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Sample records for active agents including

  1. Modified agar dilution susceptibility testing method for determining in vitro activities of antifungal agents, including azole compounds.

    PubMed Central

    Yoshida, T; Jono, K; Okonogi, K

    1997-01-01

    In vitro activities of antifungal agents, including azole compounds, against yeasts were easily determined by using RPMI-1640 agar medium and by incubating the plates in the presence of 20% CO2. The end point of inhibition was clear by this method, even in the case of azole compounds, because of the almost complete inhibition of yeast growth at high concentrations which permitted weak growth of some Candida strains by traditional methods. MICs obtained by the agar dilution method were similar to those obtained by the broth dilution method proposed by the National Committee for Clinical Laboratory Standards. PMID:9174197

  2. New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer

    PubMed Central

    La Regina, Giuseppe; Bai, Ruoli; Coluccia, Antonio; Famiglini, Valeria; Pelliccia, Sveva; Passacantilli, Sara; Mazzoccoli, Carmela; Ruggieri, Vitalba; Sisinni, Lorenza; Bolognesi, Alessio; Rensen, Whilelmina Maria; Miele, Andrea; Nalli, Marianna; Alfonsi, Romina; Di Marcotullio, Lucia; Gulino, Alberto; Brancale, Andrea; Novellino, Ettore; Dondio, Giulio; Vultaggio, Stefania; Varasi, Mario; Mercurio, Ciro; Hamel, Ernest; Lavia, Patrizia; Silvestri, Romano

    2014-01-01

    We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway. PMID:25025991

  3. 13 CFR 107.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent. 107.1620 Section 107.1620 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance...

  4. 13 CFR 108.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent. 108.1620 Section 108.1620 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION NEW MARKETS VENTURE CAPITAL (âNMVCâ) PROGRAM SBA...

  5. The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including Jun N-terminal protein kinases and p38 kinase by alkylating agents.

    PubMed Central

    Wilhelm, D; Bender, K; Knebel, A; Angel, P

    1997-01-01

    Monofunctional alkylating agents like methyl methanesulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are potent inducers of cellular stress leading to chromosomal aberrations, point mutations, and cell killing. We show that these agents induce a specific cellular stress response program which includes the activation of Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPKs), p38 mitogen-activated protein kinase, and the upstream kinase SEK1/MKK4 and which depends on the reaction mechanism of the alkylating agent in question. Similar to another inducer of cellular stress, UV irradiation, damage of nuclear DNA by alkylation is not involved in the MMS-induced response. However, in contrast to UV and other inducers of the JNK/SAPKs and p38 pathways, activation of growth factor and G-protein-coupled receptors does not play a role in the MMS response. We identified the intracellular glutathione (GSH) level as critical for JNK/SAPK activation by MMS: enhancing the GSH level by pretreatment of the cells with GSH or N-acetylcysteine inhibits, whereas depletion of the cellular GSH pool causes hyperinduction of JNK/SAPK activity by MMS. In light of the JNK/SAPK-dependent induction of c-jun and c-fos transcription, and the Jun/Fos-induced transcription of xenobiotic-metabolizing enzymes, these data provide a potential critical role of JNK/SAPK and p38 in the induction of a cellular defense program against cytotoxic xenobiotics such as MMS. PMID:9234735

  6. Agents in Safety Related Systems Including Ubiquitous Networks

    NASA Astrophysics Data System (ADS)

    Strandén, Lars

    The ADM (Autonomous Decision Maker) concept concerns the possibility of including intelligent interfaces, agent like, for supporting the use of ubiquitous networks, such as the Internet, in safety related applications. The need for such interfaces is inevitable if remote surveillance and control shall be supported. The single most important aspect of ADM is its capability of handling limited resources when making intelligent decisions. Intelligence in ADM is manifested in reasoning and learning. This paper outlines the role of ADM and especially in relation to the standard IEC 61508 and presents the overall properties that result. These are exemplified by a presentation of ADM demonstrator.

  7. Biodistribution of gadolinium-based contrast agents, including gadolinium deposition

    PubMed Central

    Aime, Silvio; Caravan, Peter

    2010-01-01

    The biodistribution of approved gadolinium (Gd) based contrast agents (GBCA) is reviewed. After intravenous injection GBCA distribute in the blood and the extracellular space and transiently through the excretory organs. Preclinical animal studies and the available clinical literature indicate that all these compounds are excreted intact. Elimination tends to be rapid and for the most part, complete. In renally insufficient patients the plasma elimination half-life increases substantially from hours to days depending on renal function. In patients with impaired renal function and nephrogenic systemic fibrosis (NSF), the agents gadodiamide, gadoversetamide, and gadopentetate dimeglumine have been shown to result in Gd deposition in the skin and internal organs. In these cases, it is likely that the Gd is no longer present as the GBCA, but this has still not been definitively shown. In preclinical models very small amounts of Gd are retained in the bone and liver, and the amount retained correlates with the kinetic and thermodynamic stability of the GBCA with respect to Gd release in vitro. The pattern of residual Gd deposition in NSF subjects may be different than that observed in preclinical rodent models. GBCA are designed to be used via intravenous administration. Altering the route of administration and/or the formulation of the GBCA can dramatically alter the biodistribution of the GBCA and can increase the likelihood of Gd deposition. PMID:19938038

  8. 28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., including chemical agents. 552.25 Section 552.25 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is...

  9. 28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., including chemical agents. 552.25 Section 552.25 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is...

  10. 28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., including chemical agents. 552.25 Section 552.25 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is...

  11. 28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., including chemical agents. 552.25 Section 552.25 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is...

  12. Mass spectrometry in identification of ecotoxicants including chemical and biological warfare agents.

    PubMed

    Lebedev, Albert T

    2005-09-01

    Mass spectrometry is a unique tool to detect and identify trace levels of organic and bioorganic compounds as well as microorganisms in the environment. The range of potential chemical warfare (CW) and biological warfare (BW) agents is very broad. An important advantage of mass spectrometry over other techniques involves potential for full spectrum detection of chemical and biological agents including mid-spectrum materials (i.e. bioactive peptides, toxins, etc.) for which biological approaches are inadequate. Being very fast (seconds and minutes), extremely sensitive (zeptomoles 10(-21)), and informative (detailed qualitative and quantitative composition of mixtures containing hundreds of chemicals), mass spectrometry is a principal analytical tool at the sites of destruction of CW. Due to its unique features, mass spectrometry is applied not only for the detection of CW agents, but for the analysis of products of metabolism and degradation of these agents in organisms or environment as well. The present paper deals with some examples of successful application of mass spectrometry for the analyses of ecotoxicants, chemical warfare agents, explosives, and microorganisms including biology warfare agents. PMID:16024060

  13. Mass spectrometry in identification of ecotoxicants including chemical and biological warfare agents

    SciTech Connect

    Lebedev, Albert T. . E-mail: lebedev@org.chem.msu.ru

    2005-09-01

    Mass spectrometry is a unique tool to detect and identify trace levels of organic and bioorganic compounds as well as microorganisms in the environment. The range of potential chemical warfare (CW) and biological warfare (BW) agents is very broad. An important advantage of mass spectrometry over other techniques involves potential for full spectrum detection of chemical and biological agents including mid-spectrum materials (i.e. bioactive peptides, toxins, etc.) for which biological approaches are inadequate. Being very fast (seconds and minutes), extremely sensitive (zeptomoles 10{sup -21}), and informative (detailed qualitative and quantitative composition of mixtures containing hundreds of chemicals), mass spectrometry is a principal analytical tool at the sites of destruction of CW. Due to its unique features, mass spectrometry is applied not only for the detection of CW agents, but for the analysis of products of metabolism and degradation of these agents in organisms or environment as well. The present paper deals with some examples of successful application of mass spectrometry for the analyses of ecotoxicants, chemical warfare agents, explosives, and microorganisms including biology warfare agents.

  14. Quantum Speedup for Active Learning Agents

    NASA Astrophysics Data System (ADS)

    Paparo, Giuseppe Davide; Dunjko, Vedran; Makmal, Adi; Martin-Delgado, Miguel Angel; Briegel, Hans J.

    2014-07-01

    Can quantum mechanics help us build intelligent learning agents? A defining signature of intelligent behavior is the capacity to learn from experience. However, a major bottleneck for agents to learn in real-life situations is the size and complexity of the corresponding task environment. Even in a moderately realistic environment, it may simply take too long to rationally respond to a given situation. If the environment is impatient, allowing only a certain time for a response, an agent may then be unable to cope with the situation and to learn at all. Here, we show that quantum physics can help and provide a quadratic speedup for active learning as a genuine problem of artificial intelligence. This result will be particularly relevant for applications involving complex task environments.

  15. Delivery of active agents from chewing gum for improved remineralization.

    PubMed

    Dodds, M W J; Chidichimo, D; Haas, M S

    2012-09-01

    Most surrogate measures of caries were developed to test products containing fluoride, typically at relatively high and closely controlled oral concentrations. However, since the primary mechanism for the remineralization of early enamel caries lesions by chewing gum is through stimulation of saliva, delivering Ca and Pi to the demineralized enamel lesion, established methods may lack the sensitivity to detect the additional benefit of an active agent without the strong remineralizing potential of fluoride. Issues related to the release of active agents from the gum matrix, dilution in the saliva, and limited oral retention time, along with taste, safety, regulatory, and cost concerns, impose further limitations. This paper reviews the efficacy of some active agents used in chewing gum for improved remineralization and includes results from in situ testing of calcium-containing gums, including calcium lactate, tetracalcium phosphate/dicalcium phosphate anhydrous, calcium citrate/encapsulated phosphate, and a calcium lactate/sodium phosphate blend. Despite promising in vitro data from these agents, they did not provide consistently superior results from in situ testing. There is a need to develop better predictive in vitro models for chewing gum, as well as improved sensitivity of in situ models to discriminate relatively small amounts of remineralization against a background of high biological variability. PMID:22899681

  16. Hypoglycemic agents and potential anti-inflammatory activity

    PubMed Central

    Kothari, Vishal; Galdo, John A; Mathews, Suresh T

    2016-01-01

    Current literature shows an association of diabetes and secondary complications with chronic inflammation. Evidence of these immunological changes include altered levels of cytokines and chemokines, changes in the numbers and activation states of various leukocyte populations, apoptosis, and fibrosis during diabetes. Therefore, treatment of diabetes and its complications may include pharmacological strategies to reduce inflammation. Apart from anti-inflammatory drugs, various hypoglycemic agents have also been found to reduce inflammation that could contribute to improved outcomes. Extensive studies have been carried out with thiazolidinediones (peroxisome proliferator-activated receptor-γ agonist), dipeptidyl peptidase-4 inhibitors, and metformin (AMP-activated protein kinase activator) with each of these classes of compounds showing moderate-to-strong anti-inflammatory action. Sulfonylureas and alpha glucosidase inhibitors appeared to exert modest effects, while the injectable agents, insulin and glucagon-like peptide-1 receptor agonists, may improve secondary complications due to their anti-inflammatory potential. Currently, there is a lack of clinical data on anti-inflammatory effects of sodium–glucose cotransporter type 2 inhibitors. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and effects related to intrinsic anti-inflammatory actions of the pharmacological class of compounds. PMID:27114714

  17. Synthesis and structure-activity relationships of neuromuscular blocking agents.

    PubMed

    Tuba, Zoltan; Maho, Sandor; Vizi, E Sylvester

    2002-08-01

    The first use of neuromuscular blocking agents (muscle relaxants) in clinical practice (1942) revolutionised the practice of anaesthesia and started the modern era of surgery. Since 1942 introduction of tubocurarine (18) neuromuscular blocking agents have been used routinely to provide skeletal muscle relaxation during surgical procedures allowing access to body cavities without hindrance from voluntary or reflex muscle movement. After the introduction of tubocurarine and the depolarizing suxamethonium chloride (4) (1949) several nondepolarizing steroidal and nonsteroidal neuromuscular blocking agents with different onset time and duration of effect were introduced e.g. gallamine triethiodide (1) (1949), methocurine (2) (1949), alcuronium chloride (3) (1963), pancuronium bromide (9) (1968), vecuronium bromide (11) (1982), pipecuronium bromide (10) (1982), atracurium besylate (5) (1982), doxacurium chloride (6) (1991), mivacurium chloride (8) (1992), rocuronium bromide (12) (1994) cisatracurium besylate (7) (1996), and rapacuronium bromide (13) (2000). SZ 1677 (14) a steroid type nondepolarizing neuromuscular blocking agent under development (preclinical phase). This review article deals with a comprehensive survey of the progress in chemical, pharmacological and, in some respects, of clinical studies of neuromuscular blocking agents used in the clinical practice and under development, including the synthesis, structure elucidation, pharmacological actions, structure activity relationships studies of steroidal and nonsteroidal derivatives. PMID:12171561

  18. Antiendotoxin activity of cationic peptide antimicrobial agents.

    PubMed Central

    Gough, M; Hancock, R E; Kelly, N M

    1996-01-01

    The endotoxin from gram-negative bacteria consists of a molecule lipopolysaccharide (LPS) which can be shed by bacteria during antimicrobial therapy. A resulting syndrome, endotoxic shock, is a leading cause of death in the developed world. Thus, there is great interest in the development of antimicrobial agents which can reverse rather than promote sepsis, especially given the recent disappointing clinical performance of antiendotoxin therapies. We describe here two small cationic peptides, MBI-27 and MBI-28, which have both antiendotoxic and antibacterial activities in vitro and in vivo in animal models. We had previously demonstrated that these peptides bind to LPS with an affinity equivalent to that of polymyxin B. Consistent with this, the peptides blocked the ability of LPS and intact cells to induce the endotoxic shock mediator, tumor necrosis factor (TNF), upon incubation with the RAW 264.7 murine macrophage cell line. MBI-28 was equivalent to polymyxin B in its ability to block LPS induction of TNF by this cell line, even when added 60 min after the TNF stimulus. Furthermore, MBI-28 offered significant protection in a galactosamine-sensitized mouse model of lethal endotoxic shock. This protection correlated with the ability of MBI-28 to reduce LPS-induced circulating TNF by nearly 90% in this mouse model. Both MBI-27 and MBI-28 demonstrated antibacterial activity against gram-negative bacteria in vitro and in vivo against Pseudomonas aeruginosa infections in neutropenic mice. PMID:8945527

  19. Recent approaches for reducing hemolytic activity of chemotherapeutic agents.

    PubMed

    Jeswani, Gunjan; Alexander, Amit; Saraf, Shailendra; Saraf, Swarnlata; Qureshi, Azra; Ajazuddin

    2015-08-10

    Drug induced hemolysis is a frequent complication associated with chemotherapy. It results from interaction of drug with erythrocyte membrane and leads to cell lysis. In recent past, various approaches were made to reduce drug-induced hemolysis, which includes drug polymer conjugation, drug delivery via colloidal carriers and hydrogels, co-administration of botanical agents and modification in molecular chemistry of drug molecules. The basic concept behind these strategies is to protect the red blood cells from membrane damaging effects of drugs. There are several examples of drug polymer conjugate that either are approved by Food and Drug Administration or are under clinical trial for delivering drugs with reduced toxicities. Likewise, colloidal carriers are also used successfully nowadays for the delivery of various chemotherapeutic agents like gemcitabine and amphotericin B with remarkable decrease in their hemolytic activity. Similarly, co-administration of botanical agents with drugs works as secondary system proving protection and strength to erythrocyte membranes. In addition to the above statement, interaction hindrance between RBC and drug molecule by molecular modification plays an important role in reducing hemolysis. This review predominantly describes the above recent approaches explored to achieve the reduced hemolytic activity of drugs especially chemotherapeutic agents. PMID:26047758

  20. Genome Sequencing of Four Strains of Rickettsia prowazekii, the Causative Agent of Epidemic Typhus, Including One Flying Squirrel Isolate.

    PubMed

    Bishop-Lilly, Kimberly A; Ge, Hong; Butani, Amy; Osborne, Brian; Verratti, Kathleen; Mokashi, Vishwesh; Nagarajan, Niranjan; Pop, Mihai; Read, Timothy D; Richards, Allen L

    2013-01-01

    Rickettsia prowazekii is a notable intracellular pathogen, the agent of epidemic typhus, and a potential biothreat agent. We present here whole-genome sequence data for four strains of R. prowazekii, including one from a flying squirrel. PMID:23814035

  1. An Active Learning Exercise for Introducing Agent-Based Modeling

    ERIC Educational Resources Information Center

    Pinder, Jonathan P.

    2013-01-01

    Recent developments in agent-based modeling as a method of systems analysis and optimization indicate that students in business analytics need an introduction to the terminology, concepts, and framework of agent-based modeling. This article presents an active learning exercise for MBA students in business analytics that demonstrates agent-based…

  2. Surface active agent for emulsion fuel

    SciTech Connect

    Aoki, Y.; Furuyama, Y.; Moriyama, N.

    1980-01-08

    A method is claimed for preparing a water-in-oil emulsion fuel which comprises emulsifying water in oil, in the presence of an emulsifying agency. The improvement comprises using as the emulsifying agent, a surfactant. The formula of this surfactant is presented.

  3. Everglades National Park Including Biscayne National Park. Activity Book.

    ERIC Educational Resources Information Center

    Ruehrwein, Dick

    Intended to help elementary school children learn about the resources of the Everglades and Biscayne National Parks, this activity book includes information, puzzles, games, and quizzes. The booklet deals with concepts related to: (1) the seasons; (2) fire ecology; (3) water; (4) fish; (5) mammals; (6) mosquitos; (7) birds; (8) venomous snakes;…

  4. In vitro antimicrobial activity of peroxide-based bleaching agents.

    PubMed

    Napimoga, Marcelo Henrique; de Oliveira, Rogério; Reis, André Figueiredo; Gonçalves, Reginaldo Bruno; Giannini, Marcelo

    2007-06-01

    Antibacterial activity of 4 commercial bleaching agents (Day White, Colgate Platinum, Whiteness 10% and 16%) on 6 oral pathogens (Streptococcus mutans, Streptococcus sobrinus, Streptococcus sanguinis, Candida albicans, Lactobacillus casei, and Lactobacillus acidophilus) and Staphylococcus aureus were evaluated. A chlorhexidine solution was used as a positive control, while distilled water was the negative control. Bleaching agents and control materials were inserted in sterilized stainless-steel cylinders that were positioned under inoculated agar plate (n = 4). After incubation according to the appropriate period of time for each microorganism, the inhibition zones were measured. Data were analyzed by 2-way analysis of variance and Tukey test (a = 0.05). All bleaching agents and the chlorhexidine solution produced antibacterial inhibition zones. Antimicrobial activity was dependent on peroxide-based bleaching agents. For most microorganisms evaluated, bleaching agents produced inhibition zones similar to or larger than that observed for chlorhexidine. C albicans, L casei, and L acidophilus were the most resistant microorganisms. PMID:17625621

  5. Structure and activity of plasmin and other direct thrombolytic agents.

    PubMed

    Novokhatny, Valery

    2008-01-01

    The physiological or pharmacological dissolution of thrombi is ultimately accomplished by the serine protease plasmin. Plasmin is derived from its precursor plasminogen in a reaction catalyzed by plasminogen activators (PAs) such as tissue-type plasminogen activator (tPA). In the middle of the last century, plasmin was investigated as a potential thrombolytic agent. However, technical obstacles led to the abandonment of this agent, and by the 1970s PAs had become the standard of care for pharmacological management of various thrombotic conditions. Talecris Biotherapeutics has developed a methodology to prepare the plasmin product (Human) TAL-05-00018 that is rendered inactive by low pH (pH 3.0-4.0) until it is delivered directly to the neutral environment of a thrombus by catheter-assisted administration. TAL-05-00018 undergoes a rigorous manufacturing process to ensure a final product free from unactivated plasminogen, streptokinase, enveloped and non-enveloped viruses and prion proteins; generating an extremely high-purity product with a shelf life of three years at ambient temperature. TAL-05-00018 has shown promise in in vitro and pre-clinical studies, and in early clinical trials, demonstrating a dose-dependant reduction in clot weight that compares favorably to that seen with tPA. Several other direct thrombolytics have also been developed, including the recombinant, modified deletion mutant of plasmin TAL6003 (Talecris Biotherapeutics), which retains all the major functional attributes of full-length plasmin. PMID:18718639

  6. Methods, microfluidic devices, and systems for detection of an active enzymatic agent

    SciTech Connect

    Sommer, Gregory J; Hatch, Anson V; Singh, Anup K; Wang, Ying-Chih

    2014-10-28

    Embodiments of the present invention provide methods, microfluidic devices, and systems for the detection of an active target agent in a fluid sample. A substrate molecule is used that contains a sequence which may cleave in the presence of an active target agent. A SNAP25 sequence is described, for example, that may be cleaved in the presence of Botulinum Neurotoxin. The substrate molecule includes a reporter moiety. The substrate molecule is exposed to the sample, and resulting reaction products separated using electrophoretic separation. The elution time of the reporter moiety may be utilized to identify the presence or absence of the active target agent.

  7. Method for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, E.A.; Fisher, W.G.; Dees, H.C.

    1998-11-10

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method includes the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention is also a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent. 13 figs.

  8. Method for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, Eric A.; Fisher, Walter G.; Dees, H. Craig

    1998-01-01

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method includes the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention is also a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent.

  9. Asphaltenes as a surface active agent

    SciTech Connect

    Sheu, E.Y.; Shields, M.B.; Storm, D.A.

    1995-12-31

    Asphaltene represents the heavy-end materials of the crude oil, conventionally defined via solvent solubility (either heptane or pentane). Chemically, it consists of polynuclear aromatics with the H/C ratio close to unity. Additionally, it contains a great deal of heteroatoms, such as sulfur, nitrogen, nickel, vanadium, etc. Several experiments have revealed the surface activity of asphaltenes in some selected solvents through measurements of their rheology or critical micelle concentrations in these solvents. The asphaltene micelles were found thermodynamically reversible. In a two phase asphaltene/water system, asphaltenes appear to vary their surface activities depending upon the polarity of the aqueous phase. Our recent experiment further showed that asphaltene/water/toluene may form, water-in-oil emulsion under certain conditions.

  10. Activity of 10 antimicrobial agents against intracellular Rhodococcus equi.

    PubMed

    Giguère, Steeve; Berghaus, Londa J; Lee, Elise A

    2015-08-01

    Studies with facultative intracellular bacterial pathogens have shown that evaluation of the bactericidal activity of antimicrobial agents against intracellular bacteria is more closely associated with in vivo efficacy than traditional in vitro susceptibility testing. The objective of this study was to determine the relative activity of 10 antimicrobial agents against intracellular Rhodococcus equi. Equine monocyte-derived macrophages were infected with virulent R. equi and exposed to erythromycin, clarithromycin, azithromycin, rifampin, ceftiofur, gentamicin, enrofloxacin, vancomycin, imipenem, or doxycycline at concentrations achievable in plasma at clinically recommended dosages in foals. The number of intracellular R. equi was determined 48h after infection by counting colony forming units (CFUs). The number of R. equi CFUs in untreated control wells were significantly higher than those of monolayers treated with antimicrobial agents. Numbers of R. equi were significantly lower in monolayers treated with enrofloxacin followed by those treated with gentamicin, and vancomycin, when compared to monolayers treated with other antimicrobial agents. Numbers of R. equi in monolayers treated with doxycycline were significantly higher than those of monolayers treated with other antimicrobial agents. Differences in R. equi CFUs between monolayers treated with other antimicrobial agents were not statistically significant. Enrofloxacin, gentamicin, and vancomycin are the most active drugs in equine monocyte-derived macrophages infected with R. equi. Additional studies will be needed to determine if these findings correlate with in vivo efficacy. PMID:26051479

  11. Chalcone derivatives as potential antifungal agents: Synthesis, and antifungal activity.

    PubMed

    Gupta, Deepa; Jain, D K

    2015-01-01

    Much research has been carried out with the aim to discover the therapeutic values of chalcone derivatives. Chalcones possess wide range of pharmacological activity such as antibacterial, antimalarial, antiprotozoal, antitubercular, anticancer, and antifungal agents etc. The presence of reactive α,β-unsaturated keto group in chalcones is found to be responsible for their biological activity. The rapid developments of resistance to antifungal agents, led to design, and synthesize the new antifungal agents. The derivatives of chalcones were prepared using Claisen-Schmidt condensation scheme with appropriate tetralone and aldehyde derivatives. Ten derivatives were synthesized and were biologically screened for antifungal activity. The newly synthesized derivatives of chalcone showed antifungal activity against fungal species, Microsporum gypseum. The results so obtained were superior or comparable to ketoconazole. It was observed that none of the compounds tested showed positive results for fungi Candida albicans nor against fungi Aspergillus niger. Chalcone derivatives showed inhibitory effect against M. gypseum species of fungus. It was found that among the chalcone derivatives so synthesized, two of them, that is, 4-chloro derivative, and unsubstituted derivative of chalcone showed antifungal activity superior to ketoconazole. Thus, these can be the potential new molecule as antifungal agent. PMID:26317075

  12. Activation of a photosensitive pharmaceutical agent by a triboluminescent material

    NASA Astrophysics Data System (ADS)

    Yuen, Stacey; Schreyer, Magdalena; Finlay, W. H.; Löbenberg, R.; Moussa, W.

    2006-03-01

    Given the recent emphasis on applications of triboluminescent materials, we investigate the ability of a triboluminescent material to activate a photosensitive pharmaceutical agent. Using compressed sucrose doped with wintergreen, which luminesces when fractured, we demonstrate the activation of riboflavin (vitamin B2), a photosensitizer. A product of activation is the highly reactive singlet oxygen. We add ascorbic acid (vitamin C), an antioxidant, and measure the amount of ascorbic acid oxidation to correlate with the amount of riboflavin activation. Up to 17% ascorbic acid oxidation is observed, indicating triboluminescence is worth exploring as a mechanism for activation of photosensitizers in photodynamic therapy.

  13. Activation of a photosensitive pharmaceutical agent by a triboluminescent material

    SciTech Connect

    Yuen, Stacey; Schreyer, Magdalena; Finlay, W.H.; Loebenberg, R.; Moussa, W.

    2006-03-20

    Given the recent emphasis on applications of triboluminescent materials, we investigate the ability of a triboluminescent material to activate a photosensitive pharmaceutical agent. Using compressed sucrose doped with wintergreen, which luminesces when fractured, we demonstrate the activation of riboflavin (vitamin B2), a photosensitizer. A product of activation is the highly reactive singlet oxygen. We add ascorbic acid (vitamin C), an antioxidant, and measure the amount of ascorbic acid oxidation to correlate with the amount of riboflavin activation. Up to 17% ascorbic acid oxidation is observed, indicating triboluminescence is worth exploring as a mechanism for activation of photosensitizers in photodynamic therapy.

  14. Keratin sponge/hydrogel II, active agent delivery

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Keratin sponge/hydrogels from oxidation and reduction hydrolysis of fine and coarse wool fibers were formed to behave as cationic hydrogels to swell and release active agents in the specific region of the gastro-intestinal (GI) tract. Their porous, interpenetrating networks (IPN) were effective for...

  15. Peganine hydrochloride dihydrate an orally active antileishmanial agent.

    PubMed

    Khaliq, Tanvir; Misra, Pragya; Gupta, Swati; Reddy, K Papi; Kant, Ruchir; Maulik, P R; Dube, Anuradha; Narender, T

    2009-05-01

    Protozoic infections caused by genus Leishmania pose an enormous public health threat in developing countries, compounded by the toxicity and resistance to current therapies. Under the aegis of our ongoing program on drug discovery and development on antileishmanial agents from plants, we carried out bioassay guided fractionation on Peganum harmala seeds which resulted in the isolation of 1 as an antileishmanial agent. 2D-NMR spectral data and single crystal X-ray crystallography data indicated 1 as peganine hydrochloride in dihydrated form. The compound 1 exhibited in-vitro activity against both extracellular promastigotes as well as intracellular amastigotes residing within murine macrophages in Leishmania donovani. Furthermore, 1 also exhibited in-vivo activity, 79.6 (+/-8.07)% against established VL in hamsters at a dose of 100mg/kgb.wt. PMID:19339182

  16. Cyclohexane triones, novel membrane-active antibacterial agents.

    PubMed Central

    Lloyd, W J; Broadhurst, A V; Hall, M J; Andrews, K J; Barber, W E; Wong-Kai-In, P

    1988-01-01

    The cyclohexane triones are a novel group of synthetic antibacterial agents that are active against gram-positive bacteria, Haemophilus influenzae, and Mycobacterium smegmatis. In general, these compounds behaved in a manner similar to that of hexachlorophene, inhibiting the transport of low-molecular-weight hydrophilic substances into bacteria. Unlike cationic detergents, such as chlorhexidine, they did not cause disruption of the bacterial cytoplasmic membrane over a short time period. The most potent antibacterial cyclohexane trione studied had a reduced ability to inhibit solute transport in comparison with certain less active analogs. Cyclohexane triones may express more than a single type of antibacterial effect. PMID:3137860

  17. Plant active components - a resource for antiparasitic agents?

    PubMed

    Anthony, Jean-Paul; Fyfe, Lorna; Smith, Huw

    2005-10-01

    Plant essential oils (and/or active components) can be used as alternatives or adjuncts to current antiparasitic therapies. Garlic oil has broad-spectrum activity against Trypanosoma, Plasmodium, Giardia and Leishmania, and Cochlospermum planchonii and Croton cajucara oils specifically inhibit Plasmodium falciparum and Leishmania amazonensis, respectively. Some plant oils have immunomodulatory effects that could modify host-parasite immunobiology, and the lipid solubility of plant oils might offer alternative, transcutaneous delivery routes. The emergence of parasites resistant to current chemotherapies highlights the importance of plant essential oils as novel antiparasitic agents. PMID:16099722

  18. Coordinating the activities of a planner and an execution agent

    NASA Technical Reports Server (NTRS)

    Tate, Austin

    1989-01-01

    A research program was defined that will explore the link between planning and execution systems. A simple scenario was defined in which a very capable off-line planning system interacts with the user and a smaller, less capable, on-line real-time system executing plans and reacting to faults. However, the on-line execution system may have a more flexible representation of the plans it is executing. This imbalance in the capabilities of the two agents involved should clarify some of the research objectives and give an experimental framework for the work. The task is to investigate the knowledge representations and communication protocols needed to link a user stating some requirements for a task to be carried out through a planning system to the (remote) execution agent that can carry out the user's wishes. The notion that a single representation can encapsulate the expression of the user's requirements, the capabilities for action, the communication to the execution agent, the successful or faulty response from the execution agent and the means of keeping the user informed, is examined. Methods of creating plan patches to update the plans separately held by each of the parties involved to keep them in step as they each react to changing circumstances in real-time is investigated. This involves the specification of plan patch attachment points that can be understood by the recipient. Transaction based methods are also investigated for coordinating the activities of the planner with those of the execution agent and user. The trial application area for the research is in the command and control of an advanced Earth Observation Space Platform.

  19. Pharmacological activity of metal binding agents that alter copper bioavailability

    PubMed Central

    Helsel, Marian E.

    2015-01-01

    Iron, copper and zinc are required nutrients for many organisms but also potent toxins if misappropriated. An overload of any of these metals can be cytotoxic and ultimately lead to organ failure, whereas deficiencies can result in anemia, weakened immune system function, and other medical conditions. Cellular metal imbalances have been implicated in neurodegenerative diseases, cancer and infection. It is therefore critical for living organisms to maintain careful control of both the total levels and subcellular distributions of these metals to maintain healthy function. This perspective explores several strategies envisioned to alter the bioavailability of metal ions by using synthetic metal-binding agents targeted for diseases where misappropriated metal ions are suspected of exacerbating cellular damage. Specifically, we discuss chemical properties that influence the pharmacological outcome of a subset of metal-binding agents known as ionophores, and review several examples that have shown multiple pharmacological activities in metal-related diseases, with a specific focus on copper. PMID:25797044

  20. Polymerization process for carboxyl containing polymers utilizing oil soluble ionic surface active agents

    SciTech Connect

    Uebele, C.E.; Ball, L.E.; Jorkasky, R.J. II; Wardlow, E. Jr.

    1987-09-08

    This patent describes a method for polymerizing olefinically unsaturated carboxylic acid monomers containing at least one activated carbon to carbon olefinic double bond and at least one carboxyl group. The monomers are polymerized in an organic media consisting essentially of organic liquids, in the presence of free radical forming catalysts and at least one oil soluble ionic surface active agent selected from the group consisting of: (a) anionic surface active agents; (b) cationic surface active agents; and (c) amphoteric surface active agents.

  1. A self-calibrating PARACEST MRI contrast agent that detects esterase enzyme activity

    PubMed Central

    Li, Yuguo; Sheth, Vipul R.; Liu, Guanshu; Pagel, Mark D.

    2016-01-01

    The CEST effect of many PARACEST MRI contrast agents changes in response to a molecular biomarker. However, other molecular biomarkers or environmental factors can influence CEST, so that a change in CEST is not conclusive proof for detecting the biomarker. To overcome this problem, a second control CEST effect may be included in the same PARACEST agent, which is responsive to all factors that alter the first CEST effect except for the biomarker to be measured. To investigate this approach, a PARACEST MRI contrast agent was developed with one CEST effect that is responsive to esterase enzyme activity and a second control CEST effect. The ratio of the two CEST effects was independent of concentration and T1 relaxation, so that this agent was self-calibrating with respect to these factors. This ratiometric method was dependent on temperature and was influenced by MR coalescence as the chemical exchange rates approached the chemical shifts of the exchangable protons as temperature was increased. The two CEST effects also showed evidence of having different pH dependencies, so that this agent was not self-calibrating with respect to pH. Therefore, a self-calibrating PARACEST MRI contrast agent can more accurately detect a molecular biomarker such as esterase enzyme activity, as long as temperature and pH are within an acceptable physiological range and remain constant. PMID:21861282

  2. Anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma

    PubMed Central

    Kwak, Tae Won; Shin, Hee Jae; Jeong, Young-Il; Han, Myoung-Eun; Oh, Sae-Ock; Kim, Hyun-Jung; Kim, Do Hyung; Kang, Dae Hwan

    2015-01-01

    Background The aim of this study is to investigate the anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma. Methods The anticancer activity of streptochlorin was evaluated in vitro in various cholangiocarcinoma cell lines for apoptosis, proliferation, invasiveness, and expression of various protein levels. A liver metastasis model was prepared by splenic injection of HuCC-T1 cholangiocarcinoma cells using a BALB/c nude mouse model to study the systemic antimetastatic efficacy of streptochlorin 5 mg/kg at 8 weeks. The antitumor efficacy of subcutaneously injected streptochlorin was also assessed using a solid tumor xenograft model of SNU478 cells for 22 days in the BALB/c nude mouse. Results Streptochlorin inhibited growth and secretion of vascular endothelial growth factor by cholangiocarcinoma cells in a dose-dependent manner and induced apoptosis in vitro. In addition, streptochlorin effectively inhibited invasion and migration of cholangiocarcinoma cells. Secretion of vascular endothelial growth factor and activity of matrix metalloproteinase-9 in cholangiocarcinoma cells were also suppressed by treatment with streptochlorin. Streptochlorin effectively regulated metastasis of HuCC-T1 cells in a mouse model of liver metastasis. In a tumor xenograft study using SNU478 cells, streptochlorin significantly inhibited tumor growth without changes in body weight when compared with the control. Conclusion These results reveal that streptochlorin is a promising chemotherapeutic agent to the treatment of cholangiocarcinoma. PMID:25931814

  3. Perspective of surface active agents in baking industry: an overview.

    PubMed

    Ahmad, Asif; Arshad, Nazish; Ahmed, Zaheer; Bhatti, Muhammad Shahbaz; Zahoor, Tahir; Anjum, Nomana; Ahmad, Hajra; Afreen, Asma

    2014-01-01

    Different researchers have previously used surfactants for improving bread qualities and revealed that these compounds result in improving the quality of dough and bread by influencing dough strength, tolerance, uniform crumb cell size, and improve slicing characteristics and gas retention. The objective of this review is to highlight the areas where surfactants are most widely used particularly in the bread industries, their role and mechanism of interaction and their contribution to the quality characteristics of the dough and bread. This review reveals some aspects of surface-active agents regarding its role physiochemical properties of dough that in turn affect the bread characteristics by improving its sensory quality and storage stability. PMID:24188269

  4. Optimal design of active and semi-active suspensions including time delays and preview

    NASA Astrophysics Data System (ADS)

    Hac', A.; Youn, I.

    1993-10-01

    Several control laws for active and semi-active suspension based on a linear half car model are derived and investigated. The strategies proposed take full advantage of the fact that the road input to the rear wheels is a delayed version of that to the front wheels, which in turn can be obtained either from the measurements of the front wheels and body motions or by direct preview of road irregularities if preview sensors are available. The suspension systems are optimized with respect to ride comfort, road holding and suspension rattle space as expressed by the mean-square-values of body acceleration (including effects of heave and pitch), tire deflections and front and rear suspension travels. The optimal control laws that minimize the given performance index and include passivity constraints in the semi-active case are derived using calculus of variation. The optimal semi-active suspension becomes piecewise linear, varying between passive and fully active systems and combinations of them. The performances of active and semi-active systems with and without preview were evaluated by numerical simulation in the time and frequency domains. The results show that incorporation of time delay between the front and rear axles in controller design improves the dynamic behavior of the rear axle and control of body pitch motion, while additional preview improves front wheel dynamics and body heave.

  5. Learning Activity Models for Multiple Agents in a Smart Space

    NASA Astrophysics Data System (ADS)

    Crandall, Aaron; Cook, Diane J.

    With the introduction of more complex intelligent environment systems, the possibilities for customizing system behavior have increased dramatically. Significant headway has been made in tracking individuals through spaces using wireless devices [1, 18, 26] and in recognizing activities within the space based on video data (see chapter by Brubaker et al. and [6, 8, 23]), motion sensor data [9, 25], wearable sensors [13] or other sources of information [14, 15, 22]. However, much of the theory and most of the algorithms are designed to handle one individual in the space at a time. Resident tracking, activity recognition, event prediction, and behavior automation becomes significantly more difficult for multi-agent situations, when there are multiple residents in the environment.

  6. Reactive oxygen species-activated nanomaterials as theranostic agents.

    PubMed

    Kim, Kye S; Lee, Dongwon; Song, Chul Gyu; Kang, Peter M

    2015-01-01

    Reactive oxygen species (ROS) are generated from the endogenous oxidative metabolism or from exogenous pro-oxidant exposure. Oxidative stress occurs when there is excessive production of ROS, outweighing the antioxidant defense mechanisms which may lead to disease states. Hydrogen peroxide (H2O2) is one of the most abundant and stable forms of ROS, implicated in inflammation, cellular dysfunction and apoptosis, which ultimately lead to tissue and organ damage. This review is an overview of the role of ROS in different diseases. We will also examine ROS-activated nanomaterials with emphasis on hydrogen peroxide, and their potential medical implications. Further development of the biocompatible, stimuli-activated agent responding to disease causing oxidative stress, may lead to a promising clinical use. PMID:26328770

  7. Reactive oxygen species-activated nanomaterials as theranostic agents

    PubMed Central

    Kim, Kye S; Lee, Dongwon; Song, Chul Gyu; Kang, Peter M

    2015-01-01

    Reactive oxygen species (ROS) are generated from the endogenous oxidative metabolism or from exogenous pro-oxidant exposure. Oxidative stress occurs when there is excessive production of ROS, outweighing the antioxidant defense mechanisms which may lead to disease states. Hydrogen peroxide (H2O2) is one of the most abundant and stable forms of ROS, implicated in inflammation, cellular dysfunction and apoptosis, which ultimately lead to tissue and organ damage. This review is an overview of the role of ROS in different diseases. We will also examine ROS-activated nanomaterials with emphasis on hydrogen peroxide, and their potential medical implications. Further development of the biocompatible, stimuli-activated agent responding to disease causing oxidative stress, may lead to a promising clinical use. PMID:26328770

  8. Cancer morbidity in British military veterans included in chemical warfare agent experiments at Porton Down: cohort study

    PubMed Central

    Linsell, L; Brooks, C; Keegan, T J; Langdon, T; Doyle, P; Maconochie, N E S; Fletcher, T; Nieuwenhuijsen, M J; Beral, V

    2009-01-01

    Objective To determine cancer morbidity in members of the armed forces who took part in tests of chemical warfare agents from 1941 to 1989. Design Historical cohort study, with cohort members followed up to December 2004. Data source Archive of UK government research facility at Porton Down, UK military personnel records, and national death and cancer records. Participants All veterans included in the cohort study of mortality, excluding those known to have died or been lost to follow-up before 1 January 1971 when the UK cancer registration system commenced: 17 013 male members of the UK armed forces who took part in tests (Porton Down veterans) and a similar group of 16 520 men who did not (non-Porton Down veterans). Main outcome measures Cancer morbidity in each group of veterans; rate ratios, with 95% confidence intervals, adjusted for age group and calendar period. Results 3457 cancers were reported in the Porton Down veterans compared with 3380 cancers in the non-Porton Down veterans. While overall cancer morbidity was the same in both groups (rate ratio 1.00, 95% confidence interval 0.95 to 1.05), Porton Down veterans had higher rates of ill defined malignant neoplasms (1.12, 1.02 to 1.22), in situ neoplasms (1.45, 1.06 to 2.00), and those of uncertain or unknown behaviour (1.32, 1.01 to 1.73). Conclusion Overall cancer morbidity in Porton Down veterans was no different from that in non-Porton Down veterans. PMID:19318700

  9. ActivitySim: large-scale agent based activity generation for infrastructure simulation

    SciTech Connect

    Gali, Emmanuel; Eidenbenz, Stephan; Mniszewski, Sue; Cuellar, Leticia; Teuscher, Christof

    2008-01-01

    The United States' Department of Homeland Security aims to model, simulate, and analyze critical infrastructure and their interdependencies across multiple sectors such as electric power, telecommunications, water distribution, transportation, etc. We introduce ActivitySim, an activity simulator for a population of millions of individual agents each characterized by a set of demographic attributes that is based on US census data. ActivitySim generates daily schedules for each agent that consists of a sequence of activities, such as sleeping, shopping, working etc., each being scheduled at a geographic location, such as businesses or private residences that is appropriate for the activity type and for the personal situation of the agent. ActivitySim has been developed as part of a larger effort to understand the interdependencies among national infrastructure networks and their demand profiles that emerge from the different activities of individuals in baseline scenarios as well as emergency scenarios, such as hurricane evacuations. We present the scalable software engineering principles underlying ActivitySim, the socia-technical modeling paradigms that drive the activity generation, and proof-of-principle results for a scenario in the Twin Cities, MN area of 2.6 M agents.

  10. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Several benzoic acid analogs showed antifungal activity against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids increased by addition of a methyl, methoxyl...

  11. Anti-invasive activities of experimental chemotherapeutic agents.

    PubMed

    Mareel, M M; De Mets, M

    1989-01-01

    We have discussed a number of agents that affect invasion and we have grouped them according to their most probable targets. This strategy is based on the following hypothesis. Invasion is the result of cellular responses to extracellular signals. Candidate signals are components of the extracellular matrix, which are rendered inactive by the flavonoid (+)-catechin (see Section III). Signals are recognized by receptors on the plasma membrane, possibly glycoproteins, that may lose their recognition function through alteration of the oligosaccharide side chains by inhibitors of protein glycosylation (see Section IV) and possibly also by alkyllysophospholipids (see Section V). Synthetic oligopeptides reflecting sequences from cell-binding domains of extracellular matrix molecules are also effective tools for blocking specific receptors (see Section VI). GTP-binding proteins (G proteins) act as signal transducers and can be inactivated by pertussis toxin (see Section VII). An intriguing aspect of both alkyllysophospholipids and pertussis toxin is that they can either inhibit the invasion of constitutively invasive cells or induce invasion of constitutively noninvasive cells. Without doubt, cellular responses implicated in invasion are many-fold. Discussed here are cell motility and directional migration with inhibition through dipyridamole and its analogs and through microtubule inhibitors, respectively (see Section VIII). Alternative hypotheses and alternative strategies for the dissection of the invasion process do exist, and alternative cellular and molecular mechanisms of action may explain the anti-invasive activity of the agents discussed earlier. The latter are mentioned in each section. It is the authors' opinion that the possibilities for exploiting the battery of anti-invasive agents have by no means been exhausted. Introducing researchers to experiments that may lead to an understanding of the mechanisms of invasion and metastasis and to new rationales for

  12. SEQUESTERING AGENTS FOR ACTIVE CAPS - REMEDIATION OF METALS AND ORGANICS

    SciTech Connect

    Knox, A; Michael Paller, M; Danny D. Reible, D; Xingmao Ma, X; Ioana G. Petrisor, I

    2007-05-10

    This research evaluated organoclays, zeolites, phosphates, and a biopolymer as sequestering agents for inorganic and organic contaminants. Batch experiments were conducted to identify amendments and mixtures of amendments for metal and organic contaminants removal and retention. Contaminant removal was evaluated by calculating partitioning coefficients. Metal retention was evaluated by desorption studies in which residue from the removal studies was extracted with 1 M MgCl{sub 2} solution. The results indicated that phosphate amendments, some organoclays, and the biopolymer, chitosan, were very effective sequestering agents for metals in fresh and salt water. Organoclays were very effective sorbents for phenanthrene, pyrene, and benzo(a)pyrene. Partitioning coefficients for the organoclays were 3000-3500 ml g{sup -1} for benzo(a)pyrene, 400-450 ml g{sup -1} for pyrene, and 50-70 ml g{sup -1} for phenanthrene. Remediation of sites with a mixture of contaminants is more difficult than sites with a single contaminant because metals and organic contaminants have different fate and transport mechanisms in sediment and water. Mixtures of amendments (e.g., organoclay and rock phosphate) have high potential for remediating both organic and inorganic contaminants under a broad range of environmental conditions, and have promise as components in active caps for sediment remediation.

  13. Activated metallic gold as an agent for direct methoxycarbonylation.

    PubMed

    Xu, Bingjun; Madix, Robert J; Friend, Cynthia M

    2011-12-21

    We have discovered that metallic gold is a highly effective vehicle for the low-temperature vapor-phase carbonylation of methanol by insertion of CO into the O-H bond to form methoxycarbonyl. This reaction contrasts sharply to the carbonylation pathway well known for homogeneously catalyzed carbonylation reactions, such as the synthesis of acetic acid. The methoxycarbonyl intermediate can be further employed in a variety of methoxycarbonylation reactions, without the use or production of toxic chemicals. More generally we observe facile, selective methoxycarbonylation of alkyl and aryl alcohols and secondary amines on metallic gold well below room temperature. A specific example is the synthesis of dimethyl carbonate, which has extensive use in organic synthesis. This work establishes a unique framework for using oxygen-activated metallic gold as a catalyst for energy-efficient, environmentally benign production of key synthetic chemical agents. PMID:22035206

  14. Laboratory activities involving transmissible spongiform encephalopathy causing agents

    PubMed Central

    Leunda, Amaya; Van Vaerenbergh, Bernadette; Baldo, Aline; Roels, Stefan; Herman, Philippe

    2013-01-01

    Since the appearance in 1986 of epidemic of bovine spongiform encephalopathy (BSE), a new form of neurological disease in cattle which also affected human beings, many diagnostic and research activities have been performed to develop detection and therapeutic tools. A lot of progress was made in better identifying, understanding and controlling the spread of the disease by appropriate monitoring and control programs in European countries. This paper reviews the recent knowledge on pathogenesis, transmission and persistence outside the host of prion, the causative agent of transmissible spongiform encephalopathies (TSE) in mammals with a particular focus on risk (re)assessment and management of biosafety measures to be implemented in diagnostic and research laboratories in Belgium. Also, in response to the need of an increasing number of European diagnostic laboratories stopping TSE diagnosis due to a decreasing number of TSE cases reported in the last years, decontamination procedures and a protocol for decommissioning TSE diagnostic laboratories is proposed. PMID:24055928

  15. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a chloro group at position 4 of the aromatic ri...

  16. Activity of catalytic silver nanoparticles modulated by capping agent hydrophobicity.

    PubMed

    Janani, Seralathan; Stevenson, Priscilla; Veerappan, Anbazhagan

    2014-05-01

    In this paper, a facile in situ method is reported for the preparation of catalytic silver nanoparticles (AgNPs) using N-acyl tyramine (NATA) with variable hydrophobic acyl length. Scanning electron microscopic analysis shows that NATA exists initially as larger aggregates in alkaline aqueous solution. The addition of AgNO3 dissociates these larger aggregate and subsequently promotes the formation of self-assembled NATA and AgNPs. Characterization of AgNPs using UV-vis spectroscopy, scanning electron microscope and transmission electron microscope revealed that the hydrophobic acyl chain length of NATA does not influence the particle size, shape and morphology. All NATA-AgNPs yielded relatively identical values in full width at half-maximum (FWHM) analysis, indicating that the AgNPs prepared with NATA are relatively polydispersed at all tested acyl chain lengths. These nanoparticles are able to efficiently catalyze the reduction of 4-nitro phenol to 4-amino phenol, 2-nitro aniline to 1,2-diamino benzene, 2,4,6-trinitro phenol to 2,4,6-triamino phenol by NaBH4 in an aqueous environment. The reduction reaction rate is determined to be pseudo-first order and the apparent rate constant is linearly dependent on the hydrophobic acyl chain length of the NATA. All reaction kinetics presented an induction period, which is dependent on the N-acyl chain length, indicating that the hydrophobic effects play a critical role in bringing the substrate to the metal nanoparticle surface to induce the catalytic reaction. In this study, however, the five catalytic systems have similar size and polydispersity, differing only in terms of capping agent hydrophobicity, and shows different catalytic activity with respect to the alkyl chain length of the capping agent. As discussed, the ability to modulate the metal nanoparticles catalytic property, by modifying the capping agent hydrophobicity represents a promising future for developing an efficient nanocatalyst without altering the size

  17. Occurrence of Surface Active Agents in the Environment

    PubMed Central

    Olkowska, Ewa; Ruman, Marek; Polkowska, Żaneta

    2014-01-01

    Due to the specific structure of surfactants molecules they are applied in different areas of human activity (industry, household). After using and discharging from wastewater treatment plants as effluent stream, surface active agents (SAAs) are emitted to various elements of the environment (atmosphere, waters, and solid phases), where they can undergo numerous physic-chemical processes (e.g., sorption, degradation) and freely migrate. Additionally, SAAs present in the environment can be accumulated in living organisms (bioaccumulation), what can have a negative effect on biotic elements of ecosystems (e.g., toxicity, disturbance of endocrine equilibrium). They also cause increaseing solubility of organic pollutants in aqueous phase, their migration, and accumulation in different environmental compartments. Moreover, surfactants found in aerosols can affect formation and development of clouds, which is associated with cooling effect in the atmosphere and climate changes. The environmental fate of SAAs is still unknown and recognition of this problem will contribute to protection of living organisms as well as preservation of quality and balance of various ecosystems. This work contains basic information about surfactants and overview of pollution of different ecosystems caused by them (their classification and properties, areas of use, their presence, and behavior in the environment). PMID:24527257

  18. Effect of various capping agents on photocatalytic, antibacterial and antibiofilm activities of ZnO nanoparticles.

    PubMed

    Akhil, K; Jayakumar, J; Gayathri, G; Khan, S Sudheer

    2016-07-01

    Zinc oxide nanoparticles (ZnO NPs) are extensively used in a wide variety of commercial products including sunscreens, textiles and paints It is a known fact that ZnO NPs are not stable when dispersed in water, therefore manufacturers use several surface modifying agents to increase the stability of ZnO NPs. In the present study, ZnO NPs were synthesized via chemical co-precipitation with and without the use of surface modifying agents including ethylene glycol (EG), gelatin, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP). Preliminary characterization was done by UV-Visible spectroscopy. Electron microscopic analysis showed that the particles were hexagonal in shape. The hydrodynamic size distribution was analyzed by using dynamic light scattering method and crystalline nature was determined by X-ray diffraction method. The study evaluated the photocatalytic, antibacterial and antibiofilm activities of the particles with and without the addition of surface modifying agents. The capping of the particle was confirmed by FT-IR spectroscopy. The photocatalytic activity was checked against methylene blue. Capping of the particles reduced the photocatalytic activity of the particles. The antibacterial and antibiofilm activities were checked against Staphylococcus aureus (MTCC 3160) and Pseudomonas aeruginosa (MTCC 1688). Antibacterial activity was analyzed by simple plate count method both under dark as well as light condition. Antibiofilm activity was checked in both pre- and post-biofilm formation period under both dark as well as light condition. The activity was evaluated via crystal violet staining method. All the particles showed good antibacterial and antibiofilm activities. PMID:27088507

  19. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure.

    PubMed

    Halbrook, R S; Shugart, L R; Watson, A P; Munro, N B; Linnabary, R D

    1992-09-01

    A biomonitoring protocol, using blood cholinesterase (ChE) activity in livestock as a monitor of potential organophosphate nerve agent exposure during the planned destruction of US unitary chemical warfare agent stockpiles, is described. The experimental design included analysis of blood ChE activity in individual healthy sheep, horses, and dairy and beef cattle during a 10- to 12-month period. Castrated and sexually intact males, pregnant and lactating females, and adult and immature animals were examined through at least one reproductive cycle. The same animals were used throughout the period of observation and were not exposed to ChE-inhibiting organophosphate or carbamate compounds. A framework for an effective biomonitoring protocol within a monitoring area includes establishing individual baseline blood ChE activity for a sentinel group of 6 animals on the bases of blood samples collected over a 6-month period, monthly collection of blood samples for ChE-activity determination during monitoring, and selection of adult animals as sentinels. Exposure to ChE-inhibiting compounds would be suspected when all blood ChE activity of all animals within the sentinel group are decreased greater than 20% from their own baseline value. Sentinel species selection is primarily a logistical and operational concern; however, sheep appear to be the species of choice because within-individual baseline ChE activity and among age and gender group ChE activity in sheep had the least variability, compared with data from other species. This protocol provides an effective and efficient means for detecting abnormal depressions in blood ChE activity in livestock and can serve as a valuable indicator of the extent of actual plume movement and/or deposition in the event of organophosphate nerve agent release. PMID:1399773

  20. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure

    SciTech Connect

    Halbrook, R.S.; Shugart, L.R.; Watson, A.P.; Munro, N.B.; Linnabary, R.D. )

    1992-09-01

    A biomonitoring protocol, using blood cholinesterase (ChE) activity in livestock as a monitor of potential organophosphate nerve agent exposure during the planned destruction of US unitary chemical warfare agent stockpiles, is described. The experimental design included analysis of blood ChE activity in individual healthy sheep, horses, and dairy and beef cattle during a 10- to 12-month period. Castrated and sexually intact males, pregnant and lactating females, and adult and immature animals were examined through at least one reproductive cycle. The same animals were used throughout the period of observation and were not exposed to ChE-inhibiting organophosphate or carbamate compounds. A framework for an effective biomonitoring protocol within a monitoring area includes establishing individual baseline blood ChE activity for a sentinel group of 6 animals on the bases of blood samples collected over a 6-month period, monthly collection of blood samples for ChE-activity determination during monitoring, and selection of adult animals as sentinels. Exposure to ChE-inhibiting compounds would be suspected when all blood ChE activity of all animals within the sentinel group are decreased greater than 20% from their own baseline value. Sentinel species selection is primarily a logistical and operational concern; however, sheep appear to be the species of choice because within-individual baseline ChE activity and among age and gender group ChE activity in sheep had the least variability, compared with data from other species. This protocol provides an effective and efficient means for detecting abnormal depressions in blood ChE activity in livestock and can serve as a valuable indicator of the extent of actual plume movement and/or deposition in the event of organophosphate nerve agent release.

  1. Detection of Sulfatase Enzyme Activity with a CatalyCEST MRI Contrast Agent.

    PubMed

    Sinharay, Sanhita; Fernández-Cuervo, Gabriela; Acfalle, Jasmine P; Pagel, Mark D

    2016-05-01

    A chemical exchange saturation transfer (CEST) MRI contrast agent has been developed that detects sulfatase enzyme activity. The agent produces a CEST signal at δ=5.0 ppm before enzyme activity, and a second CEST signal appears at δ=9.0 ppm after the enzyme cleaves a sulfate group from the agent. The comparison of the two signals improved detection of sulfatase activity. PMID:26956002

  2. pH-Sensitive Microparticles with Matrix-Dispersed Active Agent

    NASA Technical Reports Server (NTRS)

    Li, Wenyan (Inventor); Buhrow, Jerry W. (Inventor); Jolley, Scott T. (Inventor); Calle, Luz M. (Inventor)

    2014-01-01

    Methods to produce pH-sensitive microparticles that have an active agent dispersed in a polymer matrix have certain advantages over microcapsules with an active agent encapsulated in an interior compartment/core inside of a polymer wall. The current invention relates to pH-sensitive microparticles that have a corrosion-detecting or corrosion-inhibiting active agent or active agents dispersed within a polymer matrix of the microparticles. The pH-sensitive microparticles can be used in various coating compositions on metal objects for corrosion detecting and/or inhibiting.

  3. Novel antimicrobial peptides that exhibit activity against select agents and other drug resistant bacteria.

    PubMed

    Venugopal, Divakaramenon; Klapper, David; Srouji, Antoine H; Bhonsle, Jayendra B; Borschel, Richard; Mueller, Allen; Russell, Amanda L; Williams, Brittany C; Hicks, Rickey P

    2010-07-15

    One of the greatest challenges facing modern medicine is the evolution of drug resistant strains of bacteria. In addition to traditional methods of exposure to traditional bacterial organisms there is a growing concerned of the use of bacteria as bio-terrorism agents. To counter the evolution of drug resistant and potential bio-terrorism bacterial agents new antibiotic drugs must be developed. One potential source of new therapeutic agents that act via a novel mechanism of action are natural and synthetic antimicrobial peptides (AMPs). In our laboratories we have developed a series of AMPs incorporating the un-natural amino acids Tic-Oic to impart organism selectivity and potency while increasing metabolic stability. Herein the in vitro activity of these peptides, including ten new compounds, against eight potential bio-terrorism bacterial agents and three other bacterial strains is presented and discussed. These peptides exhibit a wide range of organism potency and selectivity. Calcein fluorescence leakage and circular dichroism studies were conducted to confirm that these peptides interact with zwitterionic and anionic liposomes. PMID:20558071

  4. Hormetic Effect of Berberine Attenuates the Anticancer Activity of Chemotherapeutic Agents.

    PubMed

    Bao, Jiaolin; Huang, Borong; Zou, Lidi; Chen, Shenghui; Zhang, Chao; Zhang, Yulin; Chen, Meiwan; Wan, Jian-Bo; Su, Huanxing; Wang, Yitao; He, Chengwei

    2015-01-01

    Hormesis is a phenomenon of biphasic dose response characterized by exhibiting stimulatory or beneficial effects at low doses and inhibitory or toxic effects at high doses. Increasing numbers of chemicals of various types have been shown to induce apparent hormetic effect on cancer cells. However, the underlying significance and mechanisms remain to be elucidated. Berberine, one of the major active components of Rhizoma coptidis, has been manifested with notable anticancer activities. This study aims to investigate the hormetic effect of berberine and its influence on the anticancer activities of chemotherapeutic agents. Our results demonstrated that berberine at low dose range (1.25 ~ 5 μM) promoted cell proliferation to 112% ~170% of the untreated control in various cancer cells, while berberine at high dose rage (10 ~ 80 μM) inhibited cell proliferation. Further, we observed that co-treatment with low dose berberine could significantly attenuate the anticancer activity of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX). The hormetic effect and thereby the attenuated anticancer activity of chemotherapeutic drugs by berberine may attributable to the activated protective stress response in cancer cells triggered by berberine, as evidenced by up-regulated MAPK/ERK1/2 and PI3K/AKT signaling pathways. These results provided important information to understand the potential side effects of hormesis, and suggested cautious application of natural compounds and relevant herbs in adjuvant treatment of cancer. PMID:26421434

  5. Synthesis, Antifungal Activities and Qualitative Structure Activity Relationship of Carabrone Hydrazone Derivatives as Potential Antifungal Agents

    PubMed Central

    Wang, Hao; Ren, Shuang-Xi; He, Ze-Yu; Wang, De-Long; Yan, Xiao-Nan; Feng, Jun-Tao; Zhang, Xing

    2014-01-01

    Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents. PMID:24619221

  6. [Neurotoxins with anticholinesterase activity and their possible use as warfare agents].

    PubMed

    Pita, René; Anadón, Arturo; Martínez-Larrañaga, María Rosa

    2003-10-18

    Anatoxin-a(s), onchidal and fasciculins are neurotoxins with anticholinesterase activity. An intoxication by these neurotoxins is characterized by cholinergic syndromes similar to organophosphate insecticide and nerve agent intoxications. Anticholinesterase neurotoxins, as well as other toxins, have some disadvantages if used as weapons of mass destruction. Drawbacks include difficulties to produce them in big quantities and their dissemination in form of aerosols. However, other properties such as high toxicity, improbable identification with common commercial portable detectors for chemical warfare agents and toxic industrial chemicals, as well as the lack of effectiveness of antidotal treatments with oximes may make them attractive in order to be used in military operations or terrorist attacks. For these reasons, it should be necessary to control these neurotoxins through international treaties which have real verification measures such as the Chemical Weapons Convention. PMID:14588195

  7. Biological activity assessment of a novel contraceptive antimicrobial agent.

    PubMed

    Garg, A; Anderson, R A; Zaneveld, L J D; Garg, S

    2005-01-01

    Microbicides are a new category of compounds being developed as a prophylactic approach for the prevention of transmission of sexually transmitted diseases (STDs), including the human immunodeficiency virus (HIV). These are primarily being developed as women-controlled methods, with the target of designing new compounds or formulations that can be used without the knowledge of a male partner. Microbicide screening can be initially based on their hyaluronidase-inhibiting (HI) activity, as this enzyme plays a major role in the sperm and microbe penetration into the substrate. Derivatives of hesperidin, a citrus flavonoid glycoside, have been reported in the literature for their HI effects. Hesperidin was thereby sulphonated under strictly controlled conditions and the active fraction isolated and characterized, based on its HI activity. This derivative was screened for antimicrobial and enzyme-inhibitory activities, specifically for the reproductive tract. Sulphonated hesperidin (SH) was found to completely inhibit the sperm enzymes hyaluronidase, giving an indication toward its contraceptive effects. It was also been found to inhibit various sexually transmitted pathogens, including Chlamydia trachomatis, Neisseria gonorrhoea, HIV, and Herpes Simplex virus type 2 (HSV-2). Its safety assessment was based on its noninterference in sperm motility and its penetration through the cervical mucus, and no effect on the growth of lactobacilli, the normal vaginal flora. It was also found to be nontoxic to the HIV substrate cells (MT2 cells). The study concludes that sulphonated hesperidin can be developed as a potential microbicide for a dual prophylaxis of contraception and transmission of STDs and AIDS. PMID:15867010

  8. The incorporation of activities to control dengue by community health agents

    PubMed Central

    Cazola, Luiza Helena de Oliveira; Tamaki, Edson Mamoru; Pontes, Elenir Rose Jardim Cury; de Andrade, Sonia Maria Oliveira

    2014-01-01

    OBJECTIVE To evaluate the performance of Community Health Agents when dengue control activities were added to their tasks. METHODS Performance was measured comparing the evolution of selected indicators from the Brazilian National Dengue Control Program and the Family Health Strategy for 2002 to 2008 in the municipality of Sao Gabriel do Oeste, MS, Central Western Brazil, with those of Rio Verde de Mato Grosso, neighboring municipality with demographic, socioeconomic and health services similarities. Data were collected from municipal databases of the Information System for Yellow Fever and Dengue and the Information System for Primary Healthcare of the Mato Grosso do Sul State Health Office. The variables selected for the family health strategy activities were: monthly home visits, pregnant women whose antenatal care began in the first trimester, children under one with up-to-date vaccinations and hypertensive patients. Those selected for the Brazilian National Dengue Control Program were: properties inspected with Aedes aegypti and properties not inspected. RESULTS The two municipalities maintained a similar trend in dengue control indicators in the period studied. With regard to the Family Health Strategy, in 2002 Sao Gabriel do Oeste was better off in three of the four indicators studied, however, this situation was reversed at the end of the period when the county was overtaken by Rio Verde de Mato Grosso in three of the four indicators analyzed, including, the monthly average community health worker visits per registered family, the main activity of a Family Health Strategy agent. CONCLUSIONS: Incorporating the National Dengue Control Program into the Family Health Strategy is viable and developed without prejudice to dengue control activities, however, the same did not occur with the activities of family health in Sao Gabriel do Oeste. The additional workload of the community health workers is the most likely hypothesis for the declining performance of these

  9. Activation of the chemosensing transient receptor potential channel A1 (TRPA1) by alkylating agents.

    PubMed

    Stenger, Bernhard; Zehfuss, Franziska; Mückter, Harald; Schmidt, Annette; Balszuweit, Frank; Schäfer, Eva; Büch, Thomas; Gudermann, Thomas; Thiermann, Horst; Steinritz, Dirk

    2015-09-01

    The transient receptor potential ankyrin 1 (TRPA1) cation channel is expressed in different tissues including skin, lung and neuronal tissue. Recent reports identified TRPA1 as a sensor for noxious substances, implicating a functional role in the molecular toxicology. TRPA1 is activated by various potentially harmful electrophilic substances. The chemical warfare agent sulfur mustard (SM) is a highly reactive alkylating agent that binds to numerous biological targets. Although SM is known for almost 200 years, detailed knowledge about the pathophysiology resulting from exposure is lacking. A specific therapy is not available. In this study, we investigated whether the alkylating agent 2-chloroethyl-ethylsulfide (CEES, a model substance for SM-promoted effects) and SM are able to activate TRPA1 channels. CEES induced a marked increase in the intracellular calcium concentration ([Ca(2+)]i) in TRPA1-expressing but not in TRPA1-negative cells. The TRP-channel blocker AP18 diminished the CEES-induced calcium influx. HEK293 cells permanently expressing TRPA1 were more sensitive toward cytotoxic effects of CEES compared with wild-type cells. At low CEES concentrations, CEES-induced cytotoxicity was prevented by AP18. Proof-of-concept experiments using SM resulted in a pronounced increase in [Ca(2+)]i in HEK293-A1-E cells. Human A549 lung epithelial cells, which express TRPA1 endogenously, reacted with a transient calcium influx in response to CEES exposure. The CEES-dependent calcium response was diminished by AP18. In summary, our results demonstrate that alkylating agents are able to activate TRPA1. Inhibition of TRPA1 counteracted cellular toxicity and could thus represent a feasible approach to mitigate SM-induced cell damage. PMID:25395009

  10. Discovering new agents active against methicillin-resistant Staphylococcus aureus with ligand-based approaches.

    PubMed

    Wang, Ling; Le, Xiu; Li, Long; Ju, Yingchen; Lin, Zhongxiang; Gu, Qiong; Xu, Jun

    2014-11-24

    To discover new agents active against methicillin-resistant Staphylococcus aureus (MRSA), in silico models derived from 5451 cell-based anti-MRSA assay data were developed using four machine learning methods, including naïve Bayesian, support vector machine (SVM), recursive partitioning (RP), and k-nearest neighbors (kNN). A total of 876 models have been constructed based on physicochemical descriptors and fingerprints. The overall predictive accuracies of the best models exceeded 80% for both training and test sets. The best model was employed for the virtual screening of anti-MRSA compounds, which were then validated by a cell-based assay using the broth microdilution method with three types of highly resistant MRSA strains (ST239, ST5, and 252). A total of 12 new anti-MRSA agents were confirmed, which had MIC values ranging from 4 to 64 mg/L. This work proves the capacity of combined multiple ligand-based approaches for the discovery of new agents active against MRSA with cell-based assays. We think this work may inspire other lead identification processes when cell-based assay data are available. PMID:25375651

  11. 21 CFR 700.13 - Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Use of mercury compounds in cosmetics including...) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.13 Use of mercury compounds in cosmetics..., mercury compounds have also been widely used as preservatives in cosmetics such as hand and body...

  12. 21 CFR 700.13 - Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Use of mercury compounds in cosmetics including...) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.13 Use of mercury compounds in cosmetics..., mercury compounds have also been widely used as preservatives in cosmetics such as hand and body...

  13. 21 CFR 700.13 - Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Use of mercury compounds in cosmetics including use... GENERAL Requirements for Specific Cosmetic Products § 700.13 Use of mercury compounds in cosmetics..., mercury compounds have also been widely used as preservatives in cosmetics such as hand and body...

  14. 21 CFR 700.13 - Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 7 2014-04-01 2014-04-01 false Use of mercury compounds in cosmetics including...) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.13 Use of mercury compounds in cosmetics..., mercury compounds have also been widely used as preservatives in cosmetics such as hand and body...

  15. 21 CFR 700.13 - Use of mercury compounds in cosmetics including use as skinbleaching agents in cosmetic...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 7 2012-04-01 2012-04-01 false Use of mercury compounds in cosmetics including...) COSMETICS GENERAL Requirements for Specific Cosmetic Products § 700.13 Use of mercury compounds in cosmetics..., mercury compounds have also been widely used as preservatives in cosmetics such as hand and body...

  16. The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines

    NASA Astrophysics Data System (ADS)

    Beaufils, Damien; Jepaul, Sandra; Liu, Ziwei; Boiteau, Laurent; Pascal, Robert

    2016-03-01

    The activation of dipeptides was studied in the perspective of the abiotic formation of oligopeptides of significant length as a requirement for secondary structure formation. The formation of piperazin-2,5-diones (DKP), previously considered as a dead end when activating free dipeptides, was shown in this work to be efficiently suppressed when using strong activating agents (e.g., carbodiimides). This behaviour was explained by the fast formation of a 5(4 H)-oxazolone intermediate at a rate that exceeds the time scale of the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer required for DKP formation. No DKP was observed when using strong activating agents whereas phosphate mixed anhydrides or moderately activated esters were observed to predominantly yield DKP. The DKP side-reaction no longer constitutes a drawback for the C-terminus elongation of peptides. These results are considered as additional evidence that pathways involving strong activation are required to drive the emergence of living entities rather than close to equilibrium processes.

  17. Disposal of chemical agents and munitions stored at Umatilla Depot Activity, Hermiston, Oregon

    SciTech Connect

    Zimmerman, G.P.; Hillsman, E.L.; Johnson, R.O.; Miller, R.L.; Patton, T.G.; Schoepfle, G.M.; Tolbert, V.R.; Feldman, D.L.; Hunsaker, D.B. Jr.; Kroodsma, R.L.; Morrissey, J.; Rickert, L.W.; Staub, W.P.; West, D.C.

    1993-02-01

    The Umatilla Depot Activity (UMDA) near Hermiston, Oregon, is one of eight US Army installations in the continental United States where lethal unitary chemical agents and munitions are stored, and where destruction of agents and munitions is proposed under the Chemical Stockpile Disposal Program (CSDP). The chemical agent inventory at UMDA consists of 11.6%, by weight, of the total US stockpile. The destruction of the stockpile is necessary to eliminate the risk to the public from continued storage and to dispose of obsolete and leaking munitions. In 1988 the US Army issued a Final Programmatic Environmental Impact Statement (FPEIS) for the CSDP that identified on-site disposal of agents and munitions as the environmentally preferred alternative (i.e., the alternative with the least potential to cause significant adverse impacts), using a method based on five measures of risk for potential human health and ecosystem/environmental effects; the effectiveness and adequacy of emergency preparedness capabilities also played a key role in the FPEIS selection methodology. In some instances, the FPEIS included generic data and assumptions that were developed to allow a consistent comparison of potential impacts among programmatic alternatives and did not include detailed conditions at each of the eight installations. The purpose of this Phase 1 report is to examine the proposed implementation of on-site disposal at UMDA in light of more recent and more detailed data than those included in the FPEIS. Specifically, this Phase 1 report is intended to either confirm or reject the validity of on-site disposal for the UMDA stockpile. Using the same computation methods as in the FPEIS, new population data were used to compute potential fatalities from hypothetical disposal accidents. Results indicate that onsite disposal is clearly preferable to either continued storage at UMDA or transportation of the UMDA stockpile to another depot for disposal.

  18. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... promotion activities, including paid advertising. (a) In order for a handler to receive credit for his/her own promotional activities from his/her pro rata portion of advertising assessment payments, pursuant... professional practices and rates for the type of activity conducted. In the case of claims for...

  19. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... promotion activities, including paid advertising. (a) In order for a handler to receive credit for his/her own promotional activities from his/her pro rata portion of advertising assessment payments, pursuant... professional practices and rates for the type of activity conducted. In the case of claims for...

  20. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... promotion activities, including paid advertising. (a) In order for a handler to receive credit for his/her own promotional activities from his/her pro rata portion of advertising assessment payments, pursuant... professional practices and rates for the type of activity conducted. In the case of claims for...

  1. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... promotion activities, including paid advertising. (a) In order for a handler to receive credit for his/her own promotional activities from his/her pro rata portion of advertising assessment payments, pursuant... professional practices and rates for the type of activity conducted. In the case of claims for...

  2. HURON (HUman and Robotic Optimization Network) Multi-Agent Temporal Activity Planner/Scheduler

    NASA Technical Reports Server (NTRS)

    Hua, Hook; Mrozinski, Joseph J.; Elfes, Alberto; Adumitroaie, Virgil; Shelton, Kacie E.; Smith, Jeffrey H.; Lincoln, William P.; Weisbin, Charles R.

    2012-01-01

    HURON solves the problem of how to optimize a plan and schedule for assigning multiple agents to a temporal sequence of actions (e.g., science tasks). Developed as a generic planning and scheduling tool, HURON has been used to optimize space mission surface operations. The tool has also been used to analyze lunar architectures for a variety of surface operational scenarios in order to maximize return on investment and productivity. These scenarios include numerous science activities performed by a diverse set of agents: humans, teleoperated rovers, and autonomous rovers. Once given a set of agents, activities, resources, resource constraints, temporal constraints, and de pendencies, HURON computes an optimal schedule that meets a specified goal (e.g., maximum productivity or minimum time), subject to the constraints. HURON performs planning and scheduling optimization as a graph search in state-space with forward progression. Each node in the graph contains a state instance. Starting with the initial node, a graph is automatically constructed with new successive nodes of each new state to explore. The optimization uses a set of pre-conditions and post-conditions to create the children states. The Python language was adopted to not only enable more agile development, but to also allow the domain experts to easily define their optimization models. A graphical user interface was also developed to facilitate real-time search information feedback and interaction by the operator in the search optimization process. The HURON package has many potential uses in the fields of Operations Research and Management Science where this technology applies to many commercial domains requiring optimization to reduce costs. For example, optimizing a fleet of transportation truck routes, aircraft flight scheduling, and other route-planning scenarios involving multiple agent task optimization would all benefit by using HURON.

  3. Epidemiological and clinical features of cutaneous leishmaniases in Jenin District, Palestine, including characterisation of the causative agents in clinical samples.

    PubMed

    Azmi, Kifaya; Schönian, Gabriele; Nasereddin, Abedelmajeed; Schnur, Lionel F; Sawalha, Samir; Hamarsheh, Omar; Ereqat, Suheir; Amro, Ahmad; Qaddomi, Sharif E; Abdeen, Ziad

    2012-09-01

    During 2002-2009, 466 cases of cutaneous leishmaniasis (CL) were reported from Jenin District, Palestine, affecting both genders. The average annual incidence was 23 cases per 100000 inhabitants, increasing with age in children. Most cases presented a single lesion, generally on the face. Diagnosis and species identification was done by applying internal transcribed spacer 1 (ITS1) RFLP analysis to 47 isolates, of which 44 (93.6%) were Leishmania tropica and 3 (6.4%) were L. major. RFLP analysis was also performed on 256 skin tissue scrapings spotted onto filter papers, showing that 138 (53.9%) were positive, of which 50.7% were infected with L. tropica, 17.4% with L. major and 2.9% with L. donovani s.l., and 29.0% could not be identified. This is the first report from Palestine on human CL caused by L. infantum. Nine of the strains of L. tropica were subjected to multilocus enzyme electrophoresis, six of which belonged to the zymodeme MON-137 and three to a new zymodeme (MON-307). This separation was corroborated by excreted factor serotyping. This observation modifies the classical epidemiological view of CL in Palestine. Jenin District is an active focus of CL caused by L. tropica, where Phlebotomus sergenti, the putative vector, is abundant. These data suggest that CL is a zoonotic infection, but an animal reservoir has not been found. PMID:22832019

  4. Methods for improved selectivity in photo-activation and detection of molecular diagnostic agents

    DOEpatents

    Wachter, Eric A.; Fisher, Walter G.; Dees, H. Craig

    2008-03-18

    A method for the imaging of a particular volume of plant or animal tissue, wherein the plant or animal tissue contains at least one photo-active molecular agent. The method comprises the steps of treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of the photo-active molecular agent contained in the particular volume of the plant or animal tissue, photo-activating at least one of the at least one photo-active molecular agent in the particular volume of the plant or animal tissue, thereby producing at least one photo-activated molecular agent, wherein the at least one photo-activated molecular agent emits energy, detecting the energy emitted by the at least one photo-activated molecular agent, and producing a detected energy signal which is characteristic of the particular volume of plant or animal tissue. The present invention also provides a method for the imaging of a particular volume of material, wherein the material contains at least one photo-active molecular agent.

  5. [Preparation and optimum process of walnut peel activated carbon by zinc chloride as activating agent].

    PubMed

    Liu, Xiao-hong; Wang, Xing-wei; Zhao, Bo; Lü, Jun-fang; Kang, Ni-na; Zhang, Yao-jun

    2014-12-01

    Walnut peel as raw material, zinc chloride was used as activating agent for preparation walnut peel activated carbon in the muffle furnace in this experiment, using orthogonal design. Yield, the specific surface area and iodine number of walnut peel activated carbon were determined at all designed experimental conditions and the optimum technological condition of preparation was obtained. By analysis of aperture, infrared spectra and the content of acidic group in surface with Boehm, walnut peel activated carbon of prepared at the optimum condition was characterized. The results showed the optimum technological parameters of preparation: activation temperature (600 °C), activation time (1 h), the concentration of zinc chloride (50%), the particle size (60 mesh). The specific surface area of walnut peel activated carbon obtained at optimum condition was mounting to 1258.05 m2 · g(-1), the ratio of medium porous 32.18%. Therefore, walnut peel can be used in the preparation of the high-quality activated carbon of large surface area. Agricultural wastes, as walnut peel, not only were implemented recycle, but also didn't make any pollution. Meanwhile, a cheap adsorbent was provided and it was of great significance to open a new source of activated carbon. PMID:25881437

  6. Ceftaroline versus isolates from animal bite wounds: comparative in vitro activities against 243 isolates, including 156 Pasteurella species isolates.

    PubMed

    Goldstein, Ellie J C; Citron, Diane M; Merriam, C Vreni; Tyrrell, Kerin L

    2012-12-01

    More than 5 million Americans are bitten by animals, usually dogs, annually. Bite patients comprise ∼1% of all patients who visit emergency departments (300,000/year), and approximately 10,000 require hospitalization and intravenous antibiotics. Ceftaroline is the bioactive component of the prodrug ceftaroline fosamil, which is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs), including those containing methicillin-resistant Staphylococcus aureus (MRSA). There are no in vitro data about the activity of ceftaroline against Pasteurella multocida subsp. multocida and Pasteurella multocida subsp. septica, other Pasteurella spp., or other bite wound isolates. We therefore studied the in vitro activity of ceftaroline against 243 animal bite isolates. MICs were determined using the broth microdilution method according to CLSI guidelines. Comparator drugs included cefazolin, ceftriaxone, ertapenem, ampicillin-sulbactam, azithromycin, doxycycline, and sulfamethoxazole-trimethoprim (SMX-TMP). Ceftaroline was the most active agent against all 5 Pasteurella species, including P. multocida subsp. multocida and P. multocida subsp. septica, with a maximum MIC of ≤0.008 μg/ml; more active than ceftriaxone and ertapenem (MIC(90)s, ≤0.015 μg/ml); and more active than cefazolin (MIC(90), 0.5 μg/ml) doxycycline (MIC(90), 0.125 μg/ml), azithromycin (MIC(90), 0.5 μg/ml), ampicillin-sulbactam (MIC(90), 0.125 μg/ml), and SMX-TMP (MIC(90), 0.125 μg/ml). Ceftaroline was also very active against all S. aureus isolates (MIC(90), 0.125 μg/ml) and other Staphylococcus and Streptococcus species, with a maximum MIC of 0.125 μg/ml against all bite isolates tested. Ceftaroline has potential clinical utility against infections involving P. multocida, other Pasteurella species, and aerobic Gram-positive isolates, including S. aureus. PMID:23027193

  7. Ceftaroline versus Isolates from Animal Bite Wounds: Comparative In Vitro Activities against 243 Isolates, Including 156 Pasteurella Species Isolates

    PubMed Central

    Citron, Diane M.; Merriam, C. Vreni; Tyrrell, Kerin L.

    2012-01-01

    More than 5 million Americans are bitten by animals, usually dogs, annually. Bite patients comprise ∼1% of all patients who visit emergency departments (300,000/year), and approximately 10,000 require hospitalization and intravenous antibiotics. Ceftaroline is the bioactive component of the prodrug ceftaroline fosamil, which is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs), including those containing methicillin-resistant Staphylococcus aureus (MRSA). There are no in vitro data about the activity of ceftaroline against Pasteurella multocida subsp. multocida and Pasteurella multocida subsp. septica, other Pasteurella spp., or other bite wound isolates. We therefore studied the in vitro activity of ceftaroline against 243 animal bite isolates. MICs were determined using the broth microdilution method according to CLSI guidelines. Comparator drugs included cefazolin, ceftriaxone, ertapenem, ampicillin-sulbactam, azithromycin, doxycycline, and sulfamethoxazole-trimethoprim (SMX-TMP). Ceftaroline was the most active agent against all 5 Pasteurella species, including P. multocida subsp. multocida and P. multocida subsp. septica, with a maximum MIC of ≤0.008 μg/ml; more active than ceftriaxone and ertapenem (MIC90s, ≤0.015 μg/ml); and more active than cefazolin (MIC90, 0.5 μg/ml) doxycycline (MIC90, 0.125 μg/ml), azithromycin (MIC90, 0.5 μg/ml), ampicillin-sulbactam (MIC90, 0.125 μg/ml), and SMX-TMP (MIC90, 0.125 μg/ml). Ceftaroline was also very active against all S. aureus isolates (MIC90, 0.125 μg/ml) and other Staphylococcus and Streptococcus species, with a maximum MIC of 0.125 μg/ml against all bite isolates tested. Ceftaroline has potential clinical utility against infections involving P. multocida, other Pasteurella species, and aerobic Gram-positive isolates, including S. aureus. PMID:23027193

  8. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

    2000-01-01

    An apparatus for the treatment of a particular volume of plant or animal tissue by treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue.

  9. Quaternized Chitosan as an Antimicrobial Agent: Antimicrobial Activity, Mechanism of Action and Biomedical Applications in Orthopedics

    PubMed Central

    Tan, Honglue; Ma, Rui; Lin, Chucheng; Liu, Ziwei; Tang, Tingting

    2013-01-01

    Chitosan (CS) is a linear polysaccharide with good biodegradability, biocompatibility and antimicrobial activity, which makes it potentially useful for biomedical applications, including an antimicrobial agent either alone or blended with other polymers. However, the poor solubility of CS in most solvents at neutral or high pH substantially limits its use. Quaternary ammonium CS, which was prepared by introducing a quaternary ammonium group on a dissociative hydroxyl group or amino group of the CS, exhibited improved water solubility and stronger antibacterial activity relative to CS over an entire range of pH values; thus, this quaternary modification increases the potential biomedical applications of CS in the field of anti-infection. This review discusses the current findings on the antimicrobial properties of quaternized CS synthesized using different methods and the mechanisms of its antimicrobial actions. The potential antimicrobial applications in the orthopedic field and perspectives regarding future studies in this field are also considered. PMID:23325051

  10. Improvements to the FATOLA computer program including added actively controlled landing gear subroutines

    NASA Technical Reports Server (NTRS)

    Mall, G. H.

    1983-01-01

    Modifications to a multi-degree-of-freedom flexible aircraft take-off and landing analysis (FATOLA) computer program, including a provision for actively controlled landing gears to expand the programs simulation capabilities, are presented. Supplemental instructions for preparation of data and for use of the modified program are included.

  11. P2X7 receptor antagonist activity of the anti-allergic agent oxatomide.

    PubMed

    Yoshida, Kazuki; Ito, Masaaki; Matsuoka, Isao

    2015-11-15

    Activation of the P2X7 receptor by extracellular ATP is associated with various immune responses including allergic inflammation. Anti-allergic agents, such as H1-antihistamines, are known to inhibit the effects of different chemical mediators such as acetylcholine and platelet-activating factor. Therefore, we hypothesized that some anti-allergic agents might affect P2X7 receptor function. Using N18TG2 and J774 cells, which express functional P2X7 receptors, the effects of several anti-allergic agents on P2X7 receptor function were investigated by monitoring the ATP-induced increase in intracellular Ca(2+) concentrations ([Ca(2+)]i). Among the various agents tested, oxatomide significantly inhibited P2X7 receptor-mediated [Ca(2+)]i elevation in a concentration-dependent manner without affecting the P2Y2 receptor-mediated response in both N18TG2 and J774 cells. Consistently, oxatomide inhibited P2X7 receptor-mediated membrane current and downstream responses such as mitogen-activated protein kinase activation, inflammation-related gene induction, and cell death. In addition, oxatomide inhibited P2X7 receptor-mediated degranulation in mouse bone marrow-derived mast cells. Whole cell patch clamp analyses in HEK293 cells expressing human, mouse, and rat P2X7 receptors revealed that the inhibitory effect of oxatomide on ATP-induced current was most prominent for the human P2X7 receptor and almost non-existent for the rat P2X7 receptor. The potent inhibitory effects of oxatomide on human P2X7 receptor-mediated function were confirmed in RPMI8226 human B cell-like myeloma cells, which endogenously express the P2X7 receptor. Our results demonstrated that the antihistamine oxatomide also acts as a P2X7 receptor antagonist. Future studies should thus evaluate whether P2X7 receptor antagonism contributes to the anti-allergic effects of oxatomide. PMID:26463039

  12. Structure-activity studies on organoselenium alkylating agents.

    PubMed

    Kang, S I; Spears, C P

    1990-01-01

    A variety of organoselenium alkylating agents were synthesized, using 2-hydroxyethyl and 3-hydroxypropyl selenocyanate intermediates, and studied to determine their chemical reactivities with 4-(4-nitrobenzyl)pyridine (NBP) and cytotoxicities against CCRF-CEM, L1210/0, and L1210/L-PAM cells. The comparison between the 2-chloroethyl sulfides and selenides 1-4 revealed the markedly enhanced nucleophilicity of selenium (Se) over sulfur (S) by two or more orders of magnitude. This finding indicates that a major consideration in the design of antitumor alkylating organoselenides is the reactivity of selenium. A Taft plot of the experimental first-order rate constant, knbp, and sigma* in a series of 2-chloroethylseleno compounds gave a slope of -1.73 (rho*), with the exception of 2-chloroethyl 2-nitrophenyl selenide (10). The anomalous behavior of 10 is explained in terms of the ortho-nitro stabilization effect directly interacting with the selenium atom of ethyleneselenonium ion to form a 5-membered cyclic intermediate. In the same series, a 5000-fold difference in alkylating reactivity offered only a sixfold variation in cytotoxicity against CCRF-CEM cells. Increasing the alkylating chain length from ethlene to propylene units markedly reduced alkylating reactivities. In the CH3Se(CH2)n Cl series, 16 (n = 3) was 1.5 X 10(5) times slower than 2 (n = 2) in NBP alkylation, revealing that 3-chloro-n-propyl selenides are not chemically reactive enough to be biological alkylating agents despite the presence of the highly nucleophilic selenium atom. Replacement of chloride with mesylate in 3-substituted propyl selenides, such as 17 and 20, restored desirable reactivities and cytotoxicities. PMID:2313578

  13. Ciprofloxacin-Induced Antibacterial Activity Is Atteneuated by Pretreatment with Antioxidant Agents

    PubMed Central

    Masadeh, Majed M.; Alzoubi, Karem H.; Al-azzam, Sayer I.; Khabour, Omar F.; Al-buhairan, Ahlam M.

    2016-01-01

    Ciprofloxacin works through interfering with replication and transcription of bacterial DNA, which leads to increased oxidative stress, and death of bacterial cells. Drugs with strong antioxidant such as tempol, melatonin and pentoxifylline might interfere with the antibacterial activity of ciprofloxacin. In the current study, the effect of these drugs on the cytotoxicity of ciprofloxacin was investigated against several reference bacteria. Standard bacterial strains included Escherichia coli ATCC 35218, Staphylococcus aureus ATCC29213, Pseudomonas aeruginosa ATCC 9027, Staphylococcus epidermidis ATCC 12228, Acinetobacter baumannii ATCC 17978, Proteus mirabilis ATCC 12459, Klebsiella pneumoniae ATCC 13883, methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300), and Streptococcus pneumoniae (ATCC 25923). The antibacterial activity of ciprofloxacin with or without treatment of bacterial cells by tempol, melatonin or pentoxifylline was assessed using the disc diffusion method and by measuring the minimum inhibitory concentration (MIC) and zones of inhibition of bacterial growth. All of the tested bacterial strains were sensitive to ciprofloxacin. When treated with tempol, melatonin or pentoxifylline, all bacterial strains showed significantly smaller zones of inhibition and larger MIC values compared ciprofloxacin alone. In correlation, reactive oxygen species (ROS) generation induced by ciprofloxacin antibacterial action was diminished by treatment of bacterial cells with tempol, melatonin or pentoxifylline. In conclusion, results indicate the possible antagonistic properties for agents with antioxidant properties such as tempol, melatonin and pentoxifylline when they are used concurrently with flouroquinolones. This could be related to the ability of these agents to inhibit oxidative stress in bacterial cells. PMID:27005666

  14. Ciprofloxacin-Induced Antibacterial Activity Is Atteneuated by Pretreatment with Antioxidant Agents.

    PubMed

    Masadeh, Majed M; Alzoubi, Karem H; Al-Azzam, Sayer I; Khabour, Omar F; Al-Buhairan, Ahlam M

    2016-01-01

    Ciprofloxacin works through interfering with replication and transcription of bacterial DNA, which leads to increased oxidative stress, and death of bacterial cells. Drugs with strong antioxidant such as tempol, melatonin and pentoxifylline might interfere with the antibacterial activity of ciprofloxacin. In the current study, the effect of these drugs on the cytotoxicity of ciprofloxacin was investigated against several reference bacteria. Standard bacterial strains included Escherichia coli ATCC 35218, Staphylococcus aureus ATCC29213, Pseudomonas aeruginosa ATCC 9027, Staphylococcus epidermidis ATCC 12228, Acinetobacter baumannii ATCC 17978, Proteus mirabilis ATCC 12459, Klebsiella pneumoniae ATCC 13883, methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300), and Streptococcus pneumoniae (ATCC 25923). The antibacterial activity of ciprofloxacin with or without treatment of bacterial cells by tempol, melatonin or pentoxifylline was assessed using the disc diffusion method and by measuring the minimum inhibitory concentration (MIC) and zones of inhibition of bacterial growth. All of the tested bacterial strains were sensitive to ciprofloxacin. When treated with tempol, melatonin or pentoxifylline, all bacterial strains showed significantly smaller zones of inhibition and larger MIC values compared ciprofloxacin alone. In correlation, reactive oxygen species (ROS) generation induced by ciprofloxacin antibacterial action was diminished by treatment of bacterial cells with tempol, melatonin or pentoxifylline. In conclusion, results indicate the possible antagonistic properties for agents with antioxidant properties such as tempol, melatonin and pentoxifylline when they are used concurrently with flouroquinolones. This could be related to the ability of these agents to inhibit oxidative stress in bacterial cells. PMID:27005666

  15. Antimicrobial characterisation of CEM-101 activity against respiratory tract pathogens, including multidrug-resistant pneumococcal serogroup 19A isolates.

    PubMed

    Farrell, David J; Sader, Helio S; Castanheira, Mariana; Biedenbach, Douglas J; Rhomberg, Paul R; Jones, Ronald N

    2010-06-01

    CEM-101 is a novel fluorinated macrolide-ketolide with potent activity against bacterial pathogens that are susceptible or resistant to other macrolide-lincosamide-streptogramin B (MLS(B))-ketolide agents. CEM-101 is being developed for oral and parenteral use in moderate to moderately severe community-acquired bacterial pneumonia. The objective of this study was to assess the activity of CEM-101 and comparators against contemporary respiratory tract infection (RTI) isolates. A worldwide sample of organisms was used, including Streptococcus pneumoniae [n=168; 59.3% erythromycin-resistant and 18 multidrug-resistant (MDR) serogroup 19A strains], Moraxella catarrhalis (n=21; 11 beta-lactamase positive), Haemophilus influenzae (n=100; 48 beta-lactamase positive), Haemophilus parainfluenzae and Haemophilus haemolyticus (n=12), and Legionella pneumophila (n=30). Testing and interpretation were performed using reference Clinical and Laboratory Standards Institute methods. CEM-101 was very potent against S. pneumoniae [minimum inhibitory concentration for 90% of the organisms (MIC90)=0.25 mg/L; highest MIC at 0.5 mg/L] and was 2- and > or =32-fold more active than telithromycin and clindamycin, respectively. CEM-101 also demonstrated potent activity against S. pneumoniae MDR-19A strains (MIC90=0.5 mg/L). CEM-101 was the most potent antimicrobial agent tested against L. pneumophila, with all MIC values at < or = 0.015 mg/L (telithromycin MIC90=0.03 mg/L). CEM-101 was as potent as azithromycin against Haemophilus spp. RTI pathogens (MIC90=2 mg/L), with no variations for beta-lactamase production. CEM-101 MIC values against M. catarrhalis were all at < or =0.5mg/L. Interestingly, CEM-101 potency was ca. 6 log(2) dilutions greater than telithromycin MIC results among 44 beta-haemolytic streptococci having telithromycin MICs > or = 2 mg/L. CEM-101 exhibited the greatest potency and widest spectrum of activity against RTI pathogens among the tested MLS(B)-ketolide agents

  16. Effects of surface active agents on DNAPL migration and distribution in saturated porous media.

    PubMed

    Cheng, Zhou; Gao, Bin; Xu, Hongxia; Sun, Yuanyuan; Shi, Xiaoqing; Wu, Jichun

    2016-11-15

    Dissolved surface active agents such as surfactant and natural organic matter can affect the distribution and fate of dense nonaqueous liquids (DNAPLs) in soil and groundwater systems. This work investigated how two common groundwater surface active agents, humic acid (HA) and Tween 80, affected tetrachloroethylene (PCE) migration and source zone architecture in saturated porous media under environmentally relevant conditions. Batch experiments were first conducted to measure the contact angles and interfacial tensions (IFT) between PCE and quartz surface in water containing different amount of surface active agents. Results showed that the contact angle increased and IFT decreased with concentration of surface active agent increasing, and Tween 80 was much more effective than HA. Five 2-D flow cell experiments were then conducted. Correspondingly, Tween 80 showed strong effects on the migration and distribution of PCE in the porous media due to its ability to change the medium wettability from water-wet into intermediate/NAPL-wet. The downward migration velocities of the PCE in three Tween 80 cells were slower than those in the other two cells. In addition, the final saturation of the PCE in the cells containing surface active agents was higher than that in the water-only cell. Results from this work indicate that the presence of surface active agents in groundwater may strongly affect the fate and distribution of DNAPL through altering porous medium wettability. PMID:27450259

  17. IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity.

    PubMed

    Soussi, Mohamed Ali; Provot, Olivier; Bernadat, Guillaume; Bignon, Jérome; Desravines, Déborah; Dubois, Joëlle; Brion, Jean-Daniel; Messaoudi, Samir; Alami, Mouad

    2015-08-01

    A series of novel isocombretaquinazolines (isoCoQ) 4 were quickly prepared by coupling N-toluenesulfonylhydrazones with 4-chloroquinazolines under palladium catalysis. These compounds, which can be regarded as isocombretastatin A-4 (isoCA-4) analogues that lack the 3,4,5-trimethoxyphenyl ring, displayed nanomolar-level cytotoxicity against various human cancer cell lines and were observed to effectively inhibit tubulin polymerization. The isoCoQ compounds 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)phenol (4 b), 4-[1-(3-fluoro-4-methoxyphenyl)vinyl]-2-methylquinazoline (4 c), and 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)aniline (4 d), which respectively bear the greatest resemblance to isoCA-4, isoFCA-4, and isoNH2 CA-4, are able to arrest HCT116 cancer cells in the G2 /M cell-cycle phase at very low concentrations. Preliminary in vitro antivascular assay results show that 4 d is able to disrupt a network of capillary-like structures formed by human umbilical vein endothelial cells on Matrigel. All these results clearly demonstrate that replacement of the 3,4,5-trimethoxyphenyl ring of isoCA-4 with a quinazoline nucleus is a feasible approach toward new and highly promising derivatives with the potential for further development as antitubulin agents. PMID:26076053

  18. Activity of tigecycline tested against a global collection of Enterobacteriaceae, including tetracycline-resistant isolates.

    PubMed

    Fritsche, Thomas R; Strabala, Patty A; Sader, Helio S; Dowzicky, Michael J; Jones, Ronald N

    2005-07-01

    Steadily increasing resistance among the Enterobacteriaceae to beta-lactams, fluoroquinolones, aminoglycosides, tetracyclines, and trimethoprim/sulfamethoxazole has compromised the utility of these commonly used antimicrobial classes for many community- or hospital-acquired infections. The development of tigecycline, the sentinel representative of a novel class of broad-spectrum agents (the glycylcyclines), represents an important milestone in addressing this critical need. Resistance to tigecycline might be expected to occur via the same mechanisms that produce tetracycline resistance; however, tigecycline remains stable and largely unaffected by the commonly occurring efflux and ribosomal protection resistance mechanisms. In this study, an international collection of Enterobacteriaceae (11327 isolates; 32.8% tetracycline-resistant) from global surveillance studies (2000-2004) were evaluated against tigecycline and other comparator antimicrobials. Although the most active agents were the carbapenems and aminoglycosides (97.5-99.7% susceptible), tigecycline displayed high potency (MIC50 and MIC90, 0.25 and 1 microg/mL) with 95.7% of all strains being inhibited at < or =2 microg/mL. Despite higher MIC values observed with Serratia spp. and Proteae, between 90.5% and 97.5% of isolates were inhibited by < or =4 microg/mL of tigecycline. Tetracycline-resistant populations demonstrated only modest decreases in potency to tigecycline, which appeared to be species-dependent (up to 2-fold only for Escherichia coli, Salmonella spp., Shigella spp., and Panteoa agglomerans; and up to 4-fold for Klebsiella spp., Enterobacter spp., and Citrobacter spp.). Among E. coli (263 isolates) and Klebsiella spp. (356) that meet recognized screening definitions for extended-spectrum beta-lactamase production, 100.0% and 94.4% were inhibited by tigecycline at 2 microg/mL, respectively. These findings confirm that tigecycline exhibits potency, breadth of spectrum, and stability to the

  19. Preparation of activated carbons from coffee husks utilizing FeCl3 and ZnCl2 as activating agents.

    PubMed

    Oliveira, Luiz C A; Pereira, Elaine; Guimaraes, Iara R; Vallone, Andrea; Pereira, Márcio; Mesquita, João P; Sapag, Karim

    2009-06-15

    Ferric chloride was used as a new activating agent, to obtain activated carbons (AC) from agro industrial waste (coffee husks). This material was compared with two samples from the same raw material: one of them activated by using the classical activating agent, zinc chloride, and the other, activated with a mixture of the two mentioned activating agents in the same mass proportion. The carbonaceous materials obtained after the activation process showed high specific surface areas (BET), with values higher than 900 m(2)g(-1). It is interesting to observe that the activation with FeCl(3) produces smaller pores compared to the activation with ZnCl(2). An important fact to emphasize in the use of FeCl(3) as activating agent is the activation temperature at 280 degrees C, which is clearly below to the temperature commonly employed for chemical or physical activation, as described in the bibliography. All the studied materials showed different behaviors in the adsorption of methylene blue dye and phenol from aqueous solutions. PMID:18996644

  20. Nerve agent hydrolysis activity designed into a human drug metabolism enzyme.

    PubMed

    Hemmert, Andrew C; Otto, Tamara C; Chica, Roberto A; Wierdl, Monika; Edwards, Jonathan S; Lewis, Steven M; Lewis, Steven L; Edwards, Carol C; Tsurkan, Lyudmila; Cadieux, C Linn; Kasten, Shane A; Cashman, John R; Mayo, Stephen L; Potter, Philip M; Cerasoli, Douglas M; Redinbo, Matthew R

    2011-01-01

    Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning. PMID:21445272

  1. Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme

    PubMed Central

    Hemmert, Andrew C.; Otto, Tamara C.; Chica, Roberto A.; Wierdl, Monika; Edwards, Jonathan S.; Lewis, Steven L.; Edwards, Carol C.; Tsurkan, Lyudmila; Cadieux, C. Linn; Kasten, Shane A.; Cashman, John R.; Mayo, Stephen L.; Potter, Philip M.; Cerasoli, Douglas M.; Redinbo, Matthew R.

    2011-01-01

    Organophosphorus (OP) nerve agents are potent suicide inhibitors of the essential neurotransmitter-regulating enzyme acetylcholinesterase. Due to their acute toxicity, there is significant interest in developing effective countermeasures to OP poisoning. Here we impart nerve agent hydrolysis activity into the human drug metabolism enzyme carboxylesterase 1. Using crystal structures of the target enzyme in complex with nerve agent as a guide, a pair of histidine and glutamic acid residues were designed proximal to the enzyme's native catalytic triad. The resultant variant protein demonstrated significantly increased rates of reactivation following exposure to sarin, soman, and cyclosarin. Importantly, the addition of these residues did not alter the high affinity binding of nerve agents to this protein. Thus, using two amino acid substitutions, a novel enzyme was created that efficiently converted a group of hemisubstrates, compounds that can start but not complete a reaction cycle, into bona fide substrates. Such approaches may lead to novel countermeasures for nerve agent poisoning. PMID:21445272

  2. Direct gas-phase detection of nerve and blister warfare agents utilizing active capillary plasma ionization mass spectrometry.

    PubMed

    Wolf, J-C; Schaer, M; P Siegenthaler, P; Zenobi, R

    2015-01-01

    Ultrasensitive direct gas-phase detection of chemical warfare agents (CWAs) is demonstrated utilizing active capillary plasma ionization and triple quadrupole mass spectrometry (MS) instrumentation. Four G- agents, two V-agents and various blistering agents [including sulfur mustard (HD)] were detected directly in the gas phase with limits of detection in the low parts per trillion (ng m(-3)) range. The direct detection of HD was shown for dry carrier gas conditions, but signals vanished when humidity was present, indicating a possible direct detection of HD after sufficient gas phase pretreatment. The method provided sufficient sensitivity to monitor directly the investigated volatile CWAs way below their corresponding minimal effect dose, and in most cases even below the eight hours worker exposure concentration. In general, the ionization is very soft, with little to no in-source fragmentation. Especially for the G-agents, some dimer formation occurred at higher concentrations. This adds complexity, but also further selectivity, to the corresponding mass spectra. Our results show that the active capillary plasma ionization is a robust, sensitive, "plug and play" ambient ionization source suited (but not exclusively) to the very sensitive detection of CWAs. It has the potential to be used with portable MS instrumentation. PMID:26307710

  3. Structure activity relationships of 4-hydroxy-2-pyridones: A novel class of antituberculosis agents.

    PubMed

    Ng, Pearly Shuyi; Manjunatha, Ujjini H; Rao, Srinivasa P S; Camacho, Luis R; Ma, Ngai Ling; Herve, Maxime; Noble, Christian G; Goh, Anne; Peukert, Stefan; Diagana, Thierry T; Smith, Paul W; Kondreddi, Ravinder Reddy

    2015-12-01

    Pyridone 1 was identified from a high-throughput cell-based phenotypic screen against Mycobacterium tuberculosis (Mtb) including multi-drug resistant tuberculosis (MDR-TB) as a novel anti-TB agent and subsequently optimized series using cell-based Mtb assay. Preliminary structure activity relationship on the isobutyl group with higher cycloalkyl groups at 6-position of pyridone ring has enabled us to significant improvement of potency against Mtb. The lead compound 30j, a dimethylcyclohexyl group on the 6-position of the pyridone, displayed desirable in vitro potency against both drug sensitive and multi-drug resistant TB clinical isolates. In addition, 30j displayed favorable oral pharmacokinetic properties and demonstrated in vivo efficacy in mouse model. These results emphasize the importance of 4-hydroxy-2-pyridones as a new chemotype and further optimization of properties to treat MDR-TB. PMID:26544629

  4. Novel anticancer agent, SQAP, binds to focal adhesion kinase and modulates its activity

    PubMed Central

    Izaguirre-Carbonell, Jesus; Kawakubo, Hirofumi; Murata, Hiroshi; Tanabe, Atsushi; Takeuchi, Toshifumi; Kusayanagi, Tomoe; Tsukuda, Senko; Hirakawa, Takeshi; Iwabata, Kazuki; Kanai, Yoshihiro; Ohta, Keisuke; Miura, Masahiko; Sakaguchi, Kengo; Matsunaga, Sachihiro; Sahara, Hiroeki; Kamisuki, Shinji; Sugawara, Fumio

    2015-01-01

    SQAP is a novel and promising anticancer agent that was obtained by structural modifications from a natural compound. SQAP inhibits angiogenesis in vivo resulting in increased hypoxia and reduced tumor volume. In this study, the mechanism by which SQAP modifies the tumor microenvironment was revealed through the application of a T7 phage display screening. This approach identified five SQAP-binding proteins including sterol carrier protein 2, multifunctional enzyme type 2, proteasomal ubiquitin receptor, UV excision repair protein and focal adhesion kinase (FAK). All the interactions were confirmed by surface plasmon resonance analysis. Since FAK plays an important role in cell turnover and angiogenesis, the influence of SQAP on FAK was the principal goal of this study. SQAP decreased FAK phosphorylation and cell migration in human umbilical vein endothelial cells and A549 cancer cells. These findings suggest that inhibition of FAK phosphorylation works as the mechanism for the anti-angiogenesis activity of SQAP. PMID:26456697

  5. Solar sail attitude control including active nutation damping in a fixed-momentum wheel satellite

    NASA Technical Reports Server (NTRS)

    Azor, Ruth

    1992-01-01

    In geostationary cruise of a momentum biased satellite, it is necessary to stabilize the roll/yaw attitude due to disturbances, caused mainly by solar radiation pressure. This work presents a roll/yaw control which is obtained by the use of solar arrays and fixed flaps as actuators, with a horizon sensor for roll measurement. The design also includes an active nutation damping.

  6. Population and Human Development: A Course Curriculum Including Lesson Plans, Activities, and Bibliography. Revised.

    ERIC Educational Resources Information Center

    Murphy, Elaine M.; Long, Alison T.

    This course outline suggests materials and learning activities on the interrelated causes and consequences of population growth and other population matters. The document describes 15 class sessions which integrate information for sociology, anthropology, psychology, biology, animal behavior, and education. Topics include the history of human…

  7. Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents.

    PubMed

    Tiwari, Rohit; Moraski, Garrett C; Krchňák, Viktor; Miller, Patricia A; Colon-Martinez, Mariangelli; Herrero, Eliza; Oliver, Allen G; Miller, Marvin J

    2013-03-01

    The development of multidrug resistant (MDR) and extensively drug resistant (XDR) forms of tuberculosis (TB) has stimulated research efforts globally to expand the new drug pipeline. Nitroaromatic compounds, including 1,3-benzothiazin-4-ones (BTZs) and related agents, are a promising new class for the treatment of TB. Research has shown that the nitroso intermediates of BTZs that are generated in vivo cause suicide inhibition of decaprenylphosphoryl-β-D-ribose 2' oxidase (DprE1), which is responsible for cell wall arabinogalactan biosynthesis. We have designed and synthesized novel anti-TB agents inspired from BTZs and other nitroaromatic compounds. Computational studies indicated that the unsubstituted aromatic carbons of BTZ043 and related nitroaromatic compounds are the most electron-deficient and might be prone to nucleophilic attack. Our chemical studies on BTZ043 and the additional nitroaromatic compounds synthesized by us and others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide, and hydride induce nonenzymatic reduction of the nitro groups present in these compounds to the corresponding nitroso intermediates by addition at the unsubstituted electron-deficient aromatic carbon present in these compounds. Furthermore, we demonstrate here that these compounds are good candidates for the classical von Richter reaction. These chemical studies offer an alternate hypothesis for the mechanism of action of nitroaromatic anti-TB agents, in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to the nitroso intermediates, to initiate the inhibition of DprE1. PMID:23402278

  8. Molecular characteristics and in vitro susceptibility to antimicrobial agents, including the des-fluoro(6) quinolone DX-619, of Panton-Valentine leucocidin-positive methicillin-resistant Staphylococcus aureus isolates from the community and hospitals.

    PubMed

    Yamamoto, Tatsuo; Dohmae, Soshi; Saito, Kohei; Otsuka, Taketo; Takano, Tomomi; Chiba, Megumi; Fujikawa, Katsuko; Tanaka, Mayumi

    2006-12-01

    Highly virulent, community-acquired methicillin-resistant Staphylococcus aureus (MRSA) strains with Panton-Valentine leucocidin (PVL) genes have been found increasingly worldwide. Among a total of 2,101 MRSA strains isolated from patients in hospitals in Japan, two were positive for PVL genes. One strain was identified as a community-acquired MRSA strain with genotype sequence type 30 (ST30) and spa (staphylococcal protein A gene) type 19 from Japan and was resistant only to beta-lactam antimicrobial agents. The other strain was closely related to PVL+ multidrug-resistant, hospital-acquired MRSA strains (ST30, spa type 43) derived from nosocomial outbreaks in the 1980s to 1990s in Japan but with a divergent sequence type, ST765 (a single-locus variant of ST30). Twenty-two PVL+ MRSA strains, including those from Japan and those from other countries with various sequence types (ST1, ST8, ST30, ST59, and ST80) and genotypes, were examined for susceptibility to 31 antimicrobial agents. Among the agents, DX-619, a des-fluoro(6) quinolone, showed the greatest activity, followed by rifampin and sitafloxacin, a fluoroquinolone. The data suggest that DX-619 exhibits a superior activity against PVL+ MRSA strains with various virulence genetic traits from the community as well as from hospitals. PMID:17043124

  9. The human host as active agent in malaria epidemiology.

    PubMed

    MacCormack, C P

    1987-09-01

    The literature on malaria epidemiology tends to view the human host as a passive or constant factor. However, for at least 2000 years people have been an active factor, causing vast changes in epidemiological patterns. They have cut forest and increased the breeding area of An. gambiae, or changed salinity in rice swamps causing a different change in the dominant vector. Human activity not only increases risk, but influences control by killing mosquito larvae, killing adult mosquitos or preventing mosquitos from feeding. For example, people prefer chloroquine or other anti-malarials to traditional herbal remedies that do not kill parasites, and in some areas introduce larvivorous fish into swamp rice fields and cattle ponds. Bed nets impregnated with residual insecticide simultaneously prevent mosquitos from feeding on people and kill adult mosquitos. Preferences and practices in bed net use in the Gambia are described. PMID:3432961

  10. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.

    PubMed

    Wang, Hui; Liu, Xiufei; Long, Min; Huang, Yi; Zhang, Linlin; Zhang, Rui; Zheng, Yi; Liao, Xiaoyu; Wang, Yuren; Liao, Qian; Li, Wenjie; Tang, Zili; Tong, Qiang; Wang, Xiaocui; Fang, Fang; Rojo de la Vega, Montserrat; Ouyang, Qin; Zhang, Donna D; Yu, Shicang; Zheng, Hongting

    2016-04-13

    Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis. PMID:27075625

  11. Screening of Pharmacologically Active Small Molecule Compounds Identifies Antifungal Agents Against Candida Biofilms

    PubMed Central

    Watamoto, Takao; Egusa, Hiroshi; Sawase, Takashi; Yatani, Hirofumi

    2015-01-01

    Candida species have emerged as important and common opportunistic human pathogens, particularly in immunocompromised individuals. The current antifungal therapies either have toxic side effects or are insufficiently effect. The aim of this study is develop new small-molecule antifungal compounds by library screening methods using Candida albicans, and to evaluate their antifungal effects on Candida biofilms and cytotoxic effects on human cells. Wild-type C. albicans strain SC5314 was used in library screening. To identify antifungal compounds, we screened a small-molecule library of 1,280 pharmacologically active compounds (LOPAC1280TM) using an antifungal susceptibility test (AST). To investigate the antifungal effects of the hit compounds, ASTs were conducted using Candida strains in various growth modes, including biofilms. We tested the cytotoxicity of the hit compounds using human gingival fibroblast (hGF) cells to evaluate their clinical safety. Only 35 compounds were identified by screening, which inhibited the metabolic activity of C. albicans by >50%. Of these, 26 compounds had fungistatic effects and nine compounds had fungicidal effects on C. albicans. Five compounds, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate, ellipticine and CV-3988, had strong fungicidal effects and could inhibit the metabolic activity of Candida biofilms. However, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate and ellipticine were cytotoxic to hGF cells at low concentrations. CV-3988 showed no cytotoxicity at a fungicidal concentration. Four of the compounds identified, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate and ellipticine, had toxic effects on Candida strains and hGF cells. In contrast, CV-3988 had fungicidal effects on Candida strains, but low cytotoxic effects on hGF cells. Therefore, this screening reveals agent, CV-3988 that was previously unknown to be antifungal agent, which could be a novel therapies for superficial mucosal candidiasis. PMID

  12. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

    1999-01-01

    A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material.

  13. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, Walter G.; Wachter, Eric A.; Dees, H. Craig

    1998-01-01

    A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material.

  14. Method for improved selectivity in photo-activation of molecular agents

    DOEpatents

    Fisher, W.G.; Wachter, E.A.; Dees, H.C.

    1998-11-03

    A method for the treatment of a particular volume of plant or animal tissue comprising the steps of treating the plant or animal tissue with at least one photo-active molecular agent, wherein the particular volume of the plant or animal tissue retains at least a portion of the at least one photo-active molecular agent, and then treating the particular volume of the plant or animal tissue with light sufficient to promote a simultaneous two-photon excitation of at least one of the at least one photo-active molecular agent retained in the particular volume of the plant or animal tissue, wherein the at least one photo-active molecular agent becomes active in the particular volume of the plant or animal tissue. There is also disclosed a method for the treatment of cancer in plant or animal tissue and a method for producing at least one photo-activated molecular agent in a particular volume of a material. 23 figs.

  15. Examination of the activities of 43 chemotherapeutic agents against Neospora caninum tachyzoites in cultured cells.

    PubMed

    Lindsay, D S; Rippey, N S; Cole, R A; Parsons, L C; Dubey, J P; Tidwell, R R; Blagburn, B L

    1994-07-01

    Neospora caninum causes serious disease in dogs, and it, or a similar parasite, is a major cause of abortion in cattle. Little is known about the susceptibility of this protozoan to antimicrobial agents. We studied several antimicrobial agents to determine which classes might have activity against this parasite. We also determined whether activity of such agents was coccidiocidal or coccidiostatic. A 2-day of treatment, monoclonal antibody-based enzyme immunoassay and a 5-day of treatment, cell culture flask (CCF), lesion-based assay were developed to examine the ability of test agents to inhibit tachyzoite multiplication. Seven sulfonamides were examined, with the following activities observed: sulfathiazole > or = sulfamethoxazole > sulfadiazine > sulfaquinoxaline > or = sulfamethazine > sulfadimethoxine > sulfamerazine. Dapsone, a sulfone, had little activity. Six dihydrofolate reductase/thymidylate synthase inhibitors were examined, with the following activities observed: piritrexim > pyrimethamine > ormetoprim > trimethoprim = diaveridine > methotrexate. Six ionophorous antibiotics were examined; lasalocid, maduramicin, monensin, narasin, and salinomycin had equivalent activities, but alborixin was toxic for host cells at the lowest concentration examined. Three macrolide antibiotics--azithromycin, clarithromycin, and erythromycin--were examined and had equivalent activities. Two tetracycline antibiotics, doxycycline and minocycline, were examined and had equivalent activities. Three lincosamide antibiotics were examined, with the following activities observed: clindamycin hydrochloride > clindamycin phosphate > lincomycin hydrochloride. Pentamidine and 6 of its analogs were examined, and only hexamidine and 1,4-Di[4-(2-imidazolinyl)-2-methoxy-phenoxy]butane had activity. Eight miscellaneous antiprotozoal agents were examined for activity. Amprolium, metronidazole, paromomycin, and roxarsone had little activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7978638

  16. ['In vitro' activity of different antimicrobial agents on Gram-negative nonfermentative bacilli, excluding Pseudomonas aeruginosa and Acinetobacter spp].

    PubMed

    Vay, C A; Almuzara, M N; Rodríguez, C H; Pugliese, M L; Lorenzo Barba, F; Mattera, J C; Famiglietti, A M R

    2005-01-01

    Gram-negative nonfermentative bacilli (NFB) are widely spread in the environment. Besides of difficulties for identification, they often have a marked multiresistance to antimicrobial agents, including those active against Pseudomonas aeruginosa. The objective of this study was to evaluate the 'in vitro' activity of different antimicrobial agents on 177 gram-negative nonfermentative bacilli isolates (excluding Pseudomonas aeruginosa and Acinetobacter spp.) isolated from clinical specimens. Minimum inhibitory concentrations (MIC) were determined according to the Mueller Hinton agar dilution method against the following antibacterial agents: ampicillin, piperacillin, piperacillin-tazobactam, sulbactam, cefoperazone, cefoperazone-sulbactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem, colistin, gentamicin, amikacin, trimethoprim-sulfamethoxazole, chloramphenicol, erythromycin, rifampin, norfloxacin, ciprofloxacin and minocycline. Seven isolates: Sphingobacterium multivorum (2), Sphingobacteriumspiritivorum (1), Empedobacterbrevis (1), Weeksella virosa (1), Bergeyella zoohelcum (1) and Oligella urethralis (1), were tested for amoxicillin-clavulanic acid and ampicillin-sulbactam susceptibility, and susceptibility to cefoperazone or sulbactam was not determined. Multiresistance was generally found in Stenotrophomonas maltophilia, Burkholderia cepacia, Chryseobacterium spp., Myroides spp., Achromobacter xylosoxidans, and Ochrobactrum anthropi isolates. On the other hand, Pseudomonas stutzeri, Shewanella putrefaciens-algae, Sphingomonas paucimobilis, and Pseudomonas oryzihabitans, Bergeyella zoohelcum, Weeksella virosa and Oligella urethralis were widely susceptible to the antibacterial agents tested. As a result of the wide variation in antimicrobial susceptibility shown by different species, a test on susceptibility to different antibacterial agents is essential in order to select an adequate therapy. The marked multiresistance evidenced by some species

  17. Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact.

    PubMed

    Kiss, Zoltán; Elliott, Steven; Jedynasty, Kinga; Tesar, Vladimír; Szegedi, János

    2010-04-01

    Cloning of the human erythropoietin (EPO) gene and development of the first recombinant human erythropoietin (rHuEPO) drug were truly breakthroughs. This allowed a deeper understanding of the structure and pharmacology of rHuEpo, which in turn inspired the discovery and development of additional erythropoiesis-stimulating agents (ESAs). In vivo specific activity and serum half-life of rHuEPO are influenced by the amount and structure of the attached carbohydrate. Increased numbers of sialic acids on carbohydrate attached to rHuEPO correlated with a relative increase in in-vivo-specific activity and increased serum half-life. The effect of increasing the number of sialic-acid-containing carbohydrates on in-vivo-specific activity was explored. Initial research focused on solving the problem of how the protein backbone could be engineered so a cell would add more carbohydrate to it. Additional work resulted in darbepoetin alfa, a longer-acting molecule with two additional carbohydrate chains. PMID:20127232

  18. Pharmacological activity and toxicity of some neurotropic agents under conditions of experimental hypodynamia

    NASA Technical Reports Server (NTRS)

    Kirichek, L. T.

    1980-01-01

    The indices of pharmacological range, risk coefficients, ED50, LD50, the size of the area of toxic activity, and maximal tolerated and absolute lethal doses were compared in hypodynamic mice. The pharmacological activity of the test neurotropic agents exhibiting a central action underwent change, but their toxicity remained unchanged.

  19. Activity of faropenem tested against Neisseria gonorrhoeae isolates including fluoroquinolone-resistant strains.

    PubMed

    Jones, Ronald N; Critchley, Ian A; Whittington, William L H; Janjic, Nebojsa; Pottumarthy, Sudha

    2005-12-01

    , California, Washington, and Hawaii. Faropenem retained its potency against these recent clinical strains and also quinolone-resistant strains from Japan (MIC90, < or =0.25 microg/mL). In summary, the excellent activity of faropenem against the gonococcal strains analyzed irrespective of the resistance phenotype, along with its beta-lactamase stability, makes it an ideal contender for further development as an oral beta-lactam agent to treat uncomplicated gonococcal infections due to strains emerging with resistant to penicillins, tetracyclines, and fluoroquinolones. PMID:16269221

  20. Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents

    PubMed Central

    Chang, Jinhong; Guo, Ju-Tao; Du, Yanming; Block, Timothy

    2013-01-01

    Ebola virus and Marburg virus are members of the family of Filoviridae and are etiological agents of a deadly hemorrhagic fever disease. The clinical symptoms of Ebola and Marburg hemorrhagic fevers are difficult to distinguish and there are currently no specific antiviral therapies against either of the viruses. Therefore, a drug that is safe and effective against both would be an enormous breakthrough. We and others have shown that the folding of the glycoproteins of many enveloped viruses, including the filoviruses, is far more dependent upon the calnexin pathway of protein folding than are most host glycoproteins. Drugs that inhibit this pathway would be expected to be selectively antiviral. Indeed, as we summarize in this review, imino sugars that are competitive inhibitors of the host endoplasmic reticular α-glucosidases I and II, which are enzymes that process N-glycan on nascent glycoproteins and thereby inhibit calnexin binding to the nascent glycoproteins, have been shown to have antiviral activity against a number of enveloped viruses including filoviruses. In this review, we describe the state of development of imino sugars for use against the filoviruses, and provide an explanation for the basis of their antiviral activity as well as limitations. PMID:26038444

  1. Multimodality PET/MRI agents targeted to activated macrophages.

    PubMed

    Tu, Chuqiao; Ng, Thomas S C; Jacobs, Russell E; Louie, Angelique Y

    2014-02-01

    The recent emergence of multimodality imaging, particularly the combination of PET and MRI, has led to excitement over the prospect of improving detection of disease. Iron oxide nanoparticles have become a popular platform for the fabrication of PET/MRI probes owing to their advantages of high MRI detection sensitivity, biocompatibility, and biodegradability. In this article, we report the synthesis of dextran-coated iron oxide nanoparticles (DIO) labeled with the positron emitter (64)Cu to generate a PET/MRI probe, and modified with maleic anhydride to increase the negative surface charge. The modified nanoparticulate PET/MRI probe (MDIO-(64)Cu-DOTA) bears repetitive anionic charges on the surface that facilitate recognition by scavenger receptor type A (SR-A), a ligand receptor found on activated macrophages but not on normal vessel walls. MDIO-(64)Cu-DOTA has an average iron oxide core size of 7-8 nm, an average hydrodynamic diameter of 62.7 nm, an r1 relaxivity of 16.8 mM(-1) s(-1), and an r 2 relaxivity of 83.9 mM(-1) s(-1) (37 °C, 1.4 T). Cell studies confirmed that the probe was nontoxic and was specifically taken up by macrophages via SR-A. In comparison with the nonmodified analog, the accumulation of MDIO in macrophages was substantially improved. These characteristics demonstrate the promise of MDIO-(64)Cu-DOTA for identification of vulnerable atherosclerotic plaques via the targeting of macrophages. PMID:24166283

  2. ΔPK oncolytic activity includes modulation of the tumour cell milieu.

    PubMed

    Bollino, Dominique; Colunga, Aric; Li, Baiquan; Aurelian, Laure

    2016-02-01

    Oncolytic virotherapy is a unique cancer therapeutic that encompasses tumour cell lysis through both virus replication and programmed cell death (PCD) pathways. Nonetheless, clinical efficacy is relatively modest, likely related to the immunosuppressive tumour milieu. Our studies use the herpes simplex virus type 2 (HSV-2)-based oncolytic virus ΔPK that has documented anti-tumour activity associated with virus replication, PCD and cancer stem cell lysis. They are designed to examine whether ΔPK-mediated oncolysis includes the ability to reverse the immunosuppressive tumour microenvironment by altering the balance of cytokines directly secreted by the melanoma cells and to define its mechanism. Here, we show that melanoma cells secreted the immunosuppressive cytokine IL-10, and that secretion was inhibited by ΔPK through virus replication and c-Jun N-terminal kinase/c-Jun activation. ΔPK-induced IL-10 inhibition upregulated surface expression of MHC class I chain-related protein A, the ligand for the activating NKG2D receptor expressed on NK- and cytotoxic T-cells. Concomitantly, ΔPK also upregulated the secretion of inflammatory cytokines TNF-α, granulocyte macrophage colony-stimulating factor and IL-1β through autophagy-mediated activation of Toll-like receptor 2 pathways and pyroptosis, and it inhibited the expression of the negative immune checkpoint regulator cytotoxic T-lymphocyte antigen 4. Pharmacologic inhibition of these processes significantly reduces the oncolytic activity of ΔPK. PMID:26602205

  3. Activation of aluminum as an effective reducing agent by pitting corrosion for wet-chemical synthesis.

    PubMed

    Li, Wei; Cochell, Thomas; Manthiram, Arumugam

    2013-01-01

    Metallic aluminum (Al) is of interest as a reducing agent because of its low standard reduction potential. However, its surface is invariably covered with a dense aluminum oxide film, which prevents its effective use as a reducing agent in wet-chemical synthesis. Pitting corrosion, known as an undesired reaction destroying Al and is enhanced by anions such as F⁻, Cl⁻, and Br⁻ in aqueous solutions, is applied here for the first time to activate Al as a reducing agent for wet-chemical synthesis of a diverse array of metals and alloys. Specifically, we demonstrate the synthesis of highly dispersed palladium nanoparticles on carbon black with stabilizers and the intermetallic Cu₂Sb/C, which are promising candidates, respectively, for fuel cell catalysts and lithium-ion battery anodes. Atomic hydrogen, an intermediate during the pitting corrosion of Al in protonic solvents (e.g., water and ethylene glycol), is validated as the actual reducing agent. PMID:23390579

  4. Activation of Aluminum as an Effective Reducing Agent by Pitting Corrosion for Wet-chemical Synthesis

    PubMed Central

    Li, Wei; Cochell, Thomas; Manthiram, Arumugam

    2013-01-01

    Metallic aluminum (Al) is of interest as a reducing agent because of its low standard reduction potential. However, its surface is invariably covered with a dense aluminum oxide film, which prevents its effective use as a reducing agent in wet-chemical synthesis. Pitting corrosion, known as an undesired reaction destroying Al and is enhanced by anions such as F−, Cl−, and Br− in aqueous solutions, is applied here for the first time to activate Al as a reducing agent for wet-chemical synthesis of a diverse array of metals and alloys. Specifically, we demonstrate the synthesis of highly dispersed palladium nanoparticles on carbon black with stabilizers and the intermetallic Cu2Sb/C, which are promising candidates, respectively, for fuel cell catalysts and lithium-ion battery anodes. Atomic hydrogen, an intermediate during the pitting corrosion of Al in protonic solvents (e.g., water and ethylene glycol), is validated as the actual reducing agent. PMID:23390579

  5. Ion channel modifying agents influence the electrical activity generated by canine intrinsic cardiac neurons in situ.

    PubMed

    Thompson, G W; Horackova, M; Armour, J A

    2000-04-01

    This study was designed to establish whether agents known to modify neuronal ion channels influence the behavior of mammalian intrinsic cardiac neurons in situ and, if so, in a manner consistent with that found previously in vitro. The activity generated by right atrial neurons was recorded extracellularly in varying numbers of anesthetized dogs before and during continuous local arterial infusion of several neuronal ion channel modifying agents. Veratridine (7.5 microM), the specific modifier of Na+-selective channels, increased neuronal activity (95% above control) in 80% of dogs tested (n = 25). The membrane depolarizing agent potassium chloride (40 mM) reduced neuronal activity (43% below control) in 84% of dogs tested (n = 19). The inhibitor of voltage-sensitive K+ channels, tetraethylammonium (10 mM), decreased neuronal activity (42% below control) in 73% of dogs tested (n = 11). The nonspecific potassium channel inhibitor barium chloride (5 mM) excited neurons (47% above control) in 13 of 19 animals tested. Cadmium chloride (200 microM), which inhibits Ca2+-selective channels and Ca2+-dependent K+ channels, increased neuronal activity (65% above control) in 79% of dogs tested (n = 14). The specific L-type Ca2+ channel blocking agent nifedipine (5 microM) reduced neuronal activity (52% blow control in 72% of 11 dogs tested), as did the nonspecific inhibitor of L-type Ca2+ channels, nickel chloride (5 mM) (36% below control in 69% of 13 dogs tested). Each agent induced either excitatory or inhibitory responses, depending on the agent tested. It is concluded that specific ion channels (I(Na), I(CaL), I(Kv), and I(KCa)) that have been associated with intrinsic cardiac neurons in vitro are involved in their capacity to generate action potentials in situ. PMID:10772056

  6. Screening of antimicrobial agents for in vitro radiation protection and mitigation capacity, including those used in supportive care regimens for bone marrow transplant recipients.

    PubMed

    Epperly, Michael W; Franicola, Darcy; Shields, Donna; Rwigema, Jean-Claude; Stone, Brandon; Zhang, Xichen; McBride, William; Georges, George; Wipf, Peter; Greenberger, Joel S

    2010-01-01

    Antibiotic and antifungal agents used in supportive care regimens for bone marrow transplantation recipients contribute to a significant dose-modifying effect of otherwise lethal total body irradiation. To determine whether drugs used in supportive care and other commonly used antibiotics such as tetracycline function as radiation protectors or damage mitigators in vitro, 13 drugs were tested for radiation protection and radiation damage mitigation of 32D cl 3 hematopoietic progenitor cells in clonagenic survival curves in vitro. Antibiotic/Antifungal agents including cilastatin, amikacin, ceftazidine, vancomycin, tetracycline, doxycycline, ciprofloxacin, metronidazole, methacycline, minocycline, meclocycline, oxytetracycline and rolitetracycline were added in 1, 10, or 100 micromolar concentrations to murine interleukin-3-dependent hematopoietic progenitor cell line 32D cl 3 cells either before or after irradiation of 0 to 8 Gy. Control irradiated 32D cl 3 cells showed radiosensitivity comparable to freshly explanted mouse marrow hematopoietic progenitor cells (D(0) 1.1+/-0.1 Gy, N 1.5+/-0.4). Positive control GS-nitroxide JP4-039 (known radiation mitigator) treated 32D cl 3 cells were radioresistant (D(0) 1.2+/-0.1, N 5.8+/-2.4 (p=0.009)). Of the 13 drugs tested, tetracycline was found to be a significant radiation mitigator (D(0) 0.9+/-0.1, N 13.9+/-0.4 (p=0.0027)). Thus, the radiation dose-modifying effect of some antibiotics, but not those currently used in the supportive care (antibiotic/antifungal regimens) for marrow transplant patients, may act as radiation damage mitigators for hematopoietic cells as well as decreasing the growth and inflammatory response to microbial pathogens. PMID:20133970

  7. Active extravasation of gadolinium-based contrast agent into the subdural space following lumbar puncture.

    PubMed

    Kothari, Pranay D; Hanser, Evelyn M; Wang, Harrison; Farid, Nikdokht

    2016-01-01

    A 38year-old male presented with cauda equina syndrome following multiple lumbar puncture attempts. Lumbar spine magnetic resonance imaging (MRI) showed a subdural hematoma and an area of apparent contrast enhancement in the spinal canal on sagittal post-contrast images. Axial post-contrast images obtained seven minutes later demonstrated an increase in size and change in shape of the region of apparent contrast enhancement, indicating active extravasation of the contrast agent. This is the first reported case of active extravasation of gadolinium-based contrast agent in the spine. PMID:27317202

  8. Active seat suspension for a small vehicle: considerations for control system including observer

    NASA Astrophysics Data System (ADS)

    Katsumata, Hiroyuki; Shiino, Hiroshi; Oshinoya, Yasuo; Ishibashi, Kazuhisa; Ozaki, Koichi; Ogino, Hirohiko

    2007-12-01

    We have examined the improvement of ride quality and the reduction of riding fatigue brought about by the active control of the seat suspension of small vehicles such as one-seater electric automobiles. A small active seat suspension, which is easy to install, was designed and manufactured for one-seater electric automobiles. For the actuator, a maintenance-free voice coil motor used as a direct drive was adopted. For fundamental considerations, we designed a one-degree-of-freedom model for the active seat suspension system. Then, we designed a disturbance cancellation control system that includes the observer for a two-degree-of-freedom model. In an actual driving test, a test road, in which the concavity and convexity of an actual road surface were simulated using hard rubber, was prepared and the control performance of vertical vibrations of the seat surface during driving was examined. As a result, in comparison with the one-degree-of-freedom control system, it was confirmed that the control performance was improved by the two-degree-of-freedom control system that includes the observer.

  9. Current state of evidence on 'off-label' therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland--a consensus report.

    PubMed

    Aringer, M; Burkhardt, H; Burmester, G R; Fischer-Betz, R; Fleck, M; Graninger, W; Hiepe, F; Jacobi, A M; Kötter, I; Lakomek, H J; Lorenz, H M; Manger, B; Schett, G; Schmidt, R E; Schneider, M; Schulze-Koops, H; Smolen, J S; Specker, C; Stoll, T; Strangfeld, A; Tony, H P; Villiger, P M; Voll, R; Witte, T; Dörner, T

    2012-04-01

    Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence. PMID:22072024

  10. Trends in the susceptibility of commonly encountered clinically significant anaerobes and susceptibilities of blood isolates of anaerobes to 16 antimicrobial agents, including fidaxomicin and rifaximin, 2008-2012, northern Taiwan.

    PubMed

    Wang, F D; Liao, C H; Lin, Y T; Sheng, W H; Hsueh, P R

    2014-11-01

    We investigated the antimicrobial resistance trends and profiles of clinical anaerobic isolates in northern Taiwan. Trends in the susceptibility of five commonly encountered clinical anaerobic isolates to seven agents from 2008 to 2012 were measured using the Cochran-Armitage trend test. The minimum inhibitory concentrations (MICs) of 16 antimicrobial agents, including fidaxomicin and rifaximin, against anaerobic blood isolates from two medical centers were determined using the agar dilution method. During the study period, susceptibility data on 11,105 isolates were evaluated. Metronidazole and chloramphenicol retained excellent activities. Around 20-30 % of isolates of Bacteroides and Prevotella species were resistant to ampicillin-sulbactam, cefmetazole, flomoxef, and clindamycin. Of the 507 tested blood isolates, the rates of resistance to commonly used agents were much higher, namely, 16.2 % for amoxicillin-clavulanate, 15.6 % for ampicillin-sulbactam, 24.7 % for cefmetazole, and 36.1 % for clindamycin. Notably, 13.5 % of B. fragilis isolates were resistant to ertapenem. Also, 15.2 % of B. uniformis, 17.2 % of other Bacteroides species, 14.3 % of Prevotella species, and 14 % of Clostridium other than C. perfringens isolates were resistant to moxifloxacin. Cefoperazone-sulbactam was active against most isolates, except for Clostridium species other than perfringens (resistance rate, 18.6 %). Fidaxomicin exerted poor activities against most anaerobes tested (MIC90 of >128 μg/ml for B. fragilis and all isolates), except for C. perfringens (MIC90 of 0.03 μg/ml) and Peptostreptococcus micros (MIC90 of 2 μg/ml). However, rifaximin showed a wide range of susceptibilities against the tested anaerobes (MIC90 of 0.5 μg/ml for B. fragilis). The emergence of resistance to ertapenem and moxifloxacin among bacteremic anaerobes highlights the need for continuous monitoring. PMID:24930042

  11. Are language-based activities in science effective for all students, including low achievers?

    NASA Astrophysics Data System (ADS)

    Rivard, Léonard P.

    2004-05-01

    The study investigated achievement status as a factor determining the use of language-based activities for learning science. A total of 154 eighth-grade students were randomly assigned to four groups, all stratified for gender and achievement level. The treatments involved various combinations of talk and writing, and descriptive and explanatory tasks. The dependent measures included scores on multiple choice tests obtained at three times during the study. Records of student talk and writing were also analyzed to identify patterns of differences between groups of achievers. The findings suggested that low achievers complete more problems, and develop better understanding and comprehension of ecology concepts when they have engaged in peer discussions of explanatory tasks. In comparison, high achievers benefit more from writing than talking, and writing explanations enhances comprehension more than restricted writing activities.

  12. Activity of Debio1452, a FabI Inhibitor with Potent Activity against Staphylococcus aureus and Coagulase-Negative Staphylococcus spp., Including Multidrug-Resistant Strains

    PubMed Central

    Rhomberg, Paul R.; Kaplan, Nachum; Jones, Ronald N.; Farrell, David J.

    2015-01-01

    Staphylococcus aureus and coagulase-negative staphylococci (CoNS) are responsible for a wide variety of human infections. The investigational antibacterial Debio1450 (previously AFN-1720), a prodrug of Debio1452 (previously AFN-1252), specifically targets staphylococci without significant activity against other Gram-positive or Gram-negative species. Debio1452 inhibits FabI, an enzyme critical to fatty acid biosynthesis in staphylococci. The activity of Debio1452 against CoNS, methicillin-susceptible S. aureus (MSSA), and methicillin-resistant S. aureus (MRSA), including significant clones, was determined. A globally diverse collection of 574 patient isolates from 35 countries was tested that included CoNS (6 species, 103 strains), MSSA (154 strains), MRSA (163 strains), and molecularly characterized strains (including spa-typed MRSA clones; 154 strains). The isolates were tested for susceptibility by CLSI broth microdilution methods against Debio1452 and 10 comparators. The susceptibility rates for the comparators were determined using CLSI and EUCAST breakpoint criteria. All S. aureus and CoNS strains were inhibited by Debio1452 concentrations of ≤0.12 and ≤0.5 μg/ml, respectively. The MIC50s for MSSA, MRSA, and molecularly characterized MRSA strains were 0.004 μg/ml, and the MIC90s ranged from 0.008 to 0.03 μg/ml. The MICs were higher for the CoNS isolates (MIC50/90, 0.015/0.12 μg/ml). Among S. aureus strains, resistance was common for erythromycin (61.6%), levofloxacin (49.0%), clindamycin (27.6%), tetracycline (15.7%), and trimethoprim-sulfamethoxazole (7.0%). Debio1452 demonstrated potent activity against MSSA, MRSA, and CoNS. Debio1452 showed significantly greater activity overall (MIC50, 0.004 μg/ml) than the other agents tested against these staphylococcal species, which included dominant MRSA clones and strains resistant to currently utilized antimicrobial agents. PMID:25691627

  13. Measuring and Reducing Off-Target Activities of Programmable Nucleases Including CRISPR-Cas9.

    PubMed

    Koo, Taeyoung; Lee, Jungjoon; Kim, Jin-Soo

    2015-06-01

    Programmable nucleases, which include zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and RNA-guided engineered nucleases (RGENs) repurposed from the type II clustered, regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system are now widely used for genome editing in higher eukaryotic cells and whole organisms, revolutionising almost every discipline in biological research, medicine, and biotechnology. All of these nucleases, however, induce off-target mutations at sites homologous in sequence with on-target sites, limiting their utility in many applications including gene or cell therapy. In this review, we compare methods for detecting nuclease off-target mutations. We also review methods for profiling genome-wide off-target effects and discuss how to reduce or avoid off-target mutations. PMID:25985872

  14. Multi-Agent System for Managing Human Activities in Space Operations

    NASA Technical Reports Server (NTRS)

    Schrenkenghost, Debra; Bonasso, R. Peter

    2006-01-01

    In manned space operations today, the astronauts' activity schedules are preplanned and adjusted daily on Earth. We have developed the Distributed Collaboration and Interaction (DCI) multi-agent system to investigate automating aspects of human activity management. The DCI System assists (1) plan generation, (2) human activity tracking, (3) plan revision, and (4) mixed initiative interaction with the plan. We have deployed and evaluated the DCI system at JSC to assist control engineers in managing anomaly handling activities for automated life support systems. DCI operated round the clock for 20 months in the Water Research Facility at JSC. Using this software, we reduced anomaly response time by engineers from up to 10 hours in previous tests to under an hour. Based on this evaluation, we conclude that agent assistance for schedule management has potential to improve astronaut activity awareness and reduce response time in situations where crew are interrupted to handle anomalies.

  15. Design of Protease Activated Optical Contrast Agents That Exploit a Latent Lysosomotropic Effect for Use in Fluorescence-Guided Surgery

    PubMed Central

    2015-01-01

    There is a need for new molecular-guided contrast agents to enhance surgical procedures such as tumor resection that require a high degree of precision. Cysteine cathepsins are highly up-regulated in a wide variety of cancers, both in tumor cells and in the tumor-supporting cells of the surrounding stroma. Therefore, tools that can be used to dynamically monitor their activity in vivo could be used as imaging contrast agents for intraoperative fluorescence image guided surgery (FGS). Although multiple classes of cathepsin-targeted substrate probes have been reported, most suffer from overall fast clearance from sites of protease activation, leading to reduced signal intensity and duration in vivo. Here we describe the design and synthesis of a series of near-infrared fluorogenic probes that exploit a latent cationic lysosomotropic effect (LLE) to promote cellular retention upon protease activation. These probes show tumor-specific retention, fast activation kinetics, and rapid systemic distribution. We demonstrate that they are suitable for detection of diverse cancer types including breast, colon and lung tumors. Most importantly, the agents are compatible with the existing, FDA approved, da Vinci surgical system for fluorescence guided tumor resection. Therefore, our data suggest that the probes reported here can be used with existing clinical instrumentation to detect tumors and potentially other types of inflammatory lesions to guide surgical decision making in real time. PMID:26039341

  16. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells.

    PubMed

    Bauer, Matthias R; Joerger, Andreas C; Fersht, Alan R

    2016-09-01

    The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53's oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1(MET)(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells. PMID:27551077

  17. [Resistance to antimicrobial agents, hemolytic activity and plasmids in Aeromonas species].

    PubMed

    Morita, K; Watanabe, N; Kanamori, M

    1990-06-01

    A total of 174 Aeromonas isolates consisting of 100 strains from patients with diarrhea being mainly overseas travellers nd healthy subjects, and 74 strains from environmental sources including foods, fish, fresh water, sea water and river soil collected in the area of Tokyo Metropolis and Kanagawa Prefecture was examined for the antimicrobial resistance, presence of plasmids and hemolytic activity. Almost all the isolates (99.4%) were resistant to aminobenzyl penicillin. The isolation frequency of chloramphenicol- or tetracycline-resistant strain was low. Most environmental isolates of A. hydrophila were resistant to multiple antimicrobial agents. Thirty-seven percent of environmental isolates and 39% of human fecal ones carried plasmids. In environmental isolates, seven A. hydrophila and three A. sobria strains carried 63- to 150-kilobase pair (kb) conjugative R plasmids. Two A. hydrophila strains from both the healthy subject and domestic case with diarrhea carried 58- to 90-kb conjugative R plasmids, respectively. None of the isolates from the feces of overseas traveller's diarrhea carried the plasmid. Irrespective of the sources. A. hydrophila showed the highest hemolytic activity among three Aeromonas species. Eighty percent or more of A. hydrophila isolates were of hemolysin positive. The hemolytic titer of A. hydrophila strains from human feces was higher than that of the strains from environmental sources. PMID:2401817

  18. Antipneumococcal Activity of ABT-773 Compared to Those of 10 Other Agents

    PubMed Central

    Davies, Todd A.; Ednie, Lois M.; Hoellman, Dianne M.; Pankuch, Glenn A.; Jacobs, Michael R.; Appelbaum, Peter C.

    2000-01-01

    MICs, time-kills, and postantibiotic effects (PAEs) of ABT-773 (a new ketolide) and 10 other agents were determined against 226 pneumococci. Against 78 ermB- and 44 mefE-containing strains, ABT-773 MICs at which 50% of the isolates tested were inhibited (MIC50s) and MIC90s were 0.016 to 0.03 and 0.125 μg/ml, respectively. Clindamycin was active only against macrolide-resistant strains containing mefE (MIC50, 0.06 μg/ml; MIC90, 0.125 μg/ml). Activities of pristinamycin (MIC90, 0.5 μg/ml) and vancomycin (MIC90, 0.25 μg/ml) were unaffected by macrolide or penicillin resistance, while β-lactam MICs rose with those of penicillin G. Against 19 strains with L4 ribosomal protein mutations and two strains with mutations in domain V of 23S rRNA, ABT-773 MICs were 0.03 to 0.25 μg/ml, while macrolide and azalide MICs were all ≥16.0 μg/ml. ABT-773 was bactericidal at twice the MIC after 24 h for 8 of 12 strains (including three strains with erythromycin MICs greater than or equal to 64.0 μg/ml). Kill kinetics of erythromycin, azithromycin, clarithromycin, and roxithromycin against macrolide-susceptible strains were slower than those of ABT-773. ABT-773 had longer PAEs than macrolides, azithromycin, clindamycin, or β-lactams, including against ermB-containing strains. ABT-773, therefore, shows promising in vitro activity against macrolide-susceptible as well as -resistant pneumococci. PMID:10858350

  19. Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents.

    PubMed

    Busso, N; Nicodeme, E; Chesne, C; Guillouzo, A; Belin, D; Hyafil, F

    1994-07-01

    We examined the effects of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha and transforming growth factor-beta) on the plasminogen activator system (urokinase, tissue-type plasminogen activator, type 1 plasminogen activator inhibitor) in primary cultures of human hepatocytes. We show that interleukin-1 beta and tumor necrosis factor-alpha increase urokinase-type plasminogen activator production, reinforcing the concept that increased urokinase production is associated with inflammatory processes. By contrast, the same agents (i.e., interleukin-1 beta and tumor necrosis factor-alpha) do not stimulate plasminogen activator inhibitor type 1 production. This latter observation rules out hepatocytes as a major cellular source of plasmatic plasminogen activator inhibitor type 1 during acute-phase-related responses. Among the inflammatory agents used, transforming growth factor-beta was found to be the most effective modulator of both urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, inducing severalfold increases of activity of urokinase-type plasminogen activator, antigen and the corresponding mRNA and increasing plasminogen activator inhibitor type 1 antigen and mRNA levels. Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 modulation by transforming growth factor-beta may play a critical role in hepatic pathophysiology. PMID:8020888

  20. Should Cost-Effectiveness Analysis Include the Cost of Consumption Activities? AN Empirical Investigation.

    PubMed

    Adarkwah, Charles Christian; Sadoghi, Amirhossein; Gandjour, Afschin

    2016-02-01

    There has been a debate on whether cost-effectiveness analysis should consider the cost of consumption and leisure time activities when using the quality-adjusted life year as a measure of health outcome under a societal perspective. The purpose of this study was to investigate whether the effects of ill health on consumptive activities are spontaneously considered in a health state valuation exercise and how much this matters. The survey enrolled patients with inflammatory bowel disease in Germany (n = 104). Patients were randomized to explicit and no explicit instruction for the consideration of consumption and leisure effects in a time trade-off (TTO) exercise. Explicit instruction to consider non-health-related utility in TTO exercises did not influence TTO scores. However, spontaneous consideration of non-health-related utility in patients without explicit instruction (60% of respondents) led to significantly lower TTO scores. Results suggest an inclusion of consumption costs in the numerator of the cost-effectiveness ratio, at least for those respondents who spontaneously consider non-health-related utility from treatment. Results also suggest that exercises eliciting health valuations from the general public may include a description of the impact of disease on consumptive activities. PMID:25684073

  1. Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex.

    PubMed Central

    Katz, D H; Marcelletti, J F; Khalil, M H; Pope, L E; Katz, L R

    1991-01-01

    This article reports that 1-docosanol, a 22-carbon-long saturated alcohol, exerts a substantial inhibitory effect on replication of certain viruses (e.g., herpes simplex virus and respiratory syncytial virus) within primary target cells in vitro. To study the basis for its viral inhibitory activity, a suspension of 1-docosanol was formulated in an inert and nontoxic surfactant, Pluronic F-68; this suspension exerted potent inhibitory activity on the ability of susceptible viruses to infect cultured target cells. Susceptible viruses included wild-type herpes simplex viruses 1 and 2 as well as acyclovir-resistant herpes simplex virus 2 and also respiratory syncytial virus--all of which are lipid-enveloped. In contrast, nonenveloped poliovirus was not susceptible to the inhibitory action of 1-docosanol. Although the precise mechanism has yet to be defined, current evidence suggests that 1-docosanol inhibits viral replication by interfering with the early intracellular events surrounding viral entry into target cells. It is possible that interaction between the highly lipophilic compound and components of target cell membranes renders such target cells less susceptible to viral fusion and/or entry. If this mechanism proves to be correct, 1-docosanol may provide a broad spectrum activity against many different viruses, especially those with lipid-containing envelopes. Images PMID:1660151

  2. Synthesis and In Vitro Cytotoxic Activity of Novel Chalcone-Like Agents

    PubMed Central

    Letafat, Bahram; Shakeri, Raheleh; Emami, Saeed; Noushini, Saeedeh; Mohammadhosseini, Negar; Shirkavand, Nayyereh; Kabudanian Ardestani, Sussan; Safavi, Maliheh; Samadizadeh, Marjaneh; Letafat, Aida; Shafiee, Abbas; Foroumadi, Alireza

    2013-01-01

    Objective(s): Chalcones and their rigid analogues represent an important class of small molecules having anticancer activities. Therefore, in this study the synthesis and cytotoxic activity of new 3-benzylidenchroman-4-ones were described as rigid chalcone analogues. Materials and Methods: The reaction of resorcinol with 3-chloropropionic acid in the presence of CF3SO3H was afforded corresponding propiophenone. It was cyclized using 2M NaOH to give 7-hydroxy-4-chromanone. O-Alkylation of 7-hydroxy-4-chromanone with alkyl iodide in the presence of K2CO3 gave 7-alkoxychroman-4-one. Finally, condensation of chroman-4-one derivatives with different aldehydes afforded target compounds in good yields. The newly synthesized compounds were tested in vitro against different human cancer cell lines including K562 (human erythroleukemia), MDA-MB-231 (human breast cancer), and SK-N-MC (human neuroblastoma) cells. The cell viability was evaluated using MTT colorimetric assay. Results: Most of the compounds showed good inhibitory activity against cancer cells. Among them, compound 4a containing 7-hydroxy group on chromanone ring and 3-bromo-4-hydroxy-5-methoxy substitution pattern on benzylidene moiety was the most potent compound with IC50 values ≤ 3.86 µg/ml. It was 6-17 times more potent than etoposide against tested cell lines. Conclusion: We described synthesis and cytotoxic activity of poly-functionalized 3-benzylidenechroman-4-ones as new chalcone-like agents. These compounds can be considered as conformationally constrained congeners of chalcones to tolerate the poly-functionalization on the core structures for further optimization. PMID:24494068

  3. 21 CFR 178.3400 - Emulsifiers and/or surface-active agents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... citations affecting § 178.3400, see the List of CFR Sections Affected, which appears in the Finding Aids... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Emulsifiers and/or surface-active agents. 178.3400 Section 178.3400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  4. 21 CFR 178.3400 - Emulsifiers and/or surface-active agents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... citations affecting § 178.3400, see the List of CFR Sections Affected, which appears in the Finding Aids... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Emulsifiers and/or surface-active agents. 178.3400 Section 178.3400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  5. 21 CFR 178.3400 - Emulsifiers and/or surface-active agents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... citations affecting § 178.3400, see the List of CFR Sections Affected, which appears in the Finding Aids... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Emulsifiers and/or surface-active agents. 178.3400 Section 178.3400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

  6. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... interpretative signs; (4) Provision for non-motorized trail activities including pedestrians and bicycles; (5) Provision for motorized trail activities including all terrain vehicles, motorcycles, snowmobiles, etc.; (6...; (8) Maintenance and restoration of existing recreational trails; (9) Development and...

  7. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... interpretative signs; (4) Provision for non-motorized trail activities including pedestrians and bicycles; (5) Provision for motorized trail activities including all terrain vehicles, motorcycles, snowmobiles, etc.; (6...; (8) Maintenance and restoration of existing recreational trails; (9) Development and...

  8. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... interpretative signs; (4) Provision for non-motorized trail activities including pedestrians and bicycles; (5) Provision for motorized trail activities including all terrain vehicles, motorcycles, snowmobiles, etc.; (6...; (8) Maintenance and restoration of existing recreational trails; (9) Development and...

  9. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... interpretative signs; (4) Provision for non-motorized trail activities including pedestrians and bicycles; (5) Provision for motorized trail activities including all terrain vehicles, motorcycles, snowmobiles, etc.; (6...; (8) Maintenance and restoration of existing recreational trails; (9) Development and...

  10. Antibacterial activities and release kinetics of a newly developed recoverable controlled agent-release system.

    PubMed

    Ehara, A; Torii, M; Imazato, S; Ebisu, S

    2000-03-01

    We attempted to develop a resin with a recoverable antibacterial activity based on the desorption/adsorption of a cationic bactericide by the ion-exchange mechanism. The aims of this study were to investigate the release kinetics of the agent and the antibacterial activity of this newly designed resin system. An experimental resin was prepared by the addition of methacrylic acid as a cation-exchanger and a cationic antibacterial agent, cetylpyridinium chloride (CPC), to triethyleneglycol dimethacrylate. The amount of CPC desorbed from the experimental resin into buffer solutions at pH 4-8 was measured. The adsorption of CPC to control resin and re-adsorption of CPC to the experimental resin, which had once desorbed the agent, were also determined. The antibacterial activity of experimental resin against Streptococcus mutans was evaluated, and the relationship between bacterial acid production and antibacterial effect was assessed. The experimental resin desorbed CPC at pH < or = 6, and the amount of agent desorbed increased with increasing acidity. The control resin adsorbed CPC when immersed in CPC aqueous solution at a rate determined by the concentration of the agent and immersion time. The experimental resin, once desorbed CPC, could re-adsorb the bactericide by being exposed to a solution of the agent. Less plaque formed on the experimental resin, and the growth and survival of S. mutans was inhibited in the condition in which acid was produced. These results demonstrate that the resin system proposed was able to desorb and re-adsorb the cationic bactericide by an ion-exchange mechanism and could show an inhibitory effect on S. mutans growth and plaque formation. PMID:10765955

  11. Lung cancer chemotherapy agents increase procoagulant activity via protein disulfide isomerase-dependent tissue factor decryption.

    PubMed

    Lysov, Zakhar; Swystun, Laura L; Kuruvilla, Sara; Arnold, Andrew; Liaw, Patricia C

    2015-01-01

    Lung cancer patients undergoing chemotherapy have an elevated risk for thrombosis. However, the mechanisms by which chemotherapy agents increase the risk for thrombosis remains unclear. The aim of this study was to determine the mechanism(s) by which lung cancer chemotherapy agents cisplatin, carboplatin, gemcitabine, and paclitaxel elicit increased tissue factor activity on endothelial cells, A549 cells, and monocytes. Tissue factor activity, tissue factor antigen, and phosphatidylserine exposure were measured on chemotherapy-treated human umbilical vein endothelial cells (HUVEC), A549 cells, and monocytes. Cell surface protein disulfide isomerase (PDI) and cell surface free thiol levels were measured on HUVEC and A549 non-small cell lung carcinoma cells. Treatment of HUVECs, A549 cells, and monocytes with lung cancer chemotherapy significantly increased cell surface tissue factor activity. However, elevated tissue factor antigen levels were observed only on cisplatin-treated and gemcitabine-treated monocytes. Cell surface levels of phosphatidylserine were increased on HUVEC and monocytes treated with cisplatin/gemcitabine combination therapy. Chemotherapy also resulted in increased cell surface levels of PDI and reduced cell surface free thiol levels. Glutathione treatment and PDI inhibition, but not phosphatidylserine inhibition, attenuated tissue factor activity. Furthermore, increased tissue factor activity was reversed by reducing cysteines with dithiothreitol. These studies are the first to demonstrate that lung cancer chemotherapy agents increase procoagulant activity on endothelial cells and A549 cells by tissue factor decryption through a disulfide bond formation in a PDI-dependent mechanism. PMID:24911456

  12. Some Anticancer Agents Act on Human Serum Paraoxonase-1 to Reduce Its Activity.

    PubMed

    Alim, Zuhal; Beydemir, Şükrü

    2016-08-01

    Human serum paraoxonase (hPON1) is an important antioxidant enzyme. It protects low-density lipoproteins against oxidative stress and prevents atherosclerosis development. Anticancer agents have cardiotoxic effects, and this situation can lead to significant complications. Our aim was to evaluate the in vitro effects of some of the anticancer agents such as cetuximab, paclitaxel, etoposide, docetaxel, and ifosfamide on the activity of hPON1 in this study. For this reason, PON1 was purified from human serum with a specific activity of 3654.2 EU/mg and 16.84% yield using simple chromatographic methods. The five chemotherapeutic agents dose dependently decreased in vitro hPON1 activity. IC50 values for cetuximab, paclitaxel, etoposide, docetaxel, and ifosfamide were 0.0111, 0.042, 0.226, 0.665, and 23.3 mm, respectively. Ki constants were 0.0194, 0.0165, 0.131, 0.291, and 8.973 mm, respectively. The inhibition mechanisms of cetuximab, etoposide, docetaxel, and ifosfamide were non-competitive, and for paclitaxel was competitive. Consequently, inhibition of hPON1 by these anticancer agents may explain some of the cardiotoxic actions of these drugs. PMID:26873069

  13. Monitoring active volcanoes and mitigating volcanic hazards: the case for including simple approaches

    NASA Astrophysics Data System (ADS)

    Stoiber, Richard E.; Williams, Stanley N.

    1990-07-01

    Simple approaches to problems brought about eruptions and their ensuing hazardous effects should be advocated and used by volcanologists while awaiting more sophisticated remedies. The expedients we advocate have all or many of the following attributes: only locally available materials are required; no extensive training of operators or installation is necessary; they are affordable and do not require foreign aid or exports; they are often labor intensive and are sustainable without outside assistance. Where appropriate, the involvement of local residents is advocated. Examples of simple expedients which can be used in forecasting or mitigating the effects of crises emphasize the relative ease and the less elaborate requirements with which simple approaches can be activated. Emphasis is on visual observations often by untrained observers, simple meteorogical measurements, observations of water level in lakes, temperature and chemistry of springs and fumaroles, new springs and collapse areas and observations of volcanic plumes. Simple methods are suggested which can be applied to mitigating damage from mudflows, nuées ardentes, tephra falls and gas discharge. A review in hindsight at Ruiz includes the use of both chemical indicators and simple mudflow alarms. Simple expedients are sufficiently effective that any expert volcanologist called to aid in a crisis must include them in the package of advice offered. Simple approaches are a critical and logical complement to highly technical solutions to hazardous situations.

  14. Prospective teratology of retinoic acid metabolic blocking agents (RAMBAs) and loss of CYP26 activity.

    PubMed

    McCaffery, P; Simons, C

    2007-01-01

    All-trans retinoic acid (atRA) is the transcriptionally active product of vitamin A and induces gene expression via specific receptors at nM concentrations. Essential enzymes that regulate the local levels of atRA are the CYP26 members of the cytochrome P450 family, which catabolize atRA. Compounds that have been designed to inhibit these enzymes are known as Retinoic Acid Metabolic Blocking Agents (RAMBAs). Treatment with these compounds will raise endogenous atRA levels and may be therapeutic for the treatment of diseases that respond to high atRA concentrations, including several types of cancer as well as skin conditions such as psoriasis and acne. This review describes the mechanism of action of the RAMBAs and discusses the potential side effects of these compounds. atRA is highly teratogenic and the potential teratogenicity of the RAMBAs is described by comparison with the abnormalities resulting from null mutation of individual CYP26 genes. The possible effects of RAMBAs on the adult brain are also described that have the potential for harm but, in the right circumstances, may also be beneficial. PMID:17979744

  15. Balancing the stability and the catalytic specificities of OP hydrolases with enhanced V-agent activities.

    PubMed

    Reeves, T E; Wales, M E; Grimsley, J K; Li, P; Cerasoli, D M; Wild, J R

    2008-06-01

    Rational site-directed mutagenesis and biophysical analyses have been used to explore the thermodynamic stability and catalytic capabilities of organophosphorus hydrolase (OPH) and its genetically modified variants. There are clear trade-offs in the stability of modifications that enhance catalytic activities. For example, the H254R/H257L variant has higher turnover numbers for the chemical warfare agents VX (144 versus 14 s(-1) for the native enzyme (wild type) and VR (Russian VX, 465 versus 12 s(-1) for wild type). These increases are accompanied by a loss in stability in which the total Gibb's free energy for unfolding is 19.6 kcal/mol, which is 5.7 kcal/mol less than that of the wild-type enzyme. X-ray crystallographic studies support biophysical data that suggest amino acid residues near the active site contribute to the chemical and thermal stability through hydrophobic and cation-pi interactions. The cation-pi interactions appear to contribute an additional 7 kcal/mol to the overall global stability of the enzyme. Using rational design, it has been possible to make amino acid changes in this region that restored the stability, yet maintained effective V-agent activities, with turnover numbers of 68 and 36 s(-1) for VX and VR, respectively. This study describes the first rationally designed, stability/activity balance for an OPH enzyme with a legitimate V-agent activity, and its crystal structure. PMID:18434422

  16. Agent-based power sharing scheme for active hybrid power sources

    NASA Astrophysics Data System (ADS)

    Jiang, Zhenhua

    The active hybridization technique provides an effective approach to combining the best properties of a heterogeneous set of power sources to achieve higher energy density, power density and fuel efficiency. Active hybrid power sources can be used to power hybrid electric vehicles with selected combinations of internal combustion engines, fuel cells, batteries, and/or supercapacitors. They can be deployed in all-electric ships to build a distributed electric power system. They can also be used in a bulk power system to construct an autonomous distributed energy system. An important aspect in designing an active hybrid power source is to find a suitable control strategy that can manage the active power sharing and take advantage of the inherent scalability and robustness benefits of the hybrid system. This paper presents an agent-based power sharing scheme for active hybrid power sources. To demonstrate the effectiveness of the proposed agent-based power sharing scheme, simulation studies are performed for a hybrid power source that can be used in a solar car as the main propulsion power module. Simulation results clearly indicate that the agent-based control framework is effective to coordinate the various energy sources and manage the power/voltage profiles.

  17. Evaluation of Colloids and Activation Agents for Determination of Melamine Using UV-SERS

    PubMed Central

    2012-01-01

    UV-SERS measurements offer a great potential for environmental or food (detection of food contaminats) analytics. Here, the UV-SERS enhancement potential of various kinds of metal colloids, such as Pd, Pt, Au, Ag, Au–Ag core–shell, and Ag–Au core–shell with different shapes and sizes, were studied using melamine as a test molecule. The influence of different activation (KF, KCl, KBr, K2SO4) agents onto the SERS activity of the nanomaterials was investigated, showing that the combination of a particular nanoparticle with a special activation agent is extremely crucial for the observed SERS enhancement. In particular, the size dependence of spherical nanoparticles of one particular metal on the activator has been exploited. By doing so, it could be shown that the SERS enhancement increases or decreases for increasing or decreasing size of a nanoparticle, respectively. Overall, the presented results demonstrate the necessity to adjust the nanoparticle size and the activation agent for different experiments in order to achieve the best possible UV-SERS results. PMID:22428076

  18. Biological Agents

    MedlinePlus

    ... to Z Index Contact Us FAQs What's New Biological Agents This page requires that javascript be enabled ... and Health Topics A-Z Index What's New Biological agents include bacteria, viruses, fungi, other microorganisms and ...

  19. Be BOLD: Encouraging Girls to Include Unstructured Bouts of Physical Activity into Daily Routines

    ERIC Educational Resources Information Center

    Hill, Kory; Williams, Gwynne M.

    2014-01-01

    Adolescent girls are less active than their male counterparts and physical activity levels tend to decline as one ages. One of the goals of concerned physical educators is to promote a physically active lifestyle and to teach skills and promote behaviors that will allow students to be active both in and out of school. This article presents a…

  20. Effects of various agents on flagellar activity, flagellar autotomy and cell viability in four species of Chlamydomonas (chlorophyta: volvocales).

    PubMed

    Lewin, R A; Lee, T H; Fang, L S

    1982-01-01

    Over 200 strains of green algal flagellates, representing about 100 species, were examined for their suitability as experimental organisms for studies of flagellar activity. The cells of all species shed their flagella under unfavourable conditions of temperature or pH, or in the presence of alcohols, detergents or toxic agents of various kinds. For further studies of flagellar activity, motility and autotomy (biologically induced shedding) in particular, we selected four species of Chlamydomonas: C. dysosmos Moewus, C. moewusii Gerloff, C. monoica Strehlow and C. reinhardtii Dangeard. Agents found to inhibit motility without inducing death or flagellar autotomy included azide, arsenite, thiosulphate, cyanide, ferricyanide, hydroxylamine, chloral hydrate, malonate, p-chloro-mercury benzoate and cytochalasin-B, each in a limited range of concentrations which differed according to species and strain. Higher concentrations of these agents caused the flagella to be shed. Since flagellar autotomy is a means by which a cell can quickly reduce the area of its permeable surface, it may have a positive survival value for species liable to be subjected to unfavourable physicochemical conditions. PMID:6764045

  1. Using an agent-based model to simulate children’s active travel to school

    PubMed Central

    2013-01-01

    Background Despite the multiple advantages of active travel to school, only a small percentage of US children and adolescents walk or bicycle to school. Intervention studies are in a relatively early stage and evidence of their effectiveness over long periods is limited. The purpose of this study was to illustrate the utility of agent-based models in exploring how various policies may influence children’s active travel to school. Methods An agent-based model was developed to simulate children’s school travel behavior within a hypothetical city. The model was used to explore the plausible implications of policies targeting two established barriers to active school travel: long distance to school and traffic safety. The percent of children who walk to school was compared for various scenarios. Results To maximize the percent of children who walk to school the school locations should be evenly distributed over space and children should be assigned to the closest school. In the case of interventions to improve traffic safety, targeting a smaller area around the school with greater intensity may be more effective than targeting a larger area with less intensity. Conclusions Despite the challenges they present, agent based models are a useful complement to other analytical strategies in studying the plausible impact of various policies on active travel to school. PMID:23705953

  2. Disposal of chemical agents and munitions stored at Umatilla Depot Activity, Hermiston, Oregon. Final Phase 1 environmental report

    SciTech Connect

    Zimmerman, G.P.; Hillsman, E.L.; Johnson, R.O.; Miller, R.L.; Patton, T.G.; Schoepfle, G.M.; Tolbert, V.R.; Feldman, D.L.; Hunsaker, D.B. Jr.; Kroodsma, R.L.; Morrissey, J.; Rickert, L.W.; Staub, W.P.; West, D.C.

    1993-02-01

    The Umatilla Depot Activity (UMDA) near Hermiston, Oregon, is one of eight US Army installations in the continental United States where lethal unitary chemical agents and munitions are stored, and where destruction of agents and munitions is proposed under the Chemical Stockpile Disposal Program (CSDP). The chemical agent inventory at UMDA consists of 11.6%, by weight, of the total US stockpile. The destruction of the stockpile is necessary to eliminate the risk to the public from continued storage and to dispose of obsolete and leaking munitions. In 1988 the US Army issued a Final Programmatic Environmental Impact Statement (FPEIS) for the CSDP that identified on-site disposal of agents and munitions as the environmentally preferred alternative (i.e., the alternative with the least potential to cause significant adverse impacts), using a method based on five measures of risk for potential human health and ecosystem/environmental effects; the effectiveness and adequacy of emergency preparedness capabilities also played a key role in the FPEIS selection methodology. In some instances, the FPEIS included generic data and assumptions that were developed to allow a consistent comparison of potential impacts among programmatic alternatives and did not include detailed conditions at each of the eight installations. The purpose of this Phase 1 report is to examine the proposed implementation of on-site disposal at UMDA in light of more recent and more detailed data than those included in the FPEIS. Specifically, this Phase 1 report is intended to either confirm or reject the validity of on-site disposal for the UMDA stockpile. Using the same computation methods as in the FPEIS, new population data were used to compute potential fatalities from hypothetical disposal accidents. Results indicate that onsite disposal is clearly preferable to either continued storage at UMDA or transportation of the UMDA stockpile to another depot for disposal.

  3. Salinomycin: A Novel Anti-Cancer Agent with Known Anti-Coccidial Activities

    PubMed Central

    Zhou, Shuang; Wang, Fengfei; Wong, Eric T.; Fonkem, Ekokobe; Hsieh, Tze-Chen; Wu, Joseph M.; Wu, Erxi

    2014-01-01

    Salinomycin, traditionally used as an anti-coccidial drug, has recently been shown to possess anti-cancer and anti-cancer stem cell (CSC) effects, as well as activities to overcome multi-drug resistance based on studies using human cancer cell lines, xenograft mice, and in case reports involving cancer patients in pilot clinical trials. Therefore, salinomycin may be considered as a promising novel anti-cancer agent despite its largely unknown mechanism of action. This review summarizes the pharmacologic effects of salinomycin and presents possible mechanisms by which salinomycin exerts its anti-tumorigenic activities. Recent advances and potential complications that might limit the utilization of salinomycin as an anti-cancer and anti-CSC agent are also presented and discussed. PMID:23931281

  4. Vulnerable families as active agents of their own change process: a bidirectional perspective.

    PubMed

    Goh, Esther C L

    2015-04-01

    The literature on successful practice with vulnerable families reports social workers' efforts in forging therapeutic bonds with clients, their ability to both recognize clients' strengths and pain and support them as they work through adversity. Vulnerable families' own contribu- tions to their change process, however, have remained largely opaque. This article offers concrete conceptual tools to consider both social workers and clients from vulnerable families as active agents in the change process. Empirical evidence collected by practitioner-researchers through in-depth discussions with 10 vulnerable families illustrates clients' agentic capacities for autonomy, construction, and action as well as joint construction and maintenance of the helping relationships with social workers, thereby illustrating their active contribution to the process of change. PMID:25929012

  5. Structure and activity of the anticaking agent iron(iii) meso-tartrate.

    PubMed

    Bode, Arno A C; Granneman, Sanne J C; Feiters, Martin C; Verwer, Paul; Jiang, Shanfeng; Meijer, Jan A M; van Enckevort, Willem J P; Vlieg, Elias

    2016-04-12

    Iron(iii) meso-tartrate, a metal-organic complex, is a new anticaking agent for sodium chloride. A molecular structure in solution is proposed, based on a combination of experimental and molecular modelling results. We show that the active complex is a binuclear iron(iii) complex with two bridging meso-tartrate ligands. The iron atoms are antiferromagnetically coupled, resulting in a reduced paramagnetic nature of the solution. In solution, a water molecule coordinates to each iron atom as a sixth ligand, resulting in an octahedral symmetry around each iron atom. When the water molecule is removed, a flat and charged site is exposed, matching the charge distribution of the {100} sodium chloride crystal surface. This charge distribution is also found in the iron(iii) citrate complex, another anticaking agent. This gives a possible adsorption geometry on the crystal surface, which in turn explains the anticaking activity of the iron(iii) meso-tartrate complex. PMID:26974191

  6. Decontamination of adsorbed chemical warfare agents on activated carbon using hydrogen peroxide solutions.

    PubMed

    Osovsky, Ruth; Kaplan, Doron; Nir, Ido; Rotter, Hadar; Elisha, Shmuel; Columbus, Ishay

    2014-09-16

    Mild treatment with hydrogen peroxide solutions (3-30%) efficiently decomposes adsorbed chemical warfare agents (CWAs) on microporous activated carbons used in protective garments and air filters. Better than 95% decomposition of adsorbed sulfur mustard (HD), sarin, and VX was achieved at ambient temperatures within 1-24 h, depending on the H2O2 concentration. HD was oxidized to the nontoxic HD-sulfoxide. The nerve agents were perhydrolyzed to the respective nontoxic methylphosphonic acids. The relative rapidity of the oxidation and perhydrolysis under these conditions is attributed to the microenvironment of the micropores. Apparently, the reactions are favored due to basic sites on the carbon surface. Our findings suggest a potential environmentally friendly route for decontamination of adsorbed CWAs, using H2O2 without the need of cosolvents or activators. PMID:25133545

  7. Comparison of inhibition kinetics of several organophosphates, including some nerve agent surrogates, using human erythrocyte and rat and mouse brain acetylcholinesterase.

    PubMed

    Coban, Alper; Carr, Russell L; Chambers, Howard W; Willeford, Kenneth O; Chambers, Janice E

    2016-04-25

    Because testing of nerve agents is limited to only authorized facilities, our laboratory developed several surrogates that resemble nerve agents because they phosphylate the acetylcholinesterase (AChE) with the same moiety as the actual nerve agents. The inhibition kinetic parameters were determined for AChE by surrogates of cyclosarin (NCMP), sarin (NIMP, PIMP and TIMP) and VX (NEMP and TEMP) and other organophosphorus compounds derived from insecticides. All compounds were tested with rat brain and a subset was tested with mouse brain and purified human erythrocyte AChE. Within the compounds tested on all AChE sources, chlorpyrifos-oxon had the highest molecular rate constant followed by NCMP and NEMP. This was followed by NIMP then paraoxon and DFP with rat and mouse brain AChE but DFP was a more potent inhibitor than NIMP and paraoxon with human AChE. With the additional compounds tested only in rat brain, TEMP was slightly less potent than NEMP but more potent than PIMP which was more potent than NIMP. Methyl paraoxon was slightly less potent than paraoxon but more potent than TIMP which was more potent than DFP. Overall, this study validates that the pattern of inhibitory potencies of our surrogates is comparable to the pattern of inhibitory potencies of actual nerve agents (i.e., cyclosarin>VX>sarin), and that these are more potent than insecticidal organophosphates. PMID:26965078

  8. Sensitive detection of chemical agents and toxic industrial chemicals using active open-path FTIRs

    NASA Astrophysics Data System (ADS)

    Walter, William T.

    2004-03-01

    Active open-path FTIR sensors provide more sensitive detection of chemical agents than passive FTIRs, such as the M21 RSCAAL and JSLSCAD, and at the same time identify and quantify toxic industrial chemicals (TIC). Passive FTIRs are bistatic sensors relying on infrared sources of opportunity. Utilization of earth-based sources of opportunity limits the source temperatures available for passive chemical-agent FTIR sensors to 300° K. Active FTIR chemical-agent sensors utilize silicon carbide sources, which can be operated at 1500° K. The higher source temperature provides more than an 80-times increase in the infrared radiant flux emitted per unit area in the 7 to 14 micron spectral fingerprint region. Minimum detection limits are better than 5 μgm/m3 for GA, GB, GD, GF and VX. Active FTIR sensors can (1) assist first responders and emergency response teams in their assessment of and reaction to a terrorist threat, (2) provide information on the identification of the TIC present and their concentrations and (3) contribute to the understanding and prevention of debilitating disorders analogous to the Gulf War Syndrome for military and civilian personnel.

  9. Novel generation of agents with proven clinical activity in multiple myeloma.

    PubMed

    Mateos, María-Victoria; Ocio, Enrique M; San Miguel, Jesús F

    2013-10-01

    The activity observed with proteasome inhibitors and immunomodulatory drugs (IMIDs) in multiple myeloma (MM) has prompted the development of second- and third-generation agents with similar, but not exactly the same, mechanisms of action as their predecessors. This review summarizes the mechanism of action and the available data on the clinical activity of novel proteasome inhibitors (carfilzomib, oprozomib, ixazomib, and marizomib) and novel IMIDs (pomalidomide), stressing the similarities and differences with bortezomib, and with thalidomide and lenalidomide, respectively. In summary, these novel agents have shown clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their parental drugs; moreover, they may even overcome resistance, indicating that there are some differences in their mechanisms of action and resistance. These data indicate that both the inhibition of the proteasome and the modulation of the immune system are good strategies to target MM tumor cells and this, along with the absence of complete cross-resistance observed among these drugs, open new avenues to optimize their use through the most appropriate sequencing and combinations. PMID:24135407

  10. Insect-gene-activity detection system for chemical and biological warfare agents and toxic industrial chemicals

    NASA Astrophysics Data System (ADS)

    Mackie, Ryan S.; Schilling, Amanda S.; Lopez, Arturo M.; Rayms-Keller, Alfredo

    2002-02-01

    Detection of multiple chemical and biological weapons (CBW) agents and/or complex mixtures of toxic industrial chemicals (TIC) is imperative for both the commercial and military sectors. In a military scenario, a multi-CBW attack would create confusion, thereby delaying decontamination and therapeutic efforts. In the commercial sector, polluted sites invariably contain a mixture of TIC. Novel detection systems capable of detecting CBW and TIC are sorely needed. While it may be impossible to build a detector capable of discriminating all the possible combinations of CBW, a detection system capable of statistically predicting the most likely composition of a given mixture is within the reach of current emerging technologies. Aquatic insect-gene activity may prove to be a sensitive, discriminating, and elegant paradigm for the detection of CBW and TIC. We propose to systematically establish the expression patterns of selected protein markers in insects exposed to specific mixtures of chemical and biological warfare agents to generate a library of biosignatures of exposure. The predicting capabilities of an operational library of biosignatures of exposures will allow the detection of emerging novel or genetically engineered agents, as well as complex mixtures of chemical and biological weapons agents. CBW and TIC are discussed in the context of war, terrorism, and pollution.

  11. A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI.

    PubMed

    von Zur Muhlen, Constantin; Sibson, Nicola R; Peter, Karlheinz; Campbell, Sandra J; Wilainam, Panop; Grau, Georges E; Bode, Christoph; Choudhury, Robin P; Anthony, Daniel C

    2008-03-01

    Human and murine cerebral malaria are associated with elevated levels of cytokines in the brain and adherence of platelets to the microvasculature. Here we demonstrated that the accumulation of platelets in the brain microvasculature can be detected with MRI, using what we believe to be a novel contrast agent, at a time when the pathology is undetectable by conventional MRI. Ligand-induced binding sites (LIBS) on activated platelet glycoprotein IIb/IIIa receptors were detected in the brains of malaria-infected mice 6 days after inoculation with Plasmodium berghei using microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody specific for the LIBS (LIBS-MPIO). No binding of the LIBS-MPIO contrast agent was detected in uninfected animals. A combination of LIBS-MPIO MRI, confocal microscopy, and transmission electron microscopy revealed that the proinflammatory cytokine TNF-alpha, but not IL-1beta or lymphotoxin-alpha (LT-alpha), induced adherence of platelets to cerebrovascular endothelium. Peak platelet adhesion was found 12 h after TNF-alpha injection and was readily detected with LIBS-MPIO contrast-enhanced MRI. Temporal studies revealed that the level of MPIO-induced contrast was proportional to the number of platelets bound. Thus, the LIBS-MPIO contrast agent enabled noninvasive detection of otherwise undetectable cerebral pathology by in vivo MRI before the appearance of clinical disease, highlighting the potential of targeted contrast agents for diagnostic, mechanistic, and therapeutic studies. PMID:18274670

  12. A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI

    PubMed Central

    von zur Muhlen, Constantin; Sibson, Nicola R.; Peter, Karlheinz; Campbell, Sandra J.; Wilainam, Panop; Grau, Georges E.; Bode, Christoph; Choudhury, Robin P.; Anthony, Daniel C.

    2008-01-01

    Human and murine cerebral malaria are associated with elevated levels of cytokines in the brain and adherence of platelets to the microvasculature. Here we demonstrated that the accumulation of platelets in the brain microvasculature can be detected with MRI, using what we believe to be a novel contrast agent, at a time when the pathology is undetectable by conventional MRI. Ligand-induced binding sites (LIBS) on activated platelet glycoprotein IIb/IIIa receptors were detected in the brains of malaria-infected mice 6 days after inoculation with Plasmodium berghei using microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody specific for the LIBS (LIBS-MPIO). No binding of the LIBS-MPIO contrast agent was detected in uninfected animals. A combination of LIBS-MPIO MRI, confocal microscopy, and transmission electron microscopy revealed that the proinflammatory cytokine TNF-α, but not IL-1β or lymphotoxin-α (LT-α), induced adherence of platelets to cerebrovascular endothelium. Peak platelet adhesion was found 12 h after TNF-α injection and was readily detected with LIBS-MPIO contrast-enhanced MRI. Temporal studies revealed that the level of MPIO-induced contrast was proportional to the number of platelets bound. Thus, the LIBS-MPIO contrast agent enabled noninvasive detection of otherwise undetectable cerebral pathology by in vivo MRI before the appearance of clinical disease, highlighting the potential of targeted contrast agents for diagnostic, mechanistic, and therapeutic studies. PMID:18274670

  13. In Vitro and In Vivo Antidermatophyte Activities of NND-502, a Novel Optically Active Imidazole Antimycotic Agent

    PubMed Central

    Niwano, Yoshimi; Kuzuhara, Naoki; Kodama, Hiroki; Yoshida, Masanori; Miyazaki, Tsuneo; Yamaguchi, Hideyo

    1998-01-01

    In vitro and in vivo antidermatophyte activities of NND-502, a new imidazole antimycotic agent, were compared with those of two existing antifungal agents, lanoconazole and terbinafine. NND-502 exhibited strong in vitro antifungal activity against Trichophyton spp.; its MIC was 1 to 4 times lower than that of lanoconazole or terbinafine. In an in vivo study with a guinea pig model of tinea pedis, 7-day topical treatment with a 0.5% solution of NND-502 (dissolved in polyethylene glycol 400) was more effective than that with a 0.5% solution of either lanoconazole or terbinafine for eradicating fungi from the infected feet. When the duration of treatment was shortened to 3 days, a topical 1% solution of NND-502 achieved a complete mycological cure, while topical 1% solutions of lanoconazole and terbinafine did not. PMID:9559824

  14. Cilofungin (LY121019), an antifungal agent with specific activity against Candida albicans and Candida tropicalis.

    PubMed Central

    Hall, G S; Myles, C; Pratt, K J; Washington, J A

    1988-01-01

    Cilofungin (LY121019) is an antifungal agent that interferes with beta-glucan synthesis in the cells walls of fungi. The activity of this agent against 256 clinical isolates of yeasts was determined. It was found to be very active in vitro against Candida albicans (MIC for 90% of isolates [MIC90], less than or equal to 0.31 microgram/ml; minimal fungicidal concentration for 90% of isolates [MFC90], less than or equal to 0.31 micrograms/ml) and C. tropicalis (MIC90, less than or equal to 0.31 microgram/ml; MFC90, less than or equal to 0.31 microgram/ml) and moderately active against Torulopsis glabrata (MIC90 and MFC90, less than or equal to 20 micrograms/ml). All C. parapsilosis, Cryptococcus, and Saccharomyces cerevisiae strains were resistant. The activity of cilofungin was affected by medium and inoculum size. Antibiotic medium no. 3 was used as the standard medium. Isolates of C. albicans and C. tropicalis demonstrated a paradoxical effect in Sabouraud dextrose broth and yeast nitrogen base broth in that growth was partially inhibited at MICs equivalent to those in antibiotic medium no. 3, but growth continued, in many instances, throughout all concentrations tested. There was decreased activity of cilofungin with inocula greater than 10(5) CFU/ml. The temperature and duration of incubation did not affect its activity. Images PMID:3058017

  15. [Synthesis and antifungal activity of butenafine hydrochloride (KP-363), a new benzylamine antifungal agent].

    PubMed

    Maeda, T; Takase, M; Ishibashi, A; Yamamoto, T; Sasaki, K; Arika, T; Yokoo, M; Amemiya, K

    1991-02-01

    In screening of new antifungal agents, bis(naphthalenemethyl)amines were found to have more potent antifungal activity than clotrimazole. Studies on their structure-activity relationships indicated that benzylamines had potent antifungal activity. Among them, butenafine hydrochloride (N-p-tert-butylbenzyl-N-methyl-1-naphthalenemethylamine hydrochloride, KP-363) has proved to show the strongest activity. It exhibits a wide spectrum activity in vitro against particularly dermatophytes (87 strains; minimal inhibitory concentration (MIC) range, 0.0015 to 0.05 microgram/ml), and also against Aspergillus (15 strains; MIC range, 0.025 to 0.78 microgram/ml), Cryptococcus neoformans (4 strains; MICs 0.78 and 1.56 micrograms/ml) and yeasts of genus Candida (67 strains; MIC range, 3.13 to greater than 100 micrograms/ml). PMID:2056447

  16. Design, diversity-oriented synthesis and structure activity relationship studies of quinolinyl heterocycles as antimycobacterial agents.

    PubMed

    Rachakonda, Venkatesham; Alla, Manjula; Kotipalli, Sudha Sravanti; Ummani, Ramesh

    2013-01-01

    The current study reports design and diversity oriented synthesis of novel bis heterocycles with a common 2-methyl, C-4 unsubstituted quinoline moiety as the central key heterocycle. Employing reagent based skeletal diversity approach; a facile synthesis of bis heterocycles with different heterocyclic rings at C-3 position of the quinoline moiety has been accomplished. A broad range of heterocyclic frameworks thus obtained were evaluated for their antimycobacterial activity. The active scaffolds were further explored by a parallel library generation in order to establish SAR. Further, low cytotoxicity against A549 cell line enhances the potential of the synthesized molecules as promising antimycobacterial agents. PMID:24189497

  17. Using Assistive Technology Adaptations To Include Students with Learning Disabilities in Cooperative Learning Activities.

    ERIC Educational Resources Information Center

    Bryant, Diane Pedrotty; Bryant, Brian R.

    1998-01-01

    Discusses a process for integrating technology adaptations for students with learning disabilities into cooperative-learning activities in terms of three components: (1) selecting adaptations; (2) monitoring use of adaptations during cooperative-learning activities; and (3) evaluating the adaptations' effectiveness. Barriers to and support systems…

  18. Interest Inventory. [Includes Academic Interest Measure, Pupil Activity Inventory, and Semantic Differential].

    ERIC Educational Resources Information Center

    Harvard Univ., Cambridge, MA. Harvard Project Physics.

    This Interest Inventory contains three inventories: Academic Interest Measure (AIM), Pupil Activity Inventory (PAI), and Semantic Differential test (SD). The AIM measures six subscales of academic interests; the PAI measures non-school activities in science; and the SD measures attitudes toward science and physics. The inventories are designed for…

  19. A structure-activity analysis of the variation in oxime efficacy against nerve agents.

    PubMed

    Maxwell, Donald M; Koplovitz, Irwin; Worek, Franz; Sweeney, Richard E

    2008-09-01

    A structure-activity analysis was used to evaluate the variation in oxime efficacy of 2-PAM, obidoxime, HI-6 and ICD585 against nerve agents. In vivo oxime protection and in vitro oxime reactivation were used as indicators of oxime efficacy against VX, sarin, VR and cyclosarin. Analysis of in vivo oxime protection was conducted with oxime protective ratios (PR) from guinea pigs receiving oxime and atropine therapy after sc administration of nerve agent. Analysis of in vitro reactivation was conducted with second-order rate contants (k(r2)) for oxime reactivation of agent-inhibited acetylcholinesterase (AChE) from guinea pig erythrocytes. In vivo oxime PR and in vitro k(r2) decreased as the volume of the alkylmethylphosphonate moiety of nerve agents increased from VX to cyclosarin. This effect was greater with 2-PAM and obidoxime (>14-fold decrease in PR) than with HI-6 and ICD585 (<3.7-fold decrease in PR). The decrease in oxime PR and k(r2) as the volume of the agent moiety conjugated to AChE increased was consistent with a steric hindrance mechanism. Linear regression of log (PR-1) against log (k(r2)[oxime dose]) produced two offset parallel regression lines that delineated a significant difference between the coupling of oxime reactivation and oxime protection for HI-6 and ICD585 compared to 2-PAM and obidoxime. HI-6 and ICD585 appeared to be 6.8-fold more effective than 2-PAM and obidoxime at coupling oxime reactivation to oxime protection, which suggested that the isonicotinamide group that is common to both of these oximes, but absent from 2-PAM and obidoxime, is important for oxime efficacy. PMID:18508103

  20. A structure-activity analysis of the variation in oxime efficacy against nerve agents

    SciTech Connect

    Maxwell, Donald M. Koplovitz, Irwin; Worek, Franz; Sweeney, Richard E.

    2008-09-01

    A structure-activity analysis was used to evaluate the variation in oxime efficacy of 2-PAM, obidoxime, HI-6 and ICD585 against nerve agents. In vivo oxime protection and in vitro oxime reactivation were used as indicators of oxime efficacy against VX, sarin, VR and cyclosarin. Analysis of in vivo oxime protection was conducted with oxime protective ratios (PR) from guinea pigs receiving oxime and atropine therapy after sc administration of nerve agent. Analysis of in vitro reactivation was conducted with second-order rate contants (k{sub r2}) for oxime reactivation of agent-inhibited acetylcholinesterase (AChE) from guinea pig erythrocytes. In vivo oxime PR and in vitro k{sub r2} decreased as the volume of the alkylmethylphosphonate moiety of nerve agents increased from VX to cyclosarin. This effect was greater with 2-PAM and obidoxime (> 14-fold decrease in PR) than with HI-6 and ICD585 (< 3.7-fold decrease in PR). The decrease in oxime PR and k{sub r2} as the volume of the agent moiety conjugated to AChE increased was consistent with a steric hindrance mechanism. Linear regression of log (PR-1) against log (k{sub r2} {center_dot} [oxime dose]) produced two offset parallel regression lines that delineated a significant difference between the coupling of oxime reactivation and oxime protection for HI-6 and ICD585 compared to 2-PAM and obidoxime. HI-6 and ICD585 appeared to be 6.8-fold more effective than 2-PAM and obidoxime at coupling oxime reactivation to oxime protection, which suggested that the isonicotinamide group that is common to both of these oximes, but absent from 2-PAM and obidoxime, is important for oxime efficacy.

  1. Novel ROS-activated agents utilize a tethered amine to selectively target acute myeloid leukemia

    PubMed Central

    Bell-Horwath, Tiffany R.; Vadukoot, Anish Kizhakkekkara; Thowfeik, Fathima Shazna; Li, Guorui; Wunderlich, Mark; Mulloy, James C.; Merino, Edward J.

    2013-01-01

    This study explores the possible use of reactive oxygen-activated DNA modifying agents against acute myeloid leukemia (AML). A key amine on the lead agent was investigated via cytotoxicity assays and was found necessary for potency. The two best compounds were screened via the NCI-60 cell panel. These two compounds had potency between 200 and 800 nM against many of the leukemia cancer cell types. Subsequent experiments explored activity against a transformed AML model that mimics the molecular signatures identified in primary AML patient samples. A lead compound had an IC50 of 760 nM against this AML cell line as well as a therapeutic index of 7.7 ± 3 between the transformed AML model cell line and non-cancerous human CD34+ blood stem/progenitor cells (UCB). The selectivity was much greater than the mainstays of AML treatment: doxorubicin and cytarabine. This manuscript demonstrates that this novel type of agent may be useful against AML. PMID:23578690

  2. NIR-activated iron oxides as a new multi-functional contrast agent of photoacoustic imaging

    NASA Astrophysics Data System (ADS)

    Ting, Pei-Hsien; Huang, Chih-Chia; Li, Meng-Lin

    2014-03-01

    Iron oxide nanoparticles are commonly used contrast agents for theranostic nanomedicines because of their advantages of good biocompatibility, high stability in physiological conditions, low cytotoxicity and excellent safety record in clinical settings for human use. In this study, we developed a NIR-activated iron oxide (NIR-Fe3O4) nanoparticle as a new multi-functional contrast agent of photoacoustic (PA) imaging. Unlike traditional iron oxides, the developed NIR-Fe3O4 owns biocompatibility and optical tunability capable of providing strong optical absorption in the NIR range for PA signal generation. Its intrinsic magnetic property enables the active magnetic tumor targeting. Phantom experiments were performed to confirm the tunability of NIR-Fe3O4's optical absorption in NIR and demonstrate its magnetic targeting capability. The PA signal response of NIR-Fe3O4 as a function of concentration was also investigated. The results showed that the PA signal of NIR-Fe3O4 with OD=1.25 was comparable to that of blood at 715 nm - the wavelength of peak absorption of the used NIR-Fe3O4. Moreover, the PA signal from NIR-Fe3O4 could be further improved by magnetic targeting. Overall, we proved that the potential of the developed NIR-Fe3O4 as a good tumor targeting contrast agent of PA imaging.

  3. Antibacterial activity and ion release of bonding agent containing amorphous calcium phosphate nanoparticles

    PubMed Central

    Chen, Chen; Weir, Michael D.; Cheng, Lei; Lin, Nancy; Lin-Gibson, Sheng; Chow, Laurence C.; Zhou, Xuedong; Xu, Hockin H. K.

    2015-01-01

    Objectives Recurrent caries at the margins is a primary reason for restoration failure. The objectives of this study were to develop bonding agent with the double benefits of antibacterial and remineralizing capabilities, to investigate the effects of NACP filler level and solution pH on Ca and P ion release from adhesive, and to examine the antibacterial and dentin bond properties. Methods Nanoparticles of amorphous calcium phosphate (NACP) and a quaternary ammonium monomer (dimethylaminododecyl methacrylate, DMADDM) were synthesized. Scotchbond Multi-Purpose (SBMP) primer and adhesive served as control. DMADDM was incorporated into primer and adhesive at 5% by mass. NACP was incorporated into adhesive at filler mass fractions of 10%, 20%, 30% and 40%. A dental plaque microcosm biofilm model was used to test the antibacterial bonding agents. Calcium (Ca) and phosphate (P) ion releases from the cured adhesive samples were measured vs. filler level and solution pH of 7, 5.5 and 4. Results Adding 5% DMADDM and 10–40% NACP into bonding agent, and water-aging for 28 days, did not affect dentin bond strength, compared to SBMP control at 1 day (p > 0.1). Adding DMADDM into bonding agent substantially decreased the biofilm metabolic activity and lactic acid production. Total microorganisms, total streptococci, and mutans streptococci were greatly reduced for bonding agents containing DMADDM. Increasing NACP filler level from 10% to 40% in adhesive increased the Ca and P ion release by an order of magnitude. Decreasing solution pH from 7 to 4 increased the ion release from adhesive by 6–10 folds. Significance Bonding agents containing antibacterial DMADDM and remineralizer NACP were formulated to have Ca and P ion release, which increased with NACP filler level from 10% to 40% in adhesive. NACP adhesive was “smart” and dramatically increased the ion release at cariogenic pH 4, when these ions would be most-needed to inhibit caries. Therefore, bonding agent

  4. The application of click chemistry in the synthesis of agents with anticancer activity

    PubMed Central

    Ma, Nan; Wang, Ying; Zhao, Bing-Xin; Ye, Wen-Cai; Jiang, Sheng

    2015-01-01

    The copper(I)-catalyzed 1,3-dipolar cycloaddition between alkynes and azides (click chemistry) to form 1,2,3-triazoles is the most popular reaction due to its reliability, specificity, and biocompatibility. This reaction has the potential to shorten procedures, and render more efficient lead identification and optimization procedures in medicinal chemistry, which is a powerful modular synthetic approach toward the assembly of new molecular entities and has been applied in anticancer drugs discovery increasingly. The present review focuses mainly on the applications of this reaction in the field of synthesis of agents with anticancer activity, which are divided into four groups: topoisomerase II inhibitors, histone deacetylase inhibitors, protein tyrosine kinase inhibitors, and antimicrotubule agents. PMID:25792812

  5. The in vitro activity of 15 antimicrobial agents against bacterial isolates from dogs.

    PubMed

    Awji, Elias Gebru; Damte, Dereje; Lee, Seung-Jin; Lee, Joong-Su; Kim, Young-Hoan; Park, Seung-Chun

    2012-08-01

    The in vitro activity of 15 antimicrobial agents against clinical isolates of Staphylococcus pseudintermedius, Staphylococcus aureus, Escherichia coli, Pasteurella spp. and Streptococcus canis from dogs was investigated. For Staphylococcus spp., the highest frequency of resistance was observed for penicillin, followed by ampicillin, tetracycline and chloramphenicol. The highest frequency of resistance in E. coli isolates was recorded for tetracycline and streptomycin. Pasteurella spp. and S. canis had the highest resistance rate for tetracycline and chloramphenicol. Most isolates showed full susceptibility to low-level resistance to colistin, florfenicol and fluoroquinolones. Further studies using larger number of isolates from both healthy and diseased dogs would provide a broader picture of antimicrobial resistance at a national level and promote prudent use of antimicrobial agents in companion animals. PMID:22516694

  6. Intracellular activity of clinical concentrations of phenothiazines including thioridiazine against phagocytosed Staphylococcus aureus.

    PubMed

    Ordway, Diane; Viveiros, Miguel; Leandro, Clara; Arroz, Maria Jorge; Amaral, Leonard

    2002-07-01

    The effect of thioridazine (TZ) was studied on the killing activity of human peripheral blood monocyte derived macrophages (HPBMDM) and of human macrophage cell line THP-1 at extracellular concentrations below those achievable clinically. These macrophages have nominal killing activity against bacteria and therefore, would not influence any activity that the compounds may have against intracellular localised Staphylococcus aureus. The results indicated that whereas TZ has an in vitro minimum inhibitory concentration (MIC) against the strains of S. aureus of 18, 0.1 mg/l of TZ in the medium completely inhibits the growth of S. aureus that has been phagocytosed by macrophages. The latter concentration was non-toxic to macrophages, did not cause cellular expression of activation marker CD69 nor induction of CD3+ T cell production of IFN-gamma, but blocked cellular proliferation and down-regulated the production of T cell-derived cytokines (IFN-gamma, IL-5). These results suggest that TZ induces intracellular bactericidal activities independent of the capacity to generate Type 1 responses against S. aureus. PMID:12127709

  7. Diffractive laser beam homogenizer including a photo-active material and method of fabricating the same

    DOEpatents

    Bayramian, Andy J; Ebbers, Christopher A; Chen, Diana C

    2014-05-20

    A method of manufacturing a plurality of diffractive optical elements includes providing a partially transmissive slide, providing a first piece of PTR glass, and directing first UV radiation through the partially transmissive slide to impinge on the first piece of PTR glass. The method also includes exposing predetermined portions of the first piece of PTR glass to the first UV radiation and thermally treating the exposed first piece of PTR glass. The method further includes providing a second piece of PTR glass and directing second UV radiation through the thermally treated first piece of PTR glass to impinge on the second piece of PTR glass. The method additionally includes exposing predetermined portions of the second piece of PTR glass to the second UV radiation, thermally treating the exposed second piece of PTR glass, and repeating providing and processing of the second piece of PTR glass using additional pieces of PTR glass.

  8. Surface-Active Agents for Isolation of the Core Component of Avian Myeloblastosis Virus 1

    PubMed Central

    Stromberg, Kurt

    1972-01-01

    Sixty-one surface-active agents were evaluated in a procedure designed to assess their ability to remove the envelope from the core component of avian myeloblastosis virus (AMV). The procedure consisted of centrifugation of intact AMV through a series of sucrose gradients each containing an upper layer of agent at one of eight concentrations between 0.01 and 10%. The effectiveness of an agent in producing AMV cores was indicated by (i) the appearance of light-scattering bands in the region of core buoyant density in gradient tubes; (ii) the range of surfactant concentration over which these bands appeared; and (iii) an electron microscopy assessment by the negative-staining technique of the relative proportion of core to non-core material in each of these bands. Six nonionic surfactants were selected by this screening method for comparison in regard to recovery of core protein and endogenous ribonucleic acid (RNA)-dependent deoxyribonucleic acid (DNA) polymerase activity, as well as further morphologic evaluation by electron microscopy. The nonionic surfactants of the polyoxyethylene alcohol class (particularly, Sterox SL) were most effective. Nonionic surfactants of the polyoxyethylene alkylphenol class (particularly, Nonidet P-40) were also effective. Sterox SL and Nonidet P-40 each gave a more than fivefold increase in specific activity of endogenous RNA-dependent DNA polymerase, and each gave a low recovery of core protein. Sterox SL did not interfere to the extent that Nonidet P-40 did in procedures which involved spectrophotometric assay at 260 nm. The use of Sterox SL resulted in the least envelope contamination of core preparations by electron microscopy examination, the most recovery of protein and endogenous RNA-dependent DNA polymerase activity, and a core buoyant density in sucrose of 1.27 g/ml. Images PMID:4112071

  9. Hypoxia-directed and activated theranostic agent: Imaging and treatment of solid tumor.

    PubMed

    Kumar, Rajesh; Kim, Eun-Joong; Han, Jiyou; Lee, Hyunseung; Shin, Weon Sup; Kim, Hyun Min; Bhuniya, Sankarprasad; Kim, Jong Seung; Hong, Kwan Soo

    2016-10-01

    Hypoxia, a distinguished feature of various solid tumors, has been considered as a key marker for tumor progression. Inadequate vasculature and high interstitial pressures result in relatively poor drug delivery to these tumors. Herein, we developed an antitumor theranostic agent, 4, which is activated in hypoxic conditions and can be used for the diagnosis and treatment of solid tumors. Compound 4, bearing biotin, a tumor-targeting unit, and SN38, an anticancer drug, proved to be an effective theranostic agent for solid tumors. SN38 plays a dual role: as an anticancer drug for therapy and as a fluorophore for diagnosis, thus avoids an extra fluorophore and limits cytotoxicity. Compound 4, activated in the hypoxic environment, showed high therapeutic activity in A549 and HeLa cells and spheroids. In vivo imaging of solid tumors confirmed the tumor-specific localization, deep tissue penetration and activation of compound 4, as well as the production of a strong anticancer effect through the inhibition of tumor growth in a xenograft mouse model validating it as a promising strategy for the treatment of solid tumors. PMID:27449948

  10. Electrode including porous particles with embedded active material for use in a secondary electrochemical cell

    DOEpatents

    Vissers, Donald R.; Nelson, Paul A.; Kaun, Thomas D.; Tomczuk, Zygmunt

    1978-04-25

    Particles of carbonaceous matrices containing embedded electrode active material are prepared for vibratory loading within a porous electrically conductive substrate. In preparing the particles, active materials such as metal chalcogenides, solid alloys of alkali or alkaline earth metals along with other metals and their oxides in powdered or particulate form are blended with a thermosetting resin and particles of a volatile to form a paste mixture. The paste is heated to a temperature at which the volatile transforms into vapor to impart porosity at about the same time as the resin begins to cure into a rigid, solid structure. The solid structure is then comminuted into porous, carbonaceous particles with the embedded active material.

  11. In vitro activities of antimicrobial agents against clinical isolates of Flavimonas oryzihabitans obtained from patients with cancer.

    PubMed

    Rolston, K V; Ho, D H; LeBlanc, B; Bodey, G P

    1993-11-01

    We evaluated the in vitro activities of 21 different antimicrobial agents against nine clinical isolates of Flavimonas oryzihabitans obtained from patients with cancer. The organisms were susceptible to most agents commonly used for the empiric therapy (aminoglycosides, ureidopenicillins, extended-spectrum cephalosporins, monobactams, and carbapenems) and prevention of infections (quinolones and trimethoprim-sulfamethoxazole) in this patient population. PMID:8285645

  12. Sixty Minutes of Physical Activity per Day Included within Preschool Academic Lessons Improves Early Literacy

    ERIC Educational Resources Information Center

    Kirk, Stacie M.; Kirk, Erik P.

    2016-01-01

    Background: The effects of increases in physical activity (PA) on early literacy skills in preschool children are not known. Methods: Fifty-four African-American preschool children from a low socioeconomic urban Head Start participated over 8 months. A 2-group, quasi-experimental design was used with one preschool site participating in the PA…

  13. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... AGRICULTURE ALMONDS GROWN IN CALIFORNIA Administrative Rules and Regulations § 981.441 Credit for market... each activity shall be to promote the sale, consumption or use of California almonds, and nothing... in California almond growing counties with more than 1,000 bearing acres: Provided, That...

  14. Observing a fictitious stressful event: haematological changes, including circulating leukocyte activation.

    PubMed

    Mian, Rubina; Shelton-Rayner, Graham; Harkin, Brendan; Williams, Paul

    2003-03-01

    The aim of this study was to assess the effect of watching a psychological stressful event on the activation of leukocytes in healthy human volunteers. Blood samples were obtained from 32 healthy male and female subjects aged between 20 and 26 years before, during and after either watching an 83-minute horror film that none of the subjects had previously seen (The Texas Chainsaw Massacre, 1974) or by sitting quietly in a room (control group). Total differential cell counts, leukocyte activation as measured by the nitroblue tetrazolium (NBT) test, heart rate and blood pressure (BP) measurements were taken at defined time points. There were significant increases in peripheral circulating leukocytes, the number of activated circulating leukocytes, haemoglobin (Hb) concentration and haematocrit (Hct) in response to the stressor. These were accompanied by significant increases in heart rate, systolic and diastolic BP (P<0.05 from baseline). This is the first reported study on the effects of observing a psychologically stressful, albeit fictitious event on circulating leukocyte numbers and the state of leukocyte activation as determined by the nitrotetrazolium test. PMID:12637206

  15. Backyards and Butterflies: Ways to Include Children with Disabilities in Outdoor Activities.

    ERIC Educational Resources Information Center

    Greenstein, Doreen; And Others

    This sourcebook is designed for children, parents, and families, detailing ideas for outdoor play and learning activities, with emphasis on involving children with disabilities in outdoor play. A rural perspective permeates the guide, although each chapter contains ideas for making outdoor environments more accessible and safer for all children,…

  16. Beyond Right or Wrong: Challenges of Including Creative Design Activities in the Classroom

    ERIC Educational Resources Information Center

    Brennan, Karen

    2015-01-01

    In this article, we explore challenges encountered by K-12 educators in establishing classroom cultures that support creative learning activities with the Scratch programming language. Providing opportunities for students to understand and to build capacities for creative work was described by many of the teachers that we interviewed as a central…

  17. Physical Activity Programs in Higher Education: Modifying Net/Wall Games to Include Individuals with Disabilities

    ERIC Educational Resources Information Center

    Braga, Luciana; Tracy, Julia F.; Taliaferro, Andrea R.

    2015-01-01

    The growing number of students with disabilities in higher education settings has presented challenges for instructors with regards to appropriate inclusion. Concerning physical activity courses in higher education, instructors may not have the knowledge or resources to make modifications and accommodations that will ultimately result in…

  18. Population and Human Development: A Course Curriculum Including Lesson Plans, Activities and Bibliography.

    ERIC Educational Resources Information Center

    Murphy, Elaine M.

    This course outline suggests materials and learning activities on the interrelated causes and consequences of population growth and other population concerns. Designed to educate general college audiences, it is also intended for use as a preservice course for teachers. In addition, the course can be modified for high school students. The course…

  19. A novel peptide inhibitor of classical and lectin complement activation including ABO incompatibility

    PubMed Central

    Mauriello, Clifford T.; Pallera, Haree K.; Sharp, Julia A.; Woltmann, Jon L.; Qian, Shizhi; Hair, Pamela S.; van der Pol, Pieter; van Kooten, Cees; Thielens, Nicole M.; Lattanzio, Frank A.; Cunnion, Kenji M.; Krishna, Neel K.

    2012-01-01

    Previous experiments from our laboratories have identified peptides derived from the human astrovirus coat protein (CP) that bind C1q and mannose binding lectin (MBL) inhibiting activation of the classical and lectin pathways of complement, respectively. The purpose of this study was to evaluate the function of these coat protein peptides (CPPs) in an in vitro model of complement-mediated disease (ABO incompatibility), preliminarily assess their in vivo complement suppression profile and develop more highly potent derivatives of these molecules. E23A, a 30 amino acid CPP derivative previously demonstrated to inhibit classical pathway activation was able to dose-dependently inhibit lysis of AB erythrocytes treated with mismatched human O serum. Additionally, when injected into rats, E23A inhibited the animals’ serum from lysing antibody-sensitized erythrocytes, providing preliminary in vivo functional evidence that this CPP can cross the species barrier to inhibit serum complement activity in rodents. A rational drug design approach was implemented to identify more potent CPP derivatives, resulting in the identification and characterization of a 15 residue peptide (Polar Assortant (PA)), which demonstrated both superior inhibition of classical complement pathway activation and robust binding to C1q collagen-like tails. PA also inhibited ABO incompatibility in vitro and demonstrated in vivo complement suppression up to 24 hours post-injection. CPP’s ability to inhibit ABO incompatibility in vitro, proof of concept in vivo inhibitory activity in rats and the development of the highly potent PA derivative set the stage for preclinical testing of this molecule in small animal models of complement-mediated disease. PMID:22906481

  20. An Updated Review of Interventions that Include Promotion of Physical Activity for Adult Men.

    PubMed

    Bottorff, Joan L; Seaton, Cherisse L; Johnson, Steve T; Caperchione, Cristina M; Oliffe, John L; More, Kimberly; Jaffer-Hirji, Haleema; Tillotson, Sherri M

    2015-06-01

    The marked disparity in life expectancy between men and women suggests men are a vulnerable group requiring targeted health promotion programs. As such, there is an increasing need for health promotion strategies that effectively engage men with their health and/or illness management. Programs that promote physical activity could significantly improve the health of men. Although George et al. (Sports Med 42(3):281, 30) reviewed physical activity programs involving adult males published between 1990 and 2010, developments in men's health have prompted the emergence of new sex- and gender-specific approaches targeting men. The purpose of this review was to: (1) extend and update the review undertaken by George et al. (Sports Med 42(3):281, 30) concerning the effectiveness of physical activity programs in males, and (2) evaluate the integration of gender-specific influences in the content, design, and delivery of men's health promotion programs. A search of MEDLINE, CINAHL, ScienceDirect, Web of Science, PsycINFO, the Cochrane Library, and the SPORTDiscus databases for articles published between January 2010 and August 2014 was conducted. In total, 35 studies, involving evaluations of 31 programs, were identified. Findings revealed that a variety of techniques and modes of delivery could effectively promote physical activity among men. Though the majority of programs were offered exclusively to men, 12 programs explicitly integrated gender-related influences in male-specific programs in ways that recognized men's interests and preferences. Innovations in male-only programs that focus on masculine ideals and gender influences to engage men in increasing their physical activity hold potential for informing strategies to promote other areas of men's health. PMID:25430599

  1. Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis.

    PubMed

    Tabata, Yuji; Takei-Masuda, Naomi; Kubota, Natsuki; Takahata, Sho; Ohyama, Makoto; Kaneda, Kaori; Iida, Maiko; Maebashi, Kazunori

    2016-02-01

    Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and an MIC50 and MIC90 of 0.5 mg/liter for both. Importantly, none of the tested isolates showed an elevated ME1111 MIC. Moreover, the antifungal activity of ME1111 was minimally affected by 5% wool keratin powder in comparison to the other antifungals tested. The ME1111 solution was able to penetrate human nails and inhibit fungal growth in a dose-dependent manner according to the TurChub assay. In contrast, 8% ciclopirox and 5% amorolfine nail lacquers showed no activity under the same conditions. ME1111 demonstrated approximately 60-fold-greater selectivity in inhibition of Trichophyton spp. than of human cell lines. Our findings demonstrate that ME1111 possesses potent antidermatophyte activity, maintains this activity in the presence of keratin, and possesses excellent human nail permeability. These results suggest that ME1111 is a promising topical medication for the treatment of onychomycosis and therefore warrants further clinical evaluation. PMID:26643333

  2. Redox-active compounds with a history of human use: antistaphylococcal action and potential for repurposing as topical antibiofilm agents

    PubMed Central

    Ooi, N.; Eady, E. A.; Cove, J. H.; O'Neill, A. J.

    2015-01-01

    Objectives To investigate the antistaphylococcal/antibiofilm activity and mode of action (MOA) of a panel of redox-active (RA) compounds with a history of human use and to provide a preliminary preclinical assessment of their potential for topical treatment of staphylococcal infections, including those involving a biofilm component. Methods Antistaphylococcal activity was evaluated by broth microdilution and by time–kill studies with growing and slow- or non-growing cells. The antibiofilm activity of RA compounds, alone and in combination with established antibacterial agents, was assessed using the Calgary Biofilm Device. Established assays were used to examine the membrane-perturbing effects of RA compounds, to measure penetration into biofilms and physical disruption of biofilms and to assess resistance potential. A living skin equivalent model was used to assess the effects of RA compounds on human skin. Results All 15 RA compounds tested displayed antistaphylococcal activity against planktonic cultures (MIC 0.25–128 mg/L) and 7 eradicated staphylococcal biofilms (minimum biofilm eradication concentration 4–256 mg/L). The MOA of all compounds involved perturbation of the bacterial membrane, whilst selected compounds with antibiofilm activity caused destructuring of the biofilm matrix. The two most promising agents [celastrol and nordihydroguaiaretic acid (NDGA)] in respect of antibacterial potency and selective toxicity against bacterial membranes acted synergistically with gentamicin against biofilms, did not damage artificial skin following topical application and exhibited low resistance potential. Conclusions In contrast to established antibacterial drugs, some RA compounds are capable of eradicating staphylococcal biofilms. Of these, celastrol and NDGA represent particularly attractive candidates for development as topical antistaphylococcal biofilm treatments. PMID:25368206

  3. Space Resources for Teachers: Biology, Including Suggestions for Classroom Activities and Laboratory Experiments.

    ERIC Educational Resources Information Center

    Lee, Tom E.; And Others

    This compilation of resource units concerns the latest developments in space biology. Some of the topics included are oxygen consumption, temperature, radiation, rhythms, weightlessness, acceleration and vibration stress, toxicity, and sensory and perceptual problems. Many of the topics are interdisciplinary and relate biology, physiology,…

  4. Activated charcoal-carboxymethylcellulose gel formulation as an antidotal agent for orally ingested aspirin.

    PubMed

    Mathur, L K; Jaffe, J M; Colaizzi, J L; Moriarty, R W

    1976-07-01

    The in vivo effect on aspirin absorption of a potentially more palatable form of activated charcoal was compared to that of a simple aqueous slurry of activated charcoal. The experimental formulation consisted of 20.0 g of activated charcoal, 2.25 g of carboxymethylcellulose (CMC) and 42.8 ml of water; it was tested with and without chocolate syrup as a flavoring agent added just prior to administration. Six subjects were treated in crossover fashion following an aspirin dose of 972 mg. Total urinary excretion of salicylate was measured over 48 hours. Although all three treatments appeared to be effective in reducing the rate and extent of aspirin absorption, the slurry was significantly more effective in reducing the total amount absorbed than the charcoal-CMC gel with chocolate syrup. The slight difference in effectiveness between the gel formulation with and without the chocolate syrup was not significant. PMID:941924

  5. Peroxisome proliferator-activated receptor ligands as antiatherogenic agents: panacea or another Pandora's box?

    PubMed

    Molavi, Behzad; Rasouli, Neda; Mehta, Jawahar L

    2002-01-01

    Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor super family that modulate gene expression upon ligand activation. They are 3 major subtypes of PPARs: alpha, delta (also called beta), and gamma. PPAR-gamma is widely expressed in the cardiovascular system and is involved in the regulation of tissue inflammation and smooth muscle cell growth pathways as well as in lipoprotein metabolism and coagulation cascades. PPAR-gamma ligands of (e.g., rosigitazone and pioglitazone) have been shown to exert antiatherogenic effects both in vitro and in vivo. PPAR-alpha ligands (e.g., clofibrate and benzofibrate) modulate lipoprotein metabolism, and affect inflammation and coagulation cascade. These effects may be helpful in resolving the dilemma arising from studies that showed significant mortality and morbidity benefits of fibrates in the face of minimal changes in HDL-cholesterol levels. The role of PPAR-delta in atherogenesis remains largely unknown, although it appears that PPAR-delta activation affects lipoprotein metabolism. PPAR ligands appear to be promising agents in limiting atherosclerosis; however, large-scale clinical trials are required to assess their safety and efficacy before they can be added to the clinicians' arsenal of antiatherosclerotic agents. PMID:12000972

  6. Irradiation system for two-photon induced activation of agents in novel intraocular lenses

    NASA Astrophysics Data System (ADS)

    Klämpfl, Florian; Roth, Stephan; Schmidt, Michael

    This paper presents a newly designed irradiation system for the photochemically triggered two-photon activation of an agent loaded in novel intraocular lenses. After activation, this agent suppresses the formation of after-cataract, a very common disease after the treatment of an eye cataract by implanting an intraocular lens. For this application, intrinsic safety is also important: the laser radiation is applied to one of the most light-sensitive organs: the eye. This has to be taken into account during development of the system. Moreover, the activation uses a two-photon process so a relatively small laser focus is required. To address these issues in combination with economic requirements, a mirror based objective was designed and built, specifically tailored to these needs. Besides the laser beam guidance elements, the irradiation system consists of a camera based monitoring module and an illumination unit. While the first part of the paper shows the design of the system, the second part presents the results of the characterization of the system. The paper closes with a conclusion and an outlook discussing what further development is needed to prepare the system for treatments of human eyes.

  7. Phytophthora infestans Has a Plethora of Phospholipase D Enzymes Including a Subclass That Has Extracellular Activity

    PubMed Central

    Meijer, Harold J. G.; Hassen, Hussen Harrun; Govers, Francine

    2011-01-01

    In eukaryotes phospholipase D (PLD) is involved in many cellular processes. Currently little is known about PLDs in oomycetes. Here we report that the oomycete plant pathogen Phytophthora infestans has a large repertoire of PLDs divided over six subfamilies: PXPH-PLD, PXTM-PLD, TM-PLD, PLD-likes, and type A and B sPLD-likes. Since the latter have signal peptides we developed a method using metabolically labelled phospholipids to monitor if P. infestans secretes PLD. In extracellular medium of ten P. infestans strains PLD activity was detected as demonstrated by the production of phosphatidic acid and the PLD specific marker phosphatidylalcohol. PMID:21423760

  8. Evaluation of school-based dental health activities including fluoride mouth-rinsing in Hiraizumi, Japan.

    PubMed

    Ohara, S; Kawaguchi, Y; Shinada, K; Sasaki, Y

    2000-06-01

    School-based dental health activities conducted in Hiraizumi over the past 20 years have remarkably improved the dental health status of schoolchildren. For example, DMFT index of 12-year-old children decreased to 1.5 in 1998, one-half that of the national average. School dental health activities, which were focused on dental health education, resulted in an increase of filled teeth rates, a decrease in the number of missing teeth, and a decline in incisor caries (1979-1986). In addition, the introduction of a school-based fluoride mouth-rinsing program (1986 - ) showed a positive effect on the prevention of dental caries; a significant decrease was observed in the overall prevalence of dental caries, particularly in the molars. In Japan it seems advantageous to promote the dental health of schoolchildren by school-based programs that combine dental health examination, dental health education and fluoride mouth-rinsing program. Especially, to prevent dental caries in the mandibular first molars more effectively, it is recommended to start fluoride mouth-rinsing at age 5. PMID:12160185

  9. In Vitro Antifungal Activity of ME1111, a New Topical Agent for Onychomycosis, against Clinical Isolates of Dermatophytes

    PubMed Central

    Isham, N.; Long, L.

    2015-01-01

    The treatment of onychomycosis has improved considerably over the past several decades following the introduction of the oral antifungals terbinafine and itraconazole. However, these oral agents suffer from certain disadvantages, including drug interactions and potential liver toxicity. Thus, there is a need for new topical agents that are effective against onychomycosis. ME1111 is a novel selective inhibitor of succinate dehydrogenase (complex II) of dermatophyte species, whose small molecular weight enhances its ability to penetrate the nail plate. In this study, we determined the antifungal activity of ME1111 against dermatophyte strains, most of which are known to cause nail infections, as measured by the MIC (n = 400) and the minimum fungicidal concentration (MFC) (n = 300). Additionally, we examined the potential for resistance development in dermatophytes (n = 4) following repeated exposure to ME1111. Our data show that the MIC90 of ME1111 against dermatophyte strains was 0.25 μg/ml, which was equivalent to that of the comparators amorolfine and ciclopirox (0.25 and 0.5 μg/ml, respectively). ME1111 was fungicidal at clinically achievable concentrations against dermatophytes, and its MFC90s against Trichophyton rubrum and Trichophyton mentagrophytes were 8 μg/ml, comparable to those of ciclopirox. Furthermore, ME1111, as well as ciclopirox, did not induce resistance in 4 dermatophytes tested. Our studies show that ME1111 possesses potent antifungal activity and suggest that it has low potential for the development of resistance in dermatophytes. PMID:26055386

  10. In vitro antifungal activity of ME1111, a new topical agent for onychomycosis, against clinical isolates of dermatophytes.

    PubMed

    Ghannoum, M; Isham, N; Long, L

    2015-09-01

    The treatment of onychomycosis has improved considerably over the past several decades following the introduction of the oral antifungals terbinafine and itraconazole. However, these oral agents suffer from certain disadvantages, including drug interactions and potential liver toxicity. Thus, there is a need for new topical agents that are effective against onychomycosis. ME1111 is a novel selective inhibitor of succinate dehydrogenase (complex II) of dermatophyte species, whose small molecular weight enhances its ability to penetrate the nail plate. In this study, we determined the antifungal activity of ME1111 against dermatophyte strains, most of which are known to cause nail infections, as measured by the MIC (n = 400) and the minimum fungicidal concentration (MFC) (n = 300). Additionally, we examined the potential for resistance development in dermatophytes (n = 4) following repeated exposure to ME1111. Our data show that the MIC90 of ME1111 against dermatophyte strains was 0.25 μg/ml, which was equivalent to that of the comparators amorolfine and ciclopirox (0.25 and 0.5 μg/ml, respectively). ME1111 was fungicidal at clinically achievable concentrations against dermatophytes, and its MFC90s against Trichophyton rubrum and Trichophyton mentagrophytes were 8 μg/ml, comparable to those of ciclopirox. Furthermore, ME1111, as well as ciclopirox, did not induce resistance in 4 dermatophytes tested. Our studies show that ME1111 possesses potent antifungal activity and suggest that it has low potential for the development of resistance in dermatophytes. PMID:26055386

  11. Synthesis and structure-activity relationship of amidine derivatives of 3,4-ethylenedioxythiophene as novel antibacterial agents.

    PubMed

    Stolić, Ivana; Čipčić Paljetak, Hana; Perić, Mihaela; Matijašić, Mario; Stepanić, Višnja; Verbanac, Donatella; Bajić, Miroslav

    2015-01-27

    Current antibacterial chemotherapeutics are facing an alarming increase in bacterial resistance pressuring the search for novel agents that would expand the available therapeutic arsenal against resistant bacterial pathogens. In line with these efforts, a series of 9 amidine derivatives of 3,4-ethylenedioxythiophene were synthesized and, together with 18 previously synthesized analogs, evaluated for their relative DNA binding affinity, in vitro antibacterial activities and preliminary in vitro safety profile. Encouraging antibacterial activity of several subclasses of tested amidine derivatives against Gram-positive (including resistant MRSA, MRSE, VRE strains) and Gram-negative bacterial strains was observed. The bis-phenyl derivatives were the most antibacterially active, while compound 19 from bis-benzimidazole class exhibited the widest spectrum of activity (with MIC of 4, 2, 0.5 and ≤0.25 μg/ml against laboratory strains of Staphyloccocus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, respectively and 4-32 μg/ml against clinical isolates of sensitive and resistant S. aureus, Staphylococcus epidermidis and Enterococcus faecium) and also demonstrated the strongest DNA binding affinity (ΔTm of 15.4 °C). Asymmetrically designed compounds and carboxamide-amidines were, in general, less active. Molecular docking indicated that the shape of the 3,4-ethylenedioxythiophene derivatives and their ability to form multiple electrostatic and hydrogen bonds with DNA, corresponds to the binding modes of other minor-groove binders. Herein reported results encourage further investigation of this class of compounds as novel antibacterial DNA binding agents. PMID:25461312

  12. A Methodology for Post Operational Clean Out of a Highly Active Facility Including Solids Behaviour - 12386

    SciTech Connect

    Edmondson, Michael J.; Ward, Tracy R.; Maxwell, Lisa J.

    2012-07-01

    The Highly Active Liquor Evaporation and Storage (HALES) plant at Sellafield handles acidic fission product containing liquor with typical activities of the order of 18x10{sup 9} Bq/ml. A strategy experimental feedback approach has been used to establish a wash regime for the Post Operational Clean Out (POCO) of the oldest storage tanks for this liquor. Two different wash reagents have been identified as being potentially suitable for removal of acid insoluble fission product precipitates. Ammonium carbamate and sodium carbonate yield similar products during the proposed wash cycle. The proposed wash reagents provide dissolution of caesium phosphomolybdate (CPM) and zirconium molybdate (ZM) solid phases but yields a fine, mobile precipitate of metal carbonates from the Highly Active Liquor (HAL) supernate. Addition of nitric acid to the wash effluent can cause CPM to precipitate where there is sufficient caesium and phosphorous available. Where they are not present (from ZM dissolution) the nitric acid addition initially produces a nitrate precipitate which then re-dissolves, along with the metal carbonates, to give a solid-free solution. The different behaviour of the two solids during the wash cycle has led to the proposal for an amended flowsheet. Additional studies on the potential to change the morphology of crystallising ZM have presented opportunities for changing the rheology of ZM sediments through doping with tellurium or particular organic acids. Two different wash reagents have been identified as being potentially suitable for the POCO of HALES Oldside HASTs. AC and SC both yield similar products during the proposed wash cycle. However, the different behaviour of the two principle HAL solids, CPM and ZM, during the wash cycle has led to the proposal for an amended flowsheet. Additional studies on the potential to change the morphology of crystallising ZM have presented opportunities for changing its rheology through doping with tellurium or certain

  13. Steady-state analysis of activated sludge processes with a settler model including sludge compression.

    PubMed

    Diehl, S; Zambrano, J; Carlsson, B

    2016-01-01

    A reduced model of a completely stirred-tank bioreactor coupled to a settling tank with recycle is analyzed in its steady states. In the reactor, the concentrations of one dominant particulate biomass and one soluble substrate component are modelled. While the biomass decay rate is assumed to be constant, growth kinetics can depend on both substrate and biomass concentrations, and optionally model substrate inhibition. Compressive and hindered settling phenomena are included using the Bürger-Diehl settler model, which consists of a partial differential equation. Steady-state solutions of this partial differential equation are obtained from an ordinary differential equation, making steady-state analysis of the entire plant difficult. A key result showing that the ordinary differential equation can be replaced with an approximate algebraic equation simplifies model analysis. This algebraic equation takes the location of the sludge-blanket during normal operation into account, allowing for the limiting flux capacity caused by compressive settling to easily be included in the steady-state mass balance equations for the entire plant system. This novel approach grants the possibility of more realistic solutions than other previously published reduced models, comprised of yet simpler settler assumptions. The steady-state concentrations, solids residence time, and the wastage flow ratio are functions of the recycle ratio. Solutions are shown for various growth kinetics; with different values of biomass decay rate, influent volumetric flow, and substrate concentration. PMID:26476681

  14. Nuclear Rocket Test Facility Decommissioning Including Controlled Explosive Demolition of a Neutron-Activated Shield Wall

    SciTech Connect

    Michael Kruzic

    2007-09-01

    Located in Area 25 of the Nevada Test Site, the Test Cell A Facility was used in the 1960s for the testing of nuclear rocket engines, as part of the Nuclear Rocket Development Program. The facility was decontaminated and decommissioned (D&D) in 2005 using the Streamlined Approach For Environmental Restoration (SAFER) process, under the Federal Facilities Agreement and Consent Order (FFACO). Utilities and process piping were verified void of contents, hazardous materials were removed, concrete with removable contamination decontaminated, large sections mechanically demolished, and the remaining five-foot, five-inch thick radiologically-activated reinforced concrete shield wall demolished using open-air controlled explosive demolition (CED). CED of the shield wall was closely monitored and resulted in no radiological exposure or atmospheric release.

  15. Quasielastic neutron scattering experiments including activation energies and mathematical modeling of methyl halide dynamics

    NASA Astrophysics Data System (ADS)

    Kirstein, O.; Prager, M.; Grimm, H.; Buchsteiner, A.; Wischnewski, A.

    2007-09-01

    Quasielastic neutron scattering experiments were carried out using the multichopper time-of-flight spectrometer V3 at the Hahn-Meitner Institut, Germany and the backscattering spectrometer at Forschungszentrum Jülich, Germany. Activation energies for CH3X, X =F, Cl, Br, and I, were obtained. In combination with results from previous inelastic neutron scattering experiments the data were taken to describe the dynamics of the halides in terms of two different models, the single particle model and the coupling model. Coupled motions of methyl groups seem to explain the dynamics of the methyl fluoride and chloride; however, the coupling vanishes with the increase of the mass of the halide atom in CH3Br and CH3I.

  16. LIPID PEROXIDATION GENERATES BIOLOGICALLY ACTIVE PHOSPHOLIPIDS INCLUDING OXIDATIVELY N-MODIFIED PHOSPHOLIPIDS

    PubMed Central

    Davies, Sean S.; Guo, Lilu

    2014-01-01

    Peroxidation of membranes and lipoproteins converts “inert” phospholipids into a plethora of oxidatively modified phospholipids (oxPL) that can act as signaling molecules. In this review, we will discuss four major classes of oxPL: mildly oxygenated phospholipids, phospholipids with oxidatively truncated acyl chains, phospholipids with cyclized acyl chains, and phospholipids that have been oxidatively N-modified on their headgroups by reactive lipid species. For each class of oxPL we will review the chemical mechanisms of their formation, the evidence for their formation in biological samples, the biological activities and signaling pathways associated with them, and the catabolic pathways for their elimination. We will end by briefly highlighting some of the critical questions that remain about the role of oxPL in physiology and disease. PMID:24704586

  17. Getting Acquainted: An Induction Training Guide for First-Year Extension Agents. Suggestions for Completing Certain Learning Experiences Included in the Induction Training Guide; a Supplement to "Getting Acquainted."

    ERIC Educational Resources Information Center

    Collings, Mary Louise; Gassie, Edward W.

    An induction guide to help the extension agent get acquainted with his role and suggestions for completing learning experiences that are included in the guide comprise this two-part publication. The training guide learning experiences, a total of 25, are made up of: Objectives of the New Worker; When Completed; Learning Experiences; Person(s)…

  18. Isolation, screening, and characterization of surface-active agent-producing, oil-degrading marine bacteria of Mumbai Harbor.

    PubMed

    Mohanram, Rajamani; Jagtap, Chandrakant; Kumar, Pradeep

    2016-04-15

    Diverse marine bacterial species predominantly found in oil-polluted seawater produce diverse surface-active agents. Surface-active agents produced by bacteria are classified into two groups based on their molecular weights, namely biosurfactants and bioemulsifiers. In this study, surface-active agent-producing, oil-degrading marine bacteria were isolated using a modified Bushnell-Haas medium with high-speed diesel as a carbon source from three oil-polluted sites of Mumbai Harbor. Surface-active agent-producing bacterial strains were screened using nine widely used methods. The nineteen bacterial strains showed positive results for more than four surface-active agent screening methods; further, these strains were characterized using biochemical and nucleic acid sequencing methods. Based on the results, the organisms belonged to the genera Acinetobacter, Alcanivorax, Bacillus, Comamonas, Chryseomicrobium, Halomonas, Marinobacter, Nesterenkonia, Pseudomonas, and Serratia. The present study confirmed the prevalence of surface-active agent-producing bacteria in the oil-polluted waters of Mumbai Harbor. PMID:26912197

  19. Fatty acid-releasing activities in Sinorhizobium meliloti include unusual diacylglycerol lipase.

    PubMed

    Sahonero-Canavesi, Diana X; Sohlenkamp, Christian; Sandoval-Calderón, Mario; Lamsa, Anne; Pogliano, Kit; López-Lara, Isabel M; Geiger, Otto

    2015-09-01

    Phospholipids are well known for their membrane-forming properties and thereby delimit any cell from the exterior world. In addition, membrane phospholipids can act as precursors for signals and other biomolecules during their turnover. Little is known about phospholipid signalling, turnover and remodelling in bacteria. Recently, we showed that a FadD-deficient mutant of Sinorhizobium meliloti, unable to convert free fatty acids to their coenzyme A derivatives, accumulates free fatty acids during the stationary phase of growth. Enzymatic activities responsible for the generation of these free fatty acids were unknown in rhizobia. Searching the genome of S. meliloti, we identified a potential lysophospholipase (SMc04041) and two predicted patatin-like phospholipases A (SMc00930, SMc01003). Although SMc00930 as well as SMc01003 contribute to the release of free fatty acids in S. meliloti, neither one can use phospholipids as substrates. Here we show that SMc01003 converts diacylglycerol to monoacylglycerol and a fatty acid, and that monoacylglycerol can be further degraded by SMc01003 to another fatty acid and glycerol. A SMc01003-deficient mutant of S. meliloti transiently accumulates diacylglycerol, suggesting that SMc01003 also acts as diacylglycerol lipase (DglA) in its native background. Expression of the DglA lipase in Escherichia coli causes lysis of cells in stationary phase of growth. PMID:25711932

  20. Ozone control of biological activity during Earth's history, including the KT catastrophe

    NASA Technical Reports Server (NTRS)

    Sheldon, W. R.

    1994-01-01

    There have been brief periods since the beginning of the Cambrian some 600 m.y. ago when mass extinctions destroyed a significant fraction of living species. The most widely studied of these events is the catastrophe at the KT boundary that ended the long dominance of the dinosaurs. In addition to mass extinctions, there is another profound discontinuity in the history of Earth's biota, the explosion of life at the end of the Precambrian era which is an episode that is not explained well at all. For some 3 b.y. before the Cambrian, life had been present on Earth, but maintained a low level of activity which is an aspect of the biota that is puzzling, especially during the last two-thirds of that period. During the last 2 b.y. before the Cambrian, conditions at the Earth's surface were suitable for a burgeoning of the biota, according to most criteria: the oceans neither boiled nor were fozen solid during this time, and the atmosphere contained sufficient O for the development of animals. The purpose of this paper is to suggest that mass extinctions and the lackluster behavior of the Precambrian biota share a common cause: an inadequate amount of ozone in the atmosphere.

  1. Design of a high-lift experiment in water including active flow control

    NASA Astrophysics Data System (ADS)

    Beutel, T.; Sattler, S.; El Sayed, Y.; Schwerter, M.; Zander, M.; Büttgenbach, S.; Leester-Schädel, M.; Radespiel, R.; Sinapius, M.; Wierach, P.

    2014-07-01

    This paper describes the structural design of an active flow-control experiment. The aim of the experiment is to investigate the increase in efficiency of an internally blown Coanda flap using unsteady blowing. The system uses tailor-made microelectromechanical (MEMS) pressure sensors to determine the state of the oncoming flow and an actuated lip to regulate the mass flow and velocity of a stream near a wall over the internally blown flap. Sensors and actuators are integrated into a highly loaded system that is extremely compact. The sensors are connected to a bus system that feeds the data into a real-time control system. The piezoelectric actuators using the d 33 effect at a comparable low voltage of 120 V are integrated into a lip that controls the blowout slot height. The system is designed for closed-loop control that efficiently avoids flow separation on the Coanda flap. The setup is designed for water-tunnel experiments in order to reduce the free-stream velocity and the system’s control frequency by a factor of 10 compared with that in air. This paper outlines the function and verification of the system’s main components and their development.

  2. An Artemisinin Derivative of Praziquantel as an Orally Active Antischistosomal Agent

    PubMed Central

    Chen, Jinglei; Sun, Huan; Qiao, Chunhua; Xia, Chao-ming

    2014-01-01

    Background Schistosomiasis is a major health problem in tropical and sub-tropical areas caused by species of trematode belonging to the genus Schistosoma. The treatment and control of this disease has been relying on the use of a single drug praziquantel. However, the drug resistance concern urged the development of new drugs against schistosoma. Here, we report our systematic biological evaluation of DW-3-15, a new lead compound developed based on our conjugation design rationale as an effective anti-schistosomal agent. Methodology/Principal Findings The antischistosomal activity of DW-3-15 was systematically evaluated in S. japonicum infected mouse model for its stage-sensitivity and dose response. The results revealed that DW-3-15 exhibited 60–85% worm reduction rate against different development stage of worm. Scanning electron microscopy (SEM) observation indicated that DW-3-15 may damage to the tegument of male schistosomes. Conclusions/Significance Our results demonstrated that DW-3-15 showed potent anti-schistosomal activities in vivo. The results strongly support our conjugation design strategy of artemisinin analogs and further development of DW-3-15 as a new lead compound as anti-schistosomal agent. PMID:25386745

  3. Induction of megakaryocytic colony-stimulating activity in mouse skin by inflammatory agents and tumor promoters

    SciTech Connect

    Clark, D.A.; Dessypris, E.N.; Koury, M.J.

    1987-03-01

    The production of megakaryocytic colony-stimulating activity (MEG-CSA) was assayed in acetic acid extracts of skin from mice topically treated with inflammatory and tumor-promoting agents. A rapid induction of MEG-CSA was found in skin treated both with phorbol 12-myristate 13-acetate (PMA), a strong tumor promoter, and with mezerein, a weak tumor promoter, but no induction was found in untreated skin. The time course of induction of MEG-CSA following treatment of skin with PMA or mezerein was very similar to that previously demonstrated for the induction of granulocyte-macrophage colony-stimulating activity in mouse skin by these agents. The induced MEG-CSA was found in both the epidermis and the dermis. Pretreatment of the skin with US -methasone abrogated the MEG-CSA induction. The cell number response curve suggests that the MEG-CSA acts directly on the progenitor cells of the megakaryocyte colonies. That topical administration of diterpene esters results in the rapid, local induction of MEG-CSA which can be blocked by US -methasone pretreatment suggests a mechanism for the thrombocytosis associated with some inflammatory states. The indirect action in which diterpene esters induce in certain cells the production or release of growth regulatory factors for other cell types may also aid in understanding their carcinogenic properties.

  4. Effects of chronic administration and withdrawal of antidepressant agents on circadian activity rhythms in rats.

    PubMed

    Wollnik, F

    1992-10-01

    Experimental and clinical studies indicate that clinical depression may be associated with disturbances of circadian rhythms. To explore the interaction between circadian rhythmicity, behavioral state, and monoaminergic systems, the present study investigated the effects of chronic administration and withdrawal of the following antidepressant agents on circadian wheel-running rhythms of laboratory rats: a) moclobemide, a reversible and selective monoamine oxidase (MAO) type A inhibitor; b) Ro 19-6327, a selective MAO type B inhibitor; c) desipramine, a preferential norepinephrine reuptake inhibitor; d) clomipramine and e) fluoxetine, both serotonin reuptake inhibitors; and f) levoprotiline, an atypical antidepressant whose biochemical mechanism is still unknown. Wheel-running activity rhythms were studied in three inbred strains of laboratory rats (ACI, BH, LEW) under constant darkness (DD). Two of these inbred strains (BH and LEW) show profound abnormalities in their circadian activity rhythms, namely, a reduced overall level of activity and bimodal or multimodal activity patterns. Chronic treatment with moclobemide and desipramine consistently increased the overall level, as well as the circadian amplitude, of the activity rhythm. Furthermore, the abnormal activity pattern of the LEW strain was changed into a unimodal activity pattern like that of other laboratory rats. The free-running period tau was slightly shortened by moclobemide and dramatically shortened by desipramine. Effects of moclobemide and desipramine treatment on overall activity level and duration were reversed shortly after termination of treatment, whereas long aftereffects were observed for the free-running period. All other substances tested had no systematic effects on the activity rhythms of any of the strains. The fact that moclobemide and desipramine altered the period, amplitude, and pattern of circadian activity rhythms is consistent with the hypothesis that monoaminergic transmitters

  5. Removal of the antiviral agent oseltamivir and its biological activity by oxidative processes.

    PubMed

    Mestankova, Hana; Schirmer, Kristin; Escher, Beate I; von Gunten, Urs; Canonica, Silvio

    2012-02-01

    The antiviral agent oseltamivir acid (OA, the active metabolite of Tamiflu(®)) may occur at high concentrations in wastewater during pandemic influenza events. To eliminate OA and its antiviral activity from wastewater, ozonation and advanced oxidation processes were investigated. For circumneutral pH, kinetic measurements yielded second-order rate constants of 1.7 ± 0.1 × 10(5) and 4.7 ± 0.2 × 10(9) M(-1) s(-1) for the reaction of OA with ozone and hydroxyl radical, respectively. During the degradation of OA by both oxidants, the antiviral activity of the treated aqueous solutions was measured by inhibition of neuraminidase activity of two different viral strains. A transient, moderate (two-fold) increase in antiviral activity was observed in solutions treated up to a level of 50% OA transformation, while for higher degrees of transformation the activity corresponded to that caused exclusively by OA. OA was efficiently removed by ozonation in a wastewater treatment plant effluent, suggesting that ozonation can be applied to remove OA from wastewater. PMID:22230064

  6. Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents.

    PubMed

    Milelli, Andrea; Tumiatti, Vincenzo; Micco, Marialuisa; Rosini, Michela; Zuccari, Guendalina; Raffaghello, Lizzia; Bianchi, Giovanna; Pistoia, Vito; Fernando Díaz, J; Pera, Benet; Trigili, Chiara; Barasoain, Isabel; Musetti, Caterina; Toniolo, Marianna; Sissi, Claudia; Alcaro, Stefano; Moraca, Federica; Zini, Maddalena; Stefanelli, Claudio; Minarini, Anna

    2012-11-01

    Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets. PMID:22819507

  7. Biological activity of sophorolipids and their possible use as antiviral agents.

    PubMed

    Borsanyiova, Maria; Patil, Amrita; Mukherji, Ruchira; Prabhune, Asmita; Bopegamage, Shubhada

    2016-01-01

    Sophorolipids are surface active glycolipids consisting of a hydrophilic sophorose unit and a hydrophobic portion composed of a fatty acid tail. Crude sophorolipid sample contains both acidic and lactonic forms of sophorolipid with different degrees of acetylation and varying lengths of the fatty acid chains depending on the substrates used in the production process. Carboxylic end in the acidic form of the fatty acid is free, whereas in the lactonic form, it is internally esterified. Sophorolipids show different physicochemical properties with wide range of applications for each structural compound. Lactonic form of sophorolipids shows surface tension reducing ability and biological activity, whereas the acidic form possesses better foam forming ability and higher solubility. Presence of acetyl groups gives hydrophilic nature to the sophorolipids which promotes its antiviral and cytokine-stimulating properties. The aim of this review is to explore and suggest the plausibility of sophorolipids as therapeutic and prophylactic agents for the treatment of viral diseases. PMID:26126789

  8. Sparfloxacin-metal complexes as antifungal agents - Their synthesis, characterization and antimicrobial activities

    NASA Astrophysics Data System (ADS)

    Sultana, Najma; Arayne, M. Saeed; Gul, Somia; Shamim, Sana

    2010-06-01

    Metal complexes with the third-generation quinolone antibacterial agent sparfloxacin (SPFX) or 5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8,di-fluoro-1-4-dihydro-4-oxo-3-quinocarboxylic acid have been synthesized and characterized with physicochemical and spectroscopic techniques such as TLC, IR, NMR and elemental analyses. In these complexes, sparfloxacin acts as bidentate deprotonated ligands bound to the metal through the pyridone oxygen and one carboxylate oxygen. The antimicrobial activity of these complexes has been evaluated against four Gram-positive and seven Gram-negative bacteria. Antifungal activity against five different fungi has been evaluated and compared with reference drug sparfloxacin. Fe 2+-SPFX and Cd 2+-SPFX complexes showed remarkable potency as compared to the parent drug.

  9. Differences in Lifestyles Including Physical Activity According to Sexual Orientation among Korean Adolescents

    PubMed Central

    YOON, Jin-Ho; SO, Wi-Young

    2013-01-01

    Abstract Background The purpose of the present study was to examine differences in lifestyle factors such as physical activity among homosexual (gay or lesbian), bisexual, and heterosexual Korean adolescents. Methods The sample consisted of 74,186 adolescents from grades 7—12 (ages 12—18) who participated in the 8th annual Korea Youth Risk Behavior Web-based Survey in 2012. Of this sample, only 11,829 provided enough information regarding their romantic and sexual experiences to define them as gay, lesbian, bisexual, or heterosexual. From this information, males were divided into gay (n = 323), bisexual (n = 243), and heterosexual (n = 6,501) groups, and females were divided into lesbian (n = 208), bisexual (n = 113), and heterosexual (n = 4,441) groups. Differences in lifestyle factors according to sexual orientation were analyzed using one-way analysis of variance. Results Males showed significant differences by sexual orientation group in terms of frequency of smoking (P = 0.029), alcohol consumption (P < 0.001), muscular strength exercises (P = 0.020), and walking for at least 10 minutes per week (P < 0.001). Females showed significant differences by sexual orientation group in terms of frequency of smoking (P < 0.001), alcohol consumption (P < 0.001), vigorous physical exercise (P < 0.001), moderate physical exercise (P < 0.001), and muscular strength exercises (P < 0.001), as well as for self-reported mental stress (P < 0.001). Conclusion We concluded those gay and bisexual males and lesbian and bisexual females had significant lifestyle differences as compared with heterosexual adolescents. This effect was stronger for females than for males. PMID:26060636

  10. RADIO PROPERTIES OF LOW-REDSHIFT BROAD-LINE ACTIVE GALACTIC NUCLEI INCLUDING EXTENDED RADIO SOURCES

    SciTech Connect

    Rafter, Stephen E.; Crenshaw, D. Michael; Wiita, Paul J.

    2011-03-15

    We present a study of the extended radio emission in a sample of 8434 low-redshift (z < 0.35) broad-line active galactic nuclei (AGNs) from the Sloan Digital Sky Survey. To calculate the jet and lobe contributions to the total radio luminosity, we have taken the 846 radio core sources detected in our previous study of this sample and performed a systematic search in the FIRST database for extended radio emission that is likely associated with the optical counterparts. We found that 51 out of 846 radio core sources have extended emission (>4'' from the optical AGN) that is positively associated with the AGN, and we have identified an additional 12 AGNs with extended radio emission but no detectable radio core emission. Among these 63 AGNs, we found 6 giant radio galaxies, with projected emission exceeding 750 kpc in length, and several other AGNs with unusual radio morphologies also seen in higher redshift surveys. The optical spectra of many of the extended sources are similar to those of typical broad-line radio galaxy spectra, having broad H{alpha} emission lines with boxy profiles and large M{sub BH}. With extended emission taken into account, we find strong evidence for a bimodal distribution in the radio-loudness parameter R ({identical_to}{nu}{sub radio} L{sub radio}/{nu}{sub opt} L{sub opt}), where the lower radio luminosity core-only sources appear as a population separate from the extended sources, with a dividing line at log(R) {approx}1.75. This dividing line ensures that these are indeed the most radio-loud AGNs, which may have different or extreme physical conditions in their central engines when compared to the more numerous radio-quiet AGNs.

  11. 45 CFR 287.130 - Can NEW Program activities include job market assessments, job creation and economic development...

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... assessments, job creation and economic development activities? 287.130 Section 287.130 Public Welfare... creation and economic development activities? (a) A Tribe may conduct job market assessments within its NEW Program. These might include the following: (1) Consultation with the Tribe's economic development...

  12. 45 CFR 287.130 - Can NEW Program activities include job market assessments, job creation and economic development...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... assessments, job creation and economic development activities? 287.130 Section 287.130 Public Welfare... creation and economic development activities? (a) A Tribe may conduct job market assessments within its NEW Program. These might include the following: (1) Consultation with the Tribe's economic development...

  13. 45 CFR 287.130 - Can NEW Program activities include job market assessments, job creation and economic development...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... assessments, job creation and economic development activities? 287.130 Section 287.130 Public Welfare... creation and economic development activities? (a) A Tribe may conduct job market assessments within its NEW Program. These might include the following: (1) Consultation with the Tribe's economic development...

  14. 45 CFR 287.130 - Can NEW Program activities include job market assessments, job creation and economic development...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... assessments, job creation and economic development activities? 287.130 Section 287.130 Public Welfare... creation and economic development activities? (a) A Tribe may conduct job market assessments within its NEW Program. These might include the following: (1) Consultation with the Tribe's economic development...

  15. 45 CFR 287.130 - Can NEW Program activities include job market assessments, job creation and economic development...

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... assessments, job creation and economic development activities? 287.130 Section 287.130 Public Welfare... creation and economic development activities? (a) A Tribe may conduct job market assessments within its NEW Program. These might include the following: (1) Consultation with the Tribe's economic development...

  16. Dynamic analysis of changing features of tumor cells incubated with antitumor agents in vitro and its application for predictive activity assay of antitumor agents.

    PubMed

    Oguro, M; Takagi, T; Takenaga, K

    1985-02-01

    Continuous observation of living malignant cells (L1210) in a specially devised glass observation chamber with an inverted microscope made it possible to classify various cellular morphological features induced by antitumor agents into the following four stages: 1) an initial stage consisting of cytoplasmic granulation and coloring, 2) an intermediate stage of shrinkage of nuclei, increases of vacuoles and cytoplasmic budding, 3) a determinate stage of cell ballooning and 4) the terminal stage (cell ghost). Both the initial and intermediate stages are characterized by cellular changes that appear at an early phase and remain opportunistic in terms of viability. Emergence of these cellular changes is largely dependent on the specific mode of action of antitumor agents. In contrast, definite irreversibility in the changes found in both the terminal and determinate stages was confirmed by continuous observation until the cells showed lytic or ghost features, using a video-recording system. A plot of the number of cells counted in both the determinate and terminal stages versus the time-dose schedule is designated as the "time-dose-response" plot, and this proved useful for estimating the characteristics of the antitumor agents tested and the actions of new antitumor agents on malignant cells (predictive activity assay graph). PMID:3920102

  17. Chitosan-Based Film of Tyrothricin for Enhanced Antimicrobial Activity against Common Skin Pathogens Including Staphylococcus aureus.

    PubMed

    Han, Sang Duk; Sung, Hyun Jung; Lee, Ga Hyeon; Jun, Joon-Ho; Son, Miwon; Kang, Myung Joo

    2016-05-28

    Chitosan-based film-forming gel is regarded as a promising vehicle for topical delivery of antimicrobial agents to skin wounds, since it protects from microbial infection and the cationic polymer itself possesses antibacterial activity. In this study, possible synergistic interaction against common skin pathogens between the cationic polymer and tyrothricin (TRC), a cyclic polypeptide antibiotic, was investigated, by determining the concentration to inhibit 90% of bacterial isolates (MIC). The addition of the polysaccharide to TRC dramatically reduced the MIC values of TRC by 1/33 and 1/4 against both methicillin-resistant and methicillinsusceptible Staphylococcus aureus, respectively. The synergism of TRC and chitosan combination against both strains was demonstrated by the checkerboard method, with a fractional inhibitory concentration index below 0.5. Moreover, co-treatment of TRC and chitosan exhibited antibacterial activity against Pseudomonas aeruginosa, due to the antibacterial activity of chitosan, whereas TRC itself did not inhibit the gram-negative bacterial growth. These findings suggested that the use of chitosan-based film for topical delivery of TRC could be an alternative to improve TRC antimicrobial activity against strains that are abundant in skin wounds. PMID:26907760

  18. Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001

    PubMed Central

    Ning, Shoucheng; Sekar, Thillai Veerapazham; Scicinski, Jan; Oronsky, Bryan; Peehl, Donna M.; Knox, Susan J.; Paulmurugan, Ramasamy

    2015-01-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulatory transcription factor that plays an important role in the antioxidant response pathway against anticancer drug-induced cytotoxic effects. RRx-001 is a new anticancer agent that generates reactive oxygen and nitrogen species, and leads to epigenetic alterations in cancer cells. Here we report the RRx-001 mediated nuclear translocation of Nrf2 and the activation of expression of its downstream enzymes HO-1 and NQO1 in tumor cells. Inhibition of intrinsic Nrf2 expression by Nrf2-specific siRNA increased cell sensitivity to RRx-001. Molecular imaging of tumor cells co-expressing pARE-Firefly luciferase and pCMV-Renilla luciferase-mRFP in vitro and in vivo in mice revealed that RRx-001 significantly increased ARE-FLUC signal in cells in a dose- and time-dependent manner, suggesting that RRx-001 is an effective activator of the Nrf2-ARE signaling pathway. The pre-treatment level of ARE-FLUC signal in cells, reflecting basal activity of Nrf2, negatively correlated with the tumor response to RRx-001. The results support the concept that RRx-001 activates Nrf2-ARE antioxidant signaling pathways in tumor cells. Hence measurement of Nrf2-mediated activation of downstream target genes through ARE signaling may constitute a useful molecular biomarker for the early prediction of response to RRx-001 treatment, and thereby guide therapeutic decision-making. PMID:26280276

  19. Should Physical Activity Be Included in Nutrition Education? A Comparison of Nutrition Outcomes with and without In-Class Activities

    ERIC Educational Resources Information Center

    Palmer-Keenan, Debra M.; Corda, Kirsten

    2014-01-01

    Limited-resource adults' dietary intakes and nutrition behaviors improve as a result of Expanded Food and Nutrition Education Program (EFNEP)/Supplemental Nutrition Assistance Program Education (SNAP-Ed) participation; however, physical activity education is needed for improved health. The experimental study reported here assessed if spending…

  20. Agent oriented programming

    NASA Technical Reports Server (NTRS)

    Shoham, Yoav

    1994-01-01

    The goal of our research is a methodology for creating robust software in distributed and dynamic environments. The approach taken is to endow software objects with explicit information about one another, to have them interact through a commitment mechanism, and to equip them with a speech-acty communication language. System-level applications include software interoperation and compositionality. A government application of specific interest is an infrastructure for coordination among multiple planners. Daily activity applications include personal software assistants, such as programmable email, scheduling, and new group agents. Research topics include definition of mental state of agents, design of agent languages as well as interpreters for those languages, and mechanisms for coordination within agent societies such as artificial social laws and conventions.

  1. Induction of DT-diaphorase by 1,2-dithiole-3-thione and increase of antitumour activity of bioreductive agents.

    PubMed Central

    Begleiter, A.; Leith, M. K.; Curphey, T. J.

    1996-01-01

    Bioreductive antitumour agents are an important new class of anticancer drugs that require activation by reduction. The two-electron reducing enzyme, DT-diaphorase, has been shown to be an important activating enzyme for the bioreductive agents, mitomycin C (MMC) and EO9. Incubation of L5178Y murine lymphoma cells in vitro with 1,2-dithiole-3-thione (D3T) increased the level of DT-diaphorase activity in these cells 22-fold. In contrast, D3T had no effect on the DT-diaphorase level in normal mouse bone marrow cells. Combination therapy with D3T and MMC or EO9, produced a 2- or 7-fold enhancement, respectively, of the cytotoxic activity of these antitumour agents in L5178Y cells. By comparison, D3T did not enhance the activity of MMC in marrow cells and produced only a small increase in EO9 cytotoxicity in these cells. The DT-diaphorase inhibitor, dicoumarol, inhibited the effect of D3T on the antitumour activity of the bioreductive agents, supporting the proposal that the enhanced anticancer activity was due to the elevated enzyme level. These findings suggest that D3T, or other inducers of DT-diaphorase, could be used to enhance the antitumour efficacy of bioreductive antitumour agents. PMID:8763837

  2. Preclinical Activity of the Vascular Disrupting Agent OXi4503 against Head and Neck Cancer.

    PubMed

    Bothwell, Katelyn D; Folaron, Margaret; Seshadri, Mukund

    2016-01-01

    Vascular disrupting agents (VDAs) represent a relatively distinct class of agents that target established blood vessels in tumors. In this study, we examined the preclinical activity of the second-generation VDA OXi4503 against human head and neck squamous cell carcinoma (HNSCC). Studies were performed in subcutaneous and orthotopic FaDu-luc HNSCC xenografts established in immunodeficient mice. In the subcutaneous model, bioluminescence imaging (BLI) along with tumor growth measurements was performed to assess tumor response to therapy. In mice bearing orthotopic tumors, a dual modality imaging approach based on BLI and magnetic resonance imaging (MRI) was utilized. Correlative histologic assessment of tumors was performed to validate imaging data. Dynamic BLI revealed a marked reduction in radiance within a few hours of OXi4503 administration compared to baseline levels. However, this reduction was transient with vascular recovery observed at 24 h post treatment. A single injection of OXi4503 (40 mg/kg) resulted in a significant (p < 0.01) tumor growth inhibition of subcutaneous FaDu-luc xenografts. MRI revealed a significant reduction (p < 0.05) in volume of orthotopic tumors at 10 days post two doses of OXi4503 treatment. Corresponding histologic (H&E) sections of Oxi4503 treated tumors showed extensive areas of necrosis and hemorrhaging compared to untreated controls. To the best of our knowledge, this is the first report, on the activity of Oxi4503 against HNSCC. These results demonstrate the potential of tumor-VDAs in head and neck cancer. Further examination of the antivascular and antitumor activity of Oxi4503 against HNSCC alone and in combination with chemotherapy and radiation is warranted. PMID:26751478

  3. Preclinical Activity of the Vascular Disrupting Agent OXi4503 against Head and Neck Cancer

    PubMed Central

    Bothwell, Katelyn D.; Folaron, Margaret; Seshadri, Mukund

    2016-01-01

    Vascular disrupting agents (VDAs) represent a relatively distinct class of agents that target established blood vessels in tumors. In this study, we examined the preclinical activity of the second-generation VDA OXi4503 against human head and neck squamous cell carcinoma (HNSCC). Studies were performed in subcutaneous and orthotopic FaDu-luc HNSCC xenografts established in immunodeficient mice. In the subcutaneous model, bioluminescence imaging (BLI) along with tumor growth measurements was performed to assess tumor response to therapy. In mice bearing orthotopic tumors, a dual modality imaging approach based on BLI and magnetic resonance imaging (MRI) was utilized. Correlative histologic assessment of tumors was performed to validate imaging data. Dynamic BLI revealed a marked reduction in radiance within a few hours of OXi4503 administration compared to baseline levels. However, this reduction was transient with vascular recovery observed at 24 h post treatment. A single injection of OXi4503 (40 mg/kg) resulted in a significant (p < 0.01) tumor growth inhibition of subcutaneous FaDu-luc xenografts. MRI revealed a significant reduction (p < 0.05) in volume of orthotopic tumors at 10 days post two doses of OXi4503 treatment. Corresponding histologic (H&E) sections of Oxi4503 treated tumors showed extensive areas of necrosis and hemorrhaging compared to untreated controls. To the best of our knowledge, this is the first report, on the activity of Oxi4503 against HNSCC. These results demonstrate the potential of tumor-VDAs in head and neck cancer. Further examination of the antivascular and antitumor activity of Oxi4503 against HNSCC alone and in combination with chemotherapy and radiation is warranted. PMID:26751478

  4. The effect of surface active agents on the relative permeability of brine and gas in porous media

    SciTech Connect

    Conway, M.W.; Schraufnagel, R.A.; Smith, K.; Thomas, T.

    1995-11-01

    All oil and gas producing wells produce hydrocarbon at some residual water saturation. Therefore, the relative permeability to the hydrocarbon at the effective water saturation dictates performance and not the absolute permeability of the formation. Surface active agents are included in most aqueous treating fluids to improve the compatibility of aqueous fluids with the hydrocarbon containing reservoir. A review of the literature indicates very little core flow data to describe the effects to be expected. Traditionally, it is believed that the reduced surface tension will reduce capillary pressure and enhance the recovery of water after the treatment. The reduced water saturation is then believed to result in higher effective gas saturation and higher relative permeability to gas after the treatment. The principal emphasis of this study has been the development of non-damaging stimulation fluids to improve the production of methane from coalbed methane and other low permeability gas reservoirs.

  5. Thiolates Chemically Induce Redox Activation of BTZ043 and Related Potent Nitro Aromatic Anti-Tuberculosis Agents

    PubMed Central

    Tiwari, Rohit; Moraski, Garrett C.; Krchňák, Viktor; Miller, Patricia A.; Colon-Martinez, Mariangelli; Herrero, Eliza; Oliver, Allen G.; Miller, Marvin J.

    2013-01-01

    The development of multidrug resistant (MDR) and extensively drug resistant (XDR) forms of tuberculosis (TB) has stimulated research efforts globally to expand the new drug pipeline. Nitro aromatic compounds, including 1, 3-Benzothiazin-4-ones (BTZs) and related agents, are a promising new class for the treatment of TB. Research has shown that the nitroso intermediates of BTZs that are generated in vivo cause suicide inhibition of decaprenylphosphoryl-β-D-ribose 2′ oxidase (DprE1), which is responsible for cell wall arabinogalactan biosynthesis. We have designed and synthesized novel anti-TB agents inspired from BTZs and other nitroaromatic compounds. Computational studies indicated that the unsubstituted aromatic carbons of BTZ043 and related nitroaromatic compounds are the most electron deficient and might be prone to nucleophilic attack. Our chemical studies on BTZ043 and the additional nitro aromatic compounds synthesized by us and the others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide and hydride induce non-enzymatic reduction of the nitro groups present in these compounds to the corresponding nitroso intermediates by addition at the unsubstituted electron deficient aromatic carbon present in these compounds. Furthermore we demonstrate here that these compounds are good candidates for the classical von Richter reaction. These chemical studies offer an alternate hypotheses for the mechanism of action of nitro aromatic anti-TB agents in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to the nitroso intermediates, to initiate the inhibition of DprE1. PMID:23402278

  6. Light-activated nanotube-porphyrin conjugates as effective antiviral agents

    NASA Astrophysics Data System (ADS)

    Banerjee, Indrani; Douaisi, Marc P.; Mondal, Dhananjoy; Kane, Ravi S.

    2012-03-01

    Porphyrins have been used for photodynamic therapy (PDT) against a wide range of targets like bacteria, viruses and tumor cells. In this work, we report porphyrin-conjugated multi-walled carbon nanotubes (NT-P) as potent antiviral agents. Specifically, we used Protoporphyrin IX (PPIX), which we attached to acid-functionalized multi-walled carbon nanotubes (MWNTs). We decided to use carbon nanotubes as scaffolds because of their ease of recovery from a solution through filtration. In the presence of visible light, NT-P was found to significantly reduce the ability of Influenza A virus to infect mammalian cells. NT-P may be used effectively against influenza viruses with little or no chance of them developing resistance to the treatment. Furthermore, NT-P can be easily recovered through filtration which offers a facile strategy to reuse the active porphyrin moiety to its fullest extent. Thus NT-P conjugates represent a new approach for preparing ex vivo reusable antiviral agents.

  7. Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells.

    PubMed

    Gray, Lachlan R; On, Hung; Roberts, Emma; Lu, Hao K; Moso, Michael A; Raison, Jacqueline A; Papaioannou, Catherine; Cheng, Wan-Jung; Ellett, Anne M; Jacobson, Jonathan C; Purcell, Damian F J; Wesselingh, Steve L; Gorry, Paul R; Lewin, Sharon R; Churchill, Melissa J

    2016-08-01

    Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid. PMID:26727904

  8. Bevacizumab is active as a single agent against recurrent malignant gliomas.

    PubMed

    Agha, Caroline A; Ibrahim, Saman; Hassan, Ahmed; Elias, Dean A; Fathallah-Shaykh, Hassan M

    2010-02-01

    Bevacizumab, a humanized monoclonal antibody designed to inhibit vascular endothelial growth factor, is effective in combination with chemotherapy against malignant gliomas. We examined the therapeutic effects and toxicity of bevacizumab as a single agent for the treatment of recurrent malignant glioma. This is a retrospective analysis of a case series of 18 adult patients, diagnosed with recurrent WHO grade III and IV gliomas. Patients were divided into two groups: group A (n=8) received bevacizumab at a dose of 10 mg/kg every two weeks; group B patients (n=10) were treated with salvage chemotherapy of lomustine (n=4), liposomal doxorubicin (n=4), temozolomide (n=1), or the combination of procarbazine, lomustine, and vincristine (n=1). The main study outcome measure was the 12-month progression-free survival probability; the objective radiological response was a secondary endpoint. Half of the patients treated with bevacizumab remained progression-free at 12 months as compared to none in group B (log-rank p=0.0067). In addition, 7/8 patients in group A showed a radiological response as compared to 4/10 in group B. Toxicity was mild and no intracranial hemorrhage was observed. The finding that bevacizumab has significant activity as a single agent against malignant glioma is important, particularly for those patients who are unable to tolerate traditional chemotherapy. PMID:20332478

  9. Antiviral agents: characteristic activity spectrum depending on the molecular target with which they interact.

    PubMed

    De Clercq, E

    1993-01-01

    The target protein (enzyme) with which antiviral agents interact determines their antiviral activity spectrum. Based on their activity spectrum, antiviral compounds could be divided into the following classes: (1) sulfated polysaccharides (i.e., dextran sulfate), which interact with the viral envelope glycoproteins and are inhibitory to a broad variety of enveloped viruses (i.e., retro-, herpes-, rhabdo-, and arenaviruses): (2) SAH hydrolase inhibitors (i.e., neplanocin A derivatives), which are particularly effective against poxvirus, (-)RNA viruses (paramyxovirus, rhabdovirus), and (+/-)RNA virus (reovirus); (3) OMP decarboxylase inhibitors (i.e., pyrazofurin) and CTP synthetase inhibitors (i.e., cyclopentenylcytosine), which are active against a broad range of DNA, (+)RNA, (-)RNA, and (+/-)RNA viruses; (4) IMP dehydrogenase inhibitors (i.e., ribavirin), which are also active against various (+)RNA and (-)RNA viruses and, in particular, ortho- and paramyxoviruses; (5) acyclic guanosine analogs (i.e., ganciclovir) and carbocyclic guanosine analogs (i.e., cyclobut-G), which are particularly active against herpesviruses (i.e., HSV-1, HSV-2, VZV, CMV); (6) thymidine analogs (i.e., BVDU, BVaraU), which are specifically active against HSV-1 and VZV because of their preferential phosphorylation by the virus-encoded thymidine kinase; (7) acyclic nucleoside phosphonates (i.e., HPMPA, HPMPC, PMEA, FPMPA), which, depending on the structure of the acyclic side chain, span an activity spectrum from DNA viruses (papova-, adeno-, herpes-, hepadna-, and poxvirus) to retroviruses (HIV); (8) dideoxynucleoside analogs (i.e., AZT, DDC), which act as chain terminators in the reverse transcriptase reaction and thus block the replication of retroviruses as well as hepadnaviruses; and (9) the TIBO, HEPT, and other TIBO-like compounds, which interact specifically with the reverse transcriptase of HIV-1 and thus block the replication of HIV-1, but not of HIV-2 or any other retrovirus

  10. [Removal of fluorescent whitening agent by hydrogen peroxide oxidation catalyzed by activated carbon].

    PubMed

    Liu, Hai-Long; Zhang, Zhong-Min; Zhao, Xia; Jiao, Ru-Yuan

    2014-06-01

    Degradation of fluorescent whitening agent VBL in the processes of activated carbon (AC) and activated carbon modified (ACM) adsorptions, hydrogen peroxide (H2O2) oxidation, and hydrogen peroxide oxidation catalyzed by activated carbon were studied. Mechanism of the above catalytic oxidation was also investigated by adding tert-Butyl alcohol (TBA), the free radical scavenger, and detecting the released gases. The results showed that: the activated carbon modified by Fe (NO3)3 (ACM)exhibited better adsorption removal than AC. Catalytic oxidation showed efficient removal of VBL, and the catalytic removal of AC (up to 95%) was significantly higher than that of ACM (58% only). Catalytic oxidation was inhibited by TBA, which indicates that the above reaction involved *OH radicals and atom oxygen generated by hydrogen peroxide with the presence of AC. The results of H2O2 decomposition and released gases detection involved in the process showed that activated carbon enhanced the decomposition of H2O2 which released oxygen and heat. More O2 was produced and higher temperature of the reactor was achieved, which indicated that H2O2 decomposition catalyzed by ACM was significantly faster than that of AC. Combining the results of VBL removal, it could be concluded that the rate of active intermediates (*OH radicals and atom oxygen) production by ACM catalytic reaction was faster than that of AC. These intermediates consumed themselves and produced O2 instead of degrading VBL. It seemed that the improper mutual matching of the forming rate of activating intermediates and the supply rate of reactants was an important reason for the lower efficiency of ACM catalytic reaction comparing with AC. PMID:25158496

  11. Robust glycogen shunt activity in astrocytes: Effects of glutamatergic and adrenergic agents.

    PubMed

    Walls, A B; Heimbürger, C M; Bouman, S D; Schousboe, A; Waagepetersen, H S

    2009-01-12

    The significance and functional roles of glycogen shunt activity in the brain are largely unknown. It represents the fraction of metabolized glucose that passes through glycogen molecules prior to entering the glycolytic pathway. The present study was aimed at elucidating this pathway in cultured astrocytes from mouse exposed to agents such as a high [K+], D-aspartate and norepinephrine (NE) known to affect energy metabolism in response to neurotransmission. Glycogen shunt activity was assessed employing [1,6-13C]glucose, and the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) to block glycogen degradation. The label intensity in lactate, reflecting glycolytic activity, was determined by mass spectrometry. In the presence of NE a substantial glycogen shunt activity was observed, accounting for almost 40% of overall glucose metabolism. Moreover, when no metabolic stimulant was applied, a compensatory increase in glycolytic activity was seen when the shunt was inhibited by DAB. Actually the labeling in lactate exceeded that obtained when glycolysis and glycogen shunt both were operational, i.e. supercompensation. A similar phenomenon was seen when astrocytes were exposed to D-aspartate. In addition to glycolysis, tricarboxylic acid (TCA) cycle activity was monitored, analyzing labeling by mass spectrometry in glutamate which equilibrates with alpha-ketoglutarate. Both an elevated [K+] and D-aspartate induced an increased TCA cycle activity, which was altered when glycogen degradation was inhibited. Thus, the present study provides evidence that manipulation of glycogen metabolism affects both glycolysis and TCA cycle metabolism. Altogether, the results reveal a highly complex interaction between glycogenolysis and glycolysis, with the glycogen shunt playing a significant role in astrocytic energy metabolism. PMID:19000744

  12. The Novel Antitubulin Agent TR-764 Strongly Reduces Tumor Vasculature and Inhibits HIF-1α Activation.

    PubMed

    Porcù, Elena; Persano, Luca; Ronca, Roberto; Mitola, Stefania; Bortolozzi, Roberta; Romagnoli, Romeo; Oliva, Paola; Basso, Giuseppe; Viola, Giampietro

    2016-01-01

    Tubulin binding agents (TBAs) are commonly used in cancer therapy as antimitotics. It has been described that TBAs, like combretastatin A-4 (CA-4), present also antivascular activity and among its derivatives we identified TR-764 as a new inhibitor of tubulin polymerization, based on the 2-(alkoxycarbonyl)-3-(3',4',5'-trimethoxyanilino)benzo[b]thiophene molecular skeleton. The antiangiogenic activity of TR-764 (1-10 nM) was tested in vitro on human umbilical endothelial cells (HUVECs), and in vivo, on the chick embryo chorioallantoic membrane (CAM) and two murine tumor models. TR-764 binding to tubulin triggers cytoskeleton rearrangement without affecting cell cycle and viability. It leads to capillary tube disruption, increased cell permeability, and cell motility reduction. Moreover it disrupts adherens junctions and focal adhesions, through mechanisms involving VE-cadherin/β-catenin and FAK/Src. Importantly, TR-764 is active in hypoxic conditions significantly reducing HIF-1α. In vivo TR-764 (1-100 pmol/egg) remarkably blocks the bFGF proangiogenic activity on CAM and shows a stronger reduction of tumor mass and microvascular density both in murine syngeneic and xenograft tumor models, compared to the lead compound CA-4P. Altogether, our results indicate that TR-764 is a novel TBA with strong potential as both antivascular and antitumor molecule that could improve the common anticancer therapies, by overcoming hypoxia-induced resistance mechanisms. PMID:27292568

  13. Synthesis and Biological Activity of Isoflavone Derivatives from Chickpea as Potent Anti-Diabetic Agents.

    PubMed

    Li, Pengshou; Shi, Xiaojuan; Wei, Ying; Qin, Lingling; Sun, Wen; Xu, Guangyuan; Xu, Tunhai; Liu, Tonghua

    2015-01-01

    A set of novel isoflavone derivatives from chickpea were synthesized. The structures of derivatives were identified by proton nuclear magnetic resonance (¹H-NMR), carbon-13 ((13)C)-NMR and mass spectrometry (MS) spectral analyses. Their anti-diabetic activities were evaluated using an insulin-resistant (IR) HepG2 cell model. Additionally, the structure-activity relationships of these derivatives were briefly discussed. Compounds 1c, 2h, 3b, and 5 and genistein exhibited significant glucose consumption-enhancing effects in IR-HepG2 cells. In addition, the combinations of genistein, 2h, and 3b (combination 6) and of 3b, genistein, and 1c (combination 10) exhibited better anti-diabetic activity than the individual compounds. At the same dosage, there was no difference in effect between the combination 10 and the positive control (p > 0.05). Aditionally, we found the differences between the combination 10 and combination 6 for the protective effect of HUVEC (human umbilical vein endothelial cells) under high glucose concentration. The protective effects of combination 10 was stronger than combination 6, which suggested that combination 10 may have a better hypoglycemic activity in future studies. This study provides useful clues for the further design and discovery of anti-diabetic agents. PMID:26393547

  14. The Novel Antitubulin Agent TR-764 Strongly Reduces Tumor Vasculature and Inhibits HIF-1α Activation

    PubMed Central

    Porcù, Elena; Persano, Luca; Ronca, Roberto; Mitola, Stefania; Bortolozzi, Roberta; Romagnoli, Romeo; Oliva, Paola; Basso, Giuseppe; Viola, Giampietro

    2016-01-01

    Tubulin binding agents (TBAs) are commonly used in cancer therapy as antimitotics. It has been described that TBAs, like combretastatin A-4 (CA-4), present also antivascular activity and among its derivatives we identified TR-764 as a new inhibitor of tubulin polymerization, based on the 2-(alkoxycarbonyl)-3-(3′,4′,5′-trimethoxyanilino)benzo[b]thiophene molecular skeleton. The antiangiogenic activity of TR-764 (1–10 nM) was tested in vitro on human umbilical endothelial cells (HUVECs), and in vivo, on the chick embryo chorioallantoic membrane (CAM) and two murine tumor models. TR-764 binding to tubulin triggers cytoskeleton rearrangement without affecting cell cycle and viability. It leads to capillary tube disruption, increased cell permeability, and cell motility reduction. Moreover it disrupts adherens junctions and focal adhesions, through mechanisms involving VE-cadherin/β-catenin and FAK/Src. Importantly, TR-764 is active in hypoxic conditions significantly reducing HIF-1α. In vivo TR-764 (1–100 pmol/egg) remarkably blocks the bFGF proangiogenic activity on CAM and shows a stronger reduction of tumor mass and microvascular density both in murine syngeneic and xenograft tumor models, compared to the lead compound CA-4P. Altogether, our results indicate that TR-764 is a novel TBA with strong potential as both antivascular and antitumor molecule that could improve the common anticancer therapies, by overcoming hypoxia-induced resistance mechanisms. PMID:27292568

  15. The Structure Activity Relationship of Urea Derivatives as Anti-Tuberculosis Agents

    PubMed Central

    Brown, Joshua R.; North, Elton J.; Hurdle, Julian G.; Morisseau, Christophe; Scarborough, Jerrod S.; Sun, Dianqing; Korduláková, Jana; Scherman, Michael S.; Jones, Victoria; Grzegorzewicz, Anna; Crew, Rebecca M.; Jackson, Mary; McNeil, Michael R.; Lee, Richard E.

    2011-01-01

    The treatment of tuberculosis is becoming more difficult due to the ever increasing prevalence of drug resistance. Thus, it is imperative that novel anti-tuberculosis agents, with unique mechanisms of action, be discovered and developed. The direct anti-tubercular testing of a small compound library led to discovery of adamantyl urea hit compound 1. In this study, the hit was followed up through the synthesis of an optimization library. This library was generated by systematically replacing each section of the molecule with a similar moiety until a clear structure activity relationship was obtained with respect to anti-tubercular activity. The best compounds in this series contained a 1-adamantyl-3-phenyl urea core and had potent activity against Mycobacterium tuberculosis plus an acceptable therapeutic index. It was noted that the compounds identified and the pharmacophore developed is consistent with inhibitors of epoxide hydrolase family of enzymes. Consequently, the compounds were tested for inhibition of representative epoxide hydrolases: M. tuberculosis EphB and EphE; and human soluble epoxide hydrolase. Many of the optimized inhibitors showed both potent EphB and EphE inhibition suggesting the antitubercular activity is through inhibition of multiple epoxide hydrolyase enzymes. The inhibitors also showed potent inhibition of humans soluble expoxide hydrolyase, but limited cytotoxicity suggesting that future studies must be towards increasing the selectivity of epoxide hydrolyase inhibition towards the M. tuberculosis enzymes. PMID:21840723

  16. Human recombinant truncated RNASET2, devoid of RNase activity; A potential cancer therapeutic agent.

    PubMed

    Nesiel-Nuttman, Liron; Schwartz, Betty; Shoseyov, Oded

    2014-11-30

    Human RNASET2 has been implicated in antitumorigenic and antiangiogenic activities, independent of its ribonuclease capacities. We constructed a truncated version of human RNASET2, starting at E50 (trT2-50) and devoid of ribonuclease activity. trT2-50 maintained its ability to bind actin and to inhibit angiogenesis and tumorigenesis. trT2-50 binds to cell surface actin and formed a complex with actin in vitro. The antiangiogenic effect of this protein was demonstrated in human umbilical vein endothelial cells (HUVECs) by its ability to arrest tube formation on Matrigel, induced by angiogenic factors. Immunofluorescence staining of HUVECs showed nuclear and cytosolic RNASET2 protein that was no longer detectable inside the cell following trT2-50 treatment. This effect was associated with disruption of the intracellular actin network. trT2-50 co-localized with angiogenin, suggesting that both molecules bind (or compete) for similar cellular epitopes. Moreover, trT2-50 led to a significant inhibition of tumor development. Histological analysis demonstrated abundant necrotic tissue and a substantial loss of endothelial structure in trT2-50-treated tumors. Collectively, the present results indicate that trT2-50, a molecule engineered to be deficient of its catalytic activity, still maintained its actin binding and anticancer-related biological activities. We therefore suggest that trT2-50 may serve as a potential cancer therapeutic agent. PMID:25426551

  17. Human recombinant truncated RNASET2, devoid of RNase activity; A potential cancer therapeutic agent

    PubMed Central

    Nesiel-Nuttman, Liron; Schwartz, Betty; Shoseyov, Oded

    2014-01-01

    Human RNASET2 has been implicated in antitumorigenic and antiangiogenic activities, independent of its ribonuclease capacities. We constructed a truncated version of human RNASET2, starting at E50 (trT2-50) and devoid of ribonuclease activity. trT2-50 maintained its ability to bind actin and to inhibit angiogenesis and tumorigenesis. trT2-50 binds to cell surface actin and formed a complex with actin in vitro. The antiangiogenic effect of this protein was demonstrated in human umbilical vein endothelial cells (HUVECs) by its ability to arrest tube formation on Matrigel, induced by angiogenic factors. Immunofluorescence staining of HUVECs showed nuclear and cytosolic RNASET2 protein that was no longer detectable inside the cell following trT2-50 treatment. This effect was associated with disruption of the intracellular actin network. trT2-50 co-localized with angiogenin, suggesting that both molecules bind (or compete) for similar cellular epitopes. Moreover, trT2-50 led to a significant inhibition of tumor development. Histological analysis demonstrated abundant necrotic tissue and a substantial loss of endothelial structure in trT2-50-treated tumors. Collectively, the present results indicate that trT2-50, a molecule engineered to be deficient of its catalytic activity, still maintained its actin binding and anticancer-related biological activities. We therefore suggest that trT2-50 may serve as a potential cancer therapeutic agent. PMID:25426551

  18. A robust screening method for dietary agents that activate tumour-suppressor microRNAs

    PubMed Central

    Hagiwara, Keitaro; Gailhouste, Luc; Yasukawa, Ken; Kosaka, Nobuyoshi; Ochiya, Takahiro

    2015-01-01

    Certain dietary agents, such as natural products, have been reported to show anti-cancer effects. However, the underlying mechanisms of these substances in human cancer remain unclear. We recently found that resveratrol exerts an anti-cancer effect by upregulating tumour-suppressor microRNAs (miRNAs). In the current study, we aimed to identify new dietary products that have the ability to activate tumour-suppressor miRNAs and that therefore may serve as novel tools for the prevention and treatment of human cancers. We describe the generation and use of an original screening system based on a luciferase-based reporter vector for monitoring miR-200c tumour-suppressor activity. By screening a library containing 139 natural substances, three natural compounds — enoxolone, magnolol and palmatine chloride — were identified as being capable of inducing miR-200c expression in breast cancer cells at 10 μM. Moreover, these molecules suppressed the invasiveness of breast cancer cells in vitro. Next, we identified a molecular pathway by which the increased expression of miR-200c induced by natural substances led to ZEB1 inhibition and E-cadherin induction. These results indicate that our method is a valuable tool for a fast identification of natural molecules that exhibit tumour-suppressor activity in human cancer through miRNA activation. PMID:26423775

  19. In Vitro Activities of Dalbavancin and Nine Comparator Agents against Anaerobic Gram-Positive Species and Corynebacteria

    PubMed Central

    Goldstein, Ellie J. C.; Citron, Diane M.; Merriam, C. Vreni; Warren, Yumi; Tyrrell, Kerin; Fernandez, Helen T.

    2003-01-01

    Dalbavancin is a novel semisynthetic glycopeptide with enhanced activity against gram-positive species. Its comparative in vitro activities and those of nine comparator agents, including daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin, against 290 recent gram-positive clinical isolates strains, as determined by the NCCLS agar dilution method, were studied. The MICs of dalbavancin at which 90% of various isolates tested were inhibited were as follows: Actinomyces spp., 0.5 μg/ml; Clostridium clostridioforme, 8 μg/ml; C. difficile, 0.25 μg/ml; C. innocuum, 0.25 μg/ml; C. perfringens, 0.125 μg/ml; C. ramosum, 1 μg/ml; Eubacterium spp., 1 μg/ml; Lactobacillus spp., >32 μg/ml, Propionibacterium spp., 0.5 μg/ml; and Peptostreptococcus spp., 0.25 μg/ml. Dalbavancin was 1 to 3 dilutions more active than vancomycin against most strains. Dalbavancin exhibited excellent activity against gram-positive strains tested and warrants clinical evaluation. PMID:12760876

  20. In search of uracil derivatives as bioactive agents. Uracils and fused uracils: Synthesis, biological activity and applications.

    PubMed

    Pałasz, Aleksandra; Cież, Dariusz

    2015-06-01

    This review article is an effort to summarize recent developments in researches providing uracil derivatives with promising biological potential. This article also aims to discuss potential future directions on the development of more potent and specific uracil analogues for various biological targets. Uracils are considered as privileged structures in drug discovery with a wide array of biological activities and synthetic accessibility. Antiviral and anti-tumour are the two most widely reported activities of uracil analogues however they also possess herbicidal, insecticidal and bactericidal activities. Their antiviral potential is based on the inhibition of key step in viral replication pathway resulting in potent activities against HIV, hepatitis B and C, the herpes viruses etc. Uracil derivatives such as 5-fluorouracil or 5-chlorouracil were the first pharmacological active derivatives to be generated. Poor selectivity limits its therapeutic application, resulting in high incidences of gastrointestinal tract or central nervous toxicity. Numerous modifications of uracil structure have been performed to tackle these problems resulting in the development of derivatives exhibiting better pharmacological and pharmacokinetic properties including increased bioactivity, selectivity, metabolic stability, absorption and lower toxicity. Researches of new uracils and fused uracil derivatives as bioactive agents are related with modifications of substituents at N(1), N(3), C(5) and C(6) positions of pyrimidine ring. This review is an endeavour to highlight the progress in the chemistry and biological activity of the uracils, predominately after the year 2000. In particular are presented synthetic methods and biological study for such analogues as: 5-fluorouracil or 5-chlorouracil derivatives, tegafur analogues, arabinopyranonucleosides of uracil, glucopyranonucleosides of uracil, liposidomycins, caprazamycins or tunicamycins, tritylated uridine analogues, nitro or cyano

  1. Active defense scheme against DDoS based on mobile agent and network control in network confrontation

    NASA Astrophysics Data System (ADS)

    Luo, Rong; Li, Junshan; Ye, Xia; Wang, Rui

    2013-03-01

    In order to effective defend DDoS attacks in network confrontation, an active defense scheme against DDoS is built based on Mobile Agent and network control. A distributed collaborative active defense model is constructed by using mobile agent technology and encapsulating a variety of DDoS defense techniques. Meanwhile the network control theory is applied to establish a network confrontation's control model for DDoS to control the active defense process. It provides a new idea to solve the DDoS problem.

  2. Direct quantification of chemical warfare agents and related compounds at low ppt levels: comparing active capillary dielectric barrier discharge plasma ionization and secondary electrospray ionization mass spectrometry.

    PubMed

    Wolf, Jan-Christoph; Schaer, Martin; Siegenthaler, Peter; Zenobi, Renato

    2015-01-01

    A novel active capillary dielectric barrier discharge plasma ionization (DBDI) technique for mass spectrometry is applied to the direct detection of 13 chemical warfare related compounds, including sarin, and compared to secondary electrospray ionization (SESI) in terms of selectivity and sensitivity. The investigated compounds include an intact chemical warfare agent and structurally related molecules, hydrolysis products and/or precursors of highly toxic nerve agents (G-series, V-series, and "new" nerve agents), and blistering and incapacitating warfare agents. Well-defined analyte gas phase concentrations were generated by a pressure-assisted nanospray with consecutive thermal evaporation and dilution. Identification was achieved by selected reaction monitoring (SRM). The most abundant fragment ion intensity of each compound was used for quantification. For DBDI and SESI, absolute gas phase detection limits in the low ppt range (in MS/MS mode) were achieved for all compounds investigated. Although the sensitivity of both methods was comparable, the active capillary DBDI sensitivity was found to be dependent on the applied AC voltage, thus enabling direct tuning of the sensitivity and the in-source fragmentation, which may become a key feature in terms of field applicability. Our findings underline the applicability of DBDI and SESI for the direct, sensitive detection and quantification of several CWA types and their degradation products. Furthermore, they suggest the use of DBDI in combination with hand-held instruments for CWAs on-site monitoring. PMID:25427190

  3. Towards Pro-active Embodied Agents: On the Importance of Neural Mechanisms Suitable to Process Time Information

    NASA Astrophysics Data System (ADS)

    de Croon, G.; Nolfi, S.; Postma, E. O.

    In Embodied Cognitive Science, many studies have focused on reactive agents, i.e. agents that have no internal state and always respond in the same way to the same stimulus. However, this particular focus is not due to a rejection of the importance of internal states. Rather, it is due to the difficulty of developing pro-active embodied and situated agents, that is agents able to: (a) extract internal states by integrating sensorymotor information through time and, (b) later use these internal states to modulate their motor behaviour according to the current environmental circumstances. In this chapter we will focus on how pro-active agents can be developed and, more specifically, on which are the neural mechanisms that might favour the development of pro-active agents. By comparing the results of five sets of evolutionary experiments in which simulated robots are provided with different types of recurrent neural networks, we gain insight into the relation between the robots` capabilities and the characteristics of their neural controllers. We show how special mechanisms for processing information in time facilitate the exploitation of internal states.

  4. pH and Antimicrobial Activity of Portland Cement Associated with Different Radiopacifying Agents

    PubMed Central

    Guerreiro-Tanomaru, Juliane Maria; Cornélio, Ana Lívia G.; Andolfatto, Carolina; Salles, Loise P.; Tanomaru-Filho, Mário

    2012-01-01

    Objective. The aim of this study was to evaluate the antimicrobial activity and pH changes induced by Portland cement (PC) alone and in association with radiopacifiers. Methods. The materials tested were pure PC, PC + bismuth oxide, PC + zirconium oxide, PC + calcium tungstate, and zinc oxide and eugenol cement (ZOE). Antimicrobial activity was evaluated by agar diffusion test using the following strains: Micrococcus luteus, Streptococcus mutans, Enterococcus faecalis, Pseudomonas aeruginosa, and Candida albicans. After 24 hours of incubation at 37°C, inhibition of bacterial growth was observed and measured. For pH analysis, material samples (n = 10) were placed in polyethylene tubes and immersed in 10 mL of distilled water. After 12, 24, 48, and 72 hours, the pH of the solutions was determined using a pH meter. Results. All microbial species were inhibited by the cements evaluated. All materials composed of PC with radiopacifying agents promoted pH increase similar to pure Portland cement. ZOE had the lowest pH values throughout all experimental periods. Conclusions. All Portland cement-based materials with the addition of different radiopacifiers (bismuth oxide, calcium tungstate, and zirconium oxide) presented antimicrobial activity and pH similar to pure Portland cement. PMID:23119173

  5. Broad-spectrum in vivo antiviral activity of 7-thia-8-oxoguanosine, a novel immunopotentiating agent.

    PubMed Central

    Smee, D F; Alaghamandan, H A; Cottam, H B; Sharma, B S; Jolley, W B; Robins, R K

    1989-01-01

    A novel immunopotentiating agent, 5-amino-3-beta-D-ribofuranosylthiazolo [4,5-d]pyrimidine-2,7(3H,6H)-dione (7-thia-8-oxoguanosine), lacks virus-inhibitory properties in vitro but induces interferon and potentiates immune functions, such as natural killer cell activity. It was evaluated in rodent models to determine the spectrum of antiviral activity and effective treatment regimens. At 50 to 200 mg/kg given as single or divided intraperitoneal (i.p.) doses 1 day before virus inoculation, significant protection was afforded to mice infected i.p. with Semliki Forest, San Angelo, banzi, and encephalomyocarditis viruses. Similarly, suckling rats were protected from an intranasal challenge with rat coronavirus. Against San Angelo virus, treatments could be delayed to 1 day post-virus inoculation and still show a beneficial effect. The compound was moderately effective in mice infected i.p. with herpes simplex virus type 2 or intranasally with vesicular stomatitis virus. No activity was seen against influenza B virus in mice when the analog was administered one time pre-virus inoculation or in multiple doses given before and after the virus inoculation. Nor was there a prophylactic effect against herpetic skin lesions on mice. This immune modulator may have promise for the treatment of a variety of virus infections. PMID:2817849

  6. pH and Antimicrobial Activity of Portland Cement Associated with Different Radiopacifying Agents.

    PubMed

    Guerreiro-Tanomaru, Juliane Maria; Cornélio, Ana Lívia G; Andolfatto, Carolina; Salles, Loise P; Tanomaru-Filho, Mário

    2012-01-01

    Objective. The aim of this study was to evaluate the antimicrobial activity and pH changes induced by Portland cement (PC) alone and in association with radiopacifiers. Methods. The materials tested were pure PC, PC + bismuth oxide, PC + zirconium oxide, PC + calcium tungstate, and zinc oxide and eugenol cement (ZOE). Antimicrobial activity was evaluated by agar diffusion test using the following strains: Micrococcus luteus, Streptococcus mutans, Enterococcus faecalis, Pseudomonas aeruginosa, and Candida albicans. After 24 hours of incubation at 37°C, inhibition of bacterial growth was observed and measured. For pH analysis, material samples (n = 10) were placed in polyethylene tubes and immersed in 10 mL of distilled water. After 12, 24, 48, and 72 hours, the pH of the solutions was determined using a pH meter. Results. All microbial species were inhibited by the cements evaluated. All materials composed of PC with radiopacifying agents promoted pH increase similar to pure Portland cement. ZOE had the lowest pH values throughout all experimental periods. Conclusions. All Portland cement-based materials with the addition of different radiopacifiers (bismuth oxide, calcium tungstate, and zirconium oxide) presented antimicrobial activity and pH similar to pure Portland cement. PMID:23119173

  7. An attempt to assess functionally minimal acetylcholinesterase activity necessary for survival of rats intoxicated with nerve agents.

    PubMed

    Bajgar, Jiri; Fusek, Josef; Kassa, Jiri; Jun, Daniel; Kuca, Kamil; Hajek, Petr

    2008-09-25

    Acetylcholinesterase (AChE, EC 3.1.1.7) is an important enzyme for cholinergic nerve transmission. The action of toxic organophosphates such as nerve agents is based on AChE inhibition. The death following acute nerve agent poisoning is due to central or peripheral respiratory/cardiac failure. Therefore, the changes in AChE activity following nerve agents acting predominantly on the central (sarin, soman) or peripheral (VX) level were studied. It is known that AChE activity in different structures exists in relative excess. Female Wistar rats intoxicated with sarin, soman, and VX in different doses (0.5-2.0 x LD(50)) were divided into groups of survived and died animals. AChE activities in diaphragm, brain parts (pontomedullar area, frontal cortex, basal ganglia, in some cases other parts of the brain) were determined and the rest of activity (in %) was correlated with survival/death of animals. More precise elucidation of action of nerve agents and the assessment of minimal AChE activity in different organs compatible with the survival of organism poisoned with nerve agents were the aims of this study. PMID:18579126

  8. QSAR modeling, synthesis and bioassay of diverse leukemia RPMI-8226 cell line active agents.

    PubMed

    Katritzky, Alan R; Girgis, Adel S; Slavov, Svetoslav; Tala, Srinivasa R; Stoyanova-Slavova, Iva

    2010-11-01

    A rigorous QSAR modeling procedure employing CODESSA PRO descriptors has been utilized for the prediction of more efficient anti-leukemia agents. Experimental data concerning the effect on leukemia RPMI-8226 cell line tumor growth of 34 compounds (treated at a dose of 10 μM) was related to their chemical structures by a 4-descriptor QSAR model. Four bis(oxy)bis-urea and bis(sulfanediyl)bis-urea derivatives (4a, 4b, 8, 11a) predicted as active by this model, together with 11b predicted to be of low activity, were synthesized and screened for anti-tumor activity utilizing 55 different tumor cell lines. Compounds 8 and 11a showed anti-tumor properties against most of the adopted cell lines with growth inhibition exceeding 50%. The highly promising preliminary anti-tumor properties of compounds 8 and 11a, were screened at serial dilutions (10(-4)-10(-8) μM) for determination of their GI(50) and TGI against the screened human tumor cell lines. Compound 11a (GI(50) = 1.55, TGI = 8.68 μM) is more effective than compound 8 (GI(50)=58.30, TGI = > 100 μM) against the target leukemia RPMI-8226 cell line. Compound 11a also exhibits highly pronounced anti-tumor properties against NCI-H226, NCI-H23 (non-small cell lung cancer), COLO 205 (colon cancer), SNB-75 (CNS cancer), OVCAR-3, SK-OV-3 (ovarian cancer), A498 (renal cancer) MDA-MB-231/ATCC and MDA-MB-468 (breast cancer) cell lines (GI(50) = 1.95, 1.61, 1.38, 1.56, 1.30, 1.98, 1.18, 1.85, 1.08, TGI = 8.35, 6.01, 2.67, 8.59, 4.01, 7.01, 5.62, 6.38, 5.63 μM, respectively). Thus 11a could be a suitable lead towards the design of broad spectrum anti-tumor active agents targeting various human tumor cell lines. PMID:20843586

  9. Identification of actinomycetes from plant rhizospheric soils with inhibitory activity against Colletotrichum spp., the causative agent of anthracnose disease

    PubMed Central

    2011-01-01

    Background Colletotrichum is one of the most widespread and important genus of plant pathogenic fungi worldwide. Various species of Colletotrichum are the causative agents of anthracnose disease in plants, which is a severe problem to agricultural crops particularly in Thailand. These phytopathogens are usually controlled using chemicals; however, the use of these agents can lead to environmental pollution. Potential non-chemical control strategies for anthracnose disease include the use of bacteria capable of producing anti-fungal compounds such as actinomycetes spp., that comprise a large group of filamentous, Gram positive bacteria from soil. The aim of this study was to isolate actinomycetes capable of inhibiting the growth of Colletotrichum spp, and to analyze the diversity of actinomycetes from plant rhizospheric soil. Results A total of 304 actinomycetes were isolated and tested for their inhibitory activity against Colletotrichum gloeosporioides strains DoA d0762 and DoA c1060 and Colletotrichum capsici strain DoA c1511 which cause anthracnose disease as well as the non-pathogenic Saccharomyces cerevisiae strain IFO 10217. Most isolates (222 out of 304, 73.0%) were active against at least one indicator fungus or yeast. Fifty four (17.8%) were active against three anthracnose fungi and 17 (5.6%) could inhibit the growth of all three fungi and S. cerevisiae used in the test. Detailed analysis on 30 selected isolates from an orchard at Chanthaburi using the comparison of 16S rRNA gene sequences revealed that most of the isolates (87%) belong to the genus Streptomyces sp., while one each belongs to Saccharopolyspora (strain SB-2) and Nocardiopsis (strain CM-2) and two to Nocardia (strains BP-3 and LK-1). Strains LC-1, LC-4, JF-1, SC-1 and MG-1 exerted high inhibitory activity against all three anthracnose fungi and yeast. In addition, the organic solvent extracts prepared from these five strains inhibited conidial growth of the three indicator fungi

  10. The influence of oxazaphosphorines alkylating agents on autonomic nervous system activity in rat experimental cystitis model.

    PubMed

    Dobrek, Łukasz; Baranowska, Agnieszka; Thor, Piotr J

    2013-01-01

    The oxazaphosphorines alkylating agents (cyclophosphamide; CP and ifosfamide; IF) are often used in common clinical practice. However, treatment with CP/IF is burdened with the risk of many adverse drug reactions, especially including hemorrhagic cystitis (HC) that is associated with bladder overactivity symptoms (OAB). The HC pathophysiology is still not fully displayed; it seems that autonomic nervous system (ANS) functional abnormalities play important role in this disturbance. The aim of our study was to reveal the potential ANS differences in rat experimental HC model, evoked by CP and IF by an indirect ANS assessment--heart rate variability (HRV) study. We carried out our experimental research in three essential groups: control group (group 1), cyclophosphamide-induced HC (CP-HC; group 2) one and ifosfamide-induced HC (IF-HC; group 3) one. CP was i.p. administrated four times in dose of 75 mg/kg body weight while IF-treated rats received i.p. five drug doses; 50 mg/kg body weight. Control rats were administrated i.p. vehicle in appropriate volumes as CP/IF treated animals. HRV studies were performed the next day after the last oxazaphosphorines dose. Standard time- and spectral (frequency) domain parameters were estimated. We confirmed the HC development after both CP/IF in macroscopic assessment and bladder wet weight measurement; however, it was more aggravated in CP-HC group. Moreover, we demonstrated HRV disturbances, suggesting ANS impairment after both studied oxazaphosphorines, however, consistent with the findings mentioned above, the autonomic dysfunction was more emphasized after CP. CP treatment was also associated with changes of non-normalized HRV spectral components percentage distribution--a marked very low frequency--VLF [%] increase together with low frequency--LF [%] and high frequency--HF [%] decrease were observed. Taking into consideration the next findings, demonstrating the lack of both normalized power spectral components (nLF and n

  11. Modulation of KvAP Unitary Conductance and Gating by 1-Alkanols and Other Surface Active Agents

    PubMed Central

    Finol-Urdaneta, Rocio K.; McArthur, Jeffrey R.; Juranka, Peter F.; French, Robert J.; Morris, Catherine E.

    2010-01-01

    Abstract The actions of alcohols and anesthetics on ion channels are poorly understood. Controversy continues about whether bilayer restructuring is relevant to the modulatory effects of these surface active agents (SAAs). Some voltage-gated K channels (Kv), but not KvAP, have putative low affinity alcohol-binding sites, and because KvAP structures have been determined in bilayers, KvAP could offer insights into the contribution of bilayer mechanics to SAA actions. We monitored KvAP unitary conductance and macroscopic activation and inactivation kinetics in PE:PG/decane bilayers with and without exposure to classic SAAs (short-chain 1-alkanols, cholesterol, and selected anesthetics: halothane, isoflurane, chloroform). At levels that did not measurably alter membrane specific capacitance, alkanols caused functional changes in KvAP behavior including lowered unitary conductance, modified kinetics, and shifted voltage dependence for activation. A simple explanation is that the site of SAA action on KvAP is its entire lateral interface with the PE:PG/decane bilayer, with SAA-induced changes in surface tension and bilayer packing order combining to modulate the shape and stability of various conformations. The KvAP structural adjustment to diverse bilayer pressure profiles has implications for understanding desirable and undesirable actions of SAA-like drugs and, broadly, predicts that channel gating, conductance and pharmacology may differ when membrane packing order differs, as in raft versus nonraft domains. PMID:20197029

  12. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... other information required under 25 CFR 1000 subpart K. ... self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  13. Effects of Leisure Education Programme Including Sportive Activities on Perceived Freedom in Leisure of Adolescents with Intellectual Disabilities

    ERIC Educational Resources Information Center

    Ertuzun, Ezgi

    2015-01-01

    The objective of this experimental study is to determine the effect of leisure education programme including sportive activities on the perceived freedom in leisure of adolescents with mild intellectual disabilities. The research was designed with an experimental group (n = 37) and a control group (n = 34), and was conducted among a total of 71…

  14. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false What types of activities can a recreation, tourism, and trails program include? 170.137 Section 170.137 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Indian Reservation Roads Program Policy and Eligibility Recreation, Tourism and Trails...

  15. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... other information required under 25 CFR 1000 subpart K. ... self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  16. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... other information required under 25 CFR 1000 subpart K. ... self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  17. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... other information required under 25 CFR 1000 subpart K. ... self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  18. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... other information required under 25 CFR 1000 subpart K. ... self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  19. Anti-AIDS agents. 30. Anti-HIV activity of oleanolic acid, pomolic acid, and structurally related triterpenoids.

    PubMed

    Kashiwada, Y; Wang, H K; Nagao, T; Kitanaka, S; Yasuda, I; Fujioka, T; Yamagishi, T; Cosentino, L M; Kozuka, M; Okabe, H; Ikeshiro, Y; Hu, C Q; Yeh, E; Lee, K H

    1998-09-01

    Oleanolic acid (1) was identified as an anti-HIV principle from several plants, including Rosa woodsii (leaves), Prosopis glandulosa (leaves and twigs), Phoradendron juniperinum (whole plant), Syzygium claviflorum (leaves), Hyptis capitata (whole plant), and Ternstromia gymnanthera (aerial part). It inhibited HIV-1 replication in acutely infected H9 cells with an EC50 value of 1.7 microg/mL, and inhibited H9 cell growth with an IC50 value of 21.8 microg/mL [therapeutic index (T. I.) 12.8]. Pomolic acid, isolated from R. woodsii and H. capitata, was also identified as an anti-HIV agent (EC50 1.4 microg/mL, T. I. 16.6). Although ursolic acid did show anti-HIV activity (EC50 2.0 microg/mL), it was slightly toxic (IC50 6.5 microg/mL, T. I. 3.3). A new triterpene (11) was also isolated from the CHCl3-soluble fraction of R. woodsii, though it showed no anti-HIV activity. The structure of 11 was determined to be 1beta-hydroxy-2-oxopomolic acid by spectral examination. Based on these results, we examined the anti-HIV activity of oleanolic acid- or pomolic acid-related triterpenes isolated from several plants. In addition, we previously demonstrated that derivatives of betulinic acid, isolated from the leaves of S. claviflorum as an anti-HIV principle, exhibited extremely potent anti-HIV activity. Accordingly, we prepared derivatives of oleanolic acid and evaluated their anti-HIV activity. Among the oleanolic acid derivatives, 18 demonstrated most potent anti-HIV activity, with an EC50 value of 0. 0005 microg/mL and a T. I. value of 22 400. PMID:9748372

  20. An Ultrasound Contrast Agent targeted to P-selectin detects Activated Platelets at Supra-arterial Shear Flow Conditions

    PubMed Central

    Guenther, Felix; von zur Muhlen, Constantin; Ferrante, Elisa A.; Grundmann, Sebastian; Bode, Christoph; Klibanov, Alexander L.

    2012-01-01

    Objectives To evaluate targeting of a microbubble contrast agent to platelets under high shear flow using the natural selectin ligand sialyl Lewisa. Materials and Methods Biotinylated polyacrylamide Sialyl Lewisa or biotinylated carbohydrate-free polymer (used as a control) were attached to biotinylated microbubbles via a streptavidin linker. Activated human platelets were isolated and attached to fibrinogen-coated culture dishes. Fibrinogen-coated dishes without platelets or platelet dishes blocked by an anti-P-selectin antibody served as negative control substrates. Dishes coated by recombinant P-selectin served as a positive control substrate. Microbubble adhesion was assessed by microscopy in an inverted parallel plate flow chamber, with wall shear stress values of 40, 30, 20, 10 and 5 dynes/cm2. The ratio of binding and passing microbubbles was defined as capture efficiency. Results There was no significant difference between the groups regarding the number of microbubbles in the fluid flow at each shear rate. Sialyl Lewisa-targeted microbubbles were binding and slowly rolling on the surface of activated platelets and P-selectin-coated dishes at all the flow conditions including 40 dynes/cm2. Capture efficiency of targeted microbubbles to activated platelets and recombinant P-selectin decreased with increasing shear flow: at 5 dynes/cm2, capture efficiency was 16.11% on activated platelets vs. 21.83 % on P-selectin, and, at 40 dynes/cm2, adhesion efficiency was still 3.4 % in both groups. There was neither significant adhesion of Sialyl Lewisa-targeted microbubbles to control substrates, nor adhesion of control microbubbles to activated platelets or to recombinant P-selectin. Conclusions Microbubble targeting using sialyl Lewisa, a fast-binding ligand to P-selectin, is a promising strategy for the design of ultrasound contrast binding to activated platelets under high shear stress conditions. PMID:20808239

  1. Influence of the quantity of coloring agent in bleaching gels activated with LED/laser appliances on bleaching efficiency.

    PubMed

    Torres, Carlos Rocha Gomes; Batista, Graziela Ribeiro; César, Patrícia Desiderio; Barcellos, Daphne Câmara; Pucci, César Rogério; Borges, Alessandra Buhler

    2009-01-01

    The aim of this study was to assess the influence of the quantity of coloring agent on the bleaching efficiency of gels containing 35% H2O2. Sixty human third molars were sectioned mesiodistally, darkened in a coffee solution and sectioned in the occlusal-cervical direction, resulting in mesial (not bleached) and distal halves (bleached). They were distributed into three groups: Whiteness HP, Total Bleach, and Whiteform Perox Red Gel; and subdivided into four sub-groups: no coloring agent, manufacturer's standard, double the standard, and triple the standard. The gels were activated with light-ermitting diode/laser appliances. The images were analyzed with the Adobe Photoshop program (deltaEL*a*b*). The variation was submitted to the ANOVA test (two factors: type of gel and quantity of coloring agent) and Tukey test. Differences were observed for the quantity of coloring agent. The mean (+/-SD) was determined for each quantity of coloring used: no coloring agent -6.85 (+/-2.26)a, manufacturer's standard -794 (+/-2.55)ab, double the standard -8.65 (+/-2.47)b, triple the standard -9.05 (+/-2.72)b. In conclusion, the standard quantity of coloring agent did not provide significantly more intense bleaching than when it was completely absent. The use of double and triple the amount provided greater bleaching than that observed for the gel without coloring agent. No significant differences were observed between the tested gels. PMID:19655654

  2. Characterizations of Clinical Isolates of Clostridium difficile by Toxin Genotypes and by Susceptibility to 12 Antimicrobial Agents, Including Fidaxomicin (OPT-80) and Rifaximin: a Multicenter Study in Taiwan

    PubMed Central

    Liao, Chun-Hsing; Ko, Wen-Chien; Lu, Jang-Jih

    2012-01-01

    A total of 403 nonduplicate isolates of Clostridium difficile were collected at three major teaching hospitals representing northern, central, and southern Taiwan from January 2005 to December 2010. Of these 403 isolates, 170 (42.2%) were presumed to be nontoxigenic due to the absence of genes for toxins A or B or binary toxin. The remaining 233 (57.8%) isolates carried toxin A and B genes, and 39 (16.7%) of these also had binary toxin genes. The MIC90 of all isolates for fidaxomicin and rifaximin was 0.5 μg/ml (range, ≤0.015 to 0.5 μg/ml) and >128 μg/ml (range, ≤0.015 to >128 μg/ml), respectively. All isolates were susceptible to metronidazole (MIC90 of 0.5 μg/ml; range, ≤0.03 to 4 μg/ml). Two isolates had reduced susceptibility to vancomycin (MICs, 4 μg/ml). Only 13.6% of isolates were susceptible to clindamycin (MIC of ≤2 μg/ml). Nonsusceptibility to moxifloxacin (n = 81, 20.1%) was accompanied by single or multiple mutations in gyrA and gyrB genes in all but eight moxifloxacin-nonsusceptible isolates. Two previously unreported gyrB mutations might independently confer resistance (MIC, 16 μg/ml), Ser416 to Ala and Glu466 to Lys. Moxifloxacin-resistant isolates were cross-resistant to ciprofloxacin and levofloxacin, but some moxifloxacin-nonsusceptible isolates remained susceptible to gemifloxacin or nemonoxacin at 0.5 μg/ml. This study found the diversity of toxigenic and nontoxigenic strains of C. difficile in the health care setting in Taiwan. All isolates tested were susceptible to metronidazole and vancomycin. Fidaxomicin exhibited potent in vitro activity against all isolates tested, while the more than 10% of Taiwanese isolates with rifaximin MICs of ≥128 μg/ml raises concerns. PMID:22508299

  3. Characterizations of clinical isolates of clostridium difficile by toxin genotypes and by susceptibility to 12 antimicrobial agents, including fidaxomicin (OPT-80) and rifaximin: a multicenter study in Taiwan.

    PubMed

    Liao, Chun-Hsing; Ko, Wen-Chien; Lu, Jang-Jih; Hsueh, Po-Ren

    2012-07-01

    A total of 403 nonduplicate isolates of Clostridium difficile were collected at three major teaching hospitals representing northern, central, and southern Taiwan from January 2005 to December 2010. Of these 403 isolates, 170 (42.2%) were presumed to be nontoxigenic due to the absence of genes for toxins A or B or binary toxin. The remaining 233 (57.8%) isolates carried toxin A and B genes, and 39 (16.7%) of these also had binary toxin genes. The MIC(90) of all isolates for fidaxomicin and rifaximin was 0.5 μg/ml (range, ≤ 0.015 to 0.5 μg/ml) and >128 μg/ml (range, ≤ 0.015 to >128 μg/ml), respectively. All isolates were susceptible to metronidazole (MIC(90) of 0.5 μg/ml; range, ≤ 0.03 to 4 μg/ml). Two isolates had reduced susceptibility to vancomycin (MICs, 4 μg/ml). Only 13.6% of isolates were susceptible to clindamycin (MIC of ≤ 2 μg/ml). Nonsusceptibility to moxifloxacin (n = 81, 20.1%) was accompanied by single or multiple mutations in gyrA and gyrB genes in all but eight moxifloxacin-nonsusceptible isolates. Two previously unreported gyrB mutations might independently confer resistance (MIC, 16 μg/ml), Ser416 to Ala and Glu466 to Lys. Moxifloxacin-resistant isolates were cross-resistant to ciprofloxacin and levofloxacin, but some moxifloxacin-nonsusceptible isolates remained susceptible to gemifloxacin or nemonoxacin at 0.5 μg/ml. This study found the diversity of toxigenic and nontoxigenic strains of C. difficile in the health care setting in Taiwan. All isolates tested were susceptible to metronidazole and vancomycin. Fidaxomicin exhibited potent in vitro activity against all isolates tested, while the more than 10% of Taiwanese isolates with rifaximin MICs of ≥ 128 μg/ml raises concerns. PMID:22508299

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

    SciTech Connect

    Asmis, Lars; Tanner, Felix C.; Sudano, Isabella; Luescher, Thomas F.; Camici, Giovanni G.

    2010-01-22

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

  5. Effect of reducing agents and uncouplers on the electrical potential generated by mitochondrial ATPase activity.

    PubMed

    Encío, I; de Miguel, C; López-Moratalla, N; Santiago, E

    1989-12-01

    Beef heart submitochondrial particles bound to phospholipids impregnated filters generated an electrical potential upon the addition of ATP. The magnitude of the electrical potential reached depended on the phospholipid mixture composition used for filter impregnation, phosphatidylethanolamine being the active component for the electrical potential generation. Uncoupler FCCP (p-trifluoromethoxy carbonyl cyanide phenylhydrazone) inhibited the transmembrane electrical potential generation by diminishing the electrical resistance of the system as a result of its protonophoric action. However, uncouplers 2, 4-dinitrophenol and dicoumarol did not provoke large modifications of the electrical resistance under the conditions of pH and concentration used, and their action varied with the time elapsed after the submitochondrial particles purification, favouring the idea of the uncoupler interaction with a specific site on the membrane. Addition of sodium dithionite resulted in a higher plateau value for the electrical potential consistent with the promoted increase in ATPase activity. The effect of this agent was reversed by the 2,6-dichlorophenol-indophenol added at equivalent concentrations. PMID:2561021

  6. An imaging agent to detect androgen receptor and its active splice variants in prostate cancer

    PubMed Central

    Imamura, Yusuke; Tien, Amy H.; Pan, Jinhe; Leung, Jacky K.; Banuelos, Carmen A.; Jian, Kunzhong; Wang, Jun; Mawji, Nasrin R.; Fernandez, Javier Garcia; Lin, Kuo-Shyan; Andersen, Raymond J.; Sadar, Marianne D.

    2016-01-01

    Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD–targeted (AR LBD–targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V–positive lesions to determine whether they will benefit from further AR LBD–targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs. AR activation function-1 (AF-1) is common to the N-terminal domains of full-length AR and AR-Vs. Here, we provide proof of concept for developing imaging compounds that directly bind AR AF-1 to detect both AR-Vs and full-length AR. 123I-EPI-002 had specific binding to AR AF-1, which enabled direct visualization of CRPC xenografts that express full-length AR and AR-Vs. Our findings highlight the potential of 123I-EPI-002 as an imaging agent for the detection of full-length AR and AR-Vs in CRPC. PMID:27525313

  7. Oral manganese as an MRI contrast agent for the detection of nociceptive activity.

    PubMed

    Jacobs, Kathleen E; Behera, Deepak; Rosenberg, Jarrett; Gold, Garry; Moseley, Michael; Yeomans, David; Biswal, Sandip

    2012-04-01

    The ability of divalent manganese to enter neurons via calcium channels makes manganese an excellent MRI contrast agent for the imaging of nociception, the afferent neuronal encoding of pain perception. There is growing evidence that nociceptive neurons possess increased expression and activity of calcium channels, which would allow for the selective accumulation of manganese at these sites. In this study, we show that oral manganese chloride leads to increased enhancement of peripheral nerves involved in nociception on T(1)-weighted MRI. Oral rather than intravenous administration was chosen for its potentially better safety profile, making it a better candidate for clinical translation with important applications, such as pain diagnosis, therapy and research. The spared nerve injury (SNI) model of neuropathic pain was used for the purposes of this study. SNI rats were given, sequentially, increasing amounts of manganese chloride (lowest, 2.29 mg/100 g weight; highest, 20.6 mg/100 g weight) with alanine and vitamin D(3) by oral gavage. Compared with controls, SNI rats demonstrated increased signal-to-background ratios on T(1)-weighted fast spin echo MRI, which was confirmed by and correlated strongly with spectrometry measurements of nerve manganese concentration. We also found the difference between SNI and control rats to be greater at 48 h than at 24 h after dosing, indicating increased manganese retention in addition to increased manganese uptake in nociceptive nerves. This study demonstrates that oral manganese is a viable method for the imaging of nerves associated with increased nociceptive activity. PMID:22447731

  8. Synthesis, biological evaluation and structure-activity relationship of 2-styrylquinazolones as anti-tubercular agents.

    PubMed

    Jadhavar, Pradeep S; Dhameliya, Tejas M; Vaja, Maulikkumar D; Kumar, Dinesh; Sridevi, Jonnalagadda Padma; Yogeeswari, Perumal; Sriram, Dharmarajan; Chakraborti, Asit K

    2016-06-01

    2-Styrylquinazolones are reported as a novel class of potent anti-mycobacterial agents. Forty-six target compounds have been synthesized using one pot reaction involving isatoic anhydride, amine, and triethyl orthoacetate followed by aldehyde to construct the 2-styrylquinazolone scaffold. The anti-mycobacterial potency of the compounds was determined against H37Rv strain. Twenty-six compounds exhibited anti-Mtb activity in the range of 0.40-6.25μg/mL. Three compounds 8c, 8d and 8ab showed MIC of 0.78μg/mL and were found to be non-toxic (<50% inhibition at 50μg/mL) to HEK 293T cell lines with the therapeutic index >64. The most potent compound 8ar showed MIC of 0.40μg/mL with the therapeutic index >125. An early structure activity relationship for this class of compounds has been established. The computational studies indicate the possibility of these compounds binding to the penicillin binding proteins (PBPs). PMID:27095514

  9. Improving the promiscuous nerve agent hydrolase activity of a thermostable archaeal lactonase.

    PubMed

    Merone, Luigia; Mandrich, Luigi; Porzio, Elena; Rossi, Mosé; Müller, Susanne; Reiter, Georg; Worek, Franz; Manco, Giuseppe

    2010-12-01

    The thermostable Phosphotriesterase-Like Lactonase from Sulfolobus solfataricus (SsoPox) hydrolyzes lactones and, at a lower rate, neurotoxic organophosphorus compounds. The persistent demand of detoxification tools in the field of agricultural wastes and restoring of conditions after terrorist acts prompted us to exploit SsoPox as a "starter" to evolve its ancillary nerve agents hydrolytic capability. A directed evolution strategy yielded, among several variants, the single mutant W263F with k(cat) and specificity constant against paraoxon 16- and 6-fold enhanced, respectively, compared to the wild type. Furthermore, a phenomenon of enzyme activation by SDS has been observed, which allowed to increase those values 150- and 28-fold, respectively. The activity of SsoPox against the deadly nerve gas Cyclosarin has been reported for the first time and proved to be substantially unaffected for variant W263F. Finally, outperforming efficiency of W263F was demonstrated, under severe stressing conditions, with respect to the best known phosphotriesterase PTE from Brevundimonas diminuta. PMID:20667718

  10. Comparative in vitro activity of faropenem and 11 other antimicrobial agents against 250 invasive Streptococcus pneumoniae isolates from France.

    PubMed

    Decousser, J W; Pina, P; Picot, F; Allouch, P Y

    2003-09-01

    The aim of the study presented here was to evaluate the in vitro activity of faropenem, a new member of the penem class intended for oral administration, compared with 11 other antimicrobial agents against a large number of Streptococcus pneumoniae strains isolated from adults and children with bloodstream infections in France. The minimum inhibitory concentration of faropenem against 90% of the pediatric strains tested was generally one to two dilutions lower than the most potent beta-lactam agents (i.e., 0.5 micro g/ml for faropenem vs. 1 for amoxicillin, 1 for cefotaxime and 0.5 micro g/ml for ceftriaxone). Against the adult strains, only moxifloxacin had a MIC(90) value similar to faropenem (i.e., 0.25 micro g/ml for both agents). Faropenem seems to be a promising antimicrobial agent for the treatment of adult and pediatric Streptococcus pneumoniae infections. PMID:12942341

  11. Iron-chelating agent, deferasirox, inhibits neutrophil activation and extracellular trap formation.

    PubMed

    Kono, Mari; Saigo, Katsuyasu; Yamamoto, Shiori; Shirai, Kohei; Iwamoto, Shuta; Uematsu, Tomoko; Takahashi, Takayuki; Imoto, Shion; Hashimoto, Makoto; Minami, Yosuke; Wada, Atsushi; Takenokuchi, Mariko; Kawano, Seiji

    2016-10-01

    Iron-chelating agents, which are frequently prescribed to transfusion-dependent patients, have various useful biological effects in addition to chelation. Reactive oxygen species (ROS) produced by neutrophils can cause pulmonary endothelial cell damage, which can lead to acute lung injury (ALI). We previously reported that deferasirox (DFS), an iron-chelating agent, inhibits phorbol myristate acetate (PMA) or formyl-methionyl-leucyl-phenylalanine (fMLP)-induced ROS production in neutrophils, in vitro. Here, we investigate whether DFS inhibits vacuolization in neutrophils and neutrophil extracellular trap (NET) formation. Human neutrophils were incubated with DFS and stimulated with PMA or fMLP. Human neutrophils were separated from heparinized peripheral blood using density gradient centrifugation, and subsequently incubated with DFS. After 10 minutes, neutrophils were stimulated by PMA or fMLP. Vacuole formation was observed by electron microscopy. For observing NET formations using microscopes, immunohistological analyses using citrullinated histone H3 and myeloperoxidase antibodies, and SYTOX Green (an impermeable DNA detection dye) staining, were conducted. NET formation was measured as the quantity of double-stranded DNA (dsDNA), using the AccuBlue Broad Range dsDNA Quantitation Kit. DFS (50 μmol/L) inhibited vacuole formation in the cytoplasm and NET formation. Additionally, 5-100 μmol/L concentration of DFS inhibited the release of dsDNA in a dose-independent manner. We demonstrate that DFS inhibits not only ROS production but also vacuolization and NET formation in neutrophils. These results suggest the possibility of protective effects of DFS against NET-related adverse effects, including ALI and thrombosis. PMID:27333499

  12. Comparative in vitro activity of 16 antimicrobial agents against Actinobacillus pleuropneumoniae.

    PubMed

    Yoshimura, H; Takagi, M; Ishimura, M; Endoh, Y S

    2002-01-01

    Sixteen antimicrobial agents were tested for their activity against 68 isolates of Actinobacillus pleuropneumoniae by determining the minimum inhibitory concentrations (MICs). Ceftiofur and the fluoroquinolones danofloxacin and enrofloxacin were the most active compounds, with a MIC for 90% of the isolates (MIC90) of (0.05 microg/ml. The MIC90 values of benzylpenicillin, amoxicillin and aspoxicillin were 0.78 units/ml, 0.39 microg/ml and < or = 0.05 microg/ml, respectively. Three isolates (4.4%) were resistant to penicillins, but aspoxicillin was as active as ceftiofur against the susceptible isolates, with MICs of < or = 0.05 microg/ml for all isolates. Resistance to oxytetracycline, chloramphenicol and thiamphenicol occurred in 22 (32.4%), 14 (20.6%) and 15 (22.1%) of the isolates, respectively. Doxycycline was more active than oxytetracycline, with a MIC90 of 1.56 microg/ml as against 25 microg/ml. Florfenicol was not only as active as thiamphenicol, with a MIC for 50% of the isolates (MIC50) of 0.39 microg/ml, but also active against thiamphenicol-resistant isolates. All the isolates were susceptible to florfenicol. All the isolates were also susceptible to gentamicin, spectinomycin, tilmicosin, colistin and tiamulin. Of these, spectinomycin was the least active, with a MIC50 of 25 microg/ml, followed by tiamulin, with a MIC50 of 6.25 microg/ml. Of the 68 isolates tested, 49 (72.0%) were of serotype 2; 14 (20.5%) were of serotype 1; 2 each (3.0%) were of serotypes 5 and 6; and one was of serotype 7. Of the isolates, 23 (33.8%) were resistant to one or more of the major antibiotics. Antibiotic resistance was found only infrequently among serotype 2, with 5 (10.2%) of 49 isolates being resistant to chloramphenicol and/or oxytetracycline, while it occurred in 18 (94.7%) of the 19 isolates of other serotypes. PMID:11860083

  13. Effects of different bulking agents on the maturity, enzymatic activity, and microbial community functional diversity of kitchen waste compost.

    PubMed

    Wang, Xiaojuan; Zhang, Wenwei; Gu, Jie; Gao, Hua; Qin, Qingjun

    2016-10-01

    Aerobic composting is an effective method for the disposal and utilization of kitchen waste. However, the addition of a bulking agent is necessary during kitchen waste composting because of its high moisture content and low C/N ratio. In order to select a suitable bulking agent, we investigated the influence of leaf litter (LL), sawdust (SD), and wheat straw (WS) on the enzymatic activity, microbial community functional diversity, and maturity indices during the kitchen waste composting process. The results showed that the addition of WS yielded the highest maturity (the C/N ratio decreased from 25 to 13, T value = 0.5, and germination index (GI) = 114.7%), whereas the compost containing SD as a bulking agent had the lowest maturity (GI = 32.4%). The maximum cellulase and urease activities were observed with the WS treatment on day 8, whereas the SD treatment had the lowest cellulase activity and the LL treatment had the lowest urease activity. The compost temperature and microbial activity (as the average well color development) showed that bulking the composts with SD prolonged the composting process. The diversity index based on the community-level physiological profile showed that the composts bulked with LL and WS had greater microbial community functional diversity compared with those bulked with SD. Thus, the maturity indexes and enzymatic activities suggest that WS is a suitable bulking agent for use in kitchen waste composting systems. PMID:26895274

  14. Comparative Study of Activities of a Diverse Set of Antimycobacterial Agents against Mycobacterium tuberculosis and Mycobacterium ulcerans.

    PubMed

    Scherr, Nicole; Pluschke, Gerd; Panda, Manoranjan

    2016-05-01

    A library of compounds covering a broad chemical space was selected from a tuberculosis drug development program and was screened in a whole-cell assay against Mycobacterium ulcerans, the causative agent of the necrotizing skin disease Buruli ulcer. While a number of potent antitubercular agents were only weakly active or inactive against M. ulcerans, five compounds showed high activity (90% inhibitory concentration [IC90], ≤1 μM), making screening of focused antitubercular libraries a good starting point for lead generation against M. ulcerans. PMID:26883701

  15. In vitro activity of ceftazidime/avibactam against Gram-negative pathogens isolated from pneumonia in hospitalised patients, including ventilated patients.

    PubMed

    Flamm, Robert K; Nichols, Wright W; Sader, Helio S; Farrell, David J; Jones, Ronald N

    2016-03-01

    The activities of the novel β-lactam/non-β-lactam β-lactamase inhibitor combination ceftazidime/avibactam and comparators were evaluated against isolates from pneumonia in hospitalised patients including ventilated patients (PHP, pneumonia not designated as VABP; VABP, pneumonia in ventilated patients). Isolates were from the European-Mediterranean region (EuM), China and the USA collected in the SENTRY Antimicrobial Surveillance Program between 2009 and 2011 inclusive. A total of 2393 organisms from PHP were from the EuM, 888 from China and 3213 from the USA; from VABP patients there were 918, 97 and 692 organisms collected, respectively. Among Enterobacteriaceae from PHP, ceftazidime/avibactam MIC90 values against Escherichia coli ranged from 0.25-0.5mg/L and Klebsiella spp. MIC90 values were 0.5mg/L in each region. Among VABP isolates, MIC90 values for ceftazidime/avibactam against E. coli were 0.25mg/L; for Klebsiella spp. from VABP patients, MIC90 values were similar to those obtained against PHP isolates. The MIC of ceftazidime/avibactam was ≤8mg/L against 92-96% of Pseudomonas aeruginosa isolated from PHP patients. Isolates of P. aeruginosa from VABP patients were of lower susceptibility to all antibacterial agents (e.g. depending on region, meropenem susceptibilities were 51.2-69.4% in contrast to 68.3-76.7% among PHP patients). However, ceftazidime/avibactam inhibited 79.2-95.4% of VABP isolates at an MIC of ≤8mg/L. Acinetobacter spp. were resistant to many agents and only rates of susceptibility to colistin were >90% across all regions both for PHP and VABP isolates. Ceftazidime/avibactam was generally active against a high proportion of isolates resistant to ceftazidime from PHP and VAPB patients. PMID:26920105

  16. Peroxides with antiplasmodial activity inhibit proliferation of Perkinsus olseni, the causative agent of Perkinsosis in bivalves.

    PubMed

    Araujo, N C P; Afonso, R; Bringela, A; Cancela, M L; Cristiano, M L S; Leite, R B

    2013-12-01

    Perkinsus olseni, the causative agent of Perkinsosis, can drastically affect the survival of target marine mollusks, with dramatic economic consequences for aquaculture. P. olseni is a member of the Alveolata group, which also comprises parasites that are highly relevant for medical and veterinary sciences such as Plasmodium falciparum and Toxoplasma. P. olseni shares several unique metabolic pathways with those pathological parasites but is not toxic to humans. In this work, six antimalarially active peroxides, derived from the natural product artemisinin or synthetic trioxolanes, were synthesized and tested on P. olseni proliferation and survival. All peroxides tested revealed an inhibitory effect on P. olseni proliferation at micromolar concentrations. The relevance of the peroxide functionality on toxicity and the effect of Fe(II)-intracellular concentration on activity were also evaluated. Results demonstrated that the peroxide functionality is the toxofore and intracellular iron concentration also proved to be a crucial co-factor on the activation of peroxides in P. olseni. These data points to a mechanism of bioactivation in P. olseni sharing similarities with the one proposed in P. falciparum parasites. Preliminary studies on bioaccumulation were conducted using fluorescent-labeled peroxides. Results show that synthetic trioxolanes tend to accumulate on a vacuole while the labeled artemisinin accumulates in the cytoplasm. Preliminary experiments on differential genes expression associated to Fe(II) transport protein (Nramp) and calcium transport protein (ATP6/SERCA) were also conducted by qPCR. Results point to a fourfold increase in expression of both genes upon exposure to trioxolanes and approximately twofold upon exposure to artemisinin derivatives. Data obtained in this investigation is relevant for better understanding of the biology of Perkinsus and may also be important in the development of new strategies for Perkinsosis prevention and control

  17. Antifungal agents.

    PubMed

    Ryder, N S

    1999-12-01

    At this year's ICAAC Meeting, new data on approximately 20 different antifungal agents were presented, while no new agents were disclosed. Drugs in late development include the triazoles, voriconazole (Pfizer Ltd) and Sch-56592 (Schering-Plough Corp), and the echinocandins, caspofungin (Merck & Co Inc) and FK-463 (Fujisawa Pharmaceutical Co Ltd). In contrast to previous years, presentations on these and earlier developmental compounds were relatively modest in scope, with few significant new data. Little new information appeared on the most recent novel class of agents, the sordarins (Glaxo Wellcome plc). Early clinical results were presented for FK-463, showing acceptable tolerability and dose-dependent efficacy in AIDS-associated esophageal candidiasis. A new liposomal formulation of nystatin (Nyotran; Aronex Pharmaceuticals Inc) was shown to be equivalent to conventional amphotericin B in empiric therapy of presumed fungal infection in neutropenic patients, but with reduced toxicity. Intravenous itraconazole (Janssen Pharmaceutica NV) was an effective prophylactic therapy in invasive pulmonary aspergillosis, while oral itraconazole was discussed as a treatment for fungal infection in heart and liver transplant patients. The allylamine compound, terbinafine (Novartis AG), showed good clinical efficacy against fungal mycetoma, a serious tropical infection. A major highlight was the first presentation of inhibitors of fungal efflux pumps as a strategy for overcoming resistance. MC-510027 (milbemycin alpha-9; Microcide Pharmaceuticals Inc) and its derivatives, potentiated the antifungal activity of triazoles and terbinafine in a number of Candida spp. Another pump inhibitor, MC-005172 (Microcide Pharmaceuticals Inc) showed in vivo potentiation of fluconazole in a mouse kidney infection model. Microcide Pharmaceuticals Inc also presented inhibitors of bacterial efflux pumps. PMID:16113946

  18. A novel small molecule agent displays potent anti-myeloma activity by inhibiting the JAK2-STAT3 signaling pathway

    PubMed Central

    Zhu, Jingyu; Xu, Yujia; Wang, Siyu; Xu, Xin; Ji, Peng; Yu, Yang; Cao, Biyin; Han, Kunkun; Hou, Tingjun; Xu, Zhuan; Kong, Yan; Jiang, Gaofeng; Tang, Xiaowen; Qiao, Chunhua; Mao, Xinliang

    2016-01-01

    The oncogenic STAT3 signaling pathway is emerging as a promising target for the treatment of multiple myeloma (MM). In the present study, we identified a novel STAT3 inhibitor SC99 in a target-based high throughput screen. SC99 inhibited JAK2-STAT3 activation but had no effects on other transcription factors such as NF-κB, and kinases such as AKT, ERK, and c-Src that are in association with STAT3 signaling pathway. Furthermore, SC99 downregulated the expression of STAT3-modulated genes, including Bcl-2, Bcl-xL, VEGF, cyclin D2, and E2F-1. By inhibiting the STAT3 signaling, SC99 induced MM cell apoptosis which could be partly abolished by the ectopic expression of STAT3. Furthermore, SC99 displayed potent anti-MM activity in two independent MM xenograft models in nude mice. Oral administration of SC99 led to marked decrease of tumor growth within 10 days at a daily dosage of 30 mg/kg, but did not raise toxic effects. Taken together, this study identified a novel oral JAK2/STAT3 inhibitor that could be developed as an anti-myeloma agent. PMID:26814430

  19. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma

    PubMed Central

    LaPlant, Betsy; Chng, Wee Joo; Zonder, Jeffrey; Callander, Natalie; Fonseca, Rafael; Fruth, Briant; Roy, Vivek; Erlichman, Charles; Stewart, A. Keith

    2015-01-01

    Dysregulation of cyclin-dependent kinases is a hallmark of myeloma, and specifically, cdk5 inhibition can enhance the activity of proteasome inhibitors in vitro. Dinaciclib is a novel potent small molecule inhibitor of cyclin-dependent kinases (CDK)1, CDK2, CDK5, and CDK9. Patients with relapsed multiple myeloma and ≤5 prior lines of therapy, with measurable disease, were enrolled. Dinaciclib was administered on day 1 of a 21-day cycle at doses of 30 to 50 mg/m2. Overall, 27 evaluable patients were accrued; the median number of prior therapies was 4. The dose level of 50 mg/m2 was determined to be the maximally tolerated dose. The overall confirmed partial response rate (PR) was 3 of 27 (11%), including 1 patient at the 30 mg/m2 dose (1 very good PR [VGPR]) and 2 patients at the 40 mg/m2 dose (1 VGPR and 1 PR). In addition, 2 patients at the 50 mg/mg2 dose achieved a minimal response (clinical benefit rate, 19%). Leukopenia, thrombocytopenia, gastrointestinal symptoms, alopecia, and fatigue were the most common adverse events. The current study demonstrates single agent activity of dinaciclib in relapsed myeloma, with 2 patients achieving a deep response (VGPR) and 10 patients obtaining some degree of M protein stabilization or decrease. This trial was registered at www.clinicaltrials.gov as #NCT01096342. PMID:25395429

  20. 78 FR 60317 - Agency Information Collection Activities: Proposed Collection; Comments Requested: Special Agent...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-01

    ... Collection; Comments Requested: Special Agent Medical Preplacement ACTION: 60-Day notice. The Department of... other technological collection techniques or other forms of information technology, e.g., permitting...: Revision of a currently approved collection. (2) Title of the Form/Collection: Special Agent...

  1. Quantitative comparison of the convulsive activity of combinations of twelve fluoroquinolones with five nonsteroidal antiinflammatory agents.

    PubMed

    Kim, Jahye; Ohtani, Hisakazu; Tsujimoto, Masayuki; Sawada, Yasufumi

    2009-01-01

    Concomitant administration of certain fluoroquinolone antimicrobials and nonsteroidal antiinflammatory agents (NSAIDs) induces serious convulsion in humans. There are differences in convulsive activity among fluoroquinolones and in the potentiation of fluoroquinolone-induced convulsion among NSAIDs, but a comprehensive, quantitative comparison has not been carried out. This study evaluates the inhibitory effects of twelve fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pazufloxacin, prulifloxacin, sparfloxacin, and tosufloxacin) alone or in the presence of an NSAID (4-biphenylacetic acid, diclofenac sodium, loxoprofen, lornoxicam or zaltoprofen) on the GABA(A) receptor binding of [(3)H]muscimol in an in vitro study using mice synaptic plasma membrane. The rank order of inhibitory effects of the fluoroquinolones was prulifloxacin asymptotically equal to norfloxacin > ciprofloxacin > or = enoxacin > gatifloxacin > or = ofloxacin asymptotically equal to tosufloxacin asymptotically equal to lomefloxacin > levofloxacin > or = sparfloxacin > or = pazufloxacin asymptotically equal to fleroxacin. 4-Biphenylacetic acid most potently enhanced the inhibitory effects of the fluoroquinolones, while zaltoprofen, loxoprofen, lornoxicam and diclofenac had essentially no effect. The clinical risk of convulsion for each combination was estimated using a pharmacodynamic model based on receptor occupancy using the in vitro data set obtained and pharmacokinetic parameters in humans collected from the literature. The combinations of 4-biphenylacetic acid with prulifloxacin and enoxacin were concluded to be the most hazardous. PMID:19430173

  2. Use of the Crohn’s disease activity index in clinical trials of biological agents

    PubMed Central

    Freeman, Hugh James

    2008-01-01

    The Crohn’s disease activity index (CDAI) has been commonly used to assess the effects of treatment with different agents in Crohn’s disease (CD). However, these studies may be compromised, if the results compared to a placebo or standard therapy group (in the absence of a placebo) substantially differ from the expected response. In addition, significant concerns have been raised regarding the reliability and validity of the CDAI. Reproducibility of the CDAI may be limited as significant inter-observer error has been recorded, even if measurements are done by experienced clinicians with expertise in the diagnosis and treatment of CD. Finally, many CDAI endpoints are open to subjective interpretation and have the potential for manipulation. This is worrisome as there is the potential for significant financial gain, if the results of a clinical trial appear to provide a positive result. Physicians caring for patients should be concerned about the positive results in clinical trials that are sponsored by industry, even if the trials involve respected centers and the results appear in highly ranked medical journals. PMID:18636655

  3. Azido Auxins: Synthesis and Biological Activity of Fluorescent Photoaffinity Labeling Agents 12

    PubMed Central

    Melhado, L. Lee; Jones, Alan M.; Leonard, Nelson J.; Vanderhoef, Larry N.

    1981-01-01

    Three auxin analogs, 4−, 5−, and 6-azido-3-indoleacetic acid (4-N3-IAA, 5-N3-IAA, and 6-N3-IAA) have been synthesized for use as fluorescent photoaffinity labeling agents. The pKa values of these compounds (4-N3-IAA, 4.67; 5-N3-IAA, 4.65; 6-N3-IAA, 4.66; all ± 0.04) are experimentally indistinguishable from the pKa of 3-indoleacetic acid (IAA, 4.69 ± 0.04). The auxin activity of these IAA derivatives has been determined in several systems. In soybean, pea, and corn straight growth assays, all three analogs induce growth comparable to that caused by IAA. In the tobacco pith assay, all three analogs elicit a maximum increase in fresh weight at least 40 to 50% of that caused by IAA. Optimal growth is attained in the tobacco pith assay at slightly higher concentrations of 4-N3-IAA and 6-N3-IAA (30 micromolar) than required for IAA (10 micromolar); however, maximal growth is achieved at a slightly lower concentration of 5-N3-IAA (3 micromolar). The N3-IAAs, like IAA, are transported basipetally through tobacco pith tissue. PMID:16661939

  4. In vitro activity of antimicrobial agents against oxacillin resistant staphylococci with special reference to Staphylococcus haemolyticus.

    PubMed

    Chaudhury, A; Kumar, A G

    2007-01-01

    One hundred and sixty seven isolates of staphylococci isolated from the inpatients of a tertiary care referral hospital in South India were speciated and activity of oxacillin, glycopeptides, linezolid and quinupristin/dalfopristin against these isolates was tested by broth microdilution method. Of the 114 coagulase negative staphylococci (CoNS), 49.1 % were S. haemolyticus, isolated predominantly from urine (64.6%), while the rest belonged to 11 other species. More than half the isolates of S. aureus (52.8%) and 68.4% of the CoNS were oxacillin resistant. All the strains were uniformly susceptible to vancomycin, linezolid and quinupristin/dalfopristin; but 25.6% isolates of S. haemolyticus showed reduced susceptibility to teicoplanin (MIC: 8-16 mg/L). Our study demonstrates the high prevalence of oxacillin resistance among hospital isolates of S. aureus and CoNS in India. Vancomycin, along with the newer agents like linezolid and quinupristin/dalfopristin remains the drug of choice for treating multi drug resistant staphylococcal infections. PMID:17377353

  5. Anti-inflammatory activity of Yanshu spraying agent in animal models

    PubMed Central

    ZHANG, JIANQIAO; WANG, HONGSHENG; WANG, TIAN; CHONG, YATING; YU, PENGFEI; LU, CHENGWEN; XUE, YUNLI; FU, FENGHUA; ZHANG, LEIMING

    2013-01-01

    Acute pharyngitis is characterized by an inflammation of the mucous membranes in the pharynx. Yanshu spraying agent was prepared according to the traditional Chinese formulation for the treatment of acute pharyngitis. The present study aimed to investigate the anti-inflammatory effect of Yanshu in xylene-induced ear edema in mice and carrageenan-induced paw edema in rats by measuring the degree of edema in the animal models. The histopathology and the levels of prostaglandin E2 (PGE2) and cycloxygenase-2 (COX-2) in the hind paws of the carrageenan-treated rats were also analyzed. The results showed that Yanshu significantly reduced ear edema in the mice and paw edema in the rats. Furthermore, treatment with Yanshu also reduced the number of inflammatory cells in tissue and decreased the production of PGE2 and COX-2. These results suggest that Yanshu possesses potent anti-inflammatory activity mediated by the inhibition of COX-2 expression which, in turn, downregulates the inflammatory mediator PGE2. PMID:23251244

  6. In vitro activities of polycationic peptides alone and in combination with clinically used antimicrobial agents against Rhodococcus equi.

    PubMed

    Giacometti, A; Cirioni, O; Ancarani, F; Del Prete, M S; Fortuna, M; Scalise, G

    1999-08-01

    The in vitro activities of magainin II, nisin, and ranalexin alone and in combination with other antimicrobial agents against six clinical isolates of Rhodococcus equi were investigated by MIC and time-kill studies. All isolates were more susceptible to nisin. A positive interaction was observed when the peptides were combined with ampicillin, ceftriaxone, rifabutin, rifampin, azithromycin, clarithromycin, and vancomycin. PMID:10428947

  7. Successful use of oral linezolid as a single active agent in endocarditis unresponsive to conventional antibiotic therapy.

    PubMed

    Ravindran, V; John, J; Kaye, G C; Meigh, R E

    2003-08-01

    Treatment of resistant gram-positive endocarditis is difficult. We report a case of resistant Staphylococcus epidermidis endocarditis that failed to respond to conventional antibiotic therapy but was treated successfully with an oral regimen of a new antibiotic, linezolid as a single active agent. This case report demonstrates the use of linezolid as an effective alternative to conventional antibiotics in such cases. PMID:12860152

  8. Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents.

    PubMed Central

    Doherty, G. P.; Leith, M. K.; Wang, X.; Curphey, T. J.; Begleiter, A.

    1998-01-01

    DT-diaphorase is a two-electron-reducing enzyme that is an important activator of bioreductive anti-tumour agents, such as mitomycin C (MMC) and EO9, and is inducible by many compounds, including 1,2-dithiole-3-thiones (D3Ts). We showed previously that D3T selectively increased DT-diaphorase activity in mouse lymphoma cells compared with normal mouse marrow cells, and also increased MMC or EO9 cytotoxic activity in the lymphoma cells with only minor effects in the marrow cells. In this study, we found that D3T significantly increased DT-diaphorase activity in 28 of 38 human tumour cell lines representing ten tissue types with no obvious relationships between the tumour type, or the base level of DT-diaphorase activity, and the ability of D3T to increase the enzyme activity. Induction of DT-diaphorase activity in human tumour cell lines by 12 D3T analogues varied markedly with the D3T structure. D3T also increased DT-diaphorase activity in normal human bone marrow and kidney cells but the increases were small in these cells. In addition, D3T increased the level of enzyme activity in normal human lung cells. Pretreatment of human tumour cells with D3T analogues significantly increased the cytotoxic activity of MMC or EO9 in these cells, and the level of enhancement of anti-tumour activity paralleled the level of DT-diaphorase induction. In contrast, D3T did not effect the toxicity of EO9 in normal kidney cells. These results demonstrate that D3T analogues can increase DT-diaphorase activity in a wide variety of human tumour cells and that this effect can enhance the anti-tumour activity of the bioreductive agents MMC and EO9. PMID:9579829

  9. Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study.

    PubMed

    Rana, Sandeep; Blowers, Elizabeth C; Tebbe, Calvin; Contreras, Jacob I; Radhakrishnan, Prakash; Kizhake, Smitha; Zhou, Tian; Rajule, Rajkumar N; Arnst, Jamie L; Munkarah, Adnan R; Rattan, Ramandeep; Natarajan, Amarnath

    2016-05-26

    Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-μM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents. PMID:27077228

  10. Activity of Eravacycline against Enterobacteriaceae and Acinetobacter baumannii, Including Multidrug-Resistant Isolates, from New York City

    PubMed Central

    Abdallah, Marie; Olafisoye, Olawole; Cortes, Christopher; Urban, Carl; Landman, David

    2014-01-01

    Eravacycline demonstrated in vitro activity against a contemporary collection of more than 4,000 Gram-negative pathogens from New York City hospitals, with MIC50/MIC90 values, respectively, for Escherichia coli of 0.12/0.5 μg/ml, Klebsiella pneumoniae of 0.25/1 μg/ml, Enterobacter aerogenes of 0.25/1 μg/ml, Enterobacter cloacae 0.5/1 μg/ml, and Acinetobacter baumannii of 0.5/1 μg/ml. Activity was retained against multidrug-resistant isolates, including those expressing KPC and OXA carbapenemases. For A. baumannii, eravacycline MICs correlated with increased expression of the adeB gene. PMID:25534744

  11. Antifungal Activities of SCY-078 (MK-3118) and Standard Antifungal Agents against Clinical Non-Aspergillus Mold Isolates

    PubMed Central

    Lamoth, Frédéric

    2015-01-01

    The limited armamentarium of active and oral antifungal drugs against emerging non-Aspergillus molds is of particular concern. Current antifungal agents and the new orally available beta-1,3-d-glucan synthase inhibitor SCY-078 were tested in vitro against 135 clinical non-Aspergillus mold isolates. Akin to echinocandins, SCY-078 showed no or poor activity against Mucoromycotina and Fusarium spp. However, SCY-078 was highly active against Paecilomyces variotii and was the only compound displaying some activity against notoriously panresistant Scedosporium prolificans. PMID:25896696

  12. Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children

    PubMed Central

    Wetmore, Cynthia; Boyett, James; Li, Shaoyu; Lin, Tong; Bendel, Anne; Gajjar, Amar; Orr, Brent A.

    2015-01-01

    Background Aurora Kinase A (AURKA) encodes a protein that regulates the formation and stability of the mitotic spindle and is highly active in atypical teratoid rhabdoid tumors (ATRT) through loss of the INI1 tumor suppressor gene. Alisertib (MLN8237) inhibits AURKA in vitro and in vivo. Given the strong preclinical data supporting the use of alisertib for ATRT patients, we sought and obtained permission to use alisertib in single patient treatment plans for 4 recurrent pediatric ATRT patients. Methods Patients with recurrent or progressive ATRT received alisertib 80 mg/m2 by mouth once daily for 7 days of a 21-day treatment cycle. Disease evaluation (MRI of brain and spine and lumbar puncture) was done after 2 cycles of alisertib and every 2–3 cycles thereafter for as long as the patients remained free from tumor progression. Results Four patients with median age of 2.5 years (range, 1.39–4.87 y) at diagnosis received alisertib 80 mg/m2 by mouth once daily for 7 days of a 21-day treatment cycle, and all 4 patients had disease stabilization and/or regression after 3 cycles of alisertib therapy. Two patients continued to have stable disease regression for 1 and 2 years, respectively, on therapy. Conclusions Single-agent alisertib produced marked and durable regression in disease burden, as detected by brain and spine MRI and by evaluation of spinal fluid cytology. Alisertib has moderate but manageable toxicities, and its chronic administration appears feasible in this pediatric population. These novel data support the incorporation of alisertib in future therapeutic trials for children with ATRT. PMID:25688119

  13. Redesigning the DNA-Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

    PubMed Central

    Pickard, Amanda J.; Liu, Fang; Bartenstein, Thomas F.; Haines, Laura G.; Levine, Keith E.; Kucera, Gregory L.; Bierbach, Ulrich

    2014-01-01

    Platinum–acridine hybrid agents show low-nanomolar potency in chemoresistant non-small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7-Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent (P1–B1) that maintained submicromolar activity in several of the DNA-repair proficient and p53-mutant cancer models, while showing improved tolerability in mice by 32-fold compared to the parent platinum–acridine (P1–A1). The distribution and DNA/RNA adduct levels produced by the acridine- and benz[c]acridine-based analogues in NCI-H460 cells (confocal microscopy, ICP-MS), and their ability to bind G-quadruplex forming DNA sequences (CD spectroscopy, HR-ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target-selective hybrid agent than P1–A1. PMID:25302716

  14. Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis.

    PubMed

    Raza, Ahmad; Jacobson, Blake A; Benoit, Adam; Patel, Manish R; Jay-Dixon, Joe; Hiasa, Hiroshi; Ferguson, David M; Kratzke, Robert Arthur

    2012-08-01

    Human topoisomerase II (hTopoII) inhibitors are important chemotherapeutic agents in many different settings including treatment of malignant mesothelioma. Topoisomerase poisons, such as etoposide and doxorubicin, function by trapping the DNA-enzyme covalent complex producing DNA strand breaks which can ultimately lead to cancer cell death, as well as development of secondary malignancies. While these compounds have been used successfully in treating a wide variety of cancers, their use against mesothelioma has been limited. This study evaluates the anti-proliferative activity of series of acridine-based catalytic inhibitors of hTopoII using four mesothelioma cell lines (H513, H2372, H2461, and H2596). The results indicate these compounds inhibit malignant cell proliferation with EC(50) values ranging from 6.9 to 32 μM. Experiments are also performed that show that combination therapies may be used to increase potency. Based on the results of PARP cleavage and Guava Nexin assay, it is concluded that the primary mode of cell death is by apoptosis. The results are consistent with prior work involving pancreatic cancer and hTopoII catalytic inhibitors and suggest substituted acridines may hold promise in treating malignant mesothelioma. PMID:21789510

  15. A new arylbenzofuran derivative functions as an anti-tumour agent by inducing DNA damage and inhibiting PARP activity

    PubMed Central

    Chen, Hongbo; Zeng, Xiaobin; Gao, Chunmei; Ming, Pinghong; Zhang, Jianping; Guo, Caiping; Zhou, Lanzhen; Lu, Yin; Wang, Lijun; Huang, Laiqiang; He, Xiangjiu; Mei, Lin

    2015-01-01

    We previously reported that 7-hydroxy-5, 4’-dimethoxy-2-arylbenzofuran (HDAB) purified from Livistona chinensis is a key active agent. The present study investigated the function and molecular mechanism of HDAB. HDAB treatment of cervical cancer cells resulted in S phase arrest and apoptosis, together with cyclin A2 and CDK2 upregulation. Cyclin A2 siRNA and a CDK inhibitor efficiently relieved S phase arrest but increased the apoptosis rate. Mechanistic studies revealed that HDAB treatment significantly increased DNA strand breaks in an alkaline comet assay and induced ATM, CHK1, CHK2 and H2A.X phosphorylation. Wortmannin (a broad inhibitor of PIKKs) and CGK733 (a specific ATM inhibitor), but not LY294002 (a phosphatidylinositol 3-kinase inhibitor) or NU7026 (a DNA-PK specific inhibitor), prevented H2A.X phosphorylation and γH2A.X-positive foci formation in the nuclei, reversed S phase arrest and promoted the HDAB-induced apoptosis, suggesting that HDAB is a DNA damaging agent that can activate the ATM-dependent DNA repair response, thereby contributing to cell cycle arrest. In addition, molecular docking and in vitro activity assays revealed that HDAB can correctly dock into the hydrophobic pocket of PARP-1 and suppress PARP-1 ADP-ribosylation activity. Thus, the results indicated that HDAB can function as an anti-cancer agent by inducing DNA damage and inhibiting PARP activity. PMID:26041102

  16. Increasing resource allocation and research into tobacco control activities: a comprehensive approach including primary prevention, treatment and brief intervention.

    PubMed

    Richmond, R

    1993-01-01

    The range of tobacco control activities should be viewed as essential parts of a complex multi-component puzzle. Intervention strategies designed to address tobacco control should be comprehensive and include both primary and secondary prevention activities and be multi-faceted and capable of bringing about change at both the individual and broader social and cultural levels. In this paper I argue for a mutually inclusive framework in which the various components contribute in important and different ways. I examine the prevalence of smoking and identify the high risk groups, then I examine the range of available strategies and present the evidence for their success. I discuss the primary prevention approaches such as warning labels, taxes, price increases, workplace bans, education in schools, mass media and self-help materials, as well as brief interventions and treatment strategies which are conducted at the worksite, general practice and specialized cessation clinics. The areas for future research are delineated for increased resource allocation and include: the best ways to disseminate brief interventions to smokers, methods to motivate smokers; training of health professionals to deliver brief interventions; enhancing quitting and access to existing treatment resources among specific disadvantaged minority groups, e.g. migrants, unemployed youth, the effect on smoking prevalence of warning labels on cigarette packets and price rises on cigarettes. PMID:16818330

  17. An Antimicrobial Metabolite from Bacillus sp.: Significant Activity Against Pathogenic Bacteria Including Multidrug-Resistant Clinical Strains

    PubMed Central

    Chalasani, Ajay G.; Dhanarajan, Gunaseelan; Nema, Sushma; Sen, Ramkrishna; Roy, Utpal

    2015-01-01

    In this study, the cell free modified tryptone soya broth (pH 7.4 ± 0.2) of Bacillus subtilis URID 12.1 showed significant antimicrobial activity against multidrug-resistant strains of Staphylococcus aureus, S. epidermidis, Streptococcus pyogenes and Enterococcus faecalis. The partially purified antimicrobial molecule was found to be resistant to extremes of pH and temperatures and also to higher concentrations of trypsin and proteinase K. The antimicrobial molecule was purified by a three-step method that included reversed-phase high performance liquid chromatography (RP-HPLC). The minimum inhibitory concentration (MIC) values were determined for 14 species of bacteria using a microbroth dilution technique. The HPLC-purified fraction showed the MICs ranging from 0.5 to 16 μg/ml for methicillin and vancomycin-resistant Staphylococcus aureus (MVRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) strains. The molecular mass of the antimicrobial compound was determined to be 842.37 Da. The same antimicrobial fraction showed negligible haemolytic activity against human red blood cells even at a concentration as high as 100 μg/ml. Because of its significant antimicrobial activity at low MIC values coupled with its non-haemolytic property, it may prove to be a novel antimicrobial lead molecule. PMID:26696963

  18. Use of esterase activities for the detection of chemical neurotoxic agents.

    PubMed

    Manco, Giuseppe; Nucci, Roberto; Febbraio, Ferdinando

    2009-01-01

    The quest for a quick and easy detection of the neurotoxin levels in the environment has fostered the search for systems alternative to currently employed analytical methods such as spectrophotometer, gas-liquid chromatography, thin-layer chromatography, and more recently mass spectrometry. These drawbacks lead to intense research efforts to develop biosensor devices for the determination of these compounds. In this review, we present an overview of the actual development of research in neurotoxin detection by using enzymatic biosensors based on esterase activity, in particular cholinesterases, and carboxylesterases. Detection by enzymatic activity could be carried out measuring the hydrolysis products or the residual enzymatic activity after inhibition, using a transducer system that makes possible the correlation between the determined activity and the analyte concentration. Several transducer systems were adopted for the neurotoxins identification using esterases, including electrochemical, optical, conductimetric and piezoelectric procedures. The differences in the used transducer determine the final sensitivity and specificity of the biosensor. Moreover, a brief description of immobilization procedure, that is an important step in the biosensor development and could affect the final characteristic of biosensor (sensibility, stability, response time and reproducibility), was accomplished. Final considerations on advantages and problems, related to actual development of these technologies, and its prospective were discussed. PMID:19508179

  19. Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents

    PubMed Central

    Carreño, Leandro J; Saavedra-Ávila, Noemí A; Porcelli, Steven A

    2016-01-01

    Certain types of glycolipids have been found to have remarkable immunomodulatory properties as a result of their ability to activate specific T lymphocyte populations with an extremely wide range of immune effector properties. The most extensively studied glycolipid reactive T cells are known as invariant natural killer T (iNKT) cells. The antigen receptors of these cells specifically recognize certain glycolipids, most notably glycosphingolipids with α-anomeric monosaccharides, presented by the major histocompatibility complex class I-like molecule CD1d. Once activated, iNKT cells can secrete a very diverse array of pro- and anti-inflammatory cytokines to modulate innate and adaptive immune responses. Thus, glycolipid-mediated activation of iNKT cells has been explored for immunotherapy in a variety of disease states, including cancer and a range of infections. In this review, we discuss the design of synthetic glycolipid activators for iNKT cells, their impact on adaptive immune responses and their use to modulate iNKT cell responses to improve immunity against infections and cancer. Current challenges in translating results from preclinical animal studies to humans are also discussed. PMID:27195112

  20. Haloprogin: a Topical Antifungal Agent

    PubMed Central

    Harrison, E. F.; Zwadyk, P.; Bequette, R. J.; Hamlow, E. E.; Tavormina, P. A.; Zygmunt, W. A.

    1970-01-01

    Haloprogin was shown to be a highly effective agent for the treatment of experimentally induced topical mycotic infections in guinea pigs. Its in vitro spectrum of activity also includes yeasts, yeastlike fungi (Candida species), and certain gram-positive bacteria. The in vitro and in vivo antifungal activity of haloprogin against dermatophytes was equal to that observed with tolnaftate. The striking differences between the two agents were the marked antimonilial and selective antibacterial activities shown by haloprogin, contrasted with the negligible activities found with tolnaftate. Addition of serum decreased the in vitro antifungal activity of haloprogin to a greater extent than that of tolnaftate; however, diminished antifungal activity was not observed when haloprogin was applied topically to experimental dermatophytic infections. Based on its broad spectrum of antimicrobial activity, haloprogin may prove to be a superior topical agent in the treatment of dermatophytic and monilial infections in man. PMID:5422306

  1. [In vitro antibacterial activities of cefteram and other beta-lactam agents against recent clinical isolates].

    PubMed

    Yamaguchi, K; Ohno, A; Takahashi, S; Hayashi, M; Yamanaka, K; Hirakata, Y; Mitsuyama, J

    1998-01-01

    In vitro antibacterial activity of the third-generation oral cephem cefteram (CFTM)--ten years after its first use in the clinical setting--against recent clinical isolates was evaluated and compared with those of other oral cephems. A total of 851 clinical isolates belonging to 13 species used in this study were collected from five medical institutions across Japan during 1996. CFTM showed excellent antibacterial activity against methicillin-susceptible S. aureus and S. pyogenes, equivalent to those of other third-generation oral cephems, except cefixime. Of the S. pneumoniae strains, a high proportion, 34.1%, were penicillin-resistant strains (PRSP), with MIC values of 2.0 micrograms/ml or above, but the MIC50 of CFTM against PRSP was 1.0 microgram/ml. CFTM and the other third-generation oral cephems showed potent antibacterial activity against E. coli, K. pneumoniae, and P. mirabilis. A few strains of E. coli, however, were highly resistant to third-generation oral cephems; that might include extended-spectrum beta-lactamase producing strains. MIC values against P. vulgaris varied significantly, depending on whether they were determined by the broth micro-dilution method or the agar dilution method; growth was observed at high concentrations in the broth micro-dilution method, in which the skip phenomenon was demonstrated, but not in the agar dilution method. The reason for this discrepancy is unknown. Most strains of S. marcescens, C. freundii, and E. cloacae demonstrated resistance to CFTM and the other third-generation oral cephems. CFTM and the other third-generation oral cephems showed excellent antibacterial activities against M. (B.) catarrhalis, N. gonorrhoeae, and H. influenzae, including ampicillin-resistant strains. PMID:9557273

  2. In Vitro Activities of Linezolid Combined with Other Antimicrobial Agents against Staphylococci, Enterococci, Pneumococci, and Selected Gram-Negative Organisms

    PubMed Central

    Sweeney, Michael T.; Zurenko, Gary E.

    2003-01-01

    The activities of linezolid, an oxazolidinone antibacterial agent active against gram-positive organisms, alone and in combination with 35 antimicrobial agents were tested in vitro against methicillin-sensitive (n = 1 to 2 strains) and methicillin-resistant (n = 8 to 10) Staphylococcus aureus strains; vancomycin-sensitive (n = 6) and vancomycin-resistant (n = 6 to 8) Enterococcus faecalis strains; vancomycin-sensitive (n = 5) and vancomycin-resistant (n = 6) Enterococcus faecium strains; penicillin-sensitive (n = 2 to 5), penicillin-intermediate (n = 5 to 6), and penicillin-resistant (n = 5 to 6) Streptococcus pneumoniae strains; Escherichia coli (n = 6); and Klebsiella pneumoniae (n = 6). The fractional inhibitory concentration indices of linezolid in combination with other antimicrobial agents for the organisms tested were generated on checkerboard broth microdilution plates prepared by a semiautomated method. Of 1,380 organism-drug combinations, 1,369 (99.2%) combinations of linezolid with 28 antimicrobial drugs were indifferent, 9 combinations (0.65%) of linezolid with 6 drugs (amoxicillin, erythromycin, imipenem, sparfloxacin, teicoplanin, and tetracycline) were synergistic, and 2 combinations (0.15%) of linezolid with 2 drugs (ofloxacin and sparfloxacin) were antagonistic. Overall, the in vitro data demonstrated that linezolid combined with other antimicrobial agents primarily produces an indifferent response, with infrequent occurrences of synergism and antagonism. PMID:12760865

  3. Improving the Catalytic Activity of Hyperthermophilic Pyrococcus horikoshii Prolidase for Detoxification of Organophosphorus Nerve Agents over a Broad Range of Temperatures

    PubMed Central

    Theriot, Casey M.; Semcer, Rebecca L.; Shah, Saumil S.; Grunden, Amy M.

    2011-01-01

    Prolidases hydrolyze Xaa-Pro dipeptides and can also cleave the P-F and P-O bonds found in organophosphorus (OP) compounds, including the nerve agents soman and sarin. Ph1prol (PH0974) has previously been isolated and characterized from Pyrococcus horikoshii and was shown to have higher catalytic activity over a broader pH range, higher affinity for metal, and increased thermostability compared to P. furiosus prolidase, Pfprol (PF1343). To obtain a better enzyme for OP nerve agent decontamination and to investigate the structural factors that may influence protein thermostability and thermoactivity, randomly mutated Ph1prol enzymes were prepared. Four Ph1prol mutants (A195T/G306S-, Y301C/K342N-, E127G/E252D-, and E36V-Ph1prol) were isolated which had greater thermostability and improved activity over a broader range of temperatures against Xaa-Pro dipeptides and OP nerve agents compared to wild type Pyrococcus prolidases. PMID:22162664

  4. Improving the catalytic activity of hyperthermophilic Pyrococcus horikoshii prolidase for detoxification of organophosphorus nerve agents over a broad range of temperatures.

    PubMed

    Theriot, Casey M; Semcer, Rebecca L; Shah, Saumil S; Grunden, Amy M

    2011-01-01

    Prolidases hydrolyze Xaa-Pro dipeptides and can also cleave the P-F and P-O bonds found in organophosphorus (OP) compounds, including the nerve agents soman and sarin. Ph1prol (PH0974) has previously been isolated and characterized from Pyrococcus horikoshii and was shown to have higher catalytic activity over a broader pH range, higher affinity for metal, and increased thermostability compared to P. furiosus prolidase, Pfprol (PF1343). To obtain a better enzyme for OP nerve agent decontamination and to investigate the structural factors that may influence protein thermostability and thermoactivity, randomly mutated Ph1prol enzymes were prepared. Four Ph1prol mutants (A195T/G306S-, Y301C/K342N-, E127G/E252D-, and E36V-Ph1prol) were isolated which had greater thermostability and improved activity over a broader range of temperatures against Xaa-Pro dipeptides and OP nerve agents compared to wild type Pyrococcus prolidases. PMID:22162664

  5. In-vitro activity of cationic peptides alone and in combination with clinically used antimicrobial agents against Pseudomonas aeruginosa.

    PubMed

    Giacometti, A; Cirioni, O; Barchiesi, F; Fortuna, M; Scalise, G

    1999-11-01

    The in-vitro activity of cecropin P1, indolicidin, magainin II, nisin and ranalexin alone and in combination with nine clinically used antimicrobial agents was investigated against a control strain, Pseudomonas aeruginosa ATCC 27853 and 40 clinical isolates of P. aeruginosa. Antimicrobial activities were measured by MIC, MBC and viable count. In the combination study, the clinically used antibiotics were used at concentrations close to their mean serum level in humans in order to establish the clinical relevance of the results. To select peptide-resistant mutants, P. aeruginosa ATCC 27853 was treated with consecutive cycles of exposure to each peptide at 1 x MIC. The peptides had a varied range of inhibitory values: all isolates were more susceptible to cecropin P1, while ranalexin showed the lowest activity. Nevertheless, synergy was observed when the peptides were combined with polymyxin E and clarithromycin. Consecutive exposures to each peptide at 1 x MIC resulted in the selection of stable resistant mutants. Cationic peptides might be valuable as new antimicrobial agents. Our findings show that they are effective against P. aeruginosa, and that their activity is enhanced when they are combined with clinically used antimicrobial agents, particularly with polymyxin E and clarithromycin. PMID:10552980

  6. PITBUL: a physics-based modeling package for imaging and tracking of airborne targets for HEL applications including active illumination

    NASA Astrophysics Data System (ADS)

    Van Zandt, Noah R.; McCrae, Jack E.; Fiorino, Steven T.

    2013-05-01

    Aimpoint acquisition and maintenance is critical to high energy laser (HEL) system performance. This study demonstrates the development by the AFIT/CDE of a physics-based modeling package, PITBUL, for tracking airborne targets for HEL applications, including atmospheric and sensor effects and active illumination, which is a focus of this work. High-resolution simulated imagery of the 3D airborne target in-flight as seen from the laser position is generated using the HELSEEM model, and includes solar illumination, laser illumination, and thermal emission. Both CW and pulsed laser illumination are modeled, including the effects of illuminator scintillation, atmospheric backscatter, and speckle, which are treated at a first-principles level. Realistic vertical profiles of molecular and aerosol absorption and scattering, as well as optical turbulence, are generated using AFIT/CDE's Laser Environmental Effects Definition and Reference (LEEDR) model. The spatially and temporally varying effects of turbulence are calculated and applied via a fast-running wave optical method known as light tunneling. Sensor effects, for example blur, sampling, read-out noise, and random photon arrival, are applied to the imagery. Track algorithms, including centroid and Fitts correlation, as a part of a closed loop tracker are applied to the degraded imagery and scored, to provide an estimate of overall system performance. To gauge performance of a laser system against a UAV target, tracking results are presented as a function of signal to noise ratio. Additionally, validation efforts to date involving comparisons between simulated and experimental tracking of UAVs are presented.

  7. A practical approach for active camera coordination based on a fusion-driven multi-agent system

    NASA Astrophysics Data System (ADS)

    Bustamante, Alvaro Luis; Molina, José M.; Patricio, Miguel A.

    2014-04-01

    In this paper, we propose a multi-agent system architecture to manage spatially distributed active (or pan-tilt-zoom) cameras. Traditional video surveillance algorithms are of no use for active cameras, and we have to look at different approaches. Such multi-sensor surveillance systems have to be designed to solve two related problems: data fusion and coordinated sensor-task management. Generally, architectures proposed for the coordinated operation of multiple cameras are based on the centralisation of management decisions at the fusion centre. However, the existence of intelligent sensors capable of decision making brings with it the possibility of conceiving alternative decentralised architectures. This problem is approached by means of a MAS, integrating data fusion as an integral part of the architecture for distributed coordination purposes. This paper presents the MAS architecture and system agents.

  8. Effects of cerebro-protective agents on enzyme activities of rat primary glial cultures and rat cerebral cortex.

    PubMed

    Bielenberg, G W; Hayn, C; Krieglstein, J

    1986-08-15

    The effects of different cerebro-protective agents on selected key enzymes of the energy metabolism of rat primary glial cultures and rat cerebral cortex were studied. As indicators for the capacity of the most important pathways of energy metabolism the following enzyme activities were determined: hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G-6-P-DH), malate dehydrogenase (MDH), glutamate dehydrogenase (GDH), and cytochrome-c-reductase (CCR). After a one week growth period, rat glial cultures were incubated for 3 or 4 weeks with the substances to be tested. Bencyclane (5 X 10(-5) mol/l) increased the activities of HK, G-6-P-DH, and LDH, whereas PFK and CCR were reduced. Pyritinol (10(-4) mol/l) led to a higher G-6-P-DH activity, simultaneously lowering the values for PFK, CCR, PK, LDH, and MDH. Under the influence of an extract of the leaves of Ginkgo bilobae (EGB; 100 mg/l) PFK, LDH, and MDH activities were reduced. All these alterations in enzyme activities went along with simultaneous reductions in protein content, therefore not allowing to exclude toxic effects with regard to the doses used. Moreover, direct interference with the analytical procedure was demonstrable for bencyclane and EGB. Piracetam (10(-3) mol/l), flunarizine (10(-6) mol/l), dihydroergocristine (5 X 10(-6) mol/l), and nicergoline (5 X 10(-6) mol/l) failed to induce any alteration in the employed doses. The most striking effects were obtained with meclofenoxate which was tested at 10(-3) and 10(-4) mol/l. The higher dose caused an elevation of HK, PFK, CCR, G-6-P-DH, GDH and MDH activities, while slightly reducing PK. With the lower dose of meclofenoxate CCR and G-6-P-DH activities were increased. Short-term incubation of the cultures with 10(-3) mol/l meclofenoxate for 24 hr led to an increase in LDH, G-6-P-DH, and GDH activities. Chronic incubation with meclofenoxate (10(-3) mol/l) followed by 48 hr

  9. Inhibitory activity of chelating agent against bacteria associated with poultry processing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ethylenediaminetetraacetic acid (EDTA) and ethylenediamine-N, N’-disuccinic acid (EDDS) are chelating agents that can bind minerals that produce water hardness. By sequestering minerals in hard water, chelators reduce water hardness and increase the ability of cleansers to remove dirt and debris dur...

  10. In vitro activity of dalbavancin and five comparator agents against common and uncommon Gram-positive organisms isolated from cancer patients.

    PubMed

    Rolston, Kenneth V I; Wang, Weiqun; Nesher, Lior; Shelburne, Samuel A; Prince, Randall A

    2016-05-01

    Dalbavancin is a long acting, bactericidal lipoglycopeptide. Its in vitro activity was compared with that of vancomycin, daptomycin, linezolid, trimethoprim/sulfamethoxazole (TMP/SMX) and levofloxacin against 241 Gram-positive organisms isolated from cancer patients. The rank order of potency for the glycopeptides based on MIC90 (μg ml(-1)), that is, the concentration of antimicrobial agent required to inhibit 90% of isolates tested was dalbavancin (0.12 μg ml(-1))>daptomycin (1.0 μg ml(-1))>vancomycin (2.0 μg ml(-1)) for coagulase-negative staphylococci and Staphylococcus aureus isolates (including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains). Dalbavancin had potent activity against staphylococcal isolates with vancomycin MICs⩾1.0 μg ml(-1). TMP/SMX also had potent activity against staphylococci including methicillin-resistant strains, whereas levofloxacin had moderate to poor anti-staphylococcal activity. Dalbavancin also exhibited more potent activity than vancomycin and daptomycin against Bacillus spp., Corynebacterium spp., Micrococcus spp. and various streptococci (including Streptococcus pneumoniae, viridans group streptococci (VGS), beta-hemolytic streptococci and gamma-hemolytic streptococci). MBC determinations showed that dalbavancin had potent bactericidal activity against MRSA with no tolerance being detected. These data suggest that dalbavancin may be considered as an alternative to vancomycin, especially in institutions wherein a substantial proportion of infections are caused by organisms with vancomycin MICs⩾1.0 μg ml(-1). PMID:26626876

  11. ZSM-5 zeolite nanosheets with improved catalytic activity synthesized using a new class of structure-directing agents.

    PubMed

    Kore, Rajkumar; Srivastava, Rajendra; Satpati, Biswarup

    2014-09-01

    A new series of multiquaternary ammonium structure-directing agents, based on 1,4-diazabicyclo[2.2.2]octane, was prepared. ZSM-5 zeolites with nanosheet morphology (10 nm crystal thickness) were synthesized under hydrothermal conditions using multiquaternary ammonium surfactants as the zeolite structure-generating agents. Both wide-angle and small-angle diffraction patterns were obtained using only a suitable structure-directing agent under a specific zeolite synthesis composition. A mechanism of zeolite formation is proposed based on the results obtained from various physicochemical characterizations. ZSM-5 materials were investigated in catalytic reactions requiring medium to strong acidity, which are important for the synthesis of a wide range of industrially important fine and specialty chemicals. The catalytic activity of ZSM-5 materials was compared with that of the conventional ZSM-5 and amorphous mesoporous aluminosilicate Al-MCM-41. The synthesis strategy of the present investigation using the new series of structure-directing agents could be extended for the synthesis of other related zeolites or other porous materials in the future. Zeolite with a structural feature as small as the size of a unit cell (5-10 nm) with hierarchically ordered porous structure would be very promising for catalysis. PMID:25056112

  12. Design, synthesis and investigation on the structure-activity relationships of N-substituted 2-aminothiazole derivatives as antitubercular agents.

    PubMed

    Pieroni, Marco; Wan, Baojie; Cho, Sanghyun; Franzblau, Scott G; Costantino, Gabriele

    2014-01-24

    Tuberculosis (TB) is one of the deadliest infectious diseases of all times, and its recent resurgence is a supreme matter of concern. Co-infection with HIV and, in particular, the continuous isolation of new resistant strains, makes the discovery of novel anti-TB agents a strategic priority. The research of novel agents should be driven by the accessibility of the synthetic procedure and, in particular, by the lack of cross-resistance with the drugs already marketed. Moreover, in order to shorten the duration of the therapy, and therefore decrease the rate of resistance, these molecules should be active also against the nonreplicating persistent form (NRP-TB) of the infection. The availability of an in-house small library of compounds prompted us to investigate their anti-TB activity. Two compounds, embodying a 2-aminothiazole scaffold, were found to possess a certain inhibitory activity toward Mycobacterium tuberculosis H37Rv, and therefore a medicinal chemistry campaign was initiated in order to increase the activity of the hit compounds and, especially, construct a plausible body of structure-activity relationships. The potency of the hit compound was successfully improved, and, much more importantly, some of the molecules synthesized were found to be active toward the persistent phenotype, and, also, toward a panel of resistant strains. These findings encourage further investigations around this interesting antitubercular chemotype. PMID:24333612

  13. Antibacterial activity of water extracts and essential oils of various aromatic plants against Paenibacillus larvae, the causative agent of American Foulbrood.

    PubMed

    González, M J; Marioli, J M

    2010-07-01

    Vegetal water extracts, namely the water remaining after hydro-distillation and decoctions, and essential oils of 10 plant species were tested as inhibitors for the growth of Paenibacillus larvae, the causative agent of American Foulbrood. Achyrocline satureioides, Chenopodium ambrosioide, Eucalyptus cinerea, Gnaphalium gaudichaudianum, Lippia turbinata, Marrubium vulgare,Minthostachys verticillata, Origanum vulgare, Tagetes minuta and Thymus vulgaris were included in the study. The water remaining after hydro-distillation showed the highest antibacterial activities, the growth of almost all the P. larvae strains tested was inhibited by these extracts. Regarding the plants tested, E. cinerea and M. verticillata were the plant species with the highest biological activity with 100% efficacy (all its extracts inhibited the growth of all P. larvae strains). Essential oils were less active for the inhibition of P. larvae growth. PMID:20398671

  14. Hypochlorous acid-activated carbon: an oxidizing agent capable of producing hydroxylated polychlorinated biphenyls

    SciTech Connect

    Voudrias, E.A.; Larson, R.A.; Snoeyink, V.L.; Chen, A.S.C.; Stapleton, P.L.

    1986-11-01

    Granular activated carbon (GAC), in the presence of dilute aqueous hypochlorite solutions typical of those used in water treatment, was converted to a reagent capable of carrying out free-radical coupling reactions and other oxidations of dilute aqueous solutions of phenols. The products included biphenyls with chlorine and hydroxyl substitution (hydroxylated polychlorinated biphenyls). For example, 2,4-dichlorophenol, a common constituent of waste waters and also natural waters treated with hypochlorite, was converted to 3,5,5'trichloro-2,4'-dihydroxybiphenyl and several related compounds in significant amounts. It is possible that these products pose more of a health hazard than either the starting phenols or the unhydroxylated polychlorinated biphenyl derivatives.

  15. A highly fluorescent AIE-active theranostic agent with anti-tumor activity to specific cancer cells.

    PubMed

    Zhao, Yueyue; Kwok, Ryan T K; Lam, Jacky W Y; Tang, Ben Zhong

    2016-07-01

    A tetraphenylethene derivative with a structure resembling Tamoxifen is designed and synthesized as a theranostic agent for cell imaging and anti-breast cancer therapy. Its high brightness, excellent photostability and long-term cell tracing properties enable elucidation of its working mechanism and hence provide new insights into drug development. PMID:26781935

  16. Synthesis and evaluation of asiatic acid derivatives as anti-fibrotic agents: structure/activity studies.

    PubMed

    Li, Yong; Yang, Fang; Yuan, Mingxing; Jiang, Lijuan; Yuan, Li; Zhang, Xiaowei; Li, Ying; Dong, Lin; Bao, Xu; Yin, Shufan

    2015-04-01

    Fibrotic diseases are characterized by the over-accumulation of fibrous components in the extracellular matrix and the liver, which can lead to liver cirrhosis. Current treatment options cannot reverse or halt liver fibrosis, motivating a search for newer treatment options. Previously, we showed that asiaticoside, a bioactive triterpene glycoside from Centella asiatica, has anti-fibrotic properties. Here, the aglycone asiatic acid was chemically modified, and these derivatives were evaluated for their potential as anti-fibrotic agents. The data obtained from in vivo testing of these compounds in a rodent CCl4-induced liver injury model are discussed. The information obtained from these studies may be useful in the design of novel anti-fibrotic agents. PMID:25461275

  17. Antidiabetic Agents.

    ERIC Educational Resources Information Center

    Plummer, Nancy; Michael, Nancy, Ed.

    This module on antidiabetic agents is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

  18. VP-16 and alkylating agents activate a common metabolic pathway for suppression of DNA replication

    SciTech Connect

    Das, S.K.; Berger, N.A.

    1986-05-01

    The cytotoxic effects of etoposide (VP-16) are mediated by topoisomerase II production of protein crosslinked DNA strand breaks. Previous studies have shown that alkylating agent induced DNA damage results in expansion of dTTP pools and reduction of dCTP pools and DNA replication. Studies were conducted with V79 cells to determine whether the metabolic consequences of VP-16 treatment were similar to those induced by alkylating agents. Treatment with 0.5..mu..M VP-16 prolonged the doubling time of V79 cells from 12 to 18 hrs and caused cell volume to increase from 1.1 to 1.6 x 10/sup -12/l. 2mM caffeine completely blocked the volume increase and substantially prevented the prolongation of doubling time. 5..mu..M VP-16 reduced the rate of (/sup 3/H)TdR incorporation by 70%, whereas in the presence of 2mM caffeine, VP-16 caused only a 10% decrease in the rate of (/sup 3/H)TdR incorporation. 4 hr treatment with 5.0..mu..M VP-16 increased dTTP levels from 65 +/- 10 pmol/10/sup 6/ cells to 80 +/- 13 pmol/10/sup 6/ cells and caused dCTP level to decline from 113 +/- 23 pmol/10/sup 6/ cells to 92 +/- 17 pmol/10/sup 6/ cells. These results indicate that the metabolic consequences of VP-16 treatment are similar to alkylating agent treatment and that an increase in dTTP pools with a subsequent effect on ribonucleotide reductase may be a final common pathway by which many cytotoxic agents suppress DNA synthesis.

  19. Comparison of the In Vitro Activities of Newer Triazoles and Established Antifungal Agents against Trichophyton rubrum

    PubMed Central

    Deng, Shuwen; Zhang, Chao; Seyedmousavi, Seyedmojtaba; Zhu, Shuang; Tan, Xin; Wen, Yiyang; Huang, Xin; Lei, Wenzhi; Zhou, Zhaojing; Fang, Wenjie; Shen, Shuaishuai; Deng, Danqi

    2015-01-01

    One hundred eleven clinical Trichophyton rubrum isolates were tested against 7 antifungal agents. The geometric mean MICs of all isolates were, in increasing order: terbinafine, 0.03 mg/liter; voriconazole, 0.05 mg/liter; posaconazole, 0.11 mg/liter; isavuconazole, 0.13 mg/liter; itraconazole, 0.26 mg/liter; griseofulvin, 1.65 mg/liter; and fluconazole, 2.12 mg/liter. PMID:25896691

  20. Understanding Toxicities of Targeted Agents: Implications for Anti-tumor Activity and Management.

    PubMed

    Liu, Sariah; Kurzrock, Razelle

    2015-12-01

    Targeted treatments have distinctive side effects: dermatologic problems (rash, hand-food skin reaction, skin/hair whitening), endocrine dysfunction (hyperglycemia, hypothyroidism, dyslipidemia), as well as hypertension, diarrhea, liver problems, ocular toxicity and proteinuria. Toxicities can be classified as: (1) on-target, mechanism-driven toxicities that are either related or unrelated to response; and (2) off-target side effects. Off-target toxicities may be specific to the class of agent, eg, small molecule tyrosine kinase inhibitor versus antibody versus cytotoxic; alternatively, they may also be mediated by metabolites or immune reactions. Both on- and off-target toxicities can be amplified or attenuated by drug concentrations or end-organ sensitivity, which in turn can be attributable to genetic polymorphisms regulating metabolism or tissue responsiveness. On-target side effects are important to identify as some are associated with response and, therefore, controlling these side effects is preferable to dose reduction or treatment discontinuation. Side effects caused by relevant target impact may be recognized when different types of agents, eg, small molecule inhibitors and antibodies, with the same target have the same side effect. These on-target effects may also correlate with better outcomes. We discuss toxicity of targeted agents in the context of understanding target impact, drug-drug interactions, and implications for optimized management. PMID:26615131

  1. Improving the catalytic activity of hyperthermophilic Pyrococcus prolidases for detoxification of organophosphorus nerve agents over a broad range of temperatures.

    PubMed

    Theriot, Casey M; Du, Xuelian; Tove, Sherry R; Grunden, Amy M

    2010-08-01

    Prolidase isolated from the hyperthermophilic archaeon Pyrococcus furiosus has potential for application for decontamination of organophosphorus compounds in certain pesticides and chemical warfare agents under harsh conditions. However, current applications that use an enzyme-based cocktail are limited by poor long-term enzyme stability and low reactivity over a broad range of temperatures. To obtain a better enzyme for OP nerve agent decontamination and to investigate structural factors that influence protein thermostability and thermoactivity, randomly mutated P. furiosus prolidases were prepared by using XL1-red-based mutagenesis and error-prone PCR. An Escherichia coli strain JD1 (lambdaDE3) (auxotrophic for proline [DeltaproA] and having deletions in pepQ and pepP dipeptidases with specificity for proline-containing dipeptides) was constructed for screening mutant P. furiosus prolidase expression plasmids. JD1 (lambdaDE3) cells were transformed with mutated prolidase expression plasmids and plated on minimal media supplemented with 50 muM Leu-Pro as the only source of proline. By using this positive selection, Pyrococcus prolidase mutants with improved activity over a broader range of temperatures were isolated. The activities of the mutants over a broad temperature range were measured for both Xaa-Pro dipeptides and OP nerve agents, and the thermoactivity and thermostability of the mutants were determined. PMID:20422176

  2. Novel SHP-1 inhibitors TPI-1 and analogs with pre-clinical anti-tumor activities as tolerated oral agents

    PubMed Central

    Kundu, Suman; Fan, Keke; Cao, Mingli; Lindner, Daniel J.; Zhao, Zhizhaung Joe; Borden, Ernest; Yi, Taolin

    2010-01-01

    SHP-1 has been implicated as a potential cancer therapeutic target by its negative regulation of immune cell activation and the activity of the SHP-1 inhibitor SSG that induced IFNγ+ cells for anti-tumor action. To develop more potent SHP-1-targeted anti-cancer agents, inhibitory leads were identified from a library of 34,000 drug-like compounds. Among the leads and active at low nM for recombinant SHP-1, tyrosine phosphatase inhibitor-1 (TPI-1) selectively increased SHP-1 phospho-substrates (pLck-pY394, pZap70 and pSlp76) in Jurkat T cells but had little effects on pERK1/2 or pLck-pY505 regulated by phosphatases SHP-2 or CD45, respectively. TPI-1 induced mouse splenic-IFNγ+ cells in vitro, ~58-fold more effective than SSG, and increased mouse splenic-pLck-pY394 and -IFNγ+ cells in vivo. TPI-1 also induced IFNγ+ cells in human peripheral blood in vitro. Significantly, TPI-1 inhibited (~83%, p <0.002) the growth of B16 melanoma tumors in mice at a tolerated oral dose in a T cell-dependent manner but had little effects on B16 cell growth in culture. TPI-1 also inhibited B16 tumor growth and prolonged tumor mice survival as a tolerated s.c. agent. TPI-1 analogs were identified with improved activities in IFNγ+ cell induction and in anti-tumor actions. In particular, analog TPI-1a4 as a tolerated oral agent completely inhibited the growth of K1735 melanoma tumors and was more effective than the parental lead against MC-26 colon cancer tumors in mice. These results designate TPI-1 and the analogs as novel SHP-1 inhibitors with anti-tumor activity likely via an immune mechanism, supporting SHP-1 as a novel target for cancer treatment. PMID:20421638

  3. Enhanced Stability of Blood Matrices Using a Dried Sample Spot Assay to Measure Human Butyrylcholinesterase Activity and Nerve Agent Adducts

    PubMed Central

    Perez, Jonas W.; Pantazides, Brooke G.; Watson, Caroline M.; Thomas, Jerry D.; Blake, Thomas A.; Johnson, Rudolph C.

    2015-01-01

    Dried matrix spots are safer to handle and easier to store than wet blood products, but factors such as intra-spot variability and unknown sample volumes have limited their appeal as a sampling format for quantitative analyses. In this work, we introduce a dried spot activity assay for quantifying butyrylcholinesterase (BChE) specific activity which is BChE activity normalized to the total protein content in a sample spot. The method was demonstrated with blood, serum, and plasma spotted on specimen collection devices (cards) which were extracted to measure total protein and BChE activity using a modified Ellman assay. Activity recovered from dried spots was ∼80% of the initial spotted activity for blood and >90% for plasma and serum. Measuring total protein in the sample and calculating specific activity substantially improved quantification and reduced intra-spot variability. Analyte stability of nerve agent adducts was also evaluated, and the results obtained via BChE-specific activity measurements were confirmed by quantification of BChE adducts using a previously established LC-MS/MS method. The spotted samples were up to 10-times more resistant to degradation compared to unspotted control samples when measuring BChE inhibition by the nerve agents sarin and VX. Using this method, both BChE activity and adducts can be accurately measured from a dried sample spot. This use of a dried sample spot with normalization to total protein is robust, demonstrates decreased intra-spot variability without the need to control for initial sample volume, and enhances analyte stability. PMID:25955132

  4. N-Sulfonyl-aminobiaryls as Antitubulin Agents and Inhibitors of Signal Transducers and Activators of Transcription 3 (STAT3) Signaling.

    PubMed

    Lai, Mei-Jung; Lee, Hsueh-Yun; Chuang, Hsun-Yueh; Chang, Li-Hsun; Tsai, An-Chi; Chen, Mei-Chuan; Huang, Han-Lin; Wu, Yi-Wen; Teng, Che-Ming; Pan, Shiow-Lin; Liu, Yi-Min; Mehndiratta, Samir; Liou, Jing-Ping

    2015-08-27

    A series of N-sulfonyl-aminobiaryl derivatives have been examined as novel antitubulin agents. Compound 21 [N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide] exhibits remarkable antiproliferative activity against four cancer cell lines (pancreatic AsPC-1, lung A549, liver Hep3B, and prostate PC-3) with a mean GI50 value of 57.5 nM. Additional assays reveal that 21 inhibits not only tubulin polymerization but also the phosphorylation of STAT3 inhibition with an IC50 value of 0.2 μM. Four additional compounds (8, 10, 19, and 35) are also able to inhibit this phosphorylation. This study describes novel N-sulfonyl-aminobiaryl (biaryl-benzenesulfonamides) as potent anticancer agents targeting both STAT3 and tubulin. PMID:26241032

  5. Development and flight evaluation of active controls in the L-1011. [including wing load alleviation and stability augmentation

    NASA Technical Reports Server (NTRS)

    Johnston, J. F.; Urie, D. M.

    1978-01-01

    Active controls in the Lockheed L-1011 for increased energy efficiency are discussed. Active wing load alleviation for extended span, increased aspect ratio, and active stability augmentation with a smaller tail for reduced drag and weight are among the topics considered. Flight tests of active wing load alleviation on the baseline aircraft and moving-base piloted simulation developing criteria for stability augmentation are described.

  6. A highly fluorescent AIE-active theranostic agent with anti-tumor activity to specific cancer cells

    NASA Astrophysics Data System (ADS)

    Zhao, Yueyue; Kwok, Ryan T. K.; Lam, Jacky W. Y.; Tang, Ben Zhong

    2016-06-01

    A tetraphenylethene derivative with a structure resembling Tamoxifen is designed and synthesized as a theranostic agent for cell imaging and anti-breast cancer therapy. Its high brightness, excellent photostability and long-term cell tracing properties enable elucidation of its working mechanism and hence provide new insights into drug development.A tetraphenylethene derivative with a structure resembling Tamoxifen is designed and synthesized as a theranostic agent for cell imaging and anti-breast cancer therapy. Its high brightness, excellent photostability and long-term cell tracing properties enable elucidation of its working mechanism and hence provide new insights into drug development. Electronic supplementary information (ESI) available: Detailed synthesis and characterization of TPE-OH and TPE-TMX PL spectra of TPE-TMX fluorescent photographs of TPE-TMX taken under UV irradiation; various concentrations of TPE-TMX with different incubation times. See DOI: 10.1039/c5nr08782a

  7. New N,N,N',N'-tetradentate Pyrazoly Agents: Synthesis and Evaluation of their Antifungal and Antibacterial Activities.

    PubMed

    Abrigach, Farid; Bouchal, Btissam; Riant, Olivier; Macé, Yohan; Takfaoui, Abdelilah; Radi, Smaail; Oussaid, Abdelouahad; Bellaoui, Mohammed; Touzani, Rachid

    2016-01-01

    A new library of N,N,N',N' -tetradentate pyrazoly compounds containing a pyrazole moiety was synthesized by the condensation of (3,5-dimethyl-1H-pyrazol-1-yl)methanol 2a or (1H-pyrazol-1-yl)methanol 2b with a series of primary diamines in refluxed acetonitrile for 6h. The antifungal activity against the budding yeast Saccharomyces cerevisiae, as well as the antibacterial activity against Escherichia coli of these new tetradentate ligands were studied. We found that these tetradentate ligands act specifically as antifungal agents and lack antibacterial activity. Their biological activities depend on the nature of the structure of the compounds. PMID:25985861

  8. Semisynthesis and quantitative structure-activity relationship (QSAR) study of some cholesterol-based hydrazone derivatives as insecticidal agents.

    PubMed

    Yang, Chun; Shao, Yonghua; Zhi, Xiaoyan; Huan, Qu; Yu, Xiang; Yao, Xiaojun; Xu, Hui

    2013-09-01

    In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, four series of novel cholesterol-based hydrazone derivatives were synthesized, and their insecticidal activity was tested against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1mg/mL. All the derivatives showed the better insecticidal activity than their precursor cholesterol. Quantitative structure-activity relationship (QSAR) model demonstrated that six descriptors such as RDF085v, Mor06u, Mor11u, Dv, HATS0v and H-046, are likely to influence the insecticidal activity of these compounds. Among them, two important ones are the Mor06u and RDF085v. PMID:23891182

  9. EGFR activating mutations correlate with a Fanconi anemia-like cellular phenotype that includes PARP inhibitor sensitivity

    PubMed Central

    Pfäffle, Heike N.; Wang, Meng; Gheorghiu, Liliana; Ferraiolo, Natalie; Greninger, Patricia; Borgmann, Kerstin; Settleman, Jeffrey; Benes, Cyril H.; Sequist, Lecia V.; Zou, Lee; Willers, Henning

    2013-01-01

    In lung cancer patients whose tumors harbor activating mutations in the epidermal growth factor receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared to wild-type cancers. However, the mechanisms underlying this association have remained elusive. Here, we describe a cellular phenotype of crosslinker sensitivity in a subset of EGFR-mutant lung cancer cell lines that is reminiscent of the defects seen in cells impaired in the Fanconi Anemia pathway, including a pronounced G2/M cell-cycle arrest and chromosomal radial formation. We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and DNA interstrand crosslink (ICL) unhooking. The effect of EGFR mutation was epistatic with FANCD2. Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous recombination repair (HRR), EGFR-mutant cells also exhibited an impaired RAD51 foci response to ICLs, but not to DNA double-strand breaks. EGFR kinase inhibition affected RAD51 foci formation neither in EGFR mutant nor wild-type cells. In contrast, EGFR depletion or overexpression of mutant EGFR in wild-type cells suppressed RAD51 foci, suggesting an EGFR kinase-independent regulation of DNA repair. Interestingly, EGFR-mutant cells treated with the PARP inhibitor olaparib also displayed decreased FAN1 foci induction, coupled with a putative block in a late HRR step. As a result, EGFR-mutant lung cancer cells exhibited olaparib sensitivity in-vitro and in-vivo. Our findings provide insight into the mechanisms of cisplatin and PARP inhibitor sensitivity of EGFR-mutant cells, yielding potential therapeutic opportunities for further treatment individualization in this genetically defined subset of lung cancer. PMID:23966292

  10. Developing of a novel antibacterial agent by functionalization of graphene oxide with guanidine polymer with enhanced antibacterial activity

    NASA Astrophysics Data System (ADS)

    Li, Ping; Sun, Shiyu; Dong, Alideertu; Hao, Yanping; Shi, Shuangqiang; Sun, Zijia; Gao, Ge; Chen, Yuxin

    2015-11-01

    New materials with excellent antibacterial activity attract numerous research interests. Herein, a facile synthetic method of polyethylene glycol (PEG) and polyhexamethylene guanidine hydrochloride (PHGC) dual-polymer-functionalized graphene oxide (GO) (GO-PEG-PHGC), a novel antibacterial material, was reported. The as-prepared products were characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR), thermogravimetric analysis (TGA), X-ray pattern (XRD) and elemental analysis. The antibacterial effect on the bacterial strain was investigated by incubating both Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus). The results show that GO-PEG-PHGC has enhanced antibacterial activity when compared to GO, GO-PEG or GO-PHGC alone. The improved antibacterial activity was described to be related to a better dispersion of GO-PEG-PHGC in the presence of PEG. This better dispersion leads to a greater contact between the bacteria membrane and nanomaterials, therefore leading to greater cell damage. Not only Gram-negative bacteria but also Gram-positive bacteria are greatly inhibited by this antibacterial agent. With the powerful antibacterial activity as well as its low cost and facile preparation, the GO-PEG-PHGC as a novel antibacterial agent can find potential application in the areas of healthcare and environmental engineering.

  11. The antimicrobial activity of a dentin conditioner combined with antibacterial agents.

    PubMed

    Botelho, Michael G

    2005-01-01

    Dental hand instruments are not efficient in removing all infected dentin when performing carious removal for minimal intervention techniques. The use of an antibacterial dentin conditioner may therefore be useful when restoring cavities that have residual carious dentin. Antibacterial agents--chlorhexidine hydrochloride, cetylpyridinium chloride, cetrimide, benzaIkonium chloride and sodium hypochlorite, were added either to a dentin conditioner used for glass ionomer cements or distilled water at 1% concentration. Dentin conditioning solutions at pH 2.5, 4.9 and 7.7 were also prepared, along with 1% aqueous thymol. Using an agar diffusion test, 25 microl aliquots were examined for their inhibitory effects on three cariogenic bacteria. After 24 hours, an agar pellet was extracted adjacent to the agar well and placed on a second inoculated agar plate to observe sustained inhibitory effects, after which this procedure was repeated one more time. Antibacterial dentin conditioners showed significant inhibitory effect compared to the control over the three test periods (p<0.016). The combination of dentin conditioners with antibacterial agents significantly reduced the inhibitory effect compared to the antibacterial aqueous solutions (p<0.016). One-percent aqueous thymol showed no inhibitory effect against the test bacteria. The cetrimide-dentin conditioner showed the greatest inhibitory effect against all three test bacteria over the three experimental periods (p<0.016). The inhibitory effect of antibacterial agents was significantly reduced when combined with a dentin conditioner. Only the cetrimide-dentin conditioner combination produced significant inhibitory effects against all three test organisms. PMID:15765961

  12. The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models.

    PubMed

    Foster, Paul; Yamaguchi, Kyoko; Hsu, Pin P; Qian, Fawn; Du, Xiangnan; Wu, Jianming; Won, Kwang-Ai; Yu, Peiwen; Jaeger, Christopher T; Zhang, Wentao; Marlowe, Charles K; Keast, Paul; Abulafia, Wendy; Chen, Jason; Young, Jenny; Plonowski, Artur; Yakes, F Michael; Chu, Felix; Engell, Kelly; Bentzien, Frauke; Lam, Sanh T; Dale, Stephanie; Yturralde, Olivia; Matthews, David J; Lamb, Peter; Laird, A Douglas

    2015-04-01

    Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents. PMID:25637314

  13. Agent independent task planning

    NASA Technical Reports Server (NTRS)

    Davis, William S.

    1990-01-01

    Agent-Independent Planning is a technique that allows the construction of activity plans without regard to the agent that will perform them. Once generated, a plan is then validated and translated into instructions for a particular agent, whether a robot, crewmember, or software-based control system. Because Space Station Freedom (SSF) is planned for orbital operations for approximately thirty years, it will almost certainly experience numerous enhancements and upgrades, including upgrades in robotic manipulators. Agent-Independent Planning provides the capability to construct plans for SSF operations, independent of specific robotic systems, by combining techniques of object oriented modeling, nonlinear planning and temporal logic. Since a plan is validated using the physical and functional models of a particular agent, new robotic systems can be developed and integrated with existing operations in a robust manner. This technique also provides the capability to generate plans for crewmembers with varying skill levels, and later apply these same plans to more sophisticated robotic manipulators made available by evolutions in technology.

  14. Assessment of hormonally active agents in the reproductive tract of female nonhuman primates.

    PubMed

    Cline, J M; Söderqvist, G; Register, T C; Williams, J K; Adams, M R; Von Schoultz, B

    2001-01-01

    Using the ovariectomized macaque model of postmenopausal women's health, we investigated the effects of long-term treatments (5 weeks-3 years) with estradiol, conjugated equine estrogens (CEE), esterified estrogens, progestins such as medroxyprogesterone acetate (MPA) and nomegestrol acetate, CEE + MPA, tamoxifen, soybean phytoestrogens (SPEs), a variety of putative selective estrogen receptor modulators (SERMs), and androgens. Agents tested were selected on the basis of beneficial effects on arteries and/or bone. Doses were scaled on a caloric or serum-concentration basis to approximate human clinical doses. We evaluated endometrial and mammary gland histopathology and morphometry and used immunohistochemistry to evaluate cell proliferation and expression of estrogen receptor alpha and progesterone receptor (PR). Both estradiol and CEE induced endometrial hyperplasia. MPA antagonized epithelial proliferation induced by CEE in endometrium and induced pseudodecidual stromal hyperplasia in some animals. Tamoxifen induced endometrial polyps, cystic hyperplasia, stromal fibrosis, and PR expression but not Ki-67 expression. SPEs were not estrogenic at dietary doses and antagonized estrogen-induced proliferation in the endometrium and breast. Nandrolone induced mucometra and an adenomyosis-like change. The potential SERM 17 alpha dihydroequilenin did not have uterotrophic or mammotrophic effects. In general, experimental findings in macaques have been predictive of outcomes in human clinical trials of the same agents. PMID:11215689

  15. In Vitro Activities of Five Antifungal Drugs Against Opportunistic Agents of Aspergillus Nigri Complex.

    PubMed

    Badali, Hamid; Fakhim, Hamed; Zarei, Fereshteh; Nabili, Mojtaba; Vaezi, Afsane; Poorzad, Nafiseh; Dolatabadi, Somayeh; Mirhendi, Hossein

    2016-04-01

    Black aspergilli, particularly Aspergillus niger and A. tubingensis, are the most common etiological agents of otomycosis followed by onychomycosis, pulmonary aspergillosis and aspergilloma. However, so far there is no systematic study on their antifungal susceptibility profiles. A collection of 124 clinical and environmental species of black aspergilli consisted of A. niger, A. tubingensis, A. uvarum. A. acidus and A. sydowii were verified by DNA sequencing of the partial β-tubulin gene. MICs of amphotericin B, itraconazole, voriconazole, posaconazole, and MECs of caspofungin were performed based on CLSI M38-A2. Posaconazole and caspofungin had the lowest MIC range (0.016-0.125 µg/ml and 0.008-0.031 µg/ml, respectively), followed by amphotericin B (0.25-4 µg/ml), voriconazole (0.125-16 µg/ml) and itraconazole (0.25 to >16) in an increasing order. Some strains of A. niger showed high MIC value for itraconazole and voriconazole (>16 µg/ml), in contrast only environmental isolates of A. tubingensis had high itraconazole MICs (>16 µg/ml). These results confirm that posaconazole and caspofungin are potential drugs for treatment of aspergillosis due to opportunistic agents of Aspergillus Nigri complex. However, in vivo efficacy remains to be determined. PMID:26615417

  16. [Analysis and stability of suxamethonium chloride. 1. Detection and quantitative determination of the intact active agent with its degradation products].

    PubMed

    Döge, G; Pohloudek-Fabini, R; Kottke, D

    1982-10-01

    The authors developed methods permitting to follow the course of degradation in injectable solutions of suxamethonium chloride. The qualitative detection of the active agent in the presence of degradation products is achieved by thin-layer chromatography and spraying with Dragendorff's reagent and bromocresol green indicator solution. The same separation technique may be used for determining with sufficient accuracy the intact agent in the eluate, using the method of Okken and Haas. Furthermore, a modified Draganic procedure (which is based on the spectrophotometric determination of the hydrolysis products succinic acid monocholine chloride and succinic acid as a Cu-benzidine complex) is suited for estimating the degree of degradation. No previous separation is required because the molar extinction efficients of the monoester and of the acid are in agreement, so that the degree of degradation can be calculated from the sum of the molar concentrations. The value of these methods is demonstrated by analyzing experimental mixtures of the intact agent and degradation products. PMID:7178216

  17. HEPS Inventory Tool: An Inventory Tool Including Quality Assessment of School Interventions on Healthy Eating and Physical Activity

    ERIC Educational Resources Information Center

    Dadaczynski, Kevin; Paulus, Peter; de Vries, Nanne; de Ruiter, Silvia; Buijs, Goof

    2010-01-01

    The HEPS Inventory Tool aims to support stakeholders working in school health promotion to promote high quality interventions on healthy eating and physical activity. As a tool it provides a step-by-step approach on how to develop a national or regional inventory of existing school based interventions on healthy eating and physical activity. It…

  18. Potentiation activity of multiple antibacterial agents by Salvianolate from the Chinese medicine Danshen against methicillin-resistant Staphylococcus aureus (MRSA).

    PubMed

    Liu, Qing-Qing; Han, Jun; Zuo, Guo-Ying; Wang, Gen-Chun; Tang, Hua-Shu

    2016-05-01

    Salvianolate (SAL) is a prescribed medicine from the Chinese herb Danshen (Salvia miltiorrhiza Bunge). It has been widely used in treatment of coronary and other diseases with significant effects. The in vitro antimicrobial activities of SAL against infectious pathogens were assayed and its combined effects on 10 clinical isolates of SCCmec III type methicillin-resistant Staphylococcus aureus (MRSA) with ten antibiotics were evaluated. Susceptibility to each agent alone was tested using a broth microdilution method, and the chequerboard and time-kill experiments were used for the combined activities. The results showed MIC was 128-256 mg/L for SAL used alone against MRSA. Significant synergies were observed for SAL/Ampicillin (Fosfomycin, Erythromycin, Piperacillin-tazobactam or Clindamycin) combination against over half of the isolates, with their MICs reduced by times of dilution (TOD) to 4-32 (FICIs 0.375-0.5), respectively. SAL/AMP combination showed the best combined effect of synergy on bacteriostatic and bactericidal activities, while SAL/AMK combination reversed the resistance of MRSA to AMK. The results demonstrated that SAL enhanced widely the in vitro anti-MRSA efficacy of the ten antibacterial agents, which had potential for combinatory therapy of patients infected with MRSA and warrants further investigations. PMID:26639445

  19. Metabolic Activation of the Antibacterial Agent Triclocarban by Cytochrome P450 1A1 Yielding Glutathione Adducts

    PubMed Central

    Muvvala, Jaya B.; Morin, Dexter; Buckpitt, Alan R.; Hammock, Bruce D.; Rice, Robert H.

    2014-01-01

    Triclocarban (3,4,4′-trichlorocarbanilide; TCC) is an antibacterial agent used in personal care products such as bar soaps. Small amounts of chemical are absorbed through the epidermis. Recent studies show that residues of reactive TCC metabolites are bound covalently to proteins in incubations with keratinocytes, raising concerns about the potential toxicity of this antimicrobial agent. To obtain additional information on metabolic activation of TCC, this study characterized the reactive metabolites trapped as glutathione conjugates. Incubations were carried out with 14C-labeled TCC, recombinant CYP1A1 or CYP1B1, coexpressed with cytochrome P450 reductase, glutathione-S-transferases (GSH), and an NADPH-generating system. Incubations containing CYP1A1, but not 1B1, led to formation of a single TCC-GSH adduct with a conversion rate of 1% of parent compound in 2 hours. Using high-resolution mass spectrometry and diagnostic fragmentation, the adduct was tentatively identified as 3,4-dichloro-3′-glutathionyl-4′-hydroxycarbanilide. These findings support the hypothesis that TCC is activated by oxidative dehalogenation and oxidation to a quinone imine. Incubations of TCDD-induced keratinocytes with 14C-TCC yielded a minor radioactive peak coeluting with TCC-GSH. Thus, we conclude that covalent protein modification by TCC in TCDD-induced human keratinocyte incubations is mainly caused by activation of TCC by CYP1A1 via a dehalogenated TCC derivative as reactive species. PMID:24733789

  20. Metabolic activation of the antibacterial agent triclocarban by cytochrome P450 1A1 yielding glutathione adducts.

    PubMed

    Schebb, Nils Helge; Muvvala, Jaya B; Morin, Dexter; Buckpitt, Alan R; Hammock, Bruce D; Rice, Robert H

    2014-07-01

    Triclocarban (3,4,4'-trichlorocarbanilide; TCC) is an antibacterial agent used in personal care products such as bar soaps. Small amounts of chemical are absorbed through the epidermis. Recent studies show that residues of reactive TCC metabolites are bound covalently to proteins in incubations with keratinocytes, raising concerns about the potential toxicity of this antimicrobial agent. To obtain additional information on metabolic activation of TCC, this study characterized the reactive metabolites trapped as glutathione conjugates. Incubations were carried out with (14)C-labeled TCC, recombinant CYP1A1 or CYP1B1, coexpressed with cytochrome P450 reductase, glutathione-S-transferases (GSH), and an NADPH-generating system. Incubations containing CYP1A1, but not 1B1, led to formation of a single TCC-GSH adduct with a conversion rate of 1% of parent compound in 2 hours. Using high-resolution mass spectrometry and diagnostic fragmentation, the adduct was tentatively identified as 3,4-dichloro-3'-glutathionyl-4'-hydroxycarbanilide. These findings support the hypothesis that TCC is activated by oxidative dehalogenation and oxidation to a quinone imine. Incubations of TCDD-induced keratinocytes with (14)C-TCC yielded a minor radioactive peak coeluting with TCC-GSH. Thus, we conclude that covalent protein modification by TCC in TCDD-induced human keratinocyte incubations is mainly caused by activation of TCC by CYP1A1 via a dehalogenated TCC derivative as reactive species. PMID:24733789

  1. Quantitative analysis of the anti-proliferative activity of combinations of selected iron-chelating agents and clinically used anti-neoplastic drugs.

    PubMed

    Potuckova, Eliska; Jansova, Hana; Machacek, Miloslav; Vavrova, Anna; Haskova, Pavlina; Tichotova, Lucie; Richardson, Vera; Kalinowski, Danuta S; Richardson, Des R; Simunek, Tomas

    2014-01-01

    Recent studies have demonstrated that several chelators possess marked potential as potent anti-neoplastic drugs and as agents that can ameliorate some of the adverse effects associated with standard chemotherapy. Anti-cancer treatment employs combinations of several drugs that have different mechanisms of action. However, data regarding the potential interactions between iron chelators and established chemotherapeutics are lacking. Using estrogen receptor-positive MCF-7 breast cancer cells, we explored the combined anti-proliferative potential of four iron chelators, namely: desferrioxamine (DFO), salicylaldehyde isonicotinoyl hydrazone (SIH), (E)-N'-[1-(2-hydroxy-5-nitrophenyl)ethyliden] isonicotinoyl hydrazone (NHAPI), and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), plus six selected anti-neoplastic drugs. These six agents are used for breast cancer treatment and include: paclitaxel, 5-fluorouracil, doxorubicin, methotrexate, tamoxifen and 4-hydroperoxycyclophosphamide (an active metabolite of cyclophosphamide). Our quantitative chelator-drug analyses were designed according to the Chou-Talalay method for drug combination assessment. All combinations of these agents yielded concentration-dependent, anti-proliferative effects. The hydrophilic siderophore, DFO, imposed antagonism when used in combination with all six anti-tumor agents and this antagonistic effect increased with increasing dose. Conversely, synergistic interactions were observed with combinations of the lipophilic chelators, NHAPI or Dp44mT, with doxorubicin and also the combinations of SIH, NHAPI or Dp44mT with tamoxifen. The combination of Dp44mT with anti-neoplastic agents was further enhanced following formation of its redox-active iron and especially copper complexes. The most potent combinations of Dp44mT and NHAPI with tamoxifen were confirmed as synergistic using another estrogen receptor-expressing breast cancer cell line, T47D, but not estrogen receptor-negative MDA

  2. PROCESS OF TREATING OR FORMING AN INSOLUBLE PLUTONIUM PRECIPITATE IN THE PRESENCE OF AN ORGANIC ACTIVE AGENT

    DOEpatents

    Balthis, J.H.

    1961-07-18

    Carrier precipitation processes for the separation of plutonium from fission products are described. In a process in which an insoluble precipitate is formed in a solution containing plutonium and fission products under conditions whereby plutonium is carried by the precipitate, and the precipitate is then separated from the remaining solution, an organic surface active agent is added to the mixture of precipitate and solution prior to separation of the precipitate from the supernatant solution, thereby improving the degree of separation of the precipitate from the solution.

  3. An Intelligent Active Video Surveillance System Based on the Integration of Virtual Neural Sensors and BDI Agents

    NASA Astrophysics Data System (ADS)

    Gregorio, Massimo De

    In this paper we present an intelligent active video surveillance system currently adopted in two different application domains: railway tunnels and outdoor storage areas. The system takes advantages of the integration of Artificial Neural Networks (ANN) and symbolic Artificial Intelligence (AI). This hybrid system is formed by virtual neural sensors (implemented as WiSARD-like systems) and BDI agents. The coupling of virtual neural sensors with symbolic reasoning for interpreting their outputs, makes this approach both very light from a computational and hardware point of view, and rather robust in performances. The system works on different scenarios and in difficult light conditions.

  4. The effects of selected drugs, including chlorpromazine and non-steroidal anti-inflammatory agents, on polyclonal IgG synthesis and interleukin 1 production by human peripheral blood mononuclear cells in vitro.

    PubMed

    Martinez, F; Coleman, J W

    1989-05-01

    We tested a range of drugs for their effects on in vitro polyclonal IgG synthesis by human peripheral blood mononuclear cells (PBMC) stimulated with the lectin pokeweed mitogen (PWM). The test drugs were selected on the basis of reported disruptive effects on immune function in vivo. IgG production between day 4 and days 7 or 8 of culture was measured by biotin-streptavidin sandwich ELISA. The anti-psychotic agent chlorpromazine (0.55-1.7 microM) enhanced IgG synthesis to approximately double control levels. In contrast, the non-steroidal anti-inflammatory drugs (NSAIDs) indomethacin, piroxicam, ibuprofen and aspirin inhibited IgG synthesis by up to 50%, with a rank order of potency that reflects their activity as inhibitors of cyclo-oxygenase. Phenytoin, procainamide, propylthiouracil, methimazole, D-penicillamine and D-penicillamine-L-cysteine all failed to modulate IgG synthesis at non-toxic concentrations. The potentiation and inhibition of IgG synthesis by chlorpromazine and indomethacin, respectively, was observed only when the drug was present during the first 24 h of culture. Neither chlorpromazine nor indomethacin, at non-toxic concentrations, affected PHA- and PWM-stimulated proliferation of PBMC. In addition, chlorpromazine, indomethacin and piroxicam, at concentrations which produced maximal modulation of IgG synthesis, and D-penicillamine and D-penicillamine-L-cysteine at 10 microM failed to influence production of interleukin-1-like activity. We conclude that chlorpromazine and NSAIDs, although they exert opposite effects on IgG synthesis, act at an early stage of B cell differentiation that appears to be independent of interleukin 1 synthesis and early proliferative events. PMID:2788047

  5. Multimedia authoring and synchronization within ActiveM3: a system for composing active e-mail messages as subtypes of mobile agents

    NASA Astrophysics Data System (ADS)

    Schirmer, Juergen; Hayn, Ralf

    1998-09-01

    Multimedia electronic mail and active electronic mail are very well known concepts. Multimedia electronic mail is concerned with the transmission of multimedia information like images, audio and video objects within email. Moreover, active email (or enhanced email) incorporates programs in ordinary electronic mail. The active email message automatically executes at the email receiver's site and, for instance, orchestrates the presentation of the multimedia information. This kind of message can be regarded as a subtype of a mobile agent which as a user interface and which gets into contact with the enduser. Based on a realized prototype ActiveM3, the related concepts for multimedia authoring and synchronization within the active email approach are introduced in this article.

  6. Membrane-permeabilizing activity of reverse-amide 2-aminoimidazole antibiofilm agents against Acinetobacter baumannii.

    PubMed

    Stowe, Sean D; Thompson, Richele J; Peng, Lingling; Su, Zhaoming; Blackledge, Meghan S; Draughn, G Logan; Coe, William H; Johannes, Eva; Lapham, Valerie K; Mackenzie, John; Melander, Christian; Cavanagh, John

    2015-01-01

    Acinetobacter baumannii has quickly become one of the most insidious and prevalent nosocomial infections. Recently, the reverse-amide class of 2-aminoimidazole compounds (RA-2AI) was found both to prevent A. baumannii biofilm formation and also to disperse preexisting formations, putatively through interactions with cytosolic response regulators. Here we focus on how this class of antibiofilm agent traverses cellular membranes. Following the discovery of dosage-dependent growth rate changes, the cellular effects of RA-2AI were investigated using a combination of molecular assays and microscopic techniques. It was found that RA-2AI exposure has measureable effects on the bacterial membranes, resulting in a period of increased permeability and visible structural aberrations. Based on these results, we propose a model that describes how the structure of RA-2AI allows it to insert itself into and disrupt the fluidity of the membrane, creating an opportunity for increased molecular permeability. PMID:25348099

  7. Overcoming chloroquine resistance in malaria: Design, synthesis and structure-activity relationships of novel chemoreversal agents.

    PubMed

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-08-25

    Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies. PMID:27173385

  8. Synthesis and Biological Activity of 3-N-Substituted Estrogen Derivatives as Breast Cancer Agents

    PubMed Central

    Wan, Zhongliang; Musa, Musiliyu A; Joseph, Patrick; Cooperwood, John S.

    2013-01-01

    3-N-substituted-estrogen derivatives were synthesized and characterized. Their antiproliferative activities against human ER (+) MCF-7 (Breast), ER (−) MDA-MB-231 (breast) and Ishikawa (endometrial) cancer cell lines were determined after 72 hours drug exposure employing CellTiter-Glo assay at concentrations ranging from (0.01-100,000 nM). The antiproliferative activities of these compounds were compared to tamoxifen (TAM), 4-hydroxytamoxifen (4-OHT, active metabolite of tamoxifen) and raloxifene (RAL). In vitro results indicated that compound 5 (IC50 = 12μM) displayed comparable antiproliferative activity against MDA-MB 231 cell line; while compounds 6, 7 and 13 (IC50 = 12μM) displayed higher activity against MCF-7 and Ishikawa cell lines, in comparison to TAM activity (19-33μM). PMID:22876946

  9. Antiviral activity of human Vδ2 T-cells against WNV includes both cytolytic and non-cytolytic mechanisms.

    PubMed

    Agrati, Chiara; Castilletti, Concetta; Cimini, Eleonora; Romanelli, Antonella; Lapa, Daniele; Quartu, Serena; Martini, Federico; Capobianchi, Maria Rosaria

    2016-04-01

    West Nile virus (WNV) causes a severe central nervous system infection in humans, primarily in the elderly and immunocompromised subjects. Human γδ T-cells play a critical role in the immune response against viruses, and studies of WNV meningoencephalitis in laboratory mice described a role of γδ T-cells in the protective immune response. Aim of this study was to analyze the cytolytic and non-cytolytic antiviral activity of human Vδ2 T-cells against WNV replication. The anti-WNV activity of soluble factor released by zoledronic acid (ZA)-activated Vδ2 T-cell lines and the cytotoxic capability of Vδ2 T-cell lines against WNV-infected cells were tested in vitro. The activation of Vδ2 T-cell lines was able to inhibit WNV replication through the release of soluble factors. IFN-γ is massively released by activated Vδ2 T-cell lines and is involved in the anti-WNV activity. Moreover, the Vδ2 T-cell lines can efficiently kill WNV-infected cells possibly through perforin-mediated mechanism. Altogether, our results provide insight into the effector functions of human Vδ2 T-cells against WNV. The possibility to target these cells by ZA, a commercially available drug used in humans, could potentially offer a new immunotherapeutic strategy for WNV infection. PMID:27196553

  10. A Descriptive Analysis of the Del Mod System's Field Agent Component, Final Report, Volume III.

    ERIC Educational Resources Information Center

    Golts, Uldis R.

    This monograph describes the field agent of the Delaware Del Mod System. The following sections are included in the report: (1) The Duties and Activities of the Del Mod System Field Agents; (2) The Field Agents' Mode of Operation; (3) The Conduct of Projects; (4) The Hiring and Training of Del Mod Field Agents; (5) The Administration of Del Mod…

  11. GTP depletion synergizes the anti-proliferative activity of chemotherapeutic agents in a cell type-dependent manner

    SciTech Connect

    Lin, Tao; Meng, Lingjun; Tsai, Robert Y.L.

    2011-10-22

    Highlights: {yields} Strong synergy between mycophenolic acid (MPA) and 5-FU in MDA-MB-231 cells. {yields} Cell type-dependent synergy between MPA and anti-proliferative agents. {yields} The synergy of MPA on 5-FU is recapitulated by RNA polymerase-I inhibition. {yields} The synergy of MPA on 5-FU requires the expression of nucleostemin. -- Abstract: Mycophenolic acid (MPA) depletes intracellular GTP by blocking de novo guanine nucleotide synthesis. GTP is used ubiquitously for DNA/RNA synthesis and as a signaling molecule. Here, we made a surprising discovery that the anti-proliferative activity of MPA acts synergistically with specific chemotherapeutic agents in a cell type-dependent manner. In MDA-MB-231 cells, MPA shows an extremely potent synergy with 5-FU but not with doxorubicin or etoposide. The synergy between 5-FU and MPA works most effectively against the highly tumorigenic mammary tumor cells compared to the less tumorigenic ones, and does not work in the non-breast cancer cell types that we tested, with the exception of PC3 cells. On the contrary, MPA shows the highest synergy with paclitaxel but not with 5-FU in SCC-25 cells, derived from oral squamous cell carcinomas. Mechanistically, the synergistic effect of MPA on 5-FU in MDA-MB-231 cells can be recapitulated by inhibiting the RNA polymerase-I activity and requires the expression of nucleostemin. This work reveals that the synergy between MPA and anti-proliferative agents is determined by cell type-dependent factors.

  12. Let's Move! School Psychologists as Change Agents in the Domain of School-Based Physical Activity

    ERIC Educational Resources Information Center

    Fedewa, Alicia L.; Clark, Teresa P.

    2010-01-01

    Many of the students the authors have worked with see recess as a refuge from the multiple demands of school. Yet, how many school psychologists truly understand the multidimensional benefit of physical activity in schools? Increased physical activity has been associated with better physical health, improved mental health, and higher academic…

  13. O6-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and with MGMT promoter methylation in glioblastoma and anaplastic glioma

    PubMed Central

    Bobola, Michael S.; Alnoor, Mohammad; Chen, John Y.-S.; Kolstoe, Douglas D.; Silbergeld, Daniel L.; Rostomily, Robert C.; Blank, A.; Chamberlain, Marc C.; Silber, John R.

    2014-01-01

    Background CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following alkylating agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti-resistance therapies. Methods We examined the relationship of MGMT activity in 91 GBMs and 84 AGs with progression-free survival (PFS) following alkylator therapy and with promoter methylation status determined by methylation-specific PCR (MSP). Results Cox regression analysis revealed that GBMs with high activity had a significantly greater risk for progression in dichotomous (P ≤ 0.001) and continuous (P ≤ 0.003) models, an association observed for different alkylator regimens, including concurrent chemo-radiation with temozolomide. Analysis of MGMT promoter methylation status in 47 of the GBMs revealed that methylated tumors had significantly lower activity (P ≤ 0.005) and longer PFS (P ≤ 0.036) compared to unmethylated tumors, despite overlapping activities. PFS was also significantly greater in methylated vs. unmethylated GBMs with comparable activity (P ≤ 0.005), and among unmethylated tumors with less than median activity (P ≤ 0.026), suggesting that mechanisms in addition to MGMT promote alkylator resistance. Similar associations of MGMT activity with PFS and promoter methylation status were observed for AGs. Conclusions Our results provide strong support for the hypotheses that MGMT activity promotes alkylator resistance and reflects promoter methylation status in malignant gliomas. General significance MGMT activity is an attractive target for anti-resistance therapy regardless of methylation status. PMID:25558448

  14. Upstream stimulatory factor activates the vasopressin promoter via multiple motifs, including a non-canonical E-box.

    PubMed Central

    Coulson, Judy M; Edgson, Jodie L; Marshall-Jones, Zoe V; Mulgrew, Robert; Quinn, John P; Woll, Penella J

    2003-01-01

    We have described previously a complex E-box enhancer (-147) of the vasopressin promoter in small-cell lung cancer (SCLC) extracts [Coulson, Fiskerstrand, Woll and Quinn, (1999) Biochem. J. 344, 961-970]. Upstream stimulatory factor (USF) heterodimers were one of the complexes binding to this site in vitro. We now report that USF overexpression in non-SCLC (NSCLC) cells can functionally activate vasopressin promoter-driven reporters that are otherwise inactive in this type of lung cancer cell. Site-directed mutagenesis and electrophoretic mobility-shift analysis demonstrate that although the -147 E-box contributes, none of the previously predicted E-boxes (-147, -135, -34) wholly account for this USF-mediated activation in NSCLC. 5' Deletion showed the key promoter region as -52 to +42; however, USF-2 binding was not reliant on the -34 E-box, but on a novel adjacent CACGGG non-canonical E-box at -42 (motif E). This mediated USF binding in both SCLC and USF-2-transfected NSCLC cells. Mutation of motif E or the non-canonical TATA box abolished activity, implying both are required for transcriptional initiation on overexpression of USF-2. Co-transfected dominant negative USF confirmed that binding was required through motif E for function, but that the classical activation domain of USF was not essential. USF-2 bound motif E with 10-fold lower affinity than the -147 E-box. In NSCLC, endogenous USF-2 expression is low, and this basal level appears to be insufficient to activate transcription of arginine vasopressin (AVP). In summary, we have demonstrated a novel mechanism for USF activation, which contributes to differential vasopressin expression in lung cancer. PMID:12403649

  15. Comparison of the White-Nose Syndrome Agent Pseudogymnoascus destructans to Cave-Dwelling Relatives Suggests Reduced Saprotrophic Enzyme Activity

    PubMed Central

    Reynolds, Hannah T.; Barton, Hazel A.

    2014-01-01

    White-nose Syndrome (WNS) is an emerging infectious mycosis that has impacted multiple species of North American bats since its initial discovery in 2006, yet the physiology of the causal agent, the psychrophilic fungus Pseudogymnoascus destructans ( = Geomyces destructans), is not well understood. We investigated the ability of P. destructans to secrete enzymes that could permit environmental growth or affect pathogenesis and compared enzyme activity across several Pseudogymnoascus species isolated from both hibernating bats and cave sediments. We found that P. destructans produced enzymes that could be beneficial in either a pathogenic or saprotrophic context, such as lipases, hemolysins, and urease, as well as chitinase and cellulases, which could aid in saprotrophic growth. The WNS pathogen showed significantly lower activity for urease and endoglucanase compared to con-generic species (Pseudogymnoascus), which may indicate a shift in selective pressure to the detriment of P. destructans’ saprotrophic ability. Based on the positive function of multiple saprotrophic enzymes, the causal agent of White-nose Syndrome shows potential for environmental growth on a variety of substrates found in caves, albeit at a reduced level compared to environmental strains. Our data suggest that if P. destructans emerged as an opportunistic infection from an environmental source, co-evolution with its host may have led to a reduced capacity for saprotrophic growth. PMID:24466096

  16. Comparison of the white-nose syndrome agent Pseudogymnoascus destructans to cave-dwelling relatives suggests reduced saprotrophic enzyme activity.

    PubMed

    Reynolds, Hannah T; Barton, Hazel A

    2014-01-01

    White-nose Syndrome (WNS) is an emerging infectious mycosis that has impacted multiple species of North American bats since its initial discovery in 2006, yet the physiology of the causal agent, the psychrophilic fungus Pseudogymnoascus destructans ( = Geomyces destructans), is not well understood. We investigated the ability of P. destructans to secrete enzymes that could permit environmental growth or affect pathogenesis and compared enzyme activity across several Pseudogymnoascus species isolated from both hibernating bats and cave sediments. We found that P. destructans produced enzymes that could be beneficial in either a pathogenic or saprotrophic context, such as lipases, hemolysins, and urease, as well as chitinase and cellulases, which could aid in saprotrophic growth. The WNS pathogen showed significantly lower activity for urease and endoglucanase compared to con-generic species (Pseudogymnoascus), which may indicate a shift in selective pressure to the detriment of P. destructans' saprotrophic ability. Based on the positive function of multiple saprotrophic enzymes, the causal agent of White-nose Syndrome shows potential for environmental growth on a variety of substrates found in caves, albeit at a reduced level compared to environmental strains. Our data suggest that if P. destructans emerged as an opportunistic infection from an environmental source, co-evolution with its host may have led to a reduced capacity for saprotrophic growth. PMID:24466096

  17. Dieckol as a novel anti-proliferative and anti-angiogenic agent and computational anti-angiogenic activity evaluation.

    PubMed

    Li, Yong-Xin; Li, Yong; Je, Jae-Young; Kim, Se-Kwon

    2015-01-01

    In the current study it was found that dieckol isolated from edible brown algae, Ecklonia cava (EC), as potent anti-proliferative and anti-angiogenic agent. Vascular endothelial growth factor (VEGF) induced EA.hy926 cell proliferation was suppressed by dieckol treatment. Further, it showed a significant inhibition of cell migration via inhibiting the protein and gene expression levels of matrix metalloproteinases, MMP-2 and -9. The signaling cascade underlying these responses was found as the dieckol induced inhibition of mitogen-activated protein kinase (MAPK) signaling pathway molecules, ERK and p38. Docking calculations were carried out on AP-N, VEGFR-1, MMP-2, MMP-9, Akt and Erk2 proteins model. Collectively, these results demonstrate the effective anti-proliferative and anti-migratory activity of dieckol on VEGF induced EA.hy926 through MAPK molecular signaling pathways which could be effectively correlated to its potential as an anti-angiogenic candidate. Therefore, this study reveals the potential of dieckol to be used in the design of anti-angiogenic agents. PMID:25531264

  18. Effect of coupling agent on nano-ZnO modification and antibacterial activity of ZnO/HDPE nanocomposite films

    NASA Astrophysics Data System (ADS)

    Li, Y. N.; Xu, W. M.; Zhang, G. Q.

    2015-07-01

    Commercial zinc oxide nanoparticles were modified by silane coupling agent of KH550 and KH560, respectively. The obtained nanocomposite was characterized by scanning electron microscopy (SEM), Thermogravimetric analyses (TGA) and apparent sedimentation stability (Sapp). Then, nano-ZnO/high-density polyethylene (HDPE) composite films were prepared via melt blending and a hot compression-molding process. The antibacterial testing of the films against E. coli and S. aureus was carried out via plate counting. SEM, TGA and Sapp suggest the modifier of silane changed the surface hydrophilicity and effectively broke the agglomerations of nanoparticles. Antibacterial testing results indicated the antibacterial rate of the films increased with increasing nano-ZnO content. At a low doped content of 0.2 wt%, the types of coupling agent influenced the antibacterial property with that of KH560-modified nano-ZnO/HDPE KH550-modified nano-ZnO/HDPE unmodified nano-ZnO/HDPE films. When the dosage nano-ZnO was over 0.2 wt%, the differences of antibacterial activity resulted by modification was concealed by the strong antibacterial activity with near 100% of the nano- ZnO/HDPE composite films.

  19. A rationally designed mutant of plasma platelet-activating factor acetylhydrolase hydrolyzes the organophosphorus nerve agent soman.

    PubMed

    Kirby, Stephen D; Norris, Joseph; Sweeney, Richard; Bahnson, Brian J; Cerasoli, Douglas M

    2015-12-01

    Organophosphorus compounds (OPs) such as sarin and soman are some of the most toxic chemicals synthesized by man. They exert toxic effects by inactivating acetylcholinesterase (AChE) and bind secondary target protein. Organophosphorus compounds are hemi-substrates for enzymes of the serine hydrolase superfamily. Enzymes can be engineered by amino acid substitution into OP-hydrolyzing variants (bioscavengers) and used as therapeutics. Some enzymes associated with lipoproteins, such as human plasma platelet-activating factor acetylhydrolase (pPAF-AH), are also inhibited by OPs; these proteins have largely been ignored for engineering purposes because of complex interfacial kinetics and a lack of structural data. We have expressed active human pPAF-AH in bacteria and previously solved the crystal structure of this enzyme with OP adducts. Using these structures as a guide, we created histidine mutations near the active site of pPAF-AH (F322H, W298H, L153H) in an attempt to generate novel OP-hydrolase activity. Wild-type pPAF-AH, L153H, and F322H have essentially no hydrolytic activity against the nerve agents tested. In contrast, the W298H mutant displayed novel somanase activity with a kcat of 5min(-1) and a KM of 590μM at pH7.5. There was no selective preference for hydrolysis of any of the four soman stereoisomers. PMID:26343853

  20. Low Temperature Activation of Supported Metathesis Catalysts by Organosilicon Reducing Agents

    PubMed Central

    2016-01-01

    Alkene metathesis is a widely and increasingly used reaction in academia and industry because of its efficiency in terms of atom economy and its wide applicability. This reaction is notably responsible for the production of several million tons of propene annually. Such industrial processes rely on inexpensive silica-supported tungsten oxide catalysts, which operate at high temperatures (>350 °C), in contrast with the mild room temperature reaction conditions typically used with the corresponding molecular alkene metathesis homogeneous catalysts. This large difference in the temperature requirements is generally thought to arise from the difficulty in generating active sites (carbenes or metallacyclobutanes) in the classical metal oxide catalysts and prevents broader applicability, notably with functionalized substrates. We report here a low temperature activation process of well-defined metal oxo surface species using organosilicon reductants, which generate a large amount of active species at only 70 °C (0.6 active sites/W). This high activity at low temperature broadens the scope of these catalysts to functionalized substrates. This activation process can also be applied to classical industrial catalysts. We provide evidence for the formation of a metallacyclopentane intermediate and propose how the active species are formed. PMID:27610418

  1. Low Temperature Activation of Supported Metathesis Catalysts by Organosilicon Reducing Agents.

    PubMed

    Mougel, Victor; Chan, Ka-Wing; Siddiqi, Georges; Kawakita, Kento; Nagae, Haruki; Tsurugi, Hayato; Mashima, Kazushi; Safonova, Olga; Copéret, Christophe

    2016-08-24

    Alkene metathesis is a widely and increasingly used reaction in academia and industry because of its efficiency in terms of atom economy and its wide applicability. This reaction is notably responsible for the production of several million tons of propene annually. Such industrial processes rely on inexpensive silica-supported tungsten oxide catalysts, which operate at high temperatures (>350 °C), in contrast with the mild room temperature reaction conditions typically used with the corresponding molecular alkene metathesis homogeneous catalysts. This large difference in the temperature requirements is generally thought to arise from the difficulty in generating active sites (carbenes or metallacyclobutanes) in the classical metal oxide catalysts and prevents broader applicability, notably with functionalized substrates. We report here a low temperature activation process of well-defined metal oxo surface species using organosilicon reductants, which generate a large amount of active species at only 70 °C (0.6 active sites/W). This high activity at low temperature broadens the scope of these catalysts to functionalized substrates. This activation process can also be applied to classical industrial catalysts. We provide evidence for the formation of a metallacyclopentane intermediate and propose how the active species are formed. PMID:27610418

  2. Design, synthesis and biological activity of piperlongumine derivatives as selective anticancer agents.

    PubMed

    Wu, Yuelin; Min, Xiao; Zhuang, Chunlin; Li, Jin; Yu, Zhiliang; Dong, Guoqiang; Yao, Jiangzhong; Wang, Shengzheng; Liu, Yang; Wu, Shanchao; Zhu, Shiping; Sheng, Chunquan; Wei, Yunyang; Zhang, Huojun; Zhang, Wannian; Miao, Zhenyuan

    2014-07-23

    In an effort to expand the structure-activity relationship of the natural anticancer compound piperlongumine, we have prepared sixteen novel piperlongumine derivatives with halogen or morpholine substituents at C2 and alkyl substituents at C7. Most of 2-halogenated piperlongumines showed potent in vitro activity against four cancer cells and modest selectivity for lung normal cells. The highly active anticancer compound 11h exhibited obvious ROS elevation and excellent in vivo antitumor potency with suppressed tumor growth by 48.58% at the dose of 2 mg/kg. The results indicated that halogen substituents as electrophilic group at C2 played an important role in increasing cytotoxicity. PMID:24937186

  3. [Effect of sodium dodecylbenzenesulfonate and antifoaming agents on the endonuclease activity of Serratia marcescens].

    PubMed

    Serov, G D; Selina, A V

    1982-01-01

    The effect of sodium dodecylbenzene sulfonate (sulfonol) and certain froth breakers on the activity of endonuclease was studied in the cultural broth of Serratia marcescens in order to find out whether sulfonol could be used for limiting the infection. Sulfonol was found to have no effect on the cultural growth; it increased the activity of endonuclease in the cultural broth, and the peak of the activity appeared earlier than in the control medium. Propanol B-400 was shown to be the best froth breaker. PMID:6292671

  4. KGB agents

    NASA Astrophysics Data System (ADS)

    Gaina, Alex

    A short story is reported in which the activity of Communist Party of the USSR and secret KGB agents, which were payed by the State, in view of controlling of the conscience of population. The story reffers to the Physics Department of the Moscow University, Planing Institute of the Gosplan of Moldavian S.S.R. and Chishinau Technical University (actually: Technical University of Moldova), where the author has worked during Soviet times. Almost every 6-th citizen in the USSR was engaged in this activity, while actually the former communists rule in the Republic of Moldova.

  5. The Azorhizobium caulinodans nifA gene: identification of upstream-activating sequences including a new element, the 'anaerobox'.

    PubMed Central

    Nees, D W; Stein, P A; Ludwig, R A

    1988-01-01

    From nucleotide sequencing analyses, the A. caulinodans nifA gene seems to be under dual control by the Ntr (in response to available N) and Fnr (in response to available O2) transcriptional activation/repression systems. Because it fixes N2 in two contexts, the Ntr system might regulate A. caulinodans nif gene expression ex planta, while the Fnr system might similarly regulate in planta. As nifA upstream-activating elements, we have identified: (i) a gpNifA binding site allowing autogenous nifA regulation, (ii) an Ntr-dependent transcription start, presumably the target of gpNifA activation, and (iii) an "anaerobox" tetradecameric nucleotide sequence that is precisely conserved among O2 regulated enteric bacterial genes controlled by the gpFnr transcriptional activator. Because it is precisely positioned upstream of enteric bacterial transcriptional starts, the "anaerobox" sequence may constitute the gpFnr DNA binding site. If so, then a second, Ntr-independent nifA transcription start may exist. We have also deduced the A. caulinodans nifA open reading frame and have compared the gene product (gpNifA) with those of other N2-fixing organisms. These proteins exhibit strongly conserved motifs: (i) sites conserved among ATP-binding proteins, (ii) an interdomain linker region, and (iii) a C-terminal alpha-helix-turn-alpha-helix DNA binding site. PMID:3186446

  6. The activity of candidate virucidal agents, low pH and genital secretions against HIV-1 in vitro.

    PubMed

    O'Connor, T J; Kinchington, D; Kangro, H O; Jeffries, D J

    1995-01-01

    The effect of low pH, normally present in the female genital tract, on HIV viability was examined. HIV is more acid stable than previously reported with no substantial reduction in infectivity occurring until pH levels are reduced below 4.5. The virucidal activity of 3 topical spermicides and chlorhexidine was assessed in vitro using previously established and newly modified assay systems. None of the agents tested had a selectivity index (SI) greater than 5.2. Semen and cervical secretions were assessed for their ability to inhibit HIV-1. While no virucidal effect was found in the latter, seminal fluid was found to have significant activity against HIV-1 and a SI of approximately 50. PMID:7548290

  7. Enzymatic Activity and Susceptibility to Antifungal Agents of Brazilian Environmental Isolates of Hortaea werneckii.

    PubMed

    Formoso, Andrea; Heidrich, Daiane; Felix, Ciro Ramón; Tenório, Anne Carolyne; Leite, Belize R; Pagani, Danielle M; Ortiz-Monsalve, Santiago; Ramírez-Castrillón, Mauricio; Landell, Melissa Fontes; Scroferneker, Maria L; Valente, Patricia

    2015-12-01

    Four strains of Hortaea werneckii were isolated from different substrates in Brazil (a salt marsh macrophyte, a bromeliad and a marine zoanthid) and had their identification confirmed by sequencing of the 26S rDNA D1/D2 domain or ITS region. Most of the strains were able to express amylase, lipase, esterase, pectinase and/or cellulase, enzymes that recognize components of plant cells as substrates, but did not express albuminase, keratinase, phospholipase and DNAse, whose substrates are animal-related. Urease production was positive for all isolates, while caseinase, gelatinase and laccase production were variable among the strains. All the strains grew in media containing up to 30% NaCl. We propose that the primary substrate associated with H. werneckii is plant-related, in special in saline environments, where the fungus may live as a saprophyte and decomposer. Infection of animal-associated substrates would be secondary, with the fungus acting as an opportunistic animal pathogen. All strains were resistant to fluconazole and presented high MIC for amphotericin B, while they were susceptible to all the other antifungal agents tested. PMID:26162643

  8. Exploiting Innate Immune Cell Activation of a Copper-Dependent Antimicrobial Agent during Infection

    PubMed Central

    Festa, Richard A.; Helsel, Marian E.; Franz, Katherine J.; Thiele, Dennis J.

    2014-01-01

    SUMMARY Recalcitrant microbial infections demand new therapeutic options. Here we present an approach that exploits two prongs of the host immune cell antimicrobial response: the oxidative burst and the compartmentalization of copper (Cu) within phagolysosomes. The prochelator QBP is a nontoxic protected form of 8-hydroxyquinoline (8HQ) in which a pinanediol boronic ester blocks metal ion coordination by 8HQ. QBP is deprotected via reactive oxygen species produced by activated macrophages, creating 8HQ and eliciting Cu-dependent killing of the fungal pathogen Cryptococcus neoformans in vitro and in mouse pulmonary infection. 8HQ ionophoric activity increases intracellular Cu, overwhelming the Cu-resistance mechanisms of C. neoformans to elicit fungal killing. The Cu-dependent antimicrobial activity of 8HQ against a spectrum of microbial pathogens suggests that this strategy may have broad utility. The conditional activation of Cu ionophores by innate immune cells intensifies the hostile antimicrobial environment and represents a promising approach to combat infectious disease. PMID:25088681

  9. Synthesis of benzothiadiazine derivatives exhibiting dual activity as aldose reductase inhibitors and antioxidant agents.

    PubMed

    Zhu, Shaojuan; Hao, Xin; Zhang, Shuzhen; Qin, Xiangyu; Chen, Xin; Zhu, Changjin

    2016-06-15

    Several multifunctional benzothiadiazine derivatives were synthesized and examined for their inhibition to the enzyme aldose reductase and in vitro antioxidant activity to identify novel drugs for diabetes and its complications. Most of them exhibited good inhibitory activity. Importantly, a number of compounds demonstrated strong antioxidant activity and one compound in particular was extremely active in the DPPH radical scavenging and MDA inhibition analysis. The DPPH radical scavenging rate with this compound was 98.0%, 92.3% and 42.1% at concentrations of 100μM, 10μM, and 1μM, respectively, and the initial reaction rate was faster than Trolox at a concentration of 10μM. PMID:27156769

  10. MULTIDRUG RESISTANT TRANSPORT ACTIVITY PROTECTS OOCYTES FROM CHEMOTHERAPEUTIC AGENTS AND CHANGES DURING OOCYTE MATURATION

    PubMed Central

    Brayboy, Lynae M.; Oulhen, Nathalie; Witmyer, Jeannine; Robins, Jared; Carson, Sandra; Wessel, Gary M.

    2013-01-01

    Objective To determine the multidrug resistant (MDR) transporter activity in oocytes and their potential role in oocyte susceptibility to chemotherapy. Design Experimental laboratory study Setting University and Academic Center for reproductive medicine. Patients/Animals Women with eggs retrieved for ICSI cycles and adult female FVBN and B6C3F1 mouse strains. Intervention Inhibition of MDR activity in oocytes. Main Outcome measure(s) Efflux activity of MDRs using quantitative fluorescent dye efflux and oocyte cell death when exposed to chemotherapy. Results Oocytes effluxed fluorescent reporters and this activity was significantly reduced in the presence of the MDR inhibitor PSC 833. GV oocytes are more efficient at efflux compared to M2 oocytes. Human oocytes exposed to cyclophosphamide and PSC 833 showed cell death using two different viability assays compared to controls and those exposed to cyclophosphamide alone. Immunoblots detected MDR-1 in all oocytes with the greatest accumulation in the GV stage. Conclusions Oocytes have a vast repertoire of active MDRs. The implications of this study are that these protective mechanisms are important during oogenesis, and these activities change with maturation, increasing susceptibility to toxicants. Future directions may exploit the up regulation of these transporters during gonadotoxic therapy. PMID:23953328

  11. Activated carbons from potato peels: The role of activation agent and carbonization temperature of biomass on their use as sorbents for bisphenol A uptake from aqueous solutions

    NASA Astrophysics Data System (ADS)

    Arampatzidou, An; Deliyanni, Eleni A.

    2015-04-01

    Activated carbons prepared from potato peels, a solid waste by product, and activated with different activating chemicals, have been studied for the adsorption of an endocrine disruptor (Bisphenol-A) from aqueous solutions. The potato peels biomass was activated with phosphoric acid, KOH and ZnCl2. The different activating chemicals were tested in order the better activation agent to be found. The carbons were carbonized by pyrolysis, in one step procedure, at three different temperatures in order the role of the temperature of carbonization to be pointed out. The porous texture and the surface chemistry of the prepared activated carbons were characterized by Nitrogen adsorption (BET), Scanning Electron Microscope (SEM), thermal analysis (DTA) and Fourier Transform Infrared Spectroscopy (FTIR). Batch experiments were performed to investigate the effect of pH, the adsorbent dose, the initial bisphenol A concentration and temperature. Equilibrium adsorption data were analyzed by Langmuir and Freundlich isotherms. The thermodynamic parameters such as the change of enthalpy (ΔH0), entropy (ΔS0) and Gibb's free energy (ΔG0) of adsorption systems were also evaluated. The adsorption capacity calculated from the Langmuir isotherm was found to be 450 mg g-1 at an initial pH 3 at 25 °C for the phosphoric acid activated carbon, that make the activated carbon a promising adsorbent material.

  12. The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation.

    PubMed

    Iwasaki, Daichi; Hayashihara, Kayoko; Shima, Hiroki; Higashide, Mika; Terasawa, Masahiro; Gasser, Susan M; Shinohara, Miki

    2016-03-01

    Because DNA double-strand breaks (DSBs) are one of the most cytotoxic DNA lesions and often cause genomic instability, precise repair of DSBs is vital for the maintenance of genomic stability. Xrs2/Nbs1 is a multi-functional regulatory subunit of the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex, and its function is critical for the primary step of DSB repair, whether by homologous recombination (HR) or non-homologous end joining. In human NBS1, mutations result truncation of the N-terminus region, which contains a forkhead-associated (FHA) domain, cause Nijmegen breakage syndrome. Here we show that the Xrs2 FHA domain of budding yeast is required both to suppress the imprecise repair of DSBs and to promote the robust activation of Tel1 in the DNA damage response pathway. The role of the Xrs2 FHA domain in Tel1 activation was independent of the Tel1-binding activity of the Xrs2 C terminus, which mediates Tel1 recruitment to DSB ends. Both the Xrs2 FHA domain and Tel1 were required for the timely removal of the Ku complex from DSB ends, which correlates with a reduced frequency of imprecise end-joining. Thus, the Xrs2 FHA domain and Tel1 kinase work in a coordinated manner to maintain DSB repair fidelity. PMID:26990569

  13. Age-related changes in trunk neuromuscular activation patterns during a controlled functional transfer task include amplitude and temporal synergies.

    PubMed

    Quirk, D Adam; Hubley-Kozey, Cheryl L

    2014-12-01

    While healthy aging is associated with physiological changes that can impair control of trunk motion, few studies examine how spinal muscle responses change with increasing age. This study examined whether older (over 65 years) compared to younger (20-45 years) adults had higher overall amplitude and altered temporal recruitment patterns of trunk musculature when performing a functional transfer task. Surface electromyograms from twelve bilateral trunk muscle (24) sites were analyzed using principal component analysis, extracting amplitude and temporal features (PCs) from electromyographic waveforms. Two PCs explained 96% of the waveform variance. Three factor ANOVA models tested main effects (group, muscle and reach) and interactions for PC scores. Significant (p<.0125) group interactions were found for all PC scores. Post hoc analysis revealed that relative to younger adults, older adults recruited higher agonist and antagonistic activity, demonstrated continuous activation levels in specific muscle sites despite changing external moments, and had altered temporal synergies within abdominal and back musculature. In summary both older and younger adults recruit highly organized activation patterns in response to changing external moments. Differences in temporal trunk musculature recruitment patterns suggest that older adults experience different dynamic spinal stiffness and loading compared to younger adults during a functional lifting task. PMID:25457424

  14. The IKAROS Interaction with a Complex Including Chromatin Remodeling and Transcription Elongation Activities Is Required for Hematopoiesis

    PubMed Central

    Bottardi, Stefania; Mavoungou, Lionel; Pak, Helen; Daou, Salima; Bourgoin, Vincent; Lakehal, Yahia A.; Affar, El Bachir; Milot, Eric

    2014-01-01

    IKAROS is a critical regulator of hematopoietic cell fate and its dynamic expression pattern is required for proper hematopoiesis. In collaboration with the Nucleosome Remodeling and Deacetylase (NuRD) complex, it promotes gene repression and activation. It remains to be clarified how IKAROS can support transcription activation while being associated with the HDAC-containing complex NuRD. IKAROS also binds to the Positive-Transcription Elongation Factor b (P-TEFb) at gene promoters. Here, we demonstrate that NuRD and P-TEFb are assembled in a complex that can be recruited to specific genes by IKAROS. The expression level of IKAROS influences the recruitment of the NuRD-P-TEFb complex to gene regulatory regions and facilitates transcription elongation by transferring the Protein Phosphatase 1α (PP1α), an IKAROS-binding protein and P-TEFb activator, to CDK9. We show that an IKAROS mutant that is unable to bind PP1α cannot sustain gene expression and impedes normal differentiation of IkNULL hematopoietic progenitors. Finally, the knock-down of the NuRD subunit Mi2 reveals that the occupancy of the NuRD complex at transcribed regions of genes favors the relief of POL II promoter-proximal pausing and thereby, promotes transcription elongation. PMID:25474253

  15. Efflux pump activity in fluoroquinolone and tetracycline resistant Salmonella and E. coli implicated in reduced susceptibility to household antimicrobial cleaning agents.

    PubMed

    Thorrold, C A; Letsoalo, M E; Dusé, A G; Marais, E

    2007-02-15

    It has been shown that the inappropriate use of antimicrobial household agents selects for organisms with resistance mechanisms (e.g. efflux pumps), which could lead to the development of antibiotic resistance. The reverse hypothesis, that antibiotic-resistant organisms become tolerant to other antibacterial agents (e.g. disinfectants) due to the action of efflux pumps, has however not been extensively examined. The objective of this study was to establish whether there is a link between antibiotic resistance in potential gastrointestinal pathogens and reduced sensitivity of these organisms to commonly used household antimicrobial agents. In this study, tetracycline and ofloxacin sensitive and resistant Escherichia coli (9 strains) and Salmonella spp. (8 strains) were isolated from poultry and clinical samples. In order to assess whether these bacteria had active efflux pumps, ethidium bromide accumulation assays were performed. Extrusion of the active components of three commercial household agents (triclosan, sodium salicylate, and ortho-phenylphenol) by efflux pumps was tested using spectrophotometric accumulation assays. In order to simulate the kitchen environment, in-use disinfectant testing using the commercial household agents was performed to determine changes in their efficacy due to antibiotic resistance. Active efflux pump activity and extrusion of all three active ingredients was observed only in the antibiotic resistant organisms. The antibiotic sensitive bacteria were also more susceptible than the resistant isolates to the household antimicrobial agents at concentrations below that recommended by the manufacturer. These resistant bacteria could potentially be selected for and result in hard to treat infections. PMID:17126442

  16. Simultaneous BVI noise and vibration reduction in rotorcraft using actively-controlled flaps and including performance considerations

    NASA Astrophysics Data System (ADS)

    Patt, Daniel A.

    This work presents the development and application of an active control approach for reduction of both vibration and noise induced by helicopter rotor blade vortex interaction (BVI). Control is implemented through single or dual actively controlled flaps (ACFs) on each blade. Low-speed helicopter flight is prone to severe BVI, resulting in elevated vibration and noise levels. Existing research has suggested that when some form of active control is used to reduce vibration, noise will increase and vice versa. The present research achieves simultaneous reduction of noise and vibration, and also investigates the physical sources of the observed reduction. The initial portion of this work focused on developing a tool for simulating helicopter noise and vibrations in the BVI flight regime. A method for predicting compressible unsteady blade surface pressure distribution on rotor blades was developed and combined with an enhanced free-wake model and an acoustic prediction tool with provisions for blade flexibility. These elements were incorporated within an aeroelastic analysis featuring fully coupled flap-lag-torsional blade dynamics. Subsequently, control algorithms were developed that were effective for reducing noise and vibration even in the nonlinear BVI flight regime; saturation limits were incorporated constraining flap deflections to specified limits. The resulting simulation was also validated with a wide range of experimental data, achieving excellent correlation. Finally, a number of active control studies were performed. Multi-component vibration reductions of 40--80% could be achieved, while incurring a small noise penalty. Noise was reduced using an onboard feedback microphone; reductions of 4--10 dB on the advancing side were observed on a plane beneath the rotor when using dual flaps. Finally, simultaneous noise and vibration reduction was studied. A reduction of about 5 dB in noise on the advancing side combined with a 60% reduction in vibration was

  17. 5-N-Substituted-2-(substituted benzenesulphonyl) glutamines as antitumor agents. Part II: synthesis, biological activity and QSAR study.

    PubMed

    Samanta, Soma; Srikanth, K; Banerjee, Suchandra; Debnath, Bikash; Gayen, Shovanlal; Jha, Tarun

    2004-03-15

    Cancer is a major killer disease throughout human history. Thus, cancer becomes a major point of interest in life science. It was proved that cancer is a nitrogen trap and tumor cells are avid glutamine consumers. The non-essential amino acid glutamine, which is a glutamic acid derivative, supplies its amide nitrogen to tumor cells in the biosynthesis of purine and pyrimidine bases of nucleic acids as well as takes part in protein synthesis. Based on these and in continuation of our composite programme of development of new potential anticancer agents through rational drug design, 17 new 5-N-Substituted-2-(substituted benzenesulphonyl) glutamines were selected for synthesis. These compounds as well as 36 earlier synthesized glutamine analogues were screened for antitumor activity using percentage inhibition of tumor cell count as the activity parameter. QSAR study was performed with 53 compounds in order to design leads with increased effectiveness for antitumor activity using both physicochemical and topological parameters. QSAR study showed that steric effect on the aromatic ring is conducive to the activity. n-butyl substitution on aliphatic side chain and atom no 12 is important for antitumor activity of glutamine analogues. PMID:15018914

  18. Reversal of the biological activity of Escherichia coli heat-stable enterotoxin by disulfide-reducing agents.

    PubMed Central

    ElDeib, M M; Dove, C R; Parker, C D; Veum, T L; Zinn, G M; White, A A

    1986-01-01

    Various disulfide-reducing agents, mostly thiols and thiol precursors, were examined for their ability to reduce the disulfide bonds in the Escherichia coli heat-stable enterotoxin STa; reduction of the bonds results in loss of biological activity. The biological activity measured was the stimulation of guanylate cyclase in pig intestinal brush border membranes by STa. Nearly all of the compounds inactivated STa, although at different rates; a smaller number appreciably decreased guanylate cyclase activity when they were introduced into the reaction mixture after STa bound to its receptor. With dithiothreitol, the decrease in reaction rate was both time and concentration dependent and resulted in a reversal to basal activity. The anionic thiols were relatively ineffective in reversing activation, the neutral monothiols were moderately effective, and the aminothiols and neutral dithiols were the most effective. The order of effectiveness of the compounds was S-2-(3-aminopropylamino)ethanethiol greater than 2,3-dimercaptopropanol = 2-aminoethylisothiuronium bromide greater than dithiothreitol greater than 2-mercaptoethylamine greater than alpha-thioglycerol. These compounds were used in weanling pig ligated-intestinal-loop bioassays to determine if STa-induced secretion was reduced when they were injected 20 min after the STa. Instead of S-2-(3-aminopropylamino)ethanethiol we used the phosphorylated derivative S-2-(3-aminopropylamino)ethylphosphorothioic acid; this compound and 2,3-dimercaptopropanol were the only compounds that reduced STa-induced secretion and had no direct secretory or pathological effects. PMID:2867044

  19. Structure-activity relationship for Fe(III)-salen-like complexes as potent anticancer agents.

    PubMed

    Ghanbari, Zahra; Housaindokht, Mohammad R; Izadyar, Mohammad; Bozorgmehr, Mohammad R; Eshtiagh-Hosseini, Hossein; Bahrami, Ahmad R; Matin, Maryam M; Khoshkholgh, Maliheh Javan

    2014-01-01

    Quantitative structure activity relationship (QSAR) for the anticancer activity of Fe(III)-salen and salen-like complexes was studied. The methods of density function theory (B3LYP/LANL2DZ) were used to optimize the structures. A pool of descriptors was calculated: 1497 theoretical descriptors and quantum-chemical parameters, shielding NMR, and electronic descriptors. The study of structure and activity relationship was performed with multiple linear regression (MLR) and artificial neural network (ANN). In nonlinear method, the adaptive neuro-fuzzy inference system (ANFIS) was applied in order to choose the most effective descriptors. The ANN-ANFIS model with high statistical significance (R (2) train = 0.99, RMSE = 0.138, and Q (2) LOO = 0.82) has better capability to predict the anticancer activity of the new compounds series of this family. Based on this study, anticancer activity of this compound is mainly dependent on the geometrical parameters, position, and the nature of the substituent of salen ligand. PMID:24955417

  20. Structure-Activity Relationship for Fe(III)-Salen-Like Complexes as Potent Anticancer Agents

    PubMed Central

    Ghanbari, Zahra; Housaindokht, Mohammad R.; Izadyar, Mohammad; Bozorgmehr, Mohammad R.; Eshtiagh-Hosseini, Hossein; Bahrami, Ahmad R.; Matin, Maryam M.; Khoshkholgh, Maliheh Javan

    2014-01-01

    Quantitative structure activity relationship (QSAR) for the anticancer activity of Fe(III)-salen and salen-like complexes was studied. The methods of density function theory (B3LYP/LANL2DZ) were used to optimize the structures. A pool of descriptors was calculated: 1497 theoretical descriptors and quantum-chemical parameters, shielding NMR, and electronic descriptors. The study of structure and activity relationship was performed with multiple linear regression (MLR) and artificial neural network (ANN). In nonlinear method, the adaptive neuro-fuzzy inference system (ANFIS) was applied in order to choose the most effective descriptors. The ANN-ANFIS model with high statistical significance (R2train = 0.99, RMSE = 0.138, and Q2LOO = 0.82) has better capability to predict the anticancer activity of the new compounds series of this family. Based on this study, anticancer activity of this compound is mainly dependent on the geometrical parameters, position, and the nature of the substituent of salen ligand. PMID:24955417

  1. In vitro and in vivo antifungal activities of D0870, a new triazole agent.

    PubMed Central

    Yamada, H; Tsuda, T; Watanabe, T; Ohashi, M; Murakami, K; Mochizuki, H

    1993-01-01

    In vitro and in vivo antifungal activities of D0870 were evaluated in comparison with those of fluconazole. D0870, which is the R-enantiomer of ICI195,739, was found to be the mycologically active enantiomer by comparing the activities of D0870 with those of M16355 (S-enantiomer of ICI195,739). D0870 showed a broad spectrum of antifungal activity and MICs and minimum antibiotic concentrations 4- to 2,000-fold lower in synthetic amino acid medium (fungal) agar than those of fluconazole for various fungi. Although MICs of D0870 were affected by variation of the test conditions, such as type of medium, inoculum size of fungi, supplementation with fetal bovine serum, and pH of medium, they were consistently much lower than those of fluconazole under any condition. In vivo activities of D0870 in the systemic infection models with Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in normal mice and in the mice immunosuppressed with cyclophosphamide or cortisone acetate were 2- to 7-fold and 3- to 89-fold greater than those of fluconazole, respectively. In these infection models in immunosuppressed mice, the therapeutic efficacy of D0870 was almost equivalent to that in normal mice, whereas the efficacy of fluconazole was 2- to 50-fold lower than that in normal mice. PMID:8285626

  2. Synthesis, cytotoxic activity evaluation and HQSAR study of novel isosteviol derivatives as potential anticancer agents.

    PubMed

    Liu, Cong-Jun; Yu, Shu-Ling; Liu, Yan-Ping; Dai, Xing-Jie; Wu, Ya; Li, Rui-Jun; Tao, Jing-Chao

    2016-06-10

    A series of novel isosteviol derivatives bearing amino alcohol and thiourea fragments have been stereo-selectively synthesized and screened for their in vitro cytotoxic activities against three human cancer cell lines (HCT-116, HGC-27 and JEKO-1). The results demonstrated that these compounds exhibited prominent cytotoxicities. Especially, the compound Iw displayed the most potent anticancer activities against HCT-116 cell with IC50 value of 1.450 μM. On the basis of this bioassay results, these derivatives were further investigated by the hologram quantitative structure-activity relationship (HQSAR) technique. The optimal HQSAR model with q(2) = 0.663, r(2) = 0.895, SEE = 0.179 was generated using A/B/H/Ch as fragment distinction parameters and 4-7 as fragment size. This model was employed to predict the cytotoxic activities of test set compounds, and the predicted values were in good agreement with the experimental results. The contribution maps derived from the optimal model explained the individual atomic contribution to the total activity of single molecule. PMID:26994841

  3. Modulation of transglutaminase activity in mononuclear phagocytes and macrophage-like tumor cell lines by differentiation agents

    SciTech Connect

    Goldman, R.

    1987-01-01

    The effect of glucocorticosteroids, retinoids, 1,25-dihydroxyvitamin D/sub 3/ (1,25(OH)/sub 2/D/sub 3/) and the tumor promoter phorbol myristate acetate (TPA) on the expression of transglutaminase activity in in vitro differentiating bone marrow-derived mouse and rat mononuclear phagocytes (BMDMP) and mouse and human myeloid leukemia cell lines was assessed. Dexamethasone was found to induce an increase of about 100% in transglutaminase activity in mouse and rat BMDMP. The effect was time- and dose-dependent, and specific for steroids with glucocorticoid activity. Retinoic acid (RA) suppressed transglutaminase activity in mouse BMDMP and enhanced it in rat BMDMP. In murine and human myeloid leukemia cell lines, dexamethasone enhanced transglutaminase activity to a varying degree, RA suppressed it in P388D1 cells and enhanced it in the other cell lines. 1,25(OH)/sub 2/D/sub 3/ induced a rather small augmentation of enzyme expression, whereas TPA suppressed enzyme expression (70-100%). The species-specific differences previously observed by the authors for the effect of RA, dexamethasone and 1,25(OH)/sub 2/D/sub 3/ on the formation of BMDMP from mouse and rat bone marrow progenitor cells are now shown to extend also to effects on expression of transglutaminase activity. From a mechanistic point of view it is of interest that dexamethasone uniformly enhanced transglutaminase activity, whereas TPA suppressed it. The data suggest that modulation of transglutaminase activity by the four agents occurs via disparate mechanisms.

  4. MIC and time-kill studies of antipneumococcal activity of GV 118819X (sanfetrinem) compared with those of other agents.

    PubMed

    Spangler, S K; Jacobs, M R; Appelbaum, P C

    1997-01-01

    Agar dilution MIC methodology was used to test the activities of GV 118819X (sanfetrinem), ampicillin, amoxicillin, amoxicillin-clavulanate, cefpodoxime, loracarbef, levofloxacin, clarithromycin, ceftriaxone, imipenem, and vancomycin against 53 penicillin-susceptible, 84 penicillin-intermediate and 74 penicillin-resistant pneumococci isolated in the United States. GV 118819X was the most active oral beta-lactam, with MIC at which 50% of the isolates were inhibited (MIC50)/MIC90 values of 0.008/0.03, 0.06/0.5, and 0.5/1.0 micrograms/ml against penicillin-susceptible, -intermediate, and -resistant stains, respectively. Amoxicillin and amoxicillin in the presence of clavulanate (2:1) were the second most-active oral beta-lactams, followed by ampicillin and cefpodoxime; loracarbef was not active against penicillin-intermediate and -resistant strains. Clarithromycin was most active against penicillin-susceptible strains but was less active against intermediate and resistant stains. All pneumococcal stains were inhibited by ceftriaxone and imipenem at MICs of < or = 4.0 and < or = 1.0 micrograms/ml, respectively. The activities of levofloxacin and vancomycin were unaffected by penicillin susceptibility. Time-kill studies of three penicillin-susceptible, three penicillin-intermediate, and three penicillin-resistant pneumococci showed that all compounds, at the broth microdilution MIC, yielded 99.9% killing of all strains after 24 h. Kinetic patterns of all oral beta-lactams, ceftriaxone, and vancomycin were similar relative to the MIC, with 90% killing of all strains first observed after 12 h. However, killing by amoxicillin-clavulanate, imipenem, and levofloxacin was slightly faster and that by clarithromycin was slower than that by the above-described drugs. At 2 x the MIC, more strains were killed earlier than was the case at the MIC, but the pattern seen at the MIC prevailed. When MICs and kill kinetics were combined, sanfetrinem was the most active oral

  5. Ex Vivo Activity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

    PubMed Central

    Chaorattanakawee, Suwanna; Lon, Chanthap; Saunders, David L.; Rutvisuttinunt, Wiriya; Yingyuen, Kritsanai; Bathurst, Ian; Ding, Xavier C.; Tyner, Stuart D.

    2014-01-01

    Novel synthetic endoperoxides are being evaluated as new components of artemisinin combination therapies (ACTs) to treat artemisinin-resistant Plasmodium falciparum malaria. We conducted blinded ex vivo activity testing of fully synthetic (OZ78 and OZ277) and semisynthetic (artemisone, artemiside, artesunate, and dihydroartemisinin) endoperoxides in the histidine-rich protein 2 enzyme-linked immunosorbent assay against 200 P. falciparum isolates from areas of artemisinin-resistant malaria in western and northern Cambodia in 2009 and 2010. The order of potency and geometric mean (GM) 50% inhibitory concentrations (IC50s) were as follows: artemisone (2.40 nM) > artesunate (8.49 nM) > dihydroartemisinin (11.26 nM) > artemiside (15.28 nM) > OZ277 (31.25 nM) > OZ78 (755.27 nM). Ex vivo activities of test endoperoxides positively correlated with dihydroartemisinin and artesunate. The isolates were over 2-fold less susceptible to dihydroartemisinin than the artemisinin-sensitive P. falciparum W2 clone and showed sensitivity comparable to those with test endoperoxides and artesunate, with isolate/W2 IC50 susceptibility ratios of <2.0. All isolates had P. falciparum chloroquine resistance transporter mutations, with negative correlations in sensitivity to endoperoxides and chloroquine. The activities of endoperoxides (artesunate, dihydroartemisinin, OZ277, and artemisone) significantly correlated with that of the ACT partner drug, mefloquine. Isolates had mutations associated with clinical resistance to mefloquine, with 35% prevalence of P. falciparum multidrug resistance gene 1 (pfmdr1) amplification and 84.5% occurrence of the pfmdr1 Y184F mutation. GM IC50s for mefloquine, lumefantrine, and endoperoxides (artesunate, dihydroartemisinin, OZ277, OZ78, and artemisone) correlated with pfmdr1 copy number. Given that current ACTs are failing potentially from reduced sensitivity to artemisinins and partner drugs, newly identified mutations associated with artemisinin resistance

  6. The effectiveness and cost-effectiveness of erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating cancer treatment-induced anaemia (including review of technology appraisal no. 142): a systematic review and economic model.

    PubMed Central

    Crathorne, Louise; Huxley, Nicola; Haasova, Marcela; Snowsill, Tristan; Jones-Hughes, Tracey; Hoyle, Martin; Briscoe, Simon; Coelho, Helen; Long, Linda; Medina-Lara, Antonieta; Mujica-Mota, Ruben; Napier, Mark; Hyde, Chris

    2016-01-01

    BACKGROUND Anaemia is a common side effect of cancer treatments and can lead to a reduction in quality of life. Erythropoiesis-stimulating agents (ESAs) are licensed for use in conjunction with red blood cell transfusions to improve cancer treatment-induced anaemia (CIA). OBJECTIVE To investigate the effectiveness and cost-effectiveness of ESAs in anaemia associated with cancer treatment (specifically chemotherapy). DATA SOURCES The following databases were searched from 2004 to 2013: The Cochrane Library, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, British Nursing Index, Health Management Information Consortium, Current Controlled Trials and ClinicalTrials.gov. The US Food and Drug Administration and European Medicines Agency websites were also searched. Bibliographies of included papers were scrutinised for further potentially includable studies. REVIEW METHODS The clinical effectiveness review followed principles published by the NHS Centre for Reviews and Dissemination. Randomised controlled trials (RCTs), or systematic reviews of RCTs, of ESAs (epoetin or darbepoetin) for treating people with CIA were eligible for inclusion in the review. Comparators were best supportive care, placebo or other ESAs. Anaemia- and malignancy-related outcomes, health-related quality of life (HRQoL) and adverse events (AEs) were evaluated. When appropriate, data were pooled using meta-analysis. An empirical health economic model was developed comparing ESA treatment with no ESA treatment. The model comprised two components: one evaluating short-term costs and quality-adjusted life-years (QALYs) (while patients are anaemic) and one evaluating long-term QALYs. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS Of 1457 titles and abstracts screened, 23 studies assessing ESAs within their licensed

  7. Hydroxypyridonate chelating agents

    DOEpatents

    Raymond, Kenneth N.; Scarrow, Robert C.; White, David L.

    1987-01-01

    Chelating agents having 1-hydroxy-2-pyridinone (HOPO) and related moieties incorporated within their structures, including polydentate HOPO-substituted polyamines such as spermidine and spermine, and HOPO-substituted desferrioxamine. The chelating agents are useful in selectively removing certain cations from solution, and are particularly useful as ferric ion and actinide chelators. Novel syntheses of the chelating agents are provided.

  8. Agents of Possibility: Examining the Intersections of Art, Education, and Activism in Communities

    ERIC Educational Resources Information Center

    Campana, Alina

    2011-01-01

    Some art educators working in communities exemplify an alternative to the more common and stereotypical notion of the artist as autonomous, self-focused, and neutral. They view artmaking and education as vehicles for social justice and, in some cases, for social and political activism. In these broader social functions, the boundaries between art,…

  9. Organized Agents: Canadian Teacher Unions as Alternative Sites for Social Justice Activism

    ERIC Educational Resources Information Center

    Rottmann, Cindy

    2008-01-01

    Historically teachers' federations have been some of the major organizational sites for social justice leadership in K-12 public education. Despite this history of activism, social justice teacher unionism remains a relatively underdeveloped concept. This article merges four philosophical conceptions of social justice in education: liberal…

  10. ROS-Responsive Activatable Photosensitizing Agent for Imaging and Photodynamic Therapy of Activated Macrophages

    PubMed Central

    Kim, Hyunjin; Kim, Youngmi; Kim, In-Hoo; Kim, Kyungtae; Choi, Yongdoo

    2014-01-01

    The optical properties of macrophage-targeted theranostic nanoparticles (MacTNP) prepared from a Chlorin e6 (Ce6)-hyaluronic acid (HA) conjugate can be activated by reactive oxygen species (ROS) in macrophage cells. MacTNP are nonfluorescent and nonphototoxic in their native state. However, when treated with ROS, especially peroxynitrite, they become highly fluorescent and phototoxic. In vitro cell studies show that MacTNP emit near-infrared (NIR) fluorescence inside activated macrophages. The NIR fluorescence is quenched in the extracellular environment. MacTNP are nontoxic in macrophages up to a Ce6 concentration of 10 μM in the absence of light. However, MacTNP become phototoxic upon illumination in a light dose-dependent manner. In particular, significantly higher phototoxic effect is observed in the activated macrophage cells compared to human dermal fibroblasts and non-activated macrophages. The ROS-responsive MacTNP, with their high target-to-background ratio, may have a significant potential in selective NIR fluorescence imaging and in subsequent photodynamic therapy of atherosclerosis with minimum side effects. PMID:24396511

  11. Comparison of the antibacterial activity of chelating agents using the agar diffusion method

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The agar diffusion assay was used to examine antibacterial activity of 2 metal chelators. Concentrations of 0 to 40 mM of ethylenediaminetetraacetic acid (EDTA) and ethylenediamine-N,N’-disuccinic acid (EDDS) were prepared in 1.0 M potassium hydroxide (KOH). The pH of the solutions was adjusted to 1...

  12. STRUCTURE-ACTIVITY APPROACHES IN THE SCREENING OF ENVIRONMENTAL AGENTS FOR DEVELOPMENTAL TOXICITY

    EPA Science Inventory

    In drug development, SARs are an integral part of the process of finding efficacious and non-toxic analogues, and in vitro test systems which detect the biological activity of a particular chemical class have found an important role in SAR research. n contrast, SARs are not a pri...

  13. Ready, Steady, Action: What Enables Young People to Perceive Themselves as Active Agents in Their Lives?

    ERIC Educational Resources Information Center

    Sharp, Russell

    2014-01-01

    Government and educational priorities place importance on young people of secondary school age being active, having their voices heard, and participating in their community. This paper explores an understanding of the role of agency in young people's lives and how the concept is developing. Young people who perceive themselves as having…

  14. Synthesis and structure-activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents.

    PubMed

    Gao, Chao; Ye, Ting-Hong; Wang, Ning-Yu; Zeng, Xiu-Xiu; Zhang, Li-Dan; Xiong, Ying; You, Xin-Yu; Xia, Yong; Xu, Ying; Peng, Cui-Ting; Zuo, Wei-Qiong; Wei, Yuquan; Yu, Luo-Ting

    2013-09-01

    N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001 μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study. PMID:23886691

  15. Inuloxins A-D and derivatives as antileishmanial agents: structure-activity relationship study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inuloxins A-D (1-4) and a-costic acid (5), the phytotoxic compounds previously isolated from Inula viscosa, as well as synthetic derivatives of inuloxin A (compounds 6-10), inuloxin C (compound 11) and inuloxin D (compound 12) were tested in vitro for their activity against Leishmania donovani, the ...

  16. Creation of catalytically active particles from enzymes crosslinked with a natural bifunctional agent--homocysteine thiolactone.

    PubMed

    Stroylova, Yulia Y; Semenyuk, Pavel I; Asriyantz, Regina A; Gaillard, Cedric; Haertlé, Thomas; Muronetz, Vladimir I

    2014-09-01

    The current study describes an approach to creation of catalytically active particles with increased stability from enzymes by N-homocysteinylation, a naturally presented protein modification. Enzymatic activities and properties of two globular tetrameric enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase (LDH) were studied before and after N-homocysteinylation. Modification of these proteins concerns the accessible lysine residues and introduces an average of 2-2,5 homocysteine residues per protein monomer. Formation of a range of aggregates was observed for both enzymes, which assemble via formation of intermolecular noncovalent bonds and by disulfide bonds. It was demonstrated that both studied enzymes retain their catalytic activities on modification and the subsequent formation of oligomeric forms. At low concentrations of homocysteine thiolactone, modification of GAPDH leads not only to prevention of spontaneous inactivation but also increases thermal stability of this enzyme on heating to 80°C. A moderate reduction of the activity of GAPDH observed in case of its crosslinking with 50-fold excess of homocysteine thiolactone per lysine is probably caused by hindered substrate diffusion. Spherical particles of 100 nm and larger diameters were observed by transmission electron microscopy and atomic force microscope techniques after modification of GAPDH with different homocysteine thiolactone concentrations. In case of LDH, branched fibril-like aggregates were observed under the same conditions. Interestingly, crosslinked samples of both proteins were found to have reversible thermal denaturation profiles, indicating that modification with homocysteine thiolactone stabilizes the spatial structure of these enzymes. PMID:24912753

  17. Anti-infective activities of lactobacillus strains in the human intestinal microbiota: from probiotics to gastrointestinal anti-infectious biotherapeutic agents.

    PubMed

    Liévin-Le Moal, Vanessa; Servin, Alain L

    2014-04-01

    A vast and diverse array of microbial species displaying great phylogenic, genomic, and metabolic diversity have colonized the gastrointestinal tract. Resident microbes play a beneficial role by regulating the intestinal immune system, stimulating the maturation of host tissues, and playing a variety of roles in nutrition and in host resistance to gastric and enteric bacterial pathogens. The mechanisms by which the resident microbial species combat gastrointestinal pathogens are complex and include competitive metabolic interactions and the production of antimicrobial molecules. The human intestinal microbiota is a source from which Lactobacillus probiotic strains have often been isolated. Only six probiotic Lactobacillus strains isolated from human intestinal microbiota, i.e., L. rhamnosus GG, L. casei Shirota YIT9029, L. casei DN-114 001, L. johnsonii NCC 533, L. acidophilus LB, and L. reuteri DSM 17938, have been well characterized with regard to their potential antimicrobial effects against the major gastric and enteric bacterial pathogens and rotavirus. In this review, we describe the current knowledge concerning the experimental antibacterial activities, including antibiotic-like and cell-regulating activities, and therapeutic effects demonstrated in well-conducted, placebo-controlled, randomized clinical trials of these probiotic Lactobacillus strains. What is known about the antimicrobial activities supported by the molecules secreted by such probiotic Lactobacillus strains suggests that they constitute a promising new source for the development of innovative anti-infectious agents that act luminally and intracellularly in the gastrointestinal tract. PMID:24696432

  18. Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines.

    PubMed

    Dasari, Ramesh; De Carvalho, Annelise; Medellin, Derek C; Middleton, Kelsey N; Hague, Frédéric; Volmar, Marie N M; Frolova, Liliya V; Rossato, Mateus F; De La Chapa, Jorge J; Dybdal-Hargreaves, Nicholas F; Pillai, Akshita; Kälin, Roland E; Mathieu, Véronique; Rogelj, Snezna; Gonzales, Cara B; Calixto, João B; Evidente, Antonio; Gautier, Mathieu; Munirathinam, Gnanasekar; Glass, Rainer; Burth, Patricia; Pelly, Stephen C; van Otterlo, Willem A L; Kiss, Robert; Kornienko, Alexander

    2015-10-20

    Many types of cancer, including glioma, melanoma, non-small cell lung cancer (NSCLC), among others, are resistant to proapoptotic stimuli and thus poorly responsive to current therapies based on the induction of apoptosis in cancer cells. The current investigation describes the synthesis and anticancer evaluation of unique C12-Wittig derivatives of polygodial, a sesquiterpenoid dialdehyde isolated from Persicaria hydropiper (L.) Delabre. These compounds were found to undergo an unprecedented pyrrole formation with primary amines in a chemical model system, a reaction that could be relevant in the biological environment and lead to the pyrrolation of lysine residues in the target proteins. The anticancer evaluation of these compounds revealed their promising activity against cancer cells displaying various forms of drug resistance, including resistance to proapoptotic agents. Mechanistic studies indicated that compared to the parent polygodial, which displays fixative general cytotoxic action against human cells, the C12-Wittig derivatives exerted their antiproliferative action mainly through cytostatic effects explaining their activity against apoptosis-resistant cancer cells. The possibility for an intriguing covalent modification of proteins through a novel pyrrole formation reaction, as well as useful activities against drug resistant cancer cells, make the described polygodial-derived chemical scaffold an interesting new chemotype warranting thorough investigation. PMID:26360047

  19. Anti-Infective Activities of Lactobacillus Strains in the Human Intestinal Microbiota: from Probiotics to Gastrointestinal Anti-Infectious Biotherapeutic Agents

    PubMed Central

    Liévin-Le Moal, Vanessa

    2014-01-01

    SUMMARY A vast and diverse array of microbial species displaying great phylogenic, genomic, and metabolic diversity have colonized the gastrointestinal tract. Resident microbes play a beneficial role by regulating the intestinal immune system, stimulating the maturation of host tissues, and playing a variety of roles in nutrition and in host resistance to gastric and enteric bacterial pathogens. The mechanisms by which the resident microbial species combat gastrointestinal pathogens are complex and include competitive metabolic interactions and the production of antimicrobial molecules. The human intestinal microbiota is a source from which Lactobacillus probiotic strains have often been isolated. Only six probiotic Lactobacillus strains isolated from human intestinal microbiota, i.e., L. rhamnosus GG, L. casei Shirota YIT9029, L. casei DN-114 001, L. johnsonii NCC 533, L. acidophilus LB, and L. reuteri DSM 17938, have been well characterized with regard to their potential antimicrobial effects against the major gastric and enteric bacterial pathogens and rotavirus. In this review, we describe the current knowledge concerning the experimental antibacterial activities, including antibiotic-like and cell-regulating activities, and therapeutic effects demonstrated in well-conducted, placebo-controlled, randomized clinical trials of these probiotic Lactobacillus strains. What is known about the antimicrobial activities supported by the molecules secreted by such probiotic Lactobacillus strains suggests that they constitute a promising new source for the development of innovative anti-infectious agents that act luminally and intracellularly in the gastrointestinal tract. PMID:24696432

  20. The Influence of Organized Physical Activity (including Gymnastics) on Young Adult Skeletal Traits: Is Maturity Phase Important?

    PubMed Central

    Bernardoni, Brittney; Scerpella, Tamara A.; Rosenbaum, Paula F.; Kanaley, Jill A.; Raab, Lindsay N.; Li, Quefeng; Wang, Sijian; Dowthwaite, Jodi N.

    2015-01-01

    We prospectively evaluated adolescent organized physical activity (PA) as a factor in adult female bone traits. Annual DXA scans accompanied semi-annual records of anthropometry, maturity and PA for 42 participants in this preliminary analysis (criteria: appropriately timed DXA scans at ~1 year pre-menarche [predictor] and ~5 years post-menarche [dependent variable]). Regression analysis evaluated total adolescent inter-scan PA and PA over 3 maturity sub-phases as predictors of young adult bone outcomes: 1) bone mineral content (BMC), geometry and strength indices at non-dominant distal radius and femoral neck; 2) sub-head BMC; 3) lumbar spine BMC. Analyses accounted for baseline gynecological age (years pre- or post-menarche), baseline bone status, adult body size and inter-scan body size change. Gymnastics training was evaluated as a potentially independent predictor, but did not improve models for any outcomes (p<0.07). Pre-menarcheal bone traits were strong predictors of most adult outcomes (semi-partial r2 = 0.21-0.59, p≤0.001). Adult 1/3 radius and sub-head BMC were predicted by both total PA and PA 1-3 years post-menarche (p<0.03). PA 3-5 years post-menarche predicted femoral narrow neck width, endosteal diameter and buckling ratio (p<0.05). Thus, participation in organized physical activity programs throughout middle and high school may reduce lifetime fracture risk in females. PMID:25386845

  1. The Influence of Organized Physical Activity (Including Gymnastics) on Young Adult Skeletal Traits: Is Maturity Phase Important?

    PubMed

    Bernardoni, Brittney; Scerpella, Tamara A; Rosenbaum, Paula F; Kanaley, Jill A; Raab, Lindsay N; Li, Quefeng; Wang, Sijian; Dowthwaite, Jodi N

    2015-05-01

    We prospectively evaluated adolescent organized physical activity (PA) as a factor in adult female bone traits. Annual DXA scans accompanied semiannual records of anthropometry, maturity, and PA for 42 participants in this preliminary analysis (criteria: appropriately timed DXA scans at ~1 year premenarche [predictor] and ~5 years postmenarche [dependent variable]). Regression analysis evaluated total adolescent interscan PA and PA over 3 maturity subphases as predictors of young adult bone outcomes: 1) bone mineral content (BMC), geometry, and strength indices at nondominant distal radius and femoral neck; 2) subhead BMC; 3) lumbar spine BMC. Analyses accounted for baseline gynecological age (years pre- or postmenarche), baseline bone status, adult body size and interscan body size change. Gymnastics training was evaluated as a potentially independent predictor, but did not improve models for any outcomes (p > .07). Premenarcheal bone traits were strong predictors of most adult outcomes (semipartial r2 = .21-0.59, p ≤ .001). Adult 1/3 radius and subhead BMC were predicted by both total PA and PA 1-3 years postmenarche (p < .03). PA 3-5 years postmenarche predicted femoral narrow neck width, endosteal diameter, and buckling ratio (p < .05). Thus, participation in organized physical activity programs throughout middle and high school may reduce lifetime fracture risk in females. PMID:25386845

  2. Suppressive effects of anti-inflammatory agents on human endothelial cell activation and induction of heat shock proteins.

    PubMed Central

    Amberger, A.; Hala, M.; Saurwein-Teissl, M.; Metzler, B.; Grubeck-Loebenstein, B.; Xu, Q.; Wick, G.

    1999-01-01

    BACKGROUND: Studies from our laboratory have shown that the earliest stages of atherosclerosis may be mediated by an autoimmune reaction against heat shock protein 60 (Hsp60). The interactions of Hsp60-specific T cells with arterial endothelial cells (EC) require expression of both Hsp60 and certain adhesion molecules shown to be induced simultaneously in EC by mechanical and other types of stress. Recently, it was shown that suppression of T cell-mediated immune responses by cyclosporin A (CyA) enhanced atherosclerotic lesion formation in mice. In contrast, aspirin was found to lower the risk of myocardial infarction in men. These conflicting observations may be due to different effects of anti-inflammatory agents on adhesion molecule and Hsp expression in EC, respectively. MATERIAL AND METHODS: In the present study, we analyzed the effects of CyA, aspirin, and indomethacin on T cell proliferation using a proliferation assay. To explore the expression of adhesion molecules, monocyte chemoattractant protein-1 (MCP-1), and Hsp60 in human umbilical vein endothelial cells (HUVECs), Northern blot analyses were used. To examine the activation status of the transcription factors nuclear factor kappaB (NF-kappaB) and heat shock factor-1 (HSF-1), electrophoretic mobility shift assays were performed. RESULTS: With the exception of indomethacin, the used immunosuppressive and anti-inflammatory agents significantly inhibited T cell proliferation in response to influenza virus antigen in a dose-dependent manner. Interestingly, CyA and indomethacin did not suppress tumor necrosis factor-alpha (TNF-alpha)-induced adhesion molecule expression on HUVECs, whereas aspirin had an inhibitory effect. These observations correlated with the modulation of NF-kappaB activity in EC. All agents tested induced expression of Hsp60 6 hr after application. In addition, aspirin and indomethacin, but not CyA, induced Hsp70 expression in HUVECs that correlated with induction of HSF-1 activity

  3. The vascular disrupting agent STA-9584 exhibits potent antitumor activity by selectively targeting microvasculature at both the center and periphery of tumors.

    PubMed

    Foley, Kevin P; Zhou, Dan; Borella, Chris; Wu, Yaming; Zhang, Mei; Jiang, Jun; Li, Hao; Sang, Jim; Korbut, Tim; Ye, Josephine; Zhang, Xuemei; Barsoum, James; Sonderfan, Andrew J

    2012-11-01

    Vascular disrupting agents (VDAs) are an emerging class of therapeutics targeting the existing vascular network of solid tumors. However, their clinical progression has been hampered because of limited single-agent efficacy, primarily caused by the persistence of surviving cells at the well perfused "viable rim" of tumors, which allows rapid tumor regrowth to occur. In addition, off-target adverse events, including cardiovascular toxicities, underscore a need for compounds with improved safety profiles. Here, we characterize the mechanism of action, antitumor efficacy, and cardiovascular safety profile of (S)-2-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-3-phenylpropanamide hydrochloride (STA-9584), a novel tubulin-binding VDA. In vitro, 2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)aniline (STA-9122) (active metabolite of STA-9584) displayed increased potency relative to other tubulin-binding agents and was highly cytotoxic to tumor cells. STA-9584 induced significant tumor regressions in prostate and breast xenograft models in vivo and, in an aggressive syngeneic model, demonstrated superior tumor growth inhibition and a positive therapeutic index relative to combretastatin A-4 phosphate (CA4P). It is noteworthy that histological analysis revealed that STA-9584 disrupted microvasculature at both the center and periphery of tumors. Compared with CA4P, STA-9584 induced a 73% increase in central necrotic area, 77% decrease in microvasculature, and 7-fold increase in tumor cell apoptosis in the remaining viable rim 24 h post-treatment. Ultrasound imaging confirmed that STA-9584 rapidly and efficiently blocked blood flow in highly perfused tumor regions. Moreover, cardiovascular effects were evaluated in the Langendorff assay and telemetered dogs, and cardiovascular toxicity was not predicted to be dose-limiting. This bioactivity profile distinguishes STA-9584 from the combretastatin class and identifies the compound as a promising new

  4. Stimulatory Agents Simultaneously Improving the Production and Antioxidant Activity of Polyphenols from Inonotus obliquus by Submerged Fermentation.

    PubMed

    Xu, Xiangqun; Shen, Mengwei; Quan, Lili

    2015-07-01

    Polyphenols are important secondary metabolites from the edible and medicinal mushroom Inonotus obliquus. Both the rarity of I. obliquus fruit body and the low efficiency of current method of submerged fermentation lead to a low yield of polyphenols. This study was aimed to determine the effect of applying stimulatory agents to liquid cultured I. obliquus on the simultaneous accumulation of exo-polyphenols (EPC) and endo-polyphenols (IPC). Linoleic acid was the most effective out of the 17 tested stimulatory agents, the majority of which increased the EPC and IPC production. The result was totally different from the stimulatory effect of Tween 80 for polysaccharide production in previous studies. The addition of 1.0 g/L linoleic acid on day 0 resulted in 7-, 14-, and 10-fold of increase (p < 0.05) in the production of EPC extracted by ethyl acetate (EA-EPC), EPC extracted by n-butyl alcohol (NB-EPC), and IPC, and significantly increased the production of ferulic acid, gallic acid, epicatechin-3-gallate (ECG), epigallocatechin-3-gallate (EGCG), phelligridin G, inoscavin B, and davallialactone. The EA-EPC, BA-EPC, and IPC from the linoleic acid-containing medium had significantly (p < 0.05) stronger scavenging activity against 2,2-diphenyl-1-picrylhydrazyl radicals (DPPH), which was attributed to the higher content of these bioactive polyphenols. PMID:25951778

  5. Monitoring the effects of chelating agents and electrical fields on active forms of Pb and Zn in contaminated soil.

    PubMed

    Tahmasbian, Iman; Safari Sinegani, Ali Akbar

    2013-11-01

    The application of electrical fields and chelating agents is an innovative hybrid technology used for the decontamination of soil polluted by heavy metals. The effects of four center-oriented electrical fields and chelating agents on active fractions of lead and zinc were investigated in this pot experiment. Ethylenediaminetetraacetic acid (EDTA) as a synthetic chelator and cow manure extract (CME) and poultry manure extract (PME) as natural chelators were applied to the pots (2 g kg(-1)) 30 days after the first irrigation. Two weeks later, four center-oriented electrical fields were applied in each pot (in three levels of 0, 10, and 30 V) for 1 h each day for 14 days. The soil near the cathode and anodes was collected and analyzed as cathodic and anodic soil, respectively. Results indicated that the soluble-exchangeable fraction of lead and zinc were decreased in the cathodic soil, while the carbonate-bound fractions were increased. In the anodic soil, however, the opposite result was observed. EDTA enhanced the soluble-exchangeable form of the metals in both anodic and cathodic soils. Furthermore, the amounts of carbonate-bound heavy metals were increased by the application of CME in both soils. The organic-bound fraction of the metals was increased by the application of natural chelators, while electrical fields had no significant impacts on this fraction. PMID:23685981

  6. Highly Sensitive and Selective Immuno-capture/Electrochemical Assay of Acetylcholinesterase Activity in Red Blood Cells: A Biomarker of Exposure to Organophosphorus Pesticides and Nerve Agents

    SciTech Connect

    Chen, Aiqiong; Du, Dan; Lin, Yuehe

    2012-02-09

    Acetylcholinesterase (AChE) enzyme activity in red blood cells (RBCs) is a useful biomarker for biomonitoring of exposures to organophosphorus (OP) pesticides and chemical nerve agents. In this paper, we reported a new method for AChE activity assay based on selective immuno-capture of AChE from biological samples followed by enzyme activity assay of captured AChE using a disposable electrochemical sensor. The electrochemical sensor is based on multiwalled carbon nanotubes-gold nanocomposites (MWCNTs-Au) modified screen printed carbon electrode (SPCE). Upon the completion of immunoreaction, the target AChE (including active and inhibited) is captured onto the electrode surface and followed by an electrochemical detection of enzymatic activity in the presence of acetylthiocholine. A linear response is obtained over standard AChE concentration range from 0.1 to 10 nM. To demonstrate the capability of this new biomonitoring method, AChE solutions dosed with different concentration of paraoxon were used to validate the new AChE assay method. AChE inhibition in OP dosed solutions was proportional to its concentration from 0.2 to 50 nM. The new AChE activity assay method for biomonitoring of OP exposure was further validated with in-vitro paraoxon-dosed RBC samples. The established electrochemical sensing platform for AChE activity assay not only avoids the problem of overlapping substrate specificity with esterases by using selective antibody, but also eliminates potential interference from other electroactive species in biological samples. It offers a new approach for sensitive, selective, and rapid AChE activity assay for biomonitoring of exposures to OPs.

  7. Comparative antibacterial activity of silver nanoparticles synthesised by biological and chemical routes with pluronic F68 as a stabilising agent.

    PubMed

    Santos, Carolina Alves Dos; Seckler, Marcelo Martins; Ingle, Avinash P; Rai, Mahendra

    2016-08-01

    The authors report the comparative antibacterial activity of silver nanoparticles synthesised by biological (using Fusarium oxysporum) and chemical routes in the presence and absence of pluronic F68 as a stabilising agent. The production of silver nanoparticles was evidenced by UV-visible spectra, with absorbance at about 420 nm in the case of both biological and chemical synthesis. X-ray diffraction pattern confirmed the presence of face-centred cubic structure (FCC plane). The nanoparticles characterised by transmission and scanning electron microscopy showed spherical silver nanoparticles with size range of 5-40 and 10-70 nm in the case of biologically and chemically synthesised nanoparticles, respectively. Addition of pluronic F68 showed the stabilisation of silver nanoparticles. Antibacterial efficacy of silver nanoparticles demonstrated different inhibitory activity against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Overall, biologically synthesised silver nanoparticles showed higher activity as compared with chemically synthesised nanoparticles. Silver nanoparticles synthesised in the presence of pluronic F68 by the chemical route exhibited synergism in antibacterial activity as compared with those synthesised without pluronic F68. On the contrary, biogenic silver nanoparticles without pluronic F68 showed higher antibacterial potential. PMID:27463790

  8. High affinity and covalent-binding microtubule stabilizing agents show activity in chemotherapy-resistant acute myeloid leukemia cells

    PubMed Central

    Pera, Benet; Calvo-Vidal, M. Nieves; Ambati, Srikanth; Jordi, Michel; Kahn, Alissa; Díaz, J. Fernando; Fang, Weishuo; Altmann, Karl-Heinz; Cerchietti, Leandro; Moore, Malcolm A.S.

    2016-01-01

    Treatment failure in acute myeloid leukemia (AML) is frequently due to the persistence of a cell population resistant to chemotherapy through different mechanisms, in which drug efflux via ATP-binding cassette (ABC) proteins, specifically P-glycoprotein, is one of the most recognized. However, disappointing results from clinical trials employing inhibitors for these transporters have demonstrated the need to adopt different strategies. We hypothesized that microtubule targeting compounds presenting high affinity or covalent binding could overcome the effect of ABC transporters. We therefore evaluated the activity of the high-affinity paclitaxel analog CTX-40 as well as the covalent binder zampanolide (ZMP) in AML cells. Both molecules were active in chemosensitive as well as in chemoresistant cell lines overexpressing P-glycoprotein. Moreover, ZMP or CTX-40 in combination with daunorubicin showed synergistic killing without increased in vitro hematopoietic toxicity. In a primary AML sample, we further demonstrated that ZMP and CTX-40 are active in progenitor and differentiated leukemia cell populations. In sum, our data indicate that high affinity and covalent-binding anti-microtubule agents are active in AML cells otherwise chemotherapy resistant. PMID:26277539

  9. 49 CFR 40.355 - What limitations apply to the activities of service agents?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... (including, but not limited to, collections, laboratory testing, MRO, and SAP services). No one may do so on... in the transmission of individual SAP reports to the actual employer. That is, the SAP may not send... individual SAP summary reports and follow-up testing plans after they are sent to the DER, and the SAP...

  10. 49 CFR 40.355 - What limitations apply to the activities of service agents?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... (including, but not limited to, collections, laboratory testing, MRO, and SAP services). No one may do so on... in the transmission of individual SAP reports to the actual employer. That is, the SAP may not send... individual SAP summary reports and follow-up testing plans after they are sent to the DER, and the SAP...

  11. 49 CFR 40.355 - What limitations apply to the activities of service agents?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... (including, but not limited to, collections, laboratory testing, MRO, and SAP services). No one may do so on... in the transmission of individual SAP reports to the actual employer. That is, the SAP may not send... individual SAP summary reports and follow-up testing plans after they are sent to the DER, and the SAP...

  12. Long-acting contraceptive agents: structure activity relationships in a series of norethisterone and levonorgestrel esters.

    PubMed

    Bialy, G; Blye, R P; Enever, R P; Naqvi, R H; Lindberg, M C

    1983-03-01

    A large number of esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3-one) were synthesized and tested for biological activity. The test employed in these studies was the duration of estrus suppression in cycling mature rats. In the norethisterone series several esters exhibited duration of activity comparable to that of norethisterone enanthate. In the levonorgestrel series the butanoic, cyclobutylcarboxylic and cyclopropylcarboxylic esters were longer acting than medroxyprogesterone acetate (17 alpha-acetoxy-6 alpha-methylpregn-4-ene-3,20-dione) when prepared as aqueous microcrystalline suspensions. PMID:6419411

  13. The comparative activity of pefloxacin, enoxacin, ciprofloxacin and 13 other antimicrobial agents against enteropathogenic microorganisms.

    PubMed

    Vanhoof, R; Hubrechts, J M; Roebben, E; Nyssen, H J; Nulens, E; Leger, J; De Schepper, N

    1986-01-01

    In this study, we compared the activity of pefloxacin, enoxacin and ciprofloxacin against 269 enteropathogenic strains (Campylobacter jejuni, enteropathogenic Escherichia coli, Salmonella typhi, Shigella spp., Vibrio cholerae and Yersinia enterocolitica) with that of rosoxacin, flumequin, nifuroxazide, erythromycin, chloramphenicol, ampicillin, cefotaxime, tetracycline, amikacin, netilmicin, sulfamethoxazole, trimethoprim and co-trimoxazole. Pefloxacin, enoxacin and ciprofloxacin were always among the most active compounds. Furthermore, resistant strains or strains with elevated MIC values were not found. The MIC90 value for these three compounds was less than or equal to 0.25 mg/l, except for C. jejuni where it was 0.3 mg/l and 1.4 mg/l for pefloxacin and enoxacin, respectively. PMID:3546145

  14. In Vitro Activities of the New Antitubercular Agents PA-824 and BTZ043 against Nocardia brasiliensis

    PubMed Central

    Campos-Rivera, Mayra Paola; Gonzalez-Martinez, Norma Alejandra; Ocampo-Candiani, Jorge; Cole, Stewart T.

    2012-01-01

    The in vitro activity of PA-824 and BTZ043 against 30 Nocardia brasiliensis isolates was tested. The MIC50 and MIC90 values for PA-824 were both >64 μg/ml. The same values for BTZ043 were 0.125 and 0.250 μg/ml. Given the MIC values for benzothiazinone (BTZ) compounds, we consider them good candidates to be tested in vivo against N. brasiliensis. PMID:22526312

  15. In vitro activities of the new antitubercular agents PA-824 and BTZ043 against Nocardia brasiliensis.

    PubMed

    Vera-Cabrera, Lucio; Campos-Rivera, Mayra Paola; Gonzalez-Martinez, Norma Alejandra; Ocampo-Candiani, Jorge; Cole, Stewart T

    2012-07-01

    The in vitro activity of PA-824 and BTZ043 against 30 Nocardia brasiliensis isolates was tested. The MIC(50) and MIC(90) values for PA-824 were both >64 μg/ml. The same values for BTZ043 were 0.125 and 0.250 μg/ml. Given the MIC values for benzothiazinone (BTZ) compounds, we consider them good candidates to be tested in vivo against N. brasiliensis. PMID:22526312

  16. Mechanism of the antitumoral activity of deferasirox, an iron chelation agent, on mantle cell lymphoma.

    PubMed

    Vazana-Barad, Liat; Granot, Galit; Mor-Tzuntz, Rahav; Levi, Itai; Dreyling, Martin; Nathan, Ilana; Shpilberg, Ofer

    2013-04-01

    Mantle cell lymphoma (MCL) characterized by the t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression, is one of the most challenging lymphomas to treat. Iron chelators, such as deferasirox, have previously been shown to exhibit anti-proliferative properties; however, their effect on MCL cells has never been investigated. We showed that deferasirox exhibited antitumoral activity against the MCL cell lines HBL-2, Granta-519 and Jeko-1, with 50% inhibitory concentration (IC(50)) values of 7.99 ± 2.46 μM, 8.93 ± 2.25 μM and 31.86 ± 7.26 μM, respectively. Deferasirox induced apoptosis mediated through caspase-3 activation and decreased cyclin D1 protein levels resulting from increased proteasomal degradation. We also demonstrated down-regulation of phosphor-RB (Ser780) expression, which resulted in increasing levels of the E2F/RB complex and G(1)/S arrest. Finally, we showed that deferasirox activity was dependent on its iron chelating ability. The present data indicate that deferasirox, by down-regulating cyclin D1 and inhibiting its related signals, may constitute a promising adjuvant therapeutic molecule in the strategy for MCL treatment. PMID:23020673

  17. Liver δ-aminolevulinate dehydratase activity is inhibited by neonicotinoids and restored by antioxidant agents.

    PubMed

    Sauer, Elisa; Moro, Angela M; Brucker, Natália; Nascimento, Sabrina; Gauer, Bruna; Fracasso, Rafael; Gioda, Adriana; Beck, Ruy; Moreira, José C F; Eifler-Lima, Vera Lucia; Garcia, Solange Cristina

    2014-11-01

    Neonicotinoids represent the most used class of insecticides worldwide, and their precursor, imidacloprid, is the most widely marketed. The aim of this study was to evaluate the effect of imidacloprid on the activity of hepatic δ-aminolevulinate dehydratase (δ-ALA-D), protective effect of potential antioxidants against this potential effect and presence of chemical elements in the constitution of this pesticide. We observed that δ-ALA-D activity was significantly inhibited by imidacloprid at all concentrations tested in a dose-dependent manner. The IC50 value was obtained and used to evaluate the restoration of the enzymatic activity. δ-ALA-D inhibition was completely restored by addition of dithiotreitol (DTT) and partly by ZnCl2, demonstrating that the inhibition occurs by oxidation of thiol groups and by displacement of the Zn (II), which can be explained by the presence of chemical elements found in the constitution of pesticides. Reduced glutathione (GSH) had the best antioxidant effect against to δ-ALA-D inhibition caused by imidacloprid, followed by curcumin and resveratrol. It is well known that inhibition of the enzyme δ-ALA-D may result in accumulation of its neurotoxic substrate (δ-ALA), in this line, our results suggest that further studies are needed to investigate the possible neurotoxicity induced by neonicotinoids and the involvement of antioxidants in cases of poisoning by neonicotinoids. PMID:25402564

  18. Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor.

    PubMed

    Sahu, Ravi P; Ocana, Jesus A; Harrison, Kathleen A; Ferracini, Matheus; Touloukian, Christopher E; Al-Hassani, Mohammed; Sun, Louis; Loesch, Mathew; Murphy, Robert C; Althouse, Sandra K; Perkins, Susan M; Speicher, Paul J; Tyler, Douglas S; Konger, Raymond L; Travers, Jeffrey B

    2014-12-01

    Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation. PMID:25304264

  19. Pexa-Vec double agent engineered vaccinia: oncolytic and active immunotherapeutic.

    PubMed

    Breitbach, Caroline J; Parato, Kelley; Burke, James; Hwang, Tae-Ho; Bell, John C; Kirn, David H

    2015-08-01

    Oncolytic immunotherapies (OI) selectively infect, amplify within and destroy cancer cells, thereby representing a novel class of anti-cancer therapy. In addition to this primary mechanism-of-action (MOA), OI based on vaccinia have been shown to selectively target tumor-associated vasculature, triggering an acute reduction in tumor perfusion. This review focuses on a third complementary MOA for this product class: the induction of active immunotherapy. While the active immunotherapy approach has been validated by recent product approvals, the field is still faced with significant challenges. Tumors have evolved diverse mechanisms to hide from immune-mediated destruction. Here we hypothesize that oncolytic immunotherapy replication within tumors may tip the immune balance to allow for the effective induction and execution of adaptive anti-tumor immunity, resulting in long-term tumor control following OI clearance. This immune activation against the cancer can be augmented through OI 'arming' for the expression of immunostimulatory transgene products from the virus genome. With the first vaccinia OI (Pexa-Vec, thymidine kinase-inactivated vaccinia expressing Granulocyte-colony stimulating factor [GM-CSF]) now in advanced-stage clinical trials, it has become more important than ever to understand the complimentary MOA that contributes to tumor destruction and control in patients. PMID:25900822

  20. Phenylpropiophenone derivatives as potential anticancer agents: synthesis, biological evaluation and quantitative structure-activity relationship study.

    PubMed

    Ivković, Branka M; Nikolic, Katarina; Ilić, Bojana B; Žižak, Željko S; Novaković, Radmila B; Čudina, Olivera A; Vladimirov, Sote M

    2013-05-01

    Series of twelve chalcone and propafenone derivatives has been synthesized and evaluated for anticancer activities against HeLa, Fem-X, PC-3, MCF-7, LS174 and K562 cell lines. The 2D-QSAR and 3D-QSAR studies were performed for all compounds with cytotoxic activities against each cancer cell line. Partial least squares (PLS) regression has been applied for selection of the most relevant molecular descriptors and QSAR models building. Predictive potentials of the created 2D-QSAR and 3D-QSAR models for each cell line were compared, by use of leave-one-out cross-validation and external validation, and optimal QSAR models for each cancer cell line were selected. The QSAR studies have selected the most significant molecular descriptors and pharmacophores of the chalcone and propafenone derivatives and proposed structures of novel chalcone and propafenone derivatives with enhanced anticancer activity on the HeLa, Fem-X, PC-3, MCF-7, LS174 and K562 cells. PMID:23501110

  1. Influence of bulking agents and microbial activator on thermophilic aerobic transformation of sewage sludge.

    PubMed

    Pasda, N; Limtong, P; Oliver, R; Montange, D; Panichsakpatana, S

    2005-10-01

    Bangkok, while improving the wastewater treatment in order to alleviate the river pollution, faces important amounts of sewage sludge. The sewage sludge contains organic matter, nitrogen and phosphorus available for plant growth. However, it may contain pathogenic microorganisms. To be used for agricultural purposes, these pathogens should be destroyed, which can be achieved with the thermophilic phase of composting. As the sewage sludge is dense and unable to compost alone (low C/N ratio), it should be mixed with an organic by-product. Two by-products available in large quantities in Thailand (wood chips and rice husk) have been tested for mixture with sewage sludge. As these products are not easy to decompose (presence of silica in rice husk and lignin/tannins in wood chips), the addition of a microbial activator for composting has been tested in controlled conditions (small quantities of organic mixtures, 55 degrees C, moisture maintained at 60-70% of water holding capacity). The monitoring of the decomposition has been made by measuring the carbon dioxide respiration, pH, organic matter and nitrogen contents and the evolution of enzymatic activities. When mixed with sewage sludge, wood chips and rice husk do not show significant differences concerning decomposition after 63 days. The use of an activator within the experimental conditions does not improve the decomposition of organic matter contained in the mixture of sewage sludge and rice husk or wood chips. PMID:16342535

  2. Liver δ-Aminolevulinate Dehydratase Activity is Inhibited by Neonicotinoids and Restored by Antioxidant Agents

    PubMed Central

    Sauer, Elisa; Moro, Angela M.; Brucker, Natália; Nascimento, Sabrina; Gauer, Bruna; Fracasso, Rafael; Gioda, Adriana; Beck, Ruy; Moreira, José C. F.; Eifler-Lima, Vera Lucia; Garcia, Solange Cristina

    2014-01-01

    Neonicotinoids represent the most used class of insecticides worldwide, and their precursor, imidacloprid, is the most widely marketed. The aim of this study was to evaluate the effect of imidacloprid on the activity of hepatic δ-aminolevulinate dehydratase (δ-ALA-D), protective effect of potential antioxidants against this potential effect and presence of chemical elements in the constitution of this pesticide. We observed that δ-ALA-D activity was significantly inhibited by imidacloprid at all concentrations tested in a dose-dependent manner. The IC50 value was obtained and used to evaluate the restoration of the enzymatic activity. δ-ALA-D inhibition was completely restored by addition of dithiotreitol (DTT) and partly by ZnCl2, demonstrating that the inhibition occurs by oxidation of thiol groups and by displacement of the Zn (II), which can be explained by the presence of chemical elements found in the constitution of pesticides. Reduced glutathione (GSH) had the best antioxidant effect against to δ-ALA-D inhibition caused by imidacloprid, followed by curcumin and resveratrol. It is well known that inhibition of the enzyme δ-ALA-D may result in accumulation of its neurotoxic substrate (δ-ALA), in this line, our results suggest that further studies are needed to investigate the possible neurotoxicity induced by neonicotinoids and the involvement of antioxidants in cases of poisoning by neonicotinoids. PMID:25402564

  3. Activation of a chloroplast type of fructose bisphosphatase from Chlamydomonas reinhardtii by light-mediated agents

    NASA Technical Reports Server (NTRS)

    Huppe, H. C.; Buchanan, B. B.

    1989-01-01

    A chloroplast type of fructose-1,6-bisphosphatase, a central regulatory enzyme of photosynthetic carbon metabolism, has been partially purified from Chlamydomonas reinhardtii. Unlike its counterpart from spinach chloroplasts, the algal FBPase showed a strict requirement for a dithiol reductant irrespective of Mg2+ concentration. The enzymes from the two sources resembled each other immunologically, in subunit molecular mass and response to pH. In the presence of dithiothreitol, the pH optimum for both the algal and spinach enzymes shifted from 8.5 to a more physiologic value of 8.0 as the Mg2+ concentration was increased from 1 to 16 mM. At 1 mM Mg2+, a concentration estimated to be close to physiological, the Chlamydomonas FBPase was active only in the presence of reduced thioredoxin and was most active with Chlamydomonas thioredoxin f. Under these conditions, the enzyme showed a pH optimum of 8.0. The data suggest that the Chlamydomonas enzyme resembles its spinach counterpart in most respects, but it has a stricter requirement for reduction and less strict reductant specificity. A comparison of the properties of the FBPases from Chlamydomonas and spinach will be helpful for elucidating the mechanism of the reductive activation of this enzyme.

  4. Agent Orange

    MedlinePlus

    ... Index Agent Orange Agent Orange Home Facts about Herbicides Veterans' Diseases Birth Defects Benefits Exposure Locations Provider ... millions of gallons of Agent Orange and other herbicides on trees and vegetation during the Vietnam War. ...

  5. Short-Range Temporal Interactions in Sleep; Hippocampal Spike Avalanches Support a Large Milieu of Sequential Activity Including Replay.

    PubMed

    Mahoney, J Matthew; Titiz, Ali S; Hernan, Amanda E; Scott, Rod C

    2016-01-01

    Hippocampal neural systems consolidate multiple complex behaviors into memory. However, the temporal structure of neural firing supporting complex memory consolidation is unknown. Replay of hippocampal place cells during sleep supports the view that a simple repetitive behavior modifies sleep firing dynamics, but does not explain how multiple episodes could be integrated into associative networks for recollection during future cognition. Here we decode sequential firing structure within spike avalanches of all pyramidal cells recorded in sleeping rats after running in a circular track. We find that short sequences that combine into multiple long sequences capture the majority of the sequential structure during sleep, including replay of hippocampal place cells. The ensemble, however, is not optimized for maximally producing the behavior-enriched episode. Thus behavioral programming of sequential correlations occurs at the level of short-range interactions, not whole behavioral sequences and these short sequences are assembled into a large and complex milieu that could support complex memory consolidation. PMID:26866597

  6. Short-Range Temporal Interactions in Sleep; Hippocampal Spike Avalanches Support a Large Milieu of Sequential Activity Including Replay

    PubMed Central

    Mahoney, J. Matthew; Titiz, Ali S.; Hernan, Amanda E.; Scott, Rod C.

    2016-01-01

    Hippocampal neural systems consolidate multiple complex behaviors into memory. However, the temporal structure of neural firing supporting complex memory consolidation is unknown. Replay of hippocampal place cells during sleep supports the view that a simple repetitive behavior modifies sleep firing dynamics, but does not explain how multiple episodes could be integrated into associative networks for recollection during future cognition. Here we decode sequential firing structure within spike avalanches of all pyramidal cells recorded in sleeping rats after running in a circular track. We find that short sequences that combine into multiple long sequences capture the majority of the sequential structure during sleep, including replay of hippocampal place cells. The ensemble, however, is not optimized for maximally producing the behavior-enriched episode. Thus behavioral programming of sequential correlations occurs at the level of short-range interactions, not whole behavioral sequences and these short sequences are assembled into a large and complex milieu that could support complex memory consolidation. PMID:26866597

  7. Spectrum of antimicrobial activity and user acceptability of the hand disinfectant agent Sterillium Gel.

    PubMed

    Kampf, G; Rudolf, M; Labadie, J-C; Barrett, S P

    2002-10-01

    The antimicrobial efficacy of alcohol-based hand gels has been shown to be significantly less than liquid hand rubs probably because of a lower concentration of alcohol. Sterillium Gel is the first hand gel with 85% ethanol. Its antimicrobial efficacy and user acceptability was studied. Bactericidal activity was tested according to prEN 12054 against Staphylococcus aureus, Enterococcus hirae, Pseudomonas aeruginosa and Escherichia coli (suspension test) and EN 1500 (15 volunteers; four replicates), fungicidal activity according to EN 1275 against Candida albicans and spores of Aspergillus niger (suspension test) and tuberculocidal activity against Mycobacterium terrae using the DGHM suspension test. Virucidal activity was determined in suspension tests based on reduction of infectivity with and without interfering substances (10% fetal calf serum; 0.3% erythrocytes and 0.3% bovine serum albumin). Ninety-six healthcare workers in hospitals in France and the UK used the gel for four weeks and assessed it by filling out a questionnaire. The gel was bactericidal (a reduction factor of > 10(5)-fold), tuberculocidal (reduction factor > 10(5)) and fungicidal (reduction factor > 10(4)) in 30 s. Irrespective of interfering substances the gel inactivated orthopoxvirus and herpes simplex virus type 1 and 2 in 15 s, adenovirus in 2 min, poliovirus in 3 min and papovavirus in 15 min by a factor of > 10(4)-fold. Rotavirus and human immunodeficiency virus were inactivated in 30 s (without interfering substances). Under practical use conditions it was as effective in 30 s as the reference alcohol in 60 s. Most users described the tackiness, aggregation, skin feeling after use and smell as positive or acceptable. A total of 65.6% assessed the new gel to be better than a comparator irrespective of its type (gel or liquid). Overall Sterillium Gel had a unique spectrum of antimicrobial activity. It is probably the first alcohol-based hand gel to pass EN 1500 in 30 s. Due to the

  8. Product and rate determinations with chemically activated nucleotides in the presence of various prebiotic materials, including other mono- and polynucleotides

    NASA Technical Reports Server (NTRS)

    Kanavarioti, A.; Alberas, D. J.; Rosenbach, M. T.; Bernasconi, C. F.; Chang, S.

    1991-01-01

    We are investigating the reactions of ImpN's in the presence of a number of prebiotically plausible materials, such as metal ions, phosphate, amines and other nucleotides and hope to learn more about the stability/reactivity of ImpN's in a prebiotic aqueous environment. We find that, in the presence of phosphate, ImpN's form substantial amounts of diphosphate nucleotides. These diphosphate nucleotides are not very good substrates for template directed reactions, but are chemically activated and are known to revert to the phosphoimidazolides in the presence of imidazole under solid state conditions. With respect to our studies of the oligomerization reaction, the determination of the dimerization rate constant of a specific ImpN (guanosine 5'-phospho 2 methylimidazolide) both in the absence and the presence of the template leads to the conclusion that at 37 C the dimerization is not template directed, although the subsequent polymerization steps are. In other words, this specific polynucleotide synthesizing system favors the elongation of oligonucleotides as compared with the formation of dimers and trimers. This favoring of the synthesis of long as opposed to short oligonucleotides may be regarded as a rudimentary example of natural selection at the molecular level.

  9. Structure-activity predictions of properties of organophosphorus pesticides and chemical agents important for optical detection. Master`s thesis

    SciTech Connect

    Porte, R.E.

    1995-12-01

    This thesis presents the results of an investigation for estimating various physicochemical properties of chemical warfare agents and organophosphorus pesticides. The determination of aqueous solubility, - octanol/water partition coefficients, and alkaline hydrolysis rate constants will be used in the development of a chemical sensor using fiber optic spectroscopy. These three parameters will effect the limit of detection for each compound by limiting the concentration in the detector. The parameters were estimated by linear free energy relationships and quantitative structure activity relationships using experimental data for compounds of similar chemical structure. The results of this thesis showed that the hydrophobic medium represented by 1-octanol did concentrate the OP pesticides but did not significantly concentrate CWA, CWA simulants, or CWA hydrolysis products. Correlations were evaluated for six classes of organophosphorus compounds. The limitation of this approach to predicting physicochemical parameters is not in the molecular descriptors used in the regression equations but in the availability of existing experimental data.

  10. Activities of oral and parenteral agents against penicillin-susceptible and -resistant pneumococci.

    PubMed

    Pankuch, G A; Visalli, M A; Jacobs, M R; Appelbaum, P C

    1995-07-01

    This study examined bacteriostatic and bactericidal activities of oral and parenteral antibiotics for penicillin-susceptible and intermediately and fully penicillin-resistant pneumococci. beta-Lactamase inhibitors did not affect beta-lactam results. The activities of ampicillin, amoxicillin +/- clavulanate, WY-49605, cefuroxime, cefpodoxime, cefdinir, cefixime, and cefaclor against two penicillin-susceptible, two intermediately penicillin-resistant, and two fully penicillin-resistant pneumococcal strains were tested. For all three groups, bacteriostatic values of amoxicillin and WY-49605 were lower than were those of other beta-lactams tested. Of the cephalosporins, cefdinir, cefuroxime, and cefpodoxime yielded the lowest bacteriostatic values. All beta-lactams were bactericidal (reduced original counts by > or = 3 log10 CFU/ml) at 1 dilution above bacteriostatic values, except for cefpodoxime (bactericidal at 2 dilutions above bacteriostatic values for one susceptible strain and one intermediately resistant strain), cefuroxime (bactericidal at 2 dilutions above bacteriostatic values for one intermediately resistant strain), and ampicillin (bactericidal at 2 dilutions above bacteriostatic values for one intermediately resistant strain). The activities of piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftriaxone, ceftazidime, and ciprofloxacin against four penicillin-susceptible, two intermediately penicillin-resistant, and four fully penicillin-resistant pneumococcal strains were evaluated. Bacteriostatic values of piperacillin, ampicillin, and ceftriaxone for all groups were lower than were those of ticarcillin and ceftazidime. Bacteriostatic values of ciprofloxacin were unaffected by penicillin susceptibility. All beta-lactams were bactericidal at 1 dilution above the bacteriostatic value, except for piperacillin (bactericidal at 2 dilutions above the bacteriostatic value for one intermediately

  11. Effect of mixed antimicrobial agents and flavors in active packaging films.

    PubMed

    Gutiérrez, Laura; Escudero, Ana; Batlle, Ramón; Nerín, Cristina

    2009-09-23

    Active packaging is an emerging food technology to improve the quality and safety of food products. Many works have been developed to study the antimicrobial activity of essential oils. Essential oils have been traditionally used as flavorings in food, so they have an important odor impact but they have as well antimicrobial properties that could be used to protect the food. Recent developments in antimicrobial active packaging showed the efficiency of essential oils versus bread and bakery products among other applications. However, one of the main problems to face is the odor and taste they could provide to the packaged food. Using some aromas to mask the odor could be a good approach. That is why the main objective of this paper is to develop an antimicrobial packaging material based on the combination of the most active compounds of essential oils (hydrocinnamaldehyde, oregano essential oil, cinnamaldehyde, thymol, and carvacrol) together with some aromas commonly used in the food industry. A study of the concentration required to get the antimicrobial properties, the organoleptic compatibility with typical aroma present in many food systems (vanilla, banana, and strawberry), and the right combination of both systems has been carried out. Antimicrobial tests of both the mentioned aromas, the main components of some essential oils, and the combination of both groups were carried out against bacteria (Enterococcus faecalis, Listeria monocytogenes, Bacillus cereus, Staphylococcus aureus, Salmonella choleraesuis, Yersinia enterocolitica, Escherichia coli), yeasts (Candida albicans, Debaryomyces hansenii, Zygosaccharomyces rouxii), and molds (Botrytis cinerae, Aspergillus flavus, Penicillium roqueforti, Eurotium repens, Penicillium islandicum, Penicillium commune, Penicillium nalgiovensis). The sensory properties of the combinations were evaluated with a triangular test and classification was by an order test; the odor threshold of the aroma compounds was also

  12. Lipid composition and sensitivity of Prototheca wickerhamii to membrane-active antimicrobial agents.

    PubMed Central

    Sud, I J; Feingold, D S

    1979-01-01

    The lipid composition of Prototheca wickerhamii ATCC 16529 is presented and discussed in relation to the unique susceptibility of the organism to drugs of three membrane-active antimicrobial classes: the polyenes, the polymyxins, and the imidazoles. The presence of ergosterol in the neutral lipid fraction of the membrane is likely responsible for the exquisite susceptibility to amphotericin B. The presence of a large quantity of free fatty acids in the membrane appears responsible for imidazole susceptibility. The membrane determinants of polymyxin B susceptibility are less well defined. PMID:518077

  13. [Effect of nootropic agents on impulse activity of cerebral cortex neurons].

    PubMed

    Iasnetsov, V V; Pravdivtsev, V A; Krylova, I N; Kozlov, S B; Provornova, N A; Ivanov, Iu V; Iasnetsov, V V

    2001-01-01

    The effect of nootropes (semax, mexidol, and GVS-111) on the activity of individual neurons in various cerebral cortex regions was studied by microelectrode and microionophoresis techniques in cats immobilized by myorelaxants. It was established that the inhibiting effect of mexidol upon neurons in more than half of cases is prevented or significantly decreased by the GABA antagonists bicuculline and picrotoxin. The inhibiting effect of semax and GVS-111 upon neurons in more than half of cases is related to stimulation of the M-choline and NMDA receptors, respectively. PMID:11871233

  14. Antistaphylococcal Activity of Oritavancin and Its Synergistic Effect in Combination with Other Antimicrobial Agents

    PubMed Central

    Lin, Gengrong; Pankuch, Glenn; Appelbaum, Peter C.

    2014-01-01

    Oritavancin exhibited in vitro activity against 169 strains of vancomycin-susceptible, methicillin-resistant Staphylococcus aureus (MRSA) with MICs ranging from 0.03 to 1 μg/ml and against vancomycin-intermediate MRSA (VISA; n = 29), heterogeneous vancomycin-intermediate MRSA (hVISA; n = 5), and vancomycin-resistant MRSA (n = 5) strains, with MICs ranging from 0.12 to 4 μg/ml. For 10 MRSA isolates comprising 5 VISA and 5 hVISA strains, synergy between oritavancin and gentamicin, linezolid, or rifampin was observed against most of the strains tested using a time-kill method. PMID:25022588

  15. Selective Non-nucleoside Inhibitors of Human DNA Methyltransferases Active in Cancer Including in Cancer Stem Cells

    PubMed Central

    2015-01-01

    DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line. PMID:24387159

  16. Chimeric Beta-Defensin Analogs, Including the Novel 3NI Analog, Display Salt-Resistant Antimicrobial Activity and Lack Toxicity in Human Epithelial Cell Lines

    PubMed Central

    Scudiero, Olga; Galdiero, Stefania; Nigro, Ersilia; Del Vecchio, Luigi; Di Noto, Rosa; Cantisani, Marco; Colavita, Irene; Galdiero, Massimiliano; Cassiman, Jean-Jacques; Daniele, Aurora; Pedone, Carlo

    2013-01-01

    Human beta-defensins (hBDs) are crucial peptides for the innate immune response and are thus prime candidates as therapeutic agents directed against infective diseases. Based on the properties of wild-type hBD1 and hBD3 and of previously synthesized analogs (1C, 3I, and 3N), we have designed a new analog, 3NI, and investigated its potential as an antimicrobial drug. Specifically, we evaluated the antimicrobial activities of 3NI versus those of hBD1, hBD3, 1C, 3I, and 3N. Our results show that 3NI exerted greater antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecalis than did hBD1 and hBD3, even with elevated salt concentrations. Moreover, its antiviral activity against herpes simplex virus 1 was greater than that of hBD1 and similar to that of hBD3. Subsequently, we investigated the cytotoxic effects of all peptides in three human epithelial carcinoma cell lines: A549 from lung, CaCo-2 from colon, and Capan-1 from pancreas. None of the analogs significantly reduced cell viability versus wild-type hBD1 and hBD3. They did not induce genotoxicity or cause an increase in the number of apoptotic cells. Using confocal microscopy, we also investigated the localization of the peptides during their incubation with epithelial cells and found that they were distributed on the cell surface, from which they were internalized. Finally, we show that hBD1 and hBD3 are characterized by high resistance to serum degradation. In conclusion, the new analog 3NI seems to be a promising anti-infective agent, particularly given its high salt resistance—a feature that is relevant in diseases such as cystic fibrosis. PMID:23357761

  17. The Influence of Surface-Active Agent on the Micro-Morphology and Crystallinity of Spherical Hexagonal Boron Nitride.

    PubMed

    Zhang, Ning; Liu, Huan; Kan, Hongmin; Wang, Xiaoyang; Long, Haibo; Zhou, Yonghui

    2015-08-01

    This search used the low-cost boric acid and borax as a source of boron, urea as a nitrogen source, surface-active agent Dodecyl benzenesulfonic acid (SDBS) as a dispersant, and thus prepared different micro-morphology and crystallinity hexagonal boron nitride powders under a flowing ammonia atmosphere at a nitriding temperature of 900 °C. The effect of the surface-active agent (SDBS) content on the crystallinity and micro-morphology of hexagonal boron nitride powders was studied, and the corresponding relationship between micro-morphology and crystallinity was explored. The results showed that under a certain synthetic process (900 °C for 3 h), the surfactant content had affected the crystallinity and micro-morphology of h-BN powders. Without the added surfactant, the graphitization index (GI) was 3.61, and micro-morphology of h-BN powders. was spherical, the distribution of ball diameters was uneven, and there was also significant particle agglomeration, with some particles even exhibiting adhesion, sintering necks, and high sphericity and diameter. When the added SDBS percentages were 2%, 4% and 6%, the graphitization index (GI) decreased to 2.98, 2.58 and 2.41 respectively: the corresponding crystallinity improved significantly. When the surfactant SDBS content was higher (10%), the diameter distribution of the h-BN powders was even, but there was evidence of agglomeration of particles and particle adhesion. The crystallinity decreased when the GI value was increased to 4. When the surfactant SDBS content was 6%, the dispersion of h-BN powders was at its optimum, and the particle size distribution was at its most uniform. Meanwhile the GI value was at its lowest, and the crystallinity at its highest. PMID:26369229

  18. Design, Synthesis, and Structure–Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents

    PubMed Central

    2013-01-01

    Cycloxygenase-2 (COX-2) is an attractive target for molecular imaging because it is an inducible enzyme that is expressed in response to inflammatory and proliferative stimuli. Recently, we reported that conjugation of indomethacin with carboxy-X-rhodamine dyes results in the formation of effective, targeted, optical imaging agents able to detect COX-2 in inflammatory tissues and premalignant and malignant tumors (Uddin et al. Cancer Res. 2010, 70, 3618–3627). The present paper summarizes the details of the structure–activity relationship (SAR) studies performed for lead optimization of these dyes. A wide range of fluorescent conjugates were designed and synthesized, and each of them was tested for the ability to selectively inhibit COX-2 as the purified protein and in human cancer cells. The SAR study revealed that indomethacin conjugates are the best COX-2-targeted agents compared to the other carboxylic acid-containing nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors (COXIBs). An n-butyldiamide linker is optimal for tethering bulky fluorescent functionalities onto the NSAID or COXIB cores. The activity of conjugates also depends on the size, shape, and electronic properties of the organic fluorophores. These reagents are taken up by COX-2-expressing cells in culture, and the uptake is blocked by pretreatment with a COX inhibitor. In in vivo settings, these reagents become highly enriched in COX-2-expressing tumors compared to surrounding normal tissue, and they accumulate selectively in COX-2-expressing tumors as compared with COX-2-negative tumors grown in mice. Thus, COX-2-targeted fluorescent inhibitors are useful for preclinical and clinical detection of lesions containing elevated levels of COX-2. PMID:23488616

  19. In Vitro Activity of Quaternary Ammonium Surfactants against Streptococcal, Chlamydial, and Gonococcal Infective Agents.

    PubMed

    Inácio, Ângela S; Nunes, Alexandra; Milho, Catarina; Mota, Luís Jaime; Borrego, Maria J; Gomes, João P; Vaz, Winchil L C; Vieira, Otília V

    2016-06-01

    Quaternary ammonium compounds (QAC) are widely used, cheap, and chemically stable disinfectants and topical antiseptics with wide-spectrum antimicrobial activities. Within this group of compounds, we recently showed that there are significant differences between the pharmacodynamics of n-alkyl quaternary ammonium surfactants (QAS) with a short (C12) alkyl chain when in vitro toxicities toward bacterial and mammalian epithelial cells are compared. These differences result in an attractive therapeutic window that justifies studying short-chain QAS as prophylactics for sexually transmitted infections (STI) and perinatal vertically transmitted urogenital infections (UGI). We have evaluated the antimicrobial activities of short-chain (C12) n-alkyl QAS against several STI and UGI pathogens as well as against commensal Lactobacillus species. Inhibition of infection of HeLa cells by Neisseria gonorrhoeae and Chlamydia trachomatis was studied at concentrations that were not toxic to the HeLa cells. We show that the pathogenic bacteria are much more susceptible to QAS toxic effects than the commensal vaginal flora and that QAS significantly attenuate the infectivity of N. gonorrhoeae and C. trachomatis without affecting the viability of epithelial cells of the vaginal mucosa. N-Dodecylpyridinium bromide (C12PB) was found to be the most effective QAS. Our results strongly suggest that short-chain (C12) n-alkyl pyridinium bromides and structurally similar compounds are promising microbicide candidates for topical application in the prophylaxis of STI and perinatal vertical transmission of UGI. PMID:26976875

  20. Bioactive bilayered dressing for compromised epidermal tissue regeneration with sequential activity of complementary agents.

    PubMed

    Reyes-Ortega, Felisa; Cifuentes, Alberto; Rodríguez, Gema; Aguilar, María Rosa; González-Gómez, Álvaro; Solis, Raul; García-Honduvilla, Natalio; Buján, Julia; García-Sanmartin, Josune; Martínez, Alfredo; Román, Julio San

    2015-09-01

    The article deals with the design, preparation, and evaluation of a new bilayered dressing for application in the healing of compromised wounds. The system is based on the sequential release of two complementary bioactive components to enhance the activation of the regeneration of dermal tissue. The internal layer is a highly hydrophilic and biodegradable film of gelatin and hyaluronic acid (HG), crosslinked with the natural compound genipin, which reacts with the amine groups of gelatin. This film is loaded with the proangiogenic, anti-inflammatory, and antibacterial peptide, proadrenomedullin N-terminal 20 peptide (PAMP), that is released slowly in the wound site. The external layer, more stable and less hydrophilic, is constituted by a biodegradable polyurethane derived from poly(caprolactone) and pluronic L61. This layer is loaded with resorbable nanoparticles of bemiparin (a fractionated low molecular weight heparin), which promotes the activation of growth factors, FGF and VEGF, and provides a good biomechanical stability and controlled permeability of the bilayered dressing. Experiments carried out in mice demonstrate the excellent angiogenic effect of the HG film in the dermal tissue. Application of the bilayered dressing in the wound healing rabbit ear model shows an improved cicatrization of the wound in both ischemic and non-ischemic defects, favoring epithelialization and reducing noticeably the contraction and the inflammation. PMID:26022967

  1. Synthesis and characterization of novel organocobaloximes as potential catecholase and antimicrobial activity agents.

    PubMed

    Erdem-Tuncmen, Mukadder; Karipcin, Fatma; Sariboga, Bahtiyar

    2013-10-01

    An asymmetric, potentially bidentate dioxime ligand (H₂L) was formed by condensation of 4-biphenylchloroglyoxime and napthyl-1-amine. Two equivalents of H₂L were reacted with CoCl₂  · 6H₂O under appropriate conditions with deprotonation of the dioxime ligand. A series of new organocobaloxime derivatives of the type [CoR(HL)₂Py], [CoRL₂PyB₂F₄], and [CoRL₂Py(Cu(phen))₂] (H₂L = 4-(napthyl-1-amino)biphenylglyoxime; phen = 1,10-phenathroline; R = izopropyl and benzyl; Py = pyridine) were synthesized. The products were characterized by elemental analysis, molar conductance, FT-IR, ¹H NMR, and magnetic susceptibility measurements. Catecholase-like activity properties of all complexes were also studied. All complexes are catalysts for the oxidation of 3,5-di-tert-butylcatechol to 3,5-di-tert-butyl-1,2-benzoquinone in methanol. Antimicrobial activity studies of H₂L and the six complexes were carried out on standard strains (human pathogenic) of bacteria (Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Bacillus cereus, Enterococcus faecalis, Streptococcus pneumoniae, Listeria monocytogenes, Bacillus subtilis, Escherichia coli, Pseudominas aeruginosa, Salmonella typhi) and the yeast Candida albicans. The compounds showed a significant inhibition of the growth of the Gram-positive bacteria tested. Among the tested microorganisms, S. aureus was the most sensitive strain, especially to H₂L and its complexes. PMID:24003018

  2. Synthesis, Docking and Biological Activities of Novel Hybrids Celecoxib and Anthraquinone Analogs as Potent Cytotoxic Agents

    PubMed Central

    Almutairi, Maha S.; Hegazy, Gehan H.; Haiba, Mogedda E.; Ali, Hamed I.; Khalifa, Nagy M.; Soliman, Abd El-mohsen M.

    2014-01-01

    Herein, novel hybrid compounds of celecoxib and 2-aminoanthraquinone derivatives have been synthesized using condensation reactions of celecoxib with 2-aminoanthraquinone derivatives or 2-aminoanthraquinon with celecoxib derivatives. Celecoxib was reacted with different acid chlorides, 2-chloroethylisocyanate and bis (2-chloroethyl) amine hydrochloride. These intermediates were then reacted with 2-aminoanthraquinone. Also the same different acid chlorides and 2-chloroethylisocyanate were reacted with 2-aminoanthraquinone and the resulting intermediates were reacted with celecoxib to give isomers for the previous compounds. The antitumor activities against hepatic carcinoma tumor cell line (HEPG2) have been investigated in vitro, and all these compounds showed promising activities, especially compound 3c, 7, and 12. Flexible docking studies involving AutoDock 4.2 was investigated to identify the potential binding affinities and the mode of interaction of the hybrid compounds into two protein tyrosine kinases namely, SRC (Pp60v-src) and platelet-derived growth factor receptor, PDGFR (c-Kit). The compounds in this study have a preferential affinity for the c-Kit PDGFR PTK over the non-receptor tyrosine kinase SRC (Pp60v-src). PMID:25490139

  3. Synergistic antitumor activities of sepantronium bromide (YM155), a survivin suppressant, in combination with microtubule-targeting agents in triple-negative breast cancer cells.

    PubMed

    Kaneko, Naoki; Yamanaka, Kentaro; Kita, Aya; Tabata, Kenji; Akabane, Takafumi; Mori, Masamichi

    2013-01-01

    Triple-negative breast cancer (TNBC) has a poor prognosis compared to other subtypes, and effective treatment options are limited to cytotoxic agents, including microtubule-targeting agents, due to the lack of molecular targets. Here, we examined the combined effect of sepantronium bromide (YM155) and microtubule-targeting agents in TNBC models. The combination of YM155 with docetaxel showed synergistic antiproliferative and caspase 3/7-inducing effects in MRK-nu-1 and MDA-MB-453 human TNBC cell lines in vitro. YM155 also synergistically enhanced the efficacies of other microtubule-targeting agents, including paclitaxel and vinorelbine, which induced accumulation of survivin at the G2/M phase, whereas it did not affect the efficacy of doxorubicin. Combination treatment with YM155 and microtubule-targeting agents decreased the accumulation of survivin at the G2/M phase and induced greater apoptosis than either single agent alone. Further, combination treatment with YM155 and docetaxel also had a synergistic antitumor effect, achieving complete regression without exacerbation of body weight loss in all mice, in a MRK-nu-1 human TNBC xenograft model. These results suggest that survivin inhibition synergistically sensitize human TNBC cells to microtubule-targeting agents. PMID:24432379

  4. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89.

    PubMed

    Faletto, M B; Miller, W H; Garvey, E P; St Clair, M H; Daluge, S M; Good, S S

    1997-05-01

    The anabolism of 1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, a selective inhibitor of human immunodeficiency virus (HIV), was characterized in human T-lymphoblastoid CD4+ CEM cells. 1592U89 was ultimately anabolized to the triphosphate (TP) of the guanine analog (-)-carbovir (CBV), a potent inhibitor of HIV reverse transcriptase. However, less than 2% of intracellular 1592U89 was converted to CBV, an amount insufficient to account for the CBV-TP levels observed. 1592U89 was anabolized to its 5'-monophosphate (MP) by the recently characterized enzyme adenosine phosphotransferase, but neither its diphosphate (DP) nor its TP was detected. The MP, DP, and TP of CBV were found in cells incubated with either 1592U89 or CBV, with CBV-TP being the major phosphorylated species. We confirmed that CBV is phosphorylated by 5'-nucleotidase and that mycophenolic acid increased the formation of CBV-TP from CBV 75-fold. However, mycophenolic acid did not stimulate 1592U89 anabolism to CBV-TP. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) did not inhibit CBV-TP formation from CBV or 1592U89, whereas the adenylate deaminase inhibitor 2'-deoxycoformycin selectively inhibited 1592U89 anabolism to CBV-TP and reversed the antiviral activity of 1592U89. 1592U89-MP was not a substrate for adenylate deaminase but was a substrate for a distinct cytosolic deaminase that was inhibited by 2'-deoxycoformycin-5'-MP. Thus, 1592U89 is phosphorylated by adenosine phosphotransferase to 1592U89-MP, which is converted by a novel cytosolic enzyme to CBV-MP. CBV-MP is then further phosphorylated to CBV-TP by cellular kinases. This unique activation pathway enables 1592U89 to overcome the pharmacokinetic and toxicological deficiencies of CBV while maintaining potent and selective anti-HIV activity. PMID:9145876

  5. Challenge testing the lactoperoxidase system against a range of bacteria using different activation agents.

    PubMed

    Fweja, L W T; Lewis, M J; Grandison, A S

    2008-07-01

    Lactoperoxidase (LP) exerts antimicrobial effects in combination with H(2)O(2) and either thiocyanate (SCN(-)) or a halide (e.g., I(-)). Garlic extract in the presence of ethanol has also been used to activate the LP system. This study aimed to determine the effects of 3 LP activation systems (LP+SCN(-)+H(2)O(2); LP+I(-)+H(2)O(2); LP + garlic extract + ethanol) on the growth and activity of 3 test organisms (Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus cereus). Sterilized milk was used as the reaction medium, and the growth pattern of the organisms and a range of keeping quality (KQ) indicators (pH, titratable acidity, ethanol stability, clot on boiling) were monitored during storage at the respective optimum growth temperature for each organism. The LP+I(-)+ H(2)O(2) system reduced bacterial counts below the detection limit shortly after treatment for all 3 organisms, and no bacteria could be detected for the duration of the experiment (35 to 55 h). The KQ data confirmed that the milk remained unspoiled at the end of the experiments. The LP + garlic extract + ethanol system, on the other hand, had no effect on the growth or KQ with P. aeruginosa, but showed a small retardation of growth of the other 2 organisms, accompanied by small increases (5 to 10 h) in KQ. The effects of the LP+SCN(-)+H(2)O(2) system were intermediate between those of the other 2 systems and differed between organisms. With P. aeruginosa, the system exerted total inhibition within 10 h of incubation, but the bacteria regained viability after a further 5 h, following a logarithmic growth curve. This was reflected in the KQ indicators, which implied an extension of 15 h. With the other 2 bacterial species, LP+SCN(-)+H(2)O(2) exerted an obvious inhibitory effect, giving a lag phase in the growth curve of 5 to 10 h and KQ extension of 10 to 15 h. When used in combination, I(-) and SCN(-) displayed negative synergy. PMID:18565914

  6. A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

    PubMed Central

    Hingorani, Dina V.; Montano, Luis A.; Randtke, Edward A.; Lee, Yeon Sun; Cárdenas-Rodríguez, Julio; Pagel, Mark D.

    2016-01-01

    CatalyCEST MRI can detect enzyme activity by monitoring the change in chemical exchange with water after a contrast agent is cleaved by an enzyme. Often these molecules use paramagnetic metals and are delivered with an additional non-responsive reference molecule. To improve this approach for molecular imaging, a single diamagnetic agent with enzyme-responsive and enzyme-unresponsive CEST signals was synthesized and characterized. The CEST signal from the aryl amide disappeared after cleavage of a dipeptidyl ligand with cathepsin B, while a salicylic acid moiety was largely unresponsive to enzyme activity. The ratiometric comparison of the two CEST signals from the same agent allowed for concentration independent measurements of enzyme activity. The chemical exchange rate of the salicylic acid moiety was unchanged after enzyme catalysis, which further validated that this moiety was enzyme-unresponsive. The temperature dependence of the chemical exchange rate of the salicylic acid moiety was non-Arrhenius, suggesting a two-step chemical exchange mechanism for salicylic acid. The good detection sensitivity at low saturation power facilitates clinical translation, along with the potentially low toxicity of a non-metallic MRI contrast agent. The modular design of the agent constitutes a platform technology that expands the variety of agents that may be employed by catalyCEST MRI for molecular imaging. PMID:26633584

  7. β-Glucuronidase activity and mitochondrial dysfunction: the sites where flavonoid glucuronides act as anti-inflammatory agents

    PubMed Central

    Kawai, Yoshichika

    2014-01-01

    Epidemiological and experimental studies suggest that the consumption of flavonoid-rich diets decreases the risk of various chronic diseases such as cardiovascular diseases. Although studies on the bioavailability of flavonoids have been well-characterized, the tissue and cellular localizations underlying their biological mechanisms are largely unknown. The development and application of novel monoclonal antibodies revealed that macrophages could be the major target of dietary flavonoids in vivo. Using macrophage-like cell lines in vitro, we examined the molecular basis of the interaction between the macrophages and flavonoids, especially the glucuronide metabolites. We have found that extracellular β-glucuronidase secreted from macrophages is essential for the bioactivation of the glucuronide conjugates into the aglycone, and that the enzymatic activity, which requires an acidic pH, is promoted by the increased secretion of lactate in response to the mitochondrial dysfunction. This review describes our recent findings indicating the molecular mechanisms responsible for the anti-inflammatory activity of dietary flavonoids within the inflammation sites. We propose that the extracellular activity of β-glucuronidase associated with the status of the mitochondrial function in the target cells might be important biomarkers for the specific sites where the glucuronides of dietary flavonoids can act as anti-atherosclerotic and anti-inflammatory agents in vivo. PMID:24895476

  8. RNA aptamers as conformational probes and regulatory agents for plasminogen activator inhibitor-1.

    PubMed

    Madsen, Jeppe B; Dupont, Daniel M; Andersen, Thomas B; Nielsen, Anne F; Sang, Lu; Brix, Ditte M; Jensen, Jan K; Broos, Thomas; Hendrickx, Maarten L V; Christensen, Anni; Kjems, Jørgen; Andreasen, Peter A

    2010-05-18

    The hallmark of serpins is the ability to undergo the so-called "stressed-to-relaxed" switch during which the surface-exposed reactive center loop (RCL) becomes incorporated as strand 4 in central beta-sheet A. RCL insertion drives not only the inhibitory reaction of serpins with their target serine proteases but also the conversion to the inactive latent state. RCL insertion is coupled to conformational changes in the flexible joint region flanking beta-sheet A. One interesting serpin is plasminogen activator inhibitor-1 (PAI-1), a fast and specific inhibitor of the serine proteases tissue-type and urokinase-type plasminogen activator. Via its flexible joints' region, native PAI-1 binds vitronectin and relaxed, protease-complexed PAI-1 certain endocytosis receptors. From a library of 35-nucleotides long 2'-fluoropyrimidine-containing RNA oligonucleotides, we have isolated two aptamers binding PAI-1 by the flexible joint region with low nanomolar K(D) values. One of the aptamers exhibited measurable binding to native PAI-1 only, while the other also bound relaxed PAI-1. While none of the aptamers inhibited the antiproteolytic effect of PAI-1, both aptamers inhibited vitronectin binding and the relaxed PAI-1-binding aptamer also endocytosis receptor binding. The aptamer binding exclusively to native PAI-1 increased the half-life for the latency transition to more than 6 h, manyfold more than vitronectin. Contact with Lys124 in the flexible joint region was critical for strong inhibition of the latency transition and the lack of binding to relaxed PAI-1. We conclude that aptamers yield important information about the serpin conformational switch and, because they can compete with high-affinity protein-protein interactions, may provide leads for pharmacological intervention. PMID:20387790

  9. A modified HSP70 inhibitor shows broad activity as an anticancer agent

    PubMed Central

    Balaburski, Gregor M.; Leu, Julia I-Ju; Beeharry, Neil; Hayik, Seth; Andrake, Mark D.; Zhang, Gao; Herlyn, Meenhard; Villanueva, Jessie; Dunbrack, Roland L.; Yen, Tim; George, Donna L.; Murphy, Maureen E.

    2013-01-01

    The stress-induced heat shock protein 70 (HSP70) is an ATP-dependent molecular chaperone that plays a key role in refolding misfolded proteins and promoting cell survival following stress. HSP70 is marginally expressed in non-transformed cells, but is greatly overexpressed in tumor cells. Silencing HSP70 is uniformly cytotoxic to tumor but not normal cells; therefore, there has been great interest in the development of HSP70 inhibitors for cancer therapy. Here we report that the HSP70 inhibitor 2-phenylethynesulfonamide (PES) binds to the substrate-binding domain of HSP70, and requires the C-terminal helical ‘lid’ of this protein (amino acids 573-616) in order to bind. Using molecular modeling and in silico docking, we have identified a candidate binding site for PES in this region of HSP70, and we identify point mutants that fail to interact with PES. A preliminary structure-activity relationship analysis has revealed a derivative of PES, 2-(3-chlorophenyl) ethynesulfonamide (PES-Cl), which shows increased cytotoxicity and ability to inhibit autophagy, along with significantly improved ability to extend the life of mice with pre-B cell lymphoma, compared to the parent compound (p=0.015). Interestingly, we also show that these HSP70 inhibitors impair the activity of the Anaphase Promoting Complex/Cyclosome (APC/C) in cell-free extracts, and induce G2/M arrest and genomic instability in cancer cells. PES-Cl is thus a promising new anti-cancer compound with several notable mechanisms of action. PMID:23303345

  10. Anti-Resorptive Activity of Anti-Hypertensive Agent ACEi in Older Men

    NASA Technical Reports Server (NTRS)

    Rianon, Nahid; Edwards, BeJier; Nhonthachit, Phetsamong; Messick, Amanda; Gagel, Robert; Smith, Scott M.

    2016-01-01

    Hypertension (HTN) is associated with bone loss due to activation of the renin- angiotensin system (RAS) which in turn affects bone turnover. Animal studies have shown decreased bone resorption (up to 19%) and increased bone mass (up to 2%) following treatment with RAStargeted antihypertensive medications (e.g., angiotensin converting enzyme inhibitors, ACEi). Cross-sectional human studies have documented greater femoral neck BMD in older hypertensive men and women treated with ACEi compared to those not-treated with ACEi (nor other RAS-targeted medications). These findings raise the potential for ACEi use in preventing, or at a minimum slowing bone loss due to age or even microgravity. Based on this, we conducted a cohort study to investigate if ACEi treatment would decrease bone resorption in humans. We investigated changes in serum CTX and P1NP in 10 hypertensive men (45 years or older) treated with (N=5) without (N=5) exposure to ACEi for 3-months. Lisinopril was the ACEi used, and dose was adjusted as deemed appropriate by the attending physicians. Participants did not have any known skeletal health problem and were not exposed to any bisphosphonates or hydrochlorothiazides. A small sample size prevented detailed statistical analysis and hence, we present a preliminary descriptive report of our findings. Participants' age was 57+/-7 years (mean +/-SD), baseline body mass index was 27+/-5 kg/sq m, serum concentration of 25-hydroxyvitamin D was 66+/-17 nmol/L and parathyroid hormone was 30+/-13 pg/ml. After Lisinopril treatment, men demonstrated a 10% decrease in the bone resorption marker C-terminal telopeptide (CTX) and 5% decrease in formation marker procollagen type 1 amino-terminal pro-peptide (P1NP). On the contrary, serum CTX increased 41% and P1NP increased 10% in those who were not treated with ACEi. This is the first human study to report reduction in bone resorptive activity following ACEi treatment for hypertension in older men. Our results indicates

  11. Development of flexible antimicrobial films using essential oils as active agents.

    PubMed

    López, P; Sánchez, C; Batlle, R; Nerín, C

    2007-10-17

    The antimicrobial activity in the vapor-phase of laboratory-made flexible films of polypropylene (PP) and polyethylene/ethylene vinyl alcohol copolymer (PE/EVOH) incorporating essential oil of cinnamon ( Cinnamomum zeylanicum), oregano ( Origanum vulgare), clove ( Syzygium aromaticum), or cinnamon fortified with cinnamaldehyde was evaluated against a wide range of microorganisms: the Gram-negative bacteria Escherichia coli, Yersinia enterocolitica, Pseudomonas aeruginosa, and Salmonella choleraesuis; the Gram-positive bacteria Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, and Enterococcus faecalis; the molds Penicillium islandicum, Penicillium roqueforti, Penicillium nalgiovense, Eurotium repens, and A spergillus flavus and the yeasts Candida albicans, Debaryomyces hansenii, and Zigosaccharomyces rouxii. Films with a nominal concentration of 4% (w/w) of fortified cinnamon or oregano essential oil completely inhibited the growth of the fungi; higher concentrations were required to inhibit the Gram-positive bacteria (8 and 10%, respectively), and higher concentrations still were necessary to inhibit the Gram-negative bacteria. PP films were more effective than PE/EVOH films. The atmospheres generated by the antimicrobial films inside Petri dishes were quantitatively analyzed using headspace-single drop microextraction (HS-SDME) in combination with gas chromatography-mass spectrometry (GC-MS). The analyses showed that the oregano-fortified PP films released higher levels of carvacrol and thymol, and the cinnamon-fortified PP films released higher levels of cinnamaldehyde, during the first 3-6 h of incubation, than the corresponding PE/EVOH films. Shelf-life tests were also performed, demonstrating that the antifungal activities of the films persisted for more than two months after their manufacture. In addition, migration tests (overall and specific) were performed, using both aqueous and fatty simulants, to ensure that the films meet EU regulations

  12. High water-stressed population estimated by world water resources assessment including human activities under SRES scenarios

    NASA Astrophysics Data System (ADS)

    Kiguchi, M.; Shen, Y.; Kanae, S.; Oki, T.

    2009-04-01

    In an argument of the reduction and the adaptation for the climate change, the evaluation of the influence by the climate change is important. When we argue in adaptation plan from a damage scale and balance with the cost, it is particularly important. Parry et al (2001) evaluated the risks in shortage of water, malaria, food, the risk of the coast flood by temperature function and clarified the level of critical climate change. According to their evaluation, the population to be affected by the shortage of water suddenly increases in the range where temperature increases from 1.5 to 2.0 degree in 2080s. They showed how much we need to reduce emissions in order to draw-down significantly the number at risk. This evaluation of critical climate change threats and targets of water shortage did not include the water withdrawal divided by water availability. Shen et al (2008a) estimated the water withdrawal of projection of future world water resources according to socio-economic driving factors predicted for scenarios A1b, A2, B1, and B2 of the Special Report on Emission Scenarios (SRES). However, these results were in function of not temperature but time. The assessment of the highly water-stressed population considered the socioeconomic development is necessary for a function of the temperature. Because of it is easy to understand to need to reduce emission. We present a multi-GCM analysis of the global and regional populations lived in highly water-stressed basin for a function of the temperature using the socioeconomic data and the outputs of GCMs. In scenario A2, the population increases gradually with warming. On the other hand, the future projection population in scenario A1b and B1 increase gradually until the temperature anomaly exceeds around from +1 to +1.5 degree. After that the population is almost constant. From Shen et al (2008b), we evaluated the HWSP and its ratio in the world with temperature function for scenarios A1B, A2, and B1 by the index of W

  13. The Role of Very Low-Reynolds Hydrodynamics on the Transfer of Information Among Active Agents

    NASA Astrophysics Data System (ADS)

    De Rosis, Alessandro; Ubertini, Francesco; Ubertini, Stefano; Succi, Sauro

    2015-12-01

    We investigate the role of hydrodynamic interactions on the decision-making and leader-identification processes within a group of fifty small-size active individuals, immersed in a viscous fluid at very low Reynolds number, {R}e {˜ }10^{-2}. A fraction of the individuals is informed about the spatial location of the target, and moves accordingly along a privileged trajectory. The rest of the group has no access to this information, but may draw indirect benefit by following the trajectory of the informed individuals, through a process of leader-identification. Such process responds to simple behavioral rules ("social" interactions) discussed previously in the literature (Krause and Ruxton in Living in groups, 2002). The above scenario is enriched with two mechanical ingredients: the presence of an obstacle, preventing the informed individuals from following a straight trajectory to the target and hydrodynamic interactions with the surrounding fluid. It is found that hydrodynamic interactions are particularly effective in steering the uninformed individuals towards the target under neutral conditions, i.e. whenever the fraction of informed individuals is around 50 %. At lower fractions, only the informed individuals manage to reach the target, regardless of hydrodynamic interactions. Likewise, at higher fractions, all individuals reach the target, independently of hydrodynamic effects. This shows that, while hydrodynamics is subdominant under most circumstances, it may nonetheless take on a strategic role whenever the informed and uninformed individuals become comparable in number.

  14. Novel spirohydantoin derivative as a potent multireceptor-active antipsychotic and antidepressant agent.

    PubMed

    Czopek, Anna; Kołaczkowski, Marcin; Bucki, Adam; Byrtus, Hanna; Pawłowski, Maciej; Kazek, Grzegorz; Bojarski, Andrzej J; Piaskowska, Agata; Kalinowska-Tłuścik, Justyna; Partyka, Anna; Wesołowska, Anna

    2015-07-01

    A series of novel spirohydantoin derivatives with arylpiperazinylbutyl moiety were synthesized and evaluated for serotonin 5-HT1A, 5-HT2A, 5-HT7 and dopamine D2 receptors. Based on these data, four compounds were selected for further binding affinity assays on dopamine D1, D3, D4, and 5-HT2C, 5-HT6 as well as adrenergic α1 and α2C receptors, which are involved in various CNS diseases such as schizophrenia, anxiety and/or depression. The compound 14, 1-{4-[4-(2-metoxyphe-nyl)piperazin-1-yl]butyl}-3',4'-dihydro-2H,2'H,5H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione, with the most promising functional profile, mixed 5-HT2A/D2 antagonist and 5-HT1A partial agonist, was selected. In the mouse d-amphetamine-induced locomotor hyperactivity model, compound 14 produced antipsychotic-like activity, which is devoid of cataleptogenic effects and in the forced swim test in mice, it showed a significant antidepressant-like effect unlike the reference drug aripiprazole. PMID:25936259

  15. Licochalcone A, a novel antiparasitic agent with potent activity against human pathogenic protozoan species of Leishmania.

    PubMed Central

    Chen, M; Christensen, S B; Blom, J; Lemmich, E; Nadelmann, L; Fich, K; Theander, T G; Kharazmi, A

    1993-01-01

    Licochalcone A, an oxygenated chalcone isolated from the roots of Chinese licorice plant, inhibited the growth of both Leishmania major and Leishmania donovani promastigotes and amastigotes. The structure of the licochalcone A was established by mass and nuclear magnetic resonance spectroscopies and by synthesis, and its purity was verified by high-pressure liquid chromatography. The 50% inhibition of growth of logarithmic- and stationary-phase promastigotes of L. major, as measured by [3H]thymidine uptake, were 4 and 2.5 micrograms/ml, respectively. The growth of L. major promastigotes was totally inhibited after a 20-h incubation period with licochalcone A at 5 micrograms/ml. At a concentration of 0.5 microgram/ml, licochalcone A markedly reduced the infection rate of human peripheral blood monocyte-derived macrophages and U937 cells with L. major promastigotes and exhibited a strong intracellular killing of the parasite. These data show that intracellular Leishmania amastigotes are more susceptible than promastigotes to licochalcone A. Results of studies on the site of action of licochalcone A indicate that the target organelle appears to be the parasite mitochondria. These findings demonstrate that licochalcone A in concentrations that are nontoxic to host cells exhibits a strong antileishmanial activity and that appropriate substituted chalcones might be a new class of antileishmanial drugs. Images PMID:8109916

  16. Light-responsive polymer microcapsules as delivery systems for natural active agents

    NASA Astrophysics Data System (ADS)

    Bizzarro, Valentina; Carfagna, Cosimo; Cerruti, Pierfrancesco; Marturano, Valentina; Ambrogi, Veronica

    2016-05-01

    In this work we report the preparation and the release behavior of UV-responsive polymeric microcapsules containing essential oils as a core. The oil acted also as a monomer solvent during polymerization. Accordingly, the potentially toxic organic solvent traditionally used was replaced with a natural active substance, resulting in a more sustainable functional system. Polymer shell was based on a lightly cross-linked polyamide containing UV-sensitive azobenzene moieties in the main chain. The micro-sized capsules were obtained via interfacial polycondensation in o/w emulsion, and their mean size was measured via Dynamic Light Scattering. Shape and morphology were analyzed through Scanning Electron and Optical Microscopy. UV-responsive behavior was evaluated via spectrofluorimetry, by assessing the release kinetics of a fluorescent probe molecule upon UV light irradiation (λmax=360 nm). The irradiated samples showed an increase in fluorescence intensity, in accordance with the increase of the probe molecule concentration in the release medium. As for the un-irradiated sample, no changes could be detected demonstrating the effectiveness of the obtained releasing system.

  17. In vivo haematopoietic activity is induced in neurosphere cells by chromatin-modifying agents

    PubMed Central

    Schmittwolf, Carolin; Kirchhof, Nicole; Jauch, Anna; Dürr, Michael; Harder, Friedrich; Zenke, Martin; Müller, Albrecht M

    2005-01-01

    Modifications of DNA and chromatin are fundamental for the establishment and maintenance of cell type-specific gene expression patterns that constitute cellular identities. To test whether the developmental potential of fetal brain-derived cells that form floating sphere colonies (neurospheres) can be modified by destabilizing their epigenotype, neurosphere cells were treated with chemical compounds that alter the acetylation and methylation patterns of chromatin and DNA. Intravenous infusion of bulk or clonally derived neurosphere cells treated with a combination of trichostatin A (TSA) plus 5-aza-2′-deoxycytidine (AzaC) (TSA/AzaC neurosphere cells) yielded long-term, multilineage and transplantable neurosphere-derived haematopoietic repopulation. Untreated neurosphere cells exhibited no haematopoietic repopulation activity. The neurosphere-derived haematopoietic cells showed a diploid karyotype, indicating that they are unlikely to be products of cell fusion events, a conclusion strengthened by multicolour fluorescence in situ hybridization. Our results indicate that altering the epigenotype of neurosphere cells followed by transplantation enables the generation of neurosphere-derived haematopoietic cells. PMID:15660132

  18. [Repellent activity against Aedes aegypti (L.) of formulas based on natural vegetable extracts or synthetic active agents].

    PubMed

    Girgenti, P; Suss, L

    2002-01-01

    A comparison of 5 commercial mosquito repellents was made on adult male and female volunteers in laboratory trials. The products tested in forms of cream or lotion included 4 natural oil formulations (containing citronella, clover, eucalyptus, geranium, lavender, peppermint, sandalwood, thyme, etc.) and 1 synthetic chemical repellent containing 10% KBR 3023). Natural oil products showed essentially poor or no repellency against Ae, aegypti: the protection times were less than or equal to 1 hour. Only the synthetic repellent based on KBR 3023 provided satisfactory defence to human volunteers. PMID:12162118

  19. Novel derivatives of 1,3,4-oxadiazoles are potent mitostatic agents featuring strong microtubule depolymerizing activity in the sea urchin embryo and cell culture assays.

    PubMed

    Kiselyov, Alex S; Semenova, Marina N; Chernyshova, Natalya B; Leitao, Andrei; Samet, Alexandr V; Kislyi, Konstantine A; Raihstat, Mikhail M; Oprea, Tudor; Lemcke, Heiko; Lantow, Margaréta; Weiss, Dieter G; Ikizalp, Nazli N; Kuznetsov, Sergei A; Semenov, Victor V

    2010-05-01

    A series of novel 1,3,4-oxadiazole derivatives based on structural and electronic overlap with combretastatins have been designed and synthesized. Initially, we tested all new compounds in vivo using the phenotypic sea urchin embryo assay to yield a number of agents with anti-proliferative, anti-mitotic, and microtubule destabilizing activities. The experimental data led to identification of 1,3,4-oxadiazole derivatives with isothiazole (5-8) and phenyl (9-12) pharmacophores featuring activity profiles comparable to that of combretastatins, podophyllotoxin and nocodazole. Cytotoxic effects of the two lead molecules, namely 6 and 12, were further confirmed and evaluated by conventional assays with the A549 human cancer cell line including cell proliferation, cell cycle arrest at the G2/M phase, cellular microtubule distribution, and finally in vitro microtubule assembly with purified tubulin. The modeling results using 3D similarity (ROCS) and docking (FRED) correlated well with the observed activity of the molecules. Docking data suggested that the most potent molecules are likely to target the colchicine binding site. PMID:20110137

  20. Free heme pool and activity of key enzyme of heme synthesis in the rat liver under action of agents affecting reduced glutathione level.

    PubMed

    Barannik, T V; Inshina, N M; Kaliman, P A

    2005-01-01

    The decrease of GSH level in the rat liver was found to be accompanied by an increase of tryptophan 2,3-dioxygenase (TDO) heme saturation during first hours after HgCl2, phenylhydrazine (Ph) injection or rhabdomyolysis (the coefficient of correlation -0.978). The activity of the key enzyme of heme synthesis--5-aminolevulinate synthase (ALAS) was 2.5-fold increased in the first hours after Ph injection and rhabdomyolysis. Glutathione injection in vivo as well as CdCl2 caused the increase of GSH content and the inhibition of ALAS. The coefficient of correlation for GSH content and ALAS activity under the action of agents altering both these parameters (CdCl2, Ph, GSH injection and rhabdomyolysis) is 0.938. Taking into account the presence of heme regulatory motif with conserved cystein in many proteins, including ALAS and TDO (accession number in SwissProt database AAH61793 and P21643, respectively), the link between alterations of GSH content, ALAS activity and heme saturation of TDO in the rat liver could be proposed. The further experiments should be performed in order to elucidate the mechanisms of GSH level influence on free heme pool formation in the liver cells. PMID:16846079

  1. Liposomes for Targeted Delivery of Active Agents against Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease)

    PubMed Central

    Spuch, Carlos; Navarro, Carmen

    2011-01-01

    Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease represent a huge unmet medical need. The prevalence of both diseases is increasing, but the efficacy of treatment is still very limited due to various factors including the blood brain barrier (BBB). Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system. New therapeutic drugs that cross the BBB are critically needed for treatment of many brain diseases. One of the significant factors on neurotherapeutics is the constraint of the blood brain barrier and the drug release kinetics that cause peripheral serious side effects. Contrary to common belief, neurodegenerative and neurological diseases may be multisystemic in nature, and this presents numerous difficulties for their potential treatment. Overall, the aim of this paper is to summarize the last findings and news related to liposome technology in the treatment of neurodegenerative diseases and demonstrate the potential of this technology for the development of novel therapeutics and the possible applications of liposomes in the two most widespread neurodegenerative diseases, Alzheimer's disease and Parkinson's disease. PMID:22203906

  2. Biocomposite macroporous cryogels as potential carrier scaffolds for bone active agents augmenting bone regeneration.

    PubMed

    Raina, Deepak Bushan; Isaksson, Hanna; Teotia, Arun Kumar; Lidgren, Lars; Tägil, Magnus; Kumar, Ashok

    2016-08-10

    Osteoinduction can be enhanced by combining scaffolds with bone morphogenic protein-2 (BMP-2). However, BMP's are known to also cause bone resorption. This can be controlled using bisphosphonates like zoledronic acid (ZA). In this study, we produced two different scaffolds containing silk-fibroin, chitosan, agarose and hydroxyapatite (HA) with and without bioactive glass. The aims of the study were to fabricate, physico-chemically characterize and evaluate the carrier properties of the scaffolds for recombinant human BMP-2 (rhBMP-2) and ZA. Scaffolds were characterized using various methods to confirm their composition. During cell-material interactions, both scaffolds exhibited gradual but sustained proliferation of both C2C12 and MSCs for a period of 6weeks with augmentative effects on their phenotype indicated by elevated levels of alkaline phosphatase (ALP) cuing towards osteogenic differentiation. In-vitro effects of rhBMP-2 and ZA contained within both the scaffolds was assessed on MC3T3 preosteoblast cells and the results show a significant increase in the ALP activity of the cells seeded on scaffolds with rhBMP-2. Further, the scaffold with both HA and bioactive glass was considered for the animal study. In-vitro, this scaffold released nearly 25% rhBMP-2 in 21-days and the addition of ZA did not affect the release. In the animal study, the scaffolds were combined with rhBMP-2 and ZA, rhBMP-2 or implanted alone in an ectopic muscle pouch model. Significantly higher bone formation was observed in the scaffold loaded with both rhBMP-2 and ZA as seen from micro-computed tomography, histomorphometry and energy dispersive X-ray spectroscopy. PMID:27252151

  3. Modulation of attention network activation under antidepressant agents in healthy subjects.

    PubMed

    Graf, Heiko; Abler, Birgit; Hartmann, Antonie; Metzger, Coraline D; Walter, Martin

    2013-07-01

    While antidepressants are supposed to exert similar effects on mood and drive via various mechanisms of action, diverging effects are observed regarding side-effects and accordingly on neural correlates of motivation, emotion, reward and salient stimuli processing as a function of the drugs impact on neurotransmission. In the context of erotic stimulation, a unidirectional modulation of attentional functioning despite opposite effects on sexual arousal has been suggested for the selective serotonin reuptake-inhibitor (SSRI) paroxetine and the selective dopamine and noradrenaline reuptake-inhibitor (SDNRI) bupropion. To further elucidate the effects of antidepressant-related alterations of neural attention networks, we investigated 18 healthy males under subchronic administration (7 d) of paroxetine (20 mg), bupropion (150 mg) and placebo within a randomized placebo-controlled cross-over double-blind functional magnetic resonance imaging (fMRI) design during an established preceding attention task. Neuropsychological effects beyond the fMRI-paradigm were assessed by measuring alertness and divided attention. Comparing preceding attention periods of salient vs. neutral pictures, we revealed congruent effects of both drugs vs. placebo within the anterior midcingulate cortex, dorsolateral prefrontal cortex, anterior prefrontal cortex, superior temporal gyrus, anterior insula and the thalamus. Relatively decreased activation in this network was paralleled by slower reaction times in the divided attention task in both verum conditions compared to placebo. Our results suggest similar effects of antidepressant treatments on behavioural and neural attentional functioning by diverging neurochemical pathways. Concurrent alterations of brain regions within a fronto-parietal and cingulo-opercular attention network for top-down control could point to basic neural mechanisms of antidepressant action irrespective of receptor profiles. PMID:23200084

  4. Borane-protected phosphines are redox-active radioprotective agents for endothelial cells.

    PubMed

    Crowe, Megan E; Lieven, Christopher J; Thompson, Alex F; Sheibani, Nader; Levin, Leonard A

    2015-12-01

    Exposure to radiation can damage endothelial cells in the irradiated area via the production of reactive oxygen species. We synthesized phosphine-borane complexes that reduce disulfide bonds and had previously been shown to interfere with redox-mediated signaling of cell death. We hypothesized that this class of drugs could interfere with the downstream effects of oxidative stress after irradiation and rescue endothelial cells from radiation damage. Cultured bovine aortic endothelial cells were plated for clonogenic assay prior to exposure to varying doses of irradiation from a (137)Cs irradiator and treated with various concentrations of bis(3-propionic acid methyl ester)phenylphosphine borane complex (PB1) at different time points. The clone-forming ability of the irradiated cells was assessed seven days after irradiation. We compared the radioprotective effects of PB1 with the aminothiol radioprotectant WR1065 and known superoxide scavengers. PB1 significantly protected bovine aortic endothelial cells from radiation damage, particularly when treated both before and after radiation. The radioprotection with 1 µM PB1 corresponded to a dose-reduction factor of 1.24. Radioprotection by PB1 was comparable to the aminothiol WR1065, but was significantly less toxic and required much lower concentrations of drug (1 µM vs. 4 mM, respectively). Superoxide scavengers were not radioprotective in this paradigm, indicating the mechanisms for both loss of clonogenicity and PB1 radioprotection are independent of superoxide signaling. These data demonstrate that PB1 is an effective redox-active radioprotectant for endothelial cells in vitro, and is radioprotective at a concentration approximately 4 orders of magnitude lower than the aminothiol WR1065 with less toxicity. PMID:26188467

  5. Borane-protected phosphines are redox-active radioprotective agents for endothelial cells

    PubMed Central

    Crowe, Megan E.; Lieven, Christopher J.; Thompson, Alex F.; Sheibani, Nader; Levin, Leonard A.

    2015-01-01

    Exposure to radiation can damage endothelial cells in the irradiated area via the production of reactive oxygen species. We synthesized phosphine–borane complexes that reduce disulfide bonds and had previously been shown to interfere with redox-mediated signaling of cell death. We hypothesized that this class of drugs could interfere with the downstream effects of oxidative stress after irradiation and rescue endothelial cells from radiation damage. Cultured bovine aortic endothelial cells were plated for clonogenic assay prior to exposure to varying doses of irradiation from a 137Cs irradiator and treated with various concentrations of bis(3-propionic acid methyl ester)phenylphosphine borane complex (PB1) at different time points. The clone-forming ability of the irradiated cells was assessed seven days after irradiation. We compared the radioprotective effects of PB1 with the aminothiol radioprotectant WR1065 and known superoxide scavengers. PB1 significantly protected bovine aortic endothelial cells from radiation damage, particularly when treated both before and after radiation. The radioprotection with 1 µM PB1 corresponded to a dose-reduction factor of 1.24. Radioprotection by PB1 was comparable to the aminothiol WR1065, but was significantly less toxic and required much lower concentrations of drug (1 µM vs. 4 mM, respectively). Superoxide scavengers were not radioprotective in this paradigm, indicating the mechanisms for both loss of clonogenicity and PB1 radioprotection are independent of superoxide signaling. These data demonstrate that PB1 is an effective redox-active radioprotectant for endothelial cells in vitro, and is radioprotective at a concentration approximately 4 orders of magnitude lower than the aminothiol WR1065 with less toxicity. PMID:26188467

  6. HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment

    SciTech Connect

    Weigelt, Britta; Lo, Alvin T; Park, Catherine C; Gray, Joe W; Bissell, Mina J

    2009-07-27

    Development of effective and durable breast cancer treatment strategies requires a mechanistic understanding of the influence of the microenvironment on response. Previous work has shown that cellular signaling pathways and cell morphology are dramatically influenced by three-dimensional (3D) cultures as opposed to traditional two-dimensional (2D) monolayers. Here, we compared 2D and 3D culture models to determine the impact of 3D architecture and extracellular matrix (ECM) on HER2 signaling and on the response of HER2-amplified breast cancer cell lines to the HER2-targeting agents Trastuzumab, Pertuzumab and Lapatinib. We show that the response of the HER2-amplified AU565, SKBR3 and HCC1569 cells to these anti-HER2 agents was highly dependent on whether the cells were cultured in 2D monolayer or 3D laminin-rich ECM gels. Inhibition of {beta}1 integrin, a major cell-ECM receptor subunit, significantly increased the sensitivity of the HER2-amplified breast cancer cell lines to the humanized monoclonal antibodies Trastuzumab and Pertuzumab when grown in a 3D environment. Finally, in the absence of inhibitors, 3D cultures had substantial impact on HER2 downstream signaling and induced a switch between PI3K-AKT- and RAS-MAPKpathway activation in all cell lines studied, including cells lacking HER2 amplification and overexpression. Our data provide direct evidence that breast cancer cells are able to rapidly adapt to different environments and signaling cues by activating alternative pathways that regulate proliferation and cell survival, events that may play a significant role in the acquisition of resistance to targeted therapies.

  7. Antiparasitic agents.

    PubMed

    Rosenblatt, J E

    1999-11-01

    Several important developments have occurred in recent years in the chemotherapy for and prophylaxis of parasitic infections. Although mefloquine is clearly the most effective agent for prevention of chloroquine-resistant falciparum malaria, its use has been compromised by side effects, both real and imagined. Well-designed studies have shown that side effects occur no more frequently with low-dose mefloquine than with chloroquine. Use of mefloquine in pregnant women has not been associated with birth defects, but the incidence of stillbirths may be increased. Malarone is a new agent that combines atovaquone and proguanil, and it may be as effective as mefloquine; however, it is not yet available in the United States. Several newer agents have appeared in response to the development of multidrug resistant Plasmodium falciparum, especially in Southeast Asia. Halofantrine is available for the treatment of mild to moderate malaria due to P. falciparum and for P. vivax infections. Because of severe toxic effects, use of halofantrine should be restricted to only those unusual and rare situations in which other agents cannot be used. Artemisinin (an extract of the Chinese herbal remedy qinghaosu) and two derivatives, artesunate and artemether, are active against multidrug resistant P. falciparum and are widely used in Asia in oral, parenteral, and rectal forms. The antibacterial azithromycin in combination with atovaquone or quinine has now been reported to treat babesiosis effectively in experimental animals and in a few patients. Azithromycin in combination with paromomycin has also shown promise in the treatment of cryptosporidiosis (and toxoplasmosis when combined with pyrimethamine) in patients with the acquired immunodeficiency syndrome (AIDS). Albendazole is currently the only systemic agent available for treatment of microsporidiosis, an infection primarily of patients with AIDS. In addition, albendazole and ivermectin have emerged as effective broad

  8. [Effect of anticancer agents on rat prostate. Evaluation of organ weight, histological finding and 5 alpha-reductase activities].

    PubMed

    Takeda, M; Hosaka, M; Kitajima, N; Noguchi, K; Fujii, H; Oshima, H; Harada, M

    1985-01-01

    To evaluate the effect of anticancer chemotherapeutic antigens on rat prostate, ten kinds of anticancer agents corresponding to the dose generally used for humans were intraperitoneally injected to 63-day-old Wistar rats. The anticancer agents were administered as follows: Cyclophosphamide (CPM) was used at the dose of 8 mg/kg for 7 days. Methotrexate (MTX), actinomycin-D (ACD) and cis-platinum (CDDP), 163 micrograms/kg, 8 micrograms/kg and 833 micrograms/kg for 5 days, respectively. Nitrogen mustard (NM), bleomycin (BLM), peplomycin (PLM), adriamycin (ADM), vincristine (VCR), and vinblastine (VBL), 500 micrograms/kg, 250 micrograms/kg, 170 micrograms/kg, 2.5 mg/kg, 33 micrograms/kg and 83 micrograms/kg, twice in a week, respectively. The rats were killed on the fifth day after completion of the schedule. Then, the weight of the body, the prostate, the epididymis and the adrenal gland were measured. In addition, 5 alpha-reductase activities and histological findings in the prostate were examined. For determination of 5 alpha-reductase activities, cell-free homogenate obtained from the rat ventral prostate was incubated with C14-testosterone at 37 degrees C for 30 minutes in an atmosphere of 95% of O2 and 5% of CO2. Subsequently, the metabolites from testosterone were separated and purified with thin layer chromatography using the solvent system with benzene acetone, 4:1 (v/v). 5 alpha-Reductase activity was determined with the sum of dihydrotestosterone (DHT) and androstanediol converted from testosterone and indicated as pmol product/mg protein. The 5 alpha-reductase activity was employed as a biological marker for the degree of androgenic dependency in the prostate. The results were summarized as follows. CDDP significantly reduced the weight of the body (p less than 0.001, n = 7), but not the activity of 5 alpha-reductase. NM and VBL had a specific action to reduce the weight of the prostate (p less than 0.01, n = 8) without causing loss of body weight. NM and

  9. Inhibitory potential of three zinc chelating agents against the proteolytic, hemorrhagic, and myotoxic activities of Echis carinatus venom.

    PubMed

    Nanjaraj Urs, Ankanahalli N; Yariswamy, Manjunath; Ramakrishnan, Chandrasekaran; Joshi, Vikram; Suvilesh, Kanve Nagaraj; Savitha, Mysore Natarajan; Velmurugan, Devadasan; Vishwanath, Bannikuppe Sannanayak

    2015-01-01

    Viperbites undeniably cause local manifestations such as hemorrhage and myotoxicity involving substantial degradation of extracellular matrix (ECM) at the site of envenomation and lead to progressive tissue damage and necrosis. The principle toxin responsible is attributed to snake venom metalloproteases (SVMPs). Treatment of such progressive tissue damage induced by SVMPs has become a challenging task for researchers and medical practitioners who are in quest of SVMPs inhibitors. In this study, we have evaluated the inhibitory potential of three specific zinc (Zn(2+)) chelating agents; N,N,N',N'-tetrakis (2-pyridylmethyl) ethane-1,2-diamine (TPEN), diethylene triamine pentaacetic acid (DTPA), tetraethyl thiuram disulfide (TTD) on Echis carinatus venom (ECV) induced hemorrhage and myotoxicity. Amongst them, TPEN has high affinity for Zn(2+) and revealed potent inhibition of ECV metalloproteases (ECVMPs) in vitro (IC50: 6.7 μM) compared to DTPA and TTD. The specificity of TPEN towards Zn(2+) was confirmed by spectral and docking studies. Further, TPEN, DTPA, and TTD completely blocked the hemorrhagic and myotoxic activities of ECV in a dose dependent manner upon co-injection; whereas, only TPEN successfully neutralized hemorrhage and myotoxicity following independent injection. Histological examinations revealed that TPEN effectively prevents degradation of dermis and basement membrane surrounding the blood vessels in mouse skin sections. TPEN also prevents muscle necrosis and accumulation of inflammatory cells at the site of ECV injections. In conclusion, a high degree of structural and functional homology between mammalian MMPs and SVMPs suggests that specific Zn(2+) chelators currently in clinical practice could be potent first aid therapeutic agents in snakebite management, particularly for local tissue damage. PMID:25447774

  10. Laboratory Measurement of the Anticoagulant Activity of the Target-specific Oral Anticoagulant Agents: A Systematic Review

    PubMed Central

    Cuker, Adam; Siegal, Deborah M.; Crowther, Mark A.; Garcia, David A.

    2014-01-01

    Background The target-specific oral anticoagulant agents (TSOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations. Objectives This study’s objective is to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban. Methods We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Results We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R2 0.92–0.99) and ecarin-based assays (R2 0.92–1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. In terms of rivaroxaban and apixaban, anti-Xa activity is linear (R2 0.89–1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification. Conclusions Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in TSOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed. PMID:25212648

  11. Behavioral and antioxidant activity of a tosylbenz[g]indolamine derivative. A proposed better profile for a potential antipsychotic agent

    PubMed Central

    Zika, Chara A; Nicolaou, Ioannis; Gavalas, Antonis; Rekatas, George V; Tani, Ekaterini; Demopoulos, Vassilis J

    2004-01-01

    Background Tardive dyskinesia (TD) is a major limitation of older antipsychotics. Newer antipsychotics have various other side effects such as weight gain, hyperglycemia, etc. In a previous study we have shown that an indolamine molecule expresses a moderate binding affinity at the dopamine D2 and serotonin 5-HT1A receptors in in vitro competition binding assays. In the present work, we tested its p-toluenesulfonyl derivative (TPBIA) for behavioral effects in rats, related to interactions with central dopamine receptors and its antioxidant activity. Methods Adult male Fischer-344 rats grouped as: i) Untreated rats: TPBIA was administered i.p. in various doses ii) Apomorphine-treated rats: were treated with apomorphine (1 mg kg-1, i.p.) 10 min after the administration of TPBIA. Afterwards the rats were placed individually in the activity cage and their motor behaviour was recorded for the next 30 min The antioxidant potential of TPBIA was investigated in the model of in vitro non enzymatic lipid peroxidation. Results i) In non-pretreated rats, TPBIA reduces the activity by 39 and 82% respectively, ii) In apomorphine pretreated rats, TPBIA reverses the hyperactivity and stereotype behaviour induced by apomorphine. Also TPBIA completely inhibits the peroxidation of rat liver microsome preparations at concentrations of 0.5, 0.25 and 0.1 mM. Conclusion TPBIA exerts dopamine antagonistic activity in the central nervous system. In addition, its antioxidant effect is a desirable property, since TD has been partially attributed, to oxidative stress. Further research is needed to test whether TPBIA may be used as an antipsychotic agent. PMID:14711381

  12. In vitro and In vivo Antitumor Activity of a Novel Alkylating Agent Melphalan-flufenamide Against Multiple Myeloma Cells

    PubMed Central

    Chauhan, Dharminder; Ray, Arghya; Viktorsson, Kristina; Spira, Jack; Paba-Prada, Claudia; Munshi, Nikhil; Richardson, Paul; Lewensohn, Rolf; Anderson, Kenneth C.

    2014-01-01

    Purpose The alkylating agent melphalan prolongs survival in multiple myeloma (MM) patients; however, it is associated with toxicities and development of drug-resistance. Here, we evaluated the efficacy of melphalan-flufenamide (Mel-flufen), a novel dipeptide prodrug of melphalan in MM. Experimental Design MM cell lines, primary patient cells, and the human MM xenograft animal model were utilized to study the antitumor activity of mel-flufen. Results Low doses of mel-flufen triggers a more rapid and higher intracellular concentrations of melphalan in MM cells than is achievable by free melphalan. Cytotoxicity analysis showed significantly lower IC50 of mel-flufen than melphalan in MM cells. Importantly, mel-flufen induces apoptosis even in melphalan-, and bortezomib-resistant MM cells. Mechanistic studies show that siRNA knockdown of aminopeptidase N, a key enzyme mediating intracellular conversion of mel-flufen to melphalan, attenuates anti-MM activity of mel-flufen. Furthermore, mel-flufen-induced apoptosis was associated with: 1) activation of caspases and PARP cleavage; 2) ROS generation; 3) mitochondrial dysfunction and release of cytochrome-c; and 4) induction of DNA damage. Moreover, mel-flufen inhibits MM cell migration and tumor-associated angiogenesis. Human MM xenograft studies showed a more potent inhibition of tumor growth in mice treated with mel-flufen than mice receiving equimolar doses of melphalan. Finally, combining mel-flufen with lenalidomide, bortezomib, or dexamethasone triggers synergistic anti-MM activity. Conclusion Our preclinical study supports clinical evaluation of mel-flufen to enhance therapeutic potential of melphalan, overcome drug-resistance, and improve MM patient outcome. PMID:23584492

  13. Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro.

    PubMed Central

    Fuhr, U; Anders, E M; Mahr, G; Sörgel, F; Staib, A H

    1992-01-01

    Inhibition of cytochrome P450IA2 activity is an important adverse effect of quinolone antibacterial agents. It results in a prolonged half-life for some drugs that are coadministered with quinolones, such as theophylline. The objective of the study described here was to define the parameters for quantifying the inhibitory potencies of quinolones against cytochrome P450IA2 in vivo and in vitro and to investigate the relationship between the results of both approaches. Cytochrome P450IA2 activity in vitro was measured by using the 3-demethylation rate of caffeine (500 microM) in human liver microsomes. The inhibitory potency of a quinolone in vitro was determined by calculating the decrease in the activity of cytochrome P450IA2 caused by addition of the quinolone (500 microM) into the incubation medium. The mean values (percent reduction of activity without quinolone) were as follows: enoxacin, 74.9%; ciprofloxacin, 70.4%; nalidixic acid, 66.6%; pipemidic acid, 59.3%; norfloxacin, 55.7%; lomefloxacin, 23.4%; pefloxacin, 22.0%; amifloxacin, 21.4%; difloxacin, 21.3%; ofloxacin, 11.8%; temafloxacin, 10.0%; fleroxacin, no effect. The inhibitory potency of a quinolone in vivo was defined by a dose- and bioavailability-normalized parameter calculated from changes of the elimination half-life of theophylline and/or caffeine reported in previously published studies. Taking the pharmacokinetics of the quinolones into account, it was possible to differentiate between substances with and without clinically relevant inhibitory effects by using results of in vitro investigations. The in vitro test described here may help to qualitatively predict the relevant drug interactions between quinolones and methylxanthines that occur during therapy. PMID:1510417

  14. Syntheses and biological evaluation of 2-amino-3-acyl-tetrahydrobenzothiophene derivatives; antibacterial agents with antivirulence activity

    PubMed Central

    Dang, Hung The; Chorell, Erik; Uvell, Hanna; Pinkner, Jerome S.; Hultgren, Scott J.

    2014-01-01

    Developing new compounds targeting virulence factors (e.g., inhibition of pilus assembly by pilicides) is a promising approach to combating bacterial infection. A high-throughput screening campaign of a library of 17,500 small molecules identified 2-amino-3-acyl-tetrahydrobenzothiophene derivatives (hits 2 and 3) as novel inhibitors of pili-dependent biofilm formation in an uropathogenic Escherichia coli strain UTI89. Based on compounds 2 and 3 as a starting point, we designed and synthesized a series of structurally related analogs and investigated their activity against biofilm formation of E.coli UTI89. Systematic structural modification of the initial hits provided valuable information on their SARs for further optimization. In addition, small structural changes to the parent molecules resulted in low micromolar inhibitors (20–23) of E.coli biofilm development without effect on bacterial growth. The hit compound 3 and its analog 20 were confirmed to prevent pili formation in a hemagglutination (HA) titer assay and electron microscopy (EM) measurements. These findings suggest that 2-amino-3-acyl-tetrahydrobenzothiophenes may serve as a new class of compounds for further elaboration as antibacterial agents with antivirulence activity. PMID:24531242

  15. Myxobolus cerebralis (Myxozoa), the causative agent of whirling disease, reduces fecundity and feeding activity of Tubifex tubifex (Oligochaeta).

    PubMed

    Shirakashi, S; El-Matbouli, M

    2009-05-01

    Myxobolus cerebralis is the causative agent of whirling disease that has significant economical and ecological impacts on trout populations. Although intensive studies have been conducted to understand its effects on and interactions with its fish host, only limited information is available about how and to what extent M. cerebralis affects its oligochaete host, Tubifex tubifex. We investigated the effects of M. cerebralis on survival, growth, reproduction, and feeding activity of T. tubifex. Mature, immature and juvenile worms were exposed to myxospores and their infection prevalence, mortality, sexual development, reproduction and spore production were compared with unexposed worms. The parasite affected neither survival nor growth but inhibited clitellar development and reduced cocoon production by over 80%. Numbers of actinospores released from mature worms were nearly 9-fold higher than that of immature worms. When non-clitellated infected worms were kept at 30 degrees C for 4 days, spore release ceased and they re-developed a clitellum. These results suggest parasite-induced castration. Comparative monitoring of defecation rate revealed that M. cerebralis reduced feeding activity of T. tubifex by approximately 40%. Low energy intake and impaired energetic allocation may be the underlying mechanism behind reduced fecundity of infected T. tubifex. PMID:19284888

  16. Synthesis, physicochemical characterization, and biological activities of new carnosine derivatives stable in human serum as potential neuroprotective agents.

    PubMed

    Bertinaria, Massimo; Rolando, Barbara; Giorgis, Marta; Montanaro, Gabriele; Guglielmo, Stefano; Buonsanti, M Federica; Carabelli, Valentina; Gavello, Daniela; Daniele, Pier Giuseppe; Fruttero, Roberta; Gasco, Alberto

    2011-01-27

    The synthesis and the physicochemical and biological characterization of a series of carnosine amides bearing on the amido group alkyl substituents endowed with different lipophilicity are described. All synthesized products display carnosine-like properties differentiating from the lead for their high serum stability. They are able to complex Cu(2+) ions at physiological pH with the same stoichiometry as carnosine. The newly synthesized compounds display highly significant copper ion sequestering ability and are capable of protecting LDL from oxidation catalyzed by Cu(2+) ions, the most active compounds being the most hydrophilic ones. All the synthesized amides show quite potent carnosine-like HNE quenching activity; in particular, 7d, the member of the series selected for this kind of study, is able to cross the blood-brain barrier (BBB) and to protect primary mouse hippocampal neurons against HNE-induced death. These products can be considered metabolically stable analogues of carnosine and are worthy of additional investigation as potential neuroprotective agents. PMID:21182325

  17. Characterization of the biological activity of gamma-glutamyl-Se-methylselenocysteine: a novel, naturally occurring anticancer agent from garlic.

    PubMed

    Dong, Y; Lisk, D; Block, E; Ip, C

    2001-04-01

    Gamma-glutamyl-Se-methylselenocysteine (GGMSC) has recently been identified as the major Se compound in natural garlic and selenized garlic. Our working hypothesis is that GGMSC serves primarily as a carrier of Se-methylselenocysteine (MSC), which has been demonstrated in past research to be a potent cancer chemopreventive agent in animal carcinogenesis bioassays. The present study was designed to examine the in vivo responses to GGMSC or MSC using a variety of biochemical and biological end points, including (a) urinary Se excretion as a function of bolus dose; (b) tissue Se accumulation profile; (c) anticancer efficacy; and (d) gene expression changes as determined by cDNA array analysis. Our results showed that like MSC, GGMSC was well absorbed p.o., with urinary excretion as the major route for eliminating excess Se. When fed chronically, the profile of Se accumulation in various tissues was very comparable after treatment with either GGMSC or MSC. In rats that had been challenged with a carcinogen, supplementation with either GGMSC or MSC resulted in a lower prevalence of premalignant lesions in the mammary gland, and fewer mammary carcinomas when these early lesions were allowed to progress. More importantly, we found that a short term GGMSC/MSC treatment schedule of 4 weeks immediately after carcinogen dosing was sufficient to provide significant cancer protection, even in the absence of a sustained exposure past the initial 4-week period. With the use of the Clontech Atlas Rat cDNA Array, we further discovered that the gene expression changes induced in mammary epithelial cells of rats that were given either GGMSC or MSC showed a high degree of concordance. On the basis of the collective biology, biochemistry, and molecular biology data, we conclude that GGMSC is an effective anticancer agent with a mechanism of action very similar to that of MSC. PMID:11306469

  18. Magnetic Electrochemical Sensing Platform for Biomonitoring of Exposure to Organophosphorus Pesticides and Nerve Agents Based on Simultaneous Measurement of Total Enzyme Amount and Enzyme Activity

    SciTech Connect

    Du, Dan; Wang, Jun; Wang, Limin; Lu, Donglai; Smith, Jordan N.; Timchalk, Charles; Lin, Yuehe

    2011-05-15

    We report a new approach for electrochemical quantification of enzymatic inhibition and phosphorylation for biomonitoring of exposure to organophosphorus (OP) pesticides and nerve agents based on a magnetic beads (MBs) immunosensing platform. The principle of this approach is based on the combination of MBs immuno-capture based enzyme activity assay and competitive immunoassay of total amount of enzyme for simultaneous detection of enzyme inhibition and phosphorylation in biological fluids. Butyrylcholinesterase (BChE) was chosen as a model enzyme. In competitive immunoassay, the target total BChE in a sample (mixture of OP-inhibited BChE and active BChE) competes with the BChE modified on the MBs to bind to the limited anti-BChE antibody labeled with quantum dots (QDs-anti-BChE), and followed by electrochemical stripping analysis of the bound QDs conjugate on the MBs. This assay shows a linear response over the total BChE concentration range of 0.1~20 nM. Simultaneously, real time BChE activity was measured on an electrochemical carbon nanotube-based sensor coupled with microflow injection system after immuno-capture by MBs-anti-BChE conjugate. Therefore, the formed phosphorylated adduct (OP-BChE) can be estimated by the difference values of the total amount BChE (including active and OP-inhibited) and active BChE from established calibration curves. This approach not only eliminates the difficulty in screening of low-dose OP exposure (less than 20% inhibition of BChE) because of individual variation of BChE values, but also avoids the drawback of the scarce availability of OP-BChE antibody. It is sensitive enough to detect 0.5 nM OP-BChE, which is less than 2% BChE inhibition. This method offers a new method for rapid, accurate, selective and inexpensive quantification of phosphorylated adducts and enzyme inhibition for biomonitoring of OP and nerve agent exposures.

  19. Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II: broad-spectrum antibacterial agents with reduced hERG activity.

    PubMed

    Reck, Folkert; Alm, Richard; Brassil, Patrick; Newman, Joseph; Dejonge, Boudewijn; Eyermann, Charles J; Breault, Gloria; Breen, John; Comita-Prevoir, Janelle; Cronin, Mark; Davis, Hajnalka; Ehmann, David; Galullo, Vincent; Geng, Bolin; Grebe, Tyler; Morningstar, Marshall; Walker, Phil; Hayter, Barry; Fisher, Stewart

    2011-11-24

    Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. Aminopiperidines that have a bicyclic aromatic moiety linked through a carbon to an ethyl bridge, such as 1, generally show potent broad-spectrum antibacterial activity, including quinolone-resistant isolates, but suffer from potent hERG inhibition (IC(50)= 3 μM for 1). We now disclose the finding that new analogues of 1 with an N-linked cyclic amide moiety attached to the ethyl bridge, such as 24m, retain the broad-spectrum antibacterial activity of 1 but show significantly less hERG inhibition (IC(50)= 31 μM for 24m) and higher free fraction than 1. One optimized analogue, compound 24l, showed moderate clearance in the dog and promising efficacy against Staphylococcus aureus in a mouse thigh infection model. PMID:21999508

  20. Comparative in vitro activity of ceftaroline, ceftaroline-avibactam, and other antimicrobial agents against aerobic and anaerobic bacteria cultured from infected diabetic foot wounds.

    PubMed

    Goldstein, Ellie J C; Citron, Diane M; Merriam, C Vreni; Tyrrell, Kerin L

    2013-07-01

    Foot infections are the most common infectious complication of diabetes. Moderate to severe diabetic foot infections (DFI) are typically polymicrobial with both aerobic and anaerobic organisms. The role of MRSA in these wounds has become an increasing concern. To determine if the addition of avibactam, a novel non-beta-lactam beta-lactamase inhibitor, to ceftaroline would be more active than ceftaroline alone, we tested 316 aerobic pathogens and 154 anaerobic recovered from patients with moderate to severe DFI, and compared ceftaroline with and without avibactam to other agents. Testing on aerobes was done by broth microdilution and by agar dilution for anaerobes, according to CLSI M11-A8, and M7-A8 standards. Ceftaroline-avibactam MIC90 for all Staphylococcus spp. including MRSA was 0.5 μg/mL, and for enterococci was 1 μg/mL. The MIC90s for enteric Gram-negative rods was 0.125 μg/mL. The addition of avibactam to ceftaroline reduced the ceftaroline MICs for 2 strains of resistant Enterobacter spp. and for 1 strain of Morganella. Against anaerobic Gram-positive cocci ceftaroline-avibactam had an MIC90 0.125 μg/mL and for clostridia 1 μg/mL. Avibactam improved ceftaroline's MIC90s for Bacteroides fragilis from >32 to 2 μg/mL and for Prevotella spp. from >32 to 1 μg/mL. Ceftaroline alone demonstrates excellent in vitro activity against most of the aerobes found in moderate to severe DFI. The addition of avibactam provides an increased spectrum of activity including the beta-lactamase producing Prevotella, Bacteroides fragilis and ceftaroline resistant gram-negative enteric organisms. PMID:23623385