflammation/stress-associated diseases. Our data suggested that javamide analogues may contain strong anti-inflammation activities, but there is little information about their effects on p38 MAPK. Therefore, in this paper, the effects of thirty javamide analogues on p38 MAPK were investigated using in silico screening and in vitro p38 MAPK assay methods. The javamide analogues were synthesized and their chemical structures were confirmed using nuclear magnetic resonance (NMR) spectroscopic methods. Then, the javamide analogues were screened using an in silico modeling program. The screened analogues demonstrated a wide range of binding energy (ΔE; -20 to -39) and several analogues with ΔE; -34 to -39 showed strong binding affinity to p38 MAPK. In vitro p38 MAPK assay, the kinase was significantly inhibited by the analogues with great binding energy (ΔE; -34 to -39) and in silico scores (Avg. score; -27.5 to -29.3). Furthermore, the comparative analysis of both assays showed a positive correlation between the in silico scores and p38 MAPK inhibition. In fact, the javamide analogues with top five in silico scores (Avg. score; -27.5 to -29.3) were found to inhibit p38 MAPK by 27-31% ( p silico score (Avg. score; -29.2) inhibited p38 MAPK (IC 50 = 9.9 μM) a little better than its methyl ester with best in silico score (Avg. score; -29.3). To support the ability to inhibit p38 MAPK, the treatment of javamide-II-ethyl and -methyl esters could suppress the production of IL-8 and MCP-1 protein significantly by 22-73% ( p silico and in vitro assay approach may be a useful and efficient solution as a functional screening approach in searching new lead compounds for targeted molecules.

  3. Norbadione A: synthetic approach and cesium complexation studies

    International Nuclear Information System (INIS)

    Desage - El Murr, M.

    2003-10-01

    This work was dedicated to the study of the synthesis and complexation studies of norbadione A: a pigment originating from a mushroom. A synthetic approach, based on a double Suzuki-Miyaura coupling, was developed. This strategy was applied with high yields to the synthesis of various norbadione A analogues, as well as to the synthesis of simple pulvinic acids. Access to functionalized precursors of the molecule was also studied and the final coupling remains to be done. Besides, a speciation study based on electro-spray ionization mass spectrometry was conducted with norbadione A and one of the analogues. This study allowed the assessment of the cesium complexation abilities of each molecule. Structural data was also obtained and complexation constants were calculated. Finally, norbadione A and various synthetic products have been tested via high-throughput screening methods and strong antioxidant properties were observed. Other biological results are also reported. (author)

  4. Synthesis of novel 11-desmethyl analogues of laulimalide by Nozaki-Kishi coupling.

    Science.gov (United States)

    Paterson, Ian; Bergmann, Hermann; Menche, Dirk; Berkessel, Albrecht

    2004-04-15

    As a first entry into structurally simplified analogues of the anticancer agent laulimalide, 11-desmethyl compounds 2 and 3 were selected by molecular modeling. The unfavorable diastereoselectivity in the key synthetic step, a Nozaki-Kishi coupling between macrocyclic aldehyde 4 and vinyl iodide 5, was overcome either by use of catalytic amounts of DIANANE-type ligands or L-Selectride reduction of the derived enone. This methodology should allow modular introduction of other, unnatural, side chains. [reaction: see text

  5. Protolytic properties of polyamine wasp toxin analogues studied by 13C NMR spectroscopy

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Piazzi, Lorna; Olsen, Christian A

    2006-01-01

    Acid-base properties of the natural polyamine wasp toxin PhTX-433 (1) and seven synthetic analogues [PhTX-343 (2), PhTX-334 (3), PhTX-443 (4), PhTX-434 (5), PhTX-344 (6), PhTX-444 (7), and PhTX-333 (8)], each having four protolytic sites, were characterized by 13C NMR spectroscopy. Nonlinear, mul...

  6. Synthesis and antibacterial evaluation of anziaic acid and analogues as topoisomerase I inhibitors

    OpenAIRE

    Lin, Hao; Annamalai, Thirunavukkarasu; Bansod, Priyanka; Tse-Dinh, Yuk-Ching; Sun, Dianqing

    2013-01-01

    Naturally occurring anziaic acid was very recently reported as a topoisomerase I inhibitor with antibacterial activity. Herein total synthesis of anziaic acid and structural analogues is described and the preliminary structure-activity relationship (SAR) has been developed based on topoisomerase inhibition and whole cell antibacterial activity.

  7. An Analogue of the Antibiotic Teicoplanin Prevents Flavivirus Entry In Vitro

    NARCIS (Netherlands)

    De Burghgraeve, Tine; Kaptein, Suzanne J. F.; Ayala Nunez, Nilda V.; Mondotte, Juan A.; Pastorino, Boris; Printsevskaya, Svetlana S.; de Lamballerie, Xavier; Jacobs, Michael; Preobrazhenskaya, Maria; Gamarnik, Andrea V.; Smit, Jolanda M.; Neyts, Johan

    2012-01-01

    There is an urgent need for potent inhibitors of dengue virus (DENV) replication for the treatment and/or prophylaxis of infections with this virus. We here report on an aglycon analogue of the antibiotic teicoplanin (code name LCTA-949) that inhibits DENV-induced cytopathic effect (CPE) in a

  8. [From synthetic biology to synthetic humankind].

    Science.gov (United States)

    Nouvel, Pascal

    2015-01-01

    In this paper, we propose an historical survey of the expression "synthetic biology" in order to identify its main philosophical components. The result of the analysis is then used to investigate the meaning of the notion of "synthetic man". It is shown that both notions share a common philosophical background that can be summed up by the short but meaningful assertion: "biology is technology". The analysis allows us to distinguish two notions that are often confused in transhumanist literature: the notion of synthetic man and the notion of renewed man. The consequences of this crucial distinction are discussed. Copyright © 2015 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  9. Synthetic Cathinones ("Bath Salts")

    Science.gov (United States)

    ... cathinones? Behavioral therapy can be used to treat addiction to synthetic cathinones. Examples include: cognitive-behavioral therapy contingency management, or motivational incentives—providing rewards to ...

  10. A chemically stable analogue, 9 beta-methyl carbacyclin, with similar effects to epoprostenol (prostacyclin, PGI2) in man.

    OpenAIRE

    O'Grady, J; Hedges, A; Whittle, B J; Al-Sinawi, L A; Mekki, Q A; Burke, C; Moody, S G; Moti, M J; Hassan, S

    1984-01-01

    The effects of 9 beta-methyl carbacyclin, a chemically stable analogue of epoprostenol (prostacyclin, PGI2) were studied, in comparison with epoprostenol, both in vitro and in vivo in man. In vitro 9 beta-methyl carbacyclin and epoprostenol inhibited platelet aggregation induced by ADP, collagen, the endoperoxide analogue U46619 and arachidonic acid. The potency of 9 beta-methyl carbacyclin relative to epoprostenol was comparable in ADP and collagen-aggregated platelet rich plasma (PRP), 9 be...

  11. Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability.

    Science.gov (United States)

    Petersen, Asger B; Andersen, Nikolaj S; Konotop, Gleb; Hanafiah, Nur Hafzan Md; Raab, Marc S; Krämer, Alwin; Clausen, Mads H

    2017-04-21

    Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low μM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Design, Synthesis, and Cytotoxicity Evaluation of Novel Griseofulvin Analogues with Improved Water Solubility

    Directory of Open Access Journals (Sweden)

    Ahmed K. Hamdy

    2017-01-01

    Full Text Available Griseofulvin 1 is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Study of SAR of some griseofulvin analogues has led to the identification of 2′-benzyloxy griseofulvin 3, a more potent analogue which retards tumor growth through inhibition of centrosomal clustering. However, similar to griseofulvin 1, compound 3 exhibited poor aqueous solubility. In order to improve the poor water solubility, six new griseofulvin analogues 5–10 were synthesized and tested for their antiproliferative activity and water solubility. The semicarbazone 9 and aminoguanidine 10 analogues were the most potent against HCT116 and MCF-7 cell lines. In combination studies, compound 9 was found to exert synergistic effects with tamoxifen and 5-fluorouracil against MCF-7 and HCT116 cells proliferation, respectively. The flow cytometric analysis of effect of 9 on cell cycle progression revealed G2/M arrest in HCT116. In addition, compound 9 induced apoptosis in MCF-7 cells. Finally, all synthesized analogues revealed higher water solubility than griseofulvin 1 and benzyloxy analogue 3 in pH 1.2 and 6.8 buffer solutions.

  13. Differential Top10 promoter regulation by six tetracycline analogues in plant cells

    Science.gov (United States)

    Love, John; Allen, George C.; Gatz, Christiane; Thompson, William F.; Brown, C. S. (Principal Investigator)

    2002-01-01

    The effects of five tetracycline analogues, anhydrotetracycline, doxycycline, minocycline, oxytetracycline, and tetracycline, on Top10 promoter activity in NT1 tobacco tissue culture cells have been analysed. The concentration that repressed Top10 promoter activity, the level of transgene repression and the kinetics of transgene de-repression were determined for each analogue, and could not be predicted from in vitro binding affinity to the tetracycline repressor or from comparison with animal cells. Doxycycline had the most potent effect on the Top10 promoter and completely inhibited transgene expression at 4 nmol l(-1). Tetracycline was the most versatile of the analogues tested; tetracycline inhibited the Top10 promoter at 10 nmol l(-1) and was easily washed out to restore Top10-driven expression in 12-24 h. A study was also made of the suitability for plant research of a novel tetracycline analogue, GR33076X. In animal cells, GR33076X de-repressed Top10 promoter activity in the presence of inhibitory concentrations of anhydrotetracycline. In NT1, it is shown that GR 33076X can antagonize repression of the Top10 promoter in the presence of tetracycline, but not of anhydrotetracycline or of doxycycline. Different tetracycline analogues can therefore be used to regulate the Top10 promoter in plant cells and this property may be exploited in planning an optimum course of transgene regulation.

  14. Effect of chemical and microbial vitamin B₁₂ analogues on production of vitamin B₁₂.

    Science.gov (United States)

    Thirupathaiah, Yeruva; Swarupa Rani, Chiliveri; Sudhakara Reddy, Marrivada; Venkateswar Rao, Linga

    2012-05-01

    Strain improvement by genetic manipulation or optimization of fermentation conditions for overproduction of vitamin B(12) has a drawback due to feed back inhibition. To resist the feed back inhibition by analogues of vitamin B(12) in Propionibacterium freudenrechii subsps. shermanii (OLP-5), we have tested with microbially separated B(12) analogues from three different strains. Microbial analogues were differentiated from commercially available vitamin B(12) by high pressure liquid chromatography and spectrophotometric method. An analogue isolated from NRRL-B-4327 was shown to increase vitamin B(12) concentration from 18.53 ± 0.15 to 31.67 ± 0.58 mg/l in OLP-5 strain. The presence of chemical analogue (ICH(2) Co(DH)(2) (H(2)Py)(4)) increased vitamin B(12) production from 16.13 ± 0.15 to 18.53 ± 0.15 mg/l in OLP-5. These findings revealed that addition of B(12) analogues in fermentation media have developed strain resistance to feed back inhibition by vitamin B(12).

  15. Quantum synthetic aperture radar

    Science.gov (United States)

    Lanzagorta, Marco; Jitrik, Oliverio; Uhlmann, Jeffrey; Venegas-Andraca, Salvador E.

    2017-05-01

    Synthetic aperture radar (SAR) uses sensor motion to generate finer spatial resolution of a given target area. In this paper we explore the theoretical potential of quantum synthetic aperture quantum radar (QSAR). We provide theoretical analysis and simulation results which suggest that QSAR can provide improved detection performance over classical SAR in the high-noise low-brightness regime.

  16. Designing synthetic biology.

    Science.gov (United States)

    Agapakis, Christina M

    2014-03-21

    Synthetic biology is frequently defined as the application of engineering design principles to biology. Such principles are intended to streamline the practice of biological engineering, to shorten the time required to design, build, and test synthetic gene networks. This streamlining of iterative design cycles can facilitate the future construction of biological systems for a range of applications in the production of fuels, foods, materials, and medicines. The promise of these potential applications as well as the emphasis on design has prompted critical reflection on synthetic biology from design theorists and practicing designers from many fields, who can bring valuable perspectives to the discipline. While interdisciplinary connections between biologists and engineers have built synthetic biology via the science and the technology of biology, interdisciplinary collaboration with artists, designers, and social theorists can provide insight on the connections between technology and society. Such collaborations can open up new avenues and new principles for research and design, as well as shed new light on the challenging context-dependence-both biological and social-that face living technologies at many scales. This review is inspired by the session titled "Design and Synthetic Biology: Connecting People and Technology" at Synthetic Biology 6.0 and covers a range of literature on design practice in synthetic biology and beyond. Critical engagement with how design is used to shape the discipline opens up new possibilities for how we might design the future of synthetic biology.

  17. Synthesis of new 3-and 4-substituted analogues of acyl homoserine lactone quorum sensing autoinducers

    DEFF Research Database (Denmark)

    Olsen, Jacob Alsbæk; Severinsen, Rune Eg; Rasmussen, Thomas Bovbjerg

    2002-01-01

    The quorum sensing mechanism in Gram-negative bacteria uses small intercellular signal molecules, N-acyl-homoserine lactones (AHLs), to control transcription of specific genes in relation to population density. In this communication, we describe the parallel synthesis of new AHL analogues, in which...... substituents have been introduced into the 3- and 4-positions of the lactone ring. These analogues have been screened for their ability to activate and inhibit a Vibrio fischeri LuxI/LuxR-derived quorum sensing reporter system....

  18. Condensed matter analogues of cosmology

    Science.gov (United States)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the

  19. Antimicrobial Activity of Resveratrol Analogues

    Directory of Open Access Journals (Sweden)

    Malik Chalal

    2014-06-01

    Full Text Available Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew. Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold. The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups and antimicrobial activity.

  20. The antiproliferative action of [D-Arg(1), D-Phe(5), D-Trp(7,9), LEU(11)] substance P analogue antagonist against small-cell- and non-small-cell lung cancer cells could be due to the pharmacological profile of its tachykinin receptor antagonist.

    Science.gov (United States)

    Munoz, M; Recio, S; Rosso, M; Redondo, M; Covenas, R

    2015-06-01

    It is known that in human lung cancer samples, both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cells express the neurokinin-1 (NK-1) receptor; that after binding to the NK-1 receptor the peptide substance P (SP) elicits tumour cell proliferation and an antiapoptotic effect. By contrast, it has been demonstrated that non-peptide NK-1 receptor antagonists, after binding to the NK-1 receptor and hence by blocking the SP action in SCLC/NSCLC, exert an antiproliferative action (inhibit lung cancer cell proliferation and induce the death of tumour cells by apoptosis). It is also known that SP peptide NK-1 receptor antagonists also called SP analogue antagonists (broad-spectrum GPCR antagonists, broad-spectrum neuropeptide antagonists or synthetic analogues of SP), also exert antiproliferative actions against SCLC/NSCLC. However, the underlying mechanisms involved in this antiproliferative action remain unknown. By using competition assays with SP, here we demonstrate that the antiproliferative action exerted by the [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)] SP analogue on human H-69 SCLC and COR-L23 NSCLC cell lines, occurs at least through the NK-1 receptor.

  1. Synthesis and antifolate activity of 5-methyl-5,10-dideaza analogues of aminopterin and folic acid and an alternative synthesis of 5,10-dideazatetrahydrofolic acid, a potent inhibitor of glycinamide ribonucleotide formyltransferase.

    Science.gov (United States)

    Piper, J R; McCaleb, G S; Montgomery, J A; Kisliuk, R L; Gaumont, Y; Thorndike, J; Sirotnak, F M

    1988-11-01

    The title compounds were prepared in extensions of a general synthetic approach used earlier to prepare 5-alkyl-5-deaza analogues of classical antifolates. Wittig condensation of 2,4-diaminopyrido[2,3-d]pyrimidine-6-carboxaldehyde (2a) and its 5-methyl analogue 2b with [4-(methoxycarbonyl)benzylidene] triphenylphosphorane gave 9,10-ethenyl precursors 3a and 3b. Hydrogenation (DMF, ambient, 5% Pd/C) of the 9,10-ethenyl group of 3b followed by ester hydrolysis led to 4-[2-(2,4-diamino-5-methylpyrido[2,3-d]pyrimidin-6-yl)ethyl]ben zoi c acid (5), which was converted to 5-methyl-5,10-dideazaaminopterin (6) via coupling with dimethyl L-glutamate (mixed-anhydride method using i-BuOCOCl) followed by ester hydrolysis. Standard hydrolytic deamination of 6 gave 5-methyl-5,10-dideazafolic acid (7). Intermediates 3a and 3b were converted through concomitant deamination and ester hydrolysis to 8a and 8b. Peptide coupling of 8a,b (using (EtO)2POCN) with diesters of L-glutamic acid gave intermediate esters 9a and 9b. Hydrogenation of both the 9,10 double bond and the pyrido ring of 9a and 9b (MeOH-0.1 N HCl, 3.5 atm, Pt) was followed by ester hydrolysis to give 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (11a) and the 5-methyl analogue 11b. Biological evaluation of 6, 7, 11a, and 11b for inhibition of dihydrofolate reductase (DHFR) isolated from L1210 cells and for growth inhibition and transport characteristics toward L1210 cells revealed 6 to be less potent than methotrexate in the inhibition of DHFR and cell growth. Compounds 6, 11a, and 11b were transported into cells more efficiently than methotrexate. Growth inhibition IC50 values for 11a and 11b were 57 and 490 nM, respectively; the value for 11a is in good agreement with that previously reported (20-50 nM). In tests against other folate-utilizing enzymes, 11a and 11b were found to be inhibitors of glycinamide ribonucleotide formyltransferase (GAR formyltransferase) from one bacterial (Lactobacillus casei) and two mammalian

  2. Structure-dependent inhibitory effects of synthetic cannabinoids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and skin tumour promotion in mice.

    Science.gov (United States)

    Nakajima, Jun'ichi; Nakae, Dai; Yasukawa, Ken

    2013-08-01

    Whether and how synthetic cannabinoids affect inflammation and carcinogenesis has not been well studied. The present study was thus conducted to assess effects of synthetic cannabinoids on inflammation and carcinogenesis in vivo in mice. Twenty-three analogues of synthetic cannabinoids were isolated from, and identified as adulterants in, illegal drugs distributed in the Tokyo metropolitan area, and were examined for their inhibitory effects on the induction of oedema in mouse ears by 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, selected cannabinoids, JWH-018, -122 and -210, were studied for their effects on carcinogenesis induced in mouse skin initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by TPA. Among cannabinoids, naphthoylindoles mostly exhibited superior inhibitory effects against TPA-induced ear oedema and, especially, JWH-018, -122 and -210 showed potent activity with 50% inhibitory dose (ID50) values of 168, 346 and 542 nm, respectively (an activity corresponding to that of indometacin (ID50 = 908 nm)). Furthermore these three compounds also markedly suppressed the tumour-promoting activity of TPA. This is the first report indicating the structure-activity relationships for the anti-inflammatory activity of synthetic cannabinoids on TPA-induced inflammation in mice. Naphthoylindoles, JWH-018, -122 and -210, had the most potent anti-inflammatory activity and also markedly inhibited tumour promotion by TPA in the two-stage mouse skin carcinogenesis model. The present results suggest that synthetic cannabinoids, such as JWH-018, -122 and -210, may be used as cancer chemopreventive agents in the future. © 2013 Royal Pharmaceutical Society.

  3. An arsenical analogue of adenosine diphosphate.

    Science.gov (United States)

    Webster, D; Sparkes, M J; Dixon, H B

    1978-01-01

    An analogue of ADP was made in which the terminal phosphono-oxy group, -O-PO(OH)2, has been replaced by the arsonomethyl group, -CH2-AsO(OH)2. This compound cannot form a stable analogue of ATP because anhydrides of arsonic acids are rapidly hydrolysed, so that any enzyme that phosphorylates ADP and accepts this analogue as a substrate should release orthophosphate in its presence. The analogue proves to be a poor substrate for 3-phosphoglycerate kinase (V/Km is diminished by a factor of 10(2)-10(3)) and a very poor substrate for pyruvate kinase (V/Km is diminished by a factor of 10(5)-10(6)). No substrate action was detected with adenyl kinase and creatine kinase. PMID:204292

  4. International video project on natural analogues

    International Nuclear Information System (INIS)

    Guentensperger, Marcel

    1993-01-01

    A natural analogue can be defined as a natural process which has occurred in the past and is studied in order to test predictions about the future evolution of similar processes. In recent years, natural analogues have been used increasingly to test the mathematical models required for repository performance assessment. Analogues are, however, also of considerable use in public relations as they allow many of the principles involved in demonstrating repository safety to be illustrated in a clear manner using natural systems with which man is familiar. The international Natural Analogue Working Group (NAWG), organised under the auspices of the CEC, has recognised that such PR applications are of considerable importance and should be supported from a technical level. At the NAWG meeting in Pitlochry, Scotland (June 1990), it was recommended that the possibilities for making a video film on this topic be investigated and Nagra was requested to take the lead role in setting up such a project

  5. Natural analogues and radionuclide transport model validation

    International Nuclear Information System (INIS)

    Lever, D.A.

    1987-08-01

    In this paper, some possible roles for natural analogues are discussed from the point of view of those involved with the development of mathematical models for radionuclide transport and with the use of these models in repository safety assessments. The characteristic features of a safety assessment are outlined in order to address the questions of where natural analogues can be used to improve our understanding of the processes involved and where they can assist in validating the models that are used. Natural analogues have the potential to provide useful information about some critical processes, especially long-term chemical processes and migration rates. There is likely to be considerable uncertainty and ambiguity associated with the interpretation of natural analogues, and thus it is their general features which should be emphasized, and models with appropriate levels of sophistication should be used. Experience gained in modelling the Koongarra uranium deposit in northern Australia is drawn upon. (author)

  6. Bioactivity of permselective PVA hydrogels with mixed ECM analogues.

    Science.gov (United States)

    Nafea, Eman H; Poole-Warren, Laura A; Martens, Penny J

    2015-12-01

    The presentation of multiple biological cues, which simulate the natural in vivo cell environment within artificial implants, has recently been identified as crucial for achieving complex cellular functions. The incorporation of two or more biological cues within a largely synthetic network can provide a simplified model of multifunctional ECM presentation to encapsulated cells. Therefore, the aim of this study was to examine the effects of simultaneously and covalently incorporating two dissimilar biological molecules, heparin and gelatin, within a PVA hydrogel. PVA was functionalized with 7 and 20 methacrylate functional groups per chain (FG/c) to tailor the permselectivity of UV photopolymerized hydrogels. Both heparin and gelatin were covalently incorporated into PVA at an equal ratio resulting in a final PVA:heparin:gelatin composition of 19:0.5:0.5. The combination of both heparin and gelatin within a PVA network has proven to be stable over time without compromising the PVA base characteristics including its permselectivity to different proteins. Most importantly, this combination of ECM analogues supplemented PVA with the dual functionalities of promoting cellular adhesion and sequestering growth factors essential for cellular proliferation. Multi-functional PVA hydrogels with synthetically controlled network characteristics and permselectivity show potential in various biomedical applications including artificial cell implants. © 2015 Wiley Periodicals, Inc.

  7. Structural Antitumoral Activity Relationships of Synthetic Chalcones

    Directory of Open Access Journals (Sweden)

    Cesar Echeverria

    2009-01-01

    Full Text Available Relationships between the structural characteristic of synthetic chalcones and their antitumoral activity were studied. Treatment of HepG2 cells for 24 h with synthetic 2’-hydroxychalcones resulted in apoptosis induction and dose-dependent inhibition of cell proliferation. The calculated reactivity indexes and the adiabatic electron affinities using the DFT method including solvent effects, suggest a structure-activity relationship between the Chalcones structure and the apoptosis in HepG2 cells. The absence of methoxy substituents in the B ring of synthetic 2’-hydroxychalcones, showed the mayor structure-activity pattern along the series.

  8. Synthetic biological networks

    International Nuclear Information System (INIS)

    Archer, Eric; Süel, Gürol M

    2013-01-01

    Despite their obvious relationship and overlap, the field of physics is blessed with many insightful laws, while such laws are sadly absent in biology. Here we aim to discuss how the rise of a more recent field known as synthetic biology may allow us to more directly test hypotheses regarding the possible design principles of natural biological networks and systems. In particular, this review focuses on synthetic gene regulatory networks engineered to perform specific functions or exhibit particular dynamic behaviors. Advances in synthetic biology may set the stage to uncover the relationship of potential biological principles to those developed in physics. (review article)

  9. Synthetic Base Fluids

    Science.gov (United States)

    Brown, M.; Fotheringham, J. D.; Hoyes, T. J.; Mortier, R. M.; Orszulik, S. T.; Randles, S. J.; Stroud, P. M.

    The chemical nature and technology of the main synthetic lubricant base fluids is described, covering polyalphaolefins, alkylated aromatics, gas-to-liquid (GTL) base fluids, polybutenes, aliphatic diesters, polyolesters, polyalkylene glycols or PAGs and phosphate esters.Other synthetic lubricant base oils such as the silicones, borate esters, perfluoroethers and polyphenylene ethers are considered to have restricted applications due to either high cost or performance limitations and are not considered here.Each of the main synthetic base fluids is described for their chemical and physical properties, manufacture and production, their chemistry, key properties, applications and their implications when used in the environment.

  10. Exogenous ceramide-1-phosphate (C1P) and phospho-ceramide analogue-1 (PCERA-1) regulate key macrophage activities via distinct receptors.

    Science.gov (United States)

    Katz, Sebastián; Ernst, Orna; Avni, Dorit; Athamna, Muhammad; Philosoph, Amir; Arana, Lide; Ouro, Alberto; Hoeferlin, L Alexis; Meijler, Michael M; Chalfant, Charles E; Gómez-Muñoz, Antonio; Zor, Tsaffrir

    2016-01-01

    Inflammation is an ensemble of tightly regulated steps, in which macrophages play an essential role. Previous reports showed that the natural sphingolipid ceramide 1-phosphate (C1P) stimulates macrophages migration, while the synthetic C1P mimic, phospho-ceramide analogue-1 (PCERA-1), suppresses production of the key pro-inflammatory cytokine TNFα and amplifies production of the key anti-inflammatory cytokine IL-10 in LPS-stimulated macrophages, via one or more unidentified G-protein coupled receptors. We show that C1P stimulated RAW264.7 macrophages migration via the NFκB pathway and MCP-1 induction, while PCERA-1 neither mimicked nor antagonized these activities. Conversely, PCERA-1 synergistically elevated LPS-dependent IL-10 expression in RAW264.7 macrophages via the cAMP-PKA-CREB signaling pathway, while C1P neither mimicked nor antagonized these activities. Interestingly, both compounds have the capacity to additively inhibit TNFα secretion; PCERA-1, but not C1P, suppressed LPS-induced TNFα expression in macrophages in a CREB-dependent manner, while C1P, but not PCERA-1, directly inhibited recombinant TNFα converting enzyme (TACE). Finally, PCERA-1 failed to interfere with binding of C1P to either the cell surface receptor or to TACE. These results thus indicate that the natural sphingolipid C1P and its synthetic analog PCERA-1 bind and activate distinct receptors expressed in RAW264.7 macrophages. Identification of these receptors will be instrumental for elucidation of novel activities of extra-cellular sphingolipids, and may pave the way for the design of new sphingolipid mimics for the treatment of inflammatory diseases, and pathologies which depend on cell migration, as in metastatic tumors. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Large seismic source imaging from old analogue seismograms

    Science.gov (United States)

    Caldeira, Bento; Buforn, Elisa; Borges, José; Bezzeghoud, Mourad

    2017-04-01

    In this work we present a procedure to recover the ground motions by a proper digital structure, from old seismograms in analogue physical support (paper or microfilm) to study the source rupture process, by application of modern finite source inversion tools. Despite the quality that the analog data and the digitizing technologies available may have, recover the ground motions with the accurate metrics from old seismograms, is often an intricate procedure. Frequently the general parameters of the analogue instruments response that allow recover the shape of the ground motions (free periods and damping) are known, but the magnification that allow recover the metric of these motions is dubious. It is in these situations that the procedure applies. The procedure is based on assign of the moment magnitude value to the integral of the apparent Source Time Function (STF), estimated by deconvolution of a synthetic elementary seismogram from the related observed seismogram, corrected with an instrument response affected by improper magnification. Two delicate issues in the process are 1) the calculus of the synthetic elementary seismograms that must consider later phases if applied to large earthquakes (the portions of signal should be 3 or 4 times larger than the rupture time) and 2) the deconvolution to calculate the apparent STF. In present version of the procedure was used the Direct Solution Method to compute the elementary seismograms and the deconvolution was processed in time domain by an iterative algorithm that allow constrains the STF to stay positive and time limited. The method was examined using synthetic data to test the accuracy and robustness. Finally, a set of 17 real old analog seismograms from the Santa Maria (Azores) 1939 earthquake (Mw=7.1) was used in order to recover the waveforms in the required digital structure, from which by inversion allows compute the finite source rupture model (slip distribution). Acknowledgements: This work is co

  12. Design, Synthesis and Cytotoxic Evaluation of o-Carboxamido Stilbene Analogues

    Directory of Open Access Journals (Sweden)

    Mohamad Nurul Azmi

    2013-11-01

    Full Text Available Resveratrol, a natural stilbene found in grapes and wines exhibits a wide range of pharmacological properties. Resveratrol is also known as a good chemopreventive agent for inhibiting carcinogenesis processes that target kinases, cyclooxygenases, ribonucleotide reductase and DNA polymerases. A total of 19 analogues with an amide moiety were synthesized and the cytotoxic effects of the analogues on a series of human cancer cell lines are reported. Three compounds 6d, 6i and 6n showed potent cytotoxicity against prostate cancer DU-145 (IC50 = 16.68 µM, colon cancer HT-29 (IC50 = 7.51 µM and breast cancer MCF-7 (IC50 = 21.24 µM, respectively, which are comparable with vinblastine. The resveratrol analogues were synthesized using the Heck method.

  13. Synthesis and biological evaluation of andrographolide analogues as anti-cancer agents.

    Science.gov (United States)

    Preet, Ranjan; Chakraborty, Biswajit; Siddharth, Sumit; Mohapatra, Purusottam; Das, Dipon; Satapathy, Shakti Ranjan; Das, Supriya; Maiti, Nakul C; Maulik, Prakas R; Kundu, Chanakya Nath; Chowdhury, Chinmay

    2014-10-06

    A new family of andrographolide analogues were synthesized and screened in vitro against kidney (HEK-293) and breast (MCF-7) cancer cells. The anti-cancer effects of the active analogues (2b, 2c and 4c) were determined by multiple cell based assays such as MTT, immunostaining, FACS, western blotting and transcriptional inhibition of NF-κB activity. Importantly, these compounds were found to possess higher anti-cancer potency than andrographolide and low toxicity to normal (VERO and MCF-10A) cells. Increased level of Bax/Bcl-xL ratio, caspase 3, and sub G1 population, higher expression level of tumor suppressor protein p53 and lower expression level of NF-κB suggested potent apoptotic property of the active analogues. Data revealed that the andrographolide derivative-mediated cell death in cancer cells was p53 dependent. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  14. [Response of the algae Gymnodinium kovalevskii (Dinophyta) to exposure to synthetic detergents and distillation].

    Science.gov (United States)

    Aĭzdaĭcher, N A

    2000-01-01

    The effects of synthetic detergents and combined effects of synthetic detergents and water freshening on growth characteristics of the alga Gymnodinium kovalevskii (Dinophyta) were studied. Low concentrations of synthetic detergents (0.1 and 1.0 mg/l) stimulated the algal growth. Elevated concentrations inhibited cell division, affected their motility and induced morphological changes. Contamination with synthetic detergents adversely affected the adaptation plasticity of algae with respect to salinity.

  15. Phospholipid Composition in Synthetic Surfactants Is Important for Tidal Volumes and Alveolar Stability in Surfactant-Treated Preterm Newborn Rabbits.

    Science.gov (United States)

    Calkovska, Andrea; Linderholm, Bim; Haegerstrand-Björkman, Marie; Pioselli, Barbara; Pelizzi, Nicola; Johansson, Jan; Curstedt, Tore

    2016-01-01

    The development of synthetic surfactants for the treatment of lung pulmonary diseases has been going on for many years. To investigate the effects of phospholipid mixtures combined with SP-B and SP-C analogues on lung functions in an animal model of respiratory distress syndrome. Natural and synthetic phospholipid mixtures with/without SP-B and/or SP-C analogues were instilled in ventilated premature newborn rabbits. Lung functions were evaluated. Treatment with Curosurf or phospholipids from Curosurf combined with SP-B and SP-C analogues gave similar results. Treatment with phospholipids from adult rabbit lungs or liver combined with dipalmitoylphosphatidylcholine (DPPC) and palmitoyloleoylphosphatidylglycerol (POPG) gave tidal volumes (VT) well above physiological levels, but alveolar stability at end-expiration was only achieved when these phospholipids were combined with analogues of SP-B and SP-C. Treatment with egg yolk-PC mixed with DPPC with and without POPG gave small VT, but after addition of both analogues VT was only somewhat lower and lung gas volumes (LGV) similar to those obtained with Curosurf. Substitution of egg yolk-PC (≥99% PC) with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and combining them with DPPC, POPG and 2% each of the SP-B and SP-C analogue gave a completely synthetic surfactant with similar effects on VT and LGV as Curosurf. Phospholipid composition is important for VT while the SP-B and SP-C analogues increase alveolar stability at end-expiration. Synthetic surfactant consisting of unsaturated and saturated phosphatidylcholines, POPG and the analogues of SP-B and SP-C has similar activity as Curosurf regarding VT and LGV in an animal model using preterm newborn rabbits ventilated without positive end-expiratory pressure. © 2016 S. Karger AG, Basel.

  16. Synthetic Biological Membrane (SBM)

    Data.gov (United States)

    National Aeronautics and Space Administration — The ultimate goal of the Synthetic Biological Membrane project is to develop a new type of membrane that will enable the wastewater treatment system required on...

  17. A silyl andrographolide analogue suppresses Wnt/β-catenin signaling pathway in colon cancer.

    Science.gov (United States)

    Reabroi, Somrudee; Chairoungdua, Arthit; Saeeng, Rungnapha; Kasemsuk, Teerapich; Saengsawang, Witchuda; Zhu, Weiming; Piyachaturawat, Pawinee

    2018-05-01

    Hyperactivation of Wnt/β-catenin signaling implicated in oncogenesis of colorectal cancer (CRC) is a potential molecular target for chemotherapy. An andrographolide analogue, 3A.1 (19-tert-butyldiphenylsilyl-8, 17-epoxy andrographolide) has previously been reported to be potently cytotoxic toward cancer cells by unknown molecular mechanisms. The present study explored the anti-cancer activity of analogue 3A.1 on Wnt/β-catenin signaling in colon cancer cells (HT29 cells) which were more sensitive to the others (HCT116 and SW480 cells). Analogue 3A.1 inhibited viability of HT29 cells with IC 50 value of 11.1 ± 1.4 μM at 24 h, which was more potent than that of the parent andrographolide. Analogue 3A.1 also suppressed the proliferation of HT29 cells and induced cell apoptosis in a dose-dependent manner. Its apoptotic activity was accompanied with increased expressions of proteins related to DNA damages; PARP-1 and γ-H2AX. In addition, analogue 3A.1 significantly inhibited T-cell factor and lymphoid enhancer factor (TCF/LEF) promoter activity of Wnt/β-catenin signaling. Accordingly, the expressions of Wnt target genes and β-catenin protein were suppressed. Moreover, analogue 3A.1 increased the activity of GSK-3β kinase, which is a negative regulator responsible for degradation of intracellular β-catenin. This mode of action was further supported by the absence of the effects after treatment with a GSK-3β inhibitor, and over-expression of a mutant β-catenin (S33Y). Our findings reveal, for the first time, an insight into the molecular mechanism of the anti-cancer activity of analogue 3A.1 through the inhibition of Wnt/β-catenin/GSK-3β pathway and provide a therapeutic potential of the andrographolide analogue 3A.1 in CRC treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  18. Hybridization with synthetic oligonucleotides

    Energy Technology Data Exchange (ETDEWEB)

    Szostak, J.W.; Stiles, J.I.; Tye, B.K.; Sherman, F.; Wu, R.

    1978-01-01

    Procedures are described for the use of synthetic oligonucleotides for Southern blot experiments and gene bank screening, and the effect of various mismatches on the efficiency of hybridization is demonstrated. The following topics are discussed: sensitivity vs. specificity, hybridization of a 12-mer to the lambda endolysin gene; hybridization of oligonucleotide probes to the E. coli lac operator; hybridization of synthetic probes to the CYC1 gene of yeast; and cloning eucaryotic genes. (HLW)

  19. Mammalian Synthetic Biology

    OpenAIRE

    Martella, Andrea; Pollard, Steven M; Dai, Junbiao; Cai, Yizhi

    2016-01-01

    The enabling technologies of synthetic biology are opening up new opportunities for engineering and enhancement of mammalian cells. This will stimulate diverse applications in many life science sectors such as regenerative medicine, development of biosensing cell lines, therapeutic protein production, and generation of new synthetic genetic regulatory circuits. Harnessing the full potential of these new engineering-based approaches requires the design and assembly of large DNA constructs-pote...

  20. Between Analogue and Digital Diagrams

    Directory of Open Access Journals (Sweden)

    Zoltan Bun

    2012-10-01

    Full Text Available This essay is about the interstitial. About how the diagram, as a method of design, has lead fromthe analogue deconstruction of the eighties to the digital processes of the turn of the millennium.Specifically, the main topic of the text is the interpretation and the critique of folding (as a diagramin the beginning of the nineties. It is necessary then to unfold its relationship with immediatelypreceding and following architectural trends, that is to say we have to look both backwards andforwards by about a decade. The question is the context of folding, the exchange of the analogueworld for the digital. To understand the process it is easier to investigate from the fields of artand culture, rather than from the intentionally perplicated1 thoughts of Gilles Deleuze. Both fieldsare relevant here because they can similarly be used as the yardstick against which the era itselfit measured. The cultural scene of the eighties and nineties, including performing arts, movies,literature and philosophy, is a wide milieu of architecture. Architecture responds parallel to itsera; it reacts to it, and changes with it and within it. Architecture is a medium, it has always beena medium, yet the relations are transformed. That’s not to say that technical progress, for exampleusing CAD-software and CNC-s, has led to the digital thinking of certain movements ofarchitecture, (it is at most an indirect tool. But the ‘up-to-dateness’ of the discipline, however,a kind of non-servile reading of an ‘applied culture’ or ‘used philosophy’2 could be the key.(We might recall here, parenthetically, the fortunes of the artistic in contemporary mass society.The proliferation of museums, the magnification of the figure of the artist, the existence of amassive consumption of printed and televised artistic images, the widespread appetite for informationabout the arts, all reflect, of course, an increasingly leisured society, but also relateprecisely to the fact

  1. In vitro antifungal and antibiofilm activities of halogenated quinoline analogues against Candida albicans and Cryptococcus neoformans.

    Science.gov (United States)

    Zuo, Ran; Garrison, Aaron T; Basak, Akash; Zhang, Peilan; Huigens, Robert W; Ding, Yousong

    2016-08-01

    With the increasing prevalence of fungal infections coupled with emerging drug resistance, there is an urgent need for new and effective antifungal agents. Here we report the antifungal activities of 19 diverse halogenated quinoline (HQ) small molecules against Candida albicans and Cryptococcus neoformans. Four HQ analogues inhibited C. albicans growth with a minimum inhibitory concentration (MIC) of 100 nM, whilst 16 analogues effectively inhibited C. neoformans at MICs of 50-780 nM. Remarkably, two HQ analogues eradicated mature C. albicans and C. neoformans biofilms [minimum biofilm eradication concentration (MBEC) = 6.25-62.5 µM]. Several active HQs were found to penetrate into fungal cells, whilst one inactive analogue was unable to, suggesting that HQs elicit their antifungal activities through an intracellular mode of action. HQs are a promising class of small molecules that may be useful in future antifungal treatments. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  2. The Cytotoxicity of the Ajoene Analogue BisPMB in WHCO1 Oesophageal Cancer Cells Is Mediated by CHOP/GADD153

    Directory of Open Access Journals (Sweden)

    Vuyolwethu Siyo

    2017-05-01

    Full Text Available Garlic is a food and medicinal plant that has been used in folk medicine since ancient times for its beneficial health effects, which include protection against cancer. Crushed garlic cloves contain an array of small sulfur-rich compounds such as ajoene. Ajoene is able to interfere with biological processes and is cytotoxic to cancer cells in the low micromolar range. BisPMB is a synthetic ajoene analogue that has been shown in our laboratory to have superior cytotoxicity to ajoene. In the current study we have performed a DNA microarray analysis of bisPMB-treated WHCO1 oesophageal cancer cells to identify pathways and processes that are affected by bisPMB. The most significantly enriched biological pathways as assessed by gene ontology, KEGG and ingenuity pathway analysis were those involving protein processing in the endoplasmic reticulum (ER and the unfolded protein response. In support of these pathways, bisPMB was found to inhibit global protein synthesis and lead to increased levels of ubiquitinated proteins. BisPMB also induced alternate splicing of the transcription factor XBP-1; increased the expression of the ER stress sensor GRP78 and induced expression of the ER stress marker CHOP/GADD153. CHOP expression was found to be central to the cytotoxicity of bisPMB as its silencing with siRNA rendered the cells resistant to bisPMB. The MAPK proteins, JNK and ERK1/2 were activated following bisPMB treatment. However JNK activation was not critical in the cytotoxicity of bisPMB, and ERK1/2 activation was found to play a pro-survival role. Overall the ajoene analogue bisPMB appears to induce cytotoxicity in WHCO1 cells by activating the unfolded protein response through CHOP/GADD153.

  3. Opioid Receptor Activity and Analgesic Potency of DPDPE Peptide Analogues Containing a Xylene Bridge.

    Science.gov (United States)

    Stefanucci, Azzurra; Novellino, Ettore; Mirzaie, Sako; Macedonio, Giorgia; Pieretti, Stefano; Minosi, Paola; Szűcs, Edina; Erdei, Anna I; Zádor, Ferenc; Benyhe, Sándor; Mollica, Adriano

    2017-04-13

    d-Pen 2 ,d-Pen 5 enkephalin (DPDPE) is one of the most selective synthetic peptide agonists targeting the δ-opioid receptor. Three cyclic analogues of DPDPE containing a xylene bridge in place of disulfide bond have been synthesized and fully characterized as opioid receptors agonists. The in vitro activity was investigated showing a good affinity of 7a - c for μ- and δ-receptors. In vivo biological assays revealed that 7b is the most potent analogue with the ability to maintain high level of analgesia from 15 to 60 min following intracerebroventricular (i.c.v.) administration, whereas DPDPE was slightly active until 45 min. Compound 7b induced long lasting analgesia also after subcutaneous administration, whereas DPDPE was inactive.

  4. Synthesis, X-ray crystal structure and theoretical calculations of antileishmanial neolignan analogues

    International Nuclear Information System (INIS)

    Nascimento, Josenaide P. do; Santos, Lourivaldo S.; Carmo, Maria Carolina L. do; Brasil, Davi S.B.; Alves, Claudio N.; Santos, Regina Helena A.; Tozzo, Erica; Ferreira, Janaina G.

    2010-01-01

    The synthesis and X-ray crystal diffraction structure of two analogues of neolignans, 2-(4-chlorophenyl)-1-phenylethanone (20) and 2-[(4-chlorophenyl)thio]-1-(3,4-dimethoxyphenyl) propan-1-one (12) is described. The compound 12 presents activity against intracellular Leishmania donovani and Leishmania amazonensis amastigotes that cause cutaneous and visceral leishmaniasis. In addition, the density functional theory (DFT) with the B3LYP hybrid functional was employed to calculate a set of molecular descriptors for nineteen synthetic analogues of neolignans with antileishmanial activities. Afterwards, the stepwise discriminant analysis was performed to investigate possible relationship between the molecular descriptors and biological activities. Through this analysis the compounds were classified into two groups active and inactive according to their degree of biological activities, and the more important properties were charges on some key atoms, electronic affinity and ClogP. (author)

  5. Synthesis, X-ray crystal structure and theoretical calculations of antileishmanial neolignan analogues

    Energy Technology Data Exchange (ETDEWEB)

    Nascimento, Josenaide P. do; Santos, Lourivaldo S.; Carmo, Maria Carolina L. do; Brasil, Davi S.B.; Alves, Claudio N., E-mail: nahum@ufpa.b [Universidade Federal do Para (UFPA), Belem, PA (Brazil). Inst. de Ciencias Exatas e Naturais; Santos, Regina Helena A.; Tozzo, Erica; Ferreira, Janaina G. [Universidade de Sao Paulo (IQSC/USP), Sao Carlos, SP (Brazil). Inst. de Quimica

    2010-07-01

    The synthesis and X-ray crystal diffraction structure of two analogues of neolignans, 2-(4-chlorophenyl)-1-phenylethanone (20) and 2-[(4-chlorophenyl)thio]-1-(3,4-dimethoxyphenyl) propan-1-one (12) is described. The compound 12 presents activity against intracellular Leishmania donovani and Leishmania amazonensis amastigotes that cause cutaneous and visceral leishmaniasis. In addition, the density functional theory (DFT) with the B3LYP hybrid functional was employed to calculate a set of molecular descriptors for nineteen synthetic analogues of neolignans with antileishmanial activities. Afterwards, the stepwise discriminant analysis was performed to investigate possible relationship between the molecular descriptors and biological activities. Through this analysis the compounds were classified into two groups active and inactive according to their degree of biological activities, and the more important properties were charges on some key atoms, electronic affinity and ClogP. (author)

  6. Synthesis and antifungal evaluation of PCA amide analogues.

    Science.gov (United States)

    Qin, Chuan; Yu, Di-Ya; Zhou, Xu-Dong; Zhang, Min; Wu, Qing-Lai; Li, Jun-Kai

    2018-04-18

    To improve the physical and chemical properties of phenazine-1-carboxylic acid (PCA) and find higher antifungal compounds, a series of PCA amide analogues were designed and synthesized and their structures were confirmed by 1 H NMR, HRMS, and X-ray. Most compounds showed some antifungal activities in vitro. Particularly, compound 3d exhibited inhibition effect against Pyriculariaoryzac Cavgra with EC 50 value of 28.7 μM and compound 3q exhibited effect against Rhizoctonia solani with EC 50 value of 24.5 μM, more potently active than that of the positive control PCA with its EC 50 values of 37.3 μM (Pyriculariaoryzac Cavgra) and 33.2 μM (Rhizoctonia solani), respectively.

  7. Synthesis and anticancer evaluation of spermatinamine analogues

    KAUST Repository

    Moosa, Basem

    2016-02-04

    Spermatinamine was isolated from an Australian marine sponge, Pseudoceratina sp. as an inhibitor of isoprenylcystiene carboxyl methyltransferase (Icmt), an attractive and novel anticancer target. Herein, we report the synthesis of spermatinamine analogues and their cytotoxic evaluation against three human cancer cell lines i.e. cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell lines with the IC50 values in the range of 5 - 10 μM. The obtained results suggested that longer polyamine linker along with aromatic oxime substitution provided the most potent analogue compounds against cancer cell lines.

  8. Naturally Inspired Peptide Leads: Alanine Scanning Reveals an Actin-Targeting Thiazole Analogue of Bisebromoamide.

    Science.gov (United States)

    Johnston, Heather J; Boys, Sarah K; Makda, Ashraff; Carragher, Neil O; Hulme, Alison N

    2016-09-02

    Systematic alanine scanning of the linear peptide bisebromoamide (BBA), isolated from a marine cyanobacterium, was enabled by solid-phase peptide synthesis of thiazole analogues. The analogues have comparable cytotoxicity (nanomolar) to that of BBA, and cellular morphology assays indicated that they target the actin cytoskeleton. Pathway inhibition in human colon tumour (HCT116) cells was explored by reverse phase protein array (RPPA) analysis, which showed a dose-dependent response in IRS-1 expression. Alanine scanning reveals a structural dependence to the cytotoxicity, actin targeting and pathway inhibition, and allows a new readily synthesised lead to be proposed. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  9. Synthesis and evaluation of chalcone analogues based pyrimidines as angiotensin converting enzyme inhibitors.

    Science.gov (United States)

    Bukhari, S N A; Butt, A M; Amjad, M W B; Ahmad, W; Shah, V H; Trivedi, A R

    2013-11-01

    Hypertension is a widespread and frequently progressive ailment that imparts a foremost threat for cardiovascular and renal disorders. Mammoth efforts are needed for the synthesis of innovative antihypertensive agents to combat this lethal disease. Chalcones have shown antihypertensive activity through inhibition of Angiotensin Converting Enzyme (ACE). Hence, a series of chalcone analogues is synthesized and used as precursor for the synthesis of novel series of pyrimidines. Precursor chalcones were prepared by reacting aldehydes and ketones in presence of sodium hydroxide followed by synthesis of corresponding pyrimidines by reaction with urea in presence of potassium hydroxide. Both groups were then evaluated for their effects on ACE. The results depicted that pyrimidines were more active than chalcones with methoxy (C5 and P5) substitution showing best results to inhibit ACE. Given that chalcone analogues and pyrimidines show a potential as the angiotensin converting enzyme inhibitors.

  10. In Silico Screening and In Vitro Activity Measurement of Javamide Analogues as Potential p38 MAPK Inhibitors

    Directory of Open Access Journals (Sweden)

    Jae B. Park

    2017-12-01

    Full Text Available p38 Mitogen-activated protein kinase (p38 MAPK is a protein kinase critically involved in the progress of inflammation/stress-associated diseases. Our data suggested that javamide analogues may contain strong anti-inflammation activities, but there is little information about their effects on p38 MAPK. Therefore, in this paper, the effects of thirty javamide analogues on p38 MAPK were investigated using in silico screening and in vitro p38 MAPK assay methods. The javamide analogues were synthesized and their chemical structures were confirmed using nuclear magnetic resonance (NMR spectroscopic methods. Then, the javamide analogues were screened using an in silico modeling program. The screened analogues demonstrated a wide range of binding energy (ΔE; −20 to −39 and several analogues with ΔE; −34 to −39 showed strong binding affinity to p38 MAPK. In vitro p38 MAPK assay, the kinase was significantly inhibited by the analogues with great binding energy (ΔE; −34 to −39 and in silico scores (Avg. score; −27.5 to −29.3. Furthermore, the comparative analysis of both assays showed a positive correlation between the in silico scores and p38 MAPK inhibition. In fact, the javamide analogues with top five in silico scores (Avg. score; −27.5 to −29.3 were found to inhibit p38 MAPK by 27–31% (p < 0.05 better than those with less scores (ΔE < −27.0. Especially, javamide-II-O-ethyl ester with relatively high in silico score (Avg. score; −29.2 inhibited p38 MAPK (IC50 = 9.9 μM a little better than its methyl ester with best in silico score (Avg. score; −29.3. To support the ability to inhibit p38 MAPK, the treatment of javamide-II-ethyl and -methyl esters could suppress the production of IL-8 and MCP-1 protein significantly by 22–73% (p < 0.05 in the differentiated THP-1 cells, and the inhibition was slightly stronger by the ethyl ester than the methyl ester. Altogether, this study suggests that javamide-II-O-ethyl ester may

  11. Synthetic guide star generation

    Science.gov (United States)

    Payne, Stephen A [Castro Valley, CA; Page, Ralph H [Castro Valley, CA; Ebbers, Christopher A [Livermore, CA; Beach, Raymond J [Livermore, CA

    2008-06-10

    A system for assisting in observing a celestial object and providing synthetic guide star generation. A lasing system provides radiation at a frequency at or near 938 nm and radiation at a frequency at or near 1583 nm. The lasing system includes a fiber laser operating between 880 nm and 960 nm and a fiber laser operating between 1524 nm and 1650 nm. A frequency-conversion system mixes the radiation and generates light at a frequency at or near 589 nm. A system directs the light at a frequency at or near 589 nm toward the celestial object and provides synthetic guide star generation.

  12. Synthetic Aperture Sequential Beamforming

    DEFF Research Database (Denmark)

    Kortbek, Jacob; Jensen, Jørgen Arendt; Gammelmark, Kim Løkke

    2008-01-01

    A synthetic aperture focusing (SAF) technique denoted Synthetic Aperture Sequential Beamforming (SASB) suitable for 2D and 3D imaging is presented. The technique differ from prior art of SAF in the sense that SAF is performed on pre-beamformed data contrary to channel data. The objective...... is stored. The second stage applies the focused image lines from the first stage as input data. The SASB method has been investigated using simulations in Field II and by off-line processing of data acquired with a commercial scanner. The performance of SASB with a static image object is compared with DRF...

  13. Analogue alternative the electronic analogue computer in Britain and the USA, 1930-1975

    CERN Document Server

    Small, James S

    2013-01-01

    We are in the midst of a digital revolution - until recently, the majority of appliances used in everyday life have been developed with analogue technology. Now, either at home or out and about, we are surrounded by digital technology such as digital 'film', audio systems, computers and telephones. From the late 1940s until the 1970s, analogue technology was a genuine alternative to digital, and the two competing technologies ran parallel with each other. During this period, a community of engineers, scientists, academics and businessmen continued to develop and promote the analogue computer.

  14. What Are Synthetic Cannabinoids?

    Science.gov (United States)

    ... market and are intended to produce the same effects as illegal drugs. Some of these substances may have been around for years but have reentered the market in altered chemical forms, or due to renewed popularity. False Advertising Synthetic cannabinoid products are often labeled "not for ...

  15. Towards a synthetic chloroplast.

    Directory of Open Access Journals (Sweden)

    Christina M Agapakis

    2011-04-01

    Full Text Available The evolution of eukaryotic cells is widely agreed to have proceeded through a series of endosymbiotic events between larger cells and proteobacteria or cyanobacteria, leading to the formation of mitochondria or chloroplasts, respectively. Engineered endosymbiotic relationships between different species of cells are a valuable tool for synthetic biology, where engineered pathways based on two species could take advantage of the unique abilities of each mutualistic partner.We explored the possibility of using the photosynthetic bacterium Synechococcus elongatus PCC 7942 as a platform for studying evolutionary dynamics and for designing two-species synthetic biological systems. We observed that the cyanobacteria were relatively harmless to eukaryotic host cells compared to Escherichia coli when injected into the embryos of zebrafish, Danio rerio, or taken up by mammalian macrophages. In addition, when engineered with invasin from Yersinia pestis and listeriolysin O from Listeria monocytogenes, S. elongatus was able to invade cultured mammalian cells and divide inside macrophages.Our results show that it is possible to engineer photosynthetic bacteria to invade the cytoplasm of mammalian cells for further engineering and applications in synthetic biology. Engineered invasive but non-pathogenic or immunogenic photosynthetic bacteria have great potential as synthetic biological devices.

  16. Synthetic Metabolic Pathways

    DEFF Research Database (Denmark)

    topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Synthetic Metabolic Pathways: Methods and Protocols aims to ensure successful results in the further study...

  17. Synthetic growth reference charts

    NARCIS (Netherlands)

    Hermanussen, Michael; Stec, Karol; Aßmann, Christian; Meigen, Christof; Van Buuren, Stef

    2016-01-01

    Objectives: To reanalyze the between-population variance in height, weight, and body mass index (BMI), and to provide a globally applicable technique for generating synthetic growth reference charts. Methods: Using a baseline set of 196 female and 197 male growth studies published since 1831, common

  18. A formidable synthetic challenge

    Indian Academy of Sciences (India)

    Isolation and characterization of maoecrystal V, a C19 terpenoid, having potent and selective cytotoxicity towards HeLa cells was recently reported. Unusually complex pentacyclic molecular structure, presence of spirofused rings and several stereogenic centres posed a great synthetic challenge. In this short review, efforts ...

  19. Synthetic antiferromagnetic spintronics

    Science.gov (United States)

    Duine, R. A.; Lee, Kyung-Jin; Parkin, Stuart S. P.; Stiles, M. D.

    2018-03-01

    Spintronic and nanomagnetic devices often derive their functionality from layers of different materials and the interfaces between them. We discuss the opportunities that arise from synthetic antiferromagnets consisting of two or more ferromagnetic layers that are separated by metallic spacers or tunnel barriers and have antiparallel magnetizations.

  20. Bioaccumulation of the synthetic dye Basic Violet 3 and heavy metals in single and binary systems by Candida tropicalis grown in a sugarcane bagasse extract medium: Modelling optimal conditions using response surface methodology (RSM) and inhibition kinetics

    International Nuclear Information System (INIS)

    Das, Devlina; Charumathi, D.; Das, Nilanjana

    2011-01-01

    Single and binary effects of dye Basic Violet 3 and heavy metals, 'namely', Pb(II) and Cd(II), were investigated for their role in dye and heavy metal bioaccumulation by Candida tropicalis that was grown in a sugarcane bagasse extract medium containing 8 g/L, 16 g/L or 24 g/L of sugar. The optimum pH was found to be 4.0 in the single system and 5.0 in the binary system. A central composite design was successfully used to analyse the experimental results. Four numerical correlations that were fitted to a second order quadratic equation were used to estimate optimum combinations predicted by response surface methodology. In the dye-Pb(II) binary system, C. tropicalis was capable of bioaccumulating 49.5% of the dye and 49.6% of the Pb(II), in comparison to 15.9% of the dye and 55.5% of the Cd(II) in the dye-Cd(II) binary system. In these two systems, the pollutants were dispersed at minimum working concentration levels. Competitive inhibition was observed in both the single and binary systems, which was suggested by an increase in the saturation constant, K s , and a simultaneous decrease in the specific growth rate that was calculated from Lineweaver-Burk plots. Atomic force microscopy images demonstrated changes in yeast cell morphology by exposure to these contaminants in the dye-Pb(II) binary system grown in a bioaccumulation medium.

  1. An Olefin Cross-Metathesis Approach to Depudecin and Stereoisomeric Analogues.

    Science.gov (United States)

    Cheng-Sánchez, Iván; García-Ruiz, Cristina; Guerrero-Vásquez, Guillermo A; Sarabia, Francisco

    2017-05-05

    A new total synthesis of the natural product (-)-depudecin, a unique and unexplored histone deacetylase (HDAC) inhibitor, is reported. A key feature of the synthesis is the utilization of an olefin cross-metathesis strategy, which provides for an efficient and improved access to natural depudecin, compared with our previous linear synthesis. Featured by its brevity and convergency, our developed synthetic strategy was applied to the preparation of the 10-epi derivative and the enantiomer of depudecin, which represent interesting stereoisomeric analogues for structure-activity relationship studies.

  2. Synthetic Plant Defense Elicitors

    Directory of Open Access Journals (Sweden)

    Yasemin eBektas

    2015-01-01

    Full Text Available To defend themselves against invading pathogens plants utilize a complex regulatory network that coordinates extensive transcriptional and metabolic reprogramming. Although many of the key players of this immunity-associated network are known, the details of its topology and dynamics are still poorly understood. As an alternative to forward and reverse genetic studies, chemical genetics-related approaches based on bioactive small molecules have gained substantial popularity in the analysis of biological pathways and networks. Use of such molecular probes can allow researchers to access biological space that was previously inaccessible to genetic analyses due to gene redundancy or lethality of mutations. Synthetic elicitors are small drug like molecules that induce plant defense responses, but are distinct from known natural elicitors of plant immunity. While the discovery of the some synthetic elicitors had already been reported in the 1970s, recent breakthroughs in combinatorial chemical synthesis now allow for inexpensive high-throughput screens for bioactive plant defense-inducing compounds. Along with powerful reverse genetics tools and resources available for model plants and crop systems, comprehensive collections of new synthetic elicitors will likely allow plant scientists to study the intricacies of plant defense signaling pathways and networks in an unparalleled fashion. As synthetic elicitors can protect crops from diseases, without the need to be directly toxic for pathogenic organisms, they may also serve as promising alternatives to conventional biocidal pesticides, which often are harmful for the environment, farmers and consumers. Here we are discussing various types of synthetic elicitors that have been used for studies on the plant immune system, their modes-of-action as well as their application in crop protection.

  3. Total synthesis of sannanine and analogues thereof

    Indian Academy of Sciences (India)

    BADHER NAVEEN

    2018-03-02

    Mar 2, 2018 ... concise manner. The key strategies involve Friedländer quinoline synthesis, demethylation, in situ oxidation and amination process. ..... (b) Hargreaves R, David C L, Whitesell L and Skibo E. B 2003 Design of Quinolinedione-Based Geldanamycin. Analogues Bioorg. Med. Chem. Lett. 13 3075; (c) Arg-.

  4. Ultrasound exfoliation of inorganic analogues of graphene

    Czech Academy of Sciences Publication Activity Database

    Štengl, Václav; Henych, Jiří; Slušná, Michaela; Ecorchard, Petra

    2014-01-01

    Roč. 9, APR (2014), s. 1-14 ISSN 1556-276X R&D Projects: GA ČR(CZ) GA14-05146S Institutional support: RVO:61388980 Keywords : Ultrasound * Exfoliation * Graphene inorganic analogues Subject RIV: CA - Inorganic Chemistry Impact factor: 2.779, year: 2014

  5. The World Is either Digital or Analogue

    NARCIS (Netherlands)

    Berto, F.; Tagliabue, J.

    2014-01-01

    We address an argument by Floridi (Synthese 168(1):151-178, 2009; 2011a), to the effect that digital and analogue are not features of reality, only of modes of presentation of reality. One can therefore have an informational ontology, like Floridi’s Informational Structural Realism, without

  6. Somatostatin analogue scintigraphy and tuberculosis: case report

    International Nuclear Information System (INIS)

    Biancheri, I.; Rudenko, B.; Vautrin, P.; Raddoul, J.; Lamfichek, N.; Kantelip, B.; Mantion, G.

    2005-01-01

    Scintigraphy using a radiolabelled somatostatin analogue (111 In-pentetreotide) is useful in the detection of neuroendocrine tumors. But this radiopharmaceutical accumulates also in solid tumours or in inflammatory diseases such as granulomatosis. We present a case of 111 In-pentetreotide uptake in a tuberculous adenopathy. (author)

  7. Prussian Blue Analogues of Reduced Dimensionality

    NARCIS (Netherlands)

    Gengler, Regis Y. N.; Toma, Luminita M.; Pardo, Emilio; Lloret, Francesc; Ke, Xiaoxing; Van Tendeloo, Gustaaf; Gournis, Dimitrios; Rudolf, Petra

    2012-01-01

    Mixed-valence polycyanides (Prussian Blue analogues) possess a rich palette of properties spanning from room-temperature ferromagnetism to zero thermal expansion, which can be tuned by chemical modifications or the application of external stimuli (temperature, pressure, light irradiation). While

  8. The Palmottu analogue project: overview for 1993

    International Nuclear Information System (INIS)

    Ruskeeniemi, T.; Blomqvist, R.; Suksi, J.; Niini, H.

    1994-01-01

    This article gives a summary of the activities carried out within the Palmottu analogue project in 1993. It consists of (1) an introductory part, followed by (2) a geological description of the site, and (3)an up-to-date summary of the results of the project. (orig.) (33 refs., 6 figs.)

  9. Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues

    Directory of Open Access Journals (Sweden)

    Xu-Wen Li

    2013-07-01

    Full Text Available Aurachins are myxobacterial 3-farnesyl-4(1H-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad–Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure–activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization.

  10. Resveratrol analogue, HS-1793, induces apoptotic cell death and cell cycle arrest through downregulation of AKT in human colon cancer cells.

    Science.gov (United States)

    Kim, Dong Hwan; Kim, Min Jeong; Sung, Bokyung; Suh, Hongsuk; Jung, Jee H; Chung, Hae Young; Kim, Nam Deuk

    2017-01-01

    Resveratrol, a polyphenolic compound, is a naturally occurring phytochemical and is found in a variety of plants, including grapes, berries and peanuts. It has gained much attention for its potential anticancer activity against various types of human cancer. However, the usefulness of resveratrol as a chemotherapeutic agent is limited by its photosensitivity and metabolic instability. In this study the effects of a synthetic analogue of resveratrol, HS-1793, on the proliferation and apoptotic cell death were investigated using HCT116 human colon cancer cells. Although this compound has been reported to have anticancer activities in several human cancer cell lines, the therapeutic effects of HS-1793 on human colon cancer and its mechanisms of action have not been extensively studied. HS-1793 inhibited cell growth and induced apoptotic cell death in a concentration-dependent fashion. Induction of apoptosis was determined by morphological changes, cleavage of poly(ADP-ribose) polymerase, alteration of Bax/Bcl-2 expression ratio, and caspase activations. Flow cytometric analysis revealed that HS-1793 induced G2/M arrest in the cell cycle progression in HCT116 cells. Furthermore, HS-1793 showed more potent anticancer effects in several aspects than resveratrol in HCT116 cells. In addition, HS-1793 suppressed Akt and the phosphatidylinositol-3 kinase/Akt inhibitor LY294002 was found to enhance its induction of apoptosis. Thus, these findings suggest that HS-1793 have potential as a candidate chemotherapeutic agent against human colon cancer.

  11. Natural product analogues: towards a blueprint for analogue-focused synthesis.

    Science.gov (United States)

    Bebbington, Magnus W P

    2017-08-14

    For the first time a general overview of approaches to the synthesis of natural product analogues is presented. This reflects a process of evolution of natural product synthesis which has accelerated in the years since the implementation of diversity-oriented synthesis, which has emerged in parallel with collective synthesis, diverted total synthesis and the preparation of truncated natural products optimised for biological activity. A method involving computational assessment for the validation of core-modified natural product analogues is discussed.

  12. Library construction and biological evaluation of enmein-type diterpenoid analogues as potential anticancer agents.

    Science.gov (United States)

    Li, Dahong; Xu, Shengtao; Cai, Hao; Pei, Lingling; Wang, Lei; Wu, Xiaoming; Yao, Hequan; Jiang, Jieyun; Sun, Yijun; Xu, Jinyi

    2013-05-01

    A library of promising enmein-type 14-O-diterpenoid derivatives was constructed from a commercially available kaurene-type oridonin by practical and efficient synthetic methods. These synthetic derivatives were evaluated for their antiproliferative activities against a set of four human cancer cell lines. The IC50 values are similar to or improved over those of the parent molecule and paclitaxel, the latter of which was used as a positive control. Compound 29 was further investigated for its apoptotic properties against human hepatocarcinoma Bel-7402 cells to better understand its mode of action. Moreover, compound 29 was shown to have potent antitumor activity in vivo in studies with a murine model of gastric cancer (MGC-803 mice). These results warrant further preclinical investigations of these diterpenoid-based analogues as potential novel anticancer chemotherapeutics. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Synthesis and cannabinoid receptor activity of ketoalkenes from Echinacea pallida and nonnatural analogues.

    Science.gov (United States)

    Egger, Michael; Pellett, Patrina; Nickl, Kathrin; Geiger, Sarah; Graetz, Stephanie; Seifert, Roland; Heilmann, Jörg; König, Burkhard

    2008-01-01

    Despite its popularity and widespread use, the efficacy of Echinacea products remains unclear and controversial. Among the various compounds isolated from Echinacea, ketoalkenes and ketoalkenynes exclusively found in the pale purple coneflower (E. pallida) are major components of the extracts. In contrast to E. purpurea alkamides, these compounds have not been synthesized and studied for immunostimulatory effects. We present a practical and useful synthetic approach to the ketoalkenes using palladium-catalyzed cross-coupling reactions and the pharmaceutical results at the human cannabinoid receptors. The synthetic route developed provides overall good yields for the ketoalkenes and is applicable to other natural products with similar 1,4-diene motifs. No significant activity was observed at either receptor, indicating that the ketoalkenes from E. pallida are not responsible for immunomodulatory effects mediated via the cannabinergic system. However, newly synthesized non-natural analogues showed micro-molar potency at both cannabinoid receptors.

  14. Tryptophan analogues. 1. Synthesis and antihypertensive activity of positional isomers.

    Science.gov (United States)

    Safdy, M E; Kurchacova, E; Schut, R N; Vidrio, H; Hong, E

    1982-06-01

    A series of tryptophan analogues having the carboxyl function at the beta-position was synthesized and tested for antihypertensive activity. The 5-methoxy analogue 46 exhibited antihypertensive activity in the rat via the oral route and was much more potent than the normal tryptophan analogue. The methyl ester was found to be a critical structural feature for activity.

  15. Effect of GR24, a synthetic analogue of strigolactones, on gene ...

    African Journals Online (AJOL)

    Sporisorium reilianum f.sp zeae, a basidiomycetous fungus belonging to Ustilaginaceae, is the causal agent of maize head smut. Its pathogenicity is initiated by fusion of two compatible sporidia which give rise to the formation of a dikaryotic pathogenic hyphe. In addition, pathogenic dimorphic diploid strains called ...

  16. Standardization in synthetic biology.

    Science.gov (United States)

    Müller, Kristian M; Arndt, Katja M

    2012-01-01

    Synthetic Biology is founded on the idea that complex biological systems are built most effectively when the task is divided in abstracted layers and all required components are readily available and well-described. This requires interdisciplinary collaboration at several levels and a common understanding of the functioning of each component. Standardization of the physical composition and the description of each part is required as well as a controlled vocabulary to aid design and ensure interoperability. Here, we describe standardization initiatives from several disciplines, which can contribute to Synthetic Biology. We provide examples of the concerted standardization efforts of the BioBricks Foundation comprising the request for comments (RFC) and the Registry of Standardized Biological parts as well as the international Genetically Engineered Machine (iGEM) competition.

  17. Optical synthetic aperture radar

    Science.gov (United States)

    Ilovitsh, Asaf; Zach, Shlomo; Zalevsky, Zeev

    2013-06-01

    A method is proposed for increasing the resolution of an object and overcoming the diffraction limit of an optical system installed on top of a moving imaging system, such as an airborne platform or satellite. The resolution improvement is obtained via a two-step process. First, three low resolution differently defocused images are captured and the optical phase is retrieved using an improved iterative Gershberg-Saxton based algorithm. The phase retrieval allows numerical back propagation of the field to the aperture plane. Second, the imaging system is shifted and the first step is repeated. The obtained optical fields at the aperture plane are combined and a synthetically increased lens aperture is generated along the direction of movement, yielding higher imaging resolution. The method resembles a well-known approach from the microwave regime called the synthetic aperture radar in which the antenna size is synthetically increased along the platform propagation direction. The proposed method is demonstrated via Matlab simulation as well as through laboratory experiment.

  18. Dose-response of seeds of the parasitic weeds Striga and Orobanche toward the synthetic germination stimulants GR24.

    NARCIS (Netherlands)

    Wigchert, S.C.M.; Kuiper, E.; Boelhouwer, G.J.; Nefkens, G.H.L.; Verkley, J.A.C.; Zwanenburg, B.

    1999-01-01

    Striga and Orobanche seeds germinate in response to a host-derived germination stimulant. Dose-response curves of the synthetic strigolactone analogues GR 24 and Nijmegen 1 were determined, and their activities were compared to that of the naturally occurring stimulant sorgolactone. Typical

  19. A novel nucleic acid analogue shows strong angiogenic activity

    Energy Technology Data Exchange (ETDEWEB)

    Tsukamoto, Ikuko, E-mail: tukamoto@med.kagawa-u.ac.jp [Department of Pharmaco-Bio-Informatics, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan); Sakakibara, Norikazu; Maruyama, Tokumi [Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193 (Japan); Igarashi, Junsuke; Kosaka, Hiroaki [Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan); Kubota, Yasuo [Department of Dermatology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan); Tokuda, Masaaki [Department of Cell Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan); Ashino, Hiromi [The Tokyo Metropolitan Institute of Medical Science, 1-6 Kamikitazawa2-chome, Setagaya-ku, Tokyo 156-8506 (Japan); Hattori, Kenichi; Tanaka, Shinji; Kawata, Mitsuhiro [Teikoku Seiyaku Co., Ltd., Sanbonmatsu, Higashikagawa, Kagawa 769-2695 (Japan); Konishi, Ryoji [Department of Pharmaco-Bio-Informatics, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan)

    2010-09-03

    Research highlights: {yields} A novel nucleic acid analogue (2Cl-C.OXT-A, m.w. 284) showed angiogenic potency. {yields} It stimulated the tube formation, proliferation and migration of HUVEC in vitro. {yields} 2Cl-C.OXT-A induced the activation of ERK1/2 and MEK in HUVEC. {yields} Angiogenic potency in vivo was confirmed in CAM assay and rabbit cornea assay. {yields} A synthesized small angiogenic agent would have great clinical therapeutic value. -- Abstract: A novel nucleic acid analogue (2Cl-C.OXT-A) significantly stimulated tube formation of human umbilical endothelial cells (HUVEC). Its maximum potency at 100 {mu}M was stronger than that of vascular endothelial growth factor (VEGF), a positive control. At this concentration, 2Cl-C.OXT-A moderately stimulated proliferation as well as migration of HUVEC. To gain mechanistic insights how 2Cl-C.OXT-A promotes angiogenic responses in HUVEC, we performed immunoblot analyses using phospho-specific antibodies as probes. 2Cl-C.OXT-A induced robust phosphorylation/activation of MAP kinase ERK1/2 and an upstream MAP kinase kinase MEK. Conversely, a MEK inhibitor PD98059 abolished ERK1/2 activation and tube formation both enhanced by 2Cl-C.OXT-A. In contrast, MAP kinase responses elicited by 2Cl-C.OXT-A were not inhibited by SU5416, a specific inhibitor of VEGF receptor tyrosine kinase. Collectively these results suggest that 2Cl-C.OXT-A-induces angiogenic responses in HUVEC mediated by a MAP kinase cascade comprising MEK and ERK1/2, but independently of VEGF receptor tyrosine kinase. In vivo assay using chicken chorioallantoic membrane (CAM) and rabbit cornea also suggested the angiogenic potency of 2Cl-C.OXT-A.

  20. Somatostatin analogues for acute bleeding oesophageal varices

    DEFF Research Database (Denmark)

    Gøtzsche, Peter C.; Hrobjartsson, A.

    2008-01-01

    BACKGROUND: Somatostatin and its derivatives are sometimes used for emergency treatment of bleeding oesophageal varices in patients with cirrhosis of the liver. OBJECTIVES: To study whether somatostatin or its analogues improve survival or reduce the need for blood transfusions in patients...... with bleeding oesophageal varices. SEARCH STRATEGY: PubMed and The Cochrane Library were searched (November 2007). Reference lists of publications, contacts with authors. SELECTION CRITERIA: All randomised trials comparing somatostatin or analogues with placebo or no treatment in patients suspected of acute...... or recent bleeding from oesophageal varices. DATA COLLECTION AND ANALYSIS: The outcome measures extracted were: mortality, blood transfusions, use of balloon tamponade, initial haemostasis and rebleeding. Intention-to-treat analyses including all randomised patients were conducted if possible; a random...

  1. Studies of natural analogues and geological systems

    International Nuclear Information System (INIS)

    Brandberg, F.; Grundfelt, B.; Hoeglund, L.; Skagius K.; Karlsson, F.; Smellie, J.

    1993-04-01

    This review has involved studies of natural analogues and natural geological systems leading to the identification and quantification of processes and features of importance to the performance and safety of repositories for radioactive waste. The features and processes selected for the study comprise general geochemical issues related to the performance of the near- and far-field, the performance and durability of construction materials and the effects of glaciation. For each of these areas a number of potentially important processes for repository performance have been described, and evidence for their existence, as well as quantification of parameters of models describing the processes have been sought from major natural analogue studies and site investigations. The review has aimed at covering a relatively broad range of issues at the expense of in-depth analysis. The quantitative data presented are in most cases compilations of data from the literature; in a few cases results of evaluations made within the current project are included

  2. Boron hydride analogues of the fullerenes

    International Nuclear Information System (INIS)

    Quong, A.A.; Pederson, M.R.; Broughton, J.Q.

    1994-01-01

    The BH moiety is isoelectronic with C. We have studied the stability of the (BH) 60 analogue of the C 60 fullerene as well as the dual-structure (BH) 32 icosahedron, both of them being putative structures, by performing local-density-functional electronic calculations. To aid in our analysis, we have also studied other homologues of these systems. We find that the latter, i.e., the dual structure, is the more stable although the former is as stable as one of the latter's lower homologues. Boron hydrides, it seems, naturally form the dual structures used in algorithmic optimization of complex fullerene systems. Fully relaxed geometries are reported as well as electron affinities and effective Hubbard U parameters. These systems form very stable anions and we conclude that a search for BH analogues of the C 60 alkali-metal supeconductors might prove very fruitful

  3. Synthetic cannabis and respiratory depression.

    Science.gov (United States)

    Jinwala, Felecia N; Gupta, Mayank

    2012-12-01

    In recent years, synthetic cannabis use has been increasing in appeal among adolescents, and its use is now at a 30 year peak among high school seniors. The constituents of synthetic cannabis are difficult to monitor, given the drug's easy accessibility. Currently, 40 U.S. states have banned the distribution and use of some known synthetic cannabinoids, and have included these drugs in the Schedule I category. The depressive respiratory effect in humans caused by synthetic cannabis inhalation has not been thoroughly investigated in the medical literature. We are the first to report, to our knowledge, two cases of self-reported synthetic cannabis use leading to respiratory depression and necessary intubation.

  4. The synthesis and pharmacology of ephedrine analogues

    OpenAIRE

    Mullen, Aidan J

    1991-01-01

    In this report we set out to extend recent studies on substituted PAC analogues produced by the fermentation of aromatic aldehydes with Saccharomyces cerevisiae. The medium selected contained glucose as a carbon source for the biotransformation, and sodium pyruvate as an inhibitor for alcohol dehydrogenase, the enzyme responsible for the conversion of the carbinol to a benzyl alcohol derivatives. An investigation of sodium cyanoborohydride for a selective reductive ami...

  5. Electromagnetic wave analogue of electronic diode

    OpenAIRE

    Shadrivov, Ilya V.; Powell, David A.; Kivshar, Yuri S.; Fedotov, Vassili A.; Zheludev, Nikolay I.

    2010-01-01

    An electronic diode is a nonlinear semiconductor circuit component that allows conduction of electrical current in one direction only. A component with similar functionality for electromagnetic waves, an electromagnetic isolator, is based on the Faraday effect of the polarization state rotation and is also a key component of optical and microwave systems. Here we demonstrate a chiral electromagnetic diode, which is a direct analogue of an electronic diode: its functionality is underpinned by ...

  6. Geometric Analogue of Holographic Reduced Representation

    OpenAIRE

    Aerts, Diederik; Czachor, Marek; De Moor, Bart

    2007-01-01

    Holographic reduced representations (HRR) are based on superpositions of convolution-bound $n$-tuples, but the $n$-tuples cannot be regarded as vectors since the formalism is basis dependent. This is why HRR cannot be associated with geometric structures. Replacing convolutions by geometric products one arrives at reduced representations analogous to HRR but interpretable in terms of geometry. Variable bindings occurring in both HRR and its geometric analogue mathematically correspond to two ...

  7. Analogue forecasting of New Zealand climate anomalies

    Science.gov (United States)

    Mullan, A. Brett; Thompson, Craig S.

    2006-03-01

    An analogue forecast scheme is described for multifield prediction of monthly and seasonal New Zealand climate anomalies on the basis of the methodology of Livezey and Barnston ([1988]) for US seasonal temperatures. The method is applied to predicting terciles of temperature and precipitation for six regions of New Zealand. Empirical orthogonal function analysis is used to reduce sea surface temperature and sea-level pressure predictors down to a set of five independent indices, which incorporate variations due to El Niño-Southern Oscillation, Indian Ocean sea temperatures and a wave 3 pattern in the Southern Hemisphere westerlies. A full bootstrap cross-validation procedure is carried out, along with Monte Carlo tests, to assess the skill of the method on independent data and to determine the significance of the results. Significant skill is found for seasonal temperature forecasts for the summer and winter seasons; there is less success in predicting monthly temperatures or rainfall at either timescale. Considerable care is required to constrain the climate state vector, from which analogues are defined, and to constrain the search procedure itself, in order to produce results that are stable with respect to small parameter changes in the model. For the New Zealand region, 5 to 7 is found to be the optimum number of closest analogues, and the inclusion of anti-analogues improves the predictions, at least in the seasonal case. Skill in predicting regional temperature and rainfall is shown to be related to a combination of skill in predicting sea-level pressure patterns and to how strongly these patterns project onto temperature and rainfall anomalies.

  8. The Brookhaven electron analogue, 1953--1957

    International Nuclear Information System (INIS)

    Plotkin, M.

    1991-01-01

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary

  9. The Brookhaven electron analogue, 1953--1957

    Energy Technology Data Exchange (ETDEWEB)

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  10. Synthesis of D-nor steroid analogues

    Czech Academy of Sciences Publication Activity Database

    Slavíková, Barbora; Kudová, Eva

    2014-01-01

    Roč. 108, S2 (2014), s142 ISSN 0009-2770. [Conference on Isoprenoids /22./. 07.09.2014-10.09.2014, Praha] R&D Projects: GA TA ČR(CZ) TE01020028; GA ČR(CZ) GAP303/12/1464 Institutional support: RVO:61388963 Keywords : D-nor steroid analogues * patch clamp technique Subject RIV: CC - Organic Chemistry

  11. Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK & CLK Kinases

    Directory of Open Access Journals (Sweden)

    Nadège Loaëc

    2017-10-01

    Full Text Available A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton, physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases and CLKs (cdc2-like kinases and potential pharmacological leads for the treatment of several diseases, including Alzheimer’s disease and Down syndrome. We assembled a small library of marine sponge- and ascidian-derived 2-aminoimidazolone alkaloids, along with several synthetic analogues, and tested them on a panel of mammalian and protozoan kinases. Polyandrocarpamines A and B were found to be potent and selective inhibitors of DYRKs and CLKs. They inhibited cyclin D1 phosphorylation on a DYRK1A phosphosite in cultured cells. 2-Aminoimidazolones thus represent a promising chemical scaffold for the design of potential therapeutic drug candidates acting as specific inhibitors of disease-relevant kinases, and possibly other disease-relevant targets.

  12. Antiangiogenic effects of synthetic analogs of curcumin in vivo ...

    African Journals Online (AJOL)

    The active compound curcumin is isolated from the spice turmeric. Curcumin, curcuminoids and their synthetic analogs have been shown to inhibit the progression of cancer in animal models. In colon and skin carcinogenesis the genetic changes engross different genes, but curcumin is effective in preventing ...

  13. Syntheses And Evaluation Of Asymmetric Curcumin Analogues As Potential Multifunctional Agents For The Treatment Of Alzheimer's Disease.

    Science.gov (United States)

    Zhai, Peng; Xia, Chun-Li; Tan, Jia-Heng; Li, Ding; Ou, Tian-Miao; Huang, Shi-Liang; Gu, Lian-Quan; Huang, Zhi-Shu

    2015-01-01

    A series of new asymmetric curcumin analogues were synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. Our results showed that most of these synthetic compounds had better inhibitory properties against Aβ aggregation compared with curcumin, and better anti-oxidative properties compared with the reference compound Trolox through the study of oxygen radical absorbance capacity (ORAC). Some compounds showed good properties in selectively chelating metal ions such as copper and iron. Besides, some compounds were found to be able to dissociate Aβ protein which had already aggregated. The structure-activity relationships (SAR) of these synthetic compounds were studied. The present investigation indicated that our synthetic asymmetric curcumin derivatives could be potential multifunctional agents for the treatment of Alzheimer's disease (AD).

  14. Synthetic cannabinoids revealing adrenoleukodystrophy.

    Science.gov (United States)

    Fellner, Avi; Benninger, Felix; Djaldetti, Ruth

    2016-02-01

    We report a 41-year-old man who presented with a first generalized tonic-clonic seizure after recent consumption of a synthetic cannabinoid. MRI showed extensive bilateral, mainly frontal, white matter lesions. Blood analysis for very long chain fatty acids was compatible with adrenoleukodystrophy, and a missense mutation in the ABCD1 gene confirmed the diagnosis. We hypothesize that cannabinoid use might have contributed to metabolic decompensation with subacute worsening of the underlying condition. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. CASH vs. SYNTHETIC CDOs

    Directory of Open Access Journals (Sweden)

    Silviu Eduard Dinca

    2015-12-01

    Full Text Available During the past few years, in the recent post-crisis aftermath, global asset managers are constantly searching new ways to optimize their investment portfolios while financial and banking institutions around the world are exploring new alternatives to better secure their financing and refinancing demands altogether with the enhancement of their risk management capabilities. We will exhibit herewith a comparison between the true-sale and synthetic CDO securitizations as financial markets-based funding, investment and risks mitigation techniques, highlighting certain key structuring and implementation specifics on each of them.

  16. Comparative proteomics reveals that YK51, a 4-Hydroxypandurantin-A analogue, downregulates the expression of proteins associated with dengue virus infection

    Directory of Open Access Journals (Sweden)

    Wei-Lian Tan

    2018-01-01

    Full Text Available Dengue is endemic throughout tropical and subtropical regions of the world. Currently, there is no clinically approved therapeutic drug available for this acute viral infection. Although the first dengue vaccine Dengvaxia has been approved for use in certain countries, it is limited to those without a previous dengue infection while the safety and efficacy of the vaccine in those elderly and younger children still need to be identified. Therefore, it is becoming increasingly important to develop therapeutics/drugs to combat dengue virus (DENV infection. YK51 is a synthetic analogue of 4-Hydroxypandurantin A (a compound found in the crude extract of the rhizomes of Boesenbergia rotunda that has been extensively studied by our research group. It has been shown to possess outstanding antiviral activity due to its inhibitory activity against NS2B/NS3 DENV2 protease. However, it is not known how YK51 affects the proteome of DENV infected cells. Therefore, we performed a comparative proteomics analysis to identify changes in protein expression in DENV infected HepG2 cells treated with YK51. Classical two-dimensional gel electrophoresis followed by protein identification using tandem mass spectrometry was employed in this study. Thirty proteins were found to be down-regulated with YK51 treatment. In silico analysis predicted that the down-regulation of eight of these proteins may inhibit viral infection. Our results suggested that apart from inhibiting the NS2B/NS3 DENV2 protease, YK51 may also be causing the down-regulation of a number of proteins that may be responsible in, and/or essential to virus infection. However, functional characterization of these proteins will be necessary before we can conclusively determine their roles in DENV infection.

  17. Comparative proteomics reveals that YK51, a 4-Hydroxypandurantin-A analogue, downregulates the expression of proteins associated with dengue virus infection.

    Science.gov (United States)

    Tan, Wei-Lian; Lee, Yean Kee; Ho, Yen Fong; Yusof, Rohana; Abdul Rahman, Noorsaadah; Karsani, Saiful Anuar

    2018-01-01

    Dengue is endemic throughout tropical and subtropical regions of the world. Currently, there is no clinically approved therapeutic drug available for this acute viral infection. Although the first dengue vaccine Dengvaxia has been approved for use in certain countries, it is limited to those without a previous dengue infection while the safety and efficacy of the vaccine in those elderly and younger children still need to be identified. Therefore, it is becoming increasingly important to develop therapeutics/drugs to combat dengue virus (DENV) infection. YK51 is a synthetic analogue of 4-Hydroxypandurantin A (a compound found in the crude extract of the rhizomes of Boesenbergia rotunda ) that has been extensively studied by our research group. It has been shown to possess outstanding antiviral activity due to its inhibitory activity against NS2B/NS3 DENV2 protease. However, it is not known how YK51 affects the proteome of DENV infected cells. Therefore, we performed a comparative proteomics analysis to identify changes in protein expression in DENV infected HepG2 cells treated with YK51. Classical two-dimensional gel electrophoresis followed by protein identification using tandem mass spectrometry was employed in this study. Thirty proteins were found to be down-regulated with YK51 treatment. In silico analysis predicted that the down-regulation of eight of these proteins may inhibit viral infection. Our results suggested that apart from inhibiting the NS2B/NS3 DENV2 protease, YK51 may also be causing the down-regulation of a number of proteins that may be responsible in, and/or essential to virus infection. However, functional characterization of these proteins will be necessary before we can conclusively determine their roles in DENV infection.

  18. Combining molecular docking and QSAR studies for modeling the anti-tyrosinase activity of aromatic heterocycle thiosemicarbazone analogues

    Science.gov (United States)

    Dong, Huanhuan; Liu, Jing; Liu, Xiaoru; Yu, Yanying; Cao, Shuwen

    2018-01-01

    A collection of thirty-six aromatic heterocycle thiosemicarbazone analogues presented a broad span of anti-tyrosinase activities were designed and obtained. A robust and reliable two-dimensional quantitative structure-activity relationship model, as evidenced by the high q2 and r2 values (0.848 and 0.893, respectively), was gained based on the analogues to predict the quantitative chemical-biological relationship and the new modifier direction. Inhibitory activities of the compounds were found to greatly depend on molecular shape and orbital energy. Substituents brought out large ovality and high highest-occupied molecular orbital energy values helped to improve the activity of these analogues. The molecular docking results provided visual evidence for QSAR analysis and inhibition mechanism. Based on these, two novel tyrosinase inhibitors O04 and O05 with predicted IC50 of 0.5384 and 0.8752 nM were designed and suggested for further research.

  19. Synthesis and structure-activity relationship of griseofulvin analogues as inhibitors of centrosomal clustering in cancer cells.

    Science.gov (United States)

    Rønnest, Mads H; Rebacz, Blanka; Markworth, Lene; Terp, Anette H; Larsen, Thomas O; Krämer, Alwin; Clausen, Mads H

    2009-05-28

    Griseofulvin was identified as an inhibitor of centrosomal clustering in a recently developed assay. Centrosomal clustering is an important cellular event that enables bipolar mitosis for cancer cell lines harboring supernumerary centrosomes. We report herein the synthesis and SAR of 34 griseofulvin analogues as inhibitors of centrosomal clustering. The variations in the griseofulvin structure cover five positions, namely the 4, 5, 2', 3', and 4' positions. Modification of the 4 and 5 positions affords inactive molecules. The enol ether must be at the 2' position, and the 4' position needs to be sp(2) hybridized. The most active analogues were the 2'-benzyloxy and 2'-(4-methylbenzyloxy) analogues as well as the oxime of the former with a 25-fold increase of activity compared to griseofulvin. Comparison of the results obtained in this work with prior reported growth inhibition data for dermatophytic fungi showed both similarities and differences.

  20. Novel propanamide analogue and antiproliferative diketopiperazines from mangrove Streptomyces sp. Q24.

    Science.gov (United States)

    Ye, Xuewei; Chai, Weiyun; Lian, Xiao-Yuan; Zhang, Zhizhen

    2017-06-01

    A new propanamide analogue (1), along with one known alkaloid (2) and four known diketopiperazines (3-6), was isolated from a cultured broth of the actinomycete Streptomyces sp. Q24 that was obtained from a sample of mangrove soil. The structures of these isolates were characterised as 3-acetylamino-N-2-thienyl-propanamide (1), N-acetyltryptamine (2), cyclo-(l-phenylalanine-l-4-hydroxyproline) (3), cyclo-(l-leucine-l-4-hydroxyproline) (4), cyclo-(l-phenylalanine-d-4-hydroxyproline) (5) and cyclo-(l-leucine-l-proline) (6) based on their NMR and HRESIMS data as well as optical rotation. Three diketopiperazines (3, 4, 6) showed activity in inhibiting the proliferation of human glioma U87-MG and U251 cells. This type of the new propanamide analogue (1) is first found from a nature source and the antiproliferative property of these three diketopiperazines against glioma cells is also reported herein for the first time.

  1. Synthesis and GGCT Inhibitory Activity of N-Glutaryl-L-alanine Analogues.

    Science.gov (United States)

    Ii, Hiromi; Yoshiki, Tatsuhiro; Hoshiya, Naoyuki; Uenishi, Jun'ichi

    2016-01-01

    γ-Glutamylcyclotransferase (GGCT) is an important enzyme that cleaves γ-glutamyl-amino acid in the γ-glutamyl cycle to release 5-oxoproline and amino acid. Eighteen N-acyl-L-alanine analogues including eleven new compounds have been synthesized and examined for their inhibitory activity against recombinant human GGCT protein. Simple N-glutaryl-L-alanine was found to be the most potent inhibitor for GGCT. Other N-glutaryl-L-alanine analogues having methyl and dimethyl substituents at the 2-position were moderately effective, while N-(3R-aminoglutary)-L-alanine, the substrate having an (R)-amino group at the 3-position or N-(N-methyl-3-azaglutaryl)-L-alanine, the substrate having an N-methyl substituent on the 3-azaglutaryl carbon, in constract, exhibited excellent inhibition properties.

  2. Synthetic-gauge-field-induced Dirac semimetal state in an acoustic resonator system

    Science.gov (United States)

    Yang, Zhaoju; Gao, Fei; Shi, Xihang; Zhang, Baile

    2016-12-01

    Recently, a proposal of synthetic gauge field in reduced two-dimensional (2D) system from three-dimensional (3D) acoustic structure shows an analogue of the gapped Haldane model with fixed k z , and achieves the gapless Weyl semimetal phase in 3D momentum space. Here, extending this approach of synthetic gauge flux, we propose a reduced square lattice of acoustic resonators, which exhibits Dirac nodes with broken effective time-reversal symmetry. Protected by an additional hidden symmetry, these Dirac nodes with quantized values of topological charge are characterized by nonzero winding number and the finite structure exhibits flat edge modes that cannot be destroyed by perturbations.

  3. Different effects of surfactant proteins B and C - implications for development of synthetic surfactants.

    Science.gov (United States)

    Curstedt, Tore; Johansson, Jan

    2010-06-01

    Treatment of premature newborn rabbits with synthetic surfactants containing a surfactant protein C analogue in a simple phospholipid mixture gives similar tidal volumes as treatment with poractant alfa (Curosurf(R)) but ventilation with a positive end-expiratory pressure (PEEP) is needed for this synthetic surfactant to stabilize the alveoli at end-expiration. The effect on lung gas volumes seems to depend on the structure of the peptide since treatment with a synthetic surfactant containing the 21-residue peptide (LysLeu(4))(4)Lys (KL(4)) gives low lung gas volumes in experiments also performed with PEEP. Surfactant preparations containing both surfactant proteins B and C or their analogues prevent alveolar collapse at end-expiration even if ventilated without PEEP. Treatment of premature newborn rabbits with different natural surfactants indicates that both the lipid composition and the proteins are important in order to stabilize the alveoli at end-expiration. Synthetic surfactants containing two peptides may be able to replace natural surfactants within the near future but more trials need to be performed before any conclusion can be drawn about the ideal composition of this new generation of synthetic surfactants. Copyright 2010 S. Karger AG, Basel.

  4. Analogue to Digital and Digital to Analogue Converters (ADCs and DACs): A Review Update

    CERN Document Server

    Pickering, J.

    2015-06-15

    This is a review paper updated from that presented for CAS 2004. Essentially, since then, commercial components have continued to extend their performance boundaries but the basic building blocks and the techniques for choosing the best device and implementing it in a design have not changed. Analogue to digital and digital to analogue converters are crucial components in the continued drive to replace analogue circuitry with more controllable and less costly digital processing. This paper discusses the technologies available to perform in the likely measurement and control applications that arise within accelerators. It covers much of the terminology and 'specmanship' together with an application-oriented analysis of the realisable performance of the various types. Finally, some hints and warnings on system integration problems are given.

  5. Synthetic collective intelligence.

    Science.gov (United States)

    Solé, Ricard; Amor, Daniel R; Duran-Nebreda, Salva; Conde-Pueyo, Núria; Carbonell-Ballestero, Max; Montañez, Raúl

    2016-10-01

    Intelligent systems have emerged in our biosphere in different contexts and achieving different levels of complexity. The requirement of communication in a social context has been in all cases a determinant. The human brain, probably co-evolving with language, is an exceedingly successful example. Similarly, social insects complex collective decisions emerge from information exchanges between many agents. The difference is that such processing is obtained out of a limited individual cognitive power. Computational models and embodied versions using non-living systems, particularly involving robot swarms, have been used to explore the potentiality of collective intelligence. Here we suggest a novel approach to the problem grounded in the genetic engineering of unicellular systems, which can be modified in order to interact, store memories or adapt to external stimuli in collective ways. What we label as Synthetic Swarm Intelligence defines a parallel approach to the evolution of computation and swarm intelligence and allows to explore potential embodied scenarios for decision making at the microscale. Here, we consider several relevant examples of collective intelligence and their synthetic organism counterparts. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Inhibition of myotoxic activity of Bothrops asper myotoxin II by the anti-trypanosomal drug suramin.

    Science.gov (United States)

    Murakami, Mário T; Arruda, Emerson Z; Melo, Paulo A; Martinez, Ana B; Calil-Eliás, Sabrińa; Tomaz, Marcelo A; Lomonte, Bruno; Gutiérrez, José M; Arni, Raghuvir K

    2005-07-15

    Suramin, a synthetic polysulfonated compound, developed initially for the treatment of African trypanosomiasis and onchocerciasis, is currently used for the treatment of several medically relevant disorders. Suramin, heparin, and other polyanions inhibit the myotoxic activity of Lys49 phospholipase A2 analogues both in vitro and in vivo, and are thus of potential importance as therapeutic agents in the treatment of viperid snake bites. Due to its conformational flexibility around the single bonds that link the central phenyl rings to the secondary amide backbone, the symmetrical suramin molecule binds by an induced-fit mechanism complementing the hydrophobic surfaces of the dimer and adopts a novel conformation that lacks C2 symmetry in the dimeric crystal structure of the suramin-Bothrops asper myotoxin II complex. The simultaneous binding of suramin at the surfaces of the two monomers partially restricts access to the nominal active sites and significantly changes the overall charge of the interfacial recognition face of the protein, resulting in the inhibition of myotoxicity.

  7. Synthetic amphibian peptides and short amino-acids derivatives against planktonic cells and mature biofilm of Providencia stuartii clinical strains.

    Science.gov (United States)

    Ostrowska, Kinga; Kamysz, Wojciech; Dawgul, Małgorzata; Różalski, Antoni

    2014-01-01

    Over the last decade, the growing number of multidrug resistant strains limits the use of many of the currently available chemotherapeutic agents. Furthermore, bacterial biofilm, due to its complex structure, constitutes an effective barrier to conventional antibiotics. The in vitro activities of naturally occurring peptide (Citropin 1.1), chemically engineered analogue (Pexiganan), newly-designed, short amino-acid derivatives (Pal-KK-NH2, Pal-KKK-NH2, Pal-RRR-NH2) and six clinically used antimicrobial agents (Gatifloxacin, Ampicilin, Cefotaxime, Ceftriaxone, Cefuroxime and Cefalexin) were investigated against planktonic cells and mature biofilm of multidrug-resistant Providencia stuartii strains, isolated from urological catheters. The MICs, MBCs values were determined by broth microdilution technique. Inhibition of biofilm formation by antimicrobial agents as well as biofilm susceptibility assay were tested using a surrogate model based on the Crystal Violet method. The antimicrobial activity of amino-acids derivatives and synthetic peptides was compared to that of clinically used antibiotics. For planktonic cells, MICs of peptides and antibiotics ranged between 1 and 256 μg/ml and 256 and ≥ 2048 μg/ml, respectively. The MBCs values of Pexiganan, Citropin 1.1 and amino-acids derivatives were between 16 and 256 μg/ml, 64 and 256 μg/ml and 16 and 512 μg/ml, respectively. For clinically used antibiotics the MBCs values were above 2048 μg/ml. All of the tested peptides and amino-acids derivatives, showed inhibitory activity against P. stuartii biofilm formation, in relation to their concentrations. Pexiganan and Citropin 1.1 in concentration range 32 and 256 μg/ml caused both strong and complete suppression of biofilm formation. None of the antibiotics caused complete inhibition of biofilm formation process. The biofilm susceptibility assay verified the extremely poor antibiofilm activity of conventional antibiotics compared to synthetic peptides. The

  8. Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug.

    Science.gov (United States)

    Cameron, Amy R; Logie, Lisa; Patel, Kashyap; Bacon, Sandra; Forteath, Calum; Harthill, Jean; Roberts, Adam; Sutherland, Calum; Stewart, Derek; Viollet, Benoit; Sakamoto, Kei; McDougall, Gordon; Foretz, Marc; Rena, Graham

    2016-08-01

    Anti-hyperglycaemic effects of the hydroxybenzoic acid salicylate might stem from effects of the drug on mitochondrial uncoupling, activation of AMP-activated protein kinase, and inhibition of NF-κB signalling. Here, we have gauged the contribution of these effects to control of hepatocyte glucose production, comparing salicylate with inactive hydroxybenzoic acid analogues of the drug. In rat H4IIE hepatoma cells, salicylate was the only drug tested that activated AMPK. Salicylate also reduced mTOR signalling, but this property was observed widely among the analogues. In a sub-panel of analogues, salicylate alone reduced promoter activity of the key gluconeogenic enzyme glucose 6-phosphatase and suppressed basal glucose production in mouse primary hepatocytes. Both salicylate and 2,6 dihydroxybenzoic acid suppressed TNFα-induced IκB degradation, and in genetic knockout experiments, we found that the effect of salicylate on IκB degradation was AMPK-independent. Previous data also identified AMPK-independent regulation of glucose but we found that direct inhibition of neither NF-κB nor mTOR signalling suppressed glucose production, suggesting that other factors besides these cell signalling pathways may need to be considered to account for this response to salicylate. We found, for example, that H4IIE cells were exquisitely sensitive to uncoupling with modest doses of salicylate, which occurred on a similar time course to another anti-hyperglycaemic uncoupling agent 2,4-dinitrophenol, while there was no discernible effect at all of two salicylate analogues which are not anti-hyperglycaemic. This finding supports much earlier literature suggesting that salicylates exert anti-hyperglycaemic effects at least in part through uncoupling. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Space Synthetic Biology Project

    Science.gov (United States)

    Howard, David; Roman, Monsi; Mansell, James (Matt)

    2015-01-01

    Synthetic biology is an effort to make genetic engineering more useful by standardizing sections of genetic code. By standardizing genetic components, biological engineering will become much more similar to traditional fields of engineering, in which well-defined components and subsystems are readily available in markets. Specifications of the behavior of those components and subsystems can be used to model a system which incorporates them. Then, the behavior of the novel system can be simulated and optimized. Finally, the components and subsystems can be purchased and assembled to create the optimized system, which most often will exhibit behavior similar to that indicated by the model. The Space Synthetic Biology project began in 2012 as a multi-Center effort. The purpose of this project was to harness Synthetic Biology principals to enable NASA's missions. A central target for application was to Environmental Control & Life Support (ECLS). Engineers from NASA Marshall Space Flight Center's (MSFC's) ECLS Systems Development Branch (ES62) were brought into the project to contribute expertise in operational ECLS systems. Project lead scientists chose to pursue the development of bioelectrochemical technologies to spacecraft life support. Therefore, the ECLS element of the project became essentially an effort to develop a bioelectrochemical ECLS subsystem. Bioelectrochemical systems exploit the ability of many microorganisms to drive their metabolisms by direct or indirect utilization of electrical potential gradients. Whereas many microorganisms are capable of deriving the energy required for the processes of interest (such as carbon dioxide (CO2) fixation) from sunlight, it is believed that subsystems utilizing electrotrophs will exhibit smaller mass, volume, and power requirements than those that derive their energy from sunlight. In the first 2 years of the project, MSFC personnel conducted modeling, simulation, and conceptual design efforts to assist the

  10. The Greenland analogue project. Yearly report 2010

    International Nuclear Information System (INIS)

    Harper, J.; Brinkerhoff, D.; Johnson, J.; Ruskeeniemi, T.; Engstroem, J.; Kukkonen, I.

    2012-04-01

    A four-year field and modelling study of the Greenland ice sheet and subsurface conditions, Greenland Analogue Project (GAP), has been initiated collaboratively by SKB, Posiva and NWMO to advance the understanding of processes associated with glaciation and their impact on the long-term performance of a deep geological repository. The study site encompasses a land terminus portion of the Greenland ice sheet, east of Kangerlussuaq, and is in many ways considered to be an appropriate analogue of the conditions that are expected to prevail in much of Canada and Fennoscandia during future glacial cycles. The project begins in 2009 and is scheduled for completion in 2012. Our current understanding of the hydrological, hydrogeological and hydrogeochemical processes associated with cold climate conditions and glacial cycles, and their impact on the long-term performance of deep geological repositories for spent nuclear fuel, will be significantly improved by studying a modern analogue. The GAP will conduct the first in situ investigations of some of the parameters and processes needed to achieve a better understanding of how an ice sheet may impact a deep repository, and will provide measurements, observations and data that may significantly improve our safety assessments and risk analyses of glaciation scenarios. This report was produced by the GAP team members and presents an overview of the activities within the GAP during the interval January 1 to December 31, 2010, as well as research results obtained during this time frame. Research for the GAP is ongoing, and additional results related to the data presented here may become available in the future and will be presented in subsequent annual reports. (orig.)

  11. The Greenland analogue project. Yearly report 2010

    Energy Technology Data Exchange (ETDEWEB)

    Harper, J.; Brinkerhoff, D.; Johnson, J. [University of Montana, Missoula (United States); Ruskeeniemi, T.; Engstroem, J.; Kukkonen, I. [Geological Survey of Finland (Finland)] [and others

    2012-04-15

    A four-year field and modelling study of the Greenland ice sheet and subsurface conditions, Greenland Analogue Project (GAP), has been initiated collaboratively by SKB, Posiva and NWMO to advance the understanding of processes associated with glaciation and their impact on the long-term performance of a deep geological repository. The study site encompasses a land terminus portion of the Greenland ice sheet, east of Kangerlussuaq, and is in many ways considered to be an appropriate analogue of the conditions that are expected to prevail in much of Canada and Fennoscandia during future glacial cycles. The project begins in 2009 and is scheduled for completion in 2012. Our current understanding of the hydrological, hydrogeological and hydrogeochemical processes associated with cold climate conditions and glacial cycles, and their impact on the long-term performance of deep geological repositories for spent nuclear fuel, will be significantly improved by studying a modern analogue. The GAP will conduct the first in situ investigations of some of the parameters and processes needed to achieve a better understanding of how an ice sheet may impact a deep repository, and will provide measurements, observations and data that may significantly improve our safety assessments and risk analyses of glaciation scenarios. This report was produced by the GAP team members and presents an overview of the activities within the GAP during the interval January 1 to December 31, 2010, as well as research results obtained during this time frame. Research for the GAP is ongoing, and additional results related to the data presented here may become available in the future and will be presented in subsequent annual reports. (orig.)

  12. 4-N, 4-S & 4-O Chloroquine Analogues: Influence of Side Chain Length and Quinolyl Nitrogen pKa on Activity vs. Chloroquine Resistant Malaria+, #

    Science.gov (United States)

    Natarajan, Jayakumar K.; Alumasa, John; Yearick, Kimberly; Ekoue-Kovi, Kekeli A.; Casabianca, Leah B.; de Dios, Angel C.; Wolf, Christian; Roepe, Paul D.

    2009-01-01

    Using predictions from heme – quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure – function principles. We vary side chain length for both monoethyl and diethyl 4N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position, and vary side chain length for these analogues. We introduce an additional titratable amino group to the side chain of 4O analogues with promising CQR strain selectivity and increase activity while retaining selectivity. We solve atomic resolution structures for complexes formed between representative 4N, 4S and 4O derivatives vs. μ-oxo dimeric heme, measure binding constants for monomeric vs. dimeric heme, and quantify hemozoin (Hz) formation inhibition in vitro. The data provide additional insight for the design of CQ analogues with improved activity vs. CQR malaria. PMID:18512900

  13. Life after the synthetic cell

    DEFF Research Database (Denmark)

    Rasmussen, Steen

    2010-01-01

    Nature asked eight synthetic-biology experts about the implications for science and society of the “synthetic cell” made by the J. Craig Venter Institute (JCVI). The institute's team assembled, modified and implanted a synthesized genome into a DNA-free bacterial shell to make a self-replicating ......Nature asked eight synthetic-biology experts about the implications for science and society of the “synthetic cell” made by the J. Craig Venter Institute (JCVI). The institute's team assembled, modified and implanted a synthesized genome into a DNA-free bacterial shell to make a self...

  14. Synthetic biology and occupational risk.

    Science.gov (United States)

    Howard, John; Murashov, Vladimir; Schulte, Paul

    2017-03-01

    Synthetic biology is an emerging interdisciplinary field of biotechnology that involves applying the principles of engineering and chemical design to biological systems. Biosafety professionals have done an excellent job in addressing research laboratory safety as synthetic biology and gene editing have emerged from the larger field of biotechnology. Despite these efforts, risks posed by synthetic biology are of increasing concern as research procedures scale up to industrial processes in the larger bioeconomy. A greater number and variety of workers will be exposed to commercial synthetic biology risks in the future, including risks to a variety of workers from the use of lentiviral vectors as gene transfer devices. There is a need to review and enhance current protection measures in the field of synthetic biology, whether in experimental laboratories where new advances are being researched, in health care settings where treatments using viral vectors as gene delivery systems are increasingly being used, or in the industrial bioeconomy. Enhanced worker protection measures should include increased injury and illness surveillance of the synthetic biology workforce; proactive risk assessment and management of synthetic biology products; research on the relative effectiveness of extrinsic and intrinsic biocontainment methods; specific safety guidance for synthetic biology industrial processes; determination of appropriate medical mitigation measures for lentiviral vector exposure incidents; and greater awareness and involvement in synthetic biology safety by the general occupational safety and health community as well as by government occupational safety and health research and regulatory agencies.

  15. Finding Hope in Synthetic Biology.

    Science.gov (United States)

    Takala, Tuija

    2017-04-01

    For some, synthetic biology represents great hope in offering possible solutions to many of the world's biggest problems, from hunger to sustainable development. Others remain fearful of the harmful uses, such as bioweapons, that synthetic biology can lend itself to, and most hold that issues of biosafety are of utmost importance. In this article, I will evaluate these points of view and conclude that although the biggest promises of synthetic biology are unlikely to become reality, and the probability of accidents is fairly substantial, synthetic biology could still be seen to benefit humanity by enhancing our ethical understanding and by offering a boost to world economy.

  16. Natural Analogues of CO2 Geological Storage

    International Nuclear Information System (INIS)

    Perez del Villar, L.; Pelayo, M.; Recreo, F.

    2007-01-01

    Geological storage of carbon dioxide is nowadays, internationally considered as the most effective method for greenhouse gas emission mitigation, in order to minimize the global climate change universally accepted. Nevertheless, the possible risks derived of this long-term storage have a direct influence on its public acceptance. Among the favourable geological formations to store CO2, depleted oil and gas fields, deep saline reservoirs, and unamiable coal seams are highlighted. One of the most important objectives of the R and D projects related to the CO2 geological storage is the evaluation of the CO2 leakage rate through the above mentioned geological formations. Therefore, it is absolutely necessary to increase our knowledge on the interaction among CO2, storage and sealing formations, as well as on the flow paths and the physical resistance of the sealing formation. The quantification of the CO2 leakage rate is essential to evaluate the effects on the human and animal health, as well as for the ecosystem and water quality. To achieve these objectives, the study of the natural analogues is very useful in order to know the natural leakage rate to the atmosphere, its flow paths, the physical, chemical and mineralogical modifications due to the long term interaction processes among the CO2 and the storage and sealing formations, as well as the effects on the groundwaters and ecosystems. In this report, we have tried to summarise the main characteristics of the natural reservoirs and surficial sources of CO2, which are both natural analogues of the geological storage and CO2 leakage, studied in EEUU, Europe and Australia. The main objective of this summary is to find the possible applications for long-term risk prediction and for the performance assessment by means of conceptual and numerical modelling, which will allow to validate the predictive models of the CO2 storage behaviour, to design and develop suitable monitoring techniques to control the CO2 behaviour

  17. Nuclear waste geochemistry: natural and anthropic analogues

    International Nuclear Information System (INIS)

    Petit, J.C.

    1997-01-01

    The geochemical evolution of nuclear waste storage is difficult to describe, due to the long time scales involved, the radioactivity confinement complexity and the un-natural radionuclides which evolution is not known. In order to carry out a long term prediction, a special approach is used, based on a combination of experiments conducted in laboratories and in situ, modelizations and comparisons with process and material analogues (natural or man-made, such as basaltic and rhyolitic volcanic glasses, plutonium, historical and archaeological artefacts)

  18. Somatostatin analogue scintigraphy in granulomatous diseases

    Energy Technology Data Exchange (ETDEWEB)

    Vanhagen, P.M. (Dept. of Internal Medicine 3, Dijkzigt Univ. Hospital, Rotterdam (Netherlands) Dept. of Immunology, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Krenning, E.P. (Dept. of Internal Medicine 3, Dijkzigt Univ. Hospital, Rotterdam (Netherlands) Dept. of Nuclear Medicine, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Reubi, J.C. (Inst. of Pathology, Bern Univ. (Switzerland)); Kwekkeboom, D.J. (Dept. of Nuclear Medicine, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Bakker, W.H. (Dept. of Nuclear Medicine, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Mulder, A.H. (Dept. of Pathology, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Laissue, I. (Inst. of Pathology, Bern Univ. (Switzerland)); Hoogstede, H.C. (Dept. of Chest Medicine, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Lamberts, S.W.J. (Dept. of Internal Medicine 3, Dijkzigt Univ. Hospital, Rotterdam (Netherlands))

    1994-06-01

    In the present study 20 consecutive patients were investigated, 12 with sarcoidosis, one with both sarcoidosis and aspergillosis, four with tuberculosis and three with Wegener's granulomatosis. For in vivo SS-R imaging, total-body scintigraphy was performed 24 and 48 h after the administration of [sup 111]In-octreotide. Granuloma localizations could be visualized in all patients studied; additional sites were found in nine patients with sarcoidosis and in two patients with tuberculosis. In vitro autoradiography of fresh tissue biopsies, using the SS analogue [[sup 125]I-Tyr[sup 3

  19. Synthetic Aperture Compound Imaging

    DEFF Research Database (Denmark)

    Hansen, Jens Munk

    Medical ultrasound imaging is used for many purposes, e.g. for localizing and classifying cysts, lesions, and other processes. Almost any mass is first observed using B-mode imaging and later classified using e.g. color flow, strain, or attenuation imaging. It is therefore important that the B......, it is demonstrated through theoretical considerations that the compound effect achieved is close to a theoretical maximum for the amount of compounding attainable and using a -pitch convex array transducer, the first in-vivo images are created. The computational demands for an implementation are massive...... and the limiting factor is the amount of memory IO resources available. An equally high demand for memory throughput is found in the computer gaming industry, where a large part of the processing takes place on the graphics processing unit (GPU). Using the GPU, a framework for synthetic aperture imaging...

  20. Transionospheric synthetic aperture imaging

    CERN Document Server

    Gilman, Mikhail; Tsynkov, Semyon

    2017-01-01

    This landmark monograph presents the most recent mathematical developments in the analysis of ionospheric distortions of SAR images and offers innovative new strategies for their mitigation. As a prerequisite to addressing these topics, the book also discusses the radar ambiguity theory as it applies to synthetic aperture imaging and the propagation of radio waves through the ionospheric plasma, including the anisotropic and turbulent cases. In addition, it covers a host of related subjects, such as the mathematical modeling of extended radar targets (as opposed to point-wise targets) and the scattering of radio waves off those targets, as well as the theoretical analysis of the start-stop approximation, which is used routinely in SAR signal processing but often without proper justification. The mathematics in this volume is clean and rigorous – no assumptions are hidden or ambiguously stated. The resulting work is truly interdisciplinary, providing both a comprehensive and thorough exposition of the field,...

  1. Synthetic antibiofilm peptides.

    Science.gov (United States)

    de la Fuente-Núñez, César; Cardoso, Marlon Henrique; de Souza Cândido, Elizabete; Franco, Octavio Luiz; Hancock, Robert E W

    2016-05-01

    Bacteria predominantly exist as multicellular aggregates known as biofilms that are associated with at least two thirds of all infections and exhibit increased adaptive resistance to conventional antibiotic therapies. Therefore, biofilms are major contributors to the global health problem of antibiotic resistance, and novel approaches to counter them are urgently needed. Small molecules of the innate immune system called host defense peptides (HDPs) have emerged as promising templates for the design of potent, broad-spectrum antibiofilm agents. Here, we review recent developments in the new field of synthetic antibiofilm peptides, including mechanistic insights, synergistic interactions with available antibiotics, and their potential as novel antimicrobials against persistent infections caused by biofilms. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Indenes and tetralenes analogues attenuates lipopolysaccharide-induced inflammation: An in-vitro and in-vivo study.

    Science.gov (United States)

    Mohanty, Shilpa; Gautam, Yashveer; Maurya, Anil Kumar; Negi, Arvind S; Prakash, Om; Khan, Feroz; Bawankule, Dnyaneshwar Umrao

    2016-02-05

    In an effort to evaluate novel pharmacological activity of 1-chloro-2-formyl indene and tetralene analogues possessing potential antitubercular and antistaphylococcal agents, we explored its anti-inflammatory potential against lipopolysaccharide(LPS)-induced inflammation using in-vitro and in-vivo bioassay. Synthesized analogues significantly inhibited the production and expression of pro-inflammatory cytokines against LPS-induced inflammation in macrophages isolated from mice. Among all the analogues, TAF-5 (1-Chloro-2-formyl-1-tetralene) exhibited most potent anti-inflammatory activity without any cytotoxic effect. We have further evaluated the therapeutic efficacy and safety of TAF-5 in in-vivo system using LPS-induced sepsis, a systemic inflammation model and acute oral toxicity respectively in mice. Oral administration of TAF-5 inhibited the pro-inflammatory cytokines in serum, attenuated the organs injuries and improved host survival in dose dependent manner. Acute oral toxicity study showed TAF-5 is non-toxic at higher dose in mice. These results suggest the suitability of indene and tetralene analogues as new chemical entities for further investigation towards the management of inflammation related diseases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. U.S. Nuclear Regulatory Commission natural analogue research program

    International Nuclear Information System (INIS)

    Kovach, L.A.; Ott, W.R.

    1995-01-01

    This article describes the natural analogue research program of the U.S. Nuclear Regulatory Commission (US NRC). It contains information on the regulatory context and organizational structure of the high-level radioactive waste research program plan. It also includes information on the conditions and processes constraining selection of natural analogues, describes initiatives of the US NRC, and describes the role of analogues in the licensing process

  4. Antimicrobial Activity of Xanthohumol and Its Selected Structural Analogues

    Directory of Open Access Journals (Sweden)

    Monika Stompor

    2016-05-01

    Full Text Available The objective of this study was to evaluate the antimicrobial activity of structural analogues of xanthohumol 1, a flavonoid compound found in hops (Humulus lupulus. The agar-diffusion method using filter paper disks was applied. Biological tests performed for selected strains of Gram-positive (Staphylococcus aureus and Gram-negative (Escherichia coli bacteria, fungi (Alternaria sp., and yeasts (Rhodotorula rubra, Candida albicans revealed that compounds with at least one hydroxyl group—all of them have it at the C-4 position—demonstrated good activity. Our research showed that the strain S. aureus was more sensitive to chalcones than to the isomers in which the heterocyclic ring C is closed (flavanones. The strain R. rubra was moderately sensitive to only one compound: 4-hydroxy-4’-methoxychalcone 8. Loss of the hydroxyl group in the B-ring of 4’-methoxychalcones or its replacement by a halogen atom (−Cl, −Br, nitro group (−NO2, ethoxy group (−OCH2CH3, or aliphatic substituent (−CH3, −CH2CH3 resulted in the loss of antimicrobial activity towards both R. rubra yeast and S. aureus bacteria. Xanthohumol 1, naringenin 5, and chalconaringenin 7 inhibited growth of S. aureus, whereas 4-hydroxy-4′-methoxychalcone 8 was active towards two strains: S. aureus and R. rubra.

  5. Ways to Optimize Analogue Switched Circuits

    Directory of Open Access Journals (Sweden)

    J. Hospodka

    2008-12-01

    Full Text Available This paper describes how analogue switched circuits (switched-capacitor and switched-current circuits can be optimized by means of a personal computer. The optimization of this kind of circuits is not so common and their analysis is more difficult in comparison with continuously working circuits. Firstly, the nonidealities occurring in these circuits whose effect on their characteristics should be optimized are discussed. Then a few ways to analyze analogue switched circuits are shown. From all optimization algorithms applicable for this kind of optimization, two ones that seem to be the most promising are proposed. The differential evolution (one of evolutionary algorithms combined with the simplex method was found to be most appropriate from these two ones. Two types of programs are required for the optimization of these circuits: a program for implementing calculations of the used optimization algorithm and a program for the analysis of the optimized circuit. Several suitable computer programs from both of the groups together with their proper settings according to authors’ experience are proposed. At the end of the paper, an example of a switched-current circuit optimization documenting the previous description is presented.

  6. Synthetic biology and metabolic engineering.

    Science.gov (United States)

    Stephanopoulos, Gregory

    2012-11-16

    Metabolic engineering emerged 20 years ago as the discipline occupied with the directed modification of metabolic pathways for the microbial synthesis of various products. As such, it deals with the engineering (design, construction, and optimization) of native as well as non-natural routes of product synthesis, aided in this task by the availability of synthetic DNA, the core enabling technology of synthetic biology. The two fields, however, only partially overlap in their interest in pathway engineering. While fabrication of biobricks, synthetic cells, genetic circuits, and nonlinear cell dynamics, along with pathway engineering, have occupied researchers in the field of synthetic biology, the sum total of these areas does not constitute a coherent definition of synthetic biology with a distinct intellectual foundation and well-defined areas of application. This paper reviews the origins of the two fields and advances two distinct paradigms for each of them: that of unit operations for metabolic engineering and electronic circuits for synthetic biology. In this context, metabolic engineering is about engineering cell factories for the biological manufacturing of chemical and pharmaceutical products, whereas the main focus of synthetic biology is fundamental biological research facilitated by the use of synthetic DNA and genetic circuits.

  7. Synthetic cannabinoids: new matrix addiction

    Directory of Open Access Journals (Sweden)

    Antsyborov A.V.

    2017-04-01

    Full Text Available the majority of synthetic cannabinoids (SC, belongs to the group of so-called designer drugs distributed through illegal online shopping. The first reports of this group of psychoactive substances appeared in the 70s of the last century. Today, according to various estimates, there are over 160 varieties of synthetic cannabinoids, and this figure is increasing annually due to the synthesis of new substances in the group. This group of substances is designed to «copy» the psychoactive effects of cannabis. Initially, these substances were created solely for research purposes, to study the endocannabinoid system of the person. Natural THC is a partial agonist of cannabinoid receptors. Synthetic cannabinoids are full agonists CB1R and CB2R types of cannabinoid receptors. Most countries in the world, including Russia, at the legislative level have taken restrictive measures for preventing the spread of this group of substances. In order to circumvent the legislative measures, the producers of synthetic cannabinoids regularly changing the chemical formula. Each year, an increasing number of emergency hospital admissions associated with the use of synthetic cannabinoids in the peer-reviewed literature describes the deaths directly attributable to medical complications after taking synthetic cannabinoids. Numerous studies have proven the possibility of developing psychological dependence due to the use of synthetic cannabinoids. The proposed review of the literature is presented for the purpose of organizing data in the field of synthetic cannabinoids.

  8. Synthetic peptides for antibody production

    NARCIS (Netherlands)

    N.D. Zegers (Netty)

    1995-01-01

    textabstractSynthetic peptides are useful tools for the generation of antibodies. The use of antibodies as specific reagents in inununochemical assays is widely applied. In this chapter, the application of synthetic peptides for the generation of antibodies is described. The different steps

  9. Synthetic peptides for antibody production

    NARCIS (Netherlands)

    Zegers, N.D.

    1995-01-01

    Synthetic peptides are useful tools for the generation of antibodies. The use of antibodies as specific reagents in inununochemical assays is widely applied. In this chapter, the application of synthetic peptides for the generation of antibodies is described. The different steps that lead to the

  10. Imaging with Synthetic Aperture Radar

    CERN Document Server

    Massonnet, Didier

    2008-01-01

    Describing a field that has been transformed by the recent availability of data from a new generation of space and airborne systems, the authors offer a synthetic geometrical approach to the description of synthetic aperture radar, one that addresses physicists, radar specialists, as well as experts in image processing.  

  11. Synthetic biology of polyketide synthases

    DEFF Research Database (Denmark)

    Yuzawa, Satoshi; Backman, Tyler W.H.; Keasling, Jay D.

    2018-01-01

    ). The modules are composed of enzymatic domains that share sequence and functional similarity across all known PKSs. We have used the nomenclature of synthetic biology to classify the enzymatic domains and modules as parts and devices, respectively, and have generated detailed lists of both. In addition, we...... realize the potential that synthetic biology approaches bring to this class of molecules....

  12. Structure-activity relationship studies on cholecystokinin: Analogues with partial agonist activity

    Energy Technology Data Exchange (ETDEWEB)

    Galas, M.C.; Lignon, M.F.; Rodriguez, M.; Mendre, C.; Fulcrand, P.; Laur, J.; Martinez, J. (Centre de Pharmacologie-Endocrinologie, Montpellier (France))

    1988-02-01

    In the present study, hepta- and octapeptide analogues of the C-terminal part of cholecystokinin, modified on the C-terminal phenylalanine residue, were synthesized. CCK analogues were prepared in which the peptide bond between aspartic acid and phenylalanine had or had not been modified and were lacking the C-terminal primary amide function. These CCK derivatives were able to cause full stimulation of amylase release from rat pancreatic acini but without a decrease in amylase release at supramaximal concentrations. There was a close relationship between the abilities of these derivatives to stimulate amylase release and their abilities to inhibit binding of {sup 125}I-BH-CCK-9 to CCK receptors on rat and guinea pig pancreatic acini. These CCK analogues were also able to recognize the guinea pig brain CCK receptors, some of them being particularly potent. The findings indicate that the aromatic ring of phenylalanine is important for the binding to brain and pancreatic CCK receptors, whereas the C-terminal primary amide function is not essential for the binding to pancreatic CCK receptors but is crucial for biological activity of rat pancreatic acini.

  13. Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter.

    Science.gov (United States)

    Houlihan, William J; Kelly, Lawrence; Pankuch, Jessica; Koletar, Judith; Brand, Leonard; Janowsky, Aaron; Kopajtic, Theresa A

    2002-09-12

    A series of mazindol (2) and homomazindol (3) analogues with a variety of electron-donating and electron-withdrawing groups in the pendant aryl group and the benzo ring C, as well as H, methoxy, and alkyl groups replacing the hydroxyl group were synthesized, and their binding affinities at the dopamine transporter (DAT) on rat or guinea pig striatal membranes were determined. Several active analogues were also evaluated for their ability to block uptake of DA, 5-HT, and NE and inhibit binding of [(125)I] RTI-55 at HEK-hDAT, HEK-hSERT, and HEK-hNET cells. Mazindane (26) was found to be a pro-drug, oxidizing (5-H --> 5-OH) to mazindol on rat striatal membranes and HEK-hDAT cells. The 4',7,8-trichloro analogue (38) of mazindol was the most potent and selective ligand for HEK-hDAT cells (DAT K(i) = 1.1 nM; SERT/DAT = 1283 and NET/DAT = 38). Experimental results strongly favor the cyclic or ol tautomers of 2 and 3 to bind more tightly at the DAT than the corresponding keto tautomers.

  14. Synthesis and activity of novel glutathione analogues containing an urethane backbone linkage.

    Science.gov (United States)

    Cacciatore, I; Caccuri, A M; Di Stefano, A; Luisi, G; Nalli, M; Pinnen, F; Ricci, G; Sozio, P

    2003-09-01

    The new GSH analogues H-Glo(-Ser-Gly-OH)-OH (5), its O-benzyl derivative 4, and H-Glo(-Asp-Gly-OH)-OH (9), characterized by the replacement of central cysteine with either serine or aspartic acid, and containing an urethanic fragment as isosteric substitution of the scissile gamma-glutamylic junction, have been synthesized and characterized. Their ability to inhibit human GST P1-1 (hGST P1-1) in comparison with H-Glu(-Ser-Gly-OH)-OH and H-Glu(-Asp-Gly-OH)-OH, which are potent competitive inhibitors of rat GST 3-3 and 4-4, has been evaluated. In order to further investigate the effect of the isosteric substitution on the binding abilities of the new GSH analogues 4, 5 and 9, the previously reported cysteinyl-containing analogue H-Glo(-Cys-Gly-OH)-OH has been also evaluated as a co-substrate for hGSTP1-1.

  15. Computing with synthetic protocells.

    Science.gov (United States)

    Courbet, Alexis; Molina, Franck; Amar, Patrick

    2015-09-01

    In this article we present a new kind of computing device that uses biochemical reactions networks as building blocks to implement logic gates. The architecture of a computing machine relies on these generic and composable building blocks, computation units, that can be used in multiple instances to perform complex boolean functions. Standard logical operations are implemented by biochemical networks, encapsulated and insulated within synthetic vesicles called protocells. These protocells are capable of exchanging energy and information with each other through transmembrane electron transfer. In the paradigm of computation we propose, protoputing, a machine can solve only one problem and therefore has to be built specifically. Thus, the programming phase in the standard computing paradigm is represented in our approach by the set of assembly instructions (specific attachments) that directs the wiring of the protocells that constitute the machine itself. To demonstrate the computing power of protocellular machines, we apply it to solve a NP-complete problem, known to be very demanding in computing power, the 3-SAT problem. We show how to program the assembly of a machine that can verify the satisfiability of a given boolean formula. Then we show how to use the massive parallelism of these machines to verify in less than 20 min all the valuations of the input variables and output a fluorescent signal when the formula is satisfiable or no signal at all otherwise.

  16. Synthetic biology: lessons from the history of synthetic organic chemistry.

    Science.gov (United States)

    Yeh, Brian J; Lim, Wendell A

    2007-09-01

    The mid-nineteenth century saw the development of a radical new direction in chemistry: instead of simply analyzing existing molecules, chemists began to synthesize them--including molecules that did not exist in nature. The combination of this new synthetic approach with more traditional analytical approaches revolutionized chemistry, leading to a deep understanding of the fundamental principles of chemical structure and reactivity and to the emergence of the modern pharmaceutical and chemical industries. The history of synthetic chemistry offers a possible roadmap for the development and impact of synthetic biology, a nascent field in which the goal is to build novel biological systems.

  17. Space Analogue Environments: Are the Populations Comparable?

    Science.gov (United States)

    Sandal, G. M.

    Background: Much of our present understanding about psychology in space is based on studies of groups operating in so-called analogue environments where personnel are exposed to many of the same stressors as those experienced by astronauts in space. One possible problem with extrapolating results is that personnel operating in various hazardous and confined environments might differ in characteristics influencing coping, interaction, and performance. The object of this study was to compare the psychological similarity of these populations in order to get a better understanding of whether this extrapolation is justifiable. The samples investigated include polar crossings (N= 22), personnel on Antarctic research stations (N= 183), several military occupations (N= 187), and participants in space simulation studies (N=20). Methods: Personnel in each of these environments were assessed using the Personality Characteristic Inventory (PCI) and Utrecht Coping List (UCL). The PCI is a multidimensional trait assessment battery that measures various aspects of achievement orientation and social competence. The UCL is a questionnaire designed to assess habitual coping strategies when encountering stressful or demanding situations. Results: Only minor differences in use of habitual coping strategies were evident across the different samples. In relation to personality scores, the military subjects and participants in space simulation studies indicated higher competitiveness and negative instrumentality compared to both the personnel on Antarctic research stations and participants in polar expedition. Among the personnel on Antarctic research stations, significant gender differences were found with women scoring lower on competitiveness, negative instrumentality and impatience/irritability. Compared to the other samples, the participants in polar expeditions were found to be more homogeneous in personality and no significant gender differences were evident on the traits that

  18. Meglitinide analogues in the treatment of type 2 diabetes mellitus.

    Science.gov (United States)

    Landgraf, R

    2000-11-01

    Type 2 diabetes mellitus is a complex heterogenous metabolic disorder in which peripheral insulin resistance and impaired insulin release are the main pathogenetic factors. The rapid response of the pancreatic beta-cells to glucose is already markedly disturbed in the early stages of type 2 diabetes mellitus. The consequence is often postprandial hyperglycaemia, which seems to be extremely important in the development of secondary complications, especially macrovascular disease. Therefore one of the main aims of treatment is to minimise blood glucose oscillations and attain near-normal glycosylated haemoglobin levels. Meglitinide analogues belong to a new family of insulin secretagogues which stimulate insulin release by inhibiting ATP-sensitive potassium channels of the beta-cell membrane via binding to a receptor distinct from that of sulphonylureas (SUR1/KIR 6.2). The pharmacokinetic and pharmacodynamic properties of repaglinide, the first drug of these new antihyperglycaemic agents on the market, and of nateglinide, which will be available soon, differ markedly from the currently used sulphonylureas [mainly glibenclamide (glyburide) and glimepiride]. Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, are rapidly metabolised in the liver and are mainly excreted in the bile. Therefore, following preprandial administration of these drugs, insulin is more readily available during and just after the meal. This leads to a significant reduction in postprandial hyperglycaemia without the danger of hypoglycaemia between meals. The short action of these compounds and biliary elimination makes repaglinide and nateglinide especially suitable for patients with type 2 diabetes mellitus who would like to have a more flexible lifestyle, need more flexibility because of unplanned eating behaviour (e.g. geriatric patients) or in whom one of the other first-line antidiabetic drugs, i.e. metformin, is strictly contraindicated (e

  19. Vasopressin and its analogues for the treatment of refractory hypotension in neonates.

    Science.gov (United States)

    Shivanna, Binoy; Rios, Danielle; Rossano, Joseph; Fernandes, Caraciolo J; Pammi, Mohan

    2013-03-28

    Neonatal hypotension that is refractory to volume expansion, catecholamines, or corticosteroids has a mortality of about 50%. Optimization of blood pressure and tissue perfusion in refractory hypotension may be crucial to improve clinical outcomes. Vasopressin, a neuropeptide hormone, or its analogue terlipressin has been used to treat refractory hypotension in neonates and may be effective. Our primary objective was to evaluate the efficacy and safety of vasopressin and its synthetic analogues (e.g. terlipressin) in decreasing mortality and adverse neurodevelopmental outcomes, and improving survival in neonates with refractory hypotension. Our secondary objectives were to determine the effects of vasopressin and its analogues (terlipressin) on improvement in blood pressure, increase in urine output, decrease in inotrope score, necrotizing enterocolitis (NEC), periventricular leukomalacia, intraventricular hemorrhage, chronic lung disease, and retinopathy of prematurity (ROP) in neonates with refractory hypotension. We searched the literature in January 2012, using the search strategy recommended by the Cochrane Neonatal Group. We searched electronic databases (CENTRAL (The Cochrane Library), MEDLINE, CINAHL, EMBASE), abstracts of the Pediatric Academic Societies, web sites for registered trials at www.clinicaltrials.gov and www.controlled-trials.com and in the reference list of identified articles. Randomized or quasi-randomized trials evaluating vasopressin or its analogues, at any dosage or duration used as an adjunct to standard therapy (any combination of volume expansion, inotropic agents and corticosteroids) to treat refractory hypotension in neonates. We followed the standard methods of The Cochrane Collaboration for conducting a systematic review. Two review authors (BS and MP) independently assessed the titles and abstracts of studies identified by the search strategy for eligibility for inclusion. We obtained the full text version if eligibility could

  20. Jupiter analogues and planets of active stars

    Directory of Open Access Journals (Sweden)

    Henning T.

    2013-04-01

    Full Text Available Combined results are now available from a 15 year long search for Jupiter analogues around solar-type stars using the ESO CAT + CES, ESO 3.6 m + CES, and ESO 3.6 m + HARPS instruments. They comprise planet (co-discoveries (ι Hor and HR 506 and confirmations (three planets in HR 3259 as well as non-confirmations of planets (HR 4523 and ɛ Eri announced elsewhere. A long-term trend in ɛ Ind found by our survey is probably attributable to a Jovian planet with a period >30 yr, but we cannot fully exclude stellar activity effects as the cause. A 3.8 year periodic variation in HR 8323 can be attributed to stellar activity.

  1. The gravitational analogue of the Witten effect

    International Nuclear Information System (INIS)

    Foda, O.

    1984-06-01

    In the presence of massive fermions, and assuming a non-vanishing theta-parameter as the only source of CP-violation, the Witten effect [a shift in the electric charge of a magnetic monopole due to CP-non-conservation] is shown to follow from an anomalous chiral commutator. Next, given the gravitational contribution to the chiral anomaly, the corresponding anomalous commutator for Dirac fermion currents in a gravitational background is derived. From that, we infer the equivalence of a theta R-tilde R term in the Lagrangian to a shift in the mass parameter of the NUT metric, in proportion to theta. This is interpreted as the gravitational analogue of the Witten effect. Its relevance to certain Kaluza-Klein monopoles is briefly discussed. (author)

  2. Gravitational analogue of the Witten effect

    Energy Technology Data Exchange (ETDEWEB)

    Foda, O. (International Centre for Theoretical Physics, Trieste (Italy))

    1985-07-22

    In the presence of massive fermions, and assuming a non-vanishing theta-parameter as the only source of CP violation, the Witten effect (a shift in the electric charge of a magnetic monopole due to CP non-conservation) is shown to follow from an anomalous chiral commutator. Next, given the gravitational contribution to the chiral anomaly, the corresponding anomalous commutator for Dirac fermion currents in a gravitational background is derived. From that, we infer the equivalence of a thetaR tildeR term in the lagrangian to a shift in the mass parameter of the NUT metric, in proportion to theta. This is interpreted as the gravitational analogue of the Witten effect. Its relevance to certain Kaluza-Klein monopoles is briefly discussed.

  3. The gravitational analogue of the Witten effect

    International Nuclear Information System (INIS)

    Foda, O.

    1985-01-01

    In the presence of massive fermions, and assuming a non-vanishing theta-parameter as the only source of CP violation, the Witten effect (a shift in the electric charge of a magnetic monopole due to CP non-conservation) is shown to follow from an anomalous chiral commutator. Next, given the gravitational contribution to the chiral anomaly, the corresponding anomalous commutator for Dirac fermion currents in a gravitational background is derived. From that, we infer the equivalence of a thetaR tildeR term in the lagrangian to a shift in the mass parameter of the NUT metric, in proportion to theta. This is interpreted as the gravitational analogue of the Witten effect. Its relevance to certain Kaluza-Klein monopoles is briefly discussed. (orig.)

  4. Reflective analogue optical link operating issues

    CERN Document Server

    Batten, Jeremy

    1996-01-01

    The proposed readout of analogue data from CMS tracker will use an optical fibre link. The choice of transmitter/receiver technology, however, has been the subject of intense research and development by the RD23 collaboration. One solution uses passive devices, multi-quantum well modulators, at the detector front end, and continuous wave driving lasers at the readout back end. This system has been tested at Imperial College. We report on the following: problems of noise associated with multimoded behaviour of a degraded laser; measurements of laser wavelength dependence on both drive current and temperature; and modulator reflectance dependence on laser wavelength. We extrapolate the findings to system issues, highlighting the degree of temperature control required of the driving laser.

  5. The glaciogenic reservoir analogue studies project (GRASP)

    DEFF Research Database (Denmark)

    Moscariello, A.; Moreau, Julien; Vegt, P. van der

    increasing the risk associated with developing effectively these reservoirs. Therefore a analogue-based predictive stratigraphical and sedimentological model can help to steer drilling strategy and reduce uncertainties and associated risks. For this purpose the GRASP joint industry programme was established......Tunnel galleys are common features in Palaeozoic glacigenic succession in North Afrcica and Middle East and they are amongst the most challenging target for hydrocarbon exploration and developing drilling in these regions. Similarly, these buried valleys form important groundwater reservoirs...... in Quaternary glaciated areas and their nature and sediment composition is critical to drive a sustainable production strategy and assess their vulnerability. Seismic resolution however, often limits the understanding of channel valleys morphology, 3D geometry and internal reservoir distribution, thus...

  6. Spicing things up: synthetic cannabinoids.

    Science.gov (United States)

    Spaderna, Max; Addy, Peter H; D'Souza, Deepak Cyril

    2013-08-01

    Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally. The availability, acute subjective effects-including self-reports posted on Erowid-laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Spice is sold under the guise of potpourri or incense. Unlike delta-9-tetrahydrocannabinol, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned. There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug detection tests for synthetic cannabinoids need to become clinically available.

  7. Synthetic Biology and Personalized Medicine

    Science.gov (United States)

    Jain, K.K.

    2013-01-01

    Synthetic biology, application of synthetic chemistry to biology, is a broad term that covers the engineering of biological systems with structures and functions not found in nature to process information, manipulate chemicals, produce energy, maintain cell environment and enhance human health. Synthetic biology devices contribute not only to improve our understanding of disease mechanisms, but also provide novel diagnostic tools. Methods based on synthetic biology enable the design of novel strategies for the treatment of cancer, immune diseases metabolic disorders and infectious diseases as well as the production of cheap drugs. The potential of synthetic genome, using an expanded genetic code that is designed for specific drug synthesis as well as delivery and activation of the drug in vivo by a pathological signal, was already pointed out during a lecture delivered at Kuwait University in 2005. Of two approaches to synthetic biology, top-down and bottom-up, the latter is more relevant to the development of personalized medicines as it provides more flexibility in constructing a partially synthetic cell from basic building blocks for a desired task. PMID:22907209

  8. Caged ceramide 1-phosphate analogues: synthesis and properties.

    Science.gov (United States)

    Lankalapalli, Ravi S; Ouro, Alberto; Arana, Lide; Gómez-Muñoz, Antonio; Bittman, Robert

    2009-11-20

    Sphingolipid phosphate analogues bearing 7-(diethylamino)coumarin (DECM) and 4-bromo-5-hydroxy-2-nitrobenzhydryl (BHNB) groups in a photolabile ester bond were synthesized. The ability of the "caged" ceramide 1-phosphate analogues to release the bioactive parent molecule upon irradiation at 400-500 nm was demonstrated by stimulation of macrophage cell proliferation.

  9. Automated Layout Generation of Analogue and Mixed-Signal ASIC's

    DEFF Research Database (Denmark)

    Bloch, Rene

    The research and development carried out in this Ph.D. study focusses on two key areas of the design flow for analogue and mixed-signal integrated circuit design, the mixed-signal floorplanning and the analogue layout generation.A novel approach to floorplanning is presented which provides true i...

  10. Uncertainties and credibility building of safety analyses. Natural analogues

    International Nuclear Information System (INIS)

    Laciok, A.

    2001-07-01

    The substance of natural analogues and their studies is defined as a complementary method to laboratory and in-situ experiments and modelling. The role of natural analogues in the processes of development of repositories is defined, mainly in performance assessment of repository system and communication with public. The criteria for identification of natural analogues which should be evaluated in the phase of initiation of new studies are specified. Review part of this report is divided to study of natural analogues and study of anthropogenic and industrial analogues. The main natural analogue studies performed in various countries, in different geological setting, with various aims are characterized. New results acquired in recently finished studies are included: Palmottu (2nd phase of project financed by European Commission), Oklo (results of research financed also by European Commission), Maqarin (3rd phase) and other information obtained from last meetings and workshops of NAWG. In view of the fact that programmes of development of deep repositories in Czech and Slovak Republics are interconnected, the natural analogues studies carried out in the Czech republic are incorporated in separate chapter - study of uranium accumulation in Tertiary clays at Ruprechtov site and study of degradation of natural glasses. In final part the areas of natural analogue studies as an integral part of development of deep geological repository are proposed along with characterization of broader context and aspects of realization of these studies (international cooperation, preparation and evaluation of procedures, communication with public). (author)

  11. Insulin analogues and severe hypoglycaemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, P L; Hansen, L S; Jespersen, M J

    2012-01-01

    The effect of insulin analogues on glycaemic control is well-documented, whereas the effect on avoidance of severe hypoglycaemia remains tentative. We studied the frequency of severe hypoglycaemia in unselected patients with type 1 diabetes treated with insulin analogues, human insulin, or mixed...

  12. MAQARIN natural analogue study: phase III

    Energy Technology Data Exchange (ETDEWEB)

    Alexander, W.R.; Mazurek, M.; Waber, H.N. [Univ. of Berne (Switzerland). Institutes of Geology, Mineralogy and Petrology, Rock-Water Interaction Group (GGWW); Arlinger, J.; Erlandson, A.C.; Hallbeck, L.; Pedersen, K. [Goeteborg University (Sweden). Dept. of General and Marine Microbiology; Boehlmann, W.; Fritz, P.; Geyer, S.; Geyer, W.; Hanschman, G.; Kopinke, F.D.; Poerschmann, J. [Umweltforschungszentrum Leipzig-Halle (Germany); Chambers, A.V.; Haworth, A.; Ilett, D.; Linklater, C.M.; Tweed, C.J. [AEA Technology plc, Harwell (United Kingdom); Chenery, S.R.N.; Kemp, S.J.; Milodowski, A.E.; Pearce, J.M.; Reeder, S.; Rochelle, C.A.; Smith, B.; Wetton, P.D.; Wragg, J. [British Geological Survey, Keyworth (United Kingdom); Clark, I.D. [Univ. of Ottawa (Canada). Dept. of Geology; Hodginson, E.; Hughes, C.R. [Univ. of Manchester (United Kingdom). Dept. of Earth Sciences; Hyslop, E.K. [British Geological Survey, Edinburgh (United Kingdom); Karlsson, F. [Swedish Nuclear Fuel and Waste Management Co., Stockholm (Sweden); Khoury, H.N.; Salameh, E. [Univ. of Jordan, Amman (Jordan); Lagerblad, B. [Cement Institute, Stockholm (Sweden); Longworth, G. [Univ. of Manchester (United Kingdom). Dept. of Geology; Pitty, A.F. [Private consultant, Norwich (United Kingdom); Savage, D. [QuantiSci Ltd, Melton Mowbray (United Kingdom); Smellie, J.A.T. [ed.] [Conterra AB, Uppsala (Sweden)

    1998-12-01

    This report represents the conclusion to Phase III of the Maqarin Natural Analogue Study. The main thrust was to establish the origin and chemistry of the Western Springs hyper alkaline groundwaters (Na/K enriched Ca(OH){sub 2} type) and to study their interaction with rocks of different compositions, as natural analogues to key processes that might occur at an early stage within the `alkali disturbed zone` of cementitious repositories in different host rocks. Whilst earlier studies at Maqarin were very much site-specific and process-oriented, Phase III provided a regional perspective to the geological evolution of the Maqarin region. This was made possible by greater field access which allowed a more systematic structural and geomorphological study of the area. This has resulted in a greater understanding of the age and spatial relationships concerning formation of the cement zones through spontaneous combustion of the Bituminous Marls, and the subsequent formation of high pH groundwaters at the Eastern and Western Springs locations. At the Western Springs locality, hydrochemical and hydrogeological evaluation of new and published data (plus access to unpublished data), together with detailed mineralogical and geochemical studies, helped to clarify the very earliest stage of cement leachate/host rock interaction. The data were used also to test coupled flow/transport codes developed to assess the long-term evolution of a cementitious repository. Additional objectives addressed include: a) rock matrix diffusion, b) the occurrence and chemical controls on zeolite composition, e) the occurrence and chemical controls on clay stability, and d) the role of microbes, organics and colloids in trace element transport. The Maqarin site now provides a consistent picture explaining the origin of the hyperalkaline groundwaters, and is therefore a unique location for the examination of the mechanisms and processes associated with cementitious repositories. Application of these

  13. Natural analogues of nuclear waste glass corrosion

    International Nuclear Information System (INIS)

    Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

    1999-01-01

    This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses

  14. Natural analogues of nuclear waste glass corrosion.

    Energy Technology Data Exchange (ETDEWEB)

    Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

    1999-01-06

    This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.

  15. MAQARIN natural analogue study: phase III

    Energy Technology Data Exchange (ETDEWEB)

    Alexander, W.R.; Mazurek, M.; Waber, H.N. [Univ. of Berne (Switzerland). Institutes of Geology, Mineralogy and Petrology, Rock-Water Interaction Group (GGWW); Arlinger, J.; Erlandson, A.C.; Hallbeck, L.; Pedersen, K. [Goeteborg Univ. (Sweden). Dept. of General and Marine Microbiology; Boehlmann, W.; Fritz, P.; Geyer, S.; Geyer, W.; Hanschman, G.; Kopinke, F.D.; Poerschmann, J. [Umweltforschungszentrum Leipzig-Halle (Germany); Chambers, A.V.; Haworth, A.; Ilett, D.; Linklater, C.M.; Tweed, C.J. [AEA Technology plc, Harwell (United Kingdom); Chenery, S.R.N.; Kemp, S.J.; Milodowski, A.E.; Pearce, J.M.; Reeder, S.; Rochelle, C.A.; Smith, B.; Wetton, P.D.; Wragg, J. [British Geological Survey, Keyworth (United Kingdom); Clark, I.D. [Univ. of Ottawa (Canada). Dept. of Geology; Hodginson, E.; Hughes, C.R. [Univ. of Manchester (United Kingdom). Dept. of Earth Sciences; Hyslop, E.K. [British Geological Survey, Edinburgh (United Kingdom); Karlsson, F. [Swedish Nuclear Fuel and Waste Management Co., Stockholm (Sweden); Khoury, H.N.; Salameh, E. [Univ. of Jordan, Amman (Jordan); Lagerblad, B. [Cement Inst., Stockholm (Sweden); Longworth, G. [Univ. of Manchester (United Kingdom). Dept. of Geology; Pitty, A.F. [Private consultant, Norwich (United Kingdom); Savage, D. [QuantiSci Ltd, Melton Mowbray (United Kingdom); Smellie, J.A.T. [ed.] [Conterra AB, Uppsala (Sweden)

    1998-12-01

    This report represents the conclusion to Phase III of the Maqarin Natural Analogue Study. The main thrust was to establish the origin and chemistry of the Western Springs hyper alkaline groundwaters (Na/K enriched Ca(OH){sub 2} type) and to study their interaction with rocks of different compositions, as natural analogues to key processes that might occur at an early stage within the `alkali disturbed zone` of cementitious repositories in different host rocks. Whilst earlier studies at Maqarin were very much site-specific and process-oriented, Phase III provided a regional perspective to the geological evolution of the Maqarin region. This was made possible by greater field access which allowed a more systematic structural and geomorphological study of the area. This has resulted in a greater understanding of the age and spatial relationships concerning formation of the cement zones through spontaneous combustion of the Bituminous Marls, and the subsequent formation of high pH groundwaters at the Eastern and Western Springs locations. At the Western Springs locality, hydrochemical and hydrogeological evaluation of new and published data (plus access to unpublished data), together with detailed mineralogical and geochemical studies, helped to clarify the very earliest stage of cement leachate/host rock interaction. The data were used also to test coupled flow/transport codes developed to assess the long-term evolution of a cementitious repository. Additional objectives addressed include: a) rock matrix diffusion, b) the occurrence and chemical controls on zeolite composition, e) the occurrence and chemical controls on clay stability, and d) the role of microbes, organics and colloids in trace element transport. The Maqarin site now provides a consistent picture explaining the origin of the hyperalkaline groundwaters, and is therefore a unique location for the examination of the mechanisms and processes associated with cementitious repositories. Application of these

  16. Magnetic properties of Proxima Centauri b analogues

    Science.gov (United States)

    Zuluaga, Jorge I.; Bustamante, Sebastian

    2018-03-01

    The discovery of a planet around the closest star to our Sun, Proxima Centauri, represents a quantum leap in the testability of exoplanetary models. Unlike any other discovered exoplanet, models of Proxima b could be contrasted against near future telescopic observations and far future in-situ measurements. In this paper we aim at predicting the planetary radius and the magnetic properties (dynamo lifetime and magnetic dipole moment) of Proxima b analogues (solid planets with masses of ∼ 1 - 3M⊕ , rotation periods of several days and habitable conditions). For this purpose we build a grid of planetary models with a wide range of compositions and masses. For each point in the grid we run the planetary evolution model developed in Zuluaga et al. (2013). Our model assumes small orbital eccentricity, negligible tidal heating and earth-like radiogenic mantle elements abundances. We devise a statistical methodology to estimate the posterior distribution of the desired planetary properties assuming simple lprior distributions for the orbital inclination and bulk composition. Our model predicts that Proxima b would have a mass 1.3 ≤Mp ≤ 2.3M⊕ and a radius Rp =1.4-0.2+0.3R⊕ . In our simulations, most Proxima b analogues develop intrinsic dynamos that last for ≥4 Gyr (the estimated age of the host star). If alive, the dynamo of Proxima b have a dipole moment ℳdip >0.32÷2.9×2.3ℳdip , ⊕ . These results are not restricted to Proxima b but they also apply to earth-like planets having similar observed properties.

  17. MAQARIN natural analogue study: phase III

    International Nuclear Information System (INIS)

    Alexander, W.R.; Mazurek, M.; Waber, H.N.; Arlinger, J.; Erlandson, A.C.; Hallbeck, L.; Pedersen, K.; Chambers, A.V.; Haworth, A.; Ilett, D.; Linklater, C.M.; Tweed, C.J.; Chenery, S.R.N.; Kemp, S.J.; Milodowski, A.E.; Pearce, J.M.; Reeder, S.; Rochelle, C.A.; Smith, B.; Wetton, P.D.; Wragg, J.; Clark, I.D.; Karlsson, F.; Khoury, H.N.; Salameh, E.; Lagerblad, B.; Longworth, G.; Savage, D.; Smellie, J.A.T.

    1998-12-01

    This report represents the conclusion to Phase III of the Maqarin Natural Analogue Study. The main thrust was to establish the origin and chemistry of the Western Springs hyper alkaline groundwaters (Na/K enriched Ca(OH) 2 type) and to study their interaction with rocks of different compositions, as natural analogues to key processes that might occur at an early stage within the 'alkali disturbed zone' of cementitious repositories in different host rocks. Whilst earlier studies at Maqarin were very much site-specific and process-oriented, Phase III provided a regional perspective to the geological evolution of the Maqarin region. This was made possible by greater field access which allowed a more systematic structural and geomorphological study of the area. This has resulted in a greater understanding of the age and spatial relationships concerning formation of the cement zones through spontaneous combustion of the Bituminous Marls, and the subsequent formation of high pH groundwaters at the Eastern and Western Springs locations. At the Western Springs locality, hydrochemical and hydrogeological evaluation of new and published data (plus access to unpublished data), together with detailed mineralogical and geochemical studies, helped to clarify the very earliest stage of cement leachate/host rock interaction. The data were used also to test coupled flow/transport codes developed to assess the long-term evolution of a cementitious repository. Additional objectives addressed include: a) rock matrix diffusion, b) the occurrence and chemical controls on zeolite composition, e) the occurrence and chemical controls on clay stability, and d) the role of microbes, organics and colloids in trace element transport. The Maqarin site now provides a consistent picture explaining the origin of the hyperalkaline groundwaters, and is therefore a unique location for the examination of the mechanisms and processes associated with cementitious repositories. Application of these

  18. Melatonin analogue new indole hydrazide/hydrazone derivatives with antioxidant behavior: synthesis and structure-activity relationships.

    Science.gov (United States)

    Gürkök, Gökce; Coban, Tulay; Suzen, Sibel

    2009-04-01

    Melatonin (MLT) is a hormone produced in the brain by the pineal gland, from the amino acid tryptophan. It is also an antioxidant hormone with a particular role in the protection of nuclear and mitochondrial DNA. In recent years, many physiological properties of MLT have been described resulting in much attention in the development of synthetic compounds possessing the indole ring. Sixteen MLT analogue indole hydrazide/hydrazone derivatives were synthesized and in vitro antioxidant activity was investigated. Most of the compounds showed significantly higher activity than MLT at 10(-3) M and 10(-4) M concentrations.

  19. Bistatic synthetic aperture radar

    Science.gov (United States)

    Yates, Gillian

    Synthetic aperture radar (SAR) allows all-weather, day and night, surface surveillance and has the ability to detect, classify and geolocate objects at long stand-off ranges. Bistatic SAR, where the transmitter and the receiver are on separate platforms, is seen as a potential means of countering the vulnerability of conventional monostatic SAR to electronic countermeasures, particularly directional jamming, and avoiding physical attack of the imaging platform. As the receiving platform can be totally passive, it does not advertise its position by RF emissions. The transmitter is not susceptible to jamming and can, for example, operate at long stand-off ranges to reduce its vulnerability to physical attack. This thesis examines some of the complications involved in producing high-resolution bistatic SAR imagery. The effect of bistatic operation on resolution is examined from a theoretical viewpoint and analytical expressions for resolution are developed. These expressions are verified by simulation work using a simple 'point by point' processor. This work is extended to look at using modern practical processing engines for bistatic geometries. Adaptations of the polar format algorithm and range migration algorithm are considered. The principal achievement of this work is a fully airborne demonstration of bistatic SAR. The route taken in reaching this is given, along with some results. The bistatic SAR imagery is analysed and compared to the monostatic imagery collected at the same time. Demonstrating high-resolution bistatic SAR imagery using two airborne platforms represents what I believe to be a European first and is likely to be the first time that this has been achieved outside the US (the UK has very little insight into US work on this topic). Bistatic target characteristics are examined through the use of simulations. This also compares bistatic imagery with monostatic and gives further insight into the utility of bistatic SAR.

  20. Analogue Hawking radiation from astrophysical black-hole accretion

    International Nuclear Information System (INIS)

    Das, Tapas K

    2004-01-01

    We show that spherical accretion onto astrophysical black holes can be considered as a natural example of an analogue system. We provide, for the first time, an exact analytical scheme for calculating the analogue Hawking temperature and surface gravity for general relativistic accretion onto astrophysical black holes. Our calculation may bridge the gap between the theory of transonic astrophysical accretion and the theory of analogue Hawking radiation. We show that the domination of the analogue Hawking temperature over the actual Hawking temperature may be a real astrophysical phenomenon, though observational tests of this fact will at best be difficult and at worst might prove to be impossible. We also discuss the possibilities of the emergence of analogue white holes around astrophysical black holes. Our calculation is general enough to accommodate accreting black holes with any mass

  1. Synthetic biology for therapeutic applications.

    Science.gov (United States)

    Abil, Zhanar; Xiong, Xiong; Zhao, Huimin

    2015-02-02

    Synthetic biology is a relatively new field with the key aim of designing and constructing biological systems with novel functionalities. Today, synthetic biology devices are making their first steps in contributing new solutions to a number of biomedical challenges, such as emerging bacterial antibiotic resistance and cancer therapy. This review discusses some synthetic biology approaches and applications that were recently used in disease mechanism investigation and disease modeling, drug discovery and production, as well as vaccine development and treatment of infectious diseases, cancer, and metabolic disorders.

  2. The Ethics of Synthetic Biology

    DEFF Research Database (Denmark)

    Christiansen, Andreas

    The dissertation analyses and discusses a number of ethical issues that have been raised in connection with the development of synthetic biology. Synthetic biology is a set of new techniques for DNA-level design and construction of living beings with useful properties. The dissertation especially......) popular responsesto them succeed, and whether the objections are ultimately persuasive.2. Given that synthetic biology is a new technology, there is a certain degree of uncertainty about its ultimate effects, and many perceive the technology as risky. I discuss two common approaches in risk regulation...

  3. Analogue to Digital and Digital to Analogue (AD/DA) Conversion Techniques: An Overview

    CERN Multimedia

    CERN. Geneva

    2002-01-01

    The basic ideas behind modern Analogue to Digital and Digital to Analogue (AD/DA) conversion methods will be introduced: a general view of the importance of these devices will be given, along with the digital representation of time-varying, real-world analogue signals. Some CERN applications will be outlined. The variety of conversion methods, their limitations, error sources and measurement methods will form the major part of this presentation. A review of the technological progress in this field over the last 30 years will be presented, concluding with the present 'state of the art' and a quick look at what is just around the corner. This Technical Training Seminar is in the framework of the FEED-2002 Lecture Series, and it is a prerequisite to attending to any of the FEED-2002 Terms. FEED-2002 is a two-term course that will review the techniques dealing with closed loop systems, focussing on time-invariant linear systems. (free attendance, no registration required) More information on the FEED-2002 ...

  4. Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

    Science.gov (United States)

    Segal, Meirav; Fischer, Bilha

    2012-02-28

    Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

  5. A FEASIBLE APPROACH TO EVALUATE THE RELATIVE REACTIVITY OF NHS-ESTER ACTIVATED GROUP WITH PRIMARY AMINE-DERIVATIZED DNA ANALOGUE AND NON-DERIVATIZED IMPURITY

    Science.gov (United States)

    Dou, Shuping; Virostko, John; Greiner, Dale L.; Powers, Alvin C.; Liu, Guozheng

    2015-01-01

    Synthetic DNA analogues with improved stability are widely used in life science. The 3′ and/or 5′ equivalent terminuses are often derivatized by attaching an active group for further modification, but a certain amount of non-derivatized impurity often remains. It is important to know to what extent the impurity would influence further modification. The reaction of an NHS ester with primary amine is one of the most widely used options to modify DNA analogues. In this short communication, a 3′-(NH2-biotin)-derivatized morpholino DNA analogue (MORF) was utilized as the model derivatized DNA analogue. Inclusion of a biotin concomitant with the primary amine at the 3′-terminus allows for the use of streptavidin to discriminate between the products from the derivatized MORF and non-derivatized MORF impurity. To detect the MORF reaction with NHS ester, S-acetyl NHS-MAG3 was conjugated to the DNA analogue for labeling with 99mTc, a widely used nuclide in the clinic. It was found that the non-derivatized MORF also reacted with the S-acetyl NHS-MAG3. Radiolabeling of the product yielded an equally high labeling efficiency. Nevertheless, streptavidin binding indicated that under the conditions of this investigation, the non-derivatized MORF was five times less reactive than the amine-derivatized MORF. PMID:25621701

  6. RPF101, a new capsaicin-like analogue, disrupts the microtubule network accompanied by arrest in the G2/M phase, inducing apoptosis and mitotic catastrophe in the MCF-7 breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Sá-Júnior, Paulo Luiz de [Laboratory of Genetics, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo (Brazil); Pasqualoto, Kerly Fernanda Mesquita [Biochemistry and Biophysical Laboratory, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo (Brazil); Ferreira, Adilson Kleber [Laboratory of Genetics, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo (Brazil); Tavares, Maurício Temotheo; Damião, Mariana Celestina Frojuello Costa Bernstorff [Department of Pharmacy, School of Pharmaceutical Sciences, University of Sao Paulo, Prof. Lineu Prestes Avenue, 580, Postal Code: 05508-000, Sao Paulo (Brazil); Azevedo, Ricardo Alexandre de [Biochemistry and Biophysical Laboratory, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo (Brazil); Câmara, Diana Aparecida Dias; Pereira, Alexandre; Madeiro de Souza, Dener [Laboratory of Genetics, Butantan Institute, Vital Brasil Avenue 1500, Postal Code: 05503-900, Sao Paulo (Brazil); Parise Filho, Roberto, E-mail: roberto.parise@usp.br [Department of Pharmacy, School of Pharmaceutical Sciences, University of Sao Paulo, Prof. Lineu Prestes Avenue, 580, Postal Code: 05508-000, Sao Paulo (Brazil)

    2013-02-01

    Breast cancer is the world's leading cause of death among women. This situation imposes an urgent development of more selective and less toxic agents. The use of natural molecular fingerprints as sources for new bioactive chemical entities has proven to be a quite promising and efficient method. Capsaicin, which is the primary pungent compound in red peppers, was reported to selectively inhibit the growth of a variety tumor cell lines. Here, we report for the first time a novel synthetic capsaicin-like analogue, RPF101, which presents a high antitumor activity on MCF-7 cell line, inducing arrest of the cell cycle at the G2/M phase through a disruption of the microtubule network. Furthermore, it causes cellular morphologic changes characteristic of apoptosis and a decrease of Δψm. Molecular modeling studies corroborated the biological findings and suggested that RPF101, besides being a more reactive molecule towards its target, may also present a better pharmacokinetic profile than capsaicin. All these findings support the fact that RPF101 is a promising anticancer agent. -- Highlights: ► We report for the first time that RPF101 possesses anticancer properties. ► RPF101 induces apoptosis of human breast cancer cells. ► RPF 101 decreases mitochondrial potential and induces DNA fragmentation.

  7. RPF101, a new capsaicin-like analogue, disrupts the microtubule network accompanied by arrest in the G2/M phase, inducing apoptosis and mitotic catastrophe in the MCF-7 breast cancer cells

    International Nuclear Information System (INIS)

    Sá-Júnior, Paulo Luiz de; Pasqualoto, Kerly Fernanda Mesquita; Ferreira, Adilson Kleber; Tavares, Maurício Temotheo; Damião, Mariana Celestina Frojuello Costa Bernstorff; Azevedo, Ricardo Alexandre de; Câmara, Diana Aparecida Dias; Pereira, Alexandre; Madeiro de Souza, Dener; Parise Filho, Roberto

    2013-01-01

    Breast cancer is the world's leading cause of death among women. This situation imposes an urgent development of more selective and less toxic agents. The use of natural molecular fingerprints as sources for new bioactive chemical entities has proven to be a quite promising and efficient method. Capsaicin, which is the primary pungent compound in red peppers, was reported to selectively inhibit the growth of a variety tumor cell lines. Here, we report for the first time a novel synthetic capsaicin-like analogue, RPF101, which presents a high antitumor activity on MCF-7 cell line, inducing arrest of the cell cycle at the G2/M phase through a disruption of the microtubule network. Furthermore, it causes cellular morphologic changes characteristic of apoptosis and a decrease of Δψm. Molecular modeling studies corroborated the biological findings and suggested that RPF101, besides being a more reactive molecule towards its target, may also present a better pharmacokinetic profile than capsaicin. All these findings support the fact that RPF101 is a promising anticancer agent. -- Highlights: ► We report for the first time that RPF101 possesses anticancer properties. ► RPF101 induces apoptosis of human breast cancer cells. ► RPF 101 decreases mitochondrial potential and induces DNA fragmentation.

  8. An efficient synthesis and antifungal evaluation of natural product streptochlorin and its analogues.

    Science.gov (United States)

    Jia, Chen-Yang; Xu, Li-Yong; Yu, Xiang; Ding, Yu-Bing; Jin, Bing; Zhang, Ming-Zhi; Zhang, Wei-Hua; Yang, Guang-Fu

    2018-03-01

    Streptochlorin, a small indole alkaloid isolated from marine Streptomyces sp., exhibits a wide range of potent biological activities. An efficient and economic synthetic protocol for streptochlorin has been developed and validated, 4 steps from indole in a total yield of 45%, and further applied for the synthesis of its analogues. Biological testing showed that most of the target compounds exhibited potential antifungal activity in the primary assays, especially compounds 6, 7 and 9c were the most active ones, representing effective activity against the phytopathogenic fungi screened in preliminary test and might be explored for the study of mode of action in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Efficient Synthesis and Antibacterial Evaluation of (±-Yanglingmycin and Its Analogues

    Directory of Open Access Journals (Sweden)

    Wenjia Dan

    2016-01-01

    Full Text Available An efficient synthetic route was developed for the large-scale preparation of (±-Yanglingmycin and its analogues. Three series of derivatives of (±-Yanglingmycin were synthesized and the structures of all compounds were elucidated by analyses of NMR and ESI-MS spectra data. Moreover, their antibacterial activities against seven species of bacteria were systematically evaluated by the micro-broth dilution method, most of which displayed considerable activity. It was worth noting that compounds 5b, 5c, 5d, 6g, and 7 were found to be the most promising leading candidates, with peak MIC values of 0.98 μg·mL−1 for Bacillus subtilis, which is superior to positive controls (MIC = 3.91 μg·mL−1. The above results might lay the firm foundation for the design and synthesis of novel antibacterial drugs based on (±-Yanglingmycin.

  10. Effect of organic synthetic food colours on mitochondrial respiration.

    Science.gov (United States)

    Reyes, F G; Valim, M F; Vercesi, A E

    1996-01-01

    Eleven organic synthetic dyes, currently or formerly used as food colours in Brazil, were tested to determine their effect on mitochondrial respiration in mitochondria isolated from rat liver and kidney. The compounds tested were: Erythrosine, Ponceau 4R, Allura Red, Sunset yellow, Tartrazine, Amaranth, Brilliant Blue, Blue, Fast Red E, Orange GGN and Scarlet GN. All food colours tested inhibited mitochondrial respiration (State III respiration, uncoupled) supported either by alpha-ketoglutarate or succinate. This inhibition varied largely, e.g. from 100% to 16% for Erythrosine and Tartrazine respectively, at a concentration of 0.1 mg food colour per mitochondrial protein. Both rat liver and kidney mitochondria showed similar patterns of inhibition among the food colours tested. This effect was dose related and the concentration to give 50% inhibition was determined for some of the dyes. The xanthene dye Erythrosine, which showed the strongest effect, was selected for further investigation on mitochondria in vivo.

  11. Tissue Harmonic Synthetic Aperture Imaging

    DEFF Research Database (Denmark)

    Rasmussen, Joachim

    The main purpose of this PhD project is to develop an ultrasonic method for tissue harmonic synthetic aperture imaging. The motivation is to advance the field of synthetic aperture imaging in ultrasound, which has shown great potentials in the clinic. Suggestions for synthetic aperture tissue...... system complexity compared to conventional synthetic aperture techniques. In this project, SASB is sought combined with a pulse inversion technique for 2nd harmonic tissue harmonic imaging. The advantages in tissue harmonic imaging (THI) are expected to further improve the image quality of SASB....... The first part of the scientific contribution investigates an implementation of pulse inversion for THI on the experimental ultrasound system SARUS. The technique is initially implemented for linear array transducers and then expanded for convex array transducers. The technique is evaluated based on spatial...

  12. Adaptive Synthetic Forces: Situation Awareness

    National Research Council Canada - National Science Library

    Hill, Randall

    2001-01-01

    ...: perception, comprehension, and prediction. Building on these ideas, we developed techniques for improving the situation awareness in synthetic helicopter pilots for the ModSAF military simulation by giving them more human-like perception...

  13. Designing synthetic networks in silico

    NARCIS (Netherlands)

    Smith, Robert W.; Sluijs, van Bob; Fleck, Christian

    2017-01-01

    Background: Evolution has led to the development of biological networks that are shaped by environmental signals. Elucidating, understanding and then reconstructing important network motifs is one of the principal aims of Systems & Synthetic Biology. Consequently, previous research has focused

  14. Synthetic Biology for Specialty Chemicals.

    Science.gov (United States)

    Markham, Kelly A; Alper, Hal S

    2015-01-01

    In this review, we address recent advances in the field of synthetic biology and describe how those tools have been applied to produce a wide variety of chemicals in microorganisms. Here we classify the expansion of the synthetic biology toolbox into three different categories based on their primary function in strain engineering-for design, for construction, and for optimization. Next, focusing on recent years, we look at how chemicals have been produced using these new synthetic biology tools. Advances in producing fuels are briefly described, followed by a more thorough treatment of commodity chemicals, specialty chemicals, pharmaceuticals, and nutraceuticals. Throughout this review, an emphasis is placed on how synthetic biology tools are applied to strain engineering. Finally, we discuss organism and host strain diversity and provide a future outlook in the field.

  15. Is synthetic biology mechanical biology?

    Science.gov (United States)

    Holm, Sune

    2015-12-01

    A widespread and influential characterization of synthetic biology emphasizes that synthetic biology is the application of engineering principles to living systems. Furthermore, there is a strong tendency to express the engineering approach to organisms in terms of what seems to be an ontological claim: organisms are machines. In the paper I investigate the ontological and heuristic significance of the machine analogy in synthetic biology. I argue that the use of the machine analogy and the aim of producing rationally designed organisms does not necessarily imply a commitment to mechanical biology. The ideal of applying engineering principles to biology is best understood as expressing recognition of the machine-unlikeness of natural organisms and the limits of human cognition. The paper suggests an interpretation of the identification of organisms with machines in synthetic biology according to which it expresses a strategy for representing, understanding, and constructing living systems that are more machine-like than natural organisms.

  16. Programming languages for synthetic biology.

    Science.gov (United States)

    Umesh, P; Naveen, F; Rao, Chanchala Uma Maheswara; Nair, Achuthsankar S

    2010-12-01

    In the backdrop of accelerated efforts for creating synthetic organisms, the nature and scope of an ideal programming language for scripting synthetic organism in-silico has been receiving increasing attention. A few programming languages for synthetic biology capable of defining, constructing, networking, editing and delivering genome scale models of cellular processes have been recently attempted. All these represent important points in a spectrum of possibilities. This paper introduces Kera, a state of the art programming language for synthetic biology which is arguably ahead of similar languages or tools such as GEC, Antimony and GenoCAD. Kera is a full-fledged object oriented programming language which is tempered by biopart rule library named Samhita which captures the knowledge regarding the interaction of genome components and catalytic molecules. Prominent feature of the language are demonstrated through a toy example and the road map for the future development of Kera is also presented.

  17. Synthesis of thio-heterocyclic analogues from Baylis-Hillman bromides as potent cyclooxygenase-2 inhibitors.

    Science.gov (United States)

    Santhoshi, Amlipur; Mahendar, Budde; Mattapally, Saidulu; Sadhu, Partha Sarathi; Banerjee, Sanjay Kumar; Jayathirtha Rao, Vaidya

    2014-04-15

    A series of thio-substituted pyrimidine, benzoxazole, benzothiazole and triazole analogues were synthesized from Baylis-Hillman bromides in a clean and efficient way. The synthesized twenty new compounds were subjected to in vitro COX-1 and COX-2 inhibitory activity. Majority of compounds found to be highly selective COX-2 inhibitor. Seven compounds (16e, 16f, 16k, 16l, 16m, 16r and 16s) displayed anti-inflammatory activity at micromolar concentrations with IC50 values for COX-2 inhibition ranging from 2.93 to 5.34 μM compared to reference drug whose IC50 is 2.66 μM. All these seven compounds had very little COX-1 inhibition property and thus are suitable candidates for anti-inflammatory drugs with less gastrointestinal side effect. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. The Use of Natural Polymers in Tissue Engineering: A Focus on Electrospun Extracellular Matrix Analogues

    Directory of Open Access Journals (Sweden)

    Gary L. Bowlin

    2010-11-01

    Full Text Available Natural polymers such as collagens, elastin, and fibrinogen make up much of the body’s native extracellular matrix (ECM. This ECM provides structure and mechanical integrity to tissues, as well as communicating with the cellular components it supports to help facilitate and regulate daily cellular processes and wound healing. An ideal tissue engineering scaffold would not only replicate the structure of this ECM, but would also replicate the many functions that the ECM performs. In the past decade, the process of electrospinning has proven effective in creating non-woven ECM analogue scaffolds of micro to nanoscale diameter fibers from an array of synthetic and natural polymers. The ability of this fabrication technique to utilize the aforementioned natural polymers to create tissue engineering scaffolds has yielded promising results, both in vitro and in vivo, due in part to the enhanced bioactivity afforded by materials normally found within the human body. This review will present the process of electrospinning and describe the use of natural polymers in the creation of bioactive ECM analogues in tissue engineering.

  19. Development and labeling of EP-00652218 analogues, NK1 receptors antagonist, for PET and SPECT imaging

    International Nuclear Information System (INIS)

    Bagot-Gueret, C.

    2001-12-01

    The aim of this work was the synthesis and radiosynthesis of compounds labelled either with a positron emitter (fluorine-18, t 1/2 = 109 minutes) or with a gamma emitter (iodine-123, t 1/2 = 16.2 hours), for Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) studies. EP-00652218 is a novel potent antagonist, with a sub-nano-molar affinity towards the NK 1 receptors. In order to develop ligands that could be used either in PET or SPECT, we undertook the synthesis of poly-halogenated analogues of EP-00652218. Compound 17 was synthesized through two different synthetic pathways. A series of original compounds has been obtained from compound 17 by halogen exchanges on the naphthyridone or the benzene ring. These molecules were tested to determine their in vitro affinity towards NK 1 receptors. Compound 21 was labelled with fluorine-18 in 135 minutes and with a 20% radiochemical yield. Compound 26 was radioiodinated following reaction with Na 125 I (t 1/2 = 60.14 days) in a 18% radiochemical yield. Despite expectation, these analogues of EP-00652218 exhibited an insufficient affinity for NK 1 receptors (IC 50 = 10 -7 M) and thus unlikely usable for in vivo studies with PET and SPECT. (author)

  20. Generating realistic synthetic meteoroid orbits

    Science.gov (United States)

    Vida, Denis; Brown, Peter G.; Campbell-Brown, Margaret

    2017-11-01

    Context. Generating a synthetic dataset of meteoroid orbits is a crucial step in analysing the probabilities of random grouping of meteoroid orbits in automated meteor shower surveys. Recent works have shown the importance of choosing a low similarity threshold value of meteoroid orbits, some pointing out that the recent meteor shower surveys produced false positives due to similarity thresholds which were too high. On the other hand, the methods of synthetic meteoroid orbit generation introduce additional biases into the data, thus making the final decision on an appropriate threshold value uncertain. Aims. As a part of the ongoing effort to determine the nature of meteor showers and improve automated methods, it was decided to tackle the problem of synthetic meteoroid orbit generation, the main goal being to reproduce the underlying structure and the statistics of the observed data in the synthetic orbits. Methods. A new method of generating synthetic meteoroid orbits using the Kernel Density Estimation method is presented. Several types of approaches are recommended, depending on whether one strives to preserve the data structure, the data statistics or to have a compromise between the two. Results. The improvements over the existing methods of synthetic orbit generation are demonstrated. The comparison between the previous and newly developed methods are given, as well as the visualization tools one can use to estimate the influence of different input parameters on the final data.

  1. 8-Modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription.

    Directory of Open Access Journals (Sweden)

    Valérie Vivet-Boudou

    Full Text Available The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix αH in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2'-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2'-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication.

  2. The Greenland Analogue Project. Yearly Report 2009

    International Nuclear Information System (INIS)

    2010-12-01

    A deep geological repository for spent nuclear fuel needs to be designed to keep used nuclear fuel isolated from mankind and the environment for a million years. Within this time frame glacial conditions are expected in regions that have been glaciated in the past two to ten million years. Climate induced changes such as the growth of ice sheets and permafrost will influence and alter the ground surface and subsurface environment, including its hydrology, which may impact repository safety. Glaciation impact assessments have to-date used over-simplified models and conservative assumptions, for example in the representation of ice sheet hydrology, that do not reflect the complexity of natural systems and processes. This is largely due to lack of direct observations of such processes from existing ice sheets, which if more readily available could help reduce uncertainties and provide a strong scientific basis for the treatment of glacial impacts in safety assessments. Our current understanding of the hydrological, hydrogeological and hydrogeochemical processes associated with glacial cycles and their impact on the long-term performance of deep geological repositories for spent nuclear fuel will be significantly improved by studying a modern analogue. To advance the understanding of processes associated with glaciation and their impact on the long-term performance of a deep geological repository, the Greenland Analogue Project (GAP), a four-year field and modelling study of the Greenland ice sheet and sub-surface conditions, has been initiated collaboratively by SKB, Posiva and NWMO. The study site encompasses a land terminus portion of the Greenland ice sheet east of Kangerlussuaq and is in many ways considered to be an appropriate analogue of the conditions that are expected to prevail in much of Canada and Fennoscandia during future glacial cycles. The project is planned to run from 2009 until 2012. The GAP will conduct the first in situ investigations of some of

  3. The Greenland Analogue Project. Yearly Report 2009

    Energy Technology Data Exchange (ETDEWEB)

    2010-12-15

    A deep geological repository for spent nuclear fuel needs to be designed to keep used nuclear fuel isolated from mankind and the environment for a million years. Within this time frame glacial conditions are expected in regions that have been glaciated in the past two to ten million years. Climate induced changes such as the growth of ice sheets and permafrost will influence and alter the ground surface and subsurface environment, including its hydrology, which may impact repository safety. Glaciation impact assessments have to-date used over-simplified models and conservative assumptions, for example in the representation of ice sheet hydrology, that do not reflect the complexity of natural systems and processes. This is largely due to lack of direct observations of such processes from existing ice sheets, which if more readily available could help reduce uncertainties and provide a strong scientific basis for the treatment of glacial impacts in safety assessments. Our current understanding of the hydrological, hydrogeological and hydrogeochemical processes associated with glacial cycles and their impact on the long-term performance of deep geological repositories for spent nuclear fuel will be significantly improved by studying a modern analogue. To advance the understanding of processes associated with glaciation and their impact on the long-term performance of a deep geological repository, the Greenland Analogue Project (GAP), a four-year field and modelling study of the Greenland ice sheet and sub-surface conditions, has been initiated collaboratively by SKB, Posiva and NWMO. The study site encompasses a land terminus portion of the Greenland ice sheet east of Kangerlussuaq and is in many ways considered to be an appropriate analogue of the conditions that are expected to prevail in much of Canada and Fennoscandia during future glacial cycles. The project is planned to run from 2009 until 2012. The GAP will conduct the first in situ investigations of some of

  4. Design of potent substrate-analogue inhibitors of canine renin

    Science.gov (United States)

    Hui, K. Y.; Siragy, H. M.; Haber, E.

    1992-01-01

    Through a systematic study of structure-activity relationships, we designed potent renin inhibitors for use in dog models. In assays against dog plasma renin at neutral pH, we found that, as in previous studies of rat renin inhibitors, the structure at the P2 position appears to be important for potency. The substitution of Val for His at this position increases potency by one order of magnitude. At the P3 position, potency appears to depend on a hydrophobic side chain that does not necessarily have to be aromatic. Our results also support the approach of optimizing potency in a renin inhibitor by introducing a moiety that promotes aqueous solubility (an amino group) at the C-terminus of the substrate analogue. In the design of potent dog plasma renin inhibitors, the influence of the transition-state residue 4(S)-amino-3(S)-hydroxy-5-cyclohexylpentanoic acid (ACHPA)-commonly used as a substitute for the scissile-bond dipeptide to boost potency-is not obvious, and appears to be sequence dependent. The canine renin inhibitor Ac-paF-Pro-Phe-Val-statine-Leu-Phe-paF-NH2 (compound 15; IC50 of 1.7 nM against dog plasma renin at pH 7.4; statine, 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid; paF, para-aminophenylalanine) had a potent hypotensive effect when infused intravenously into conscious, sodium-depleted, normotensive dogs. Also, compound 15 concurrently inhibited plasma renin activity and had a profound diuretic effect.

  5. Acylated apelin-13 amide analogues exhibit enzyme resistance and prolonged insulin releasing, glucose lowering and anorexic properties.

    Science.gov (United States)

    O'Harte, Finbarr P M; Parthsarathy, Vadivel; Hogg, Christopher; Flatt, Peter R

    2017-12-15

    The adipokine, apelin has many biological functions but its activity is curtailed by rapid plasma degradation. Fatty acid derived apelin analogues represent a new and exciting avenue for the treatment of obesity-diabetes. This study explores four novel fatty acid modified apelin-13 analogues, namely, (Lys 8 GluPAL)apelin-13 amide, pGlu(Lys 8 GluPAL)apelin-13 amide, Lys 8 GluPAL(Tyr 13 )apelin-13 and Lys 8 GluPAL(Val 13 )apelin-13. Fatty acid modification extended the half-life of native apelin-13 to >24 h in vitro. pGlu(Lys 8 GluPAL)apelin-13 amide was the most potent insulinotropic analogue in BRIN-BD11 cells and isolated islets with maximal stimulatory effects of up to 2.7-fold (p glucose uptake in 3T3-L1 adipocytes (2.3-fold, p glucose (39-43%, p glucose tolerance tests in diet-induced obese mice. pGlu(Lys 8 GluPAL)apelin-13 amide and (Lys 8 GluPAL)apelin-13 amide also inhibited feeding (28-40%, p < .001), whereas Lys 8 GluPAL(Val 13 )apelin-13 increased food intake (8%, p < .05) in mice. These data indicate that novel enzymatically stable analogues of apelin-13 may be suitable for future development as therapeutic agents for obesity-diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Freedom and Responsibility in Synthetic Genomics: The Synthetic Yeast Project.

    Science.gov (United States)

    Sliva, Anna; Yang, Huanming; Boeke, Jef D; Mathews, Debra J H

    2015-08-01

    First introduced in 2011, the Synthetic Yeast Genome (Sc2.0) PROJECT is a large international synthetic genomics project that will culminate in the first eukaryotic cell (Saccharomyces cerevisiae) with a fully synthetic genome. With collaborators from across the globe and from a range of institutions spanning from do-it-yourself biology (DIYbio) to commercial enterprises, it is important that all scientists working on this project are cognizant of the ethical and policy issues associated with this field of research and operate under a common set of principles. In this commentary, we survey the current ethics and regulatory landscape of synthetic biology and present the Sc2.0 Statement of Ethics and Governance to which all members of the project adhere. This statement focuses on four aspects of the Sc2.0 PROJECT: societal benefit, intellectual property, safety, and self-governance. We propose that such project-level agreements are an important, valuable, and flexible model of self-regulation for similar global, large-scale synthetic biology projects in order to maximize the benefits and minimize potential harms. Copyright © 2015 by the Genetics Society of America.

  7. UK Natural Analogue Coordinating Group: fourth annual report

    International Nuclear Information System (INIS)

    Read, D.; Hooker, P.J.

    1992-01-01

    HMIP has a research programme investigating some naturally radioactive sites as geochemical analogues of radionuclide migration. All of the analogue sites under investigation, both in the U.K. and overseas, are located where elevated uranium concentrations occur naturally. Coordination of the programme is achieved through the UK Natural Analogue Co-ordinating Group (NACG) which has met three times in this reporting period. The NACG is steered by the British Geological Survey. Its purpose is to ensure that the different research projects have an integrated function aimed at increasing our understanding of natural geochemical processes. Effort is also being expended in testing research models which may be used in such assessments. (author)

  8. A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

    Directory of Open Access Journals (Sweden)

    Arno Verlee

    2017-02-01

    Full Text Available For the synthesis of m-sulfamoylbenzamide analogues, small molecules which are known for their bioactivity, a chemoselective procedure has been developed starting from m-(chlorosulfonylbenzoyl chloride. Although a chemoselective process in batch was already reported, a continuous-flow process reveals an increased selectivity at higher temperatures and without catalysts. In total, 15 analogues were synthesized, using similar conditions, with yields ranging between 65 and 99%. This is the first automated and chemoselective synthesis of m-sulfamoylbenzamide analogues.

  9. A Low-cost Multi-channel Analogue Signal Generator

    CERN Document Server

    Müller, F; The ATLAS collaboration; Shen, W; Stamen, R

    2009-01-01

    A scalable multi-channel analogue signal generator is presented. It uses a commercial low-cost graphics card with multiple outputs in a standard PC as signal source. Each color signal serves as independent channel to generate an analogue signal. A custom-built external PCB was developed to adjust the graphics card output voltage levels for a specific task, which needed differential signals. The system furthermore comprises a software package to program the signal shape. The signal generator was successfully used as independent test bed for the ATLAS Level-1 Trigger Pre-Processor, providing up to 16 analogue signals.

  10. Prevention of postpartum haemorrhage with the oxytocin analogue carbetocin.

    Science.gov (United States)

    Rath, Werner

    2009-11-01

    Postpartum haemorrhage is the leading cause of maternal mortality worldwide: 67-80% of cases are caused by uterine atony. Preventive measures include prophylactic drug use to aid uterine contraction after delivery, thus avoiding severe blood loss and reducing maternal morbidity and mortality. Carbetocin is a synthetic analogue of oxytocin with a half-life approximately 4-10 times longer than that reported for oxytocin. It combines the safety and tolerability profile of oxytocin with the sustained uterotonic activity of injectable ergot alkaloids. Furthermore, carbetocin can be administered as a single dose injection either intravenously or intramuscularly rather than as an infusion over several hours as is the case with oxytocin. Carbetocin is currently indicated for prevention of uterine atony after delivery by caesarean section in spinal or epidural anaesthesia. Data from three randomised controlled trials in caesarean delivery and a meta-analysis indicate that carbetocin significantly reduces the need for additional uterotonic agents or uterine massage to prevent excessive bleeding compared with placebo or oxytocin. The risk of headache, tremor, hypotension, flushing, nausea, abdominal pain, pruritus and feeling of warmth was similar in women who received carbetocin or oxytocin. The findings from two more recent double-blind randomised trials and one retrospective study suggest that carbetocin may also represent a good alternative to conventional uterotonic agents for prevention of postpartum haemorrhage after vaginal deliveries. A reduced need for additional uterotonics was observed with carbetocin vs. oxytocin in high-risk women and carbetocin was at least as effective as syntometrine in low-risk women. In these studies of vaginal deliveries, carbetocin was associated with a low incidence of adverse effects and demonstrated a better tolerability profile than syntometrine. Carbetocin had a long duration of action compared with intravenous oxytocin alone and a

  11. Long-term predictions using natural analogues

    International Nuclear Information System (INIS)

    Ewing, R.C.

    1995-01-01

    One of the unique and scientifically most challenging aspects of nuclear waste isolation is the extrapolation of short-term laboratory data (hours to years) to the long time periods (10 3 -10 5 years) required by regulatory agencies for performance assessment. The direct validation of these extrapolations is not possible, but methods must be developed to demonstrate compliance with government regulations and to satisfy the lay public that there is a demonstrable and reasonable basis for accepting the long-term extrapolations. Natural systems (e.g., open-quotes natural analoguesclose quotes) provide perhaps the only means of partial open-quotes validation,close quotes as well as data that may be used directly in the models that are used in the extrapolation. Natural systems provide data on very large spatial (nm to km) and temporal (10 3 -10 8 years) scales and in highly complex terranes in which unknown synergisms may affect radionuclide migration. This paper reviews the application (and most importantly, the limitations) of data from natural analogue systems to the open-quotes validationclose quotes of performance assessments

  12. Inhibition of HIF-1{alpha} activity by BP-1 ameliorates adjuvant induced arthritis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Shankar, J. [Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago (United States); Thippegowda, P.B., E-mail: btprabha@uic.edu [Department of Pharmacology, (M/C 868), College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612 (United States); Kanum, S.A. [Department of Chemistry, Yuvaraj' s College, University of Mysore, Mysore (India)

    2009-09-18

    Rheumatoid arthritis (RA) is a chronic inflammatory, angiogenic disease. Inflamed synovitis is a hallmark of RA which is hypoxic in nature. Vascular endothelial growth factor (VEGF), one of the key regulators of angiogenesis, is overexpressed in the pathogenesis of RA. VEGF expression is regulated by hypoxia-inducible factor-1{alpha} (HIF-1{alpha}), a master regulator of homeostasis which plays a pivotal role in hypoxia-induced angiogenesis. In this study we show that synthetic benzophenone analogue, 2-benzoyl-phenoxy acetamide (BP-1) can act as a novel anti-arthritic agent in an experimental adjuvant induced arthritis (AIA) rat model by targeting VEGF and HIF-1{alpha}. BP-1 administered hypoxic endothelial cells and arthritic animals clearly showed down regulation of VEGF expression. Further, BP-1 inhibits nuclear translocation of HIF-1{alpha}, which in turn suppresses transcription of the VEGF gene. These results suggest a further possible clinical application of the BP-1 derivative as an anti-arthritic agent in association with conventional chemotherapeutic agents.

  13. Meeting Report: Synthetic Biology Jamboree for Undergraduates

    Science.gov (United States)

    Campbell, A. Malcolm

    2005-01-01

    The field of synthetic biology (the name is derived from an analogy to synthetic chemistry) has recognized itself as a "field" only since about 2002. Synthetic biology has gotten some high-profile attention recently, but most people are not aware the field even exists. Synthetic biologists apply engineering principles to genomic circuits to…

  14. Antioxidant activity and electrochemical elucidation of the enigmatic redox behavior of curcumin and its structurally modified analogues

    International Nuclear Information System (INIS)

    Jha, Niki S.; Mishra, Satyendra; Jha, Shailendra K.; Surolia, Avadhesha

    2015-01-01

    Highlights: • Structural analogues of curcumin have been synthesized. • Confirmation of redox behaviour emanates from H- shift from central methylene group in curcumin. • Mechanism of curcumin oxidation has been proposed. • Correlation between redox behavior and antioxidant activity has been established. - Abstract: Here, we report studies on the antioxidant activity and redox behavior of curcumin and its structurally modified synthetic analogues. We have synthesized a number of analogues of curcumin which abrogate its keto-enol tautomerism or substitute the methylene group at the centre of its heptadione moiety implicated in the hydride transfer and studied their redox property. From cyclic voltammetric studies, it is demonstrated that H- atom transfer from CH 2 group at the center of the heptadione link also plays an important role in the antioxidant properties of curcumin along with that of its phenolic –OH group. In addition, we also show that the conversion of 1, 3- dicarbonyl moiety of curcumin to an isosteric heterocycle as in pyrazole curcumin, which decreases its rotational freedom, leads to an improvement of its redox properties as well as its antioxidant activity

  15. Control theory meets synthetic biology.

    Science.gov (United States)

    Del Vecchio, Domitilla; Dy, Aaron J; Qian, Yili

    2016-07-01

    The past several years have witnessed an increased presence of control theoretic concepts in synthetic biology. This review presents an organized summary of how these control design concepts have been applied to tackle a variety of problems faced when building synthetic biomolecular circuits in living cells. In particular, we describe success stories that demonstrate how simple or more elaborate control design methods can be used to make the behaviour of synthetic genetic circuits within a single cell or across a cell population more reliable, predictable and robust to perturbations. The description especially highlights technical challenges that uniquely arise from the need to implement control designs within a new hardware setting, along with implemented or proposed solutions. Some engineering solutions employing complex feedback control schemes are also described, which, however, still require a deeper theoretical analysis of stability, performance and robustness properties. Overall, this paper should help synthetic biologists become familiar with feedback control concepts as they can be used in their application area. At the same time, it should provide some domain knowledge to control theorists who wish to enter the rising and exciting field of synthetic biology. © 2016 The Author(s).

  16. Synthetic biology, metaphors and responsibility.

    Science.gov (United States)

    McLeod, Carmen; Nerlich, Brigitte

    2017-08-29

    Metaphors are not just decorative rhetorical devices that make speech pretty. They are fundamental tools for thinking about the world and acting on the world. The language we use to make a better world matters; words matter; metaphors matter. Words have consequences - ethical, social and legal ones, as well as political and economic ones. They need to be used 'responsibly'. They also need to be studied carefully - this is what we want to do through this editorial and the related thematic collection. In the context of synthetic biology, natural and social scientists have become increasingly interested in metaphors, a wave of interest that we want to exploit and amplify. We want to build on emerging articles and books on synthetic biology, metaphors of life and the ethical and moral implications of such metaphors. This editorial provides a brief introduction to synthetic biology and responsible innovation, as well as a comprehensive review of literature on the social, cultural and ethical impacts of metaphor use in genomics and synthetic biology. Our aim is to stimulate an interdisciplinary and international discussion on the impact that metaphors can have on science, policy and publics in the context of synthetic biology.

  17. Curcumin and Its Analogue Induce Apoptosis in Leukemia Cells and Have Additive Effects with Bortezomib in Cellular and Xenograft Models

    Directory of Open Access Journals (Sweden)

    L. I. Nagy

    2015-01-01

    Full Text Available Combination therapy of bortezomib with other chemotherapeutics is an emerging treatment strategy. Since both curcumin and bortezomib inhibit NF-κB, we tested the effects of their combination on leukemia cells. To improve potency, a novel Mannich-type curcumin derivative, C-150, was synthesized. Curcumin and its analogue showed potent antiproliferative and apoptotic effects on the human leukemia cell line, HL60, with different potency but similar additive properties with bortezomib. Additive antiproliferative effects were correlated well with LPS-induced NF-κB inhibition results. Gene expression data on cell cycle and apoptosis related genes, obtained by high-throughput QPCR, showed that curcumin and its analogue act through similar signaling pathways. In correlation with in vitro results similar additive effect could be obsereved in SCID mice inoculated systemically with HL60 cells. C-150 in a liposomal formulation given intravenously in combination with bortezomib was more efficient than either of the drugs alone. As our novel curcumin analogue exerted anticancer effects in leukemic cells at submicromolar concentration in vitro and at 3 mg/kg dose in vivo, which was potentiated by bortezomib, it holds a great promise as a future therapeutic agent in the treatment of leukemia alone or in combination.

  18. Pharmacological, Physiochemical, and Drug-Relevant Biological Properties of Short Chain Fatty Acid Hexosamine Analogues Used in Metabolic Glycoengineering.

    Science.gov (United States)

    Saeui, Christopher T; Liu, Lingshu; Urias, Esteban; Morrissette-McAlmon, Justin; Bhattacharya, Rahul; Yarema, Kevin J

    2018-03-05

    In this study, we catalog structure activity relationships (SAR) of several short chain fatty acid (SCFA)-modified hexosamine analogues used in metabolic glycoengineering (MGE) by comparing in silico and experimental measurements of physiochemical properties important in drug design. We then describe the impact of these compounds on selected biological parameters that influence the pharmacological properties and safety of drug candidates by monitoring P-glycoprotein (Pgp) efflux, inhibition of cytochrome P450 3A4 (CYP3A4), hERG channel inhibition, and cardiomyocyte cytotoxicity. These parameters are influenced by length of the SCFAs (e.g., acetate vs n-butyrate), which are added to MGE analogues to increase the efficiency of cellular uptake, the regioisomeric arrangement of the SCFAs on the core sugar, the structure of the core sugar itself, and by the type of N-acyl modification (e.g., N-acetyl vs N-azido). By cataloging the influence of these SAR on pharmacological properties of MGE analogues, this study outlines design considerations for tuning the pharmacological, physiochemical, and the toxicological parameters of this emerging class of small molecule drug candidates.

  19. Solistatinol, a novel phenolic compactin analogue from Penicillium solitum

    DEFF Research Database (Denmark)

    Larsen, Thomas Ostenfeld; Lange, Lene; Schnorr, Kirk

    2007-01-01

    Solistatinol, a novel phenolic compactin analogue, has been isolated from Penicillium solitum using a UV-guided strategy. The structure and relative stereochemistry were determined by NMR spectroscopy and mass spectrometry. The absolute stereochemistry was determined by chemical degradation...

  20. Trustworthiness and Influence: A Reexamination in an Extended Counseling Analogue.

    Science.gov (United States)

    Rothmeier, Rosemarie C.; Dixon, David N.

    1980-01-01

    The study demonstrated that: (1) interviewer trustworthiness can be manipulated in an analogue interview setting; and (2) interviewer trustworthiness is related to interpersonal influence in the interview setting. Findings follow a pattern of outcomes predicted by cognitive dissonance theory. (Author)

  1. Synthesis and antifungal activity of two novel spermidine analogues.

    Science.gov (United States)

    Mackintosh, C A; Slater, L A; McClintock, C A; Walters, D R; Havis, N D; Robins, D J

    1997-03-01

    Two spermidine analogues were synthesised and examined for antifungal activity. Both compounds used as 1 mM post-inoculation sprays reduced infection of barley seedlings by the powdery mildew fungus, Erysiphe graminis f.sp. hordei, infection of broad bean seedlings by the rust fungus, Uromyces viciae-fabae, and infection of apple seedlings by the powdery mildew fungus, Podosphaera leucotricha. Since these fungal pathogens cannot be cultured axenically, the effects of the two spermidine analogues on mycelial growth in vitro, as well as preliminary investigations on polyamine biosynthesis, were undertaken using the oat stripe pathogen, Pyrenophora avenae. Although neither compound affected radial growth of the fungus on plates, both analogues reduced fungal biomass in liquid culture substantially. The two spermidine analogues, used at a concentration of 1 mM, had no significant effect on the conversion of labelled ornithine into polyamines in P. avenae.

  2. Current prodrug strategies for improving oral absorption of nucleoside analogues

    Directory of Open Access Journals (Sweden)

    Youxi Zhang

    2014-04-01

    Full Text Available Nucleoside analogues are first line chemotherapy in various severe diseases: AIDS (acquired immunodeficiency disease syndrome, cytomegalovirus infections, cancer, etc. However, many nucleoside analogues exhibit poor oral bioavailability because of their high polarity and low intestinal permeability. In order to get around this drawback, prodrugs have been utilized to improve lipophilicity by chemical modification of the parent drug. Alternatively, prodrugs targeting transporters present in the intestine have been applied to promote the transport of the nucleoside analogues. Valacyclovir and valganciclovir are two classic valine ester prodrugs transported by oligopeptide transporter 1. The ideal prodrug achieves delivery of a parent drug by attaching a non-toxic moiety that is stable during transport, but is readily degraded to the parent drug once at the target. This article presents advances of prodrug approaches for enhancing oral absorption of nucleoside analogues.

  3. Insulin analogues in pregnancy and specific congenital anomalies

    DEFF Research Database (Denmark)

    de Jong, Josta; Garne, Ester; Wender-Ozegowska, Ewa

    2016-01-01

    women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analysed to compare the congenital anomaly rate among foetuses of mothers using insulin analogues with foetuses of mothers using human insulin. Of 29 studies, we...... included 1286 foetuses of mothers using short-acting insulin analogues with 1089 references of mothers using human insulin and 768 foetuses of mothers using long-acting insulin analogues with 685 references of mothers using long-acting human insulin (Neutral Protamine Hagedorn). The congenital anomaly rate...... was 4.84% and 4.29% among the foetuses of mothers using lispro and aspart. For glargine and detemir, the congenital anomaly rate was 2.86% and 3.47%, respectively. No studies on the use of insulin glulisine and degludec in pregnancy were found. There was no statistically significant difference...

  4. Analogue Signal Processing: Collected Papers 1996-97

    DEFF Research Database (Denmark)

    1997-01-01

    This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of the Department of Information Technology, Technical University of Denmark, in 1996 and 1997....

  5. Studies on the specificity of immunological reactions of synthetic and natural Thomsen-Friedenreich antigens

    International Nuclear Information System (INIS)

    Hoeppner, W.

    1982-01-01

    A number of derivatives of disaccharide β-D-Gal-(1,3)-D-GalNAc, the carbohydrate component of T-antigen, and four different synthetic antigens having this disaccharide structure have been investigated. The immunological reactions with native human antibodies and rabbit immune antibodies have been studied in the haemagglutination inhibition test and in RIA. The findings are relevant to the use of synthetic carbohydrate antigens as model substances for immunological studies. (orig./MG) [de

  6. Ultrasound exfoliation of inorganic analogues of graphene.

    Science.gov (United States)

    Stengl, Václav; Henych, Jiří; Slušná, Michaela; Ecorchard, Petra

    2014-04-05

    High-intensity ultrasound exfoliation of a bulk-layered material is an attractive route for large-scale preparation of monolayers. The monolayer slices could potentially be prepared with a high yield (up to 100%) in a few minutes. Exfoliation of natural minerals (such as tungstenite and molybdenite) or bulk synthetic materials (including hexagonal boron nitride (h-BN), hexagonal boron carbon nitride (h-BCN), and graphitic carbon nitride (g-C3N4)) in liquids leads to the breakdown of the 3D graphitic structure into a 2D structure; the efficiency of this process is highly dependent upon the physical effects of the ultrasound. Atomic force microscopy (AFM), transmission electron microscopy (TEM), and selected area electron diffraction (SAED) were employed to verify the quality of the exfoliation. Herein, this new method of exfoliation with ultrasound assistance for application to mono- and bilayered materials in hydrophobic and hydrophilic environments is presented.

  7. Syntheses and antifolate activity of 5-methyl-5-deaza analogues of aminopterin, methotrexate, folic acid, and N10-methylfolic acid.

    Science.gov (United States)

    Piper, J R; McCaleb, G S; Montgomery, J A; Kisliuk, R L; Gaumont, Y; Sirotnak, F M

    1986-06-01

    Evidence indicating that modifications at the 5- and 10-positions of classical folic acid antimetabolites lead to compounds with favorable differential membrane transport in tumor vs. normal proliferative tissue prompted an investigation of 5-alkyl-5-deaza analogues. 2-Amino-4-methyl-3,5-pyridinedicarbonitrile, prepared by hydrogenolysis of its known 6-chloro precursor, was treated with guanidine to give 2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile which was converted via the corresponding aldehyde and hydroxymethyl compound to 6-(bromomethyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine. Reductive condensation of the nitrile 8 with diethyl N-(4-amino-benzoyl)-L-glutamate followed by ester hydrolysis gave 5-methyl-5-deazaaminopterin. Treatment of 12 with formaldehyde and Na(CN)BH3 afforded 5-methyl-5-deazamethotrexate, which was also prepared from 15 and dimethyl N-[(4-methylamino)benzoyl]-L-glutamate followed by ester hydrolysis. 5-Methyl-10-ethyl-5-deazaaminopterin was similarly prepared from 15. Biological evaluation of the 5-methyl-5-deaza analogues together with previously reported 5-deazaaminopterin and 5-deazamethotrexate for inhibition of dihydrofolate reductase (DHFR) isolated from L1210 cells and for their effect on cell growth inhibition, transport characteristics, and net accumulation of polyglutamate forms in L1210 cells revealed the analogues to have essentially the same properties as the appropriate parent compound, aminopterin or methotrexate (MTX), except that 20 and 21 were approximately 10 times more growth inhibitory than MTX. In in vivo tests against P388/0 and P388/MTX leukemia in mice, the analogues showed activity comparable to that of MTX, with the more potent 20 producing the same response in the P388/0 test as MTX but at one-fourth the dose; none showed activity against P388/MTX. Hydrolytic deamination of 12 and 20 produced 5-methyl-5-deazafolic acid and 5,10-dimethyl-5-deazafolic acid, respectively. In bacterial studies on

  8. Microfluidic Technologies for Synthetic Biology

    Directory of Open Access Journals (Sweden)

    Sung Kuk Lee

    2011-06-01

    Full Text Available Microfluidic technologies have shown powerful abilities for reducing cost, time, and labor, and at the same time, for increasing accuracy, throughput, and performance in the analysis of biological and biochemical samples compared with the conventional, macroscale instruments. Synthetic biology is an emerging field of biology and has drawn much attraction due to its potential to create novel, functional biological parts and systems for special purposes. Since it is believed that the development of synthetic biology can be accelerated through the use of microfluidic technology, in this review work we focus our discussion on the latest microfluidic technologies that can provide unprecedented means in synthetic biology for dynamic profiling of gene expression/regulation with high resolution, highly sensitive on-chip and off-chip detection of metabolites, and whole-cell analysis.

  9. Analysis of binding centers in nicotinic receptors with the aid of synthetic peptides.

    Science.gov (United States)

    Kasheverov, I E; Kryukova, E V; Kudryavtsev, D S; Ivanov, I A; Egorova, N V; Zhmak, M N; Spirova, E N; Shelukhina, I V; Odinokov, A V; Alfimov, M V; Tsetlin, V I

    2016-09-01

    We studies the receptor-binding specificity of the synthetic peptide HAP (High Affinity Peptide) and its analogues, which are regarded as a model of the orthosteric site nicotinic acetylcholine receptors (nAChR). Using radioligand analysis, electrophysiology tests, and calcium imaging, we assessed the ability of HAP to interact with nAChR antagonists: long α-neurotoxins and α-conotoxins. A high affinity of HAP for α-bungarotoxin and the absence of its interaction with α-cobratoxin and α-conotoxins was found. The synthesized analogues of HAP in general retained the properties of the original peptide. Thus, HAP cannot be a model of a ligand-binding site.

  10. Analogue Signal Processing: Collected Papers 1994-95

    DEFF Research Database (Denmark)

    1996-01-01

    This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of Electronics Institute, Technical University of Denmark, in 1994 and 1995.......This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of Electronics Institute, Technical University of Denmark, in 1994 and 1995....

  11. Biochemical and chemical characterization of phenylglyoxal bis(guanylhydrazone), an aromatic analogue of mitoguazone.

    Science.gov (United States)

    Elo, H; Koskinen, M; Mutikainen, I; Tilus, P; Lampio, A; Keso, L; Vainio, A; Joutsjoki, V; Alli, K; Yliniva, A

    1996-10-01

    Since little has been known about the properties of aromatic analogues of the antineoplastic agent methylglyoxal bis(guanylhydrazone) (MGBG), an investigation was performed on phenylglyoxal bis(guanylhydrazone) (PhGBG). PhGBG competitively inhibited yeast adenosylmethionine decarboxylase (AdoMetDC) with a Ki of 65 microM. As compared to MGBG (Ki 0.23 microM), PhGBG is a much weaker inhibitor, being even weaker than the unsubstituted congener glyoxal bis(guanylhydrazone) (GBG, Ki 18 microM). PhGBG inhibited porcine kidney diamine oxidase (DAO) non-competitively, being a more potent inhibitor (Ki 0.12 microM) than GBG (Ki 0.17 microM) or MGBG (Ki 0.33 microM). Thus, PhGBG has an unfavourably high ratio of Ki(AdoMetDC)/Ki(DAO) for potential use for selectively inhibiting polyamine biosynthesis. This does not exclude the possibility that PhGBG or other aromatic congeners might have therapeutic value since the corresponding ratio of the antileukaemic congeners GBG and MGBG is also high as compared to many aliphatic non-antileukaemic analogues. The pKa1 and pKa2 values of PhGBG dication were found to be 6.39 +/- 0.02 and 8.64 +/- 0.02 respectively, their difference being distinctly larger than in the case of GBG or its C-alkylated analogues. This may result from decreased stability of the dication form, caused by the resonance effect or possibly by the inductive effect of the phenyl group. The species distribution of PhGBG (proportion of free base 5.5%, predominant species the monocation) at 37 degrees C resembles that of GBG and MGBG but is clearly different from that of non-antileukaemic C-alkylated analogues. These similarities suggest that PhGBG and its derivatives may be worth antitumour screening. Depending on the conditions used in the crystallization, three different types of crystals of PhGBG sulphate were obtained. Crystallography indicated that, in two of the types, the crystal consisted exclusively of the anti-anti isomer, i.e. the same isomer as has been

  12. The Greenland Analogue Project, Yearly Report 2009

    International Nuclear Information System (INIS)

    2011-08-01

    To advance the understanding of processes associated with glaciation and their impact on the long-term performance of a deep geological repository, the Greenland Analogue Project (GAP), a four-year field and modelling study of the Greenland ice sheet and sub-surface conditions, has been initiated collaboratively by SKB, Posiva and NWMO. The study site encompasses a land terminus portion of the Greenland ice sheet east of Kangerlussuaq and is in many ways considered to be an appropriate analogue of the conditions that are expected to prevail in much of Canada and Fennoscandia during future glacial cycles. The project is planned to run from 2009 until 2012. The GAP will conduct the first in situ investigations of some of the parameters and processes needed to achieve a realistic understanding of how an ice sheet may impact a deep repository, and will provide measurements, observations and data that may significantly improve our safety assessments and risk analyses of glaciation scenarios. The project includes three sub-projects (A-C) with specific individual objectives, which collectively aim at contributing knowledge and input to the overall project aim. Three field campaigns were carried out in SPA during 2009. These campaigns focused on: (1) deployment and maintenance of AWS and GPS stations and to test the deep-look radar equipment; (2) investigating the hydrological processes and feedbacks and testing of passive seismic equipment; (3) downloading of weather station data and GPS data and winterizing the equipment. An extensive archive of real-time satellite remote sensing datasets has been obtained to be able to better constraint the surface elevation and dynamics of basal hydrological mechanisms. From this archive it has been possible to obtain Russell Glacier Cachment (RGC)-wide constraints on annual, seasonal and specific temporal snapshots of surface speed, initial lake and moulin distribution, drainage and network connections along with the temporal

  13. US Competitiveness in Synthetic Biology.

    Science.gov (United States)

    Gronvall, Gigi Kwik

    2015-01-01

    Synthetic biology is an emerging technical field that aims to make biology easier to engineer; the field has applications in strategically important sectors for the US economy. While the United States currently leads in synthetic biology R&D, other nations are heavily investing in order to boost their economies, which will inevitably diminish the US leadership position. This outcome is not entirely negative--additional investments will expand markets--but it is critical that the US government take steps to remain competitive: There are applications from which the US population and economy may benefit; there are specific applications with importance for national defense; and US technical leadership will ensure that US experts have a leading role in synthetic biology governance, regulation, and oversight. Measures to increase competitiveness in S&T generally are broadly applicable for synthetic biology and should be pursued. However, the US government will also need to take action on fundamental issues that will affect the field's development, such as countering anti-GMO (genetically modified organism) sentiments and anti-GMO legislation. The United States should maintain its regulatory approach so that it is the product that is regulated, not the method used to create a product. At the same time, the United States needs to ensure that the regulatory framework is updated so that synthetic biology products do not fall into regulatory gaps. Finally, the United States needs to pay close attention to how synthetic biology applications may be governed internationally, such as through the Nagoya Protocol of the Convention on Biological Diversity, so that beneficial applications may be realized.

  14. Synthetic biology as red herring.

    Science.gov (United States)

    Preston, Beth

    2013-12-01

    It has become commonplace to say that with the advent of technologies like synthetic biology the line between artifacts and living organisms, policed by metaphysicians since antiquity, is beginning to blur. But that line began to blur 10,000 years ago when plants and animals were first domesticated; and has been thoroughly blurred at least since agriculture became the dominant human subsistence pattern many millennia ago. Synthetic biology is ultimately only a late and unexceptional offshoot of this prehistoric development. From this perspective, then, synthetic biology is a red herring, distracting us from more thorough philosophical consideration of the most truly revolutionary human practice-agriculture. In the first section of this paper I will make this case with regard to ontology, arguing that synthetic biology crosses no ontological lines that were not crossed already in the Neolithic. In the second section I will construct a parallel case with regard to cognition, arguing that synthetic biology as biological engineering represents no cognitive advance over what was required for domestication and the new agricultural subsistence pattern it grounds. In the final section I will make the case with regard to human existence, arguing that synthetic biology, even if wildly successful, is not in a position to cause significant existential change in what it is to be human over and above the massive existential change caused by the transition to agriculture. I conclude that a longer historical perspective casts new light on some important issues in philosophy of technology and environmental philosophy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Habitability & Astrobiology Research in Mars Terrestrial Analogues

    Science.gov (United States)

    Foing, Bernard

    2014-05-01

    We performed a series of field research campaigns (ILEWG EuroMoonMars) in the extreme Utah desert relevant to Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL), or Moon geochemistry (SMART-1, LRO). We shall give an update on the sample analysis in the context of habitability and astrobiology. Methods & Results: In the frame of ILEWG EuroMoonMars campaigns (2009 to 2013) we deployed at Mars Desert Research station, near Hanksville Utah, a suite of instruments and techniques [A, 1, 2, 9-11] including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. Among the important findings are the diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed [3,4,9]. A dominant factor seems to be soil porosity and lower clay-sized particle content [6-8]. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples [10, 11]. We compare the 2009 campaign results [1-9] to new measurements from 2010-2013 campaigns [10-12] relevant to: comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life. Keywords: field analogue research, astrobiology, habitability, life detection, Earth-Moon-Mars, organics References [A] Foing, Stoker & Ehrenfreund (Editors, 2011) "Astrobiology field Research in Moon/Mars Analogue Environments", Special Issue of International

  16. Application of natural analogues in the Yucca Mountain project - overview

    International Nuclear Information System (INIS)

    Simmons, Ardyth M.

    2003-01-01

    The Natural Analogue Synthesis Report (NASR) [1] provides a compilation of information from analogues that test, corroborate, and add confidence to process models and model predictions pertinent to total system performance assessment (TSPA). The report updated previous work [2] with new literature examples and results of quantitative studies conducted by the Yucca Mountain Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate greater understanding of processes expected to occur during postclosure of a proposed Yucca Mountain repository. Natural analogues, as used here, refer to either natural or anthropogenic systems in which processes similar to those expected to occur in a nuclear waste repository are thought to have occurred over long time periods (decades to millenia) and large spatial scales (up to tens of kilometers). In the past, the YMP has used analogues for testing and building confidence in conceptual and numerical process models in a number of ways. Yucca Mountain mineral alteration phases provided a self-analogue for postclosure alteration [3]. Thermodynamic parameters for silica minerals of the Wairakai, New Zealand geothermal field were added to databases used in geochemical modeling [4]. Scoping calculations of radionuclide transport using the Yucca Mountain TSPA numerical model were conducted for the Peqa Blanca site [5]. Eruption parameters from the Cerro Negro volcano, Nicaragua, were used to verify codes that model ash plume dispersion [6]. Analogues have also been used in supplemental science and performance analyses to provide multiple lines of evidence in support of both analyses and model reports (AMRs) [7]; in screening arguments for inclusion or exclusion of features, events, and processes (FEP)s in TSPAs; in the quantification of uncertainties [7]; in expert elicitations of volcanic and seismic hazards [8, 9] and in peer reviews [10]. Natural analogues may be applied

  17. Characterisation of insulin analogues therapeutically available to patients

    KAUST Repository

    Adams, Gary G.

    2018-03-29

    The structure and function of clinical dosage insulin and its analogues were assessed. This included \\'native insulins\\' (human recombinant, bovine, porcine), \\'fast-acting analogues\\' (aspart, glulisine, lispro) and \\'slow-acting analogues\\' (glargine, detemir, degludec). Analytical ultracentrifugation, both sedimentation velocity and equilibrium experiments, were employed to yield distributions of both molar mass and sedimentation coefficient of all nine insulins. Size exclusion chromatography, coupled to multi-angle light scattering, was also used to explore the function of these analogues. On ultracentrifugation analysis, the insulins under investigation were found to be in numerous conformational states, however the majority of insulins were present in a primarily hexameric conformation. This was true for all native insulins and two fast-acting analogues. However, glargine was present as a dimer, detemir was a multi-hexameric system, degludec was a dodecamer (di-hexamer) and glulisine was present as a dimer-hexamer-dihexamer system. However, size-exclusion chromatography showed that the two hexameric fast-acting analogues (aspart and lispro) dissociated into monomers and dimers due to the lack of zinc in the mobile phase. This comprehensive study is the first time all nine insulins have been characterised in this way, the first time that insulin detemir have been studied using analytical ultracentrifugation and the first time that insulins aspart and glulisine have been studied using sedimentation equilibrium. The structure and function of these clinically administered insulins is of critical importance and this research adds novel data to an otherwise complex functional physiological protein.

  18. Synthetic Phage for Tissue Regeneration

    Directory of Open Access Journals (Sweden)

    So Young Yoo

    2014-01-01

    Full Text Available Controlling structural organization and signaling motif display is of great importance to design the functional tissue regenerating materials. Synthetic phage, genetically engineered M13 bacteriophage has been recently introduced as novel tissue regeneration materials to display a high density of cell-signaling peptides on their major coat proteins for tissue regeneration purposes. Structural advantages of their long-rod shape and monodispersity can be taken together to construct nanofibrous scaffolds which support cell proliferation and differentiation as well as direct orientation of their growth in two or three dimensions. This review demonstrated how functional synthetic phage is designed and subsequently utilized for tissue regeneration that offers potential cell therapy.

  19. Synthetic biology and its promises

    Directory of Open Access Journals (Sweden)

    José Manuel De Cózar Escalante

    2016-12-01

    Full Text Available Synthetic biology is a new science and emerging technology, or rather a technoscience, which converges with others such as nanotechnology, information technology, robotics, artificial intelligence and neuroscience. All have common features that could have highly concerning social and environmental impacts. With its ambitious goals of controlling complexity, redesigning and creating new living entities, synthetic biology perfectly exemplifies the new bioeconomic reality. This requires expanding the focus of the discussion beyond the limited comparative analysis of risks and benefits, to address uncertainties, reassign responsibilities and initiate a thorough social assessment of what is at stake.

  20. Synthetic methodologies for carbon nanomaterials.

    Science.gov (United States)

    Liu, Zhaoping; Zhou, Xufeng; Qian, Yitai

    2010-05-04

    Carbon nanomaterials have advanced rapidly over the last two decades and are among the most promising materials that have already changed and will keep on changing human life. Development of synthetic methodologies for these materials, therefore, has been one of the most important subjects of carbon nanoscience and nanotechnology, and forms the basis for investigating the physicochemical properties and applications of carbon nanomaterials. In this Research News article, several synthetic strategies, including solvothermal reduction, solvothermal pyrolysis, hydrothermal carbonization, and soft-chemical exfoliation are specifically discussed and highlighted, which have been developed for the synthesis of novel carbon nanomaterials over the last decade.

  1. Transcription control engineering and applications in synthetic biology

    Directory of Open Access Journals (Sweden)

    Michael D. Engstrom

    2017-09-01

    Full Text Available In synthetic biology, researchers assemble biological components in new ways to produce systems with practical applications. One of these practical applications is control of the flow of genetic information (from nucleic acid to protein, a.k.a. gene regulation. Regulation is critical for optimizing protein (and therefore activity levels and the subsequent levels of metabolites and other cellular properties. The central dogma of molecular biology posits that information flow commences with transcription, and accordingly, regulatory tools targeting transcription have received the most attention in synthetic biology. In this mini-review, we highlight many past successes and summarize the lessons learned in developing tools for controlling transcription. In particular, we focus on engineering studies where promoters and transcription terminators (cis-factors were directly engineered and/or isolated from DNA libraries. We also review several well-characterized transcription regulators (trans-factors, giving examples of how cis- and trans-acting factors have been combined to create digital and analogue switches for regulating transcription in response to various signals. Last, we provide examples of how engineered transcription control systems have been used in metabolic engineering and more complicated genetic circuits. While most of our mini-review focuses on the well-characterized bacterium Escherichia coli, we also provide several examples of the use of transcription control engineering in non-model organisms. Similar approaches have been applied outside the bacterial kingdom indicating that the lessons learned from bacterial studies may be generalized for other organisms.

  2. Transcription control engineering and applications in synthetic biology.

    Science.gov (United States)

    Engstrom, Michael D; Pfleger, Brian F

    2017-09-01

    In synthetic biology, researchers assemble biological components in new ways to produce systems with practical applications. One of these practical applications is control of the flow of genetic information (from nucleic acid to protein), a.k.a. gene regulation. Regulation is critical for optimizing protein (and therefore activity) levels and the subsequent levels of metabolites and other cellular properties. The central dogma of molecular biology posits that information flow commences with transcription, and accordingly, regulatory tools targeting transcription have received the most attention in synthetic biology. In this mini-review, we highlight many past successes and summarize the lessons learned in developing tools for controlling transcription. In particular, we focus on engineering studies where promoters and transcription terminators ( cis -factors) were directly engineered and/or isolated from DNA libraries. We also review several well-characterized transcription regulators ( trans- factors), giving examples of how cis- and trans -acting factors have been combined to create digital and analogue switches for regulating transcription in response to various signals. Last, we provide examples of how engineered transcription control systems have been used in metabolic engineering and more complicated genetic circuits. While most of our mini-review focuses on the well-characterized bacterium Escherichia coli , we also provide several examples of the use of transcription control engineering in non-model organisms. Similar approaches have been applied outside the bacterial kingdom indicating that the lessons learned from bacterial studies may be generalized for other organisms.

  3. Oral administration of synthetic human urogastrone promotes healing of chronic duodenal ulcers in rats

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba

    1986-01-01

    The effect of oral administration of synthetic human epidermal growth factor/urogastrone (EGF/URO) on healing of chronic duodenal ulcers induced by cysteamine in rats was investigated and compared with that of cimetidine, a H2-receptor antagonist. After 25 and 50 days of treatment, synthetic human...... effective than cimetidine alone. These results show that a combination of an agent inhibiting gastric acid secretion and the cytoprotective and growth-stimulating peptide EGF/URO seems to be more effective with regard to duodenal ulcer healing than individual administration of the two substances. Synthetic...

  4. OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance.

    Science.gov (United States)

    Kuang, Ye-Hong; Patel, Jay P; Sodani, Kamlesh; Wu, Chung-Pu; Liao, Li-Qiu; Patel, Atish; Tiwari, Amit K; Dai, Chun-Ling; Chen, Xiang; Fu, Li-Wu; Ambudkar, Suresh V; Korlipara, Vijaya L; Chen, Zhe-Sheng

    2012-09-15

    OSI-930, a dual c-Kit and KDR tyrosine kinase inhibitor, is reported to have undergone a Phase I dose escalation study in patients with advanced solid tumors. A series of fifteen pyridyl and phenyl analogues of OSI-930 were designed and synthesized. Extensive screening of these compounds led to the discovery that nitropyridyl and ortho-nitrophenyl analogues, VKJP1 and VKJP3, were effective in reversing ABC subfamily G member 2 (ABCG2) transporter-mediated multidrug resistance (MDR). VKJP1 and VKJP3 significantly sensitized ABCG2-expressing cells to established substrates of ABCG2 including mitoxantrone, SN-38, and doxorubicin in a concentration-dependent manner, but not to the non-ABCG2 substrate cisplatin. However, they were unable to reverse ABCB1- or ABCC1-mediated MDR indicating their selectivity for ABCG2. Western blotting analysis was performed to evaluate ABCG2 expression and it was found that neither VKJP1 nor VKJP3 significantly altered ABCG2 protein expression for up to 72 h. [(3)H]-mitoxantrone accumulation study demonstrated that VKJP1 and VKJP3 increased the intracellular accumulation of [(3)H]-mitoxantrone, a substrate of ABCG2. VKJP1 and VKJP3 also remarkably inhibited the transport of [(3)H]-methotrexate by ABCG2 membrane vesicles. Importantly, both VKJP1 and VKJP3 were efficacious in stimulating the activity of ATPase of ABCG2 and inhibited the photoaffinity labeling of this transporter by its substrate [(125)I]-iodoarylazidoprazosin. The results suggested that VKJP1 and VKJP3, specifically inhibit the function of ABCG2 through direct interaction with its substrate binding site(s). Thus VKJP1 and VKJP3 represent a new class of drugs for reducing MDR in ABCG2 over-expressing tumors. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. A Common Mechanism for Resistance to Oxime Reactivation of Acetylcholinesterase Inhibited by Organophosphorus Compounds

    Science.gov (United States)

    2013-01-01

    reactivators, we conducted a QSAR analysis for oxime reactivation of AChE inhibited by OP agents and their analogues. Our objective was to identify...reactivation as tabun-inhibited AChE. QSAR analysis of oxime reactivation of AChE inhibited by these OP compounds and others suggested that the presence of...organophosphorus; QSAR , quan- titative structure–activity relationship; VR, O-isobutyl methylphosphonofluoridate. ⇑ Corresponding author. Tel.: +1 410

  6. Regulation of the tryptophan synthetic enzymes in Clostridium butyricum.

    Science.gov (United States)

    Baskerville, E N; Twarog, R

    1972-10-01

    Experiments concerned with the regulation of the tryptophan synthetic enzymes in anaerobes were carried out with a strain of Clostridium butyricum. Enzyme activities for four of the five synthetic reactions were readily detected in wild-type cells grown in minimal medium. The enzymes mediating reactions 3, 4, and 5 were derepressed 4- to 20-fold, and the data suggest that these enzymes are coordinately controlled in this anaerobe. The first enzyme of the pathway, anthranilate synthetase, could be derepressed approximately 90-fold under these conditions, suggesting that this enzyme is semicoordinately controlled. Mutants resistant to 5-methyl tryptophan were isolated, and two of these were selected for further analysis. Both mutants retained high constitutive levels of the tryptophan synthetic enzymes even in the presence of repressing concentrations of tryptophan. The anthranilate synthetase from one mutant was more sensitive to feedback inhibition by tryptophan than the enzyme from wild-type cells. The enzyme from the second mutant was comparatively resistant to feedback inhibition by tryptophan. Neither strain excreted tryptophan into the culture fluid. Tryptophan inhibits anthranilate synthetase from wild-type cells noncompetitively with respect to chorismate and uncompetitively with respect to glutamine. The Michaelis constants calculated for chorismate and glutamine are 7.6 x 10(-5)m and 6.7 x 10(-5)m, respectively. The molecular weights of the enzymes estimated by zonal centrifugation in sucrose and by gel filtration ranged from 24,000 to 89,000. With the possible exception of a tryptophan synthetase complex, there was no evidence for the existence of other enzyme aggregates. The data indicate that tryptophan synthesis is regulated by repression control of the relevant enzymes and by feedback inhibition of anthranilate synthetase. That this enzyme system more closely resembles that found in Bacillus than that found in enteric bacteria is discussed.

  7. Regulation of the Tryptophan Synthetic Enzymes in Clostridium butyricum1

    Science.gov (United States)

    Baskerville, E. N.; Twarog, Robert

    1972-01-01

    Experiments concerned with the regulation of the tryptophan synthetic enzymes in anaerobes were carried out with a strain of Clostridium butyricum. Enzyme activities for four of the five synthetic reactions were readily detected in wild-type cells grown in minimal medium. The enzymes mediating reactions 3, 4, and 5 were derepressed 4- to 20-fold, and the data suggest that these enzymes are coordinately controlled in this anaerobe. The first enzyme of the pathway, anthranilate synthetase, could be derepressed approximately 90-fold under these conditions, suggesting that this enzyme is semicoordinately controlled. Mutants resistant to 5-methyl tryptophan were isolated, and two of these were selected for further analysis. Both mutants retained high constitutive levels of the tryptophan synthetic enzymes even in the presence of repressing concentrations of tryptophan. The anthranilate synthetase from one mutant was more sensitive to feedback inhibition by tryptophan than the enzyme from wild-type cells. The enzyme from the second mutant was comparatively resistant to feedback inhibition by tryptophan. Neither strain excreted tryptophan into the culture fluid. Tryptophan inhibits anthranilate synthetase from wild-type cells noncompetitively with respect to chorismate and uncompetitively with respect to glutamine. The Michaelis constants calculated for chorismate and glutamine are 7.6 × 10−5m and 6.7 × 10−5m, respectively. The molecular weights of the enzymes estimated by zonal centrifugation in sucrose and by gel filtration ranged from 24,000 to 89,000. With the possible exception of a tryptophan synthetase complex, there was no evidence for the existence of other enzyme aggregates. The data indicate that tryptophan synthesis is regulated by repression control of the relevant enzymes and by feedback inhibition of anthranilate synthetase. That this enzyme system more closely resembles that found in Bacillus than that found in enteric bacteria is discussed. PMID

  8. Where Synthetic Biology Meets ET

    Science.gov (United States)

    Rothschild, Lynn J.

    2016-01-01

    Synthetic biology - the design and construction of new biological parts and systems and the redesign of existing ones for useful purposes - has the potential to transform fields from pharmaceuticals to fuels. Our lab has focused on the potential of synthetic biology to revolutionize all three major parts of astrobiology: Where do we come from? Where are we going? and Are we alone? For the first and third, synthetic biology is allowing us to answer whether the evolutionary narrative that has played out on planet earth is likely to have been unique or universal. For example, in our lab we are re-evolving the biosynthetic pathways of amino acids in order to understand potential capabilities of an early organism with a limited repertoire of amino acids and developing techniques for the recovery of metals from spent electronics on other planetary bodies. And what about the limits for life? Can we create organisms that expand the envelope for life? In the future synthetic biology will play an increasing role in human activities both on earth, in fields as diverse as human health and the industrial production of novel bio-composites. Beyond earth, we will rely increasingly on biologically-provided life support, as we have throughout our evolutionary history. In order to do this, the field will build on two of the great contributions of astrobiology: studies of the origin of life and life in extreme environments.

  9. Future of synthetic aperture radar

    Science.gov (United States)

    Barath, F. T.

    1978-01-01

    The present status of the applications of Synthetic Aperture Radars (SARs) is reviewed, and the technology state-of-the art as represented by the Seasat-A and SIR-A SARs examined. The potential of SAR applications, and the near- and longer-term technology trends are assessed.

  10. Digital 'faces' of synthetic biology.

    Science.gov (United States)

    Friedrich, Kathrin

    2013-06-01

    In silicio design plays a fundamental role in the endeavour to synthesise biological systems. In particular, computer-aided design software enables users to manage the complexity of biological entities that is connected to their construction and reconfiguration. The software's graphical user interface bridges the gap between the machine-readable data on the algorithmic subface of the computer and its human-amenable surface represented by standardised diagrammatic elements. Notations like the Systems Biology Graphical Notation (SBGN), together with interactive operations such as drag & drop, allow the user to visually design and simulate synthetic systems as 'bio-algorithmic signs'. Finally, the digital programming process should be extended to the wet lab to manufacture the designed synthetic biological systems. By exploring the different 'faces' of synthetic biology, I argue that in particular computer-aided design (CAD) is pushing the idea to automatically produce de novo objects. Multifaceted software processes serve mutually aesthetic, epistemic and performative purposes by simultaneously black-boxing and bridging different data sources, experimental operations and community-wide standards. So far, synthetic biology is mainly a product of digital media technologies that structurally mimic the epistemological challenge to take both qualitative as well as quantitative aspects of biological systems into account in order to understand and produce new and functional entities. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Synthetic peptides for diagnostic use

    NARCIS (Netherlands)

    Meloen, R.H.; Langedijk, J.P.M.; Langeveld, J.P.M.

    1997-01-01

    Synthetic peptides representing relevant B-cell epitopes are, potentially, ideal antigens to be used in diagnostic assays because of their superior properties with respect to quality control as compared to those of biologically derived molecules and the much higher specificity that sometimes can be

  12. Analysis of the Synthetic Jet

    Czech Academy of Sciences Publication Activity Database

    Dančová, Petra; Vít, Tomáš

    2009-01-01

    Roč. 2, č. 1 (2009), s. 11-17 ISSN 1803-0203 R&D Projects: GA AV ČR(CZ) IAA200760801 Institutional research plan: CEZ:AV0Z20760514 Keywords : synthetic jet * actuator * nominal frequency Subject RIV: BJ - Thermodynamics

  13. Synthetic peptides that cause F-actin bundling and block actin depolymerization

    Science.gov (United States)

    Sederoff, Heike [Raleigh, NC; Huber, Steven C [Savoy, IL; Larabell, Carolyn A [Berkeley, CA

    2011-10-18

    Synthetic peptides derived from sucrose synthase, and having homology to actin and actin-related proteins, sharing a common motif, useful for causing acting bundling and preventing actin depolymerization. Peptides exhibiting the common motif are described, as well as specific synthetic peptides which caused bundled actin and inhibit actin depolymerization. These peptides can be useful for treating a subject suffering from a disease characterized by cells having neoplastic growth, for anti-cancer therapeutics, delivered to subjects solely, or concomitantly or sequentially with other known cancer therapeutics. These peptides can also be used for stabilizing microfilaments in living cells and inhibiting growth of cells.

  14. Analogues of the Frog-skin Antimicrobial Peptide Temporin 1Tb Exhibit a Wider Spectrum of Activity and a Stronger Antibiofilm Potential as Compared to the Parental Peptide

    Science.gov (United States)

    Grassi, Lucia; Maisetta, Giuseppantonio; Maccari, Giuseppe; Esin, Semih; Batoni, Giovanna

    2017-04-01

    The frog skin-derived peptide Temporin 1Tb (TB) has gained increasing attention as novel antimicrobial agent for the treatment of antibiotic-resistant and/or biofilm-mediated infections. Nevertheless, such a peptide possesses a preferential spectrum of action against Gram-positive bacteria. In order to improve the therapeutic potential of TB, the present study evaluated the antibacterial and antibiofilm activities of two TB analogues against medically relevant bacterial species. Of the two analogues, TB_KKG6A has been previously described in the literature, while TB_L1FK is a new analogue designed by us through statistical-based computational strategies. Both TB analogues displayed a faster and stronger bactericidal activity than the parental peptide, especially against Gram-negative bacteria in planktonic form. Differently from the parental peptide, TB_KKG6A and TB_L1FK were able to inhibit the formation of Staphylococcus aureus biofilms by more than 50% at 12 μM, while only TB_KKG6A prevented the formation of Pseudomonas aeruginosa biofilms at 24 μM. A marked antibiofilm activity against preformed biofilms of both bacterial species was observed for the two TB analogues when used in combination with EDTA. Analysis of synergism at the cellular level suggested that the antibiofilm activity exerted by the peptide-EDTA combinations against mature biofilms might be due mainly to a disaggregating effect on the extracellular matrix in the case of S. aureus, and to a direct activity on biofilm-embedded cells in the case of P. aeruginosa. Both analogues displayed a low hemolytic effect at the active concentrations and, overall, TB_L1FK resulted less cytotoxic towards mammalian cells. Collectively, the results obtained demonstrated that subtle changes in the primary sequence of TB may provide TB analogues that, used alone or in combination with adjuvant molecules such as EDTA, exhibit promising features against both planktonic and biofilm cells of medically relevant

  15. Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues.

    Directory of Open Access Journals (Sweden)

    Geoffrey D Coxon

    Full Text Available Defining the pharmacological target(s of currently used drugs and developing new analogues with greater potency are both important aspects of the search for agents that are effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis. Thiacetazone (TAC is an anti-tubercular drug that was formerly used in conjunction with isoniazid, but removed from the antitubercular chemotherapeutic arsenal due to toxic side effects. However, several recent studies have linked the mechanisms of action of TAC to mycolic acid metabolism and TAC-derived analogues have shown increased potency against M. tuberculosis. To obtain new insights into the molecular mechanisms of TAC resistance, we isolated and analyzed 10 mutants of M. tuberculosis that were highly resistant to TAC. One strain was found to be mutated in the methyltransferase MmaA4 at Gly101, consistent with its lack of oxygenated mycolic acids. All remaining strains harbored missense mutations in either HadA (at Cys61 or HadC (at Val85, Lys157 or Thr123, which are components of the β-hydroxyacyl-ACP dehydratase complex that participates in the mycolic acid elongation step. Separately, a library of 31 new TAC analogues was synthesized and evaluated against M. tuberculosis. Two of these compounds, 15 and 16, exhibited minimal inhibitory concentrations 10-fold lower than the parental molecule, and inhibited mycolic acid biosynthesis in a dose-dependent manner. Moreover, overexpression of HadAB HadBC or HadABC in M. tuberculosis led to high level resistance to these compounds, demonstrating that their mode of action is similar to that of TAC. In summary, this study uncovered new mutations associated with TAC resistance and also demonstrated that simple structural optimization of the TAC scaffold was possible and may lead to a new generation of TAC-derived drug candidates for the potential treatment of tuberculosis as mycolic acid inhibitors.

  16. Protease-sensitive synthetic prions.

    Directory of Open Access Journals (Sweden)

    David W Colby

    2010-01-01

    Full Text Available Prions arise when the cellular prion protein (PrP(C undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrP(Sc. Frequently, PrP(Sc is protease-resistant but protease-sensitive (s prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic prions were generated in vitro during polymerization of recombinant (rec PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, but not recPrP monomers or oligomers, transmitted disease to transgenic mice (n = 164, denoted Tg9949 mice, that overexpress N-terminally truncated PrP. Tg9949 control mice (n = 174 did not spontaneously generate prions although they were prone to late-onset spontaneous neurological dysfunction. When synthetic prion isolates from infected Tg9949 mice were serially transmitted in the same line of mice, they exhibited sPrP(Sc and caused neurodegeneration. Interestingly, these protease-sensitive prions did not shorten the life span of Tg9949 mice despite causing extensive neurodegeneration. We inoculated three synthetic prion isolates into Tg4053 mice that overexpress full-length PrP; Tg4053 mice are not prone to developing spontaneous neurological dysfunction. The synthetic prion isolates caused disease in 600-750 days in Tg4053 mice, which exhibited sPrP(Sc. These novel synthetic prions demonstrate that conformational changes in wild-type PrP can produce mouse prions composed exclusively of sPrP(Sc.

  17. Incorporation of tryptophan analogues into the lantibiotic nisin.

    Science.gov (United States)

    Zhou, Liang; Shao, Jinfeng; Li, Qian; van Heel, Auke J; de Vries, Marcel P; Broos, Jaap; Kuipers, Oscar P

    2016-05-01

    Lantibiotics are posttranslationally modified peptides with efficient inhibitory activity against various Gram-positive bacteria. In addition to the original modifications, incorporation of non-canonical amino acids can render new properties and functions to lantibiotics. Nisin is the most studied lantibiotic and contains no tryptophan residues. In this study, a system was constructed to incorporate tryptophan analogues into nisin, which included the modification machinery (NisBTC) and the overexpression of tryptophanyl-tRNA synthetase (TrpRS). Tryptophan and three different tryptophan analogues (5-fluoroTrp (5FW), 5-hydroxyTrp (5HW) and 5-methylTrp (5MeW)) were successfully incorporated at four different positions of nisin (I1W, I4W, M17W and V32W). The incorporation efficiency of tryptophan analogues into mutants I1W, M17W and V32W was over 97 %, while the mutant I4W showed relatively low incorporation efficiency (69-93 %). The variants with 5FW showed relatively higher production yield, while 5MeW-containing variants showed the lowest yield. The dehydration efficiency of serines or threonines was affected by the tryptophan mutants of I4W and V32W. The affinity of the peptides for the cation-ion exchange and reverse phase chromatography columns was significantly reduced when 5HW was incorporated. The antimicrobial activity of IIW and its 5FW analogue both decreased two times compared to that of nisin, while that of its 5HW analogue decreased four times. The 5FW analogue of I4W also showed two times decreased activity than nisin. However, the mutant M17W and its 5HW analogue both showed 32 times reduced activity relative to that of nisin.

  18. Insulin analogues and cancer: a note of caution

    Directory of Open Access Journals (Sweden)

    Joseph A.M.J.L. eJanssen

    2014-05-01

    Full Text Available Abstract In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. At present, the available data suggest that insulin analogues are safe. In line with these findings, we observed that serum of diabetic patients treated with insulin analogues, compared to that of diabetic patients treated with human insulin, did not induce an increased phosphorylation of tyrosine residues of the insulin-like growth factor-I receptor (IGF-IR. However, the classical model of the IGF-IR signaling may be insufficient to explain (all mitogenic effects of insulin analogues since also non-canonical signaling pathways of the IGF-IR may play a major role in this respect. Although phosphorylation of tyrosine residues of the IGF-IR is generally considered to be the initial activation step within the intracellular IGF-IR signaling pathway, it has been found that cells undergo a signaling switch under hyperglycemic conditions. After this switch, a completely different mechanism is utilized to activate the mitogenic (mitogen-activated protein kinase (MAPK pathways of the IGF-IR that is independent from tyrosine phosphorylation of the IGF-IR. At present it is unknown whether activation of this alternative intracellular pathway of the IGF-IR occurs during hyperglycemia in vivo and whether it is stronger in patients treated with (some insulin analogues than in patients treated with human insulin. In addition, it is unknown whether the insulin receptors (IRs also undergo a signaling switch during hyperglycemia. This should be investigated in future studies. Finally, relative overexpression of IR isoform A (IR-A in (pre cancer tissues may play a key role in the development and progression of human cancers during treatment with insulin (analogues. Further

  19. Pharmacological Analysis of Vorinostat Analogues as Potential Anti-tumor Agents Targeting Human Histone Deacetylases: an Epigenetic Treatment Stratagem for Cancers.

    Science.gov (United States)

    Praseetha, Sugathan; Bandaru, Srinivas; Nayarisseri, Anuraj; Sureshkumar, Sivanpillai

    2016-01-01

    Alteration of the acetylation status of chromatin and other non-histone proteins by HDAC inhibitors has evolved as an excellent epigenetic strategy in treatment of cancers. The present study was sought to identify compounds with positive pharmacological profiles targeting HDAC1. Analogues of Vorinostat synthesized by Cai et al, 2015 formed the test compounds for the present pharmacological evaluation. Hydroxamte analogue 6H showed superior pharmacological profile in comparison to all the compounds in the analogue dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify compounds with even better high affinity and pharmacological profile than 6H and Vorinostat, virtual screening was performed. A total of 83 compounds similar to Vorinostat and 154 compounds akin to analogue 6H were retrieved. SCHEMBL15675695 (PubCid: 15739209) and AKOS019005527 (PubCid: 80442147) similar to Vorinostat and 6H, were the best docked compounds among the virtually screened compounds. However, in spite of having good affinity, none of the virtually screened compounds had better affinity than that of 6H. In addition SCHEMBL15675695 was predicted to be a carcinogen while AKOS019005527 is Ames toxic. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report Vorinostat hydroxamate analogue 6H to be a potential candidate for HDAC inhibition in treatment of cancers through an epigenetic strategy.

  20. Canabinoides: análogos y perspectivas terapéuticas II Cannabinoids: analogues and therapeutical perspectivas II

    Directory of Open Access Journals (Sweden)

    Juan E. Tacoronte Morales

    2008-12-01

    Full Text Available Actualmente se han generado valiosísimas fuentes de información que correlacionan la especie botánica Cannabis sativa L y sus metabolitos secundarios con la medicina (tratamiento terapéutico, farmacología (modelos experimentales y química sintética (diseño y generación de nuevas estructuras y análogos bioisósteres, que avalan la significación del estudio de esta planta, sus extractos, metabolitos, precursores y análogos naturales y sintéticos como fuente de agentes terapéuticos. Por tal motivo se presenta una revisión de la información existente sobre las potenciales implicaciones terapéuticas de sistemas moleculares canabinoidales (endógenos, naturales y sintéticos en el tratamiento de diversas afecciones del sistema nervioso central, que incluye: conceptos de tipos de canabinoides; sistemas de receptores canabinoides CB1 y CB2 y sus ligandos así como evidencias preclínicas de los efectos terapéuticos de canabinoides desde 1970 hasta el 2006.At present, a great amount of valuable information and experimental data has been generated that correlate Cannabis sativa and its secondary metabolites with medicine (therapeutic treatment, pharmacology (experimental animal models and synthetic chemistry (design and generation of new structures and biososteric analogues, showing the importance of the study about this plant, its extracts, metabolite precursors and natural and synthetic analogues as therapeutic agents. Taking theses points into consideration, this article reviews the therapeutic implications of cannabinoid systems (endogenous, natural, and synthetic on several pathologies of central nervous system, including: cannabinoid type concepts, cannabinoid receptor systems CB1 and CB2 and preclinical studies devoted to therapeutic effects of the cannabinoids since 1970 until 2006