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Sample records for identify active compounds

  1. High Throughput Screening Identifies Novel Lead Compounds with Activity against Larval, Juvenile and Adult Schistosoma mansoni.

    PubMed

    Mansour, Nuha R; Paveley, Ross; Gardner, J Mark F; Bell, Andrew S; Parkinson, Tanya; Bickle, Quentin

    2016-04-01

    An estimated 600 million people are affected by the helminth disease schistosomiasis caused by parasites of the genus Schistosoma. There is currently only one drug recommended for treating schistosomiasis, praziquantel (PZQ), which is effective against adult worms but not against the juvenile stage. In an attempt to identify improved drugs for treating the disease, we have carried out high throughput screening of a number of small molecule libraries with the aim of identifying lead compounds with balanced activity against all life stages of Schistosoma. A total of almost 300,000 compounds were screened using a high throughput assay based on motility of worm larvae and image analysis of assay plates. Hits were screened against juvenile and adult worms to identify broadly active compounds and against a mammalian cell line to assess cytotoxicity. A number of compounds were identified as promising leads for further chemical optimization. PMID:27128493

  2. High Throughput Screening Identifies Novel Lead Compounds with Activity against Larval, Juvenile and Adult Schistosoma mansoni

    PubMed Central

    Gardner, J. Mark F.; Bell, Andrew S.; Parkinson, Tanya; Bickle, Quentin

    2016-01-01

    An estimated 600 million people are affected by the helminth disease schistosomiasis caused by parasites of the genus Schistosoma. There is currently only one drug recommended for treating schistosomiasis, praziquantel (PZQ), which is effective against adult worms but not against the juvenile stage. In an attempt to identify improved drugs for treating the disease, we have carried out high throughput screening of a number of small molecule libraries with the aim of identifying lead compounds with balanced activity against all life stages of Schistosoma. A total of almost 300,000 compounds were screened using a high throughput assay based on motility of worm larvae and image analysis of assay plates. Hits were screened against juvenile and adult worms to identify broadly active compounds and against a mammalian cell line to assess cytotoxicity. A number of compounds were identified as promising leads for further chemical optimization. PMID:27128493

  3. 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

  4. Calcium Imaging of Neuronal Activity in Drosophila Can Identify Anticonvulsive Compounds

    PubMed Central

    Streit, Anne K.; Fan, Yuen Ngan; Masullo, Laura; Baines, Richard A.

    2016-01-01

    Although there are now a number of antiepileptic drugs (AEDs) available, approximately one-third of epilepsy patients respond poorly to drug intervention. The reasons for this are complex, but are probably reflective of the increasing number of identified mutations that predispose individuals to this disease. Thus, there is a clear requirement for the development of novel treatments to address this unmet clinical need. The existence of gene mutations that mimic a seizure-like behaviour in the fruit fly, Drosophila melanogaster, offers the possibility to exploit the powerful genetics of this insect to identify novel cellular targets to facilitate design of more effective AEDs. In this study we use neuronal expression of GCaMP, a potent calcium reporter, to image neuronal activity using a non-invasive and rapid method. Expression in motoneurons in the isolated CNS of third instar larvae shows waves of calcium-activity that pass between segments of the ventral nerve cord. Time between calcium peaks, in the same neurons, between adjacent segments usually show a temporal separation of greater than 200 ms. Exposure to proconvulsants (picrotoxin or 4-aminopyridine) reduces separation to below 200 ms showing increased synchrony of activity across adjacent segments. Increased synchrony, characteristic of epilepsy, is similarly observed in genetic seizure mutants: bangsenseless1 (bss1) and paralyticK1270T (paraK1270T). Exposure of bss1 to clinically-used antiepileptic drugs (phenytoin or gabapentin) significantly reduces synchrony. In this study we use the measure of synchronicity to evaluate the effectiveness of known and novel anticonvulsive compounds (antipain, isethionate, etopiside rapamycin and dipyramidole) to reduce seizure-like CNS activity. We further show that such compounds also reduce the Drosophila voltage-gated persistent Na+ current (INaP) in an identified motoneuron (aCC). Our combined assays provide a rapid and reliable method to screen unknown compounds

  5. Potent Plasmodium falciparum gametocytocidal activity of diaminonaphthoquinones, lead antimalarial chemotypes identified in an antimalarial compound screen.

    PubMed

    Tanaka, Takeshi Q; Guiguemde, W Armand; Barnett, David S; Maron, Maxim I; Min, Jaeki; Connelly, Michele C; Suryadevara, Praveen Kumar; Guy, R Kiplin; Williamson, Kim C

    2015-03-01

    Forty percent of the world's population is threatened by malaria, which is caused by Plasmodium parasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. If Plasmodium falciparum gametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria. PMID:25512421

  6. Potent Plasmodium falciparum Gametocytocidal Activity of Diaminonaphthoquinones, Lead Antimalarial Chemotypes Identified in an Antimalarial Compound Screen

    PubMed Central

    Tanaka, Takeshi Q; Guiguemde, W. Armand; Barnett, David S.; Maron, Maxim I.; Min, Jaeki; Connelly, Michele C.; Suryadevara, Praveen Kumar; Guy, R. Kiplin

    2014-01-01

    Forty percent of the world's population is threatened by malaria, which is caused by Plasmodium parasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. If Plasmodium falciparum gametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria. PMID:25512421

  7. Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi

    PubMed Central

    Bilsland, Elizabeth; Bean, Daniel M.; Devaney, Eileen; Oliver, Stephen G.

    2016-01-01

    Background Lymphatic filariasis is caused by the parasitic worms Wuchereria bancrofti, Brugia malayi or B. timori, which are transmitted via the bites from infected mosquitoes. Once in the human body, the parasites develop into adult worms in the lymphatic vessels, causing severe damage and swelling of the affected tissues. According to the World Health Organization, over 1.2 billion people in 58 countries are at risk of contracting lymphatic filariasis. Very few drugs are available to treat patients infected with these parasites, and these have low efficacy against the adult stages of the worms, which can live for 7–15 years in the human body. The requirement for annual treatment increases the risk of drug-resistant worms emerging, making it imperative to develop new drugs against these devastating diseases. Methodology/Principal Findings We have developed a yeast-based, high-throughput screening system whereby essential yeast genes are replaced with their filarial or human counterparts. These strains are labeled with different fluorescent proteins to allow the simultaneous monitoring of strains with parasite or human genes in competition, and hence the identification of compounds that inhibit the parasite target without affecting its human ortholog. We constructed yeast strains expressing eight different Brugia malayi drug targets (as well as seven of their human counterparts), and performed medium-throughput drug screens for compounds that specifically inhibit the parasite enzymes. Using the Malaria Box collection (400 compounds), we identified nine filarial specific inhibitors and confirmed the antifilarial activity of five of these using in vitro assays against Brugia pahangi. Conclusions/Significance We were able to functionally complement yeast deletions with eight different Brugia malayi enzymes that represent potential drug targets. We demonstrated that our yeast-based screening platform is efficient in identifying compounds that can discriminate between

  8. Identifying non-point sources of endocrine active compounds and their biological impacts in freshwater lakes.

    PubMed

    Baker, Beth H; Martinovic-Weigelt, Dalma; Ferrey, Mark; Barber, Larry B; Writer, Jeffery H; Rosenberry, Donald O; Kiesling, Richard L; Lundy, James R; Schoenfuss, Heiko L

    2014-10-01

    Contaminants of emerging concern, particularly endocrine active compounds (EACs), have been identified as a threat to aquatic wildlife. However, little is known about the impact of EACs on lakes through groundwater from onsite wastewater treatment systems (OWTS). This study aims to identify specific contributions of OWTS to Sullivan Lake, Minnesota, USA. Lake hydrology, water chemistry, caged bluegill sunfish (Lepomis macrochirus), and larval fathead minnow (Pimephales promelas) exposures were used to assess whether EACs entered the lake through OWTS inflow and the resultant biological impact on fish. Study areas included two OWTS-influenced near-shore sites with native bluegill spawning habitats and two in-lake control sites without nearby EAC sources. Caged bluegill sunfish were analyzed for plasma vitellogenin concentrations, organosomatic indices, and histological pathologies. Surface and porewater was collected from each site and analyzed for EACs. Porewater was also collected for laboratory exposure of larval fathead minnow, before analysis of predator escape performance and gene expression profiles. Chemical analysis showed EACs present at low concentrations at each study site, whereas discrete variations were reported between sites and between summer and fall samplings. Body condition index and liver vacuolization of sunfish were found to differ among study sites as did gene expression in exposed larval fathead minnows. Interestingly, biological exposure data and water chemistry did not match. Therefore, although results highlight the potential impacts of seepage from OWTS, further investigation of mixture effects and life history factor as well as chemical fate is warranted. PMID:24974177

  9. Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compounds.

    PubMed

    Sawamura, Seishiro; Hatano, Masahiko; Takada, Yoshinori; Hino, Kyosuke; Kawamura, Tetsuya; Tanikawa, Jun; Nakagawa, Hiroshi; Hase, Hideharu; Nakao, Akito; Hirano, Mitsuru; Rotrattanadumrong, Rachapun; Kiyonaka, Shigeki; Mori, Masayuki X; Nishida, Motohiro; Hu, Yaopeng; Inoue, Ryuji; Nagata, Ryu; Mori, Yasuo

    2016-03-01

    Transient receptor potential canonical (TRPC) proteins form Ca(2+)-permeable cation channels activated upon stimulation of metabotropic receptors coupled to phospholipase C. Among the TRPC subfamily, TRPC3 and TRPC6 channels activated directly by diacylglycerol (DAG) play important roles in brain-derived neurotrophic factor (BDNF) signaling, promoting neuronal development and survival. In various disease models, BDNF restores neurologic deficits, but its therapeutic potential is limited by its poor pharmacokinetic profile. Elucidation of a framework for designing small molecules, which elicit BDNF-like activity via TRPC3 and TRPC6, establishes a solid basis to overcome this limitation. We discovered, through library screening, a group of piperazine-derived compounds that activate DAG-activated TRPC3/TRPC6/TRPC7 channels. The compounds [4-(5-chloro-2-methylphenyl)piperazin-1-yl](3-fluorophenyl)methanone (PPZ1) and 2-[4-(2,3-dimethylphenyl)piperazin-1-yl]-N-(2-ethoxyphenyl)acetamide (PPZ2) activated, in a dose-dependent manner, recombinant TRPC3/TRPC6/TRPC7 channels, but not other TRPCs, in human embryonic kidney cells. PPZ2 activated native TRPC6-like channels in smooth muscle cells isolated from rabbit portal vein. Also, PPZ2 evoked cation currents and Ca(2+) influx in rat cultured central neurons. Strikingly, both compounds induced BDNF-like neurite growth and neuroprotection, which were abolished by a knockdown or inhibition of TRPC3/TRPC6/TRPC7 in cultured neurons. Inhibitors of Ca(2+) signaling pathways, except calcineurin, impaired neurite outgrowth promotion induced by PPZ compounds. PPZ2 increased activation of the Ca(2+)-dependent transcription factor, cAMP response element-binding protein. These findings suggest that Ca(2+) signaling mediated by activation of DAG-activated TRPC channels underlies neurotrophic effects of PPZ compounds. Thus, piperazine-derived activators of DAG-activated TRPC channels provide important insights for future development of a

  10. Triptolide, an active compound identified in a traditional Chinese herb, induces apoptosis of rheumatoid synovial fibroblasts

    PubMed Central

    Kusunoki, Natsuko; Yamazaki, Ryuta; Kitasato, Hidero; Beppu, Moroe; Aoki, Haruhito; Kawai, Shinichi

    2004-01-01

    Background Extracts of Tripterygium wilfordii Hook F (TWHF), a traditional Chinese herb, have been reported to show efficacy in patients with rheumatoid arthritis (RA). Since RA is not only characterized by inflammation but also by synovial proliferation in the joints, we examined whether triptolide (a constituent of TWHF) could influence the proliferation of rheumatoid synovial fibroblasts (RSF) by induction of apoptosis. Results RSF were obtained from RA patients during surgery and were treated with triptolide under various conditions. The viability and proliferation of RSF were measured by the 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) assay and by 5-bromo-2'-deoxyuridine incorporation, respectively. Apoptosis was identified by detection of DNA fragmentation using an enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL). The role of caspases in apoptosis of RSF was analyzed by measuring caspase-3 activity. Activation of the peroxisome proliferator-activated receptor (PPAR) γ was assessed by a luciferase reporter gene assay using RSF transfected with a plasmid containing the peroxisome proliferator response element. Triptolide decreased viability, inhibited proliferation, and induced apoptosis of RSF in a concentration-dependent manner at very low (nM) concentrations. Caspase-3 activity was increased by treatment with triptolide and was suppressed by caspase inhibitors. Although PPARγ activation was induced by 15-deoxy-Δ12,14-prostaglandin J2, triptolide did not induce it under the same experimental conditions. An extract of TWHF also induced DNA fragmentation in RSF. Conclusion The mechanism of action remains to be studied; however, triptolide may possibly have a disease-modifying effect in patients with RA. PMID:15040811

  11. Development and application of a sensitive, phenotypic, high-throughput image-based assay to identify compound activity against Trypanosoma cruzi amastigotes

    PubMed Central

    Sykes, Melissa L.; Avery, Vicky M.

    2015-01-01

    We have developed a high content 384-well, image-based assay to estimate the effect of compound treatment on Trypanosoma cruzi amastigotes in 3T3 fibroblasts. In the same well, the effect of compound activity on host cells can also be determined, as an initial indicator of cytotoxicity. This assay has been used to identify active compounds from an in-house library of compounds with either known biological activity or that are FDA approved, and separately, from the Medicines for Malaria Venture Malaria Box collection. Active compounds were screened against T. cruzi trypomastigotes, utilising an assay developed with the viability dye resazurin. Twelve compounds with reconfirmed solid sample activity, with IC50 values of less than 10 μM and selectivity indices to T. cruzi amastigotes over 3T3 host cells of between >22 and 319 times were identified from these libraries. As 3T3 cells are contact inhibited, with limited proliferation in the assay, selective compounds of interest were profiled in a separate assay to estimate the viability of compound treated, replicating HEK293 cells. Selective compounds that were not previously reported in the literature were further profiled by extending the incubation time against amastigote infected 3T3 cells to determine if there were residual amastigotes post-treatment, important for the consideration of the exposure time required for further biological characterisation. The assay development process and the suitability of identified compounds as hit molecules for Chagas disease research are discussed. PMID:27120069

  12. Zebrafish behavioral profiling identifies multitarget antipsychotic-like compounds.

    PubMed

    Bruni, Giancarlo; Rennekamp, Andrew J; Velenich, Andrea; McCarroll, Matthew; Gendelev, Leo; Fertsch, Ethan; Taylor, Jack; Lakhani, Parth; Lensen, Dennis; Evron, Tama; Lorello, Paul J; Huang, Xi-Ping; Kolczewski, Sabine; Carey, Galen; Caldarone, Barbara J; Prinssen, Eric; Roth, Bryan L; Keiser, Michael J; Peterson, Randall T; Kokel, David

    2016-07-01

    Many psychiatric drugs act on multiple targets and therefore require screening assays that encompass a wide target space. With sufficiently rich phenotyping and a large sampling of compounds, it should be possible to identify compounds with desired mechanisms of action on the basis of behavioral profiles alone. Although zebrafish (Danio rerio) behavior has been used to rapidly identify neuroactive compounds, it is not clear what types of behavioral assays would be necessary to identify multitarget compounds such as antipsychotics. Here we developed a battery of behavioral assays in larval zebrafish to determine whether behavioral profiles can provide sufficient phenotypic resolution to identify and classify psychiatric drugs. Using the antipsychotic drug haloperidol as a test case, we found that behavioral profiles of haloperidol-treated zebrafish could be used to identify previously uncharacterized compounds with desired antipsychotic-like activities and multitarget mechanisms of action. PMID:27239787

  13. Novel compound for identifying Escherichia coli.

    PubMed Central

    Watkins, W D; Rippey, S R; Clavet, C R; Kelley-Reitz, D J; Burkhardt, W

    1988-01-01

    A new chromogenic compound, 5-bromo-4-chloro-3-indoxyl-beta-D-glucuronide, was found to be useful for the rapid, specific, differential identification of Escherichia coli in the sanitary analysis of shellfish and wastewater. Of 1,025 presumptively positive colonies (blue) and 583 presumptively negative colonies (nonblue), only 1% false-negative and 5% false-positive results were found. PMID:3046494

  14. Screen of FDA-approved drug library identifies maprotiline, an antibiofilm and antivirulence compound with QseC sensor-kinase dependent activity in Francisella novicida

    PubMed Central

    Dean, Scott N; van Hoek, Monique L

    2015-01-01

    Development of new therapeutics against Select Agents such as Francisella is critical preparation in the event of bioterrorism. Testing FDA-approved drugs for this purpose may yield new activities unrelated to their intended purpose and may hasten the discovery of new therapeutics. A library of 420 FDA-approved drugs was screened for antibiofilm activity against a model organism for human tularemia, Francisella (F.) novicida, excluding drugs that significantly inhibited growth. The initial screen was based on the 2-component system (TCS) dependent biofilm effect, thus, the QseC dependence of maprotiline anti-biofilm action was demonstrated. By comparing their FDA-approved uses, chemical structures, and other properties of active drugs, toremifene and polycyclic antidepressants maprotiline and chlorpromazine were identified as being highly active against F. novicida biofilm formation. Further down-selection excluded toremifene for its membrane active activity and chlorpromazine for its high antimicrobial activity. The mode of action of maprotiline against F. novicida was sought. It was demonstrated that maprotiline was able to significantly down-regulate the expression of the virulence factor IglC, encoded on the Francisella Pathogenicity Island (FPI), suggesting that maprotiline is exerting an effect on bacterial virulence. Further studies showed that maprotiline significantly rescued F. novicida infected wax worm larvae. In vivo studies demonstrated that maprotiline treatment could prolong time to disease onset and survival in F. novicida infected mice. These results suggest that an FDA-approved drug such as maprotiline has the potential to combat Francisella infection as an antivirulence agent, and may have utility in combination with antibiotics. PMID:26155740

  15. A Novel Way To Identify Precursors That Degrade To Perfluourinated Compounds In Activated Sludge Using Ion-Trap Time-Of-Flight Mass Spectrometer

    EPA Science Inventory

    An increasing number of studies have been conducted to investigate the environmental distribution of perfluorinated alkyl compounds (PFCs), many of which are known to be toxic in laboratory animals. Despite growing public concerns, the fate and transport of PFCs are little under...

  16. A Novel Way To Identify Precursors That Degrade To Perfluorinated Compounds In Activated Sludge Using Ion-Trap Time-Of-Flight Mass Spectrometry

    EPA Science Inventory

    An increasing number of studies have been conducted to investigate the environmental distribution of perfluorinated alkyl compounds (PFCs), many of which are known to be toxic in laboratory animals. Despite growing public concerns, fate and transport of PFCs are little known. M...

  17. A staining protocol for identifying secondary compounds in Myrtaceae1

    PubMed Central

    Retamales, Hernan A.; Scharaschkin, Tanya

    2014-01-01

    • Premise of the study: Here we propose a staining protocol using toluidine blue (TBO) and ruthenium red to reliably identify secondary compounds in the leaves of some species of Myrtaceae. • Methods and Results: Leaves of 10 species representing 10 different genera of Myrtaceae were processed and stained using five different combinations of ruthenium red and TBO. Optimal staining conditions were determined as 1 min of ruthenium red (0.05% aqueous) and 45 s of TBO (0.1% aqueous). Secondary compounds clearly identified under this treatment include mucilage in the mesophyll, polyphenols in the cuticle, lignin in fibers and xylem, tannins and carboxylated polysaccharides in the epidermis, and pectic substances in the primary cell walls. • Conclusions: Potential applications of this protocol include systematic, phytochemical, and ecological investigations in Myrtaceae. It might be applicable to other plant families rich in secondary compounds and could be used as a preliminary screening method for extraction of these elements. PMID:25309840

  18. Zebrafish screen identifies novel compound with selective toxicity against leukemia

    PubMed Central

    Ridges, Suzanne; Heaton, Will L.; Joshi, Deepa; Choi, Henry; Eiring, Anna; Batchelor, Lance; Choudhry, Priya; Manos, Elizabeth J.; Sofla, Hossein; Sanati, Ali; Welborn, Seth; Agarwal, Archana; Spangrude, Gerald J.; Miles, Rodney R.; Cox, James E.; Frazer, J. Kimble; Deininger, Michael; Balan, Kaveri; Sigman, Matthew; Müschen, Markus; Perova, Tatiana; Johnson, Radia; Montpellier, Bertrand; Guidos, Cynthia J.; Jones, David A.

    2012-01-01

    To detect targeted antileukemia agents we have designed a novel, high-content in vivo screen using genetically engineered, T-cell reporting zebrafish. We exploited the developmental similarities between normal and malignant T lymphoblasts to screen a small molecule library for activity against immature T cells with a simple visual readout in zebrafish larvae. After screening 26 400 molecules, we identified Lenaldekar (LDK), a compound that eliminates immature T cells in developing zebrafish without affecting the cell cycle in other cell types. LDK is well tolerated in vertebrates and induces long-term remission in adult zebrafish with cMYC-induced T-cell acute lymphoblastic leukemia (T-ALL). LDK causes dephosphorylation of members of the PI3 kinase/AKT/mTOR pathway and delays sensitive cells in late mitosis. Among human cancers, LDK selectively affects survival of hematopoietic malignancy lines and primary leukemias, including therapy-refractory B-ALL and chronic myelogenous leukemia samples, and inhibits growth of human T-ALL xenografts. This work demonstrates the utility of our method using zebrafish for antineoplastic candidate drug identification and suggests a new approach for targeted leukemia therapy. Although our efforts focused on leukemia therapy, this screening approach has broad implications as it can be translated to other cancer types involving malignant degeneration of developmentally arrested cells. PMID:22490804

  19. IDENTIFYING COMPOUNDS DESPITE CHROMATOGRAPHY LIMITATIONS: ORGANOPHOSPHATES IN TREATED SEWAGE

    EPA Science Inventory

    Highly concentrated extracts of sewage treatment plant (STP) effluents contain detectable
    levels of dozens of compounds resulting from human activities. Recent concern over use and
    disposal of Pharmaceuticals and Personal Care Products (PPCPS) (1) has stimulated interest ...

  20. Transcriptional Inhibitors Identified in a 160,000-Compound Small-Molecule DUX4 Viability Screen.

    PubMed

    Choi, Si Ho; Bosnakovski, Darko; Strasser, Jessica M; Toso, Erik A; Walters, Michael A; Kyba, Michael

    2016-08-01

    Facioscapulohumeral muscular dystrophy is a genetically dominant, currently untreatable muscular dystrophy. It is caused by mutations that enable expression of the normally silent DUX4 gene, which encodes a pathogenic transcription factor. A screen based on Tet-on DUX4-induced mouse myoblast death previously uncovered compounds from a 44,000-compound library that protect against DUX4 toxicity. Many of those compounds acted downstream of DUX4 in an oxidative stress pathway. Here, we extend this screen to an additional 160,000 compounds and, using greater stringency, identify a new set of DUX4-protective compounds. From 640 hits, we performed secondary screens, repurchased 46 of the most desirable, confirmed activity, and tested each for activity against other cell death-inducing insults. The majority of these compounds also protected against oxidative stress. Of the 100 repurchased compounds identified through both screens, only SHC40, 75, and 98 inhibited DUX4 target genes, but they also inhibited dox-mediated DUX4 expression. Using a target gene readout on the 640-compound hit set, we discovered three overlooked compounds, SHC351, 540, and 572, that inhibit DUX4 target gene upregulation without nonspecific effects on the Tet-on system. These novel inhibitors of DUX4 transcriptional activity may thus act on pathways or cofactors needed by DUX4 for transcriptional activation in these cells. PMID:27245141

  1. High Throughput Screening Identifies a Novel Compound Protecting Cardiomyocytes from Doxorubicin-Induced Damage

    PubMed Central

    Gergely, Szabolcs; Hegedűs, Csaba; Lakatos, Petra; Kovács, Katalin; Gáspár, Renáta; Csont, Tamás; Virág, László

    2015-01-01

    Antracyclines are effective antitumor agents. One of the most commonly used antracyclines is doxorubicin, which can be successfully used to treat a diverse spectrum of tumors. Application of these drugs is limited by their cardiotoxic effect, which is determined by a lifetime cumulative dose. We set out to identify by high throughput screening cardioprotective compounds protecting cardiomyocytes from doxorubicin-induced injury. Ten thousand compounds of ChemBridge's DIVERSet compound library were screened to identify compounds that can protect H9C2 rat cardiomyocytes against doxorubicin-induced cell death. The most effective compound proved protective in doxorubicin-treated primary rat cardiomyocytes and was further characterized to demonstrate that it significantly decreased doxorubicin-induced apoptotic and necrotic cell death and inhibited doxorubicin-induced activation of JNK MAP kinase without having considerable radical scavenging effect or interfering with the antitumor effect of doxorubicin. In fact the compound identified as 3-[2-(4-ethylphenyl)-2-oxoethyl]-1,2-dimethyl-1H-3,1-benzimidazol-3-ium bromide was toxic to all tumor cell lines tested even without doxorubicine treatment. This benzimidazole compound may lead, through further optimalization, to the development of a drug candidate protecting the heart from doxorubicin-induced injury. PMID:26137186

  2. High-Throughput Yeast-Based Reporter Assay to Identify Compounds with Anti-inflammatory Potential.

    PubMed

    Garcia, G; Santos, C Nunes do; Menezes, R

    2016-01-01

    The association between altered proteostasis and inflammatory responses has been increasingly recognized, therefore the identification and characterization of novel compounds with anti-inflammatory potential will certainly have a great impact in the therapeutics of protein-misfolding diseases such as degenerative disorders. Although cell-based screens are powerful approaches to identify potential therapeutic compounds, establishing robust inflammation models amenable to high-throughput screening remains a challenge. To bridge this gap, we have exploited the use of yeasts as a platform to identify lead compounds with anti-inflammatory properties. The yeast cell model described here relies on the high-degree homology between mammalian and yeast Ca(2+)/calcineurin pathways converging into the activation of NFAT and Crz1 orthologous proteins, respectively. It consists of a recombinant yeast strain encoding the lacZ gene under the control of Crz1-recongition elements to facilitate the identification of compounds interfering with Crz1 activation through the easy monitoring of β-galactosidase activity. Here, we describe in detail a protocol optimized for high-throughput screening of compounds with potential anti-inflammatory activity as well as a protocol to validate the positive hits using an alternative β-galactosidase substrate. PMID:27613055

  3. An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies.

    PubMed

    O'Neil, Jennifer; Benita, Yair; Feldman, Igor; Chenard, Melissa; Roberts, Brian; Liu, Yaping; Li, Jing; Kral, Astrid; Lejnine, Serguei; Loboda, Andrey; Arthur, William; Cristescu, Razvan; Haines, Brian B; Winter, Christopher; Zhang, Theresa; Bloecher, Andrew; Shumway, Stuart D

    2016-06-01

    Combination drug therapy is a widely used paradigm for managing numerous human malignancies. In cancer treatment, additive and/or synergistic drug combinations can convert weakly efficacious monotherapies into regimens that produce robust antitumor activity. This can be explained in part through pathway interdependencies that are critical for cancer cell proliferation and survival. However, identification of the various interdependencies is difficult due to the complex molecular circuitry that underlies tumor development and progression. Here, we present a high-throughput platform that allows for an unbiased identification of synergistic and efficacious drug combinations. In a screen of 22,737 experiments of 583 doublet combinations in 39 diverse cancer cell lines using a 4 by 4 dosing regimen, both well-known and novel synergistic and efficacious combinations were identified. Here, we present an example of one such novel combination, a Wee1 inhibitor (AZD1775) and an mTOR inhibitor (ridaforolimus), and demonstrate that the combination potently and synergistically inhibits cancer cell growth in vitro and in vivo This approach has identified novel combinations that would be difficult to reliably predict based purely on our current understanding of cancer cell biology. Mol Cancer Ther; 15(6); 1155-62. ©2016 AACR. PMID:26983881

  4. Identifying Sexual Harassment: A Classroom Activity

    ERIC Educational Resources Information Center

    Madson, Laura; Shoda, Jennifer

    2002-01-01

    We created a classroom activity to illustrate the complexity involved in identifying sexual harassment. In the activity, students decided whether 6 fictional scenarios constituted sexual harassment. The activity stimulates animated discussion, and evaluation data indicate that it received positive feedback from students and refined students'…

  5. Phenolic compounds with IL-6 inhibitory activity from Aster yomena.

    PubMed

    Kim, A Ryun; Jin, Qinglong; Jin, Hong-Guang; Ko, Hae Ju; Woo, Eun-Rhan

    2014-07-01

    A new biflavonoid, named asteryomenin (1), as well as six known phenolic compounds, esculetin (2), 4-O-β-D-glucopyranoside-3-hydroxy methyl benzoate (3), caffeic acid (4), isoquercitrin (5), isorhamnetin-3-O-glucoside (6), and apigenin (7) were isolated from the aerial parts of Aster yomena. The structures of compounds (1-7) were identified based on 1D and 2D NMR, including (1)H-(1)H COSY, HSQC, HMBC and NOESY spectroscopic analyses. Compounds 2-7 were isolated from this plant for the first time. For these isolates, the inhibitory activity of IL-6 production in the TNF-α stimulated MG-63 cell was examined. Among these isolates, compounds 4 and 7 appeared to have potent inhibitory activity of IL-6 production in the TNF-α stimulated MG-63 cell, while compounds 1-3 and 5-6 showed moderate activity. PMID:24014305

  6. Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit Toxoplasma gondii Growth

    PubMed Central

    Dittmar, Ashley J.; Drozda, Allison A.

    2016-01-01

    ABSTRACT The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of <5 µM. A significant number of these compounds are established inhibitors of dopamine or estrogen signaling. Follow-up experiments with the dopamine receptor inhibitor pimozide revealed that the drug impacted both parasite invasion and replication but did so independently of inhibition of dopamine or other neurotransmitter receptor signaling. Tamoxifen, which is an established inhibitor of the estrogen receptor, also reduced parasite invasion and replication. Even though Toxoplasma can activate the estrogen receptor, tamoxifen inhibits parasite growth independently of this transcription factor. Tamoxifen is also a potent inducer of autophagy, and we find that the drug stimulates recruitment of the autophagy marker light chain 3-green fluorescent protein onto the membrane of the vacuolar compartment in which the parasite resides and replicates. In contrast to other antiparasitic drugs, including pimozide, tamoxifen treatment of infected cells leads to a time-dependent elimination of intracellular parasites. Taken together, these data suggest that tamoxifen restricts Toxoplasma growth by inducing xenophagy or autophagic destruction of this obligate intracellular parasite. IMPORTANCE There is an urgent need to develop new therapies to treat microbial infections, and the repurposing of well-characterized compounds is emerging as one approach to achieving this goal. Using the protozoan parasite Toxoplasma gondii, we screened a library of 1,120 compounds and identified several

  7. Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit Toxoplasma gondii Growth.

    PubMed

    Dittmar, Ashley J; Drozda, Allison A; Blader, Ira J

    2016-01-01

    The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of <5 µM. A significant number of these compounds are established inhibitors of dopamine or estrogen signaling. Follow-up experiments with the dopamine receptor inhibitor pimozide revealed that the drug impacted both parasite invasion and replication but did so independently of inhibition of dopamine or other neurotransmitter receptor signaling. Tamoxifen, which is an established inhibitor of the estrogen receptor, also reduced parasite invasion and replication. Even though Toxoplasma can activate the estrogen receptor, tamoxifen inhibits parasite growth independently of this transcription factor. Tamoxifen is also a potent inducer of autophagy, and we find that the drug stimulates recruitment of the autophagy marker light chain 3-green fluorescent protein onto the membrane of the vacuolar compartment in which the parasite resides and replicates. In contrast to other antiparasitic drugs, including pimozide, tamoxifen treatment of infected cells leads to a time-dependent elimination of intracellular parasites. Taken together, these data suggest that tamoxifen restricts Toxoplasma growth by inducing xenophagy or autophagic destruction of this obligate intracellular parasite. IMPORTANCE There is an urgent need to develop new therapies to treat microbial infections, and the repurposing of well-characterized compounds is emerging as one approach to achieving this goal. Using the protozoan parasite Toxoplasma gondii, we screened a library of 1,120 compounds and identified several

  8. Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds.

    PubMed

    Bilsland, Elizabeth; Sparkes, Andrew; Williams, Kevin; Moss, Harry J; de Clare, Michaela; Pir, Pinar; Rowland, Jem; Aubrey, Wayne; Pateman, Ron; Young, Mike; Carrington, Mark; King, Ross D; Oliver, Stephen G

    2013-02-01

    We have developed a robust, fully automated anti-parasitic drug-screening method that selects compounds specifically targeting parasite enzymes and not their host counterparts, thus allowing the early elimination of compounds with potential side effects. Our yeast system permits multiple parasite targets to be assayed in parallel owing to the strains' expression of different fluorescent proteins. A strain expressing the human target is included in the multiplexed screen to exclude compounds that do not discriminate between host and parasite enzymes. This form of assay has the advantages of using known targets and not requiring the in vitro culture of parasites. We performed automated screens for inhibitors of parasite dihydrofolate reductases, N-myristoyltransferases and phosphoglycerate kinases, finding specific inhibitors of parasite targets. We found that our 'hits' have significant structural similarities to compounds with in vitro anti-parasitic activity, validating our screens and suggesting targets for hits identified in parasite-based assays. Finally, we demonstrate a 60 per cent success rate for our hit compounds in killing or severely inhibiting the growth of Trypanosoma brucei, the causative agent of African sleeping sickness. PMID:23446112

  9. Screening of antitubercular compound library identifies novel shikimate kinase inhibitors of Mycobacterium tuberculosis.

    PubMed

    Rajput, Vikrant S; Mehra, Rukmankesh; Kumar, Sanjay; Nargotra, Amit; Singh, Parvinder Pal; Khan, Inshad Ali

    2016-06-01

    Shikimate kinase of Mycobacterium tuberculosis is involved in the biosynthesis of aromatic amino acids through shikimate pathway. The enzyme is essential for the survival of M. tuberculosis and is absent from mammals, thus providing an excellent opportunity for identifying new chemical entities to combat tuberculosis with a novel mechanism of action. In this study, an antitubercular library of 1000 compounds was screened against M. tuberculosis shikimate kinase (MtSK). This effort led to the identification of 20 inhibitors, among which five promising leads exhibited half maximal inhibitory concentration (IC50) values below 10 μM. The most potent inhibitor ("5631296") showed an IC50 value of 5.10 μM ± 0.6. The leads were further evaluated for the activity against multidrug-resistant (MDR)-TB, Gram-positive and Gram-negative bacterial strains, mode of action, docking simulations, and combinatorial study with three frontline anti-TB drugs. Compound "5491210" displayed a nearly synergistic activity with rifampicin, isoniazid, and ethambutol while compound "5631296" was synergistic with rifampicin. In vitro cytotoxicity against HepG2 cell line was evaluated and barring one compound; all were found to be non-toxic (SI > 10). In order to rule out mitochondrial toxicity, the promising inhibitors were also evaluated for cell cytotoxicity using galactose medium where compounds "5631296" and "5122752" appeared non-toxic. Upon comprehensive analysis, compound "5631296" was found to be the most promising MtSK inhibitor that was safe, synergistic with rifampicin, and bactericidal against M. tuberculosis. PMID:26887318

  10. Multiplexing high-content flow (HCF) and quantitative high-throughput screening (qHTS) to identify compounds capable of decreasing cell viability, activating caspase 3/7, expressing annexin V, and changing mitochondrial membrane integrity.

    PubMed

    Mathews, Lesley A; Keller, Jonathan M; McKnight, Crystal; Michael, Sam; Shinn, Paul; Liu, Dongbo; Staudt, Louis M; Thomas, Craig J; Ferrer, Marc

    2013-01-01

    High-content flow (HCF) screening systems, such as the iQue Screener and HTFC Screening System from IntelliCyt, have facilitated the implementation of flow cytometry assays for high-throughput screening. HCF screening systems enable the use of smaller sample volumes and multiplexed assays to simultaneously assess different cellular parameters from a single well. This becomes invaluable when working with cells or compounds that are available in limited quantities or when conducting large-scale screens. When assays can be miniaturized to a 384- or 1536-well microplate format, it is possible to implement dose-response-based high-throughput screens, also known as quantitative HTS or qHTS. This article describes how qHTS at the new National Center for Advancing Translational Science (NCATS) has been systematically coupled with the HTFC Screening System and Multimetric Apoptosis Screening Kit from IntelliCyt to biologically validate active compounds from primary cell proliferation screens using a model of diffuse large B cell lymphoma (DLBCL). PMID:24391083

  11. A small molecule screen identifies a novel compound that induces a homeotic transformation in Hydra.

    PubMed

    Glauber, Kristine M; Dana, Catherine E; Park, Steve S; Colby, David A; Noro, Yukihiko; Fujisawa, Toshitaka; Chamberlin, A Richard; Steele, Robert E

    2013-12-01

    Developmental processes such as morphogenesis, patterning and differentiation are continuously active in the adult Hydra polyp. We carried out a small molecule screen to identify compounds that affect patterning in Hydra. We identified a novel molecule, DAC-2-25, that causes a homeotic transformation of body column into tentacle zone. This transformation occurs in a progressive and polar fashion, beginning at the oral end of the animal. We have identified several strains that respond to DAC-2-25 and one that does not, and we used chimeras from these strains to identify the ectoderm as the target tissue for DAC-2-25. Using transgenic Hydra that express green fluorescent protein under the control of relevant promoters, we examined how DAC-2-25 affects tentacle patterning. Genes whose expression is associated with the tentacle zone are ectopically expressed upon exposure to DAC-2-25, whereas those associated with body column tissue are turned off as the tentacle zone expands. The expression patterns of the organizer-associated gene HyWnt3 and the hypostome-specific gene HyBra2 are unchanged. Structure-activity relationship studies have identified features of DAC-2-25 that are required for activity and potency. This study shows that small molecule screens in Hydra can be used to dissect patterning processes. PMID:24255098

  12. A small molecule screen identifies a novel compound that induces a homeotic transformation in Hydra

    PubMed Central

    Glauber, Kristine M.; Dana, Catherine E.; Park, Steve S.; Colby, David A.; Noro, Yukihiko; Fujisawa, Toshitaka; Chamberlin, A. Richard; Steele, Robert E.

    2013-01-01

    Developmental processes such as morphogenesis, patterning and differentiation are continuously active in the adult Hydra polyp. We carried out a small molecule screen to identify compounds that affect patterning in Hydra. We identified a novel molecule, DAC-2-25, that causes a homeotic transformation of body column into tentacle zone. This transformation occurs in a progressive and polar fashion, beginning at the oral end of the animal. We have identified several strains that respond to DAC-2-25 and one that does not, and we used chimeras from these strains to identify the ectoderm as the target tissue for DAC-2-25. Using transgenic Hydra that express green fluorescent protein under the control of relevant promoters, we examined how DAC-2-25 affects tentacle patterning. Genes whose expression is associated with the tentacle zone are ectopically expressed upon exposure to DAC-2-25, whereas those associated with body column tissue are turned off as the tentacle zone expands. The expression patterns of the organizer-associated gene HyWnt3 and the hypostome-specific gene HyBra2 are unchanged. Structure-activity relationship studies have identified features of DAC-2-25 that are required for activity and potency. This study shows that small molecule screens in Hydra can be used to dissect patterning processes. PMID:24255098

  13. Artificial neural network cascade identifies multi-P450 inhibitors in natural compounds

    PubMed Central

    Li, Zhangming; Li, Yan; Sun, Lu; Tang, Yun; Liu, Lanru

    2015-01-01

    Substantial evidence has shown that most exogenous substances are metabolized by multiple cytochrome P450 (P450) enzymes instead of by merely one P450 isoform. Thus, multi-P450 inhibition leads to greater drug-drug interaction risk than specific P450 inhibition. Herein, we innovatively established an artificial neural network cascade (NNC) model composed of 23 cascaded networks in a ladder-like framework to identify potential multi-P450 inhibitors among natural compounds by integrating 12 molecular descriptors into a P450 inhibition score (PIS). Experimental data reporting in vitro inhibition of five P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) were obtained for 8,148 compounds from the Cytochrome P450 Inhibitors Database (CPID). The results indicate significant positive correlation between the PIS values and the number of inhibited P450 isoforms (Spearman’s ρ = 0.684, p < 0.0001). Thus, a higher PIS indicates a greater possibility for a chemical to inhibit the enzyme activity of at least three P450 isoforms. Ten-fold cross-validation of the NNC model suggested an accuracy of 78.7% for identifying whether a compound is a multi-P450 inhibitor or not. Using our NNC model, 22.2% of the approximately 160,000 natural compounds in TCM Database@Taiwan were identified as potential multi-P450 inhibitors. Furthermore, chemical similarity calculations suggested that the prevailing parent structures of natural multi-P450 inhibitors were alkaloids. Our findings show that dissection of chemical structure contributes to confident identification of natural multi-P450 inhibitors and provides a feasible method for virtually evaluating multi-P450 inhibition risk for a known structure. PMID:26719820

  14. Biologically active compounds from Aphyllophorales (polypore) fungi.

    PubMed

    Zjawiony, Jordan K

    2004-02-01

    This review describes biologically active natural products isolated from Aphyllophorales, many of which are known as polypores. Polypores are a large group of terrestrial fungi of the phylum Basdiomycota (basidiomycetes), and they along with certain Ascomycota are a major source of pharmacologically active substances. There are about 25 000 species of basidiomycetes, of which about 500 are members of the Aphyllophorales, a polyphyletic group that contains the polypores. Many of these fungi have circumboreal distributions in North America, Europe, and Asia and broad distributions on all inhabited continents and Africa; only a small number of the most common species with the most obvious fruiting bodies (basidiocarps) have been evaluated for biological activity. An estimated 75% of polypore fungi that have been tested show strong antimicrobial activity, and these may constitute a good source for developing new antibiotics. Numerous compounds from these fungi also display antiviral, cytotoxic, and/or antineoplastic activities. Additional important components of this vast arsenal of compounds are polysaccharides derived from the fungal cell walls. These compounds have attracted significant attention in recent years because of their immunomodulatory activities, resulting in antitumor effects. These high molecular weight compounds, often called biological response modifiers (BRM), or immunopotentiators, prevent carcinogenesis, show direct anticancer effects, and prevent tumor metastasis. Some of the protein-bound polysaccharides from polypores and other basidiomycetes have found their way to the market in Japan as anticancer drugs. Finally, numerous compounds with cardiovascular, phytotoxic, immunomodulatory, analgesic, antidiabetic, antioxidant, insecticidal, and nematocidal activities, isolated from polypores, are also presented. In fact many of the fungi mentioned in this paper have long been used in herbal medicine, including polypores such as Ganoderma lucidum

  15. Identifying Crucial Parameter Correlations Maintaining Bursting Activity

    PubMed Central

    Doloc-Mihu, Anca; Calabrese, Ronald L.

    2014-01-01

    Recent experimental and computational studies suggest that linearly correlated sets of parameters (intrinsic and synaptic properties of neurons) allow central pattern-generating networks to produce and maintain their rhythmic activity regardless of changing internal and external conditions. To determine the role of correlated conductances in the robust maintenance of functional bursting activity, we used our existing database of half-center oscillator (HCO) model instances of the leech heartbeat CPG. From the database, we identified functional activity groups of burster (isolated neuron) and half-center oscillator model instances and realistic subgroups of each that showed burst characteristics (principally period and spike frequency) similar to the animal. To find linear correlations among the conductance parameters maintaining functional leech bursting activity, we applied Principal Component Analysis (PCA) to each of these four groups. PCA identified a set of three maximal conductances (leak current, Leak; a persistent K current, K2; and of a persistent Na+ current, P) that correlate linearly for the two groups of burster instances but not for the HCO groups. Visualizations of HCO instances in a reduced space suggested that there might be non-linear relationships between these parameters for these instances. Experimental studies have shown that period is a key attribute influenced by modulatory inputs and temperature variations in heart interneurons. Thus, we explored the sensitivity of period to changes in maximal conductances of Leak, K2, and P, and we found that for our realistic bursters the effect of these parameters on period could not be assessed because when varied individually bursting activity was not maintained. PMID:24945358

  16. Identifying Bioaccumulative Halogenated Organic Compounds Using a Nontargeted Analytical Approach: Seabirds as Sentinels

    PubMed Central

    Millow, Christopher J.; Mackintosh, Susan A.; Lewison, Rebecca L.; Dodder, Nathan G.; Hoh, Eunha

    2015-01-01

    Persistent organic pollutants (POPs) are typically monitored via targeted mass spectrometry, which potentially identifies only a fraction of the contaminants actually present in environmental samples. With new anthropogenic compounds continuously introduced to the environment, novel and proactive approaches that provide a comprehensive alternative to targeted methods are needed in order to more completely characterize the diversity of known and unknown compounds likely to cause adverse effects. Nontargeted mass spectrometry attempts to extensively screen for compounds, providing a feasible approach for identifying contaminants that warrant future monitoring. We employed a nontargeted analytical method using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC/TOF-MS) to characterize halogenated organic compounds (HOCs) in California Black skimmer (Rynchops niger) eggs. Our study identified 111 HOCs; 84 of these compounds were regularly detected via targeted approaches, while 27 were classified as typically unmonitored or unknown. Typically unmonitored compounds of note in bird eggs included tris(4-chlorophenyl)methane (TCPM), tris(4-chlorophenyl)methanol (TCPMOH), triclosan, permethrin, heptachloro-1'-methyl-1,2'-bipyrrole (MBP), as well as four halogenated unknown compounds that could not be identified through database searching or the literature. The presence of these compounds in Black skimmer eggs suggests they are persistent, bioaccumulative, potentially biomagnifying, and maternally transferring. Our results highlight the utility and importance of employing nontargeted analytical tools to assess true contaminant burdens in organisms, as well as to demonstrate the value in using environmental sentinels to proactively identify novel contaminants. PMID:26020245

  17. A Virtual Screening Approach For Identifying Plants with Anti H5N1 Neuraminidase Activity

    PubMed Central

    2016-01-01

    Recent outbreaks of highly pathogenic and occasional drug-resistant influenza strains have highlighted the need to develop novel anti-influenza therapeutics. Here, we report computational and experimental efforts to identify influenza neuraminidase inhibitors from among the 3000 natural compounds in the Malaysian-Plants Natural-Product (NADI) database. These 3000 compounds were first docked into the neuraminidase active site. The five plants with the largest number of top predicted ligands were selected for experimental evaluation. Twelve specific compounds isolated from these five plants were shown to inhibit neuraminidase, including two compounds with IC50 values less than 92 μM. Furthermore, four of the 12 isolated compounds had also been identified in the top 100 compounds from the virtual screen. Together, these results suggest an effective new approach for identifying bioactive plant species that will further the identification of new pharmacologically active compounds from diverse natural-product resources. PMID:25555059

  18. A virtual screening approach for identifying plants with anti H5N1 neuraminidase activity.

    PubMed

    Ikram, Nur Kusaira Khairul; Durrant, Jacob D; Muchtaridi, Muchtaridi; Zalaludin, Ayunni Salihah; Purwitasari, Neny; Mohamed, Nornisah; Rahim, Aisyah Saad Abdul; Lam, Chan Kit; Normi, Yahaya M; Rahman, Noorsaadah Abd; Amaro, Rommie E; Wahab, Habibah A

    2015-02-23

    Recent outbreaks of highly pathogenic and occasional drug-resistant influenza strains have highlighted the need to develop novel anti-influenza therapeutics. Here, we report computational and experimental efforts to identify influenza neuraminidase inhibitors from among the 3000 natural compounds in the Malaysian-Plants Natural-Product (NADI) database. These 3000 compounds were first docked into the neuraminidase active site. The five plants with the largest number of top predicted ligands were selected for experimental evaluation. Twelve specific compounds isolated from these five plants were shown to inhibit neuraminidase, including two compounds with IC50 values less than 92 μM. Furthermore, four of the 12 isolated compounds had also been identified in the top 100 compounds from the virtual screen. Together, these results suggest an effective new approach for identifying bioactive plant species that will further the identification of new pharmacologically active compounds from diverse natural-product resources. PMID:25555059

  19. Compounds identified in-flight by ROSETTA-COSIMA before the comet encounter

    NASA Astrophysics Data System (ADS)

    Hilchenbach, M.; Fischer, H.; Krüger, H.; Thirkell, L.; Rynö, J.

    2013-09-01

    Secondary ion mass spectrometry (SIMS) is a laboratory surface analyzing technique and, with the COSIMA instrument onboard ROSETTA, it will be applied for the first time to in-situ measurements of cometary grains, once ROSETTA encounters its target comet, 67P/Churyumov-Gerasimenko, in the September 2014. The COmetary Secondary Ion Mass analyzer (COSIMA) onboard ROSETTA will expose metal targets, collect cometary dust grains in the inner coma and analyze these with an optical microscope as well as secondary ion mass spectrometry [1]. The COSIMA instrument has been operated in-flight for commissioning in the first months after launch in March 2004 and on a regular basis during the passive and active spacecraft check-out time intervals up to ROSETTA hibernation from June 2011 onwards. The secondary ion mass spectra background and /or contamination level of the COSIMA metal targets has been identified prior to launch and these had been selected accordingly to avoid masking of single elements or compounds by carrying different metal targets for cometary grain collection. The main compounds identified in-flight are silicon polymers and hydrocarbons. We will discuss the surface analysis results with COSIMA, carried out far off any comet or asteroid in interplanetary space, their time evolution and their potential sources within ROSETTA.

  20. USING AN ACCURATE MASS, TRIPLE QUADRUPOLE MASS SPECTROMETER AND AN ION CORRELATION PROGRAM TO IDENTIFY COMPOUNDS

    EPA Science Inventory

    Most compounds are not found in mass spectral libraries and must be identified by other means. Often, compound identities can be deduced from the compositions of the ions in their mass spectra and review of the chemical literature. Confirmation is provided by mass spectra and r...

  1. Identifying developmental vascular disruptor compounds using a predictive signature and alternative toxicity models

    EPA Science Inventory

    Identifying Developmental Vascular Disruptor Compounds Using a Predictive Signature and Alternative Toxicity Models Presenting Author: Tamara Tal Affiliation: U.S. EPA/ORD/ISTD, RTP, NC, USA Chemically induced vascular toxicity during embryonic development can result in a wide...

  2. Novel Anti-Campylobacter Compounds Identified Using High Throughput Screening of a Pre-selected Enriched Small Molecules Library

    PubMed Central

    Kumar, Anand; Drozd, Mary; Pina-Mimbela, Ruby; Xu, Xiulan; Helmy, Yosra A.; Antwi, Janet; Fuchs, James R.; Nislow, Corey; Templeton, Jillian; Blackall, Patrick J.; Rajashekara, Gireesh

    2016-01-01

    Campylobacter is a leading cause of foodborne bacterial gastroenteritis worldwide and infections can be fatal. The emergence of antibiotic-resistant Campylobacter spp. necessitates the development of new antimicrobials. We identified novel anti-Campylobacter small molecule inhibitors using a high throughput growth inhibition assay. To expedite screening, we made use of a “bioactive” library of 4182 compounds that we have previously shown to be active against diverse microbes. Screening for growth inhibition of Campylobacter jejuni, identified 781 compounds that were either bactericidal or bacteriostatic at a concentration of 200 μM. Seventy nine of the bactericidal compounds were prioritized for secondary screening based on their physico-chemical properties. Based on the minimum inhibitory concentration against a diverse range of C. jejuni and a lack of effect on gut microbes, we selected 12 compounds. No resistance was observed to any of these 12 lead compounds when C. jejuni was cultured with lethal or sub-lethal concentrations suggesting that C. jejuni is less likely to develop resistance to these compounds. Top 12 compounds also possessed low cytotoxicity to human intestinal epithelial cells (Caco-2 cells) and no hemolytic activity against sheep red blood cells. Next, these 12 compounds were evaluated for ability to clear C. jejuni in vitro. A total of 10 compounds had an anti-C. jejuni effect in Caco-2 cells with some effective even at 25 μM concentrations. These novel 12 compounds belong to five established antimicrobial chemical classes; piperazines, aryl amines, piperidines, sulfonamide, and pyridazinone. Exploitation of analogs of these chemical classes may provide Campylobacter specific drugs that can be applied in both human and animal medicine. PMID:27092106

  3. Antimicrobial Activities of Mefloquine and a Series of Related Compounds

    PubMed Central

    Kunin, C. M.; Ellis, W. Y.

    2000-01-01

    Mefloquine was found to have bactericidal activity against methicillin- and fluoroquinolone-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis and gentamicin- and vancomycin-resistant strains of Enterococcus faecalis and Enterococcus faecium. The MICs were 16 μg/ml, and the minimal bactericidal concentrations (MBCs) were 16 to 32 μg/ml. These concentrations cannot be achieved in serum. Mefloquine was active at a more achievable concentration against penicillin-susceptible and -resistant Streptococcus pneumoniae, with MICs of 0.2 to 1.5 μg/ml. Mefloquine was not active against gram-negative bacteria and yeasts. In an attempt to find more active derivatives, 400 mefloquine-related compounds were selected from the chemical inventory of The Walter Reed Army Institute of Research. We identified a series of compounds containing a piperidine methanol group attached to pyridine, quinoline, and benzylquinoline ring systems. These had activities similar to that of mefloquine against S. pneumoniae but were far more active against other gram-positive bacteria (MICs for staphylococci, 0.8 to 6.3 μg/ml). They had activities similar to that of amphotericin B against Candida spp. and Cryptococcus neoformans. Combinations of the compounds with gentamicin and vancomycin were additive against staphylococci and pneumococci. The MIC and MBC of gentamicin were decreased by four- to eightfold when this drug was combined with limiting dilutions of the compounds. There was no antagonism with other antimicrobial drugs. The compounds were rapidly bactericidal. They appear to act by disrupting cell membranes. Combinations of the compounds with aminoglycoside antibiotics may have potential for therapeutic use. PMID:10722480

  4. Compounds active against cell walls of medically important fungi.

    PubMed Central

    Hector, R F

    1993-01-01

    A number of substances that directly or indirectly affect the cell walls of fungi have been identified. Those that actively interfere with the synthesis or degradation of polysaccharide components share the property of being produced by soil microbes as secondary metabolites. Compounds specifically interfering with chitin or beta-glucan synthesis have proven effective in studies of preclinical models of mycoses, though they appear to have a restricted spectrum of coverage. Semisynthetic derivatives of some of the natural products have offered improvements in activity, toxicology, or pharmacokinetic behavior. Compounds which act on the cell wall indirectly or by a secondary mechanism of action, such as the azoles, act against diverse fungi but are usually fungistatic in nature. Overall, these compounds are attractive candidates for further development. PMID:8457977

  5. Antitumor activity of chemical modified natural compounds.

    PubMed

    de Oliveira, M M

    1991-01-01

    Search of new activity substances starting from chemotherapeutic agents, continuously appears in international literature. Perhaps this search has been done more frequently in the field of antitumor chemotherapy on account of the unsuccess in saving advanced stage patients. The new point in this matter during the last decade was computer aid in planning more rational drugs. In near future "the accessibility of super computers and emergence of computer net systems, will open new avenues to rational drug design" (Portoghese, P. S., J. Med. Chem. 1989, 32, 1). Unknown pharmacological active compounds synthetized by plants can be found even without this electronic devices, as traditional medicine has pointed out in many countries, and give rise to a new drug. These compounds used as found in nature or after chemical modifications have produced successful experimental medicaments as FAA, "flavone acetic acid" with good results as inhibitors of slow growing animal tumors currently in preclinical evaluation for human treatment. In this lecture some international contributions in the field of chemical modified compounds as antineoplastic drugs will be examined, particularly those done by Brazilian researches. PMID:1842015

  6. Identifying an active case of tuberculosis.

    PubMed

    Williams, G; Alarcon, E; Jittimanee, S; Walusimbi, M; Sebek, M; Berga, E; Villa, T S

    2008-04-01

    The best practice standards set out in chapter 2 of the Best Practice guide focus on the various aspects of identifying an active case of TB and aim to address some of the challenges associated with case detection. The importance of developing a good relationship with the patient from the start, when he or she is often most vulnerable, is emphasised. The first standard focuses on the assessment of someone who might have TB and the second gives detailed guidance about the collection of sputum for diagnosis. The standards are aimed at the health care worker, who assesses the patient when he or she presents at a health care facility and therefore needs to be familiar with the signs, symptoms and risk factors associated with TB. Having suspected TB, the health care worker then needs to ensure that the correct tests are ordered and procedures are followed so that the best quality samples possible are sent to the laboratory and all documentation is filled out clearly and correctly. The successful implementation of these standards can be measured by the accurate and prompt reporting of results, the registration of every case detected and the continued attendance of every patient who needs treatment. PMID:18371262

  7. Natural products as a resource for biologically active compounds

    SciTech Connect

    Hanke, F.J.

    1986-01-01

    The goal of this study was to investigate various sources of biologically active natural products in an effort to identify the active pesticidal compounds involved. The study is divided into several parts. Chapter 1 contains a discussion of several new compounds from plant and animal sources. Chapter 2 introduces a new NMR technique. In section 2.1 a new technique for better utilizing the lanthanide relaxation agent Gd(fod)/sub 3/ is presented which allows the predictable removal of resonances without line broadening. Section 2.2 discusses a variation of this technique for use in an aqueous solvent by applying this technique towards identifying the binding sites of metals of biological interest. Section 2.3 presents an unambiguous /sup 13/C NMR assignment of melibiose. Chapter 3 deals with work relating to the molting hormone of most arthropods, 20-hydroxyecdysone. Section 3.1 discusses the use of two-dimensional NMR (2D NMR) to assign the /sup 1/H NMR spectrum of this biologically important compound. Section 3.2 presents a new application for Droplet countercurrent chromatography (DCCC). Chapter 4 presents a basic improvement to the commercial DCCC instrument that is currently being applied to future commercial instruments. Chapter 5 discusses a curious observation of the effects that two previously known compounds, nagilactone C and (-)-epicatechin, have on lettuce and rice and suggest a possible new role for the ubiquitous flavanol (-)-epicatechin in plants.

  8. A cell-based screening for TAZ activators identifies ethacridine, a widely used antiseptic and abortifacient, as a compound that promotes dephosphorylation of TAZ and inhibits adipogenesis in C3H10T1/2 cells.

    PubMed

    Kawano, Shodai; Maruyama, Junichi; Nagashima, Shunta; Inami, Kazutoshi; Qiu, Wenzhe; Iwasa, Hiroaki; Nakagawa, Kentaro; Ishigami-Yuasa, Mari; Kagechika, Hiroyuki; Nishina, Hiroshi; Hata, Yutaka

    2015-11-01

    Transcriptional co-activator with PSD-95/Dlg-A/ZO-1 (PDZ)-binding motif (TAZ) regulates in cell proliferation and differentiation. In mesenchymal stem cells it promotes osteogenesis and myogenesis, and suppresses adipogenesis. TAZ activators are expected to prevent osteoporosis, obesity and muscle atrophy. TAZ activation induces epithelial-mesenchymal transition, confers stemness to cancer cells and leads to poor clinical prognosis in cancer patients. In this point of view, TAZ inhibitors should contribute to cancer therapy. Thus, TAZ attracts attention as a two-faced drug target. We screened for TAZ modulators by using human lung cancer A549 cells expressing the fluorescent reporter. Through this assay, we obtained TAZ activator candidates. We unexpectedly found that ethacridine, a widely used antiseptic and abortifacient, enhances the interaction of TAZ and protein phosphatases and increases unphosphorylated and nuclear TAZ. Ethacridine inhibits adipogenesis in mesenchymal C3H10T1/2 cells through the activation of TAZ. This finding suggests that ethacridine is a bona fide TAZ activator and supports that our assay is useful to discover TAZ activators. PMID:25979969

  9. N alpha-(1-deoxy-D-fructos-1-yl)-L-arginine, an antioxidant compound identified in aged garlic extract.

    PubMed

    Ryu, K; Ide, N; Matsuura, H; Itakura, Y

    2001-03-01

    Aged garlic extract (AGE) has been shown to have antioxidant activity. The organosulfur compounds, S-allyl-L-cysteine and S-allylmercapto-L-cysteine, are responsible, at least in part, for the antioxidant activity of AGE. To identify major active components, we fractionated AGE, using hydrogen peroxide scavenging activity as an antioxidative index. Strong activity in the amino acid fraction was found and the major active compound was identified as N alpha-(1-deoxy-D-fructos-1-yl)-L-arginine (Fru-Arg). Antioxidant activity of Fru-Arg was comparable to that of ascorbic acid, scavenging hydrogen peroxide completely at 50 micromol/L and 37% at 10 micromol/L. Quantitative analysis using the established HPLC system revealed that AGE contained 2.1-2.4 mmol/L of Fru-Arg, but none was detected in either raw or heated garlic juice. Furthermore, it was shown that a minimum of 4 mo aging incubation was required for Fru-Arg to be generated. These findings indicate that the aging process is critical for the production of the antioxidant compound, Fru-Arg. These results may explain some of the variation in benefits among different commercially available garlic preparations. PMID:11238799

  10. Identifying inhibitory compounds in lignocellulosic biomass hydrolysates using an exometabolomics approach

    PubMed Central

    2014-01-01

    Background Inhibitors are formed that reduce the fermentation performance of fermenting yeast during the pretreatment process of lignocellulosic biomass. An exometabolomics approach was applied to systematically identify inhibitors in lignocellulosic biomass hydrolysates. Results We studied the composition and fermentability of 24 different biomass hydrolysates. To create diversity, the 24 hydrolysates were prepared from six different biomass types, namely sugar cane bagasse, corn stover, wheat straw, barley straw, willow wood chips and oak sawdust, and with four different pretreatment methods, i.e. dilute acid, mild alkaline, alkaline/peracetic acid and concentrated acid. Their composition and that of fermentation samples generated with these hydrolysates were analyzed with two GC-MS methods. Either ethyl acetate extraction or ethyl chloroformate derivatization was used before conducting GC-MS to prevent sugars are overloaded in the chromatograms, which obscure the detection of less abundant compounds. Using multivariate PLS-2CV and nPLS-2CV data analysis models, potential inhibitors were identified through establishing relationship between fermentability and composition of the hydrolysates. These identified compounds were tested for their effects on the growth of the model yeast, Saccharomyces. cerevisiae CEN.PK 113-7D, confirming that the majority of the identified compounds were indeed inhibitors. Conclusion Inhibitory compounds in lignocellulosic biomass hydrolysates were successfully identified using a non-targeted systematic approach: metabolomics. The identified inhibitors include both known ones, such as furfural, HMF and vanillin, and novel inhibitors, namely sorbic acid and phenylacetaldehyde. PMID:24655423

  11. Taste-active compounds in a traditional Italian food: 'lampascioni'.

    PubMed

    Borgonovo, Gigliola; Caimi, Sara; Morini, Gabriella; Scaglioni, Leonardo; Bassoli, Angela

    2008-06-01

    Nature is a rich source of taste-active compounds, in particular of plant origin, many of which have unusual tastes. Many of these are found in traditional food, where spontaneous plants are used as ingredients. Some taste-active compounds were identified in the bulbs of Muscari comosum, a spontaneous plant belonging to the family of the Liliaceae, very common in the Mediterranean area, and used in traditional gastronomy (called 'lampascioni' in South Italy). The bulbs were extracted with a series of solvents of different polarity. The different fractions were submitted to a preliminary sensory evaluation, and the most interesting ones, characterized by a strong bitter taste and some chemestetic properties, were submitted to further purification and structural analysis. From the ethereal extract, several 3-benzyl-4-chromanones and one stilbene derivative were isolated. Pure compounds were examined for their taste activity by means of sensory evaluation, and proved to be responsible for the characteristic taste of this food. Some of these compounds have been synthesized de novo to confirm their structure. PMID:18618404

  12. Identification of Oct4-activating compounds that enhance reprogramming efficiency.

    PubMed

    Li, Wendong; Tian, E; Chen, Zhao-Xia; Sun, Guoqiang; Ye, Peng; Yang, Su; Lu, Dave; Xie, Jun; Ho, Thach-Vu; Tsark, Walter M; Wang, Charles; Horne, David A; Riggs, Arthur D; Yip, M L Richard; Shi, Yanhong

    2012-12-18

    One of the hurdles for practical application of induced pluripotent stem cells (iPSC) is the low efficiency and slow process of reprogramming. Octamer-binding transcription factor 4 (Oct4) has been shown to be an essential regulator of embryonic stem cell (ESC) pluripotency and key to the reprogramming process. To identify small molecules that enhance reprogramming efficiency, we performed a cell-based high-throughput screening of chemical libraries. One of the compounds, termed Oct4-activating compound 1 (OAC1), was found to activate both Oct4 and Nanog promoter-driven luciferase reporter genes. Furthermore, when added to the reprogramming mixture along with the quartet reprogramming factors (Oct4, Sox2, c-Myc, and Klf4), OAC1 enhanced the iPSC reprogramming efficiency and accelerated the reprogramming process. Two structural analogs of OAC1 also activated Oct4 and Nanog promoters and enhanced iPSC formation. The iPSC colonies derived using the Oct4-activating compounds along with the quartet factors exhibited typical ESC morphology, gene-expression pattern, and developmental potential. OAC1 seems to enhance reprogramming efficiency in a unique manner, independent of either inhibition of the p53-p21 pathway or activation of the Wnt-β-catenin signaling. OAC1 increases transcription of the Oct4-Nanog-Sox2 triad and Tet1, a gene known to be involved in DNA demethylation. PMID:23213213

  13. Antileishmanial Activity of Compounds Isolated from Sassafras albidum.

    PubMed

    Pulivarthi, Divya; Steinberg, Kelly Marie; Monzote, Lianet; Piñón, Abel; Setzer, William N

    2015-07-01

    Leishmaniasis is a neglected tropical disease caused by Leishmania parasitic protozoa, which currently lacks efficient treatment. Natural products have shown promise as a potential source for antiprotozoal drugs. This work focuses on the antileishmanial potential of Sassafras albidum (Lauraceae) bark extract. The crude bark extract of S. albidum showed excellent antileishmanial activity with an IC50 value less than 12.5 μg/mL against promastigotes of L. amazonensis. The chloroform stem bark extract of S. albidum was subjected to preparative column chromatography. Five compounds were isolated, purified by recrystallization, and identified as sesamin, spinescin, β-sitosterol, hexatriacontanal, and 1-triacontanol. Antileishmanial and cytotoxic screening were performed on these compounds. Sesamin exhibited the best activity against L. amazonensis with an IC50 of 15.8 μg/mL and was not cytotoxic to mouse macrophage cells (CC50 > 100 μg/mL). PMID:26411017

  14. Electrophysiological and behavioral responses of female Helicoverpa armigera to compounds identified in flowers of African marigold, Tagetes erecta.

    PubMed

    Bruce, T J; Cork, A

    2001-06-01

    Seven electrophysiologically active compounds were detected in air-entrained headspace samples of live flowers of Tagetes erecta analyzed by gas chromatography (GC) linked to a female Helicoverpa armigera electroantennograph (EAG) using polar and nonpolar capillary columns. These compounds were subsequently identified using GC linked to mass spectrometry as benzaldehyde, (S)-(-)-limonene, (R,S)-(+/-)-linalool, (E)-myroxide, (Z)-beta-ocimene, phenylacetaldehyde, and (R)-(-)-piperitone. Electrophysiological activity was confirmed by EAG with a 1-microg dose of each compound on filter paper eliciting EAG responses that were significantly greater than the solvent control response from female moths. Wind-tunnel bioassays with T. erecta headspace samples, equivalent to 0.4 flower/hr emission from a live flower, elicited a significant increase in the number of upwind approaches from female H. armigera relative to a solvent control. Similarly, a seven-component synthetic blend of EAG-active compounds identified from T. erecta presented in the same ratio (1.0:1.6:0.7:1.4:0.4:5.0:2.7, respectively) and concentration (7.2 microg) as found in the natural sample elicited a significant increase in the number of upwind approaches relative to a solvent control during a 12-min bioassay that was equivalent to that elicited by the natural T. erecta floral volatiles. PMID:11504018

  15. A framework for identifying characteristic odor compounds in municipal wastewater effluent.

    PubMed

    Agus, Eva; Zhang, Lifeng; Sedlak, David L

    2012-11-15

    Municipal wastewater often contains trace amounts of organic compounds that can compromise aesthetics of drinking water and undermine public confidence if a small amount of effluent enters the raw water source of a potable water supply. To efficiently identify compounds responsible for odors in wastewater effluent, an analytical framework consisting of gas chromatography with mass spectrometry (GC-MS) and gas chromatography with olfactometry detection (GC-Olf) coupled with flavor profile analysis (FPA) was used to identify and monitor compounds that could affect the aesthetics of drinking water. After prioritizing odor peaks detected in wastewater effluent by GC-Olf, the odorous components were tentatively identified using retention indices, mass spectra and odor descriptors. Wastewater effluent samples were typically dominated by earthy-musty odors with additional odors in the amine, sulfidic and fragrant categories. 2,4,6-trichloroanisole (246TCA), geosmin and 2-methylisoborneol (2MIB) were the main sources of the earthy/musty odors in wastewater effluent. The other odors were attributable to a suite of compounds, which were detected in some but not all of the wastewater effluents at levels well in excess of their odor thresholds. In most cases, the identities of odorants were confirmed using authentic standards. The fate of these odorous compounds, including 2-pyrrolidone, methylnaphthalenes, vanillin and 5-hydroxyvanillin (5-OH-vanillin), should be considered in future studies of water systems that receive effluent from upstream sources. PMID:22981490

  16. Identifying physical activity gender differences among youth

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Physical activity (PA) is an important part of a healthy lifestyle and reduces risk of certain chronic diseases. Many youth do not currently meet PA guidelines; evidence suggests that girls are less active than boys are at all ages. PA differences need to be understood, so that gender-specific inter...

  17. A Yeast/Drosophila Screen to Identify New Compounds Overcoming Frataxin Deficiency

    PubMed Central

    Seguin, Alexandra; Monnier, Véronique; Palandri, Amandine; Bihel, Frédéric; Rera, Michael; Schmitt, Martine; Camadro, Jean-Michel; Tricoire, Hervé; Lesuisse, Emmanuel

    2015-01-01

    Friedreich's ataxia (FA) is a rare neurodegenerative disease which is very debilitating for the patients who progressively lose their autonomy. The lack of efficient therapeutic treatment of the disease strongly argues for urgent need to search for new active compounds that may stop the progression of the disease or prevent the appearance of the symptoms when the genetic defect is diagnosed early enough. In the present study, we used a yeast strain with a deletion of the frataxin homologue gene as a model of FA cells in a primary screen of two chemical libraries, a fraction of the French National Chemical Library (5500 compounds) and the Prestwick collection (880 compounds). We ran a secondary screen on Drosophila melanogaster flies expressing reduced levels of frataxin during larval development. Half of the compounds selected in yeast appeared to be active in flies in this developmental paradigm, and one of the two compounds with highest activities in this assay partially rescued the heart dilatation phenotype resulting from heart specific depletion of frataxin. The unique complementarity of these two frataxin-deficient models, unicellular and multicellular, appears to be very efficient to select new compounds with improved selectivity, bringing significant perspectives towards improvements in FA therapy. PMID:26523199

  18. A Yeast/Drosophila Screen to Identify New Compounds Overcoming Frataxin Deficiency.

    PubMed

    Seguin, Alexandra; Monnier, Véronique; Palandri, Amandine; Bihel, Frédéric; Rera, Michael; Schmitt, Martine; Camadro, Jean-Michel; Tricoire, Hervé; Lesuisse, Emmanuel

    2015-01-01

    Friedreich's ataxia (FA) is a rare neurodegenerative disease which is very debilitating for the patients who progressively lose their autonomy. The lack of efficient therapeutic treatment of the disease strongly argues for urgent need to search for new active compounds that may stop the progression of the disease or prevent the appearance of the symptoms when the genetic defect is diagnosed early enough. In the present study, we used a yeast strain with a deletion of the frataxin homologue gene as a model of FA cells in a primary screen of two chemical libraries, a fraction of the French National Chemical Library (5500 compounds) and the Prestwick collection (880 compounds). We ran a secondary screen on Drosophila melanogaster flies expressing reduced levels of frataxin during larval development. Half of the compounds selected in yeast appeared to be active in flies in this developmental paradigm, and one of the two compounds with highest activities in this assay partially rescued the heart dilatation phenotype resulting from heart specific depletion of frataxin. The unique complementarity of these two frataxin-deficient models, unicellular and multicellular, appears to be very efficient to select new compounds with improved selectivity, bringing significant perspectives towards improvements in FA therapy. PMID:26523199

  19. IDENTIFYING COMPOUNDS USING SOURCE CID ON AN ORTHOGONAL ACCELERATION TIME-OF-FLIGHT MASS SPECTROMETER

    EPA Science Inventory

    Exact mass libraries of ESI and APCI mass spectra are not commercially available In-house libraries are dependent on CID parameters and are instrument specific. The ability to identify compounds without reliance on mass spectral libraries is therefore more crucial for liquid sam...

  20. ION COMPOSITION ELUCIDATION (ICE): A HIGH RESOLUTION MASS SPECTROMETRIC TECHNIQUE FOR IDENTIFYING COMPOUNDS IN COMPLEX MIXTURES

    EPA Science Inventory

    When tentatively identifying compounds in complex mixtures using mass spectral libraries, multiple matches or no plausible matches due to a high level of chemical noise or interferences can occur. Worse yet, most analytes are not in the libraries. In each case, Ion Composition El...

  1. A NEW MASS SPECTROMETRIC TECHNIQUE FOR IDENTIFYING TRACE-LEVEL ORGANIC COMPOUNDS IN COMPLEX MIXTURES

    EPA Science Inventory



    Most organic compounds are not found in mass spectral libraries and cannot be easily identified from low resolution mass spectra. Ion Composition Elucidation (ICE) utilizes selected ion recording with a double focusing mass spectrometer in a new way to determine exact mas...

  2. Identifying Diverse Means for Assessing Physical Activity

    ERIC Educational Resources Information Center

    Perlman, Dana J.; Pearson, Phil

    2012-01-01

    Physical inactivity is of concern for the majority of age groups within the United States. Limited engagement in physical activity (PA) has been linked with an increased risk for a host of health problems, including but not limited to heart disease, diabetes and cancer. Benefits of PA are widely documented and accepted yet many people, especially…

  3. Automated microwave double resonance spectroscopy: A tool to identify and characterize chemical compounds

    NASA Astrophysics Data System (ADS)

    Martin-Drumel, Marie-Aline; McCarthy, Michael C.; Patterson, David; McGuire, Brett A.; Crabtree, Kyle N.

    2016-03-01

    Owing to its unparalleled structural specificity, rotational spectroscopy is a powerful technique to unambiguously identify and characterize volatile, polar molecules. We present here a new experimental approach, automated microwave double resonance (AMDOR) spectroscopy, to rapidly determine the rotational constants of these compounds without a priori knowledge of elemental composition or molecular structure. This task is achieved by rapidly acquiring the classical (frequency vs. intensity) broadband spectrum of a molecule using chirped-pulse Fourier transform microwave (FTMW) spectroscopy and subsequently analyzing it in near real-time using complementary cavity FTMW detection and double resonance. AMDOR measurements provide a unique "barcode" for each compound from which rotational constants can be extracted. To illustrate the power of this approach, AMDOR spectra of three aroma compounds — trans-cinnamaldehyde, α-, and β-ionone — have been recorded and analyzed. The prospects to extend this approach to mixture characterization and purity assessment are described.

  4. Automated microwave double resonance spectroscopy: A tool to identify and characterize chemical compounds.

    PubMed

    Martin-Drumel, Marie-Aline; McCarthy, Michael C; Patterson, David; McGuire, Brett A; Crabtree, Kyle N

    2016-03-28

    Owing to its unparalleled structural specificity, rotational spectroscopy is a powerful technique to unambiguously identify and characterize volatile, polar molecules. We present here a new experimental approach, automated microwave double resonance (AMDOR) spectroscopy, to rapidly determine the rotational constants of these compounds without a priori knowledge of elemental composition or molecular structure. This task is achieved by rapidly acquiring the classical (frequency vs. intensity) broadband spectrum of a molecule using chirped-pulse Fourier transform microwave (FTMW) spectroscopy and subsequently analyzing it in near real-time using complementary cavity FTMW detection and double resonance. AMDOR measurements provide a unique "barcode" for each compound from which rotational constants can be extracted. To illustrate the power of this approach, AMDOR spectra of three aroma compounds - trans-cinnamaldehyde, α-, and β-ionone - have been recorded and analyzed. The prospects to extend this approach to mixture characterization and purity assessment are described. PMID:27036441

  5. Antibacterial and Cytotoxic Activity of Compounds Isolated from Flourensia oolepis.

    PubMed

    Joray, Mariana Belén; Trucco, Lucas Daniel; González, María Laura; Napal, Georgina Natalia Díaz; Palacios, Sara María; Bocco, José Luis; Carpinella, María Cecilia

    2015-01-01

    The antibacterial and cytotoxic effects of metabolites isolated from an antibacterial extract of Flourensia oolepis were evaluated. Bioguided fractionation led to five flavonoids, identified as 2',4'-dihydroxychalcone (1), isoliquiritigenin (2), pinocembrin (3), 7-hydroxyflavanone (4), and 7,4'-dihydroxy-3'-methoxyflavanone (5). Compound 1 showed the highest antibacterial effect, with minimum inhibitory concentration (MIC) values ranging from 31 to 62 and 62 to 250 μg/mL, against Gram-positive and Gram-negative bacteria, respectively. On further assays, the cytotoxic effect of compounds 1-5 was determined by MTT assay on acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) cell lines including their multidrug resistant (MDR) phenotypes. Compound 1 induced a remarkable cytotoxic activity toward ALL cells (IC50 = 6.6-9.9 μM) and a lower effect against CML cells (IC50 = 27.5-30.0 μM). Flow cytometry was used to analyze cell cycle distribution and cell death by PI-labeled cells and by Annexin V/PI staining, respectively. Upon treatment, 1 induced cell cycle arrest in the G2/M phase accompanied by a strong induction of apoptosis. These results describe for the first time the antibacterial metabolites of F. oolepis extract, with 1 being the most effective. This chalcone also emerges as a selective cytotoxic agent against sensitive and resistant leukemic cells, highlighting its potential as a lead compound. PMID:26819623

  6. Antibacterial and Cytotoxic Activity of Compounds Isolated from Flourensia oolepis

    PubMed Central

    Joray, Mariana Belén; Trucco, Lucas Daniel; González, María Laura; Napal, Georgina Natalia Díaz; Palacios, Sara María; Bocco, José Luis; Carpinella, María Cecilia

    2015-01-01

    The antibacterial and cytotoxic effects of metabolites isolated from an antibacterial extract of Flourensia oolepis were evaluated. Bioguided fractionation led to five flavonoids, identified as 2′,4′-dihydroxychalcone (1), isoliquiritigenin (2), pinocembrin (3), 7-hydroxyflavanone (4), and 7,4′-dihydroxy-3′-methoxyflavanone (5). Compound 1 showed the highest antibacterial effect, with minimum inhibitory concentration (MIC) values ranging from 31 to 62 and 62 to 250 μg/mL, against Gram-positive and Gram-negative bacteria, respectively. On further assays, the cytotoxic effect of compounds 1–5 was determined by MTT assay on acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) cell lines including their multidrug resistant (MDR) phenotypes. Compound 1 induced a remarkable cytotoxic activity toward ALL cells (IC50 = 6.6–9.9 μM) and a lower effect against CML cells (IC50 = 27.5–30.0 μM). Flow cytometry was used to analyze cell cycle distribution and cell death by PI-labeled cells and by Annexin V/PI staining, respectively. Upon treatment, 1 induced cell cycle arrest in the G2/M phase accompanied by a strong induction of apoptosis. These results describe for the first time the antibacterial metabolites of F. oolepis extract, with 1 being the most effective. This chalcone also emerges as a selective cytotoxic agent against sensitive and resistant leukemic cells, highlighting its potential as a lead compound. PMID:26819623

  7. Profiling of the Tox21 Chemical Collection for Mitochondrial Function to Identify Compounds that Acutely Decrease Mitochondrial Membrane Potential

    PubMed Central

    Attene-Ramos, Matias S.; Huang, Ruili; Michael, Sam; Witt, Kristine L.; Richard, Ann; Tice, Raymond R.; Simeonov, Anton; Austin, Christopher P.

    2014-01-01

    Background: Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of disorders including cancer, diabetes, and neurodegenerative and cardiovascular diseases. Understanding whether different environmental chemicals and druglike molecules impact mitochondrial function represents an initial step in predicting exposure-related toxicity and defining a possible role for such compounds in the onset of various diseases. Objectives: We sought to identify individual chemicals and general structural features associated with changes in mitochondrial membrane potential (MMP). Methods: We used a multiplexed [two end points in one screen; MMP and adenosine triphosphate (ATP) content] quantitative high throughput screening (qHTS) approach combined with informatics tools to screen the Tox21 library of 10,000 compounds (~ 8,300 unique chemicals) at 15 concentrations each in triplicate to identify chemicals and structural features that are associated with changes in MMP in HepG2 cells. Results: Approximately 11% of the compounds (913 unique compounds) decreased MMP after 1 hr of treatment without affecting cell viability (ATP content). In addition, 309 compounds decreased MMP over a concentration range that also produced measurable cytotoxicity [half maximal inhibitory concentration (IC50) in MMP assay/IC50 in viability assay ≤ 3; p < 0.05]. More than 11% of the structural clusters that constitute the Tox21 library (76 of 651 clusters) were significantly enriched for compounds that decreased the MMP. Conclusions: Our multiplexed qHTS approach allowed us to generate a robust and reliable data set to evaluate the ability of thousands of drugs and environmental compounds to decrease MMP. The use of structure-based clustering analysis allowed us to identify molecular features that are likely responsible for the observed activity. Citation: Attene-Ramos MS, Huang R, Michael S, Witt KL, Richard A, Tice RR, Simeonov A, Austin CP, Xia M. 2015. Profiling of the Tox

  8. Identifying antimalarial compounds targeting dihydrofolate reductase-thymidylate synthase (DHFR-TS) by chemogenomic profiling.

    PubMed

    Aroonsri, Aiyada; Akinola, Olugbenga; Posayapisit, Navaporn; Songsungthong, Warangkhana; Uthaipibull, Chairat; Kamchonwongpaisan, Sumalee; Gbotosho, Grace O; Yuthavong, Yongyuth; Shaw, Philip J

    2016-07-01

    The mode of action of many antimalarial drugs is unknown. Chemogenomic profiling is a powerful method to address this issue. This experimental approach entails disruption of gene function and phenotypic screening for changes in sensitivity to bioactive compounds. Here, we describe the application of reverse genetics for chemogenomic profiling in Plasmodium. Plasmodium falciparum parasites harbouring a transgenic insertion of the glmS ribozyme downstream of the dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene were used for chemogenomic profiling of antimalarial compounds to identify those which target DHFR-TS. DHFR-TS expression can be attenuated by exposing parasites to glucosamine. Parasites with attenuated DHFR-TS expression were significantly more sensitive to antifolate drugs known to target DHFR-TS. In contrast, no change in sensitivity to other antimalarial drugs with different modes of action was observed. Chemogenomic profiling was performed using the Medicines for Malaria Venture (Switzerland) Malaria Box compound library, and two compounds were identified as novel DHFR-TS inhibitors. We also tested the glmS ribozyme in Plasmodium berghei, a rodent malaria parasite. The expression of reporter genes with downstream glmS ribozyme could be attenuated in transgenic parasites comparable with that obtained in P. falciparum. The chemogenomic profiling method was applied in a P. berghei line expressing a pyrimethamine-resistant Toxoplasma gondii DHFR-TS reporter gene under glmS ribozyme control. Parasites with attenuated expression of this gene were significantly sensitised to antifolates targeting DHFR-TS, but not other drugs with different modes of action. In conclusion, these data show that the glmS ribozyme reverse genetic tool can be applied for identifying primary targets of antimalarial compounds in human and rodent malaria parasites. PMID:27150044

  9. Antitrypanosomal activity of 5-nitro-2-aminothiazole-based compounds.

    PubMed

    Papadopoulou, Maria V; Bloomer, William D; Rosenzweig, Howard S; Wilkinson, Shane R; Szular, Joanna; Kaiser, Marcel

    2016-07-19

    A small series of 5-nitro-2-aminothiazole-based amides containing arylpiperazine-, biphenyl- or aryloxyphenyl groups in their core were synthesized and evaluated as antitrypanosomatid agents. All tested compounds were active or moderately active against Trypanosoma cruzi amastigotes in infected L6 cells and Trypanosoma brucei brucei, four of eleven compounds were moderately active against Leishmania donovani axenic parasites while none were deemed active against T. brucei rhodesiense. For the most active/moderately active compounds a moderate selectivity against each parasite was observed. There was good correlation between lipophilicity (clogP value) and antileishmanial activity or toxicity against L6 cells. Similarly, good correlation existed between clogP values and IC50 values against T. cruzi in structurally related subgroups of compounds. Three compounds were more potent as antichagasic agents than benznidazole but were not activated by the type I nitrorectusase (NTR). PMID:27092415

  10. Histone markers identify the mode of action for compounds positive in the TK6 micronucleus assay.

    PubMed

    Cheung, Jennifer R; Dickinson, Donna A; Moss, Jocelyn; Schuler, Maik J; Spellman, Richard A; Heard, Pamela L

    2015-01-01

    The in vitro micronucleus assay with TK6 cells is frequently used as part of the genotoxicity testing battery for pharmaceuticals. Consequently, follow-up testing strategies are needed for positive compounds to determine their mode of action, which would then allow for deployment of appropriate in vivo follow-up strategies. We have chosen 3 micronucleus positive compounds, the clastogen etoposide, the aneugen noscapine and the cytotoxicant tunicamycin to evaluate different approaches to determine their aneugenic or clastogenic properties. Each of the three compounds were evaluated following 4 and 24h of continuous treatment by flow cytometry for micronucleus induction, the aneugenicity markers phosphorylated-histone 3 (p-H3) and polyploidy, the clastogenicity marker γH2AX and the apoptosis marker cleaved caspase 3. They were further evaluated by Western blot for mono-ubiquitinated and γH2AX. Results show that the clastogen etoposide produced a dose related increase in γH2AX and mono-ubiquitinated H2AX and a dose related decrease in p-H3 positive mitotic cells. Conversely, the aneugen produced increases in p-H3 and polyploidy with no significant increases seen in mono-ubiquitinated H2AX or γH2AX. Lastly, the cytotoxicant tunicamycin induced neither an increase in p-H3 nor γH2AX. All three compounds produced dose-related increases in cleaved caspase 3. The results from this study provide evidence that adding clastogenicity and aneugenicity markers to the in vitro micronucleus assay in TK6 cells could help to identify the mode of action of positive compounds. The combination of endpoints suggested here needs to be further evaluated by a broader set of test compounds. PMID:25726170

  11. A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions

    PubMed Central

    Kraft, Robert; Kahn, Allon; Medina-Franco, José L.; Orlowski, Mikayla L.; Baynes, Cayla; López-Vallejo, Fabian; Barnard, Kobus; Maggiora, Gerald M.; Restifo, Linda L.

    2013-01-01

    SUMMARY The actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the ‘filagree’ phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity) and 48 fascin-pathway enhancers (with potential cognitive-enhancer activity). The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the ‘beads-on-a-string’ defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery. PMID:22917928

  12. Quinolone Amides as Antitrypanosomal Lead Compounds with In Vivo Activity.

    PubMed

    Hiltensperger, Georg; Hecht, Nina; Kaiser, Marcel; Rybak, Jens-Christoph; Hoerst, Alexander; Dannenbauer, Nicole; Müller-Buschbaum, Klaus; Bruhn, Heike; Esch, Harald; Lehmann, Leane; Meinel, Lorenz; Holzgrabe, Ulrike

    2016-08-01

    Human African trypanosomiasis (HAT) is a major tropical disease for which few drugs for treatment are available, driving the need for novel active compounds. Recently, morpholino-substituted benzyl amides of the fluoroquinolone-type antibiotics were identified to be compounds highly active against Trypanosoma brucei brucei Since the lead compound GHQ168 was challenged by poor water solubility in previous trials, the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its in vitro antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3.5 h after intraperitoneal administration (4 mice/compound), moderate to strong human serum albumin binding for GHQ168 (80%) and GHQ243 (45%), and very high human serum albumin binding (>99%) for GHQ242. For the lead compound, GHQ168, the apparent clearance was 112 ml/h and the apparent volume of distribution was 14 liters/kg of body weight (BW). Mice infected with T. b. rhodesiense (STIB900) were treated in a stringent study scheme (2 daily applications between days 3 and 6 postinfection). Exposure to spray-dried GHQ168 in contrast to the control treatment resulted in mean survival durations of 17 versus 9 days, respectively, a difference that was statistically significant. Results that were statistically insignificantly different were obtained between the control and the GHQ242 and GHQ243 treatments. Therefore, GHQ168 was further profiled in an early-treatment scheme (2 daily applications at days 1 to 4 postinfection), and the results were compared with those obtained with a control treatment. The result was statistically significant mean survival times exceeding 32 days (end of the observation period) versus 7 days for the GHQ168 and control treatments

  13. From Leaf Metabolome to In Vivo Testing: Identifying Antifeedant Compounds for Ecological Studies of Marsupial Diets.

    PubMed

    Marsh, Karen J; Yin, Baofa; Singh, Inder Pal; Saraf, Isha; Choudhary, Alka; Au, Jessie; Tucker, David J; Foley, William J

    2015-06-01

    Identifying specific plant secondary metabolites that influence feeding behavior can be challenging, but a solid understanding of animal preferences can guide efforts. Common brushtail possums (Trichosurus vulpecula) predominantly eat Eucalyptus species belonging to the subgenus Symphyomyrtus, and avoid eating those belonging to the Monocalyptus subgenus (also called subgenus Eucalyptus). Using an unbiased (1)H NMR metabolomics approach, a previous study identified unsubstituted B ring flavanones in most species of monocalypts examined, whereas these compounds were absent from symphyomyrtles. We hypothesised that unsubstituted B ring flavanones act as feeding deterrents for common brushtail possums. In the current study, we tested this hypothesis by comparing how much possums ate of a basal diet, with diets containing one of four structurally related compounds; pinocembrin, flavanone (unsubstituted B ring flavanones), chrysin (the flavone analogue of pinocembrin), and naringenin (a flavanone with B ring substitution). We found that pinocembrin and flavanone deterred feeding relative to the basal diet, but that chrysin and naringenin did not at equivalent concentrations. Thus, unsubstituted B-ring flavanones may explain why brushtail possums avoid eating monocalypt species. Furthermore, small differences in the structure of secondary compounds can have a large impact on antifeedant properties. These results demonstrate that metabolomics can be a valuable tool for ecologists seeking to understand herbivore feeding preferences. PMID:25994224

  14. Composition and topology of activity cliff clusters formed by bioactive compounds.

    PubMed

    Stumpfe, Dagmar; Dimova, Dilyana; Bajorath, Jürgen

    2014-02-24

    The assessment of activity cliffs has thus far mostly focused on compound pairs, although the majority of activity cliffs are not formed in isolation but in a coordinated manner involving multiple active compounds and cliffs. However, the composition of coordinated activity cliff configurations and their topologies are unknown. Therefore, we have identified all activity cliff configurations formed by currently available bioactive compounds and analyzed them in network representations where activity cliff configurations occur as clusters. The composition, topology, frequency of occurrence, and target distribution of activity cliff clusters have been determined. A limited number of large cliff clusters with unique topologies were identified that were centers of activity cliff formation. These clusters originated from a small number of target sets. However, most clusters were of small to moderate size. Three basic topologies were sufficient to describe recurrent activity cliff cluster motifs/topologies. For example, frequently occurring clusters with star topology determined the scale-free character of the global activity cliff network and represented a characteristic activity cliff configuration. Large clusters with complex topology were often found to contain different combinations of basic topologies. Our study provides a first view of activity cliff configurations formed by currently available bioactive compounds and of the recurrent topologies of activity cliff clusters. Activity cliff clusters of defined topology can be selected, and from compounds forming the clusters, SAR information can be obtained. The SAR information of activity cliff clusters sharing a/one specific activity and topology can be compared. PMID:24437577

  15. Evaluation of compounds for insecticidal activity on adult mosquitos*

    PubMed Central

    Hadaway, A. B.; Barlow, F.; Grose, J. E. H.; Turner, C. R.; Flower, L. S.

    1970-01-01

    New pyrethrin-like compounds are compared with earlier synthetic pyrethroids and natural pyrethrins for intrinsic toxicity to adult mosquitos and for residual contact activity. Two of the compounds are at least as toxic as pyrethrin I to female Anopheles stephensi and Aedes aegypti. Residues of these compounds are very persistent in the dark or in very subdued lighting but they decompose on exposure to normal intensities of daylight and rapidly lose their insecticidal activity. PMID:4392939

  16. Screening Active Compounds from Garcinia Species Native to China Reveals Novel Compounds Targeting the STAT/JAK Signaling Pathway.

    PubMed

    Xu, Linfeng; Lao, Yuanzhi; Zhao, Yanhui; Qin, Jian; Fu, Wenwei; Zhang, Yingjia; Xu, Hongxi

    2015-01-01

    Natural compounds from medicinal plants are important resources for drug development. In a panel of human tumor cells, we screened a library of the natural products from Garcinia species which have anticancer potential to identify new potential therapeutic leads and discovered that caged xanthones were highly effective at suppressing multiple cancer cell lines. Their anticancer activities mainly depended on apoptosis pathways. For compounds in sensitive cancer line, their mechanisms of mode of action were evaluated. 33-Hydroxyepigambogic acid and 35-hydroxyepigambogic acid exhibited about 1 μM IC50 values against JAK2/JAK3 kinases and less than 1 μM IC50 values against NCI-H1650 cell which autocrined IL-6. Thus these two compounds provided a new antitumor molecular scaffold. Our report describes 33-hydroxyepigambogic acid and 35-hydroxyepigambogic acid that inhibited NCI-H1650 cell growth by suppressing constitutive STAT3 activation via direct inhibition of JAK kinase activity. PMID:26090459

  17. Screening Active Compounds from Garcinia Species Native to China Reveals Novel Compounds Targeting the STAT/JAK Signaling Pathway

    PubMed Central

    Xu, Linfeng; Lao, Yuanzhi; Zhao, Yanhui; Qin, Jian; Fu, Wenwei; Zhang, Yingjia; Xu, Hongxi

    2015-01-01

    Natural compounds from medicinal plants are important resources for drug development. In a panel of human tumor cells, we screened a library of the natural products from Garcinia species which have anticancer potential to identify new potential therapeutic leads and discovered that caged xanthones were highly effective at suppressing multiple cancer cell lines. Their anticancer activities mainly depended on apoptosis pathways. For compounds in sensitive cancer line, their mechanisms of mode of action were evaluated. 33-Hydroxyepigambogic acid and 35-hydroxyepigambogic acid exhibited about 1 μM IC50 values against JAK2/JAK3 kinases and less than 1 μM IC50 values against NCI-H1650 cell which autocrined IL-6. Thus these two compounds provided a new antitumor molecular scaffold. Our report describes 33-hydroxyepigambogic acid and 35-hydroxyepigambogic acid that inhibited NCI-H1650 cell growth by suppressing constitutive STAT3 activation via direct inhibition of JAK kinase activity. PMID:26090459

  18. Anti-allergic activity of compounds from Kaempferia parviflora.

    PubMed

    Tewtrakul, Supinya; Subhadhirasakul, Sanan; Kummee, Sopa

    2008-02-28

    Kaempferia parviflora is one of the plants in the Zingiberaceae family, locally known in Thai as kra-chai-dam. In Thai traditional medicine, the decoction of Kaempferia parviflora powder with alcohol has been reported to cure allergy, asthma, impotence, gout, diarrhea, dysentery, peptic ulcer and diabetes. Therefore, the present study aimed to investigate anti-allergic substances from this plant. Bioassay-guided fractionation led to the isolation of seven methoxyflavone derivatives (1-7) from Kaempferia parviflora extract and they were identified on the basis of spectroscopic methods. Among the compounds tested, 5-hydroxy-3,7,3',4'-tetramethoxyflavone (5) possessed the highest anti-allergic activity against antigen-induced beta-hexosaminidase release as a marker of degranulation in RBL-2H3 cells with an IC(50) value of 8.0 microM, followed by 5-hydroxy-7-methoxyflavone (2, IC(50)=20.6 microM) and 5-hydroxy-7,4'-dimethoxyflavone (4, IC(50)=26.0 microM), whereas others showed moderate activities (IC(50)=37.5-66.5 microM). Structure-activity trends of 7-methoxyflavone derivatives on anti-allergic activity can be summarized as follows: (1) substitution with vicinal methoxyl groups at positions 3' and 4' conferred higher activity than only one methoxylation, (2) methoxylation at position 3 reduced activity and (3) methoxylation at position 5 showed higher activity than hydroxylation. Compounds 2, 4 and 5 were also determined for their mechanisms on ionomycin-induced beta-hexosaminidase release. The results indicated that the mechanism on inhibition of cell degranulation of compounds 2 and 5 mainly involve the inhibition of Ca(2+) influx to the cells, whereas that of 4 may be partly due to this inhibition. In regards to the active constituents for anti-allergic activity of Kaempferia parviflora, 5-hydroxy-3,7,3',4'-tetramethoxyflavone (5), 5-hydroxy-7-methoxyflavone (2) and 5-hydroxy-7,4'-dimethoxyflavone (4) are responsible for anti-allergic effect of this plant. The

  19. Biologically active compounds of semi-metals.

    PubMed

    Rezanka, Tomás; Sigler, Karel

    2008-02-01

    Semi-metals (boron, silicon, arsenic and selenium) form organo-metal compounds, some of which are found in nature and affect the physiology of living organisms. They include, e.g., the boron-containing antibiotics aplasmomycin, borophycin, boromycin, and tartrolon or the silicon compounds present in "silicate" bacteria, relatives of the genus Bacillus, which release silicon from aluminosilicates through the secretion of organic acids. Arsenic is incorporated into arsenosugars and arsenobetaines by marine algae and invertebrates, and fungi and bacteria can produce volatile methylated arsenic compounds. Some prokaryotes can use arsenate as a terminal electron acceptor while others can utilize arsenite as an electron donor to generate energy. Selenium is incorporated into selenocysteine that is found in some proteins. Biomethylation of selenide produces methylselenide and dimethylselenide. Selenium analogues of amino acids, antitumor, antibacterial, antifungal, antiviral, anti-infective drugs are often used as analogues of important pharmacological sulfur compounds. Other metalloids, i.e. the rare and toxic tellurium and the radioactive short-lived astatine, have no biological significance. PMID:17991498

  20. Identification of new compounds with high activity against stationary phase Borrelia burgdorferi from the NCI compound collection.

    PubMed

    Feng, Jie; Shi, Wanliang; Zhang, Shuo; Zhang, Ying

    2015-01-01

    Lyme disease is the leading tick-borne disease in the USA. Whereas the majority of Lyme disease patients with early disease can be cured with standard treatment, some patients suffer from chronic fatigue and joint and muscular pain despite treatment, a syndrome called posttreatment Lyme disease syndrome. Although the cause is unclear, ineffective killing of Borrelia burgdorferi persisters by current Lyme disease antibiotics is one possible explanation. We took advantage of our recently developed high-throughput viability assay and screened the National Cancer Institute compound library collection consisting of 2526 compounds against stationary phase B. burgdorferi. We identified the top 30 new active hits, including the top six anthracycline antibiotics daunomycin 3-oxime, dimethyldaunomycin, daunomycin, NSC299187, NSC363998 and nogalamycin, along with other compounds, including prodigiosin, mitomycin, nanaomycin and dactinomycin, as having excellent activity against B. burgdorferi stationary phase culture. The anthracycline or anthraquinone compounds, which are known to have both anti-cancer and antibacterial activities, also had high activity against growing B. burgdorferi with low minimum inhibitory concentration. Future studies on the structure-activity relationship and mechanisms of action of anthracyclines/anthraquinones are warranted. In addition, drug combination studies with the anthracycline class of compounds and the current Lyme antibiotics to eradicate B. burgdorferi persisters in vitro and in animal models are needed to determine if they improve the treatment of Lyme disease. PMID:26954881

  1. High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection.

    PubMed

    Islam, Md Koushikul; Baudin, Maria; Eriksson, Jonas; Öberg, Christopher; Habjan, Matthias; Weber, Friedemann; Överby, Anna K; Ahlm, Clas; Evander, Magnus

    2016-04-01

    Rift Valley fever virus (RVFV) is an emerging virus that causes serious illness in humans and livestock. There are no approved vaccines or treatments for humans. The purpose of the study was to identify inhibitory compounds of RVFV infection without any preconceived idea of the mechanism of action. A whole-cell-based high-throughput drug screening assay was developed to screen 28,437 small chemical compounds targeting RVFV infection. To accomplish both speed and robustness, a replication-competent NSs-deleted RVFV expressing a fluorescent reporter gene was developed. Inhibition of fluorescence intensity was quantified by spectrophotometry and related to virus infection in human lung epithelial cells (A549). Cell toxicity was assessed by the Resazurin cell viability assay. After primary screening, 641 compounds were identified that inhibited RVFV infection by ≥80%, with ≥50% cell viability at 50 µM concentration. These compounds were subjected to a second screening regarding dose-response profiles, and 63 compounds with ≥60% inhibition of RVFV infection at 3.12 µM compound concentration and ≥50% cell viability at 25 µM were considered hits. Of these, six compounds with high inhibitory activity were identified. In conclusion, the high-throughput assay could efficiently and safely identify several promising compounds that inhibited RVFV infection. PMID:26762502

  2. SURVEY OF INDUSTRIAL APPLICATIONS OF VAPOR-PHASE ACTIVATED-CARBON ADSORPTION FOR CONTROL OF POLLUTANT COMPOUNDS FROM MANUFACTURE OF ORGANIC COMPOUNDS

    EPA Science Inventory

    This study covers industrial use of activated carbon for vapor-phase applications. A listing of over 700 applications of vapor-phase carbon systems is made available for use in identifying sites where a given compound is being removed.

  3. Analogue Experiments Identify Possible Precursor Compounds for Chlorohydrocarbons Detected in SAM

    NASA Astrophysics Data System (ADS)

    Miller, K.; Summons, R. E.; Eigenbrode, J. L.; Freissinet, C.; Glavin, D. P.; Martin, M. G.; Team, M.

    2013-12-01

    Since landing at Gale Crater on August 6, 2012, the Sample Analysis at Mars (SAM) instrument suite, aboard the Curiosity Rover, has conducted multiple analyses of scooped and drilled samples and has identified a suite of chlorohydrocarbons including chloromethane, dichloromethane, trichloromethane, chloromethylpropene, and chlorobenzene (Glavin et al., 2013; Leshin et al., 2013). These compounds were identified after samples were pyrolysed at temperatures up to ~835°C through a combination of Evolved Gas Analysis (EGA) and Gas Chromatography Mass Spectrometry (GCMS). Since these chlorinated species were well above the background levels determined by empty cup blanks analyzed prior to solid sample analyses, thermal degradation of oxychlorine phases, such as perchlorate, present in the Martian soil, are the most likely source of chlorine needed to generate these chlorohydrocarbons. Laboratory analogue experiments show that terrestrial organics internal to SAM, such as N-methyl-N(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA), a derivatization agent, can react with perchlorates to produce all of the chlorohydrocarbons detected by SAM. However, in pyrolysis-trap-GCMS laboratory experiments with MTBSTFA, C4 compounds are the predominant chlorohydrocarbon observed, whereas on SAM the C1 chlorohydrocarbons dominate (Glavin et al., 2013). This, in addition to the previous identification of chloromethane and dichloromethane by the 1976 Viking missions (Biemann et al., 1977), suggest that there could be another, possibly Martian, source of organic carbon contributing to the formation of the C1 chlorohydrocarbons, or other components of the solid samples analyzed by SAM are having a catalytic effect on chlorohydrocarbon generation. Laboratory analogue experiments investigated a suite of organic compounds that have the potential to accumulate on Mars (Benner et al., 2000) and thus serve as sources of carbon for the formation of chlorohydrocarbons detected by the SAM and

  4. Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex.

    PubMed

    Golubovskaya, Vita M; Ho, Baotran; Conroy, Jeffrey; Liu, Song; Wang, Dan; Cance, William G

    2014-01-01

    Focal Adhesion Kinase (FAK) is a non-receptor kinase that plays an important role in many cellular processes: adhesion, proliferation, invasion, angiogenesis, metastasis and survival. Recently, we have shown that Roslin 2 or R2 (1-benzyl-15,3,5,7-tetraazatricyclo[3.3.1.1~3,7~]decane) compound disrupts FAK and p53 proteins, activates p53 transcriptional activity, and blocks tumor growth. In this report we performed a microarray gene expression analysis of R2-treated HCT116 p53+/+ and p53-/- cells and detected 1484 genes that were significantly up- or down-regulated (p < 0.05) in HCT116 p53+/+ cells but not in p53-/- cells. Among up-regulated genes in HCT p53+/+ cells we detected critical p53 targets: Mdm-2, Noxa-1, and RIP1. Among down-regulated genes, Met, PLK2, KIF14, BIRC2 and other genes were identified. In addition, a combination of R2 compound with M13 compound that disrupts FAK and Mmd-2 complex or R2 and Nutlin-1 that disrupts Mdm-2 and p53 decreased clonogenicity of HCT116 p53+/+ colon cancer cells more significantly than each agent alone in a p53-dependent manner. Thus, the report detects gene expression profile in response to R2 treatment and demonstrates that the combination of drugs targeting FAK, Mdm-2, and p53 can be a novel therapy approach. PMID:24452144

  5. Compounds from Gum Ammoniacum with Acetylcholinesterase Inhibitory Activity

    PubMed Central

    Adhami, Hamid-Reza; Lutz, Johannes; Kählig, Hanspeter; Zehl, Martin; Krenn, Liselotte

    2013-01-01

    The use of herbal medicinal preparations in dementia therapy has been studied based on experience from traditional medicine. A dichloromethane extract of gum ammoniacum, the gum-resin from Dorema ammoniacum D. Don had shown acetylcholinesterase (AChE) inhibitory activity in a previous study. The aim of this study was the isolation and characterization of the active compounds from this resin. The extract was investigated by a respective colorimetric microplate assay and the active zones were identified via TLC bioautography and isolated using several chromatographic techniques. The structures of the active components were characterized by one- and two-dimensional 1H and 13C NMR spectroscopy and mass spectrometry as (2′S,5′S)-2′-ethenyl-5′-(3-hy-droxy-6-methyl-4-oxohept-5-en-2-yl)-7-methoxy-2′-methyl-4H-spiro[chromene-3,1′-cyclopentane]-2,4-dione (1), which is an analogue of doremone A and a new natural compound, and as (2′S,5′R)-2′-ethenyl-5′-[(2R,4R)-4-hydroxy-6-methyl-3-oxohept-5-en-2-yl]-7-methoxy-2′-methyl-4H-spiro[chromene-3,1′-cyclo-pentane]-2,4-dione (2 = doremone A), (4E,8E)-1-(2,4-dihydroxyphenyl)-5,9,13-trimethyltetradeca-4,8,12-trien-1-one (3 = dshamirone), and 4,7-dihydroxy-3-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]-2H-chromen-2-one (4 = am-moresinol). Dshamirone turned out to be the most active compound with an IC50 value for AChE inhibitory activity of 23.5 μM, whereas the other substances showed weak activity. The concentrations of the analytes in the resin were determined by HPLC as 3.1%, 4.6%, 1.9%, and 9.9%, respectively. PMID:24106674

  6. E-prescribing errors identified in a compounding pharmacy: a quality-improvement project.

    PubMed

    Reed-Kane, Dana; Kittell, Katrina; Adkins, Jacquelyn; Flocks, Sarah; Nguyen, Thu

    2014-01-01

    Errors during the prescribing process can cause problems for patients. When the pharmacist intercepts a prescribing error, it can cause a delay, as the patient may not receive the medication until the problem is resolved. Electronic prescriptions are purported to reduce prescribing errors. However, studies have shown that electronic prescriptions can be prone to certain types of errors. Compounding pharmacies may present an additional obstacle for e-prescribing, as the prescribed medications are not commercially available and may not be listed in the e-prescribing software. The objectives of this study were to estimate the electronic prescription error rate in a compounding pharmacy, determine the most common error types, list the most common interventions pharmacists made, and estimate how long it took to resolve these errors. The study design was quality improvement with descriptive data. During the four weeks of data collection, the pharmacists were trained to complete a standardized data collection form when they identified an electronic prescription error. Percentages were calculated for new prescriptions, electronic prescriptions with errors, error types, and error resolution methods. In the four-week period of the study, there were 982 new prescriptions, 111 of which were electronic prescriptions. Of those 111 electronic prescriptions, 70 had errors. The electronic prescriptions error rate was 63%. The most common type of error was wrong entry field (70.3%). For this project, wrong entry field was defined to mean that the drug name was in the wrong field (81%) or that multiple entries were in the wrong field (7%). Pharmacists usually used their own judgment to resolve an error (67%). Many e-prescription errors were identified in this compounding pharmacy. When prescription errors happen, workflow and patient care are disrupted. Our goal is to discuss these findings with Surescripts and e-prescribing software companies to seek systems-based solutions. PMID

  7. Bacterial biofilm formation inhibitory activity revealed for plant derived natural compounds.

    PubMed

    Artini, M; Papa, R; Barbato, G; Scoarughi, G L; Cellini, A; Morazzoni, P; Bombardelli, E; Selan, L

    2012-01-15

    Use of herbal plant remedies to treat infectious diseases is a common practice in many countries in traditional and alternative medicine. However to date there are only few antimicrobial agents derived from botanics. Based on microbiological screening tests of crude plant extracts we identified four compounds derived from Krameria, Aesculus hippocastanum and Chelidonium majus that showed a potentially interesting antimicrobial activity. In this work we present an in depth characterization of the inhibition activity of these pure compounds on the formation of biofilm of Staphylococcus aureus as well as of Staphylococcus epidermidis strains. We show that two of these compounds possess interesting potential to become active principles of new drugs. PMID:22182580

  8. Screening of Panamanian Plant Extracts for Pesticidal Properties and HPLC-Based Identification of Active Compounds

    PubMed Central

    Guldbrandsen, Niels; De Mieri, Maria; Gupta, Mahabir; Seiser, Tobias; Wiebe, Christine; Dickhaut, Joachim; Reingruber, Rüdiger; Sorgenfrei, Oliver; Hamburger, Matthias

    2015-01-01

    A library of 600 taxonomically diverse Panamanian plant extracts was screened for fungicidal, insecticidal, and herbicidal activities. A total of 19 active extracts were submitted to HPLC-based activity profiling, and extracts of Bocconia frutescens, Miconia affinis, Myrcia splendens, Combretum aff. laxum, and Erythroxylum macrophyllum were selected for the isolation of compounds. Chelerythrine (2), macarpine (3), dihydrosanguinarine (5), and arjunolic acid (8) showed moderate-to-good fungicidal activity. Myricetin-3-O-(6’’-O-galloyl)-β-galactopyranoside (13) showed moderate insecticidal activity, but no compound with herbicidal activity was identified. PMID:26839818

  9. Anti-tubercular drug development: computational strategies to identify potential compounds.

    PubMed

    Rajkhowa, Sanchaita; Jha, Anupam Nath; Deka, Ramesh Chandra

    2015-11-01

    InhA is an attractive target to combat tuberculosis (TB), which is targeted by many pro-drugs (isoniazid, etc.) and drugs such as triclosan. However, triclosan is less useful as an antitubercular drug due to its low bioavailability and therefore, in order to overcome this difficulty, many derivatives of triclosan were prepared. Here, we have combined various computational techniques to virtually screen out four potential triclosan derivatives. Molecular docking methods have been employed to screen out 32 out of 62 triclosan derivatives considering the mode of binding and the top re-rank scores. A comparative study on the chemical properties of triclosan and some of its derivatives has been performed using density functional theory (DFT) calculations. DFT based global reactivity descriptors (GRD), such as hardness, chemical potential, chemical softness, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries were used to investigate the usefulness of these descriptors for understanding the reactive nature and sites of the molecules. QSAR equations were built using these descriptors considering these 32 compounds. Four common compounds showing the best correlation and the best docking scores were considered for the ADMET property calculations and their dynamical movements have been studied using molecular dynamics simulations. Our results showed that these four compounds are chemically more active than triclosan and have the potential to inhibit the Mycobacterium tuberculosis enoyl acyl carrier protein reductase. This work shows that combination of different computational techniques may help to screen out potential drug candidates from a list of possible ones. PMID:26386453

  10. Structure-Activity Relationships in Nitro-Aromatic Compounds

    NASA Astrophysics Data System (ADS)

    Vogt, R. A.; Rahman, S.; Crespo-Hernández, C. E.

    Many nitro-aromatic compounds show mutagenic and carcinogenic properties, posing a potential human health risk. Despite this potential health hazard, nitro-aromatic compounds continue to be emitted into ambient air from municipal incinerators, motor vehicles, and industrial power plants. As a result, understanding the structural and electronic factors that influence mutagenicity in nitro-aromatic compounds has been a long standing objective. Progress toward this goal has accelerated over the years, in large part due to the synergistic efforts among toxicology, computational chemistry, and statistical modeling of toxicological data. The concerted influence of several structural and electronic factors in nitro-aromatic compounds makes the development of structure-activity relationships (SARs) a paramount challenge. Mathematical models that include a regression analysis show promise in predicting the mutagenic activity of nitro-aromatic compounds as well as in prioritizing compounds for which experimental data should be pursued. A major challenge of the structure-activity models developed thus far is their failure to apply beyond a subset of nitro-aromatic compounds. Most quantitative structure-activity relationship papers point to statistics as the most important confirmation of the validity of a model. However, the experimental evidence shows the importance of the chemical knowledge in the process of generating models with reasonable applicability. This chapter will concisely summarize the structural and electronic factors that influence the mutagenicity in nitro-aromatic compounds and the recent efforts to use quantitative structure-activity relationships to predict those physicochemical properties.

  11. Radical scavenging activities of niacin-related compounds.

    PubMed

    Ogata, Shin; Takeuchi, Masayo; Teradaira, Shin; Yamamoto, Naokuni; Iwata, Keiko; Okumura, Katsuzumi; Taguchi, Hiroshi

    2002-03-01

    We investigated whether niacin-related compounds had radical-scavenging activity by electron spin resonance methods. Many compounds, but not trigonelline, had radical-scavenging activity against hydroxyl radicals. However, for the nitric oxide radical and 1,1-diphenyl-2-picrylhydrazyl radical, only nicotinic acid hydrazide and isonicotinic acid hydrazide had scavenging activities. These results suggest that the moiety of hydrazide might have an important role in scavenging abilities of various radicals. PMID:12005062

  12. Fractionation of Phenolic Compounds Extracted from Propolis and Their Activity in the Yeast Saccharomyces cerevisiae

    PubMed Central

    Petelinc, Tanja; Polak, Tomaž; Demšar, Lea; Jamnik, Polona

    2013-01-01

    We have here investigated the activities of Slovenian propolis extracts in the yeast Saccharomyces cerevisiae, and identified the phenolic compounds that appear to contribute to these activities. We correlated changes in intracellular oxidation and cellular metabolic energy in these yeasts with the individual fractions of the propolis extracts obtained following solid-phase extraction. The most effective fraction was further investigated according to its phenolic compounds. PMID:23409133

  13. Gametocytocidal Screen Identifies Novel Chemical Classes with Plasmodium falciparum Transmission Blocking Activity

    PubMed Central

    Sanders, Natalie G.; Sullivan, David J.; Mlambo, Godfree; Dimopoulos, George; Tripathi, Abhai K.

    2014-01-01

    Discovery of transmission blocking compounds is an important intervention strategy necessary to eliminate and eradicate malaria. To date only a small number of drugs that inhibit gametocyte development and thereby transmission from the mosquito to the human host exist. This limitation is largely due to a lack of screening assays easily adaptable to high throughput because of multiple incubation steps or the requirement for high gametocytemia. Here we report the discovery of new compounds with gametocytocidal activity using a simple and robust SYBR Green I- based DNA assay. Our assay utilizes the exflagellation step in male gametocytes and a background suppressor, which masks the staining of dead cells to achieve healthy signal to noise ratio by increasing signal of viable parasites and subtracting signal from dead parasites. By determining the contribution of exflagellation to fluorescent signal and using appropriate cutoff values, we were able to screen for gametocytocidal compounds. After assay validation and optimization, we screened an FDA approved drug library of approximately 1500 compounds, as well as the 400 compound MMV malaria box and identified 44 gametocytocidal compounds with sub to low micromolar IC50s. Major classes of compounds with gametocytocidal activity included quaternary ammonium compounds with structural similarity to choline, acridine-like compounds similar to quinacrine and pyronaridine, as well as antidepressant, antineoplastic, and anthelminthic compounds. Top drug candidates showed near complete transmission blocking in membrane feeding assays. This assay is simple, reproducible and demonstrated robust Z-factor values at low gametocytemia levels, making it amenable to HTS for identification of novel and potent gametocytocidal compounds. PMID:25157792

  14. Cytotoxicity and antiviral activity of the compounds from Euphorbia kansui.

    PubMed

    Zheng, W F; Cui, Z; Zhu, Q

    1998-12-01

    Eleven compounds including four triterpenes, one sterol, and six diterpenes from E kansui had been assayed for their cytotoxicity and activiral activity. The relations between structures and bioactivities have also been noted. PMID:9933994

  15. Antifeedant compounds from three species of Apiaceae active against the field slug, Deroceras reticulatum (Muller).

    PubMed

    Birkett, Michael A; Dodds, Catherine J; Henderson, Ian F; Leake, Lucy D; Pickett, John A; Selby, Martin J; Watson, Peter

    2004-03-01

    Extracts of volatiles from foliage of three plants in the Apiaceae, Conium maculatum L. (hemlock), Coriandrum sativum L. (coriander), and Petroselinum crispum Mill. (Nym.) (parsley), previously shown to exhibit antifeedant activity in assays with the field slug, Deroceras reticulatum (Muller) (Limacidae: Pulmonata), were studied further to identify the active components. Coupled gas chromatography-mass spectrometry (GC-MS) and neurophysiological assays using tentacle nerve preparations resulted in the identification of 11 active compounds from the three extracts. Wheat flour feeding bioassays were used to determine which of these compounds had the highest antifeedant activity. One of the most active compounds was the alkaloid gamma-coniceine, from C. maculatum. The role of potentially toxic alkaloids as semiochemicals and the potential for using such compounds as crop protection agents to prevent slug feeding damage is discussed. PMID:15139308

  16. Analysis of chlorocarbon compounds identified in the SAM Investigation of the Mars Science Laboratory mission

    NASA Astrophysics Data System (ADS)

    Freissinet, Caroline; Mahaffy, P.; Glavin, D.; Buch, A.; Brunner, A.; Eigenbrode, J.; Martin, M.; Miller, K.; Steele, A.; Szopa, C.; SAM; MSL science Team

    2013-10-01

    The gas chromatograph mass spectrometer (GCMS) mode of the Sample Analysis at Mars (SAM) experiment was designed for the separation and identification of the chemical components of the gases released from a solid sample or trapped from the atmosphere. Gases from solid samples are either produced by heating a cell from ambient to >800-1100oC (EGA mode) or by wet chemistry extraction and reactions (not yet employed on Mars). Prior to EGA analysis of portions of the first 3 solid samples (Rocknest, John Klein and Cumberland) collected by MSL and delivered to SAM, an internal SAM blank run was carried out with an empty quartz cup. These blank analyses are required to understand the background signal intrinsic to the GCMS and its gas manifolds and traps. Several peaks have been identified as part of SAM background, some of them below the nmol level, which attests of the sensitivity of the instrument and as-designed performance of the GCMS. The origin of each peak has been investigated, and two major contributors are revealed; residual vapor from one of the chemicals used for SAM wet chemistry experiment: N-methyl-N-tert-butyldimethylsilyl-trifluoroacetamide (MTBSTFA), and the Tenax from the hydrocarbon trap. Supporting lab experiments are in progress to understand the reaction pathways of the molecules identified in the SAM background. These experiments help elucidate which molecules may be interpreted as indigenous to Mars. Of the three solid samples analyzed on 11 runs, it was possible to detect and identify several chlorinated compounds including several chlorohydrocarbons. The chlorine is likely derived from the decomposition of martian perchlorates or other indigenous Cl-containing species while the origin of the carbon is presently under investigation for each detected molecule. To date, a subset these molecules have been identified in lab studies and a terrestrial contribution to the observed products are more easily explained. The combined results from SAM and

  17. Compounds with Antifouling Activities from the Roots of Notopterygium franchetii.

    PubMed

    Yu, Chun; Cheng, Liqing; Zhang, Zhongling; Zhang, Yu; Yuan, Chunmao; Liu, Weiwei; Hao, Xiaojiang; Ma, Weiguang; He, Hongping

    2015-12-01

    In antifouling screening, the extract of Notopterygium franchetii de Boiss showed obvious activity. Two new phenylpropanoids (1-2) and five known coumarins (3-7) were isolated from the methanol extract of the roots of this species. The structures of the isolated compounds were determined on the basis of spectroscopic analysis. Compounds 1-2 showed definite antifouling activity against larval settlement of Bugula neritina. PMID:26882679

  18. Activation of shallow dopants in II-VI compounds

    SciTech Connect

    Walukiewicz, W.

    1995-08-01

    The amphoteric native defect model is applied to the understanding of the variations in the dopant activation efficiency in II-VI compounds. It is shown that the location of the common energy reference, the Fermi level stabilization energy, relative to the band edges can be used to determine the doping induced reduction of the formation energy and the enhancement of the concentration of compensating native defects. The model is applied to the most extensively studied compound semiconductors as well as to ternary and quaternary alloys. The effects of the compound ionicity on the dopant activation are briefly discussed.

  19. A high-content screening assay in transgenic zebrafish identifies two novel activators of fgf signaling.

    PubMed

    Saydmohammed, Manush; Vollmer, Laura L; Onuoha, Ezenwa Obi; Vogt, Andreas; Tsang, Michael

    2011-09-01

    Zebrafish have become an invaluable vertebrate animal model to interrogate small molecule libraries for modulators of complex biological pathways and phenotypes. We have recently described the implementation of a quantitative, high-content imaging assay in multi-well plates to analyze the effects of small molecules on Fibroblast Growth Factor (FGF) signaling in vivo. Here we have evaluated the capability of the assay to identify compounds that hyperactivate FGF signaling from a test cassette of agents with known biological activities. Using a transgenic zebrafish reporter line for FGF activity, we screened 1040 compounds from an annotated library of known bioactive agents, including FDA-approved drugs. The assay identified two molecules, 8-hydroxyquinoline sulfate and pyrithione zinc, that enhanced FGF signaling in specific areas of the brain. Subsequent studies revealed that both compounds specifically expanded FGF target gene expression. Furthermore, treatment of early stage embryos with either compound resulted in dorsalized phenotypes characteristic of hyperactivation of FGF signaling in early development. Documented activities for both agents included activation of extracellular signal-related kinase (ERK), consistent with FGF hyperactivation. To conclude, we demonstrate the power of automated quantitative high-content imaging to identify small molecule modulators of FGF. PMID:21932436

  20. Selenium compounds activate early barriers of tumorigenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Selenium chemoprevention by apoptosis has been well studied, but it is not clear whether selenium can activate early barriers of tumorigenesis, namely senescence and DNA damage response. To address this issue, we treated normal and cancerous cells with a gradient concentration of sodium selenite, me...

  1. Thin-layer chromatographic (TLC) separations and bioassays of plant extracts to identify antimicrobial compounds.

    PubMed

    Kagan, Isabelle A; Flythe, Michael D

    2014-01-01

    A common screen for plant antimicrobial compounds consists of separating plant extracts by paper or thin-layer chromatography (PC or TLC), exposing the chromatograms to microbial suspensions (e.g. fungi or bacteria in broth or agar), allowing time for the microbes to grow in a humid environment, and visualizing zones with no microbial growth. The effectiveness of this screening method, known as bioautography, depends on both the quality of the chromatographic separation and the care taken with microbial culture conditions. This paper describes standard protocols for TLC and contact bioautography with a novel application to amino acid-fermenting bacteria. The extract is separated on flexible (aluminum-backed) silica TLC plates, and bands are visualized under ultraviolet (UV) light. Zones are cut out and incubated face down onto agar inoculated with the test microorganism. Inhibitory bands are visualized by staining the agar plates with tetrazolium red. The method is applied to the separation of red clover (Trifolium pratense cv. Kenland) phenolic compounds and their screening for activity against Clostridium sticklandii, a hyper ammonia-producing bacterium (HAB) that is native to the bovine rumen. The TLC methods apply to many types of plant extracts and other bacterial species (aerobic or anaerobic), as well as fungi, can be used as test organisms if culture conditions are modified to fit the growth requirements of the species. PMID:24747583

  2. Thin-layer Chromatographic (TLC) Separations and Bioassays of Plant Extracts to Identify Antimicrobial Compounds

    PubMed Central

    Kagan, Isabelle A.; Flythe, Michael D.

    2014-01-01

    A common screen for plant antimicrobial compounds consists of separating plant extracts by paper or thin-layer chromatography (PC or TLC), exposing the chromatograms to microbial suspensions (e.g. fungi or bacteria in broth or agar), allowing time for the microbes to grow in a humid environment, and visualizing zones with no microbial growth. The effectiveness of this screening method, known as bioautography, depends on both the quality of the chromatographic separation and the care taken with microbial culture conditions. This paper describes standard protocols for TLC and contact bioautography with a novel application to amino acid-fermenting bacteria. The extract is separated on flexible (aluminum-backed) silica TLC plates, and bands are visualized under ultraviolet (UV) light. Zones are cut out and incubated face down onto agar inoculated with the test microorganism. Inhibitory bands are visualized by staining the agar plates with tetrazolium red. The method is applied to the separation of red clover (Trifolium pratense cv. Kenland) phenolic compounds and their screening for activity against Clostridium sticklandii, a hyper ammonia-producing bacterium (HAB) that is native to the bovine rumen. The TLC methods apply to many types of plant extracts and other bacterial species (aerobic or anaerobic), as well as fungi, can be used as test organisms if culture conditions are modified to fit the growth requirements of the species. PMID:24747583

  3. Bioorthogonal Enzymatic Activation of Caged Compounds.

    PubMed

    Ritter, Cornelia; Nett, Nathalie; Acevedo-Rocha, Carlos G; Lonsdale, Richard; Kräling, Katja; Dempwolff, Felix; Hoebenreich, Sabrina; Graumann, Peter L; Reetz, Manfred T; Meggers, Eric

    2015-11-01

    Engineered cytochrome P450 monooxygenase variants are reported as highly active and selective catalysts for the bioorthogonal uncaging of propargylic and benzylic ether protected substrates, including uncaging in living E. coli. observed selectivity is supported by induced-fit docking and molecular dynamics simulations. This proof-of-principle study points towards the utility of bioorthogonal enzyme/protecting group pairs for applications in the life sciences. PMID:26356324

  4. Antioxidant Activity of Marine Algal Polyphenolic Compounds: A Mechanistic Approach.

    PubMed

    Fernando, I P Shanura; Kim, Misook; Son, Kwang-Tae; Jeong, Yoonhwa; Jeon, You-Jin

    2016-07-01

    Polyphenolic compounds isolated from marine algae exhibit a broad spectrum of beneficial biological properties, including antioxidant, anticancer, antimicrobial, anti-inflammatory, and antidiabetic activities, along with several other bioactivities centered on their antioxidant properties. Consequently, polyphenolic compounds are increasingly being investigated for their potential use in food, cosmetic, and pharmaceutical applications. The antioxidant activities of these compounds have been explored widely through experimental studies. Nonetheless, a theoretical understanding of the structural and electronic properties could broaden research perspectives, leading to the identification and synthesis of efficient structural analogs with prophylactic uses. This review briefly summarizes the current state of knowledge regarding antioxidant polyphenolic compounds in marine algae with an attempt to describe the structure-activity relationship. PMID:27332715

  5. Cell-Based Small-Molecule Compound Screen Identifies Fenretinide as Potential Therapeutic for Translocation-Positive Rhabdomyosarcoma

    PubMed Central

    Herrero Martín, David; Boro, Aleksandar; Schäfer, Beat W.

    2013-01-01

    A subset of paediatric sarcomas are characterized by chromosomal translocations encoding specific oncogenic transcription factors. Such fusion proteins represent tumor specific therapeutic targets although so far it has not been possible to directly inhibit their activity by small-molecule compounds. In this study, we hypothesized that screening a small-molecule library might identify already existing drugs that are able to modulate the transcriptional activity of PAX3/FOXO1, the fusion protein specifically found in the pediatric tumor alveolar rhabdomyosarcoma (aRMS). Towards this end, we established a reporter cell line based on the well characterized PAX3/FOXO1 target gene AP2ß. A library enriched in mostly FDA approved drugs was screened using specific luciferase activity as read-out and normalized for cell viability. The most effective inhibitor identified from this screen was Fenretinide. Treatment with this compound resulted in down-regulation of PAX3/FOXO1 mRNA and protein levels as well as in reduced expression of several of its direct target genes, but not of wild-type FOXO1, in a dose- and time-dependent manner. Moreover, fenretinide induced reactive oxygen species and apoptosis as shown by caspase 9 and PARP cleavage and upregulated miR-9. Importantly, it demonstrated a significant anti-tumor effect in vivo. These results are similar to earlier reports for two other pediatric tumors, namely neuroblastoma and Ewing sarcoma, where fenretinide is under clinical development. Our results suggest that fenretinide might represent a novel treatment option also for translocation-positive rhabdomyosarcoma. PMID:23372815

  6. Cell-based small-molecule compound screen identifies fenretinide as potential therapeutic for translocation-positive rhabdomyosarcoma.

    PubMed

    Herrero Martín, David; Boro, Aleksandar; Schäfer, Beat W

    2013-01-01

    A subset of paediatric sarcomas are characterized by chromosomal translocations encoding specific oncogenic transcription factors. Such fusion proteins represent tumor specific therapeutic targets although so far it has not been possible to directly inhibit their activity by small-molecule compounds. In this study, we hypothesized that screening a small-molecule library might identify already existing drugs that are able to modulate the transcriptional activity of PAX3/FOXO1, the fusion protein specifically found in the pediatric tumor alveolar rhabdomyosarcoma (aRMS). Towards this end, we established a reporter cell line based on the well characterized PAX3/FOXO1 target gene AP2ß. A library enriched in mostly FDA approved drugs was screened using specific luciferase activity as read-out and normalized for cell viability. The most effective inhibitor identified from this screen was Fenretinide. Treatment with this compound resulted in down-regulation of PAX3/FOXO1 mRNA and protein levels as well as in reduced expression of several of its direct target genes, but not of wild-type FOXO1, in a dose- and time-dependent manner. Moreover, fenretinide induced reactive oxygen species and apoptosis as shown by caspase 9 and PARP cleavage and upregulated miR-9. Importantly, it demonstrated a significant anti-tumor effect in vivo. These results are similar to earlier reports for two other pediatric tumors, namely neuroblastoma and Ewing sarcoma, where fenretinide is under clinical development. Our results suggest that fenretinide might represent a novel treatment option also for translocation-positive rhabdomyosarcoma. PMID:23372815

  7. Refractory Organic Compounds in Enceladus' Ice Grains and Hydrothermal Activity

    NASA Astrophysics Data System (ADS)

    Postberg, F.; Khawaja, N.; Hsu, H. W.; Sekine, Y.; Shibuya, T.

    2015-12-01

    Cassini's Cosmic Dust Analyzer (CDA) generates time-of-flight mass spectra of individual grains impinging on the instruments target-plate. Following the analysis of salt rich ice grains emitted by Enceladus that indicated a salt-water ocean in contact with the moon's rocky core [1,2] a recent CDA analysis of nano-phase silica particles pointed at hydrothermal activity at the moon's rock/water interface [3]. The results imply temperatures above 80 - 90°C and alkaline pH values around 10 reminiscent of alkaline hydrothermal vents on Earth like the Lost City Hydrothermal Field. In this context the compositional analysis of organic components in CDA mass spectra of the ejected ice grains is of particular relevance. A multitude of volatile organic species has already been identified in the gas component of the plume [4]. As expected, we find more complex organic molecules in ice grains than in the gas indicating aromatic species, amines, and carbonyl group species. The composition of organic-bearing ice grains displays a great diversity indicating a variety of different organic species in varying concentrations. Recent spatially resolved CDA in situ measurements inside Enceladus' plume indicate that these organic compounds are especially frequent in 'young' ice grains that have just been ejected by high velocity jets. We investigate the implications of our findings with respect to ice grain formation at the water surface and inside the icy vents. We constrain the generation of organic compounds at the rock/water interface in the light of hydrothermal activity and the potential for the formation of life precursor molecules in Enceladus' ocean. Ref:[1] Postberg et al., Nature 459, 1098-1101 (2009). [2] Postberg et al., Nature 474, 620-622 (2011). [3]. Hsu, Postberg, Sekine et al., Nature, 519, 207-210 (2015). [4] Waite et al., Nature 460, 487-490 (2009).

  8. Fungal proteinaceous compounds with multiple biological activities.

    PubMed

    Ng, Tzi Bun; Cheung, Randy Chi Fai; Wong, Jack Ho; Chan, Yau Sang; Dan, Xiuli; Pan, Wenliang; Wang, Hexiang; Guan, Suzhen; Chan, Ki; Ye, Xiuyun; Liu, Fang; Xia, Lixin; Chan, Wai Yee

    2016-08-01

    Fungi comprise organisms like molds, yeasts and mushrooms. They have been used as food or medicine for a long time. A large number of fungal proteins or peptides with diverse biological activities are considered as antibacterial, antifungal, antiviral and anticancer agents. They encompass proteases, ribosome inactivating proteins, defensins, hemolysins, lectins, laccases, ribonucleases, immunomodulatory proteins, and polysaccharopeptides. The target of the present review is to update the status of the various bioactivities of these fungal proteins and peptides and discuss their therapeutic potential. PMID:27338574

  9. Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni

    PubMed Central

    Panic, Gordana; Vargas, Mireille; Scandale, Ivan; Keiser, Jennifer

    2015-01-01

    Background As plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel antischistosomal compounds. Drug repurposing might be an inexpensive and effective source of novel antischistosomal leads. Methodology 1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 µM. Active compounds identified from this screen were advanced to the adult worm screen at 33.33 µM, followed by hit characterization. Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies. Principal Findings The in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively. Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates. Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively. Conclusions/Significance The work presented here expands the knowledge of antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories. The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation. PMID:26230921

  10. Identification of Telomerase-activating Blends From Naturally Occurring Compounds.

    PubMed

    Ait-Ghezala, Ghania; Hassan, Samira; Tweed, Miles; Paris, Daniel; Crynen, Gogce; Zakirova, Zuchra; Crynen, Stefan; Crawford, Fiona

    2016-06-01

    Context • Telomeres are repeated deoxyribonucleic acid (DNA) sequences (TTAGGG) that are located on the 5' ends of chromosomes, and they control the life span of eukaryotic cells. Compelling evidence has shown that the length of a person's life is dictated by the limited number of times that a human cell can divide. The enzyme telomerase has been shown to bind to and extend the length of telomeres. Thus, strategies for activating telomerase may help maintain telomere length and, thus, may lead to improved health during aging. Objective • The current study intended to investigate the effects of several natural compounds on telomerase activity in an established cell model of telomere shortening (ie, IMR90 cells). Design • The research team designed an in vitro study. Setting • The study was conducted at Roskamp Institute in Sarasota, FL, USA. Intervention • The tested single compounds were (1) α-lipoic acid, (1) green tea extract, (2) dimethylaminoethanol L-bitartrate (DMAE L-bitartrate), (3) N-acetyl-L-cysteine hydrochloride (HCL), (4) chlorella powder, (5) L-carnosine, (6) vitamin D3, (7) rhodiola PE 3%/1%, (8) glycine, (9) French red wine extract, (10) chia seed extract, (11) broccoli seed extract, and (12) Astragalus (TA-65). The compounds were tested singly and as blends. Outcome Measures • Telomerase activity for single compounds and blends of compounds was measured by the TeloTAGGG telomerase polymerase chain reaction (PCR) enzyme-linked immunosorbent assay (ELISA). The 4 most potent blends were investigated for their effects on cancer-cell proliferation and for their potential effects on the cytotoxicity and antiproliferative activity of a chemotherapeutic agent, the topoisomerase I inhibitor topotecan. The benefits of 6 population doublings (PDs) were measured for the single compounds, and the 4 blends were compared to 3 concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Results • Certain of the compounds increased

  11. Identification of orthologous target pairs with shared active compounds and comparison of organism-specific activity patterns.

    PubMed

    Dimova, Dilyana; Stumpfe, Dagmar; Bajorath, Jürgen

    2015-11-01

    A systematic search for active small molecules shared by orthologous targets was carried out, leading to the identification of 803 compound-based orthologous target pairs covering a total of 938 orthologues, 358 unique targets and 98 organisms. Many orthologous target pairs were found to have substantial compound coverage, enabling the introduction of an orthologous target pairs classification including 'organism cliffs' and 'potency-retaining' pairs. A total of 158 orthologous target pairs involving human orthologues were identified, which were typically associated with drug discovery-relevant targets, organism combinations and compound data. Orthologous target pairs with human orthologues included 83 potency-retaining orthologous target pairs covering a variety of targets and organisms. On the basis of these orthologous target pairs, the compound search was further extended and 1149 potent compounds were identified that only had reported activities for non-human orthologues of 48 therapeutic targets, but not their human counterparts, hence providing a large pool of candidate compounds for further evaluation. The complete set of orthologous target pairs identified in our analysis, the orthologous target pairs classification including associated data and all candidate compounds are made freely available. PMID:25931211

  12. Antioxidant Activity of Phenolic Compounds from Fava Bean Sprouts.

    PubMed

    Okumura, Koharu; Hosoya, Takahiro; Kawarazaki, Kai; Izawa, Norihiko; Kumazawa, Shigenori

    2016-06-01

    Fava beans are eaten all over the world and recently, marketing for their sprouts began in Japan. Fava bean sprouts contain more polyphenols and l-3,4-dihydroxyphenylalanine (l-DOPA) than the bean itself. Our antioxidant screening program has shown that fava bean sprouts also possess a higher antioxidant activity than other commercially available sprouts and mature beans. However, the individual constituents of fava bean sprouts are not entirely known. In the present study, we investigated the phenolic compounds of fava bean sprouts and their antioxidant activity. Air-dried fava bean sprouts were treated with 80% methanol and the extract was partitioned in water with chloroform and ethyl acetate. HPLC analysis had shown that the ethyl acetate-soluble parts contained phenolic compounds, separated by preparative HPLC to yield 5 compounds (1-5). Structural analysis using NMR and MS revealed that the compounds isolated were kaempferol glycosides. All isolated compounds had an α-rhamnose at the C-7 position with different sugars attached at the C-3 position. Compounds 1-5 had β-galactose, β-glucose, α-rhamnose, 6-acetyl-β-galactose and 6-acetyl-β-glucose, respectively, at the C-3 position. The amount of l-DOPA in fava bean sprouts was determined by the quantitative (1) H NMR technique. The l-DOPA content was 550.45 mg ± 11.34 /100 g of the raw sprouts. The antioxidant activities of compounds 2-5 and l-DOPA were evaluated using the 2,2-diphenyl-1-picrylhydrazyl scavenging assay. l-DOPA showed high antioxidant activity, but the isolated kaempferol glycosides showed weak activity. Therefore, it can be suggested that l-DOPA contributed to the antioxidant activity of fava bean sprouts. PMID:27155370

  13. Antifungal Activity of Extractable Conifer Heartwood Compounds Toward Phytophthora ramorum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Individual compounds and ethyl acetate extracts from heartwood of seven conifer species were tested for fungicidal activity against Phytophthora ramorum. Extracts from incense and western redcedar exhibited the strongest activity (EC50 589 and 646 ppm, respectively), yellow-cedar, western juniper, ...

  14. Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy.

    PubMed

    Rzuczek, Suzanne G; Southern, Mark R; Disney, Matthew D

    2015-12-18

    There are many RNA targets in the transcriptome to which small molecule chemical probes and lead therapeutics are desired. However, identifying compounds that bind and modulate RNA function in cellulo is difficult. Although rational design approaches have been developed, they are still in their infancies and leave many RNAs "undruggable". In an effort to develop a small molecule library that is biased for binding RNA, we computationally identified "drug-like" compounds from screening collections that have favorable properties for binding RNA and for suitability as lead drugs. As proof-of-concept, this collection was screened for binding to and modulating the cellular dysfunction of the expanded repeating RNA (r(CUG)(exp)) that causes myotonic dystrophy type 1. Hit compounds bind the target in cellulo, as determined by the target identification approach Competitive Chemical Cross-Linking and Isolation by Pull-down (C-ChemCLIP), and selectively improve several disease-associated defects. The best compounds identified from our 320-member library are more potent in cellulo than compounds identified by high-throughput screening (HTS) campaigns against this RNA. Furthermore, the compound collection has a higher hit rate (9% compared to 0.01-3%), and the bioactive compounds identified are not charged; thus, RNA can be "drugged" with compounds that have favorable pharmacological properties. Finally, this RNA-focused small molecule library may serve as a useful starting point to identify lead "drug-like" chemical probes that affect the biological (dys)function of other RNA targets by direct target engagement. PMID:26414664

  15. Identifying Emotions on the Basis of Neural Activation.

    PubMed

    Kassam, Karim S; Markey, Amanda R; Cherkassky, Vladimir L; Loewenstein, George; Just, Marcel Adam

    2013-01-01

    We attempt to determine the discriminability and organization of neural activation corresponding to the experience of specific emotions. Method actors were asked to self-induce nine emotional states (anger, disgust, envy, fear, happiness, lust, pride, sadness, and shame) while in an fMRI scanner. Using a Gaussian Naïve Bayes pooled variance classifier, we demonstrate the ability to identify specific emotions experienced by an individual at well over chance accuracy on the basis of: 1) neural activation of the same individual in other trials, 2) neural activation of other individuals who experienced similar trials, and 3) neural activation of the same individual to a qualitatively different type of emotion induction. Factor analysis identified valence, arousal, sociality, and lust as dimensions underlying the activation patterns. These results suggest a structure for neural representations of emotion and inform theories of emotional processing. PMID:23840392

  16. In vitro anti-HIV-1 activity of salicylidene acylhydrazide compounds.

    PubMed

    Forthal, Donald N; Phan, Tran B; Slepenkin, Anatoly V; Landucci, Gary; Chu, Hencelyn; Elofsson, Mikael; Peterson, Ellena

    2012-10-01

    Salicylidene acylhydrazide compounds have been shown to inhibit bacterial pathogens, including Chlamydia and Neisseria gonorrhoeae. If such compounds could also target HIV-1, their potential use as topical microbicides to prevent sexually transmitted infections would be considerable. In this study, the in vitro anti-HIV-1 activity, cytotoxicity and mechanism of action of several salicylidene acylhydrazides were determined. Inhibitory activity was assessed using TZM-bl cells and primary peripheral blood mononuclear cells (PBMCs) as targets for HIV-1 infection. Antiviral activity was measured against cell-free and cell-associated virus and in vaginal fluid and semen simulants. Since the antibacterial activity of salicylidene acylhydrazides is reversible by Fe(2+), the ability of Fe(2+) and other cations to reverse the anti-HIV-1 activity of the compounds was determined. Real-time PCR was also employed to determine the stage affected in the HIV-1 replication cycle. Four compounds with 50% inhibitory concentrations against HIV-1 of 1-7 μM were identified. In vitro toxicity varied but was generally limited. Activity was similar against three R5 clade B primary isolates and whether the target for virus replication was TZM-bl cells or PBMCs. Compounds inhibited cell-free and cell-associated virus and were active in vaginal fluid and semen simulants. Fe(2+), but not other cations, reversed the anti-HIV-1 effect. Finally, the inhibitory effect of the compounds occurred at a post-integration step. In conclusion, salicylidene acylhydrazides were identified with in vitro anti-HIV-1 activity in the micromolar range. The activity of these compounds against other sexually transmitted pathogens makes them potential candidates to formulate for use as a broad-spectrum topical genital microbicide. PMID:22819150

  17. Nematicidal Activity of Cassia and Cinnamon Oil Compounds and Related Compounds toward Bursaphelenchus xylophilus (Nematoda: Parasitaphelenchidae)

    PubMed Central

    Kong, Jeong-Ok; Lee, Sang-Myung; Moon, Yil-Seong; Lee, Sang-Gil; Ahn, Young-Joon

    2007-01-01

    The nematicidal activity of two cassia, Cinnamomum cassia, oils (Especial and true), four cinnamon, Cinnamomum zey-lanicum, oils (technical, #500, bark and green leaf), and their compounds (e.g., trans-cinnamaldehyde and trans-cinnamic acid) toward adult Bursaphelenchus xylophilus was examined by a direct contact bioassay. Results were compared with those of 34 related compounds. As judged by 24-hour LC50 values, two cassia oils (0.084–0.085 mg/ml) and four cinnamon oils (0.064–0.113 mg/ml) were toxic toward adult B. xylophilus. Of 45 test compounds, trans-cinnamaldehyde (0.061 mg/ml) was the most active nematicide, followed by ethyl cinnamate, α-methyl-trans-cinnamaldehyde, methyl cinnamate and allyl cinnamate (0.114–0.195 mg/ml). Potent nematicidal activity was also observed with 4-methoxycinnamonitrile, trans-4-methoxycinnamaldehyde, trans-2-methoxy-cinnamaldehyde, ethyl α-cyanocinnamate, cinnamonitrile and cinnamyl bromide (0.224–0.502 mg/ml). Structure-activity relationships indicate that structural characteristics, such as types of functional groups, saturation and carbon skeleton, appear to play a role in determining the toxicities to adult B. xylophilus. Cassia and cinnamon oils and test compounds described merit further study as potential nematicides or leads for the control of pine wilt disease caused by B. xylophilus. PMID:19259472

  18. Nematicidal Activity of Cassia and Cinnamon Oil Compounds and Related Compounds toward Bursaphelenchus xylophilus (Nematoda: Parasitaphelenchidae).

    PubMed

    Kong, Jeong-Ok; Lee, Sang-Myung; Moon, Yil-Seong; Lee, Sang-Gil; Ahn, Young-Joon

    2007-03-01

    The nematicidal activity of two cassia, Cinnamomum cassia, oils (Especial and true), four cinnamon, Cinnamomum zey-lanicum, oils (technical, #500, bark and green leaf), and their compounds (e.g., trans-cinnamaldehyde and trans-cinnamic acid) toward adult Bursaphelenchus xylophilus was examined by a direct contact bioassay. Results were compared with those of 34 related compounds. As judged by 24-hour LC(50) values, two cassia oils (0.084-0.085 mg/ml) and four cinnamon oils (0.064-0.113 mg/ml) were toxic toward adult B. xylophilus. Of 45 test compounds, trans-cinnamaldehyde (0.061 mg/ml) was the most active nematicide, followed by ethyl cinnamate, alpha-methyl-trans-cinnamaldehyde, methyl cinnamate and allyl cinnamate (0.114-0.195 mg/ml). Potent nematicidal activity was also observed with 4-methoxycinnamonitrile, trans-4-methoxycinnamaldehyde, trans-2-methoxy-cinnamaldehyde, ethyl alpha-cyanocinnamate, cinnamonitrile and cinnamyl bromide (0.224-0.502 mg/ml). Structure-activity relationships indicate that structural characteristics, such as types of functional groups, saturation and carbon skeleton, appear to play a role in determining the toxicities to adult B. xylophilus. Cassia and cinnamon oils and test compounds described merit further study as potential nematicides or leads for the control of pine wilt disease caused by B. xylophilus. PMID:19259472

  19. Terpenoid bioactive compound from Streptomyces rochei (M32): taxonomy, fermentation and biological activities.

    PubMed

    Pazhanimurugan, Raasaiyah; Radhakrishnan, Manikkam; Shanmugasundaram, Thangavel; Gopikrishnan, Venugopal; Balagurunathan, Ramasamy

    2016-10-01

    The present study emphasized the production of biologically active terpenoid compound from Streptomyces rochei M32, which was isolated from Western Ghats ecosystem, South India. The presence of resistant genes like mecA, vanA of Staphylococcus aureus and bla SHV, bla TEM of Pseudomonas aeruginosa was confirmed by molecular studies. The isolated compound from Streptomyces rochei M32 inhibited wide range of standard and clinical drug resistant pathogens and enteric pathogens. The rice bran supplemented basal medium influenced the active compound production on 8th day of fermentation and yielded 1875 mg of crude extract from 10 g of rice bran substrate. Purification and characterization of crude ethyl acetate extract was achieved by preparative thin layer chromatography. The active fraction was identified as terpenoid class compound by chemical screening. Based on the results of spectral studies (NMR, LC-MS, FTIR, etc.), the active compound was tentatively identified as 1, 19-bis (3-hydroxyazetidin-1-yl) nonadeca-5, 14-diene-1, 8, 12, 19-tetraone with molecular weight 462.41 g/mol. Minimum inhibitory concentration value ranges between 7.6 and 31.2 µg/mL against test organisms was observed. The cytotoxicity results on cervical cancer (HeLa) cell line showed IC50 value of 2.034 µg/mL. The corresponding compound is not previously reported from any microbial resources. PMID:27562595

  20. Biological Activities of Phenolic Compounds Present in Virgin Olive Oil

    PubMed Central

    Cicerale, Sara; Lucas, Lisa; Keast, Russell

    2010-01-01

    The Mediterranean diet is associated with a lower incidence of atherosclerosis, cardiovascular disease, neurodegenerative diseases and certain types of cancer. The apparent health benefits have been partially ascribed to the dietary consumption of virgin olive oil by Mediterranean populations. Much research has focused on the biologically active phenolic compounds naturally present in virgin olive oils to aid in explaining reduced mortality and morbidity experienced by people consuming a traditional Mediterranean diet. Studies (human, animal, in vivo and in vitro) have demonstrated that olive oil phenolic compounds have positive effects on certain physiological parameters, such as plasma lipoproteins, oxidative damage, inflammatory markers, platelet and cellular function, antimicrobial activity and bone health. This paper summarizes current knowledge on the bioavailability and biological activities of olive oil phenolic compounds. PMID:20386648

  1. Phenolic compounds from the bark of Oroxylum indicum activate the Ngn2 promoter.

    PubMed

    Fuentes, Rolly G; Arai, Midori A; Sadhu, Samir K; Ahmed, Firoj; Ishibashi, Masami

    2015-10-01

    A reporter gene assay that detects neurogenin 2 (Ngn2) promoter activity was utilized to identify compounds that induce neuronal differentiation. Ngn2 is a basic helix-loop-helix transcription factor that activates transcription of pro-neural genes. Using this assay system and an activity-guided approach, seven phenolic compounds were isolated from the methanol extract of Oroxylum indicum: 1 oroxylin A, 2 chrysin, 3 hispidulin, 4 baicalein, 5 apigenin, 6 baicalin, and 7 isoverbascoside. Compounds 1 and 2 induced an estimated 2.7-fold increase in Ngn2 promoter activity, whereas 3 increased the activity by 2.5-fold. Furthermore, 1 and 2 enhanced neuronal differentiation of C17.2 cells, which are multipotent stem cells. PMID:26014045

  2. Identification of active compounds in vegetal extracts based on correlation between activity and HPLC-MS data.

    PubMed

    Roldán, Cristina; de la Torre, Angel; Mota, Sonia; Morales-Soto, Aránzazu; Menéndez, Javier; Segura-Carretero, Antonio

    2013-01-15

    We propose a method identifying candidates for active compounds in vegetal extracts. From a collection of samples, the method requires, for each sample, a HPLC-MS analysis and a measurement of the activity. By applying a correlation analysis between the activity and the chromatographic area for each interval of elution time and m/z ratio, the peaks corresponding to candidates for active compounds can be identified. Additionally, when peaks are identified, a model can be estimated to predict the activity in new samples. Both methods are evaluated in one experiment involving the phenolic extract (PE) from 22 samples of extra virgin olive oil (EVOO) where the activity is a cytotoxicity index against JIMT-1 breast cancer cells. In this experiment, the samples were separated into two disjunct partitions: one was used for training (identification of candidates and estimation of prediction model), while the other was used for validation (by comparing the predicted and the measured activities). Three compounds were identified as candidates to be responsible for the cytotoxicity of the EVOO-PE against JIMT-1 cells. The prediction model provided an accurate estimation of the activity. PMID:23122076

  3. Prediction of antifungal activity of gemini imidazolium compounds.

    PubMed

    Pałkowski, Łukasz; Błaszczyński, Jerzy; Skrzypczak, Andrzej; Błaszczak, Jan; Nowaczyk, Alicja; Wróblewska, Joanna; Kożuszko, Sylwia; Gospodarek, Eugenia; Słowiński, Roman; Krysiński, Jerzy

    2015-01-01

    The progress of antimicrobial therapy contributes to the development of strains of fungi resistant to antimicrobial drugs. Since cationic surfactants have been described as good antifungals, we present a SAR study of a novel homologous series of 140 bis-quaternary imidazolium chlorides and analyze them with respect to their biological activity against Candida albicans as one of the major opportunistic pathogens causing a wide spectrum of diseases in human beings. We characterize a set of features of these compounds, concerning their structure, molecular descriptors, and surface active properties. SAR study was conducted with the help of the Dominance-Based Rough Set Approach (DRSA), which involves identification of relevant features and relevant combinations of features being in strong relationship with a high antifungal activity of the compounds. The SAR study shows, moreover, that the antifungal activity is dependent on the type of substituents and their position at the chloride moiety, as well as on the surface active properties of the compounds. We also show that molecular descriptors MlogP, HOMO-LUMO gap, total structure connectivity index, and Wiener index may be useful in prediction of antifungal activity of new chemical compounds. PMID:25961015

  4. Prediction of Antifungal Activity of Gemini Imidazolium Compounds

    PubMed Central

    Pałkowski, Łukasz; Błaszczyński, Jerzy; Skrzypczak, Andrzej; Błaszczak, Jan; Nowaczyk, Alicja; Wróblewska, Joanna; Kożuszko, Sylwia; Gospodarek, Eugenia; Słowiński, Roman; Krysiński, Jerzy

    2015-01-01

    The progress of antimicrobial therapy contributes to the development of strains of fungi resistant to antimicrobial drugs. Since cationic surfactants have been described as good antifungals, we present a SAR study of a novel homologous series of 140 bis-quaternary imidazolium chlorides and analyze them with respect to their biological activity against Candida albicans as one of the major opportunistic pathogens causing a wide spectrum of diseases in human beings. We characterize a set of features of these compounds, concerning their structure, molecular descriptors, and surface active properties. SAR study was conducted with the help of the Dominance-Based Rough Set Approach (DRSA), which involves identification of relevant features and relevant combinations of features being in strong relationship with a high antifungal activity of the compounds. The SAR study shows, moreover, that the antifungal activity is dependent on the type of substituents and their position at the chloride moiety, as well as on the surface active properties of the compounds. We also show that molecular descriptors MlogP, HOMO-LUMO gap, total structure connectivity index, and Wiener index may be useful in prediction of antifungal activity of new chemical compounds. PMID:25961015

  5. Cdc25B Dual-Specificity Phosphatase Inhibitors Identified in a High-Throughput Screen of the NIH Compound Library

    PubMed Central

    Foster, Caleb A.; Tierno, Marni Brisson; Shun, Tong Ying; Shinde, Sunita N.; Paquette, William D.; Brummond, Kay M.; Wipf, Peter; Lazo, John S.

    2009-01-01

    Abstract The University of Pittsburgh Molecular Library Screening Center (Pittsburgh, PA) conducted a screen with the National Institutes of Health compound library for inhibitors of in vitro cell division cycle 25 protein (Cdc25) B activity during the pilot phase of the Molecular Library Screening Center Network. Seventy-nine (0.12%) of the 65,239 compounds screened at 10 μM met the active criterion of ≥50% inhibition of Cdc25B activity, and 25 (31.6%) of these were confirmed as Cdc25B inhibitors with 50% inhibitory concentration (IC50) values <50 μM. Thirteen of the Cdc25B inhibitors were represented by singleton chemical structures, and 12 were divided among four clusters of related structures. Thirteen (52%) of the Cdc25B inhibitor hits were quinone-based structures. The Cdc25B inhibitors were further characterized in a series of in vitro secondary assays to confirm their activity, to determine their phosphatase selectivity against two other dual-specificity phosphatases, mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-3, and to examine if the mechanism of Cdc25B inhibition involved oxidation and inactivation. Nine Cdc25B inhibitors did not appear to affect Cdc25B through a mechanism involving oxidation because they did not generate detectable amounts of H2O2 in the presence of dithiothreitol, and their Cdc25B IC50 values were not significantly affected by exchanging the dithiothreitol for β-mercaptoethanol or reduced glutathione or by adding catalase to the assay. Six of the nonoxidative hits were selective for Cdc25B inhibition versus MKP-1 and MKP-3, but only the two bisfuran-containing hits, PubChem substance identifiers 4258795 and 4260465, significantly inhibited the growth of human MBA-MD-435 breast and PC-3 prostate cancer cell lines. To confirm the structure and biological activity of 4260465, the compound was resynthesized along with two analogs. Neither of the substitutions to the two analogs was tolerated, and only the

  6. Antifungal activity of fractions and two pure compounds of flowers from Wedelia paludosa (Acmela brasiliensis) (Asteraceae).

    PubMed

    Sartori, M R K; Pretto, J B; Cruz, A B; Bresciani, L F V; Yunes, R A; Sortino, M; Zacchino, S A; Cechinel, V Filho

    2003-08-01

    Wedelia paludosa (Acmela brasiliensis) (Asteraceae), a traditionally used native Brazilian medicinal plant, showed antifungal activity against dermatophytes in dilution tests. The hexane, dichloromethane and butanol fractions displayed activity against Epidermophyton floccosum, Trichophyton rubrum and Trichophyton mentagrophytes, with minimal inhibitory concentrations between 250 and 1000 microg/mL. Two pure compounds, identified as kaurenoic acid (1) and luteolin (2), also showed activity against these dermatophytes. PMID:12967035

  7. Emodin is identified as the active component of ether extracts from Rhizoma Polygoni Cuspidati, for anti-MRSA activity.

    PubMed

    Cao, Feng; Peng, Wei; Li, Xiaoli; Liu, Ming; Li, Bin; Qin, Rongxin; Jiang, Weiwei; Cen, Yanyan; Pan, Xichun; Yan, Zifei; Xiao, Kangkang; Zhou, Hong

    2015-06-01

    This study investigated the anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity and chemical compositions of ether extracts from Rhizoma Polygoni Cuspidati (ET-RPC). Significant anti-MRSA activities of ET-RPC against MRSA252 and MRSA clinical strains were tested in in vitro antibacterial experiments, such as inhibition zone diameter test, minimal inhibitory concentration test, and dynamic bacterial growth assay. Subsequently, 7 major compounds of ET-RPC were purified and identified as polydatin, resveratrol-4-O-d-(6'-galloyl)-glucopyranoside, resveratrol, torachryson-8-O-glucoside, emodin-8-O-glucoside, 6-hydroxy-emodin, and emodin using liquid chromatography - electrospray ionization - tandem mass spectrometry. After investigation of anti-MRSA activities of the 7 major compounds, only emodin had significant anti-MRSA activity. Further, transmission electron microscopy was used to observe morphological changes in the cell wall of MRSA252, and the result revealed that emodin could damage the integrity of cell wall, leading to loss of intracellular components. In summary, our results showed ET-RPC could significantly inhibit bacterial growth of MRSA strains. Emodin was identified as the major compound with anti-MRSA activity; this activity was related to destruction of the integrity of the cell wall and cell membrane. PMID:25966789

  8. [Biological activity of selenorganic compounds at heavy metal salts intoxication].

    PubMed

    Rusetskaya, N Y; Borodulin, V B

    2015-01-01

    Possible mechanisms of the antitoxic action of organoselenium compounds in heavy metal poisoning have been considered. Heavy metal toxicity associated with intensification of free radical oxidation, suppression of the antioxidant system, damage to macromolecules, mitochondria and the genetic material can cause apoptotic cell death or the development of carcinogenesis. Organic selenium compounds are effective antioxidants during heavy metal poisoning; they exhibit higher bioavailability in mammals than inorganic ones and they are able to activate antioxidant defense, bind heavy metal ions and reactive oxygen species formed during metal-induced oxidative stress. One of promising organoselenium compounds is diacetophenonyl selenide (DAPS-25), which is characterized by antioxidant and antitoxic activity, under conditions including heavy metal intoxication. PMID:26350735

  9. Removal of pharmaceutically active compounds in nitrifying-denitrifying plants.

    PubMed

    Suárez, S; Ramil, M; Omil, F; Lema, J M

    2005-01-01

    The behaviour of nine pharmaceutically active compounds (PhACs) of different diagnostic groups is studied during a nitrifying-denitrifying process in an activated sludge system. The compounds selected cover a wide range of frequently used substances such as anti-epileptics (carbamazepine), tranquillisers (diazepam), anti-depressants (fluoxetine and citalopram), anti-inflammatories (ibuprofen, naproxen and diclofenac) and estrogens (estradiol and ethinylestradiol). The main objective of this research is to investigate the effect of acclimation of biomass on the removal rates of these compounds, either by maintaining a high sludge retention time or at long-term operation. The removal rates achieved for nitrogen and carbon in the experimental unit exceed 90% and were not affected by the addition of PhACs. Carbamazepine, diazepam and diclofenac were only removed to a small extent. On the other hand, higher removal rates have been observed for naproxen and ibuprofen (68% and 82%), respectively. PMID:16312946

  10. Identifying Clusters of Active Transportation Using Spatial Scan Statistics

    PubMed Central

    Huang, Lan; Stinchcomb, David G.; Pickle, Linda W.; Dill, Jennifer; Berrigan, David

    2009-01-01

    Background There is an intense interest in the possibility that neighborhood characteristics influence active transportation such as walking or biking. The purpose of this paper is to illustrate how a spatial cluster identification method can evaluate the geographic variation of active transportation and identify neighborhoods with unusually high/low levels of active transportation. Methods Self-reported walking/biking prevalence, demographic characteristics, street connectivity variables, and neighborhood socioeconomic data were collected from respondents to the 2001 California Health Interview Survey (CHIS; N=10,688) in Los Angeles County (LAC) and San Diego County (SDC). Spatial scan statistics were used to identify clusters of high or low prevalence (with and without age-adjustment) and the quantity of time spent walking and biking. The data, a subset from the 2001 CHIS, were analyzed in 2007–2008. Results Geographic clusters of significantly high or low prevalence of walking and biking were detected in LAC and SDC. Structural variables such as street connectivity and shorter block lengths are consistently associated with higher levels of active transportation, but associations between active transportation and socioeconomic variables at the individual and neighborhood levels are mixed. Only one cluster with less time spent walking and biking among walkers/bikers was detected in LAC, and this was of borderline significance. Age-adjustment affects the clustering pattern of walking/biking prevalence in LAC, but not in SDC. Conclusions The use of spatial scan statistics to identify significant clustering of health behaviors such as active transportation adds to the more traditional regression analysis that examines associations between behavior and environmental factors by identifying specific geographic areas with unusual levels of the behavior independent of predefined administrative units. PMID:19589451

  11. Discovery of compounds that protect tyrosine hydroxylase activity through different mechanisms.

    PubMed

    Hole, Magnus; Underhaug, Jarl; Diez, Hector; Ying, Ming; Røhr, Åsmund Kjendseth; Jorge-Finnigan, Ana; Fernàndez-Castillo, Noèlia; García-Cazorla, Angels; Andersson, K Kristoffer; Teigen, Knut; Martinez, Aurora

    2015-09-01

    Pharmacological chaperones are small compounds that correct the folding of mutant proteins, and represent a promising therapeutic strategy for misfolding diseases. We have performed a screening of 10,000 compounds searching for pharmacological chaperones of tyrosine hydroxylase (TH), the tetrahydrobiopterin (BH4)-dependent enzyme that catalyzes the rate-limiting step in the synthesis of catecholamines. A large number of compounds bound to human TH, isoform 1 (hTH1), but only twelve significantly protected wild-type (hTH1-wt) and mutant TH-R233H (hTH1-p.R202H), associated to the rare neurological disorder TH deficiency (THD), from time-dependent loss of activity. Three of them (named compounds 2, 4 and 5) were subjected to detailed characterization of their functional and molecular effects. Whereas compounds 2 and 4 had a characteristic pharmacological chaperone (stabilizing) effect, compound 5 protected the activity in a higher extent than expected from the low conformational stabilization exerted on hTH1. Compounds 4 and 5 were weak competitive inhibitors with respect to the cofactor BH4 and, as seen by electron paramagnetic resonance, they induced small changes to the first coordination sphere of the catalytic iron. Molecular docking also indicated active-site location with coordination to the iron through a pyrimidine nitrogen atom. Interestingly, compound 5 increased TH activity in cells transiently transfected with either hTH1-wt or the THD associated mutants p.L205P, p.R202H and p.Q381K without affecting the steady-state TH protein levels. This work revealed different mechanisms for the action of pharmacological chaperones and identifies a subtype of compounds that preserve TH activity by weak binding to the catalytic iron. This article is part of a Special Issue entitled: Cofactor-dependent proteins: Evolution, chemical diversity and bio-applications. PMID:25960279

  12. Effects of polyhydroxy compounds on beetle antifreeze protein activity

    PubMed Central

    Amornwittawat, Natapol; Wang, Sen; Banatlao, Joseph; Chung, Melody; Velasco, Efrain; Duman, John G.; Wen, Xin

    2016-01-01

    Antifreeze proteins (AFPs) noncolligatively depress the nonequilibrium freezing point of a solution and produce a difference between the melting and freezing points termed thermal hysteresis (TH). Some low-molecular-mass solutes can affect the TH values. The TH enhancement effects of selected polyhydroxy compounds including polyols and carbohydrates on an AFP from the beetle Dendroides canadensis were systematically investigated using differential scanning calorimetry (DSC). The number of hydroxyl groups dominates the molar enhancement effectiveness of polyhydroxy compounds having one to five hydroxyl groups. However, the above rule does not apply for polyhydroxy compounds having more than five hydroxyl groups. The most efficient polyhydroxy enhancer identified is trehalose. In a combination of enhancers the strongest enhancer plays the major role in determining the TH enhancement. Mechanistic insights into identification of highly efficient AFP enhancers are discussed. PMID:19038370

  13. Anti-Salmonella Activity of Volatile Compounds of Vietnam Coriander.

    PubMed

    Fujita, Ken-Ichi; Chavasiri, Warinthorn; Kubo, Isao

    2015-07-01

    Essential oil derived from the fresh leaves of Polygonum odoratum Lour was tested for their effects on a foodborne bacterium Salmonella choleraesuis subsp. choleraesuis ATCC 35640 using a broth dilution method. This essential oil showed a significant antibacterial activity against S. choleraesuis at the concentration of 200 µg/mL. Twenty-five volatile compounds were characterized from this essential oil by GC-MS, and aldehyde compounds were found abundant and accounted for more than three-fourths of the essential oil. Among the compounds characterized, dodecanal (C12 ) was the most abundant (55.5%), followed by decanal (C10 ) (11.6%). Both alkanals were effective against S. choleraesuis with the minimum growth inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of 100 µg/mL. The most potent antibacterial activity against this bacterium was found with two minor compounds, dodecanol (lauryl alcohol) and 2E-dodecenal, both with each MBC of 6.25 µg/mL. Their primary antibacterial action against S. choleraesuis provably comes from their ability to function as nonionic surface-active agents (surfactants), disrupting the native function of integral membrane proteins nonspecifically. Thus, the antibacterial activity is mediated by biophysical processes. In the case of 2E-alkenals, a biochemical mechanism is also somewhat involved, depending on their alkyl chain length. PMID:25870012

  14. A neural networks study of quinone compounds with trypanocidal activity.

    PubMed

    de Molfetta, Fábio Alberto; Angelotti, Wagner Fernando Delfino; Romero, Roseli Aparecida Francelin; Montanari, Carlos Alberto; da Silva, Albérico Borges Ferreira

    2008-10-01

    This work investigates neural network models for predicting the trypanocidal activity of 28 quinone compounds. Artificial neural networks (ANN), such as multilayer perceptrons (MLP) and Kohonen models, were employed with the aim of modeling the nonlinear relationship between quantum and molecular descriptors and trypanocidal activity. The calculated descriptors and the principal components were used as input to train neural network models to verify the behavior of the nets. The best model for both network models (MLP and Kohonen) was obtained with four descriptors as input. The descriptors were T5 (torsion angle), QTS1 (sum of absolute values of the atomic charges), VOLS2 (volume of the substituent at region B) and HOMO-1 (energy of the molecular orbital below HOMO). These descriptors provide information on the kind of interaction that occurs between the compounds and the biological receptor. Both neural network models used here can predict the trypanocidal activity of the quinone compounds with good agreement, with low errors in the testing set and a high correctness rate. Thanks to the nonlinear model obtained from the neural network models, we can conclude that electronic and structural properties are important factors in the interaction between quinone compounds that exhibit trypanocidal activity and their biological receptors. The final ANN models should be useful in the design of novel trypanocidal quinones having improved potency. PMID:18629551

  15. New Compound Sets Identified from High Throughput Phenotypic Screening Against Three Kinetoplastid Parasites: An Open Resource

    PubMed Central

    Peña, Imanol; Pilar Manzano, M.; Cantizani, Juan; Kessler, Albane; Alonso-Padilla, Julio; Bardera, Ana I.; Alvarez, Emilio; Colmenarejo, Gonzalo; Cotillo, Ignacio; Roquero, Irene; de Dios-Anton, Francisco; Barroso, Vanessa; Rodriguez, Ana; Gray, David W.; Navarro, Miguel; Kumar, Vinod; Sherstnev, Alexander; Drewry, David H.; Brown, James R.; Fiandor, Jose M.; Julio Martin, J.

    2015-01-01

    Using whole-cell phenotypic assays, the GlaxoSmithKline high-throughput screening (HTS) diversity set of 1.8 million compounds was screened against the three kinetoplastids most relevant to human disease, i.e. Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. Secondary confirmatory and orthogonal intracellular anti-parasiticidal assays were conducted, and the potential for non-specific cytotoxicity determined. Hit compounds were chemically clustered and triaged for desirable physicochemical properties. The hypothetical biological target space covered by these diversity sets was investigated through bioinformatics methodologies. Consequently, three anti-kinetoplastid chemical boxes of ~200 compounds each were assembled. Functional analyses of these compounds suggest a wide array of potential modes of action against kinetoplastid kinases, proteases and cytochromes as well as potential host–pathogen targets. This is the first published parallel high throughput screening of a pharma compound collection against kinetoplastids. The compound sets are provided as an open resource for future lead discovery programs, and to address important research questions. PMID:25740547

  16. CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil.

    PubMed

    Almqvist, Helena; Axelsson, Hanna; Jafari, Rozbeh; Dan, Chen; Mateus, André; Haraldsson, Martin; Larsson, Andreas; Martinez Molina, Daniel; Artursson, Per; Lundbäck, Thomas; Nordlund, Pär

    2016-01-01

    Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery. PMID:27010513

  17. CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil

    NASA Astrophysics Data System (ADS)

    Almqvist, Helena; Axelsson, Hanna; Jafari, Rozbeh; Dan, Chen; Mateus, André; Haraldsson, Martin; Larsson, Andreas; Molina, Daniel Martinez; Artursson, Per; Lundbäck, Thomas; Nordlund, Pär

    2016-03-01

    Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.

  18. CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil

    PubMed Central

    Almqvist, Helena; Axelsson, Hanna; Jafari, Rozbeh; Dan, Chen; Mateus, André; Haraldsson, Martin; Larsson, Andreas; Molina, Daniel Martinez; Artursson, Per; Lundbäck, Thomas; Nordlund, Pär

    2016-01-01

    Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery. PMID:27010513

  19. Using ILP to Identify Pathway Activation Patterns in Systems Biology

    PubMed Central

    Neaves, Samuel R; Millard, Louise A C; Tsoka, Sophia

    2016-01-01

    We show a logical aggregation method that, combined with propositionalization methods, can construct novel structured biological features from gene expression data. We do this to gain understanding of pathway mechanisms, for instance, those associated with a particular disease. We illustrate this method on the task of distinguishing between two types of lung cancer; Squamous Cell Carcinoma (SCC) and Adenocarcinoma (AC). We identify pathway activation patterns in pathways previously implicated in the development of cancers. Our method identified a model with comparable predictive performance to the winning algorithm of a recent challenge, while providing biologically relevant explanations that may be useful to a biologist. PMID:27478883

  20. Antipoliovirus Activity of the Organic Extract of Eupatorium buniifolium: Isolation of Euparin as an Active Compound

    PubMed Central

    Visintini Jaime, María Florencia; Campos, Rodolfo H.; Martino, Virginia S.; Cavallaro, Lucía V.; Muschietti, Liliana V.

    2013-01-01

    The antiviral activity of the organic extract (OE) of Eupatorium buniifolium against poliovirus type 1 was determined by in vitro assays with an effective concentration 50 (EC50) of 23.3 ± 3.3 µg/mL. Bioassay-guided fractionation of the OE allowed the isolation of an active principle that was identified by spectroscopic methods (1H- and 13C-NMR, EI-MS, UV, and IR spectroscopy) as the benzofuran euparin. The plaque reduction assay in Vero cells was used to assess the antiviral activity of euparin against poliovirus types 1, 2, and 3 with EC50 values of 0.47, 0.12, and 0.15 µg/mL, respectively. Moreover, this compound showed high selectivity indexes of 284.9, 1068, and 854.7, respectively. In order to identify the mechanism by which euparin exerts its antiviral activity, the virucidal effect, the pretreatment of Vero cells, and the time of action on one viral replication cycle were evaluated. Results obtained demonstrated that euparin exerts its effect during the early events of the replication cycle, from the virus adsorption to cells up to the first twenty minutes after infection. This is the first report on the presence of euparin in E. buniifolium and its antiviral activity. PMID:23956770

  1. Identifying Sources of Volatile Organic Compounds and Aldehydes in a High Performance Building

    SciTech Connect

    Ortiz, Anna C.; Russell, Marion; Lee, Wen-Yee; Apte, Michael; Maddalena, Randy

    2010-09-20

    The developers of the Paharpur Business Center (PBC) and Software Technology Incubator Park in New Delhi, India offer an environmentally sustainable building with a strong emphasis on energy conservation, waste minimization and superior indoor air quality (IAQ). To achieve the IAQ goal, the building utilizes a series of air cleaning technologies for treating the air entering the building. These technologies include an initial water wash followed by ultraviolet light treatment and biolfiltration using a greenhouse located on the roof and numerous plants distributed throughout the building. Even with the extensive treatment of makeup air and room air in the PBC, a recent study found that the concentrations of common volatile organic compounds and aldehydes appear to rise incrementally as the air passes through the building from the supply to the exhaust. This finding highlights the need to consider the minimization of chemical sources in buildings in combination with the use of advanced air cleaning technologies when seeking to achieve superior IAQ. The goal of this project was to identify potential source materials for indoor chemicals in the PBC. Samples of building materials, including wood paneling (polished and unpolished), drywall, and plastic from a hydroponic drum that was part of the air cleaning system, were collected from the building for testing. All materials were collected from the PBC building and shipped to the Lawrence Berkeley National Laboratory (LBNL) for testing. The materials were pre-conditioned for two different time periods before measuring material and chemical specific emission factors for a range of VOCs and Aldehydes. Of the six materials tested, we found that the highest emitter of formaldehyde was new plywood paneling. Although polish and paint contribute to some VOC emissions, the main influence of the polish was in altering the capacity of the surface to accumulate formaldehyde. Neither the new nor aged polish contributed

  2. Cytotoxic and Antimigratory Activities of Phenolic Compounds from Dendrobium brymerianum

    PubMed Central

    Klongkumnuankarn, Pornprom; Busaranon, Kesarin; Chanvorachote, Pithi; Sritularak, Boonchoo; Jongbunprasert, Vichien; Likhitwitayawuid, Kittisak

    2015-01-01

    Chromatographic separation of a methanol extract prepared from the whole plant of Dendrobium brymerianum led to the isolation of eight phenolic compounds. Among the isolated compounds (1–8), moscatilin (1), gigantol (3), lusianthridin (4), and dendroflorin (6) showed appreciable cytotoxicity against human lung cancer cell lines with IC50 values of 196.7, 23.4, 65.0, and 125.8 μg/mL, respectively, and exhibited antimigratory property at nontoxic concentrations. This study is the first report on the biological activities of this plant. PMID:25685168

  3. Machine learning models identify molecules active against the Ebola virus in vitro.

    PubMed

    Ekins, Sean; Freundlich, Joel S; Clark, Alex M; Anantpadma, Manu; Davey, Robert A; Madrid, Peter

    2015-01-01

    The search for small molecule inhibitors of Ebola virus (EBOV) has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs) with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC 50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in vitro. PMID:26834994

  4. Machine learning models identify molecules active against the Ebola virus in vitro

    PubMed Central

    Ekins, Sean; Freundlich, Joel S.; Clark, Alex M.; Anantpadma, Manu; Davey, Robert A.; Madrid, Peter

    2016-01-01

    The search for small molecule inhibitors of Ebola virus (EBOV) has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs) with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC 50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in vitro. PMID:26834994

  5. Callicarpenal and Intermedeol: Two Natural Arthropod Feeding Deterrent and Repellent Compounds Identified from the Southern Folk Remedy Plant, Callicarpa americana

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In previous studies on the American beautyberry (Callicarpa americana), it was demonstrated that callicarpenal and intermedeol were responsible for the arthropod repellent and feeding deterrent activity of this folk remedy. Both compounds showed significant bite-deterring activity against Aedes aeg...

  6. The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcome

    PubMed Central

    Harlow, Philippa H.; Perry, Simon J.; Widdison, Stephanie; Daniels, Shannon; Bondo, Eddie; Lamberth, Clemens; Currie, Richard A.; Flemming, Anthony J.

    2016-01-01

    To determine whether a C. elegans bioassay could predict mammalian developmental activity, we selected diverse compounds known and known not to elicit such activity and measured their effect on C. elegans egg viability. 89% of compounds that reduced C. elegans egg viability also had mammalian developmental activity. Conversely only 25% of compounds found not to reduce egg viability in C. elegans were also inactive in mammals. We conclude that the C. elegans egg viability assay is an accurate positive predictor, but an inaccurate negative predictor, of mammalian developmental activity. We then evaluated C. elegans as a tool to identify mechanisms affecting toxicological outcomes among related compounds. The difference in developmental activity of structurally related fungicides in C. elegans correlated with their rate of metabolism. Knockdown of the cytochrome P450s cyp-35A3 and cyp-35A4 increased the toxicity to C. elegans of the least developmentally active compounds to the level of the most developmentally active. This indicated that these P450s were involved in the greater rate of metabolism of the less toxic of these compounds. We conclude that C. elegans based approaches can predict mammalian developmental activity and can yield plausible hypotheses for factors affecting the biological potency of compounds in mammals. PMID:26987796

  7. Parallel Synthesis and Biological Evaluation of 837 Analogues of Procaspase-Activating Compound 1 (PAC-1)

    PubMed Central

    Hsu, Danny C.; Roth, Howard S.; West, Diana C.; Botham, Rachel C.; Novotny, Chris J.; Schmid, Steven C.; Hergenrother, Paul J.

    2011-01-01

    Procaspase-Activating Compound 1 (PAC-1) is an ortho-hydroxy N-acyl hydrazone that enhances the enzymatic activity of procaspase-3 in vitro and induces apoptosis in cancer cells. An analogue of PAC-1, called S-PAC-1, was evaluated in a veterinary clinical trial in pet dogs with lymphoma and found to have considerable potential as an anticancer agent. With the goal of identifying more potent compounds in this promising class of experimental therapeutics, a combinatorial library based on PAC-1 was created, and the compounds were evaluated for their ability to induce death of cancer cells in culture. For library construction, 31 hydrazides were condensed in parallel with 27 aldehydes to create 837 PAC-1 analogues, with an average purity of 91%. The compounds were evaluated for their ability to induce apoptosis in cancer cells, and through this work, six compounds were discovered to be substantially more potent than PAC-1 and S-PAC-1. These six hits were further evaluated for their ability to relieve zinc-mediated inhibition of procaspase-3 in vitro. In general, the newly identified hit compounds are two- to four-fold more potent than PAC-1 and S-PAC-1 in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3. PMID:22007686

  8. Essential requirement of cytochrome c release for caspase activation by procaspase-activating compound defined by cellular models

    PubMed Central

    Seervi, M; Joseph, J; Sobhan, P K; Bhavya, B C; Santhoshkumar, T R

    2011-01-01

    Mitochondrial cytochrome c (cyt. c) release and caspase activation are often impaired in tumors with Bcl-2 overexpression or Bax and Bak-defective status. Direct triggering of cell death downstream of Bax and Bak is an attractive strategy to kill such cancers. Small molecule compounds capable of direct caspase activation appear to be the best mode for killing such tumors. However, there is no precise model to screen such compounds. The currently employed cell-free systems possess the inherent drawback of lacking cellular contents and organelles that operate in integrating cell death signaling. We have developed highly refined cell-based approaches to validate direct caspase activation in cancer cells. Using this approach, we show that PAC-1 (first procaspase-activating compound), the first direct activator of procaspases identified in a cell-free system, in fact requires mitochondrial cyt. c release for triggering caspase activation similar to other antitumor agents. It can induce significant caspase activation and cell death in the absence of Bax and Bak, and in cells overexpressing Bcl-2 and Bcl-xL. This study for the first time defines precise criteria for the validation of direct caspase-activating compounds using specialized cellular models that is expected to accelerate the discovery of potential direct caspase activators. PMID:21900958

  9. Systematic assessment of scaffold hopping versus activity cliff formation across bioactive compound classes following a molecular hierarchy.

    PubMed

    Stumpfe, Dagmar; Dimova, Dilyana; Bajorath, Jürgen

    2015-07-01

    Scaffold hopping and activity cliff formation define opposite ends of the activity landscape feature spectrum. To rationalize these events at the level of scaffolds, active compounds involved in scaffold hopping were required to contain topologically distinct scaffolds but have only limited differences in potency, whereas compounds involved in activity cliffs were required to share the same scaffold but have large differences in potency. A systematic search was carried out for compounds involved in scaffold hopping and/or activity cliff formation. Results obtained for compound data sets covering more than 300 human targets revealed clear trends. If scaffolds represented multiple but fewer than 10 active compounds, nearly 90% of all scaffolds were exclusively involved in hopping events. With increasing compound coverage, the fraction of scaffolds involved in both scaffold hopping and activity cliff formation significantly increased to more than 50%. However, ∼40% of the scaffolds representing large numbers of active compounds continued to be exclusively involved in scaffold hopping. More than 200 scaffolds with broad target coverage were identified that consistently represented potent compounds and yielded an abundance of scaffold hops in the low-nanomolar range. These and other subsets of scaffolds we characterized are of prime interest for structure-activity relationship (SAR) exploration and compound design. Therefore, the complete scaffold classification generated in the course of our analysis is made freely available. PMID:25982076

  10. Synthesis and antitumor activity of natural compound aloe emodin derivatives.

    PubMed

    Thimmegowda, Naraganahalli R; Park, Chanmi; Shwetha, Bettaswamigowda; Sakchaisri, Krisada; Liu, Kangdong; Hwang, Joonsung; Lee, Sangku; Jeong, Sook J; Soung, Nak K; Jang, Jae H; Ryoo, In-Ja; Ahn, Jong S; Erikson, Raymond L; Kim, Bo Y

    2015-05-01

    In this study, we have synthesized novel water soluble derivatives of natural compound aloe emodin 4(a-j) by coupling with various amino acid esters and substituted aromatic amines, in an attempt to improve the anticancer activity and to explore the structure-activity relationships. The structures of the compounds were determined by (1) H NMR and mass spectroscopy. Cell growth inhibition assays revealed that the aloe emodin derivatives 4d, 4f, and 4i effectively decreased the growth of HepG2 (human liver cancer cells) and NCI-H460 (human lung cancer cells) and some of the derivatives exhibited comparable antitumor activity against HeLa (Human epithelial carcinoma cells) and PC3 (prostate cancer cells) cell lines compared to that of the parent aloe emodin at low micromolar concentrations. PMID:25323822

  11. Structure-activity analysis and antiprion mechanism of isoprenoid compounds.

    PubMed

    Hamanaka, Taichi; Nishizawa, Keiko; Sakasegawa, Yuji; Teruya, Kenta; Doh-ura, Katsumi

    2015-12-01

    The prion strain-specific mechanism by which normal prion protein is converted to abnormal prion protein remains largely unknown. This study found that insect juvenile hormone III reduced abnormal prion protein levels only in cells infected with the RML prion. We conducted a structure-activity analysis using juvenile hormone III biosynthetic intermediates in the isoprenoid pathway. Both farnesol and geranylgeraniol, the most potent inhibitors of abnormal prion protein formation, behaved in an RML prion-dependent fashion. Neither of them modified cellular and cell surface prion protein levels. Events downstream of this pathway include cholesterol biosynthesis and protein prenylation. However, neither of these isoprenoid compounds modified lipid raft microdomains and cellular cholesterol levels and neither affected the representative prenylated protein expression levels of prenylation pathways. Therefore, these isoprenoid compounds are a new class of prion strain-dependent antiprion compounds. They are useful for exploring strain-specific prion biology. PMID:26402376

  12. Hybrid energy storage systems utilizing redox active organic compounds

    DOEpatents

    Wang, Wei; Xu, Wu; Li, Liyu; Yang, Zhenguo

    2015-09-08

    Redox flow batteries (RFB) have attracted considerable interest due to their ability to store large amounts of power and energy. Non-aqueous energy storage systems that utilize at least some aspects of RFB systems are attractive because they can offer an expansion of the operating potential window, which can improve on the system energy and power densities. One example of such systems has a separator separating first and second electrodes. The first electrode includes a first current collector and volume containing a first active material. The second electrode includes a second current collector and volume containing a second active material. During operation, the first source provides a flow of first active material to the first volume. The first active material includes a redox active organic compound dissolved in a non-aqueous, liquid electrolyte and the second active material includes a redox active metal.

  13. Identification of Volatile Organic Compounds (VOCs) From Photochemical Activity in Snow Samples

    NASA Astrophysics Data System (ADS)

    Kos, G.; Ariya, P. A.

    2004-05-01

    The occurrence of VOCs in snow has been observed and can be related to anthropogenic emissions and biological activity. Photochemistry and microorganisms play a major role in the transformation of compounds in different compartments of the global ecosystem. Studies so far focused on the determination of single analytes or a class of compounds - mainly of anthropogenic origin (e.g. halogenated aromatic hydrocarbons) - that were considered important with regard to health and environmental concerns. Broader studies that describe a range of different compounds with different functionalities are relatively rare, especially for those of biological origin. The presented study investigated the formation of VOCs in snow samples and their connection with microbiological activity. The main aim was to pre-concentrate, identify and quantify volatile organic compounds. Snow samples were collected in an urban environment (Montreal, Canada) with sterilized containers. Samples were transferred into a heated reaction flask, where the sample was melted. A two-trap system was employed for pre-concentration: The first trap was used for water removal. The second trap was used for the collection of expected analytes by removing volatiles from the circulating air. Circulation was maintained with a pump at atmospheric pressure. Adsorption to glass walls of the reaction flask was prevented with halocarbon wax coating. Different sterilization methods were employed to suppress microbiological activity in order to collect background data and identify compounds of biological origin. VOC concentration and compound identification was performed with gas chromatography and mass spectrometric detection (GC-MS) by taking a sample with a gas-tight syringe through a septum-port. The sample was directly injected into the GC system. Compounds were identified by their respective mass spectra and included aldehydes and alcohols.

  14. Analysis of active compounds and antioxidant activity assessment of six popular Chinese Juhua teas.

    PubMed

    Du, Hui; Li, Shan-Shan; Wu, Qian; Ji, Kui-Xian; Wu, Jie; Liu, Yang; Wang, Liang-Sheng

    2015-03-01

    Chrysanthemum is an important traditional Chinese medicine and is drunk daily as a herbal tea. Chlorogenic acids and flavonoids are generally considered as the bioactive compounds. In this work, six kinds of Juhua Tea were analyzed and their active compounds and antioxidant activities were compared. In total, 32 phenolic compounds were profiled and identified using HPLC-DAD/ESI-MSn, composed of chlorogenic acids (10), flavones (8), chalcones (8), flavanones (4) and flavonols (2). Chalcones were the main flavonoids in Kunlun Xueju (Coreopsis tinctoria) extract, while flavones and chlorogenic acids were dominant in the five Chrysanthemum teas. Total chlorogenic acids content (TCA) was highest in Tai Ju (Chrysanthemum morifolium cv. 'Tai Ju') (8.59 ± 0.87 mg/g DW), and total flavonoids content (TF) was highest in Kunlun Xueju (87.2 ± 7.0 mg/g DW), which were both lowest in Ganye Ju (Chrysanthemum eticuspe) (TCA 0.86 ± 0.26 mg/g DW, TF 1.43 ± 0.41 mg/g DW). Huangin Ju (Anthemis tinctoria) possessed the most flavones (19.7 ± 0.6 mg/g DW). Antioxidant capacity of each drink, assessed by Folin-Ciocalteu, DPPH, ABTS and FRAP assays, consistently showed that Kunlun Xueju extract possessed stronger antioxidant activity than the other five, suggesting that the flavonoids content accounted for the free radical scavenging. The present work provides a method for the characterization and quality control of Juhua Tea. Moreover, it is a guideline for consuming choice, due to the different biological functions resulting from chalcones, chlorogenic acids, and flavones. PMID:25924537

  15. Aldose reductase inhibitory activity of compounds from Zea mays L.

    PubMed

    Kim, Tae Hyeon; Kim, Jin Kyu; Kang, Young-Hee; Lee, Jae-Yong; Kang, Il Jun; Lim, Soon Sung

    2013-01-01

    Aldose reductase (AR) inhibitors have a considerable therapeutic potential against diabetes complications and do not increase the risk of hypoglycemia. Through bioassay-guided fractionation of an EtOH extract of the kernel from purple corn (Zea mays L.), 7 nonanthocyanin phenolic compounds (compound 1-7) and 5 anthocyanins (compound 8-12) were isolated. These compounds were investigated by rat lens aldose reductase (RLAR) inhibitory assays. Kinetic analyses of recombinant human aldose reductase (rhAR) were performed, and intracellular galactitol levels were measured. Hirsutrin, one of 12 isolated compounds, showed the most potent RLAR inhibitory activity (IC(50), 4.78 μ M). In the kinetic analyses using Lineweaver-Burk plots of 1/velocity and 1/substrate concentration, hirsutrin showed competitive inhibition against rhAR. Furthermore, hirsutrin inhibited galactitol formation in rat lens and erythrocytes sample incubated with a high concentration of galactose; this finding indicates that hirsutrin may effectively prevent osmotic stress in hyperglycemia. Therefore, hirsutrin derived from Zea mays L. may be a potential therapeutic agent against diabetes complications. PMID:23586057

  16. USE OF BIOASSAY-DIRECTED CHEMICAL ANALYSIS FOR IDENTIFYING MUTAGENIC COMPOUNDS IN URBAN AIR AND COMBUSTION EMISSIONS

    EPA Science Inventory

    Bioassay-directed chemical analysis fractionation has been used for 30 years to identify mutagenic classes of compounds in complex mixtures. Most studies have used the Salmonella (Ames) mutagenicity assay, and we have recently applied this methodology to two standard reference sa...

  17. Geometric complexity identifies platelet activation in familial hypercholesterolemic patients.

    PubMed

    Bianciardi, Giorgio; Aglianò, Margherita; Volpi, Nila; Stefanutti, Claudia

    2015-06-01

    Familial hypercholesterolemia (FH), a genetic disease, is associated with a severe incidence of athero-thrombotic events, related, also, to platelet hyperreactivity. A plethora of methods have been proposed to identify those activated circulating platelets, none of these has proved really effective. We need efficient methods to identify the circulating platelet status in order to follow the patients after therapeutic procedures. We propose the use of computerized fractal analysis for an objective characterization of the complexity of circulating platelet shapes observed by means of transmission electron microscopy in order to characterize the in vivo hyperactivated platelets of familial hypercholesterolemic patients, distinguishing them from the in vivo resting platelets of healthy individuals. Platelet boundaries were extracted by means of automatically image analysis. Geometric complexity (fractal dimension, D) by box counting was automatically calculated. The platelet boundary observed by electron microscopy is fractal, the shape of the circulating platelets is more complex in FH (n = 6) than healthy subjects (n = 5, P < 0.01), with 100% correct classification in selected individuals. In vitro activated platelets from healthy subjects show an analogous increase of D. The observed high D in the platelet boundary in FH originates from the in vivo platelet activation. Computerized fractal analysis of platelet shape observed by transmission electron microscopy can provide accurate, quantitative data to study platelet activation in familial hypercholesterolemia and after administration of drugs or other therapeutic procedures. PMID:25877374

  18. Prioritizing testing of organic compounds detected as gas phase air pollutants: structure-activity study for human contact allergens.

    PubMed Central

    Johnson, R; Macina, O T; Graham, C; Rosenkranz, H S; Cass, G R; Karol, M H

    1997-01-01

    Organic compounds that are used or generated anthropogenically in large quantities in cities can be identified through their presence in the urban atmosphere and in air pollutant source emissions. Compounds identified by this method were screened to evaluate their potential to act as contact allergens. The CASE and MULTICASE computer programs, which are based on the detection of structure-activity relationships (SAR), were used to evaluate this potential. These relationships first are determined by comparing chemical structures to biological activity within a learning set comprised of 458 compounds, each of which had been tested experimentally in human trials for its sensitization potential. Using the information contained in this learning set, CASE and MULTICASE predicted the activity of 238 compounds found in the atmosphere for their ability to act as contact allergens. The analysis finds that 21 of 238 compounds are predicted to be active contact allergens (probability >0.5), with potencies ranging from mild to very strong. The compounds come from chemical classes that include chlorinated aromatics and chlorinated hydrocarbons, N-containing compounds, phenols, alkenes, and an S-containing compound. Using the measured airborne concentrations or emission rates of these compounds as an indication of the extent of their use, together with their predicted potencies, provides an efficient method to prioritize the experimental assessment of contact sensitization of untested organic compounds that can be detected as air pollutants. Images Figure 1. PMID:9300925

  19. EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen.

    PubMed

    Scheipl, Susanne; Barnard, Michelle; Cottone, Lucia; Jorgensen, Mette; Drewry, David H; Zuercher, William J; Turlais, Fabrice; Ye, Hongtao; Leite, Ana P; Smith, James A; Leithner, Andreas; Möller, Peter; Brüderlein, Silke; Guppy, Naomi; Amary, Fernanda; Tirabosco, Roberto; Strauss, Sandra J; Pillay, Nischalan; Flanagan, Adrienne M

    2016-07-01

    Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016

  20. Cancer Stem Cells: The Potential Targets of Chinese Medicines and Their Active Compounds.

    PubMed

    Hong, Ming; Tan, Hor Yue; Li, Sha; Cheung, Fan; Wang, Ning; Nagamatsu, Tadashi; Feng, Yibin

    2016-01-01

    The pivotal role of cancer stem cells (CSCs) in the initiation and progression of malignancies has been rigorously validated, and the specific methods for identifying and isolating the CSCs from the parental cancer population have also been rapidly developed in recent years. This review aims to provide an overview of recent research progress of Chinese medicines (CMs) and their active compounds in inhibiting tumor progression by targeting CSCs. A great deal of CMs and their active compounds, such as Antrodia camphorate, berberine, resveratrol, and curcumin have been shown to regress CSCs, in terms of reversing drug resistance, inducing cell death and inhibiting cell proliferation as well as metastasis. Furthermore, one of the active compounds in coptis, berbamine may inhibit tumor progression by modulating microRNAs to regulate CSCs. The underlying molecular mechanisms and related signaling pathways involved in these processes were also discussed and concluded in this paper. Overall, the use of CMs and their active compounds may be a promising therapeutic strategy to eradicate cancer by targeting CSCs. However, further studies are needed to clarify the potential of clinical application of CMs and their active compounds as complementary and alternative therapy in this field. PMID:27338343

  1. Nematicidal activity of natural ester compounds and their analogues against pine wood nematode, Bursaphelenchus xylophilus.

    PubMed

    Seo, Seon-Mi; Kim, Junheon; Koh, Sang-Hyun; Ahn, Young-Joon; Park, Il-Kwon

    2014-09-17

    In this study, we evaluated the nematicidal activity of natural ester compounds against the pine wood nematode, Bursaphelenchus xylophilus, to identify candidates for the development of novel, safe nematicides. We also tested the nematicidal activity of synthesized analogues of these ester compounds to determine the structure-activity relationship. Among 28 ester compounds tested, isobutyl 2-methylbutanoate, 3-methylbutyl 2-methylbutanoate, 3-methylbutyl tiglate, 3-methyl-2-butenyl 2-methylbutanoate, and pentyl 2-methylbutanoate showed strong nematicidal activity against the pine wood nematode at a 1 mg/mL concentration. The other ester compounds showed weak nematicidal activity. The LC50 values of 3-methylbutyl tiglate, isobutyl 2-methylbutanoate, 3-methylbutyl 2-methylbutanoate, 3-methyl-2-butenyl 2-methylbutanoate, and pentyl 2-methylbutanoate were 0.0218, 0.0284, 0.0326, 0.0402, and 0.0480 mg/mL, respectively. The ester compounds described herein merit further study as potential nematicides for pine wood nematode control. PMID:25153339

  2. Cancer Stem Cells: The Potential Targets of Chinese Medicines and Their Active Compounds

    PubMed Central

    Hong, Ming; Tan, Hor Yue; Li, Sha; Cheung, Fan; Wang, Ning; Nagamatsu, Tadashi; Feng, Yibin

    2016-01-01

    The pivotal role of cancer stem cells (CSCs) in the initiation and progression of malignancies has been rigorously validated, and the specific methods for identifying and isolating the CSCs from the parental cancer population have also been rapidly developed in recent years. This review aims to provide an overview of recent research progress of Chinese medicines (CMs) and their active compounds in inhibiting tumor progression by targeting CSCs. A great deal of CMs and their active compounds, such as Antrodia camphorate, berberine, resveratrol, and curcumin have been shown to regress CSCs, in terms of reversing drug resistance, inducing cell death and inhibiting cell proliferation as well as metastasis. Furthermore, one of the active compounds in coptis, berbamine may inhibit tumor progression by modulating microRNAs to regulate CSCs. The underlying molecular mechanisms and related signaling pathways involved in these processes were also discussed and concluded in this paper. Overall, the use of CMs and their active compounds may be a promising therapeutic strategy to eradicate cancer by targeting CSCs. However, further studies are needed to clarify the potential of clinical application of CMs and their active compounds as complementary and alternative therapy in this field. PMID:27338343

  3. Antimicrobial active herbal compounds against Acinetobacter baumannii and other pathogens.

    PubMed

    Tiwari, Vishvanath; Roy, Ranita; Tiwari, Monalisa

    2015-01-01

    Bacterial pathogens cause a number of lethal diseases. Opportunistic bacterial pathogens grouped into ESKAPE pathogens that are linked to the high degree of morbidity, mortality and increased costs as described by Infectious Disease Society of America. Acinetobacter baumannii is one of the ESKAPE pathogens which cause respiratory infection, pneumonia and urinary tract infections. The prevalence of this pathogen increases gradually in the clinical setup where it can grow on artificial surfaces, utilize ethanol as a carbon source and resists desiccation. Carbapenems, a β-lactam, are the most commonly prescribed drugs against A. baumannii. The high level of acquired and intrinsic carbapenem resistance mechanisms acquired by these bacteria makes their eradication difficult. The pharmaceutical industry has no solution to this problem. Hence, it is an urgent requirement to find a suitable alternative to carbapenem, a commonly prescribed drug for Acinetobacter infection. In order to do this, here we have made an effort to review the active compounds of plants that have potent antibacterial activity against many bacteria including carbapenem resistant strain of A. baumannii. We have also briefly highlighted the separation and identification methods used for these active compounds. This review will help researchers involved in the screening of herbal active compounds that might act as a replacement for carbapenem. PMID:26150810

  4. Antimicrobial active herbal compounds against Acinetobacter baumannii and other pathogens

    PubMed Central

    Tiwari, Vishvanath; Roy, Ranita; Tiwari, Monalisa

    2015-01-01

    Bacterial pathogens cause a number of lethal diseases. Opportunistic bacterial pathogens grouped into ESKAPE pathogens that are linked to the high degree of morbidity, mortality and increased costs as described by Infectious Disease Society of America. Acinetobacter baumannii is one of the ESKAPE pathogens which cause respiratory infection, pneumonia and urinary tract infections. The prevalence of this pathogen increases gradually in the clinical setup where it can grow on artificial surfaces, utilize ethanol as a carbon source and resists desiccation. Carbapenems, a β-lactam, are the most commonly prescribed drugs against A. baumannii. The high level of acquired and intrinsic carbapenem resistance mechanisms acquired by these bacteria makes their eradication difficult. The pharmaceutical industry has no solution to this problem. Hence, it is an urgent requirement to find a suitable alternative to carbapenem, a commonly prescribed drug for Acinetobacter infection. In order to do this, here we have made an effort to review the active compounds of plants that have potent antibacterial activity against many bacteria including carbapenem resistant strain of A. baumannii. We have also briefly highlighted the separation and identification methods used for these active compounds. This review will help researchers involved in the screening of herbal active compounds that might act as a replacement for carbapenem. PMID:26150810

  5. Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism

    PubMed Central

    Gut, Philipp; Baeza-Raja, Bernat; Andersson, Olov; Hasenkamp, Laura; Hsiao, Joseph; Hesselson, Daniel; Akassoglou, Katerina; Verdin, Eric; Hirschey, Matthew D.; Stainier, Didier Y.R.

    2012-01-01

    Improving the control of energy homeostasis can lower cardiovascular risk in metabolically compromised individuals. To identify new regulators of whole-body energy control, we conducted a high-throughput screen in transgenic reporter zebrafish for small molecules that modulate the expression of the fasting-inducible gluconeogenic gene pck1. We show that this in vivo strategy identified several drugs that impact gluconeogenesis in humans, as well as metabolically uncharacterized compounds. Most notably, we find that the Translocator Protein (TSPO) ligands PK 11195 and Ro5-4864 are glucose lowering agents despite a strong inductive effect on pck1 expression. We show that these drugs are activators of a fasting-like energy state, and importantly that they protect high-fat diet induced obese mice from hepatosteatosis and glucose intolerance, two pathological manifestations of metabolic dysregulation. Thus, using a whole-organism screening strategy, this study has identified new small molecule activators of fasting metabolism. PMID:23201900

  6. A community computational challenge to predict the activity of pairs of compounds

    PubMed Central

    Bansal, Mukesh; Yang, Jichen; Karan, Charles; Menden, Michael P; Costello, James C; Tang, Hao; Xiao, Guanghua; Li, Yajuan; Allen, Jeffrey; Zhong, Rui; Chen, Beibei; Kim, Minsoo; Wang, Tao; Heiser, Laura M; Realubit, Ronald; Mattioli, Michela; Alvarez, Mariano J; Shen, Yao; Gallahan, Daniel; Singer, Dinah; Saez-Rodriguez, Julio; Xie, Yang; Stolovitzky, Gustavo; Califano, Andrea

    2015-01-01

    Recent therapeutic successes have renewed interest in drug combinations, but experimental screening approaches are costly and often identify only small numbers of synergistic combinations. The DREAM consortium launched an open challenge to foster the development of in silico methods to computationally rank 91 compound pairs, from the most synergistic to the most antagonistic, based on gene-expression profiles of human B cells treated with individual compounds at multiple time points and concentrations. Using scoring metrics based on experimental dose-response curves, we assessed 32 methods (31 community-generated approaches and SynGen), four of which performed significantly better than random guessing. We highlight similarities between the methods. Although the accuracy of predictions was not optimal, we find that computational prediction of compound-pair activity is possible, and that community challenges can be useful to advance the field of in silico compound-synergy prediction. PMID:25419740

  7. Large-Scale Chemical Similarity Networks for Target Profiling of Compounds Identified in Cell-Based Chemical Screens

    PubMed Central

    Lo, Yu-Chen; Senese, Silvia; Li, Chien-Ming; Hu, Qiyang; Huang, Yong; Damoiseaux, Robert; Torres, Jorge Z.

    2015-01-01

    Target identification is one of the most critical steps following cell-based phenotypic chemical screens aimed at identifying compounds with potential uses in cell biology and for developing novel disease therapies. Current in silico target identification methods, including chemical similarity database searches, are limited to single or sequential ligand analysis that have limited capabilities for accurate deconvolution of a large number of compounds with diverse chemical structures. Here, we present CSNAP (Chemical Similarity Network Analysis Pulldown), a new computational target identification method that utilizes chemical similarity networks for large-scale chemotype (consensus chemical pattern) recognition and drug target profiling. Our benchmark study showed that CSNAP can achieve an overall higher accuracy (>80%) of target prediction with respect to representative chemotypes in large (>200) compound sets, in comparison to the SEA approach (60–70%). Additionally, CSNAP is capable of integrating with biological knowledge-based databases (Uniprot, GO) and high-throughput biology platforms (proteomic, genetic, etc) for system-wise drug target validation. To demonstrate the utility of the CSNAP approach, we combined CSNAP's target prediction with experimental ligand evaluation to identify the major mitotic targets of hit compounds from a cell-based chemical screen and we highlight novel compounds targeting microtubules, an important cancer therapeutic target. The CSNAP method is freely available and can be accessed from the CSNAP web server (http://services.mbi.ucla.edu/CSNAP/). PMID:25826798

  8. Historical trends in organochlorine compounds in river basins identified using sediment cores from reservoirs

    USGS Publications Warehouse

    Van Metre, P.C.; Callender, E.; Fuller, C.C.

    1997-01-01

    This study used chemical analyses of dated sediment cores from reservoirs to define historical trends in water quality in the influent river basins. This work applies techniques from paleolimnology to reservoirs, and in the process, highlights differences between sediment-core interpretations for reservoirs and natural lakes. Sediment cores were collected from six reservoirs in the central and southeastern United States, sectioned, and analyzed for 137Cs and organochlorine compounds. 137Cs analyses were used to demonstrate limited post-depositional mixing, to indicate sediment deposition dates, and to estimate sediment focusing factors. Relative lack of mixing, high sedimentation rates, and high focusing factors distinguish reservoir sediment cores from cores collected in natural lakes. Temporal trends in concentrations of PCBs, total DDT (DDT + DDD + DDE), and chlordane reflect historical use and regulation of these compounds and differences in land use between reservoir drainages. PCB and total DDT core burdens, normalized for sediment focusing, greatly exceed reported cumulative regional atmospheric fallout of PCBs and total DDT estimated using cores from peat hogs and natural lakes, indicating the dominance of fluvial inputs of both groups of compounds to the reservoirs.This study used chemical analyses of dated sediment cores from reservoirs to define historical trends in water quality in the influent river basins. This work applies techniques from paleolimnology to reservoirs, and in the process, highlights differences between sediment-core interpretations for reservoirs and natural lakes. Sediment cores were collected from six reservoirs in the central and southeastern United States, sectioned, and analyzed for 137Cs and organochlorine compounds. 137Cs analyses were used to demonstrate limited post-depositional mixing, to indicate sediment deposition dates, and to estimate sediment focusing factors. Relative lack of mixing, high sedimentation rates, and high

  9. Two new compounds from Crataegus pinnatifida and their antithrombotic activities.

    PubMed

    Zhou, Chen-Chen; Huang, Xiao-Xiao; Gao, Pin-Yi; Li, Fei-Fei; Li, Dian-Ming; Li, Ling-Zhi; Song, Shao-Jiang

    2014-01-01

    One new sesquiterpene, (1α,4aβ,8aα)-1-isopropanol-4a-methyl-8-methylenedecahydronaphthalene (1), with one new phenylpropanoid, threo-2-(4-hydroxy-3,5-dimethoxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)-3-ethoxypropan-1-ol (2), along with four known phenylpropanoids were isolated from Crataegus pinnatifida. The structures of compounds 1 and 2 were elucidated on the basis of 1D, 2D NMR analyses, and HR-ESI-MS. The antithrombotic activity in vitro of all isolates was assayed, and only compound 1 exhibited potent antithrombotic activity by inhibiting platelet aggregation in rat plasma by 81.4% at 1 mg/ml. PMID:24161196

  10. A yeast chemical genetics approach identifies the compound 3,4,5-trimethoxybenzyl isothiocyanate as a calcineurin inhibitor.

    PubMed

    Prescott, Thomas A K; Panaretou, Barry; Veitch, Nigel C; Simmonds, Monique S J

    2014-01-31

    The phosphatase enzyme calcineurin controls gene expression in a variety of biological contexts however few potent inhibitors are currently available. A screen of 360 plant extracts for inhibition of calcineurin-dependent gene expression in the model organism Saccharomyces cerevisiae identified the compound 3,4,5-trimethoxybenzyl isothiocyanate as an inhibitor. The compound was subsequently shown to inhibit human calcineurin via a mixed inhibition mechanism. To gain further mechanistic insight a yeast haploinsufficiency screen of 1152 deletion strains was carried out using a novel liquid medium screening method. The resulting haploinsufficiency profile is similar to that reported for the known calcineurin inhibitor FK506. PMID:24374339

  11. Triazolophthalazines: Easily Accessible Compounds with Potent Antitubercular Activity.

    PubMed

    Veau, Damien; Krykun, Serhii; Mori, Giorgia; Orena, Beatrice S; Pasca, Maria R; Frongia, Céline; Lobjois, Valérie; Chassaing, Stefan; Lherbet, Christian; Baltas, Michel

    2016-05-19

    Tuberculosis (TB) remains one of the major causes of death worldwide, in particular because of the emergence of multidrug-resistant TB. Herein we explored the potential of an alternative class of molecules as anti-TB agents. Thus, a series of novel 3-substituted triazolophthalazines was quickly and easily prepared from commercial hydralazine hydrochloride as starting material and were further evaluated for their antimycobacterial activities and cytotoxicities. Four of the synthesized compounds were found to effectively inhibit the Mycobacterium tuberculosis (M.tb) H37 Rv strain with minimum inhibitory concentration (MIC) values <10 μg mL(-1) , whereas no compounds displayed cytotoxicity against HCT116 human cell lines (IC50 >100 μm). More remarkably, the most potent compounds proved to be active to a similar extent against various multidrug-resistant M.tb strains, thus uncovering a mode of action distinct from that of standard antitubercular agents. Overall, their ease of preparation, combined with their attractive antimycobacterial activities, make such triazolophthalazine-based derivatives promising leads for further development. PMID:27097919

  12. Analysis of Indonesian Spice Essential Oil Compounds That Inhibit Locomotor Activity in Mice

    PubMed Central

    Muchtaridi; Diantini, Adjeng; Subarnas, Anas

    2011-01-01

    Some fragrance components of spices used for cooking are known to have an effect on human behavior. The aim of this investigation was to examine the effect of the essential oils of basil (Ocimum formacitratum L.) leaves, lemongrass (Cymbopogon citrates L.) herbs, ki lemo (Litsea cubeba L.) bark, and laja gowah (Alpinia malaccencis Roxb.) rhizomes on locomotor activity in mice and identify the active component(s) that might be responsible for the activity. The effect of the essential oils was studied by a wheel cage method and the active compounds of the essential oils were identified by GC/MS analysis. The essential oils were administered by inhalation at doses of 0.1, 0.3, and 0.5 mL/cage. The results showed that the four essential oils had inhibitory effects on locomotor activity in mice. Inhalation of the essential oils of basil leaves, lemongrass herbs, ki lemo bark, and laja gowah rhizomes showed the highest inhibitory activity at doses of 0.5 (57.64%), 0.1 (55.72%), 0.5 (60.75%), and 0.1 mL/cage (47.09%), respectively. The major volatile compounds 1,8-cineole, α-terpineol, 4-terpineol, citronelol, citronelal, and methyl cinnamate were identified in blood plasma of mice after inhalation of the four oils. These compounds had a significant inhibitory effect on locomotion after inhalation. The volatile compounds of essential oils identified in the blood plasma may correlate with the locomotor-inhibiting properties of the oil when administered by inhalation.

  13. Bioactive Compound Contents and Antioxidant Activity in Aronia (Aronia melanocarpa) Leaves Collected at Different Growth Stages.

    PubMed

    Thi, Nhuan Do; Hwang, Eun-Sun

    2014-09-01

    The bioactive compounds and antioxidant activity of aronia leaves at different stages of maturity were identified and evaluated. Young and old leaves were approximately 2 months of age and 4 months of age, respectively. The young leaves contained more polyphenols and flavonoids than the old leaves. Three phenolic compounds (i.e., chlorogenic acid, p-coumaric acid, and rutin) were detected by HPLC. Antioxidant activity was measured using 2,2-di-phenyl-1-picrylhydrazyl (DPPH) radical, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical, and superoxide anion radical scavenging assays. The reducing power of aronia leaf extracts increased in a concentration-dependent manner (0~100 μg/mL). The antioxidant activity of the 80% ethanol extract was greater than that of distilled water extract. The high phenolic compound content indicated that these compounds contribute to antioxidant activity. The overall results indicate that aronia leaves contain bioactive compounds, and that younger aronia leaves may be more favorable for extracting antioxidative ingredients because they contain more polyphenols. PMID:25320718

  14. Bioactive Compound Contents and Antioxidant Activity in Aronia (Aronia melanocarpa) Leaves Collected at Different Growth Stages

    PubMed Central

    Thi, Nhuan Do; Hwang, Eun-Sun

    2014-01-01

    The bioactive compounds and antioxidant activity of aronia leaves at different stages of maturity were identified and evaluated. Young and old leaves were approximately 2 months of age and 4 months of age, respectively. The young leaves contained more polyphenols and flavonoids than the old leaves. Three phenolic compounds (i.e., chlorogenic acid, p-coumaric acid, and rutin) were detected by HPLC. Antioxidant activity was measured using 2,2-di-phenyl-1-picrylhydrazyl (DPPH) radical, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical, and superoxide anion radical scavenging assays. The reducing power of aronia leaf extracts increased in a concentration-dependent manner (0~100 μg/mL). The antioxidant activity of the 80% ethanol extract was greater than that of distilled water extract. The high phenolic compound content indicated that these compounds contribute to antioxidant activity. The overall results indicate that aronia leaves contain bioactive compounds, and that younger aronia leaves may be more favorable for extracting antioxidative ingredients because they contain more polyphenols. PMID:25320718

  15. Repurposing of the Open Access Malaria Box for Kinetoplastid Diseases Identifies Novel Active Scaffolds against Trypanosomatids.

    PubMed

    Kaiser, Marcel; Maes, Louis; Tadoori, Leela Pavan; Spangenberg, Thomas; Ioset, Jean-Robert

    2015-06-01

    Phenotypic screening had successfully been used for hit generation, especially in the field of neglected diseases, in which feeding the drug pipeline with new chemotypes remains a constant challenge. Here, we catalyze drug discovery research using a publicly available screening tool to boost drug discovery. The Malaria Box, assembled by the Medicines for Malaria Venture, is a structurally diverse set of 200 druglike and 200 probelike compounds distilled from more than 20,000 antimalarial hits from corporate and academic libraries. Repurposing such compounds has already identified new scaffolds against cryptosporidiosis and schistosomiasis. In addition to initiating new hit-to-lead activities, screening the Malaria Box against a plethora of other parasites would enable the community to better understand the similarities and differences between them. We describe the screening of the Malaria Box and triaging of the identified hits against kinetoplastids responsible for human African trypanosomiasis (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi), and visceral leishmaniasis (Leishmania donovani and Leishmania infantum). The in vitro and in vivo profiling of the most promising active compounds with respect to efficacy, toxicity, pharmacokinetics, and complementary druggable properties are presented and a collaborative model used as a way to accelerate the discovery process discussed. PMID:25690568

  16. Orally active opioid compounds from a non-poppy source.

    PubMed

    Raffa, Robert B; Beckett, Jaclyn R; Brahmbhatt, Vivek N; Ebinger, Theresa M; Fabian, Chrisjon A; Nixon, Justin R; Orlando, Steven T; Rana, Chintan A; Tejani, Ali H; Tomazic, Robert J

    2013-06-27

    The basic science and clinical use of morphine and other "opioid" drugs are based almost exclusively on the extracts or analogues of compounds isolated from a single source, the opium poppy (Papaver somniferum). However, it now appears that biological diversity has evolved an alternative source. Specifically, at least two alkaloids isolated from the plant Mitragyna speciosa, mitragynine ((E)-2-[(2S,3S)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[3,2-h]quinolizin-2-yl]-3-methoxyprop-2-enoic acid methyl ester; 9-methoxy coryantheidine; MG) and 7-hydroxymitragynine (7-OH-MG), and several synthetic analogues of these natural products display centrally mediated (supraspinal and spinal) antinociceptive (analgesic) activity in various pain models. Several characteristics of these compounds suggest a classic "opioid" mechanism of action: nanomolar affinity for opioid receptors, competitive interaction with the opioid receptor antagonist naloxone, and two-way analgesic cross-tolerance with morphine. However, other characteristics of the compounds suggest novelty, particularly chemical structure and possible greater separation from side effects. We review the chemical and pharmacological properties of these compounds. PMID:23517479

  17. Small Molecule Activation by Constrained Phosphorus Compounds: Insights from Theory.

    PubMed

    Pal, Amrita; Vanka, Kumar

    2016-01-19

    An exciting new development in main group chemistry has been the use of a constrained, "flat", phosphorus-based complex to mediate in reactions such as the dehydrogenation of ammonia borane (AB), and the activation of the N-H bond in primary amines. Its importance is based on the fact that it shows that main group compounds, when properly designed, can be as effective as transition metal complexes for doing significant chemical transformations. What the current computational study, employing density functional theory (DFT), reveals is that a common, general mechanism exists that accounts for the behavior of the flat phosphorus compound in the different reactions that have been experimentally reported to date. This mechanism, which involves the mediation by a base as a proton transfer agent, is simpler and energetically more favorable than the previous mechanisms that have been proposed for the same reactions in the literature. It is likely that the knowledge gained from the current work about the chemical behavior of this phosphorus compound can be utilized to design new constrained phosphorus-based compounds. PMID:26700074

  18. Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound.

    PubMed

    Deodato, Davide; Maccari, Giorgio; De Luca, Filomena; Sanfilippo, Stefania; Casian, Alexandru; Martini, Riccardo; D'Arezzo, Silvia; Bonchi, Carlo; Bugli, Francesca; Posteraro, Brunella; Vandeputte, Patrick; Sanglard, Dominique; Docquier, Jean-Denis; Sanguinetti, Maurizio; Visca, Paolo; Botta, Maurizio

    2016-04-28

    We recently identified a novel family of macrocyclic amidinoureas showing potent antifungal activity against Candida spp. In this study, we demonstrate the fungicidal effect of these compounds as well as their killing activity in a dose-dependent manner. Transcriptional analysis data indicate that our molecules induce a significant change in the transcriptome involving ATP binding cassette (ABC) transporter genes. Notably, experiments against Candida albicans mutants lacking those genes showed resistance to the compound, suggesting the involvement of ABC transporters in the uptake or intracellular accumulation of the molecule. To probe the mode of action, we performed fluorescence microscopy experiments on fungal cells treated with an ad-hoc synthesized fluorescent derivative. Fluorescence microscopy images confirm the ability of the compound to cross the membrane and show a consistent accumulation within the cytoplasm. Finally, we provide data supporting the in vivo efficacy in a systemic infection murine model setup with a drug-resistant strain of C. albicans. PMID:27045868

  19. Extraction and evaluation of natural occurring bioactive compounds and change in antioxidant activity during red winemaking.

    PubMed

    Ivanova-Petropulos, Violeta; Durakova, Sanja; Ricci, Arianna; Parpinello, Giuseppina P; Versari, Andrea

    2016-06-01

    Phenolic composition of red wines from Stanušina, a grape variety indigenous of the Republic of Macedonia, was compared with the regional Vranec and the international Cabernet Sauvignon. The extent of skin contact (i.e. maceration time) on levels of phenolic compounds and antioxidant activity of wines was evaluated. A total of 19 phenolic compounds were identified and quantified. Among these malvidin-3-glucoside and its derivatives were the major compounds, while caftaric acid was the predominant cinnamic acid derivative, followed by catechin, the main flavan-3-ol. The concentration of hydroxycinnamic acids, anthocyanins and (+)-catechin ranged from 224 to 511 mg/L, 22 to 360 mg/L and 26 20 to 375 mg/L, respectively and peaked at 3rd, 6th and 9th day of maceration, respectively. However, prolong maceration slightly decreased their concentration. Stanušina wines presented high levels of hydroxycinnamic acids and antioxidant activity. PMID:27478219

  20. Apatite Formation: Why It May Not Work as Planned, and How to Conclusively Identify Apatite Compounds

    PubMed Central

    2013-01-01

    Calcium phosphate apatites are inorganic compounds encountered in many different mineralized tissues. Bone mineral, for example, is constituted of nanocrystalline nonstoichiometric apatite, and the production of “analogs” through a variety of methods is frequently reported. In another context, the ability of solid surfaces to favor the nucleation and growth of “bone-like” apatite upon immersion in supersaturated fluids such as SFB is commonly used as one evaluation index of the “bioactivity” of such surfaces. Yet, the compounds or deposits obtained are not always thoroughly characterized, and their apatitic nature is sometimes not firmly assessed by appropriate physicochemical analyses. Of particular importance are the “actual” conditions in which the precipitation takes place. The precipitation of a white solid does not automatically indicate the formation of a “bone-like carbonate apatite layer” as is sometimes too hastily concluded: “all that glitters is not gold.” The identification of an apatite phase should be carefully demonstrated by appropriate characterization, preferably using complementary techniques. This review considers the fundamentals of calcium phosphate apatite characterization discussing several techniques: electron microscopy/EDX, XRD, FTIR/Raman spectroscopies, chemical analyses, and solid state NMR. It also underlines frequent problems that should be kept in mind when making “bone-like apatites.” PMID:23984373

  1. Creatinyl amino acids: new hybrid compounds with neuroprotective activity.

    PubMed

    Burov, Sergey; Leko, Maria; Dorosh, Marina; Dobrodumov, Anatoliy; Veselkina, Olga

    2011-09-01

    Prolonged oral creatine administration resulted in remarkable neuroprotection in experimental models of brain stroke. However, because of its polar nature creatine has poor ability to penetrate the blood-brain barrier (BBB) without specific creatine transporter (CRT). Thus, synthesis of hydrophobic derivatives capable of crossing the BBB by alternative pathway is of great importance for the treatment of acute and chronic neurological diseases including stroke, traumatic brain injury and hereditary CRT deficiency. Here we describe synthesis of new hybrid compounds-creatinyl amino acids, their neuroprotective activity in vivo and stability to degradation in different media. The title compounds were synthesized by guanidinylation of corresponding sarcosyl peptides or direct creatine attachment using isobutyl chloroformate method. Addition of lipophilic counterion (p-toluenesulfonate) ensures efficient creatine dissolution in DMF with simultaneous protection of guanidino group towards intramolecular cyclization. It excludes the application of expensive guanidinylating reagents, permits to simplify synthetic procedure and adapt it to large-scale production. The biological activity of creatinyl amino acids was tested in vivo on ischemic stroke and NaNO(2) -induced hypoxia models. One of the most effective compounds-creatinyl-glycine ethyl ester increases life span of experimental animals more than two times in hypoxia model and has neuroprotective action in brain stroke model when applied both before and after ischemia. These data evidenced that creatinyl amino acids can represent promising candidates for the development of new drugs useful in stroke treatment. PMID:21644247

  2. Platelet anti-aggregation activities of compounds from Cinnamomum cassia.

    PubMed

    Kim, Sun Young; Koo, Yean Kyoung; Koo, Ja Yong; Ngoc, Tran Minh; Kang, Sam Sik; Bae, KiHwan; Kim, Yeong Sik; Yun-Choi, Hye Sook

    2010-10-01

    Cinnamomum cassia is a well-known traditional medicine for improvement of blood circulation. An extract of this plant showed both platelet anti-aggregation and blood anti-coagulation effects in preliminary testing. Among the 13 compounds obtained from this plant, eugenol (2), amygdalactone (4), cinnamic alcohol (5), 2-hydroxycinnamaldehyde (7), 2-methoxycinnamaldehyde (8), and coniferaldehyde (9) showed 1.5-73-fold greater inhibitory effects than acetylsalicylic acid (ASA) on arachidonic acid (AA)-induced aggregation (50% inhibitory concentration [IC₅₀] = 3.8, 5.16, 31.2, 40.0, 16.9, and 0.82 μM, respectively, vs. 60.3 μM) and 6.3-730-fold stronger effect than ASA on U46619 (a thromboxane A₂ mimic)-induced aggregation (IC₅₀ = 3.51, 33.9, 31.0, 51.3, 14.6, and 0.44 μM, respectively, vs. 321 μM). The other compounds, coumarin (3), cinnamaldehyde (6), cinnamic acid (10), icariside DC (11), and dihydrocinnacasside (12), also inhibited (2.5 to four times greater than ASA) U46619-induced aggregation. In addition, compounds 2, 4, 5, 6, 7, 8, and 9 were 1.3-87 times more effective than ASA against epinephrine-induced aggregation (IC₅₀ = 1.86, 1.10, 37.7, 25.0, 16.8, 15.3, and 0.57 μM, respectively, vs. 50.0 μM). However, the 13 compounds were only very mildly effective against blood coagulation, if at all. In conclusion, compounds 2, 4, 8, and 9 showed stronger inhibitory potencies than others on AA-, U46619-, and epinephrine-induced platelet aggregation. Eugenol (2) and coniferaldehyde (9) were the two of the most active anti-platelet constituents of C. cassia. PMID:20828311

  3. Jasmonate signaling in plant stress responses and development - active and inactive compounds.

    PubMed

    Wasternack, Claus; Strnad, Miroslav

    2016-09-25

    Jasmonates (JAs) are lipid-derived signals mediating plant responses to biotic and abiotic stresses and in plant development. Following the elucidation of each step in their biosynthesis and the important components of perception and signaling, several activators, repressors and co-repressors have been identified which contribute to fine-tuning the regulation of JA-induced gene expression. Many of the metabolic reactions in which JA participates, such as conjugation with amino acids, glucosylation, hydroxylation, carboxylation, sulfation and methylation, lead to numerous compounds with different biological activities. These metabolites may be highly active, partially active in specific processes or inactive. Hydroxylation, carboxylation and sulfation inactivate JA signaling. The precursor of JA biosynthesis, 12-oxo-phytodienoic acid (OPDA), has been identified as a JA-independent signaling compound. An increasing number of OPDA-specific processes is being identified. To conclude, the numerous JA compounds and their different modes of action allow plants to respond specifically and flexibly to alterations in the environment. PMID:26581489

  4. An overview of NMR-based metabolomics to identify secondary plant compounds involved in host plant resistance.

    PubMed

    Leiss, Kirsten A; Choi, Young H; Verpoorte, Robert; Klinkhamer, Peter G L

    2011-06-01

    Secondary metabolites provide a potential source for the generation of host plant resistance and development of biopesticides. This is especially important in view of the rapid and vast spread of agricultural and horticultural pests worldwide. Multiple pests control tactics in the framework of an integrated pest management (IPM) programme are necessary. One important strategy of IPM is the use of chemical host plant resistance. Up to now the study of chemical host plant resistance has, for technical reasons, been restricted to the identification of single compounds applying specific chemical analyses adapted to the compound in question. In biological processes however, usually more than one compound is involved. Metabolomics allows the simultaneous detection of a wide range of compounds, providing an immediate image of the metabolome of a plant. One of the most universally used metabolomic approaches comprises nuclear magnetic resonance spectroscopy (NMR). It has been NMR which has been applied as a proof of principle to show that metabolomics can constitute a major advancement in the study of host plant resistance. Here we give an overview on the application of NMR to identify candidate compounds for host plant resistance. We focus on host plant resistance to western flower thrips (Frankliniella occidentalis) which has been used as a model for different plant species. PMID:21765818

  5. Identifying key non-volatile compounds in ready-to-drink green tea and their impact on taste profile.

    PubMed

    Yu, Peigen; Yeo, Angelin Soo-Lee; Low, Mei-Yin; Zhou, Weibiao

    2014-07-15

    Thirty-nine non-volatile compounds in seven ready-to-drink (RTD) green tea samples were analysed and quantified using liquid chromatography. Taste reconstruction experiments using thirteen selected compounds were conducted to identify the key non-volatile tastants. Taste profiles of the reconstructed samples did not differ significantly from the RTD tea samples. To investigate the taste contribution and significance of individual compounds, omission experiments were carried out by removing individual or a group of compounds. Sensory evaluation revealed that the astringent- and bitter-tasting (-)-epigallocatechin gallate, bitter-tasting caffeine, and the umami-tasting l-glutamic acid were the main contributors to the taste of RTD green tea. Subsequently, the taste profile of the reduced recombinant, comprising of a combination of these three compounds and l-theanine, was found to not differ significantly from the sample recombinant and RTD tea sample. Lastly, regression models were developed to objectively predict and assess the intensities of bitterness and astringency in RTD green teas. PMID:24594147

  6. Descriptive Study of Activities Identified by Principals as Parental Involvement Activities through Survey Research

    ERIC Educational Resources Information Center

    Anderson, Melinda

    2009-01-01

    This study was designed to identify parental involvement activities used by successful schools. Participating schools were identified as successful by an Academic Excellence Indicator System (AEIS) rating of recognized or exemplary. Using survey methods, data was collected from the principals of the schools about parental involvement activities on…

  7. Studies on the antioxidant activities of some new chromone compounds.

    PubMed

    Kładna, Aleksandra; Berczyński, Paweł; Piechowska, Teresa; Kruk, Irena; Aboul-Enein, Hassan Y; Ceylan-Unlusoy, Meltem; Verspohl, Eugen J; Ertan, Rahmiye

    2014-11-01

    Recent reviews evidence that the naturally occurring compounds containing the chromone skeleton exhibit antiradical activities, providing protection against oxidative stress. The antioxidant activities of 13 new synthesized chromonyl-2,4-thiazolidinediones, chromonyl-2,4-imidazolidinediones and chromonyl-2-thioxoimidzolidine-4-ones were evaluated using in vitro antioxidant assays, including superoxide anion radical (O2(-•)), hydroxyl radical (HO(•)), 2,2-diphenyl-1-picryl-hydrazyl free radical (DPPH(•)) scavenging capacity and total antioxidant capacity ferric ion reducing activity. Superoxide anion radical was produced using potassium superoxide/18-crown-6-ether dissolved in dimethylsulfoxide, and the Fenton-like reaction (Fe(II) + H2O2) was a generator of hydroxyl radicals. Chemiluminescence, spectrophotometry, electron paramagnetic resonance (EPR) and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as the spin trap were the measurement techniques. The results showed that the majority of the chromone derivatives tested showed a strong scavenging effect towards free radicals, similar to the chemiluminescence reaction with superoxide anion radical with a high activity, inhibition of the DMPO-OOH radical EPR signal (24-58%), the DMPO-OH radical EPR signal (4-75%) and DPPH radical EPR signal (6-100%) at 1 mmol/L. Several of the examined compounds exhibited the high reduction potentials. The results obtained show that the new synthesized chromone derivatives may directly scavenger reactive oxygen species and thus may play a protective role against oxidative damage. PMID:24482260

  8. Screening for Antiviral Activities of Isolated Compounds from Essential Oils

    PubMed Central

    Astani, Akram; Reichling, Jürgen; Schnitzler, Paul

    2011-01-01

    Essential oil of star anise as well as phenylpropanoids and sesquiterpenes, for example, trans-anethole, eugenol, β-eudesmol, farnesol, β-caryophyllene and β-caryophyllene oxide, which are present in many essential oils, were examined for their antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro. Antiviral activity was analyzed by plaque reduction assays and mode of antiviral action was determined by addition of the drugs to uninfected cells, to the virus prior to infection or to herpesvirus-infected cells. Star anise oil reduced viral infectivity by >99%, phenylpropanoids inhibited HSV infectivity by about 60–80% and sesquiterpenes suppressed herpes virus infection by 40–98%. Both, star anise essential oil and all isolated compounds exhibited anti-HSV-1 activity by direct inactivation of free virus particles in viral suspension assays. All tested drugs interacted in a dose-dependent manner with herpesvirus particles, thereby inactivating viral infectivity. Star anise oil, rich in trans-anethole, revealed a high selectivity index of 160 against HSV, whereas among the isolated compounds only β-caryophyllene displayed a high selectivity index of 140. The presence of β-caryophyllene in many essential oils might contribute strongly to their antiviral ability. These results indicate that phenylpropanoids and sesquiterpenes present in essential oils contribute to their antiviral activity against HSV. PMID:20008902

  9. Screening for antiviral activities of isolated compounds from essential oils.

    PubMed

    Astani, Akram; Reichling, Jürgen; Schnitzler, Paul

    2011-01-01

    Essential oil of star anise as well as phenylpropanoids and sesquiterpenes, for example, trans-anethole, eugenol, β-eudesmol, farnesol, β-caryophyllene and β-caryophyllene oxide, which are present in many essential oils, were examined for their antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro. Antiviral activity was analyzed by plaque reduction assays and mode of antiviral action was determined by addition of the drugs to uninfected cells, to the virus prior to infection or to herpesvirus-infected cells. Star anise oil reduced viral infectivity by >99%, phenylpropanoids inhibited HSV infectivity by about 60-80% and sesquiterpenes suppressed herpes virus infection by 40-98%. Both, star anise essential oil and all isolated compounds exhibited anti-HSV-1 activity by direct inactivation of free virus particles in viral suspension assays. All tested drugs interacted in a dose-dependent manner with herpesvirus particles, thereby inactivating viral infectivity. Star anise oil, rich in trans-anethole, revealed a high selectivity index of 160 against HSV, whereas among the isolated compounds only β-caryophyllene displayed a high selectivity index of 140. The presence of β-caryophyllene in many essential oils might contribute strongly to their antiviral ability. These results indicate that phenylpropanoids and sesquiterpenes present in essential oils contribute to their antiviral activity against HSV. PMID:20008902

  10. Antifungal activity of schinol and a new biphenyl compound isolated from Schinus terebinthifolius against the pathogenic fungus Paracoccidioides brasiliensis

    PubMed Central

    2010-01-01

    Background The aim of this study was to isolate and identify the antifungal compounds from the extracts of Schinus terebinthifolius (Anacardiaceae) against clinical isolates of the pathogenic fungus Paracoccidioides brasiliensis. Methods The hexane and dichlomethane fractions from leaves and stems of S. terebinthifolius were fractionated using several chromatography techniques to afford four compounds. Results The compounds isolated from S. terebinthifolius were identified as schinol (1), a new biphenyl compound, namely, 4'-ethyl-4-methyl-2,2',6,6'-tetrahydroxy[1,1'-biphenyl]-4,4'-dicarboxylate (2), quercetin (3), and kaempferol (4). Compounds 1 and 2 were active against different strains of P. brasiliensis, showing a minimal inhibitory concentration value against the isolate Pb B339 of 15.6 μg/ml. The isolate Pb 1578 was more sensitive to compound 1 with a MIC value of 7.5 μg/ml. Schinol presented synergistic effect only when combined with itraconazole. The compounds isolated from S. terebinthifolius were not able to inhibit cell wall synthesis or assembly using the sorbitol assay. Conclusion This work reveals for the first time the occurrence of compound 2 and discloses activity of compounds 1 and 2 against several clinical isolates of P. brasiliensis. These results justify further studies to clarify the mechanisms of action of these compounds. PMID:20939907

  11. Identification of Thyroid Hormone Receptor Active Compounds Using a Quantitative High-Throughput Screening Platform

    PubMed Central

    Freitas, Jaime; Miller, Nicole; Mengeling, Brenda J.; Xia, Menghang; Huang, Ruili; Houck, Keith; Rietjens, Ivonne M.C.M.; Furlow, J. David; Murk, Albertinka J.

    2014-01-01

    To adapt the use of GH3.TRE-Luc reporter gene cell line for a quantitative high-throughput screening (qHTS) platform, we miniaturized the reporter gene assay to a 1536-well plate format. 1280 chemicals from the Library of Pharmacologically Active Compounds (LOPAC) and the National Toxicology Program (NTP) 1408 compound collection were analyzed to identify potential thyroid hormone receptor (TR) agonists and antagonists. Of the 2688 compounds tested, eight scored as potential TR agonists when the positive hit cut-off was defined at ≥10% efficacy, relative to maximal triiodothyronine (T3) induction, and with only one of those compounds reaching ≥20% efficacy. One common class of compounds positive in the agonist assays were retinoids such as all-trans retinoic acid, which are likely acting via the retinoid-X receptor, the heterodimer partner with the TR. Five potential TR antagonists were identified, including the antiallergy drug tranilast and the anxiolytic drug SB 205384 but also some cytotoxic compounds like 5-fluorouracil. None of the inactive compounds were structurally related to T3, nor had been reported elsewhere to be thyroid hormone disruptors, so false negatives were not detected. None of the low potency (>100µM) TR agonists resembled T3 or T4, thus these may not bind directly in the ligand-binding pocket of the receptor. For TR agonists, in the qHTS, a hit cut-off of ≥20% efficacy at 100 µM may avoid identification of positives with low or no physiological relevance. The miniaturized GH3.TRE-Luc assay offers a promising addition to the in vitro test battery for endocrine disruption, and given the low percentage of compounds testing positive, its high-throughput nature is an important advantage for future toxicological screening. PMID:24772387

  12. Using fragmentation trees and mass spectral trees for identifying unknown compounds in metabolomics

    PubMed Central

    Vaniya, Arpana

    2015-01-01

    Identification of unknown metabolites is the bottleneck in advancing metabolomics, leaving interpretation of metabolomics results ambiguous. The chemical diversity of metabolism is vast, making structure identification arduous and time consuming. Currently, comprehensive analysis of mass spectra in metabolomics is limited to library matching, but tandem mass spectral libraries are small compared to the large number of compounds found in the biosphere, including xenobiotics. Resolving this bottleneck requires richer data acquisition and better computational tools. Multi-stage mass spectrometry (MSn) trees show promise to aid in this regard. Fragmentation trees explore the fragmentation process, generate fragmentation rules and aid in sub-structure identification, while mass spectral trees delineate the dependencies in multi-stage MS of collision-induced dissociations. This review covers advancements over the past 10 years as a tool for metabolite identification, including algorithms, software and databases used to build and to implement fragmentation trees and mass spectral annotations. PMID:26213431

  13. Compounded bioidentical hormone therapy: identifying use trends and knowledge gaps among US women

    PubMed Central

    Pinkerton, JoAnn V.; Santoro, Nanette

    2015-01-01

    Abstract Objective: Two surveys (Harris and Rose surveys) were conducted to quantify the use of compounded hormone therapy (CHT; or bioidentical hormone therapy) among perimenopausal and postmenopausal women in the United States, to assess women's knowledge of CHT versus Food and Drug Administration (FDA)–approved hormone therapy, and to gather information on menopausal experience. Methods: The Harris survey was administered to 801 women aged 45 to 60 years who had experienced at least one menopausal symptom. The Rose survey was administered to 2,044 women aged 40 years or older who were ever users of hormone therapy. Women were queried about menopausal symptoms, hormone therapy use, and knowledge of CHT. Findings from the Rose survey were extrapolated using US Census Bureau data and prescription claims for FDA-approved hormone therapy to estimate the prevalence of CHT use. Results: According to extrapolations using Rose data, up to 2.5 million US women aged 40 years or older may use CHT annually, accounting for 28% to 68% of hormone therapy prescriptions. Harris data showed that 86% of women surveyed were unaware that CHT products are not FDA-approved. The Rose survey asked a subset of 1,771 women whether their hormone therapy had been personalized based on hormone levels; 21% (378) answered “yes” whereas 27% (476) did not know. In both surveys, most hormone therapy users stated that their physician had recommended the treatment. Conclusions: We estimate that 1 million to 2.5 million US women aged 40 years or older use CHT. The data suggest that many women are unaware that compounded hormones have not been evaluated or approved by the FDA. Providers have an educational opportunity to ensure that women considering hormone therapy understand the risks and benefits of inadequately regulated CHT. PMID:25692877

  14. Flavonoids, Antioxidant Activity and Aroma Compounds Analysis from Different Kinds of Tartary Buckwheat Tea.

    PubMed

    Peng, L X; Zou, L; Wang, J B; Zhao, J L; Xiang, D B; Zhao, G

    2015-01-01

    The rutin, quercetin concentrations, antioxidant activity, and aroma compounds in different commercial tartary buckwheat tea were analyzed in our study. Results revealed that the materials and the processing protocol affected the chemical composition and activity of tartary buckwheat tea. Rutin and quercetin concentrations, antioxidant activity were significantly different in various kinds of tartary buckwheat tea, where the whole bran tea and the whole plant tea had the lower rutin, but higher quercetin concentrations and higher antioxidant activity. The whole embryo tea had the converse results. There was strong correlation between quercetin concentration and antioxidant activity (r>0.98, P<0.05). Meanwhile, Twenty eight different aroma compounds in tartary buckwheat tea were identified by gas chromatography-mass spectrometry. Those compounds were mainly composed of pyrazine, aldehydes, fatty acids and ketones. The main type of aroma compounds in different tartary buckwheat tea were similar, but their relative contents were different. The implications to the quality control of buckwheat tea were extensively discussed. PMID:26997692

  15. Flavonoids, Antioxidant Activity and Aroma Compounds Analysis from Different Kinds of Tartary Buckwheat Tea

    PubMed Central

    Peng, L. X.; Zou, L.; Wang, J. B.; Zhao, J. L.; Xiang, D. B.; Zhao, G.

    2015-01-01

    The rutin, quercetin concentrations, antioxidant activity, and aroma compounds in different commercial tartary buckwheat tea were analyzed in our study. Results revealed that the materials and the processing protocol affected the chemical composition and activity of tartary buckwheat tea. Rutin and quercetin concentrations, antioxidant activity were significantly different in various kinds of tartary buckwheat tea, where the whole bran tea and the whole plant tea had the lower rutin, but higher quercetin concentrations and higher antioxidant activity. The whole embryo tea had the converse results. There was strong correlation between quercetin concentration and antioxidant activity (r>0.98, P<0.05). Meanwhile, Twenty eight different aroma compounds in tartary buckwheat tea were identified by gas chromatography-mass spectrometry. Those compounds were mainly composed of pyrazine, aldehydes, fatty acids and ketones. The main type of aroma compounds in different tartary buckwheat tea were similar, but their relative contents were different. The implications to the quality control of buckwheat tea were extensively discussed. PMID:26997692

  16. Biased and unbiased strategies to identify biologically active small molecules.

    PubMed

    Abet, Valentina; Mariani, Angelica; Truscott, Fiona R; Britton, Sébastien; Rodriguez, Raphaël

    2014-08-15

    Small molecules are central players in chemical biology studies. They promote the perturbation of cellular processes underlying diseases and enable the identification of biological targets that can be validated for therapeutic intervention. Small molecules have been shown to accurately tune a single function of pluripotent proteins in a reversible manner with exceptional temporal resolution. The identification of molecular probes and drugs remains a worthy challenge that can be addressed by the use of biased and unbiased strategies. Hypothesis-driven methodologies employs a known biological target to synthesize complementary hits while discovery-driven strategies offer the additional means of identifying previously unanticipated biological targets. This review article provides a general overview of recent synthetic frameworks that gave rise to an impressive arsenal of biologically active small molecules with unprecedented cellular mechanisms. PMID:24811300

  17. Phenolic compounds characterization and biological activities of Citrus aurantium bloom.

    PubMed

    Karimi, Ehsan; Oskoueian, Ehsan; Hendra, Rudi; Oskoueian, Armin; Jaafar, Hawa Z E

    2012-01-01

    Citrus plants are known to possess beneficial biological activities for human health. In addition, ethnopharmacological application of plants is a good tool to explore their bioactivities and active compounds. This research was carried out to evaluate the phenolic and flavonoid analysis, antioxidant properties, anti inflammatory and anti cancer activity of Citrus aurantium bloom. The total phenolics and flavonoids results revealed that methanolic extract contained high total phenolics and flavonoids compared to ethanolic and boiling water extracts. The obtained total phenolics value for methanolic Citrus aurantium bloom extract was 4.55 ± 0.05 mg gallic acid equivalent (GAE)/g dry weight (DW), and for total flavonoids it was 3.83 ± 0.05 mg rutin equivalent/g DW. In addition, the RP-HPLC analyses of phenolics and flavonoids indicated the presence of gallic acid, pyrogallol, syringic acid, caffeic acid, rutin, quercetin and naringin as bioactive compounds. The antioxidant activity of Citrus aurantium bloom were examined by the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay and the ferric reducing/antioxidant potential (FRAP). The free radical scavenging and ferric reducing power activities were higher for the methanolic extract of Citrus aurantium bloom at a concentration of 300 μg/mL, with values of 55.3% and 51.7%, respectively, as compared to the corresponding boiling water and ethanolic extracts, but the activities were lower than those of antioxidant standards such as BHT and α-tocopherol. Furthermore, the anti-inflammatory result of methanolic extract showed appreciable reduction in nitric oxide production of stimulated RAW 264.7 cells at the presence of plant extract. Apart from that, the anticancer activity of the methanolic extract was investigated in vitro against human cancer cell lines (MCF-7; MDA-MB-231), human colon adenocarcinoma (HT-29) and Chang cell as a normal human hepatocyte. The obtained result demonstrated the moderate to appreciable

  18. Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries

    PubMed Central

    Inglese, James; Auld, Douglas S.; Jadhav, Ajit; Johnson, Ronald L.; Simeonov, Anton; Yasgar, Adam; Zheng, Wei; Austin, Christopher P.

    2006-01-01

    High-throughput screening (HTS) of chemical compounds to identify modulators of molecular targets is a mainstay of pharmaceutical development. Increasingly, HTS is being used to identify chemical probes of gene, pathway, and cell functions, with the ultimate goal of comprehensively delineating relationships between chemical structures and biological activities. Achieving this goal will require methodologies that efficiently generate pharmacological data from the primary screen and reliably profile the range of biological activities associated with large chemical libraries. Traditional HTS, which tests compounds at a single concentration, is not suited to this task, because HTS is burdened by frequent false positives and false negatives and requires extensive follow-up testing. We have developed a paradigm, quantitative HTS (qHTS), tested with the enzyme pyruvate kinase, to generate concentration–response curves for >60,000 compounds in a single experiment. We show that this method is precise, refractory to variations in sample preparation, and identifies compounds with a wide range of activities. Concentration–response curves were classified to rapidly identify pyruvate kinase activators and inhibitors with a variety of potencies and efficacies and elucidate structure–activity relationships directly from the primary screen. Comparison of qHTS with traditional single-concentration HTS revealed a high prevalence of false negatives in the single-point screen. This study demonstrates the feasibility of qHTS for accurately profiling every compound in large chemical libraries (>105 compounds). qHTS produces rich data sets that can be immediately mined for reliable biological activities, thereby providing a platform for chemical genomics and accelerating the identification of leads for drug discovery. PMID:16864780

  19. SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.

    PubMed

    Quinti, Luisa; Casale, Malcolm; Moniot, Sébastien; Pais, Teresa F; Van Kanegan, Michael J; Kaltenbach, Linda S; Pallos, Judit; Lim, Ryan G; Naidu, Sharadha Dayalan; Runne, Heike; Meisel, Lisa; Rauf, Nazifa Abdul; Leyfer, Dmitriy; Maxwell, Michele M; Saiah, Eddine; Landers, John E; Luthi-Carter, Ruth; Abagyan, Ruben; Dinkova-Kostova, Albena T; Steegborn, Clemens; Marsh, J Lawrence; Lo, Donald C; Thompson, Leslie M; Kazantsev, Aleksey G

    2016-07-21

    There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders. PMID:27427231

  20. Isolation and identification of the phenolic compounds from the roots of Sanguisorba officinalis L. and their antioxidant activities.

    PubMed

    Zhang, Shuang; Liu, Xin; Zhang, Zi-Long; He, Lu; Wang, Zhe; Wang, Guang-Shu

    2012-01-01

    Four phenolic compounds were isolated from the roots of Sanguisorba officinalis L. by silica gel column chromatography and preparative HPLC. On the basis of chemical and spectroscopic methods, their structures were identified as methyl 4-O-β-D-glucopyranosy-5-hydroxy-3-methoxylbenzoate (1), 3,3′,4′-tri-O-methylellagic acid (2), fisetinidol-(4α-8)-catechin (3), and (+)-catechin (4). Compound 1 is a new phenolic glycoside and compounds 2 and 3 were isolated from the Sanguisorba genus for the first time. Compounds 1–4 were also assayed for their antioxidant activities using the DPPH free radical assay. PMID:23178307

  1. Affinity Adsorbents Based on Carriers Activated by Epoxy-compounds

    NASA Astrophysics Data System (ADS)

    Klyashchitskii, B. A.; Kuznetsov, P. V.

    1984-10-01

    The review is devoted to the synthesis and applications of affinity adsorbents based on carriers activated by epoxy-compounds. The methods for the introduction of epoxy-groups into carriers of different chemical types are discussed and conditions for the immobilisation of three-dimensional spacers and low-molecular-weight and polymeric ligands on carriers containing epoxy-groups are considered. Data are presented on the properties and applications of adsorbents of this type in affinity chromatography. The bibliography includes 144 references.

  2. A Substrate Pharmacophore for the Human Organic Cation/Carnitine Transporter Identifies Compounds Associated with Rhabdomyolysis

    PubMed Central

    Ekins, Sean; Diao, Lei; Polli, James E.

    2012-01-01

    The human Organic Cation/Carnitine Transporter (hOCTN2), is a high affinity cation/carnitine transporter expressed widely in human tissues and is physiologically important for the homeostasis of L-carnitine. The objective of this study was to elucidate the substrate requirements of this transporter via computational modelling based on published in vitro data. Nine published substrates of hOCTN2 were used to create a common features pharmacophore that was validated by mapping other known OCTN2 substrates. The pharmacophore was used to search a drug database and retrieved molecules that were then used as search queries in PubMed for instances of a side effect (rhabdomyolysis) associated with interference with L-carnitine transport. The substrate pharmacophore was comprised of two hydrogen bond acceptors, a positive ionizable feature and ten excluded volumes. The substrate pharmacophore also mapped 6 out of 7 known substrate molecules used as a test set. After searching a database of ~800 known drugs, thirty drugs were predicted to map to the substrate pharmacophore with L-carnitine shape restriction. At least 16 of these molecules had case reports documenting an association with rhabdomyolysis and represent a set for prioritizing for future testing as OCTN2 substrates or inhibitors. This computational OCTN2 substrate pharmacophore derived from published data partially overlaps a previous OCTN2 inhibitor pharmacophore and is also able to select compounds that demonstrate rhabdomyolysis, further confirming the possible linkage between this side effect and hOCTN2. PMID:22339151

  3. Laccase Catalyzed Synthesis of Iodinated Phenolic Compounds with Antifungal Activity

    PubMed Central

    Ihssen, Julian; Schubert, Mark; Thöny-Meyer, Linda; Richter, Michael

    2014-01-01

    Iodine is a well known antimicrobial compound. Laccase, an oxidoreductase which couples the one electron oxidation of diverse phenolic and non-phenolic substrates to the reduction of oxygen to water, is capable of oxidizing unreactive iodide to reactive iodine. We have shown previously that laccase-iodide treatment of spruce wood results in a wash-out resistant antimicrobial surface. In this study, we investigated whether phenolic compounds such as vanillin, which resembles sub-structures of softwood lignin, can be directly iodinated by reacting with laccase and iodide, resulting in compounds with antifungal activity. HPLC-MS analysis showed that vanillin was converted to iodovanillin by laccase catalysis at an excess of potassium iodide. No conversion of vanillin occurred in the absence of enzyme. The addition of redox mediators in catalytic concentrations increased the rate of iodide oxidation ten-fold and the yield of iodovanillin by 50%. Iodinated phenolic products were also detected when o-vanillin, ethyl vanillin, acetovanillone and methyl vanillate were incubated with laccase and iodide. At an increased educt concentration of 0.1 M an almost one to one molar ratio of iodide to vanillin could be used without compromising conversion rate, and the insoluble iodovanillin product could be recovered by simple centrifugation. The novel enzymatic synthesis procedure fulfills key criteria of green chemistry. Biocatalytically produced iodovanillin and iodo-ethyl vanillin had significant growth inhibitory effects on several wood degrading fungal species. For Trametes versicolor, a species causing white rot of wood, almost complete growth inhibition and a partial biocidal effect was observed on agar plates. Enzymatic tests indicated that the iodinated compounds acted as enzyme responsive, antimicrobial materials. PMID:24594755

  4. Laccase catalyzed synthesis of iodinated phenolic compounds with antifungal activity.

    PubMed

    Ihssen, Julian; Schubert, Mark; Thöny-Meyer, Linda; Richter, Michael

    2014-01-01

    Iodine is a well known antimicrobial compound. Laccase, an oxidoreductase which couples the one electron oxidation of diverse phenolic and non-phenolic substrates to the reduction of oxygen to water, is capable of oxidizing unreactive iodide to reactive iodine. We have shown previously that laccase-iodide treatment of spruce wood results in a wash-out resistant antimicrobial surface. In this study, we investigated whether phenolic compounds such as vanillin, which resembles sub-structures of softwood lignin, can be directly iodinated by reacting with laccase and iodide, resulting in compounds with antifungal activity. HPLC-MS analysis showed that vanillin was converted to iodovanillin by laccase catalysis at an excess of potassium iodide. No conversion of vanillin occurred in the absence of enzyme. The addition of redox mediators in catalytic concentrations increased the rate of iodide oxidation ten-fold and the yield of iodovanillin by 50%. Iodinated phenolic products were also detected when o-vanillin, ethyl vanillin, acetovanillone and methyl vanillate were incubated with laccase and iodide. At an increased educt concentration of 0.1 M an almost one to one molar ratio of iodide to vanillin could be used without compromising conversion rate, and the insoluble iodovanillin product could be recovered by simple centrifugation. The novel enzymatic synthesis procedure fulfills key criteria of green chemistry. Biocatalytically produced iodovanillin and iodo-ethyl vanillin had significant growth inhibitory effects on several wood degrading fungal species. For Trametes versicolor, a species causing white rot of wood, almost complete growth inhibition and a partial biocidal effect was observed on agar plates. Enzymatic tests indicated that the iodinated compounds acted as enzyme responsive, antimicrobial materials. PMID:24594755

  5. Sexual Differences in Chemical Composition and Aroma-active Compounds of Essential Oil from Flower Buds of Eurya japonica.

    PubMed

    Miyazawa, Mitsuo; Usami, Atsushi; Tanaka, Takio; Tsuji, Kaoru; Takehara, Manami; Hori, Yuki

    2016-04-01

    This study was conducted to determine the composition of essential oil from buds of male and female Eurya japonica flowers and to determine the aroma-active compounds of this plant by gas chromatography-mass spectrometry (GC-MS), sensory evaluation, and odor activity values (OAV). The oils contained eighty-five compounds. We identified for the first time forty-four compounds in E. japonica. Through sensory evaluation, nineteen aroma-active compounds were identified by gas chromatography-olfactometry (GC-O). Because the chemical composition can affect the interaction between plants and herbivorous insects, our results suggest that essential oils from male and female flower buds of E. japonica differently affect herbivores. Sexual differences in essential oils deserve further investigations in this plant-insect system. PMID:26972466

  6. Identification of major phenolic compounds of Chinese water chestnut and their antioxidant activity.

    PubMed

    You, Yanli; Duan, Xuewu; Wei, Xiaoyi; Su, Xinguo; Zhao, Mouming; Sun, Jian; Ruenroengklin, Neungnapa; Jiang, Yueming

    2007-01-01

    Chinese water chestnut (CWC) is one of the most popular foods among Asian people due to its special taste and medical function. Experiments were conducted to test the antioxidant activity and then determine the major phenolic compound components present in CWC. CWC phenolic extract strongly inhibited linoleic acid oxidation and exhibited a dose-dependent free-radical scavenging activity against alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) radicals, superoxide anions and hydroxyl radicals, which was superior to ascorbic acid and butylated hydroxytoluene (BHT), two commercial used antioxidants. Furthermore, the CWC extract was found to have a relatively higher reducing power, compared with BHT. The major phenolic compounds present in CWC tissues were extracted, purified and identified by high-performance liquid chromatograph (HPLC) as (-)-gallocatechin gallate, (-)-epicatechin gallate and (+)-catechin gallate. This study suggests that CWC tissues exhibit great potential for antioxidant activity and may be useful for their nutritional and medicinal functions. PMID:17851436

  7. Laboratory Infrared Spectroscopy to Identify New Compounds on Icy Moon Surfaces

    NASA Astrophysics Data System (ADS)

    Wray, James J.; Young, Cindy L.; Hand, Kevin P.; Poston, Michael J.; Carlson, Robert W.; Clark, Roger N.; Spencer, John R.; Jennings, Donald E.

    2014-11-01

    We are exploring the value of mid-infrared spectroscopy for identifying non-H2O constituents of icy moon surfaces. Recently we reported evidence for a new emissivity feature identified on Iapetus using Cassini’s Composite Infrared Spectrometer [1]. This 11.7 μm feature is consistent with emissivity minima (transparency features) of very fine-grained silicates. Its position and shape may be diagnostic of silicate type, but most lab data at these wavelengths have been acquired using coarser grains and/or at Earth surface pressures and temperatures. Infrared spectra can change substantially under low-temperature, vacuum conditions [e.g., 2,3].We prepared sieved (<0.4 mm) and very fine-grained (few μm) powders of six different silicates and measured their VNIR (0.35-2.5 μm) reflectance spectra under ambient air, and mid-IR (1.2-20 μm) spectra in a purged N2 glovebox. All silicates exhibited mid-IR transparency features (and loss of other features) in micronized form that were not observed for the coarser grain sizes. Muscovite, a phyllosilicate mineral possibly similar to those tentatively identified on Europa [4], provided the closest match to Iapetus in the mid-IR--although clear VNIR features of muscovite have not been identified on Iapetus [5]--and therefore we measured muscovite across the same wavelength range under Iapetus-like conditions (T=125 K, P<3x10^-8 torr). We will report on our ongoing analysis and plans for additional future measurements in JPL’s Icy Worlds Simulation Lab. [1] Young, C.L., et al. (2014), Workshop on the Habitability of Icy Worlds, Abstract #4038.[2] Logan, L.M., et al. (1973), J. Geophys. Res., 78(23), 4983-5003.[3] Donaldson Hanna, K.L., et al. (2012), J. Geophys. Res., 117, E00H05.[4] Shirley, J.H., et al. (2013), AGU Fall Meeting, Abstract #P54A-07.[5] Clark, R.N., et al. (2012), Icarus, 218, 831-860.

  8. Catalytic activities of zeolite compounds for decomposing aqueous ozone.

    PubMed

    Kusuda, Ai; Kitayama, Mikito; Ohta, Yoshio

    2013-12-01

    The advanced oxidation process (AOP), chemical oxidation using aqueous ozone in the presence of appropriate catalysts to generate highly reactive oxygen species, offers an attractive option for removing poorly biodegradable pollutants. Using the commercial zeolite powders with various Si/Al ratios and crystal structures, their catalytic activities for decomposing aqueous ozone were evaluated by continuously flowing ozone to water containing the zeolite powders. The hydrophilic zeolites (low Si/Al ratio) with alkali cations in the crystal structures were found to possess high catalytic activity for decomposing aqueous ozone. The hydrophobic zeolite compounds (high Si/Al ratio) were found to absorb ozone very well, but to have no catalytic activity for decomposing aqueous ozone. Their catalytic activities were also evaluated by using the fixed bed column method. When alkali cations were removed by acid rinsing or substituted by alkali-earth cations, the catalytic activities was significantly deteriorated. These results suggest that the metal cations on the crystal surface of the hydrophilic zeolite would play a key role for catalytic activity for decomposing aqueous ozone. PMID:25078817

  9. Phenolic compounds and antimicrobial activity of olive (Olea europaea L. Cv. Cobrançosa) leaves.

    PubMed

    Pereira, Ana Paula; Ferreira, Isabel C F R; Marcelino, Filipa; Valentão, Patricia; Andrade, Paula B; Seabra, Rosa; Estevinho, Leticia; Bento, Albino; Pereira, José Alberto

    2007-01-01

    We report the determination of phenolic compounds in olive leaves by reversed-phase HPLC/DAD, and the evaluation of their in vitro activity against several microorganisms that may be causal agents of human intestinal and respiratory tract infections, namely gram positive (Bacillus cereus, B. subtilis and Staphylococcus aureus), gram negative bacteria (Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae) and fungi (Candida albicans and Cryptococcus neoformans). Seven phenolic compounds were identified and quantified: caffeic acid, verbascoside, oleuropein, luteolin 7-O-glucoside, rutin, apigenin 7-O-glucoside and luteolin 4'-O-glucoside. At low concentrations olive leaves extracts showed an unusual combined antibacterial and antifungal action, which suggest their great potential as nutraceuticals, particularly as a source of phenolic compounds. PMID:17873849

  10. Influence of plasma-activated compounds on melanogenesis and tyrosinase activity

    PubMed Central

    Ali, Anser; Ashraf, Zaman; Kumar, Naresh; Rafiq, Muhammad; Jabeen, Farukh; Park, Ji Hoon; Choi, Ki Hong; Lee, SeungHyun; Seo, Sung-Yum; Choi, Eun Ha; Attri, Pankaj

    2016-01-01

    Many organic chemists around the world synthesize medicinal compounds or extract multiple compounds from plants in order to increase the activity and quality of medicines. In this work, we synthesized new eugenol derivatives (ED) and then treated them with an N2 feeding gas atmospheric pressure plasma jet (APPJ) to increase their utility. We studied the tyrosinase-inhibition activity (activity test) and structural changes (circular dichroism) of tyrosinase with ED and plasma activated eugenol derivatives (PAED) in a cell-free environment. Later, we used docking studies to determine the possible interaction sites of ED and PAED compounds with tyrosinase enzyme. Moreover, we studied the possible effect of ED and PAED on melanin synthesis and its mechanism in melanoma (B16F10) cells. Additionally, we investigated the structural changes that occurred in activated ED after plasma treatment using nuclear magnetic resonance (NMR). Hence, this study provides a new perspective on PAED for the field of plasma medicine. PMID:26931617

  11. Influence of plasma-activated compounds on melanogenesis and tyrosinase activity.

    PubMed

    Ali, Anser; Ashraf, Zaman; Kumar, Naresh; Rafiq, Muhammad; Jabeen, Farukh; Park, Ji Hoon; Choi, Ki Hong; Lee, SeungHyun; Seo, Sung-Yum; Choi, Eun Ha; Attri, Pankaj

    2016-01-01

    Many organic chemists around the world synthesize medicinal compounds or extract multiple compounds from plants in order to increase the activity and quality of medicines. In this work, we synthesized new eugenol derivatives (ED) and then treated them with an N2 feeding gas atmospheric pressure plasma jet (APPJ) to increase their utility. We studied the tyrosinase-inhibition activity (activity test) and structural changes (circular dichroism) of tyrosinase with ED and plasma activated eugenol derivatives (PAED) in a cell-free environment. Later, we used docking studies to determine the possible interaction sites of ED and PAED compounds with tyrosinase enzyme. Moreover, we studied the possible effect of ED and PAED on melanin synthesis and its mechanism in melanoma (B16F10) cells. Additionally, we investigated the structural changes that occurred in activated ED after plasma treatment using nuclear magnetic resonance (NMR). Hence, this study provides a new perspective on PAED for the field of plasma medicine. PMID:26931617

  12. How Can We Identify Ictal and Interictal Abnormal Activity?

    PubMed Central

    Fisher, Robert S.; Scharfman, Helen E.; deCurtis, Marco

    2015-01-01

    The International League Against Epilepsy (ILAE) defined a seizure as “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.” This definition has been used since the era of Hughlings Jackson, and does not take into account subsequent advances made in epilepsy and neuroscience research. The clinical diagnosis of a seizure is empirical, based upon constellations of certain signs and symptoms, while simultaneously ruling out a list of potential imitators of seizures. Seizures should be delimited in time, but the borders of ictal (during a seizure), interictal (between seizures) and postictal (after a seizure) often are indistinct. EEG recording is potentially very helpful for confirmation, classification and localization. About a half-dozen common EEG patterns are encountered during seizures. Clinicians rely on researchers to answer such questions as why seizures start, spread and stop, whether seizures involve increased synchrony, the extent to which extra-cortical structures are involved, and how to identify the seizure network and at what points interventions are likely to be helpful. Basic scientists have different challenges in use of the word ‘seizure,’ such as distinguishing seizures from normal behavior, which would seem easy but can be very difficult because some rodents have EEG activity during normal behavior that resembles spike-wave discharge or bursts of rhythmic spiking. It is also important to define when a seizure begins and stops so that seizures can be quantified accurately for pre-clinical studies. When asking what causes seizures, the transition to a seizure and differentiating the pre-ictal, ictal and post-ictal state is also important because what occurs before a seizure could be causal and may warrant further investigation for that reason. These and other issues are discussed by three epilepsy researchers with clinical and basic science expertise. PMID:25012363

  13. Compounds Released from Biomass Deconstruction: Understanding Their Effect on Cellulose Enzyme Hydrolysis and Their Biological Activity

    NASA Astrophysics Data System (ADS)

    Djioleu, Angele Mezindjou

    The effect of compounds produced during biomass pretreatment on cellulolytic enzyme was investigated. Liquid prehydrolyzates were prepared by pretreating switchgrass using 24 combinations of temperature, time, and sulfuric acid concentration based on a full factorial design. Temperature was varied from 140°C to 180°C; time ranged from 10 to 40 min; and the sulfuric acid concentrations were 0.5% or 1% (v/v). Identified products in the prehydrolyzates included xylose, glucose, hydroxymethylfurfural (HMF), furfural, acetic acid, formic acid, and phenolic compounds at concentration ranging from 0 to 21.4 g/L. Pretreatment conditions significantly affected the concentrations of compounds detected in prehydrolyzates. When assayed in the presence of switchgrass prehydrolyzates against model substrates, activities of cellulase, betaglucosidase, and exoglucanase, were significantly reduced by at least 16%, 31.8%, and 57.8%, respectively, as compared to the control. A strong positive correlation between inhibition of betaglucosidase and concentration of glucose, acetic acid, and furans in prehydrolyzate was established. Exoglucanase inhibition correlated with the presence of phenolic compounds and acetic acid. The prehydrolyzate, prepared at 160°C, 30 min, and 1% acid, was fractionated by centrifugal partition chromatography (CPC) into six fractions; the inhibition effect of these fractions on betaglucosidase and exoglucanase was determined. The initial hydrolysis rate of cellobiose by betaglucosidase was significantly reduced by the CPC sugar-rich fraction; however, exoglucanase was deactivated by the CPC phenolic-rich fraction. Finally, biological activities of water-extracted compounds from sweetgum bark and their effect on cellulase was investigated. It was determined that 12% of solid content of the bark extract could be accounted by phenolic compounds with gallic acid identified as the most concentrated phytochemical. Sweetgum bark extract inhibited Staphylococcus

  14. Prediction of cloud condensation nuclei activity for organic compounds using functional group contribution methods

    NASA Astrophysics Data System (ADS)

    Petters, M. D.; Kreidenweis, S. M.; Ziemann, P. J.

    2016-01-01

    A wealth of recent laboratory and field experiments demonstrate that organic aerosol composition evolves with time in the atmosphere, leading to changes in the influence of the organic fraction to cloud condensation nuclei (CCN) spectra. There is a need for tools that can realistically represent the evolution of CCN activity to better predict indirect effects of organic aerosol on clouds and climate. This work describes a model to predict the CCN activity of organic compounds from functional group composition. Following previous methods in the literature, we test the ability of semi-empirical group contribution methods in Köhler theory to predict the effective hygroscopicity parameter, kappa. However, in our approach we also account for liquid-liquid phase boundaries to simulate phase-limited activation behavior. Model evaluation against a selected database of published laboratory measurements demonstrates that kappa can be predicted within a factor of 2. Simulation of homologous series is used to identify the relative effectiveness of different functional groups in increasing the CCN activity of weakly functionalized organic compounds. Hydroxyl, carboxyl, aldehyde, hydroperoxide, carbonyl, and ether moieties promote CCN activity while methylene and nitrate moieties inhibit CCN activity. The model can be incorporated into scale-bridging test beds such as the Generator of Explicit Chemistry and Kinetics of Organics in the Atmosphere (GECKO-A) to evaluate the evolution of kappa for a complex mix of organic compounds and to develop suitable parameterizations of CCN evolution for larger-scale models.

  15. Prediction of cloud condensation nuclei activity for organic compounds using functional group contribution methods

    DOE PAGESBeta

    Petters, M. D.; Kreidenweis, S. M.; Ziemann, P. J.

    2016-01-19

    A wealth of recent laboratory and field experiments demonstrate that organic aerosol composition evolves with time in the atmosphere, leading to changes in the influence of the organic fraction to cloud condensation nuclei (CCN) spectra. There is a need for tools that can realistically represent the evolution of CCN activity to better predict indirect effects of organic aerosol on clouds and climate. This work describes a model to predict the CCN activity of organic compounds from functional group composition. Following previous methods in the literature, we test the ability of semi-empirical group contribution methods in Köhler theory to predict themore » effective hygroscopicity parameter, kappa. However, in our approach we also account for liquid–liquid phase boundaries to simulate phase-limited activation behavior. Model evaluation against a selected database of published laboratory measurements demonstrates that kappa can be predicted within a factor of 2. Simulation of homologous series is used to identify the relative effectiveness of different functional groups in increasing the CCN activity of weakly functionalized organic compounds. Hydroxyl, carboxyl, aldehyde, hydroperoxide, carbonyl, and ether moieties promote CCN activity while methylene and nitrate moieties inhibit CCN activity. The model can be incorporated into scale-bridging test beds such as the Generator of Explicit Chemistry and Kinetics of Organics in the Atmosphere (GECKO-A) to evaluate the evolution of kappa for a complex mix of organic compounds and to develop suitable parameterizations of CCN evolution for larger-scale models.« less

  16. Prediction of cloud condensation nuclei activity for organic compounds using functional group contribution methods

    DOE PAGESBeta

    Petters, M. D.; Kreidenweis, S. M.; Ziemann, P. J.

    2016-01-19

    A wealth of recent laboratory and field experiments demonstrate that organic aerosol composition evolves with time in the atmosphere, leading to changes in the influence of the organic fraction to cloud condensation nuclei (CCN) spectra. There is a need for tools that can realistically represent the evolution of CCN activity to better predict indirect effects of organic aerosol on clouds and climate. This work describes a model to predict the CCN activity of organic compounds from functional group composition. Following previous methods in the literature, we test the ability of semi-empirical group contribution methods in Kohler theory to predict themore » effective hygroscopicity parameter, kappa. However, in our approach we also account for liquid–liquid phase boundaries to simulate phase-limited activation behavior. Model evaluation against a selected database of published laboratory measurements demonstrates that kappa can be predicted within a factor of 2. Simulation of homologous series is used to identify the relative effectiveness of different functional groups in increasing the CCN activity of weakly functionalized organic compounds. Hydroxyl, carboxyl, aldehyde, hydroperoxide, carbonyl, and ether moieties promote CCN activity while methylene and nitrate moieties inhibit CCN activity. Furthermore, the model can be incorporated into scale-bridging test beds such as the Generator of Explicit Chemistry and Kinetics of Organics in the Atmosphere (GECKO-A) to evaluate the evolution of kappa for a complex mix of organic compounds and to develop suitable parameterizations of CCN evolution for larger-scale models.« less

  17. Prediction of cloud condensation nuclei activity for organic compounds using functional group contribution methods

    NASA Astrophysics Data System (ADS)

    Petters, M. D.; Kreidenweis, S. M.; Ziemann, P. J.

    2015-09-01

    A wealth of recent laboratory and field experiments demonstrate that organic aerosol composition evolves with time in the atmosphere, leading to changes in the influence of the organic fraction to cloud condensation nuclei (CCN) spectra. There is a need for tools that can realistically represent the evolution of CCN activity to better predict indirect effects of organic aerosol on clouds and climate. This work describes a model to predict the CCN activity of organic compounds from functional group composition. The model combines Köhler theory with semi-empirical group contribution methods to estimate molar volumes, activity coefficients and liquid-liquid phase boundaries to predict the effective hygroscopicity parameter, kappa. Model evaluation against a selected database of published laboratory measurements demonstrates that kappa can be predicted within a factor of two. Simulation of homologous series is used to identify the relative effectiveness of different functional groups in increasing the CCN activity of weakly functionalized organic compounds. Hydroxyl, carboxyl, aldehyde, hydroperoxide, carbonyl, and ether moieties promote CCN activity while methylene and nitrate moieties inhibit CCN activity. The model can be incorporated into scale-bridging testbeds such as the Generator of Explicit Chemistry and Kinetics of Organics in the Atmosphere to evaluate the evolution of kappa for a complex mix of organic compounds and to develop suitable parameterizations of CCN evolution for larger scale models.

  18. Prediction of cloud condensation nuclei activity for organic compounds using functional group contribution methods

    SciTech Connect

    Petters, M. D.; Kreidenweis, S. M.; Ziemann, P. J.

    2016-01-01

    A wealth of recent laboratory and field experiments demonstrate that organic aerosol composition evolves with time in the atmosphere, leading to changes in the influence of the organic fraction to cloud condensation nuclei (CCN) spectra. There is a need for tools that can realistically represent the evolution of CCN activity to better predict indirect effects of organic aerosol on clouds and climate. This work describes a model to predict the CCN activity of organic compounds from functional group composition. Following previous methods in the literature, we test the ability of semi-empirical group contribution methods in Köhler theory to predict the effective hygroscopicity parameter, kappa. However, in our approach we also account for liquid–liquid phase boundaries to simulate phase-limited activation behavior. Model evaluation against a selected database of published laboratory measurements demonstrates that kappa can be predicted within a factor of 2. Simulation of homologous series is used to identify the relative effectiveness of different functional groups in increasing the CCN activity of weakly functionalized organic compounds. Hydroxyl, carboxyl, aldehyde, hydroperoxide, carbonyl, and ether moieties promote CCN activity while methylene and nitrate moieties inhibit CCN activity. The model can be incorporated into scale-bridging test beds such as the Generator of Explicit Chemistry and Kinetics of Organics in the Atmosphere (GECKO-A) to evaluate the evolution of kappa for a complex mix of organic compounds and to develop suitable parameterizations of CCN evolution for larger-scale models.

  19. Naturally Produced Defensive Alkenal Compounds Activate TRPA1.

    PubMed

    Blair, Nathaniel T; Philipson, Benjamin I; Richards, Paige M; Doerner, Julia F; Segura, Abraham; Silver, Wayne L; Clapham, David E

    2016-05-01

    (E)-2-alkenals are aldehydes containing an unsaturated bond between the alpha and beta carbons. 2-alkenals are produced by many organisms for defense against predators and secretions containing (E)-2-alkenals cause predators to stop attacking and allow the prey to escape. Chemical ecologists have described many alkenal compounds with 3-20 carbons common, having varied positions of double bonds and substitutions. How do these defensive alkenals act to deter predators? We have tested the effects of (E)-2-alkenals with 6-12 carbons on transient receptor potential channels (TRP) commonly found in sensory neurons. We find that (E)-2-alkenals activate transient receptor potential ankyrin subtype 1 (TRPA1) at low concentrations-EC50s 10-100 µM (in 0 added Ca(2+) external solutions). Other TRP channels were either weakly activated (TRPV1, TRPV3) or insensitive (TRPV2, TRPV4, TRPM8). (E)-2-alkenals may activate TRPA1 by modifying cysteine side chains. However, target cysteines include others beyond the 3 in the amino-terminus implicated in activation, as a channel with cysteines at 621, 641, 665 mutated to serine responded robustly. Related chemicals, including the aldehydes hexanal and decanal, and (E)-2-hexen-1-ol also activated TRPA1, but with weaker potency. Rat trigeminal nerve recordings and behavioral experiments showed (E)-2-hexenal was aversive. Our results suggest that TRPA1 is likely a major target of these commonly used defensive chemicals. PMID:26843529

  20. Phenotypic assays to identify agents that induce reactive gliosis: a counter-screen to prioritize compounds for preclinical animal studies.

    PubMed

    Beckerman, Samuel R; Jimenez, Joaquin E; Shi, Yan; Al-Ali, Hassan; Bixby, John L; Lemmon, Vance P

    2015-09-01

    Astrocyte phenotypes change in a process called reactive gliosis after traumatic central nervous system (CNS) injury. Astrogliosis is characterized by expansion of the glial fibrillary acidic protein (GFAP) cytoskeleton, adoption of stellate morphologies, and differential expression of some extracellular matrix molecules. The astrocytic response immediately after injury is beneficial, but in the chronic injury phase, reactive astrocytes produce inhibitory factors (i.e., chondroitin sulfate proteoglycans [CSPGs]) that limit the regrowth of injured axons. There are no drugs that promote axon regeneration or functional recovery after CNS trauma in humans. To develop novel therapeutics for the injured CNS, we screened various libraries in a phenotypic assay to identify compounds that promote neurite outgrowth. However, the effects these compounds have on astrocytes are unknown. Specifically, we were interested in whether compounds could alter astrocytes in a manner that mimics the glial reaction to injury. To test this hypothesis, we developed cell-based phenotypic bioassays to measure changes in (1) GFAP morphology/localization and (2) CSPG expression/immunoreactivity from primary astrocyte cultures. These assays were optimized for six-point dose-response experiments in 96-well plates. The GFAP morphology assay is suitable for counter-screening with a Z-factor of 0.44±0.03 (mean±standard error of the mean; N=3 biological replicates). The CSPG assay is reproducible and informative, but does not satisfy common metrics for a "screenable" assay. As proof of principle, we tested a small set of hit compounds from our neurite outgrowth bioassay and identified one that can enhance axon growth without exacerbating the deleterious characteristics of reactive gliosis. PMID:26230074

  1. Mutations in a translation initiation factor identify target of a memory-enhancing compound

    PubMed Central

    Sekine, Yusuke; Zyryanova, Alisa; Crespillo-Casado, Ana; Fischer, Peter M.; Harding, Heather P.; Ron, David

    2015-01-01

    The integrated stress response (ISR) modulates mRNA translation to regulate the mammalian unfolded protein response (UPR), immunity and memory formation. A chemical ISR inhibitor, ISRIB, enhances cognitive function and modulates the UPR in vivo. To explore mechanisms involved in ISRIB action we screened cultured mammalian cells for somatic mutations that reversed its effect on the ISR. Clustered missense mutations were found at the N-terminal portion of the delta subunit of guanine nucleotide exchange factor (GEF) eIF2B. When reintroduced by CRISPR-Cas9 gene editing of wildtype cells, these mutations reversed both ISRIB-mediated inhibition of the ISR and its stimulatory effect on eIF2B GEF activity towards its substrate, eIF2, in vitro. Thus ISRIB targets an interaction between eIF2 and eIF2B that lies at the core of the ISR. PMID:25858979

  2. Rapid, Semiquantitative Assay To Discriminate among Compounds with Activity against Replicating or Nonreplicating Mycobacterium tuberculosis

    PubMed Central

    Roberts, Julia; Ling, Yan; Quezada, Landys Lopez; Glasheen, Jou; Ballinger, Elaine; Somersan-Karakaya, Selin; Warrier, Thulasi; Warren, J. David; Nathan, Carl

    2015-01-01

    The search for drugs that can kill replicating and nonreplicating Mycobacterium tuberculosis faces practical bottlenecks. Measurement of CFU and discrimination of bacteriostatic from bactericidal activity are costly in compounds, supplies, labor, and time. Testing compounds against M. tuberculosis under conditions that prevent the replication of M. tuberculosis often involves a second phase of the test in which conditions are altered to permit the replication of bacteria that survived the first phase. False-positive determinations of activity against nonreplicating M. tuberculosis may arise from carryover of compounds from the nonreplicating stage of the assay that act in the replicating stage. We mitigate these problems by carrying out a 96-well microplate liquid MIC assay and then transferring an aliquot of each well to a second set of plates in which each well contains agar supplemented with activated charcoal. After 7 to 10 days—about 2 weeks sooner than required to count CFU—fluorometry reveals whether M. tuberculosis bacilli in each well have replicated extensively enough to reduce a resazurin dye added for the final hour. This charcoal agar resazurin assay (CARA) distinguishes between bacterial biomasses in any two wells that differ by 2 to 3 log10 CFU. The CARA thus serves as a pretest and semiquantitative surrogate for longer, more laborious, and expensive CFU-based assays, helps distinguish bactericidal from bacteriostatic activity, and identifies compounds that are active under replicating conditions, nonreplicating conditions, or both. Results for 14 antimycobacterial compounds, including tuberculosis (TB) drugs, revealed that PA-824 (pretomanid) and TMC207 (bedaquiline) are largely bacteriostatic. PMID:26239979

  3. Rapid, Semiquantitative Assay To Discriminate among Compounds with Activity against Replicating or Nonreplicating Mycobacterium tuberculosis.

    PubMed

    Gold, Ben; Roberts, Julia; Ling, Yan; Quezada, Landys Lopez; Glasheen, Jou; Ballinger, Elaine; Somersan-Karakaya, Selin; Warrier, Thulasi; Warren, J David; Nathan, Carl

    2015-10-01

    The search for drugs that can kill replicating and nonreplicating Mycobacterium tuberculosis faces practical bottlenecks. Measurement of CFU and discrimination of bacteriostatic from bactericidal activity are costly in compounds, supplies, labor, and time. Testing compounds against M. tuberculosis under conditions that prevent the replication of M. tuberculosis often involves a second phase of the test in which conditions are altered to permit the replication of bacteria that survived the first phase. False-positive determinations of activity against nonreplicating M. tuberculosis may arise from carryover of compounds from the nonreplicating stage of the assay that act in the replicating stage. We mitigate these problems by carrying out a 96-well microplate liquid MIC assay and then transferring an aliquot of each well to a second set of plates in which each well contains agar supplemented with activated charcoal. After 7 to 10 days-about 2 weeks sooner than required to count CFU-fluorometry reveals whether M. tuberculosis bacilli in each well have replicated extensively enough to reduce a resazurin dye added for the final hour. This charcoal agar resazurin assay (CARA) distinguishes between bacterial biomasses in any two wells that differ by 2 to 3 log10 CFU. The CARA thus serves as a pretest and semiquantitative surrogate for longer, more laborious, and expensive CFU-based assays, helps distinguish bactericidal from bacteriostatic activity, and identifies compounds that are active under replicating conditions, nonreplicating conditions, or both. Results for 14 antimycobacterial compounds, including tuberculosis (TB) drugs, revealed that PA-824 (pretomanid) and TMC207 (bedaquiline) are largely bacteriostatic. PMID:26239979

  4. [Estrogenic activity of ultraviolet absorbers and the related compounds].

    PubMed

    Matsumoto, Hisashi; Adachi, Shinichi; Suzuki, Yasuhiko

    2005-08-01

    The estrogenic activities of ultraviolet absorbers and their related compounds were investigated using MCF-7 cell proliferation assay. Nine of 33 chemicals (benzophenone, 2,4-dihydroxybenzophenone, 2,2',4,4'-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 4-hydroxybenzophenone, 3-(4-methylbenzylidene) camphor, ethyl 2-cyano-3,3-diphenylacrylate (etocrylene) and 2-ethylhexyl-2-cyano-3,3-diphenylacrylate (octocrylene)) were positive compared with the vehicle control. Benzhydrol, ethyl cinnamate and 2,2'-dihydroxy-4-methoxybenzophenone were weakly active. When each xenoestrogen was added to the cells along with ICI 182780, an estrogen receptor (ER) antagonist, the cell growth was reduced according to its doses. Therefore, the cell proliferation was suggested to generate through ER. Most of these chemicals were also positive using CHOOSER assay, a new method of testing estrogenic activity of xenoestrogen. Each xenoestrogen was also confirmed to bind to ERalpha and ERbeta using a human ER competitive binding assay against 17beta-estradiol. The concentration order of the strength of its inhibitory effect using both ERalpha and ERbeta was similar to that of MCF-7 cell proliferation assay, except for benzyl 4-hydroxybenzoate (B4HB). B4HB showed a stronger activity on CHOOSER assay and the competitive binding assay using both ERalpha and ERbeta, although there was no activity observed on MCF-7 cell proliferation assay. Our findings were to detect the estrogenic activity of etocrylene and octocrylene in vitro, in addition to confirming the activities of some ultraviolet absorbers as previously reported. PMID:16079615

  5. Combined Rational Design and a High Throughput Screening Platform for Identifying Chemical Inhibitors of a Ras-activating Enzyme*

    PubMed Central

    Evelyn, Chris R.; Biesiada, Jacek; Duan, Xin; Tang, Hong; Shang, Xun; Papoian, Ruben; Seibel, William L.; Nelson, Sandra; Meller, Jaroslaw; Zheng, Yi

    2015-01-01

    The Ras family small GTPases regulate multiple cellular processes, including cell growth, survival, movement, and gene expression, and are intimately involved in cancer pathogenesis. Activation of these small GTPases is catalyzed by a special class of enzymes, termed guanine nucleotide exchange factors (GEFs). Herein, we developed a small molecule screening platform for identifying lead hits targeting a Ras GEF enzyme, SOS1. We employed an ensemble structure-based virtual screening approach in combination with a multiple tier high throughput experimental screen utilizing two complementary fluorescent guanine nucleotide exchange assays to identify small molecule inhibitors of GEF catalytic activity toward Ras. From a library of 350,000 compounds, we selected a set of 418 candidate compounds predicted to disrupt the GEF-Ras interaction, of which dual wavelength GDP dissociation and GTP-loading experimental screening identified two chemically distinct small molecule inhibitors. Subsequent biochemical validations indicate that they are capable of dose-dependently inhibiting GEF catalytic activity, binding to SOS1 with micromolar affinity, and disrupting GEF-Ras interaction. Mutagenesis studies in conjunction with structure-activity relationship studies mapped both compounds to different sites in the catalytic pocket, and both inhibited Ras signaling in cells. The unique screening platform established here for targeting Ras GEF enzymes could be broadly useful for identifying lead inhibitors for a variety of small GTPase-activating GEF reactions. PMID:25825487

  6. Antioxidant activities and phenolic compounds of date plum persimmon ( Diospyros lotus L.) fruits.

    PubMed

    Gao, Hui; Cheng, Ni; Zhou, Juan; Wang, Bini; Deng, Jianjun; Cao, Wei

    2014-05-01

    In the present study, phenolic compounds are extracted from the date plum persimmon fruits using water, methanol and acetone as solvents. Antioxidant activities of the phenolic extracts are measured using four different tests, namely, DPPH, hydroxyl radical scavenging activities, chelating and reducing power assays. All the extracts show dose dependent DPPH radical scavenging activity, reducing and chelating powers and moreover, they are well correlated with the total phenolic and total flavonoid substances, suggesting direct contribution of phenolic compounds to these activities. In further, the extracts are identified and quantified by HPLC-ECD. Results show that gallic acid is the most abundant phenolic compound, with amounts ranging between 45.49and 287.47 μg/g dry sample. Myricetin is the dominant flavonoid in all extracts. Its level varied from 2.75 μg/g dry sample in acetone extract to 5.28 μg/g dry sample in water extract. On the basis of the results obtained, the date plum persimmon fruits phenolic extract is a potential source of natural antioxidants owing to its significant antioxidant activities. PMID:24803703

  7. Biological Activities of Phenolic Compounds of Extra Virgin Olive Oil.

    PubMed

    Servili, Maurizio; Sordini, Beatrice; Esposto, Sonia; Urbani, Stefania; Veneziani, Gianluca; Di Maio, Ilona; Selvaggini, Roberto; Taticchi, Agnese

    2013-01-01

    Over the last few decades, multiple biological properties, providing antioxidant, anti-inflammatory, chemopreventive and anti-cancer benefits, as well as the characteristic pungent and bitter taste, have been attributed to Extra Virgin Olive Oil (EVOO) phenols. In particular, growing efforts have been devoted to the study of the antioxidants of EVOO, due to their importance from health, biological and sensory points of view. Hydrophilic and lipophilic phenols represent the main antioxidants of EVOO, and they include a large variety of compounds. Among them, the most concentrated phenols are lignans and secoiridoids, with the latter found exclusively in the Oleaceae family, of which the drupe is the only edible fruit. In recent years, therefore, we have tackled the study of the main properties of phenols, including the relationships between their biological activity and the related chemical structure. This review, in fact, focuses on the phenolic compounds of EVOO, and, in particular, on their biological properties, sensory aspects and antioxidant capacity, with a particular emphasis on the extension of the product shelf-life. PMID:26784660

  8. Biological Activities of Phenolic Compounds of Extra Virgin Olive Oil

    PubMed Central

    Servili, Maurizio; Sordini, Beatrice; Esposto, Sonia; Urbani, Stefania; Veneziani, Gianluca; Maio, Ilona Di; Selvaggini, Roberto; Taticchi, Agnese

    2013-01-01

    Over the last few decades, multiple biological properties, providing antioxidant, anti-inflammatory, chemopreventive and anti-cancer benefits, as well as the characteristic pungent and bitter taste, have been attributed to Extra Virgin Olive Oil (EVOO) phenols. In particular, growing efforts have been devoted to the study of the antioxidants of EVOO, due to their importance from health, biological and sensory points of view. Hydrophilic and lipophilic phenols represent the main antioxidants of EVOO, and they include a large variety of compounds. Among them, the most concentrated phenols are lignans and secoiridoids, with the latter found exclusively in the Oleaceae family, of which the drupe is the only edible fruit. In recent years, therefore, we have tackled the study of the main properties of phenols, including the relationships between their biological activity and the related chemical structure. This review, in fact, focuses on the phenolic compounds of EVOO, and, in particular, on their biological properties, sensory aspects and antioxidant capacity, with a particular emphasis on the extension of the product shelf-life. PMID:26784660

  9. Natural Compounds' Activity against Cancer Stem-Like or Fast-Cycling Melanoma Cells

    PubMed Central

    Majchrzak, Kinga; Hartman, Mariusz; Czyz, Malgorzata

    2014-01-01

    Background Accumulating evidence supports the concept that melanoma is highly heterogeneous and sustained by a small subpopulation of melanoma stem-like cells. Those cells are considered as responsible for tumor resistance to therapies. Moreover, melanoma cells are characterized by their high phenotypic plasticity. Consequently, both melanoma stem-like cells and their more differentiated progeny must be eradicated to achieve durable cure. By reevaluating compounds in heterogeneous melanoma populations, it might be possible to select compounds with activity not only against fast-cycling cells but also against cancer stem-like cells. Natural compounds were the focus of the present study. Methods We analyzed 120 compounds from The Natural Products Set II to identify compounds active against melanoma populations grown in an anchorage-independent manner and enriched with cells exerting self-renewing capacity. Cell viability, cell cycle arrest, apoptosis, gene expression, clonogenic survival and label-retention were analyzed. Findings Several compounds efficiently eradicated cells with clonogenic capacity and nanaomycin A, streptonigrin and toyocamycin were effective at 0.1 µM. Other anti-clonogenic but not highly cytotoxic compounds such as bryostatin 1, siomycin A, illudin M, michellamine B and pentoxifylline markedly reduced the frequency of ABCB5 (ATP-binding cassette, sub-family B, member 5)-positive cells. On the contrary, treatment with maytansine and colchicine selected for cells expressing this transporter. Maytansine, streptonigrin, toyocamycin and colchicine, even if highly cytotoxic, left a small subpopulation of slow-dividing cells unaffected. Compounds selected in the present study differentially altered the expression of melanocyte/melanoma specific microphthalmia-associated transcription factor (MITF) and proto-oncogene c-MYC. Conclusion Selected anti-clonogenic compounds might be further investigated as potential adjuvants targeting melanoma stem

  10. [The release of biologically active compounds from peat peloids].

    PubMed

    Babaskin, D V

    2011-01-01

    This work had the objective to study kinetics of the release of flavonoides from peat peloid compositions containing extracts of medicinal herbs in model systems.The key parameters of the process are defined. The rate of liberation of flavonoides is shown to depend on their initial concentration in the compositions being used. The influence of the flavonoide composition of the tested extracts and dimethylsulfoxide on the release of biologically active compounds contained in the starting material in the model environment is estimated. The possibility of the layer-by-layer deposition of the compositions and peat peloids in order to increase the efficacy of flavonoide release from the starting composition and to ensure more rational utilization of the extracts of medicinal plants is demonstrated. PMID:22165149

  11. Irreversible adsorption of phenolic compounds by activated carbons

    SciTech Connect

    Grant, T.M.; King, C.J.

    1988-12-01

    Studies were undertaken to determine the reasons why phenolic sorbates can be difficult to remove and recover from activated carbons. The chemical properties of the sorbate and the adsorbent surface, and the influences of changes in the adsorption and desorption conditions were investigated. Comparison of isotherms established after different contact times or at different temperatures indicated that phenolic compounds react on carbon surfaces. The reaction rate is a strong function of temperature. Regeneration of carbons by leaching with acetone recovered at least as much phenol as did regeneration with other solvents or with displacers. The physiochemical properties of adsorbents influences irreversible uptakes. Sorbates differed markedly in their tendencies to undergo irreversible adsorption. 64 refs., 47 figs., 32 tabs.

  12. Determination of some phenolic compounds in Crocus sativus L. corms and its antioxidant activities study

    PubMed Central

    Esmaeili, N; Ebrahimzadeh, H; Abdi, K; Safarian, S

    2011-01-01

    It is well known that phenolic compounds are constituents of many plants. In this study, the total phenolics content in Crocus sativus L. corms in dormancy and waking stages were determined by the Folin-Ciocalteu method. Analysis was carried out by gas chromatography-mass spectrometry (GC-MS) after silylation by N-methyl-N-trimethylsilyl trifluroacetamide (MSTFA) + %1 trimethyl iodosilane (TMIS). Numerous compounds were detected and 11 compounds were identified. The highest phenolics content in waking corms was observed for gentisic acid (5.693 ± 0.057 μg/g) and the lowest for gallic acid (0.416 ± 0.006 μg/g); also these two phenolic compounds are the highest (0.929 ± 0.015 μg/g) and lowest (0.017 ± 0.001 μg/g) phenolics in dormant corms, respectively. The results from quantization and GC-MS analysis showed a high concentration of phenolic compounds in waking corms than the dormant stage. Furthermore, the radical scavenging activities of saffron corms were studied by 1,1-diphenyl-2-pycrylhydrazyl (DPPH) test and EC 50values were determined about 2055 ppm and 8274 ppm for waking and dormant corms, respectively. PMID:21472084

  13. Activation tag screening to identify novel genes for trichothecene resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The goal of our research is to identify plant genes which enhance trichothecene resistance and, ultimately, Fusarium Head Blight resistance in wheat and barley. We are taking a two pronged approach using Arabidopsis to identify plant genes which confer resistance to trichothecenes. The first approac...

  14. Inhibitors of 7-Dehydrocholesterol Reductase: Screening of a Collection of Pharmacologically Active Compounds in Neuro2a Cells.

    PubMed

    Kim, Hye-Young H; Korade, Zeljka; Tallman, Keri A; Liu, Wei; Weaver, C David; Mirnics, Karoly; Porter, Ned A

    2016-05-16

    A small library of pharmacologically active compounds (the NIH Clinical Collection) was assayed in Neuro2a cells to determine their effect on the last step in the biosynthesis of cholesterol, the transformation of 7-dehydrocholesterol (7-DHC) to cholesterol promoted by 7-dehydrocholesterol reductase, DHCR7. Of some 727 compounds in the NIH Clinical Collection, over 30 compounds significantly increased 7-DHC in Neuro2a cells when assayed at 1 μM. Active compounds that increased 7-DHC with a Z-score of +3 or greater generally gave rise to modest decreases in desmosterol and increases in lanosterol levels. Among the most active compounds identified in the library were the antipsychotic, antidepressant, and anxiolytic compounds that included perospirone, nefazodone, haloperidol, aripiprazole, trazodone, and buspirone. Fluoxetine and risperidone were also active at 1 μM, and another 10 compounds in this class of pharmaceuticals were identified in the screen at concentrations of 10 μM. Increased levels of 7-DHC are associated with Smith-Lemli-Opitz syndrome (SLOS), a human condition that results from a mutation in the gene that encodes DHCR7. The SLOS phenotype includes neurological deficits and congenital malformations, and it is linked to a higher incidence of autism spectrum disorder. The significance of the current study is that it identifies common pharmacological compounds that may induce a biochemical presentation similar to SLOS. Little is known about the side effects of elevated 7-DHC postdevelopmentally, and the elevated 7-DHC that results from exposure to these compounds may also be a confounder in the diagnosis of SLOS. PMID:27097157

  15. Propolis volatile compounds: chemical diversity and biological activity: a review

    PubMed Central

    2014-01-01

    Propolis is a sticky material collected by bees from plants, and used in the hive as building material and defensive substance. It has been popular as a remedy in Europe since ancient times. Nowadays, propolis use in over-the-counter preparations, “bio”-cosmetics and functional foods, etc., increases. Volatile compounds are found in low concentrations in propolis, but their aroma and significant biological activity make them important for propolis characterisation. Propolis is a plant-derived product: its chemical composition depends on the local flora at the site of collection, thus it offers a significant chemical diversity. The role of propolis volatiles in identification of its plant origin is discussed. The available data about chemical composition of propolis volatiles from different geographic regions are reviewed, demonstrating significant chemical variability. The contribution of volatiles and their constituents to the biological activities of propolis is considered. Future perspectives in research on propolis volatiles are outlined, especially in studying activities other than antimicrobial. PMID:24812573

  16. Antioxidant activity of some foods containing phenolic compounds.

    PubMed

    Karakaya, S; El, S N; Taş, A A

    2001-11-01

    This study was designed to determine the total phenols (TP) and total antioxidant activity (TAA) of some liquid and solid plant foods that are commonly consumed in Turkey. Total phenols were analysed according to the Folin-Ciocalteu method and antioxidant activities of these compounds in aqueous phase were assessed by measuring their direct ABTS.- radical scavenging abilities. Total phenols varied from 68 to 4162 mg/l for liquid foods and from 735 to 3994 mg/kg for solid foods. TAA of liquid and solid foods ranged between 0.61-6.78 mM and 0.63-8.62 mM, respectively. Total antioxidant activities of foods were well correlated with total phenols (r2 = 0.95). According to content of total phenols per serving, liquid foods were in the order of black tea > instant coffee > coke > red wine > violet carrot juice > apricot nectar > Turkish coffee > grape molasses > sage > white wine > linden flower, and solid foods were in the order of red grape > raisins > tarhana > dried black plum > dried apricot > grape > fresh paprika > fresh black plum > Urtica sp. > cherry > fresh apricot > paprika pickle > paprika paste. PMID:11570016

  17. Natural Compounds Preventing Neurodegenerative Diseases Through Autophagic Activation.

    PubMed

    Huang, Zhe; Adachi, Hiroaki

    2016-06-01

    Neurodegenerative diseases (NDDs) are a group of intractable diseases that significantly affect human health. To date, the pathogenesis of NDDs is still poorly understood and effective disease-modifying therapies for NDDs have not been established. NDDs share the common morphological characteristic of the deposition of abnormal proteins in the nervous system, including neurons. Autophagy is one of the major processes by which damaged organelles and abnormal proteins are removed from cells. Impairment of autophagy has been found to be involved in the pathogenesis of NDDs, and the regulation of autophagy may become a therapeutic strategy for NDDs. In recent years, some active compounds from plants have been found to regulate autophagy and exert neuroprotection against NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal and bulbar muscular atrophy, spinocerebellar ataxia 3, and amyotrophic lateral sclerosis, via activating autophagy. In this paper, we review recent advances in the use of active ingredients from plants for the regulation of autophagy and treatment of NDDs. PMID:27302727

  18. Volatile compounds and antioxidative activity of Porophyllum tagetoides extracts.

    PubMed

    Jimenez, M; Guzman, A P; Azuara, E; Garcia, O; Mendoza, M R; Beristain, C I

    2012-03-01

    Porophyllum tagetoides is an annual warm-weather herb that has an intense typical smell. Its leaves are commonly used in soup preparation and traditional medicine for treatment of inflammatory diseases. Its volatile compounds and antioxidant properties were evaluated in crude, aqueous and ethanol leaf extract and an oil emulsion using different antioxidant assays in vitro, such as: DPPH radical scavenging activity, redox potential, polyphenol content, reducing power and optical density. A high antioxidative activity was found when comparing leaves with stems. The crude extract from leaves showed a very high reducing power (2.88 ± 0.20 O.D.) and DPPH radical-scavenging activity (54.63 ± 4.80%), in concordance with a major concentration of vitamin C (23.97 ± 0.36 mg/100 g). Instead, the highest polyphenol content (264.54 ± 2.17 mg GAE/g of sample) and redox potential (561.23 ± 0.15 mV) were found by the ethanol and aqueous extract, respectively. Aldehydes and terpenes such as nonanal, decanal, trans-pineno, β-myrcene and D-limonene were the major volatiles found. This study suggests that Porophyllum tagetoides extracts could be used as antioxidants. PMID:22318745

  19. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity.

    PubMed

    McMillin, Douglas W; Delmore, Jake; Weisberg, Ellen; Negri, Joseph M; Geer, D Corey; Klippel, Steffen; Mitsiades, Nicholas; Schlossman, Robert L; Munshi, Nikhil C; Kung, Andrew L; Griffin, James D; Richardson, Paul G; Anderson, Kenneth C; Mitsiades, Constantine S

    2010-04-01

    Conventional anticancer drug screening is typically performed in the absence of accessory cells of the tumor microenvironment, which can profoundly alter antitumor drug activity. To address this limitation, we developed the tumor cell-specific in vitro bioluminescence imaging (CS-BLI) assay. Tumor cells (for example, myeloma, leukemia and solid tumors) stably expressing luciferase are cultured with nonmalignant accessory cells (for example, stromal cells) for selective quantification of tumor cell viability, in presence versus absence of stromal cells or drug treatment. CS-BLI is high-throughput scalable and identifies stroma-induced chemoresistance in diverse malignancies, including imatinib resistance in leukemic cells. A stroma-induced signature in tumor cells correlates with adverse clinical prognosis and includes signatures for activated Akt, Ras, NF-kappaB, HIF-1alpha, myc, hTERT and IRF4; for biological aggressiveness; and for self-renewal. Unlike conventional screening, CS-BLI can also identify agents with increased activity against tumor cells interacting with stroma. One such compound, reversine, shows more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. Use of CS-BLI, therefore, enables refined screening of candidate anticancer agents to enrich preclinical pipelines with potential therapeutics that overcome stroma-mediated drug resistance and can act in a synthetic lethal manner in the context of tumor-stroma interactions. PMID:20228816

  20. A high-content EMT screen identifies multiple receptor tyrosine kinase inhibitors with activity on TGFβ receptor.

    PubMed

    Lotz-Jenne, Carina; Lüthi, Urs; Ackerknecht, Sabine; Lehembre, François; Fink, Tobias; Stritt, Manuel; Wirth, Matthias; Pavan, Simona; Bill, Ruben; Regenass, Urs; Christofori, Gerhard; Meyer-Schaller, Nathalie

    2016-05-01

    An epithelial to mesenchymal transition (EMT) enables epithelial tumor cells to break out of the primary tumor mass and to metastasize. Understanding the molecular mechanisms driving EMT in more detail will provide important tools to interfere with the metastatic process. To identify pharmacological modulators and druggable targets of EMT, we have established a novel multi-parameter, high-content, microscopy-based assay and screened chemical compounds with activities against known targets. Out of 3423 compounds, we have identified 19 drugs that block transforming growth factor beta (TGFβ)-induced EMT in normal murine mammary gland epithelial cells (NMuMG). The active compounds include inhibitors against TGFβ receptors (TGFBR), Rho-associated protein kinases (ROCK), myosin II, SRC kinase and uridine analogues. Among the EMT-repressing compounds, we identified a group of inhibitors targeting multiple receptor tyrosine kinases, and biochemical profiling of these multi-kinase inhibitors reveals TGFBR as a thus far unknown target of their inhibitory spectrum. These findings demonstrate the feasibility of a multi-parameter, high-content microscopy screen to identify modulators and druggable targets of EMT. Moreover, the newly discovered "off-target" effects of several receptor tyrosine kinase inhibitors have important consequences for in vitro and in vivo studies and might beneficially contribute to the therapeutic effects observed in vivo. PMID:27036020

  1. Pharmacologically active compounds in the Anoectochilus and Goodyera species.

    PubMed

    Du, Xiao-Ming; Irino, Nobuto; Furusho, Norihiro; Hayashi, Jun; Shoyama, Yukihiro

    2008-04-01

    The extract of Anoectochilus formosanus showed significant activity in decreasing the levels of the cytosolic enzymes LDH, GOT, and GPT, and the result demonstrated that A. formosanus possessed prominent hepatoprotective activity against CCl(4)-induced hepatotoxicity. Moreover, in the results of the test using aurothioglucose-induced obese mice, the extract showed a significant antihyperliposis effect. A. formosanus grown in the wild and propagated by tissue culture contain ten compounds, including a major known component, (3R)-3-(beta-D-glucopyranosyloxy)butanolide (kinsenoside; 1), and two new components, (3R)-3-(beta-D-glucopyranosyloxy)-4-hydroxybutanoic acid (2) and 2-[(beta-D-glucopyranosyloxy)methyl]-5-hydroxymethylfuran (3), along with the known compounds, isopropyl-beta-D-glucopyranoside (4), (R)-3,4-dihydroxybutanoic acid gamma-lactone (5), 4-(beta-D-glucopyranosyloxy) benzyl alcohol (6), (6R,9S)-9-(beta-D-glucopyranosyloxy)megastigma-4,7-dien-3-one (7), and (3R)-3-(beta-D-glucopyranosyloxy)-4-hydroxybutanolide (8). Since a higher concentration of kinsenoside (1) was detected in the crude drugs A. formosanus and A. koshunensis by high-performance liquid chromatography (HPLC) analysis, we proved a simple purification system for kinsenoside (1), giving 180 mg of kinsenoside (1) from 1 g of dried samples for further pharmacological experiments. In an anti-hyperliposis assay using high-fat-diet rats, 1 significantly reduced the weights of the body and the liver, and also decreased the triglyceride level in the liver compared to those of control rats. On the other hand, the epimer of 1, (3S)-3-(beta-D-glucopyranosyloxy)butanolide, goodyeroside A (9), which was isolated from the Goodyera species, had no effect for anti-hyperliposis. In aurothioglucose-induced obese mice, 1 suppressed the body and liver weight increase, significantly ameliorated the triglyceride level in the liver, and also reduced the deposition of uterine fat pads. The anti

  2. Antioxidative Activities and Active Compounds of Extracts from Catalpa Plant Leaves

    PubMed Central

    Xu, Hongyu; Hu, Gege; Dong, Juane; Wei, Qin; Shao, Hongbo; Lei, Ming

    2014-01-01

    In order to screen the Catalpa plant with high antioxidant activity and confirm the corresponding active fractions from Catalpa ovata G. Don, C. fargesii Bur., and C. bungei C. A. Mey., total flavonoid contents and antioxidant activities of the extracts/fractions of Catalpa plant leaves were determined. The determined total flavonoid content and antioxidant activity were used as assessment criteria. Those compounds with antioxidant activity were isolated with silica gel column chromatography and ODS column chromatography. Our results showed that the total flavonoid content in C. bungei C. A. Mey. (30.07 mg/g·DW) was the highest, followed by those in C. fargesii Bur. (25.55 mg/g·DW) and C. ovata G. Don (24.96 mg/g·DW). According to the determination results of total flavonoid content and antioxidant activity in 3 clones of leaves of C. bungei C. A. Mey., the total flavonoid content and antioxidant activity in crude extracts from C. bungei C. A. Mey. 6 (CA6) leaves were the highest. Moreover, the results showed that the total flavonoid content and antioxidant activities of ethyl acetate (EA) fraction in ethanol crude extracts in CA6 leaves were the highest, followed by n-butanol, petroleum ether (PE), and water fractions. Two flavonoid compounds with antioxidant activity were firstly isolated based on EA fraction. The two compounds were luteolin (1) and apigenin (2), respectively. PMID:25431795

  3. Antioxidative activities and active compounds of extracts from Catalpa plant leaves.

    PubMed

    Xu, Hongyu; Hu, Gege; Dong, Juane; Wei, Qin; Shao, Hongbo; Lei, Ming

    2014-01-01

    In order to screen the Catalpa plant with high antioxidant activity and confirm the corresponding active fractions from Catalpa ovata G. Don, C. fargesii Bur., and C. bungei C. A. Mey., total flavonoid contents and antioxidant activities of the extracts/fractions of Catalpa plant leaves were determined. The determined total flavonoid content and antioxidant activity were used as assessment criteria. Those compounds with antioxidant activity were isolated with silica gel column chromatography and ODS column chromatography. Our results showed that the total flavonoid content in C. bungei C. A. Mey. (30.07 mg/g · DW) was the highest, followed by those in C. fargesii Bur. (25.55 mg/g · DW) and C. ovata G. Don (24.96 mg/g · DW). According to the determination results of total flavonoid content and antioxidant activity in 3 clones of leaves of C. bungei C. A. Mey., the total flavonoid content and antioxidant activity in crude extracts from C. bungei C. A. Mey. 6 (CA6) leaves were the highest. Moreover, the results showed that the total flavonoid content and antioxidant activities of ethyl acetate (EA) fraction in ethanol crude extracts in CA6 leaves were the highest, followed by n-butanol, petroleum ether (PE), and water fractions. Two flavonoid compounds with antioxidant activity were firstly isolated based on EA fraction. The two compounds were luteolin (1) and apigenin (2), respectively. PMID:25431795

  4. Phenolic Profiles and Contribution of Individual Compounds to Antioxidant Activity of Apple Powders.

    PubMed

    Raudone, Lina; Raudonis, Raimondas; Liaudanskas, Mindaugas; Viskelis, Jonas; Pukalskas, Audrius; Janulis, Valdimaras

    2016-05-01

    Apples (Malus domestica L.) are the most common source of phenolic compounds in northern European diet. Besides pectins, dietary fibers, vitamins, and oligosaccharides they contain phenolic compounds of different classes. Apple powders are convenient functional forms retaining significant amounts of phenolic antioxidants. In this study reducing and radical scavenging profiles of freeze-dried powders of "Aldas,ˮ "Auksis,ˮ "Connel Red,ˮ "Ligol,ˮ "Lodel,ˮ and "Rajkaˮ were determined and phenolic constituents were identified using ultra high-performance liquid chromatography coupled to quadrupole and time-of-flight mass spectrometers. A negative ionization mode was applied and seventeen compounds: phenolic acids (coumaroylquinic, chlorogenic), flavonoids (quercetin derivatives), and procyanidin derivatives (B1, B2, and C1) were identified in all tested apple samples. Total values of Trolox equivalents varied from 7.72 ± 0.32 up to 20.02 ± 0.52 and from 11.10 ± 0.57 up to 21.42 ± 0.75 μmol/g of dry weight of apple powder in FRAP (ferric reducing antioxidant power) and ABTS (2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) postcolumn assays, respectively. The greatest Trolox equivalent values were determined for apples of "Aldasˮ cultivar. Chlorogenic acid and procyanidin C1 were the most significant contributors to total reducing and radical scavenging activity in all apple cultivars tested, therefore they could be considered as markers of antioxidant activity. PMID:27002313

  5. Activation of human peripheral blood mononuclear cells by nitric oxide-generating compounds

    SciTech Connect

    Lander, H.M.; Sehajpal, P.; Levine, D.M.; Novogrodsky, A. )

    1993-02-15

    Recent work in this laboratory has identified immune-stimulatory properties of the oxidant hemin. In this study, the authors examined whether the nitrogen-based oxidant nitric oxide (NO) had inductive effects on human lymphocytes. They found that the NO-generating compounds sodium nitroprusside and S-nitroso-N acetylpenicillamine rapidly enhanced the rate of glucose transport in resting human PBMC. In addition, NF-[kappa]B binding activity was induced by these agents as was the secretion of TNF-[alpha]. The data suggest that a cGMP-independent mechanism is involved as the cell permeant cGMP analogue, 8-Br-cGMP, had no effect in eliciting these inductive events. Activation of lymphocytes by these NO-generating compounds may be mediated through the protein tyrosine phosphorylation signal transduction pathway. It was found that membrane-associated protein tyrosine phosphatase activity was enhanced in PBMC treated with sodium nitroprusside or S-nitroso-N-acetylpenicillamine and that the src family protein tyrosine kinase p56[sup lck] was activated in these cells. Inasmuch as p56[sup lck] activity is negatively controlled by tyrosine phosphorylation, its activation may be related to the enhancement of protein tyrosine phosphatase activity. 8Br-cGMP had no effect on these enzymes. Taken together, these data suggest that NO may have immune-stimulatory properties and may signal through a hitherto undescribed cGMP-independent pathway. 30 refs., 9 figs., 2 tabs.

  6. Involvement of antioxidant activity of Lactobacillus plantarum on functional properties of olive phenolic compounds.

    PubMed

    Kachouri, Faten; Ksontini, Hamida; Kraiem, Manel; Setti, Khaoula; Mechmeche, Manel; Hamdi, Moktar

    2015-12-01

    Eight lactic acid bacteria strains isolated from traditional fermented foods were investigated for their antioxidant activity against DPPH free radicals, β-carotene bleaching assay and linoleic acid test. L. plantarum LAB 1 at a dose of 8.2 10(9) CFU/ml showed the highest DPPH scavenging activity, with inhibition rate of 57.07 ± 0.57 % and an antioxidant activity (TAA = 43.47 ± 0.663 % and AAC = 172.65 ± 5.57), which increase with cell concentrations. When L. plantarum LAB 1 was administered to oxidative enzymes, residual activities decreased significantly with cell concentrations. The use of L. plantarum LAB 1 on olives process, favours the increase of the antioxidant activity (24 %). HPLC results showed a significant increase of orthodiphenols (74 %). Viable cells of strain were implicated directly on minimum media growth with 500 mg/l of olive phenolic compounds. Results showed an increase in their antioxidant activity. CG-SM analysis, identify the presence of compounds with higher antioxidant activity as vinyl phenol and hydroxytyrosol. PMID:26604364

  7. Computational Method for the Systematic Identification of Analog Series and Key Compounds Representing Series and Their Biological Activity Profiles.

    PubMed

    Stumpfe, Dagmar; Dimova, Dilyana; Bajorath, Jürgen

    2016-08-25

    A computational methodology is introduced for detecting all unique series of analogs in large compound data sets, regardless of chemical relationships between analogs. No prior knowledge of core structures or R-groups is required, which are automatically determined. The approach is based upon the generation of retrosynthetic matched molecular pairs and analog networks from which distinct series are isolated. The methodology was applied to systematically extract more than 17 000 distinct series from the ChEMBL database. For comparison, analog series were also isolated from screening compounds and drugs. Known biological activities were mapped to series from ChEMBL, and in more than 13 000 of these series, key compounds were identified that represented substitution sites of all analogs within a series and its complete activity profile. The analog series, key compounds, and activity profiles are made freely available as a resource for medicinal chemistry applications. PMID:27501131

  8. Pomegranate fruit as a rich source of biologically active compounds.

    PubMed

    Sreekumar, Sreeja; Sithul, Hima; Muraleedharan, Parvathy; Azeez, Juberiya Mohammed; Sreeharshan, Sreeja

    2014-01-01

    Pomegranate is a widely used plant having medicinal properties. In this review, we have mainly focused on the already published data from our laboratory pertaining to the effect of methanol extract of pericarp of pomegranate (PME) and have compared it with other relevant literatures on Punica. Earlier, we had shown its antiproliferative effect using human breast (MCF-7, MDA MB-231), and endometrial (HEC-1A), cervical (SiHa, HeLa), and ovarian (SKOV3) cancer cell lines, and normal breast fibroblasts (MCF-10A) at concentration of 20-320 μg/mL. The expressions of selected estrogen responsive genes (PR, pS2, and C-Myc) were downregulated by PME. Unlike estradiol, PME did not increase the uterine weight and proliferation in bilaterally ovariectomized Swiss-Albino mice models and its cardioprotective effects were comparable to that of 17 β -estradiol. We had further assessed the protective role of PME on skeletal system, using MC3T3-E1 cells. The results indicated that PME (80 μg/mL) significantly increased ALP (Alkaline Phosphatase) activity, supporting its suggested role in modulating osteoblastic cell differentiation. The antiosteoporotic potential of PME was also evaluated in ovariectomized (OVX) rodent model. The results from our studies and from various other studies support the fact that pomegranate fruit is indeed a source of biologically active compounds. PMID:24818149

  9. Acaricidal Activity of Eugenol Based Compounds against Scabies Mites

    PubMed Central

    Pasay, Cielo; Mounsey, Kate; Stevenson, Graeme; Davis, Rohan; Arlian, Larry; Morgan, Marjorie; Vyszenski-Moher, DiAnn; Andrews, Kathy; McCarthy, James

    2010-01-01

    Backgound Human scabies is a debilitating skin disease caused by the “itch mite” Sarcoptes scabiei. Ordinary scabies is commonly treated with topical creams such as permethrin, while crusted scabies is treated with topical creams in combination with oral ivermectin. Recent reports of acaricide tolerance in scabies endemic communities in Northern Australia have prompted efforts to better understand resistance mechanisms and to identify potential new acaricides. In this study, we screened three essential oils and four pure compounds based on eugenol for acaricidal properties. Methodology/Principal Findings Contact bioassays were performed using live permethrin-sensitive S. scabiei var suis mites harvested from pigs and permethrin-resistant S. scabiei var canis mites harvested from rabbits. Results of bioassays showed that clove oil was highly toxic against scabies mites. Nutmeg oil had moderate toxicity and ylang ylang oil was the least toxic. Eugenol, a major component of clove oil and its analogues –acetyleugenol and isoeugenol, demonstrated levels of toxicity comparable to benzyl benzoate, the positive control acaricide, killing mites within an hour of contact. Conclusions The acaricidal properties demonstrated by eugenol and its analogues show promise as leads for future development of alternative topical acaricides to treat scabies. PMID:20711455

  10. Characterization of the most aroma-active compounds in cherry tomato by application of the aroma extract dilution analysis.

    PubMed

    Selli, Serkan; Kelebek, Hasim; Ayseli, Mehmet Turan; Tokbas, Habip

    2014-12-15

    Aroma and aroma-active compounds of cherry tomato (Lycopersicum esculentum) was analyzed by gas chromatography-mass spectrometry-olfactometry (GC-MS-O). According to sensory analysis, the aromatic extract obtained by liquid-liquid extraction was representative of tomato odour. A total of 49 aroma compounds were identified and quantified in fresh cherry tomato. Aldehydes were qualitatively and quantitatively the most dominant volatiles in cherry tomato, followed by alcohols. Aroma extract dilution analysis (AEDA) was used for the determination of aroma-active compounds of tomato sample. A total of 21 aroma-active compounds were detected in aromatic extract of fresh tomato, of which 18 were identified. On the basis of the flavour dilution (FD) factor, the most powerful aroma-active compounds identified in the extract were (Z)-3-hexenal (FD=1024) and (E)-2-hexenal (FD=256), which were described as the strong green-grassy and green-leafy odour, respectively. The major organic acid and sugar found were citric acid and fructose, respectively. PMID:25038709

  11. Management Development Program. Preliminary Organizing Structure for Identifying Educational Activities.

    ERIC Educational Resources Information Center

    Cloud, Sherrill

    The Management Development Program, which was designed to address the needs of executive-level administrators of higher education, is described. The program was developed by the National Center for Higher Education Management Systems (NCHEMS). Seven limitations of executive-level administrators are identified, along with the capabilities of NCHEMS…

  12. In silico inhibition of GABARAP activity using antiepileptic medicinal derived compounds

    PubMed Central

    Mathew, Shilu; Faheem, Muhammad; Al-Malki, Abdulrahman L; Kumosani, Taha A; Qadri, Ishtiaq

    2015-01-01

    Epilepsy is a neurological disorder affecting more than 50 million people worldwide. It can be controlled by antiepileptic drugs (AEDs) but more than 30% patients are still resistant to AEDs. To overcome this problem, researchers are trying to develop novel approaches to treat epilepsy including the use of herbal medicines. The γ-amino butyric acid type-A receptor associated protein (GABARAP) is ubiquitin-like modifier implicated in the intracellular trafficking of GABAAR. An in silico mutation was created at 116 amino acid position G116A, and an in silico study was carried out to identify the potential binding inhibitors (with antiepileptic properties) against the active sites of GABARAP. Five different plant derived compounds namely (a) Aconitine (b) Berberine (c) Montanine (d) Raubasine (e) Safranal were selected, and their quantitative structure-activity relationships (QSAR) have been conducted to search the inhibitory activity of the selected compounds. The results have shown maximum number of hydrogen bond (H-bond) interactions of Raubasine with highest interaction energy among all of the five compounds. So, Raubasine could be the best fit ligand of GABARAP but in vitro, and in vivo studies are necessary for further confirmation. PMID:26124559

  13. Inhibition of Peroxidase Activity of Cytochrome c: De Novo Compound Discovery and Validation

    PubMed Central

    Bakan, Ahmet; Kapralov, Alexandr A.; Bayir, Hulya; Hu, Feizhou; Kagan, Valerian E.

    2015-01-01

    Cytochrome c (cyt c) release from mitochondria is accepted to be the point of no return for eliciting a cascade of interactions that lead to apoptosis. A strategy for containing sustained apoptosis is to reduce the mitochondrial permeability pore opening. Pore opening is enhanced by peroxidase activity of cyt c gained upon its complexation with cardiolipin in the presence of reactive oxygen species. Blocking access to the heme group has been proposed as an effective intervention method for reducing, if not eliminating, the peroxidase activity of cyt c. In the present study, using a combination of druggability simulations, pharmacophore modeling, virtual screening, and in vitro fluorescence measurements to probe peroxidase activity, we identified three repurposable drugs and seven compounds that are validated to effectively inhibit the peroxidase activity of cyt c. PMID:26078313

  14. Liquid-phase adsorption of organic compounds by granular activated carbon and activated carbon fibers

    SciTech Connect

    Lin, S.H.; Hsu, F.M.

    1995-06-01

    Liquid-phase adsorption of organic compounds by granular activated carbon (GAC) and activated carbon fibers (ACFs) is investigated. Acetone, isopropyl alcohol (IPA), phenol, and tetrahydrofuran (THF) were employed as the model compounds for the present study. It is observed from the experimental results that adsorption of organic compounds by GAC and ACF is influenced by the BET (Brunauer-Emmett-Teller) surface area of adsorbent and the molecular weight, polarity, and solubility of the adsorbate. The adsorption characteristics of GAC and ACFs were found to differ rather significantly. In terms of the adsorption capacity of organic compounds, the time to reach equilibrium adsorption, and the time for complete desorption, ACFs have been observed to be considerably better than GAC. For the organic compounds tested here, the GAC adsorptions were shown to be represented well by the Langmuir isotherm while the ACF adsorption could be adequately described by the Langmuir or the Freundlich isotherm. Column adsorption tests indicated that the exhausted ACFs can be effectively regenerated by static in situ thermal desorption at 150 C, but the same regeneration conditions do not do as well for the exhausted GAC.

  15. Identification, characterization and HPLC quantification of process-related impurities in Trelagliptin succinate bulk drug: Six identified as new compounds.

    PubMed

    Zhang, Hui; Sun, Lili; Zou, Liang; Hui, Wenkai; Liu, Lei; Zou, Qiaogen; Ouyang, Pingkai

    2016-09-01

    A sensitive, selective and stability indicating reversed-phase LC method was developed for the determination of process related impurities of Trelagliptin succinate in bulk drug. Six impurities were identified by LC-MS. Further, their structures were characterized and confirmed utilizing LC-MS/MS, IR and NMR spectral data. The most probable mechanisms for the formation of these impurities were also discussed. To the best of our knowledge, six structures among these impurities are new compounds and have not been reported previously. The superior separation was achieved on an InertSustain C18 (250mm×4.6mm, 5μm) column in a gradient mixture of acetonitrile and 20mmol potassium dihydrogen phosphate with 0.25% triethylamine (pH adjusted to 3.5 with phosphate acid). The method was validated as per regulatory guidelines to demonstrate system suitability, specificity, sensitivity, linearity, robustness, and stability. PMID:27209451

  16. Tetrandrine identified in a small molecule screen to activate mesenchymal stem cells for enhanced immunomodulation

    PubMed Central

    Yang, Zijiang; Concannon, John; Ng, Kelvin S.; Seyb, Kathleen; Mortensen, Luke J.; Ranganath, Sudhir; Gu, Fangqi; Levy, Oren; Tong, Zhixiang; Martyn, Keir; Zhao, Weian; Lin, Charles P.; Glicksman, Marcie A.; Karp, Jeffrey M.

    2016-01-01

    Pre-treatment or priming of mesenchymal stem cells (MSC) prior to transplantation can significantly augment the immunosuppressive effect of MSC-based therapies. In this study, we screened a library of 1402 FDA-approved bioactive compounds to prime MSC. We identified tetrandrine as a potential hit that activates the secretion of prostaglandin E2 (PGE2), a potent immunosuppressive agent, by MSC. Tetrandrine increased MSC PGE2 secretion through the NF-κB/COX-2 signaling pathway. When co-cultured with mouse macrophages (RAW264.7), tetrandrine-primed MSC attenuated the level of TNF-α secreted by RAW264.7. Furthermore, systemic transplantation of primed MSC into a mouse ear skin inflammation model significantly reduced the level of TNF-α in the inflamed ear, compared to unprimed cells. Screening of small molecules to pre-condition cells prior to transplantation represents a promising strategy to boost the therapeutic potential of cell therapy. PMID:27457881

  17. Tetrandrine identified in a small molecule screen to activate mesenchymal stem cells for enhanced immunomodulation.

    PubMed

    Yang, Zijiang; Concannon, John; Ng, Kelvin S; Seyb, Kathleen; Mortensen, Luke J; Ranganath, Sudhir; Gu, Fangqi; Levy, Oren; Tong, Zhixiang; Martyn, Keir; Zhao, Weian; Lin, Charles P; Glicksman, Marcie A; Karp, Jeffrey M

    2016-01-01

    Pre-treatment or priming of mesenchymal stem cells (MSC) prior to transplantation can significantly augment the immunosuppressive effect of MSC-based therapies. In this study, we screened a library of 1402 FDA-approved bioactive compounds to prime MSC. We identified tetrandrine as a potential hit that activates the secretion of prostaglandin E2 (PGE2), a potent immunosuppressive agent, by MSC. Tetrandrine increased MSC PGE2 secretion through the NF-κB/COX-2 signaling pathway. When co-cultured with mouse macrophages (RAW264.7), tetrandrine-primed MSC attenuated the level of TNF-α secreted by RAW264.7. Furthermore, systemic transplantation of primed MSC into a mouse ear skin inflammation model significantly reduced the level of TNF-α in the inflamed ear, compared to unprimed cells. Screening of small molecules to pre-condition cells prior to transplantation represents a promising strategy to boost the therapeutic potential of cell therapy. PMID:27457881

  18. Cytochrome P450-mediated activation of the fragrance compound geraniol forms potent contact allergens

    SciTech Connect

    Hagvall, Lina; Baron, Jens Malte; Boerje, Anna; Weidolf, Lars; Merk, Hans; Karlberg, Ann-Therese

    2008-12-01

    Contact sensitization is caused by low molecular weight compounds which penetrate the skin and bind to protein. In many cases, these compounds are activated to reactive species, either by autoxidation on exposure to air or by metabolic activation in the skin. Geraniol, a widely used fragrance chemical, is considered to be a weak allergen, although its chemical structure does not indicate it to be a contact sensitizer. We have shown that geraniol autoxidizes and forms allergenic oxidation products. In the literature, it is suggested but not shown that geraniol could be metabolically activated to geranial. Previously, a skin-like CYP cocktail consisting of cutaneous CYP isoenzymes, was developed as a model system to study cutaneous metabolism. In the present study, we used this system to investigate CYP-mediated activation of geraniol. In incubations with the skin-like CYP cocktail, geranial, neral, 2,3-epoxygeraniol, 6,7-epoxygeraniol and 6,7-epoxygeranial were identified. Geranial was the main metabolite formed followed by 6,7-epoxygeraniol. The allergenic activities of the identified metabolites were determined in the murine local lymph node assay (LLNA). Geranial, neral and 6,7-epoxygeraniol were shown to be moderate sensitizers, and 6,7-epoxygeranial a strong sensitizer. Of the isoenzymes studied, CYP2B6, CYP1A1 and CYP3A5 showed high activities. It is likely that CYP1A1 and CYP3A5 are mainly responsible for the metabolic activation of geraniol in the skin, as they are expressed constitutively at significantly higher levels than CYP2B6. Thus, geraniol is activated through both autoxidation and metabolism. The allergens geranial and neral are formed via both oxidation mechanisms, thereby playing a large role in the sensitization to geraniol.

  19. Tracking heavy water (D2O) incorporation for identifying and sorting active microbial cells

    PubMed Central

    Berry, David; Mader, Esther; Lee, Tae Kwon; Woebken, Dagmar; Wang, Yun; Zhu, Di; Palatinszky, Marton; Schintlmeister, Arno; Schmid, Markus C.; Hanson, Buck T.; Shterzer, Naama; Mizrahi, Itzhak; Rauch, Isabella; Decker, Thomas; Bocklitz, Thomas; Popp, Jürgen; Gibson, Christopher M.; Fowler, Patrick W.; Huang, Wei E.; Wagner, Michael

    2015-01-01

    Microbial communities are essential to the function of virtually all ecosystems and eukaryotes, including humans. However, it is still a major challenge to identify microbial cells active under natural conditions in complex systems. In this study, we developed a new method to identify and sort active microbes on the single-cell level in complex samples using stable isotope probing with heavy water (D2O) combined with Raman microspectroscopy. Incorporation of D2O-derived D into the biomass of autotrophic and heterotrophic bacteria and archaea could be unambiguously detected via C-D signature peaks in single-cell Raman spectra, and the obtained labeling pattern was confirmed by nanoscale-resolution secondary ion MS. In fast-growing Escherichia coli cells, label detection was already possible after 20 min. For functional analyses of microbial communities, the detection of D incorporation from D2O in individual microbial cells via Raman microspectroscopy can be directly combined with FISH for the identification of active microbes. Applying this approach to mouse cecal microbiota revealed that the host-compound foragers Akkermansia muciniphila and Bacteroides acidifaciens exhibited distinctive response patterns to amendments of mucin and sugars. By Raman-based cell sorting of active (deuterated) cells with optical tweezers and subsequent multiple displacement amplification and DNA sequencing, novel cecal microbes stimulated by mucin and/or glucosamine were identified, demonstrating the potential of the nondestructive D2O-Raman approach for targeted sorting of microbial cells with defined functional properties for single-cell genomics. PMID:25550518

  20. Tracking heavy water (D2O) incorporation for identifying and sorting active microbial cells.

    PubMed

    Berry, David; Mader, Esther; Lee, Tae Kwon; Woebken, Dagmar; Wang, Yun; Zhu, Di; Palatinszky, Marton; Schintlmeister, Arno; Schmid, Markus C; Hanson, Buck T; Shterzer, Naama; Mizrahi, Itzhak; Rauch, Isabella; Decker, Thomas; Bocklitz, Thomas; Popp, Jürgen; Gibson, Christopher M; Fowler, Patrick W; Huang, Wei E; Wagner, Michael

    2015-01-13

    Microbial communities are essential to the function of virtually all ecosystems and eukaryotes, including humans. However, it is still a major challenge to identify microbial cells active under natural conditions in complex systems. In this study, we developed a new method to identify and sort active microbes on the single-cell level in complex samples using stable isotope probing with heavy water (D2O) combined with Raman microspectroscopy. Incorporation of D2O-derived D into the biomass of autotrophic and heterotrophic bacteria and archaea could be unambiguously detected via C-D signature peaks in single-cell Raman spectra, and the obtained labeling pattern was confirmed by nanoscale-resolution secondary ion MS. In fast-growing Escherichia coli cells, label detection was already possible after 20 min. For functional analyses of microbial communities, the detection of D incorporation from D2O in individual microbial cells via Raman microspectroscopy can be directly combined with FISH for the identification of active microbes. Applying this approach to mouse cecal microbiota revealed that the host-compound foragers Akkermansia muciniphila and Bacteroides acidifaciens exhibited distinctive response patterns to amendments of mucin and sugars. By Raman-based cell sorting of active (deuterated) cells with optical tweezers and subsequent multiple displacement amplification and DNA sequencing, novel cecal microbes stimulated by mucin and/or glucosamine were identified, demonstrating the potential of the nondestructive D2O-Raman approach for targeted sorting of microbial cells with defined functional properties for single-cell genomics. PMID:25550518

  1. Using perturbations to identify the brain circuits underlying active vision

    PubMed Central

    Wurtz, Robert H.

    2015-01-01

    The visual and oculomotor systems in the brain have been studied extensively in the primate. Together, they can be regarded as a single brain system that underlies active vision—the normal vision that begins with visual processing in the retina and extends through the brain to the generation of eye movement by the brainstem. The system is probably one of the most thoroughly studied brain systems in the primate, and it offers an ideal opportunity to evaluate the advantages and disadvantages of the series of perturbation techniques that have been used to study it. The perturbations have been critical in moving from correlations between neuronal activity and behaviour closer to a causal relation between neuronal activity and behaviour. The same perturbation techniques have also been used to tease out neuronal circuits that are related to active vision that in turn are driving behaviour. The evolution of perturbation techniques includes ablation of both cortical and subcortical targets, punctate chemical lesions, reversible inactivations, electrical stimulation, and finally the expanding optogenetic techniques. The evolution of perturbation techniques has supported progressively stronger conclusions about what neuronal circuits in the brain underlie active vision and how the circuits themselves might be organized. PMID:26240420

  2. Antiproliferative and cell apoptosis-inducing activities of compounds from Buddleja davidii in Mgc-803 cells

    PubMed Central

    2012-01-01

    Background Buddleja davidii is widely distributed in the southwestern region of China. We have undertaken a systematic analysis of B. davidii as a Chinese traditional medicine with anticancer activity by isolating natural products for their activity against the human gastric cancer cell line Mgc-803 and the human breast cancer cell line Bcap-37. Results Ten compounds were extracted and isolated from B. davidii, among which colchicine was identified in B. davidii for the first time. The inhibitory activities of these compounds were investigated in Mgc-803, Bcap-37 cells in vitro by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, and the results showed that luteolin and colchicine had potent inhibitory activities against the growth of Mgc-803 cells. Subsequent fluorescence staining and flow cytometry analysis indicated that these two compounds could induce apoptosis in Mgc-803 cells. The results also showed that the percentages of early apoptotic cells (Annexin V+/PI-, where PI is propidium iodide) and late apoptotic cells (Annexin V+/PI+) increased in a dose- and time-dependent manner. After 36 h of incubation with luteolin at 20 μM, the percentages of cells were approximately 15.4% in early apoptosis and 43.7% in late apoptosis; after 36 h of incubation with colchicine at 20 μM, the corresponding values were 7.7% and 35.2%, respectively. Conclusions Colchicine and luteolin from B. davidii have potential applications as adjuvant therapies for treating human carcinoma cells. These compounds could also induce apoptosis in tumor cells. PMID:22938042

  3. A Network-Based Multi-Target Computational Estimation Scheme for Anticoagulant Activities of Compounds

    PubMed Central

    Li, Canghai; Chen, Lirong; Song, Jun; Tang, Yalin; Xu, Xiaojie

    2011-01-01

    Background Traditional virtual screening method pays more attention on predicted binding affinity between drug molecule and target related to a certain disease instead of phenotypic data of drug molecule against disease system, as is often less effective on discovery of the drug which is used to treat many types of complex diseases. Virtual screening against a complex disease by general network estimation has become feasible with the development of network biology and system biology. More effective methods of computational estimation for the whole efficacy of a compound in a complex disease system are needed, given the distinct weightiness of the different target in a biological process and the standpoint that partial inhibition of several targets can be more efficient than the complete inhibition of a single target. Methodology We developed a novel approach by integrating the affinity predictions from multi-target docking studies with biological network efficiency analysis to estimate the anticoagulant activities of compounds. From results of network efficiency calculation for human clotting cascade, factor Xa and thrombin were identified as the two most fragile enzymes, while the catalytic reaction mediated by complex IXa:VIIIa and the formation of the complex VIIIa:IXa were recognized as the two most fragile biological matter in the human clotting cascade system. Furthermore, the method which combined network efficiency with molecular docking scores was applied to estimate the anticoagulant activities of a serial of argatroban intermediates and eight natural products respectively. The better correlation (r = 0.671) between the experimental data and the decrease of the network deficiency suggests that the approach could be a promising computational systems biology tool to aid identification of anticoagulant activities of compounds in drug discovery. Conclusions This article proposes a network-based multi-target computational estimation method for

  4. Activation of HIV-1 with Nanoparticle-Packaged Small-Molecule Protein Phosphatase-1-Targeting Compound

    PubMed Central

    Smith, Kahli A.; Lin, Xionghao; Bolshakov, Oleg; Griffin, James; Niu, Xiaomei; Kovalskyy, Dmytro; Ivanov, Andrey; Jerebtsova, Marina; Taylor, Robert E.; Akala, Emmanuel; Nekhai, Sergei

    2015-01-01

    Complete eradication of HIV-1 infection is impeded by the existence of latent HIV-1 reservoirs in which the integrated HIV-1 provirus is transcriptionally inactive. Activation of HIV-1 transcription requires the viral Tat protein and host cell factors, including protein phosphatase-1 (PP1). We previously developed a library of small compounds that targeted PP1 and identified a compound, SMAPP1, which induced HIV-1 transcription. However, this compound has a limited bioavailability in vivo and may not be able to reach HIV-1-infected cells and induce HIV-1 transcription in patients. We packaged SMAPP1 in polymeric polyethylene glycol polymethyl methacrylate nanoparticles and analyzed its release and the effect on HIV-1 transcription in a cell culture. SMAPP1 was efficiently packaged in the nanoparticles and released during a 120-hr period. Treatment of the HIV-1-infected cells with the SMAPP1-loaded nanoparticles induced HIV-1 transcription. Thus, nanoparticles loaded with HIV-1-targeting compounds might be useful for future anti-HIV-1 therapeutics. PMID:26839837

  5. Fate of selected pharmaceutically active compounds during simulated riverbank filtration.

    PubMed

    D'Alessio, Matteo; Yoneyama, Bunnie; Ray, Chittaranjan

    2015-02-01

    The objective of this study was to investigate the effect of temperature, oxygen, and organic matter on the removal of selected pharmaceutically active compounds (PhACs) during simulated riverbank filtration (RBF). The behavior of six PhACs (caffeine, carbamazepine, 17-β estradiol [E2], estrone [E1], gemfibrozil, and phenazone) was evaluated by small flow-through column experiments. Results from our study showed that RBF can be used to treat many of the PhACs found in environmental waters. Local conditions at the RBF site, however, can affect the removal of PhACs and should be investigated. Biodegradation and sorption represented the predominant mechanisms involved during the removal of the selected PhACs. All selected PhACs showed limited and slower removal during the winter. Phenazone was highly impacted by the level of oxygen; complete depletion of phenazone below the analytical limit occurred only under aerobic conditions (dissolved oxygen >8 mg L(-1)). Caffeine and E2 were highly impacted by the presence of humic acid in the feed water. Caffeine and E2 were depleted below the detection limit in the presence of humic acid regardless of the temperature and the level of oxygen. E1 was impacted by the different environmental conditions and depletion below the detection limit occurred only during the summer under aerobic conditions. Carbamazepine (10%) and gemfibrozil (<30%) showed limited removal regardless of the different levels of temperature, oxygen and humic acid. PMID:25461064

  6. Biological surface-active compounds from marine bacteria.

    PubMed

    Dang, Nga Phuong; Landfald, Bjarne; Willassen, Nils Peder

    2016-01-01

    Surface-active compounds (SACs) are widely used in different industries as well as in many daily consumption products. However, with the increasing concern for their environmental acceptability, attention has turned towards biological SACs which are biodegradable, less toxic and more environmentally friendly. In this work, 176 marine hydrocarbon-degrading bacterial isolates from petroleum-contaminated sites along the Norwegian coastline were isolated and screened for their capacity to produce biological SACs. Among them, 18 isolates were capable of reducing the surface tension of the culture medium by at least 20 mN m(-1) and/or capable of maintaining more than 40% of the emulsion volume after 24 h when growing on glucose or kerosene as carbon and energy source. These isolates were members of the genera Pseudomonas, Pseudoalteromonas, Rhodococcus, Catenovulum, Cobetia, Glaciecola, Serratia, Marinomonas and Psychromonas. Two isolates, Rhodococcus sp. LF-13 and Rhodococcus sp. LF-22, reduced surface tension of culture medium by more than 40 mN m(-1) when growing on kerosene, n-hexadecane or rapeseed oil. The biosurfactants were produced by resting cells of the two Rhodococcus strains suggesting the biosynthesis of the biosurfactants was not necessarily associated with their growth on hydrocarbons. PMID:26506920

  7. Identification of active compounds from medicinal plant extracts using gas chromatography-mass spectrometry and multivariate data analysis.

    PubMed

    Ching, Jianhong; Soh, Wei-Li; Tan, Chay-Hoon; Lee, Jun-Feng; Tan, Jiun-Yu Christina; Yang, Jun; Yap, Chun-Wei; Koh, Hwee-Ling

    2012-01-01

    Conventional methods of drug discovery from natural products include bioassay-guided fractionation, which is tedious and has low efficiency. The aim of this work is to develop a platform method to rapidly identify bioactive compounds from crude plant extracts and their partially purified fractions using multivariate data analysis (MVDA). Soxhlet extraction and liquid-liquid fractionation were used to prepare different extracts and fractions from the leaves of a medicinal plant, Ardisia elliptica. The extracts and fractions were analysed chemically using GC-MS, and their ability to inhibit platelet aggregation was investigated. Two MVDA methods were developed and optimised to analyse the results. In the first method, compounds with the highest contribution scores for biological activity calculated by different models were listed as potential antiplatelet compounds. For the second MVDA method, a correlation of the concentrations of constituents and biological activities in the various extracts and fractions for each compound was done. Compounds with the highest correlation coefficients were identified as potential antiplatelet compounds. One of the predicted components was isolated, purified and confirmed to possess antiplatelet effects. This platform method can be developed and optimised for other plant extracts and biological activities, thus reducing time and cost of drug discovery while improving efficiency. PMID:22127806

  8. Activation Tagging Identifies a Conserved MYB Regulator of Phenylpropanoid Biosynthesis

    PubMed Central

    Borevitz, Justin O.; Xia, Yiji; Blount, Jack; Dixon, Richard A.; Lamb, Chris

    2000-01-01

    Plants produce a wide array of natural products, many of which are likely to be useful bioactive structures. Unfortunately, these complex natural products usually occur at very low abundance and with restricted tissue distribution, thereby hindering their evaluation. Here, we report a novel approach for enhancing the accumulation of natural products based on activation tagging by Agrobacterium-mediated transformation with a T-DNA that carries cauliflower mosaic virus 35S enhancer sequences at its right border. Among ∼5000 Arabidopsis activation-tagged lines, we found a plant that exhibited intense purple pigmentation in many vegetative organs throughout development. This upregulation of pigmentation reflected a dominant mutation that resulted in massive activation of phenylpropanoid biosynthetic genes and enhanced accumulation of lignin, hydroxycinnamic acid esters, and flavonoids, including various anthocyanins that were responsible for the purple color. These phenotypes, caused by insertion of the viral enhancer sequences adjacent to an MYB transcription factor gene, indicate that activation tagging can overcome the stringent genetic controls regulating the accumulation of specific natural products during plant development. Our findings suggest a functional genomics approach to the biotechnological evaluation of phytochemical biodiversity through the generation of massively enriched tissue sources for drug screening and for isolating underlying regulatory and biosynthetic genes. PMID:11148285

  9. Biological activity of terpene compounds produced by biotechnological methods.

    PubMed

    Paduch, Roman; Trytek, Mariusz; Król, Sylwia K; Kud, Joanna; Frant, Maciej; Kandefer-Szerszeń, Martyna; Fiedurek, Jan

    2016-06-01

    Context Biotransformation systems are profitable tools for structural modification of bioactive natural compounds into valuable biologically active terpenoids. Objective This study determines the biological effect of (R)-(+)-limonene and (-)-α-pinene, and their oxygenated derivatives, (a) perillyl alcohol and (S)-(+)- and (R)-(-)-carvone enantiomers and (b) linalool, trans-verbenol and verbenone, respectively, on human colon tumour cells and normal colonic epithelium. Materials and methods Biotransformation procedures and in vitro cell culture tests were used in this work. Cells were incubated for 24 h with terpenes at concentrations of 5-500 μg/mL for NR, MTT, DPPH, and NO assays. IL-6 was determined by ELISA with/without 2 h pre-activation with 10 μg/mL LPS. Results trans-Verbenol and perillyl alcohol, obtained via biotransformation, produced in vitro effect against tumour cells at lower concentrations (IC50 value = 77.8 and 98.8 μg/mL, respectively) than their monoterpene precursors, (R)-(+)-limonene (IC50 value = 171.4 μg/mL) and (-)-α-pinene (IC50 value = 206.3 μg/mL). They also showed lower cytotoxicity against normal cells (IC50 > 500 and > 200 μg/mL, respectively). (S)-(+)-Carvone was 59.4% and 27.1% more toxic to tumour and normal cells, respectively, than the (R)-(-)-enantiomer. (R)-(+)-limonene derivatives decreased IL-6 production from normal cells in media with or without LPS (30.2% and 13.9%, respectively), while (-)-α-pinene derivatives induced IL-6 (verbenone had the strongest effect, 60.2% and 29.1% above control, respectively). None of the terpenes had antioxidative activity below 500 μg/mL. Discussion and conclusions Bioactivity against tumour cells decreased in the following order: alcohols > ketones > hydrocarbons. (R)-(+)-limonene, (-)-α-pinene, and their derivatives expressed diverse activity towards normal and tumour cells with noticeable enantiomeric differences. PMID:26808720

  10. Volatile compounds of Lamiaceae exhibit a synergistic antibacterial activity with streptomycin

    PubMed Central

    Araújo, Sthéfane G.; Alves, Lucas F.; Pinto, Maria Eduarda A.; Oliveira, Graziela T.; Siqueira, Ezequias P.; Ribeiro, Rosy I. M. A.; Ferreira, Jaqueline M. S.; Lima, Luciana A. R. S.

    2014-01-01

    Bacterial infections cause thousands of deaths in the world every year. In most cases, infections are more serious because the patient is already weakened, and often, the bacteria are already resistant to the antibiotics used. Counterparting this negative scenario, the interest in medicinal plants as an alternative to the synthetic antimicrobial drugs is blossoming worldwide. In the present work, we identified the volatile compounds of ethanol extracts of Melissa officinalis, Mentha sp., Ocimum basilicum, Plectranthus barbatus, and Rosmarinus officinalis by gas chromatography/mass spectrometry (GC/MS). Also was evaluated antimicrobial activity of ethanol extracts against 6 bacteria of clinical interest, and was tested the interaction of these extracts with a commercial antibiotic streptomycin. Phytol was a compound identified in all extracts by GC/MS, being majoritary component in Plectranthus barbatus and Rosmarinus officinalis. The Gram-positive bacteria were more sensitive to ethanol extracts, and Plectranthus barbatus and Rosmarinus officinalis were the most active extracts. Ethanol extracts exhibited a synergetic effect with streptomycin. These results encourage additional studies, in order to evaluate the possibilities of using ethanol extracts of Lamiaceae family as natural source for antibacterial activity. PMID:25763039

  11. Caatinga plants: Natural and semi-synthetic compounds potentially active against Trichomonas vaginalis.

    PubMed

    Vieira, Patrícia de Brum; Silva, Nícolas Luiz Feijó; da Silva, Gloria Narjara Santos; Silva, Denise Brentan; Lopes, Norberto Peporine; Gnoatto, Simone Cristina Baggio; da Silva, Márcia Vanusa; Macedo, Alexandre José; Bastida, Jaume; Tasca, Tiana

    2016-05-01

    Trichomonas vaginalis causes trichomoniasis; the most common but overlooked non-viral sexually transmitted disease worldwide. The treatment is based at 5'-nitroimidazoles, however, failure are related to resistance of T. vaginalis to chemotherapy. Caatinga is a uniquely Brazilian region representing a biome with type desert vegetation and plants present diverse biological activity, however, with few studies. The aim of this study was to investigate the activity against T. vaginalis of different plants from Caatinga and identify the compounds responsible by the activity. A bioguided fractionation of Manilkara rufula was performed and four major compounds were identified: caproate of α-amyrin (1b), acetate of β-amyrin (2a), caproate of β-amyrin (2b), and acetate of lupeol (3a). In addition, six derivatives of α-amyrin (1), β-amyrin (2) and lupeol (3) were synthesized and tested against the parasite. Ursolic acid (5) reduced about 98% of parasite viability after 2h of incubation and drastic ultrastructural alterations were observed by scanning electron microscopy. Moreover, 5 presented high cytotoxicity to HMVII and HeLa cell line and low cytotoxicity against Vero line at 50 μM (MIC against the parasite). Metronidazole effect against T. vaginalis resistant isolate was improved when in association with 5. PMID:27020521

  12. Phenolic Compounds from Olea europaea L. Possess Antioxidant Activity and Inhibit Carbohydrate Metabolizing Enzymes In Vitro

    PubMed Central

    Dekdouk, Nadia; Malafronte, Nicola; Russo, Daniela; Faraone, Immacolata; De Tommasi, Nunziatina; Ameddah, Souad; Severino, Lorella; Milella, Luigi

    2015-01-01

    Phenolic composition and biological activities of fruit extracts from Italian and Algerian Olea europaea L. cultivars were studied. Total phenolic and tannin contents were quantified in the extracts. Moreover 14 different phenolic compounds were identified, and their profiles showed remarkable quantitative differences among analysed extracts. Moreover antioxidant and enzymatic inhibition activities were studied. Three complementary assays were used to measure their antioxidant activities and consequently Relative Antioxidant Capacity Index (RACI) was used to compare and easily describe obtained results. Results showed that Chemlal, between Algerian cultivars, and Coratina, among Italian ones, had the highest RACI values. On the other hand all extracts and the most abundant phenolics were tested for their efficiency to inhibit α-amylase and α-glucosidase enzymes. Leccino, among all analysed cultivars, and luteolin, among identified phenolic compounds, were found to be the best inhibitors of α-amylase and α-glucosidase enzymes. Results demonstrated that Olea europaea fruit extracts can represent an important natural source with high antioxidant potential and significant α-amylase and α-glucosidase inhibitory effects. PMID:26557862

  13. Virtual Screening of compounds from Tabernaemontana divaricata for potential anti-bacterial activity

    PubMed Central

    Gogoi, Rashmi Rekha; Gogoi, Dhrubajyoti; Bezbaruah, Rajib Lochan

    2014-01-01

    Virtual Screening and Molecular Docking analysis for Tabernaemontana divaricata derived 66 Law Molecular Weight Compounds (LMW) was conducted and to identified and predicted novel molecules as a inhibitor of Streptococcus pneumonia. The investigation has revealed several compounds with optimum binding towards Penicillin-binding proteins, Sialidases, Aspartate betasemialdehide dehydrogenase cell membrane protein of Streptococcus pneumonia. Docking results were computed in term of binding energy, ligand efficiency and number of hydrogen bonding. Apparicine (-5.14), 5-Hydroxyvoaphylline (-4.78), Voacangine (-4.7), 19-Hydroxycoronaridine (-4.44) and Coronaridine (-4.72) are identified as most suitable to bind with N-acetylglucosamine-1- phosphate uridyltransferase receptor. Ervaticine (-6.33), Ibogamine (-6.15), Methylvoaphylline (-5.74) and Coronaridine hydroxyindolenine (-5.32) has showed novel binding against the penicillin-binding proteins. Ervaticine (-6.42), 5-oxo-11-hydroxy voaphylline (-6.18), Conolobine B (-6.02) has found optimum binding against the active site of NanB sialidase of Streptococcus pneumonia. The compounds 3S-Cyanocoronaridine (-6.71), 19-Epivoacristine (-5.48) and Ervaticine(-5.45) interacting with aspartate beta-semialdehide and found suitable with least docking score. PMID:24748755

  14. Virtual Screening of compounds from Tabernaemontana divaricata for potential anti-bacterial activity.

    PubMed

    Gogoi, Rashmi Rekha; Gogoi, Dhrubajyoti; Bezbaruah, Rajib Lochan

    2014-01-01

    Virtual Screening and Molecular Docking analysis for Tabernaemontana divaricata derived 66 Law Molecular Weight Compounds (LMW) was conducted and to identified and predicted novel molecules as a inhibitor of Streptococcus pneumonia. The investigation has revealed several compounds with optimum binding towards Penicillin-binding proteins, Sialidases, Aspartate betasemialdehide dehydrogenase cell membrane protein of Streptococcus pneumonia. Docking results were computed in term of binding energy, ligand efficiency and number of hydrogen bonding. Apparicine (-5.14), 5-Hydroxyvoaphylline (-4.78), Voacangine (-4.7), 19-Hydroxycoronaridine (-4.44) and Coronaridine (-4.72) are identified as most suitable to bind with N-acetylglucosamine-1- phosphate uridyltransferase receptor. Ervaticine (-6.33), Ibogamine (-6.15), Methylvoaphylline (-5.74) and Coronaridine hydroxyindolenine (-5.32) has showed novel binding against the penicillin-binding proteins. Ervaticine (-6.42), 5-oxo-11-hydroxy voaphylline (-6.18), Conolobine B (-6.02) has found optimum binding against the active site of NanB sialidase of Streptococcus pneumonia. The compounds 3S-Cyanocoronaridine (-6.71), 19-Epivoacristine (-5.48) and Ervaticine(-5.45) interacting with aspartate beta-semialdehide and found suitable with least docking score. PMID:24748755

  15. Bioactive Compounds and Antioxidant Activity in Different Types of Berries.

    PubMed

    Skrovankova, Sona; Sumczynski, Daniela; Mlcek, Jiri; Jurikova, Tunde; Sochor, Jiri

    2015-01-01

    Berries, especially members of several families, such as Rosaceae (strawberry, raspberry, blackberry), and Ericaceae (blueberry, cranberry), belong to the best dietary sources of bioactive compounds (BAC). They have delicious taste and flavor, have economic importance, and because of the antioxidant properties of BAC, they are of great interest also for nutritionists and food technologists due to the opportunity to use BAC as functional foods ingredients. The bioactive compounds in berries contain mainly phenolic compounds (phenolic acids, flavonoids, such as anthocyanins and flavonols, and tannins) and ascorbic acid. These compounds, either individually or combined, are responsible for various health benefits of berries, such as prevention of inflammation disorders, cardiovascular diseases, or protective effects to lower the risk of various cancers. In this review bioactive compounds of commonly consumed berries are described, as well as the factors influencing their antioxidant capacity and their health benefits. PMID:26501271

  16. Bioactive Compounds and Antioxidant Activity in Different Types of Berries

    PubMed Central

    Skrovankova, Sona; Sumczynski, Daniela; Mlcek, Jiri; Jurikova, Tunde; Sochor, Jiri

    2015-01-01

    Berries, especially members of several families, such as Rosaceae (strawberry, raspberry, blackberry), and Ericaceae (blueberry, cranberry), belong to the best dietary sources of bioactive compounds (BAC). They have delicious taste and flavor, have economic importance, and because of the antioxidant properties of BAC, they are of great interest also for nutritionists and food technologists due to the opportunity to use BAC as functional foods ingredients. The bioactive compounds in berries contain mainly phenolic compounds (phenolic acids, flavonoids, such as anthocyanins and flavonols, and tannins) and ascorbic acid. These compounds, either individually or combined, are responsible for various health benefits of berries, such as prevention of inflammation disorders, cardiovascular diseases, or protective effects to lower the risk of various cancers. In this review bioactive compounds of commonly consumed berries are described, as well as the factors influencing their antioxidant capacity and their health benefits. PMID:26501271

  17. Annotated compound data for modulators of detergent-solubilised or lipid-reconstituted respiratory type II NADH dehydrogenase activity obtained by compound library screening

    PubMed Central

    Dunn, Elyse A.; Cook, Gregory M.; Heikal, Adam

    2015-01-01

    The energy-generating membrane protein NADH dehydrogenase (NDH-2), a proposed antibacterial drug target (see “Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs” Weinstein et al. 2005 [1]), was screened for modulators of activity in either detergent-solublised or lipid reconstituted (proteolipsome) form. Here we present an annotated list of compounds identified in a small-scale screen against NDH-2. The dataset contains information regarding the libraries screened, the identities of hit compounds and the physicochemical properties governing solubility and permeability. The implications of these data for future antibiotic discovery are discussed in our associated report, “Comparison of lipid and detergent enzyme environments for identifying inhibitors of membrane-bound energy-transducing proteins” [2]. PMID:26862571

  18. JV Task 86 - Identifying the Source of Benzene in Indoor Air Using Different Compound Classes from TO-15 Data

    SciTech Connect

    Steven B. Hawthorne

    2007-04-15

    Volatile organic compound (VOC) data that had already been collected using EPA method TO-15 at four different sites under regulatory scrutiny (a school, strip mall, apartment complex, and business/residential neighborhood) were evaluated to determine whether the source of indoor air benzene was outdoor air or vapor intrusion from contaminated soil. Both the use of tracer organics characteristic of different sources and principal component statistical analysis demonstrated that the source of indoor air at virtually all indoor sampling locations was a result of outdoor air, and not contaminated soil in and near the indoor air-sampling locations. These results show that proposed remediation activities to remove benzene-contaminated soil are highly unlikely to reduce indoor air benzene concentrations. A manuscript describing these results is presently being prepared for submission to a peer-reviewed journal.

  19. GC-MS analysis of bio-active compounds in methanolic extract of Lactuca runcinata DC

    PubMed Central

    Kanthal, Lakshmi Kanta; Dey, Akalanka; Satyavathi, K.; Bhojaraju, P.

    2014-01-01

    Background: The presence of phytochemical constitutes has been reported from species of the Compositae (Asteraceae). Hitherto no reports exist on the phytochemical components and biological activity of Lactuca runcinata DC. Objective: The present study was designed to determine the bioactive compounds in the whole plant methanol extract of Lactuca runcinata. Materials and Methods: Phytochemical screening of the entire herb of Lactuca runcinata DC revealed the presence of some bio-active components. Gas chromatography-mass spectrometry (GC-MS) analysis of the whole plant methanol extract of Lactuca runcinata was performed on a GC-MS equipment (Thermo Scientific Co.) Thermo GC-TRACE ultra ver.: 5.0, Thermo MS DSQ II. Results: The phytochemical tests showed the presence of alkaloids, cardiac glycosides, flavonoids, phenols, phlobatannin, reducing sugars, saponins, steroids, tannins, terpenoids, volatile oils, carbohydrates, and protein/amino acids in methanolic extract of L. runcinata. The GC-MS analysis has shown the presence of different phytochemical compounds in the methanolic extract of Lactuca runcinata. A total of 21 compounds were identified representing 84.49% of total methanolic extract composition. Conclusion: From the results, it is evident that Lactuca runcinata contains various phytocomponents and is recommended as a plant of phytopharmaceutical importance. PMID:24497744

  20. The cell competition-based high-throughput screening identifies small compounds that promote the elimination of RasV12-transformed cells from epithelia.

    PubMed

    Yamauchi, Hajime; Matsumaru, Takanori; Morita, Tomoko; Ishikawa, Susumu; Maenaka, Katsumi; Takigawa, Ichigaku; Semba, Kentaro; Kon, Shunsuke; Fujita, Yasuyuki

    2015-01-01

    Recent studies have revealed that cell competition can occur between normal and transformed epithelial cells; normal epithelial cells recognize the presence of the neighboring transformed cells and actively eliminate them from epithelial tissues. Here, we have established a brand-new high-throughput screening platform that targets cell competition. By using this platform, we have identified Rebeccamycin as a hit compound that specifically promotes elimination of RasV12-transformed cells from the epithelium, though after longer treatment it shows substantial cytotoxic effect against normal epithelial cells. Among several Rebeccamycin-derivative compounds, we have found that VC1-8 has least cytotoxicity against normal cells but shows the comparable effect on the elimination of transformed cells. This cell competition-promoting activity of VC1-8 is observed both in vitro and ex vivo. These data demonstrate that the cell competition-based screening is a promising tool for the establishment of a novel type of cancer preventive medicine. PMID:26480891

  1. The cell competition-based high-throughput screening identifies small compounds that promote the elimination of RasV12-transformed cells from epithelia

    PubMed Central

    Yamauchi, Hajime; Matsumaru, Takanori; Morita, Tomoko; Ishikawa, Susumu; Maenaka, Katsumi; Takigawa, Ichigaku; Semba, Kentaro; Kon, Shunsuke; Fujita, Yasuyuki

    2015-01-01

    Recent studies have revealed that cell competition can occur between normal and transformed epithelial cells; normal epithelial cells recognize the presence of the neighboring transformed cells and actively eliminate them from epithelial tissues. Here, we have established a brand-new high-throughput screening platform that targets cell competition. By using this platform, we have identified Rebeccamycin as a hit compound that specifically promotes elimination of RasV12-transformed cells from the epithelium, though after longer treatment it shows substantial cytotoxic effect against normal epithelial cells. Among several Rebeccamycin-derivative compounds, we have found that VC1-8 has least cytotoxicity against normal cells but shows the comparable effect on the elimination of transformed cells. This cell competition-promoting activity of VC1-8 is observed both in vitro and ex vivo. These data demonstrate that the cell competition-based screening is a promising tool for the establishment of a novel type of cancer preventive medicine. PMID:26480891

  2. ION COMPOSITION ELUCIDATION (ICE): A HIGH RESOLUTION MASS SPECTROMETRIC TOOL FOR IDENTIFYING ORGANIC COMPOUNDS IN COMPLEX EXTRACTS OF ENVIRONMENTAL SAMPLES

    EPA Science Inventory


    Unidentified Organic Compounds. For target analytes, standards are purchased, extraction and clean-up procedures are optimized, and mass spectra and retention times for the chromatographic separation are obtained for comparison to the target compounds in environmental sample ...

  3. Acquisition of Compound Words in Chinese-English Bilingual Children: Decomposition and Cross-Language Activation

    ERIC Educational Resources Information Center

    Cheng, Chenxi; Wang, Min; Perfetti, Charles A.

    2011-01-01

    This study investigated compound processing and cross-language activation in a group of Chinese-English bilingual children, and they were divided into four groups based on the language proficiency levels in their two languages. A lexical decision task was designed using compound words in both languages. The compound words in one language contained…

  4. Human Health Relevance of Pharmaceutically Active Compounds in Drinking Water.

    PubMed

    Khan, Usman; Nicell, Jim

    2015-05-01

    In Canada, as many as 20 pharmaceutically active compounds (PhACs) have been detected in samples of treated drinking water. The presence of these PhACs in drinking water raises important questions as to the human health risk posed by their potential appearance in drinking water supplies and the extent to which they indicate that other PhACs are present but have not been detected using current analytical methods. Therefore, the goal of the current investigation was to conduct a screening-level assessment of the human health risks posed by the aquatic release of an evaluation set of 335 selected PhACs. Predicted and measured concentrations were used to estimate the exposure of Canadians to each PhAC in the evaluation set. Risk evaluations based on measurements could only be performed for 17 PhACs and, of these, all were found to pose a negligible risk to human health when considered individually. The same approach to risk evaluation, but based on predicted rather than measured environmental concentrations, suggested that 322 PhACs of the evaluation set, when considered individually, are expected to pose a negligible risk to human health due to their potential presence in drinking waters. However, the following 14 PhACs should be prioritized for further study: triiodothyronine, thyroxine, ramipril and its metabolite ramiprilat, candesartan, lisinopril, atorvastatin, lorazepam, fentanyl, atenolol, metformin, enalaprilat, morphine, and irbesartan. Finally, the currently available monitoring data for PhACs in Canadian surface and drinking waters was found to be lacking, irrespective of whether their suitability was assessed based on risk posed, predicted exposure concentrations, or potency. PMID:25739816

  5. SYNTHESIZING ORGANIC COMPOUNDS USING LIGHT-ACTIVATED TIO2

    EPA Science Inventory

    High-value organic compounds have been synthesized successfully from linear and cyclic hydrocarbons, by photocatalytic oxidation using a semiconductor material, titanium dioxide (TiO2). Various hydrocarbons were partially oxgenated in both liquid and gaseous phase reactors usi...

  6. Compositions comprising a polypeptide having cellulolytic enhancing activity and a quinone compound and uses thereof

    DOEpatents

    Quinlan, Jason; Xu, Feng; Sweeney, Matthew

    2016-03-01

    The present invention relates to compositions comprising: a polypeptide having cellulolytic enhancing activity and a quinone compound. The present invention also relates to methods of using the compositions.

  7. Compositions comprising a polypeptide having cellulolytic enhancing activity and a heterocyclic compound and uses thereof

    DOEpatents

    Xu, Feng; Sweeney, Matthew; Quinlan, Jason

    2016-08-02

    The present invention relates to compositions comprising: a polypeptide having cellulolytic enhancing activity and a heterocyclic compound. The present invention also relates to methods of using the compositions.

  8. Compositions comprising a polypeptide having cellulolytic enhancing activity and a bicycle compound and uses thereof

    DOEpatents

    Xu, Feng; Sweeney, Matthew; Quinlan, Jason

    2015-06-16

    The present invention relates to compositions comprising: a polypeptide having cellulolytic enhancing activity and a bicyclic compound. The present invention also relates to methods of using the compositions.

  9. Compositions comprising a polypeptide having cellulolytic enhancing activity and a dioxy compound and uses thereof

    DOEpatents

    Sweeney, Matthew; Xu, Feng; Quinlan, Jason

    2016-07-19

    The present invention relates to compositions comprising: a polypeptide having cellulolytic enhancing activity and a dioxy compound. The present invention also relates to methods of using the compositions.

  10. Antiproliferative activity of New Zealand propolis and phenolic compounds vs human colorectal adenocarcinoma cells.

    PubMed

    Catchpole, Owen; Mitchell, Kevin; Bloor, Stephen; Davis, Paul; Suddes, Amanda

    2015-10-01

    New Zealand propolis is a "European" type propolis obtained by honey bees mainly from exudates of poplar. European type propolis is known to have anti-inflammatory and anti-cancer properties and this activity has been attributed to some of the main constituents such as chrysin and CAPE (caffeic acid phenethyl ester). As part of our studies on how New Zealand propolis might benefit gastro-intestinal health, we carried out in vitro bioactivity-guided fractionation of "Bio30™" propolis using both anti-inflammatory (TNF-α, COX-1, COX-2) and anti-colon cancer (DLD-1 colon cancer cell viability) assays; and determined the phenolic compounds responsible for the activity. The New Zealand wax-free Bio30™ propolis tincture solids had very high levels of the dihydroflavonoids pinocembrin and pinobanksin-3-O-acetate, and high levels of the dimethylallyl, benzyl and 3-methyl-3-butenyl caffeates relative to CAPE. The DLD-1 assays identified strong anti-proliferative activity associated with these components as well as chrysin, galangin and CAPE and a number of lesser known or lower concentration compounds including benzyl ferulate, benzyl isoferulate, pinostrobin, 5-phenylpenta-2,4-dienoic acid and tectochrysin. The phenolic compounds pinocembrin, pinobanksin-3-O-acetate, tectochrysin, dimethylallyl caffeate, 3-methyl-3-butenyl caffeate, benzyl ferulate and benzyl isoferulate also showed good broad spectrum activity in anti-proliferative assays against three other gastro-intestinal cancer cell lines; HCT-116 colon carcinoma, KYSE-30 oesophageal squamous cancer, and NCI-N87 gastric carcinoma. Activity is also observed in anti-inflammatory assays although it appears to be limited to one of the first cytokines in the inflammatory cascade, TNF-α. PMID:26347954

  11. Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture

    PubMed Central

    de Wilde, Adriaan H.; Jochmans, Dirk; Posthuma, Clara C.; Zevenhoven-Dobbe, Jessika C.; van Nieuwkoop, Stefan; Bestebroer, Theo M.; van den Hoogen, Bernadette G.

    2014-01-01

    Coronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. The 2003 outbreak of severe acute respiratory syndrome (SARS) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. In 2012, a similar previously unknown coronavirus emerged, Middle East respiratory syndrome coronavirus (MERS-CoV), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being recorded over recent months. The human MERS fatality rate of ∼30% is alarmingly high, even though many deaths were associated with underlying medical conditions. Registered therapeutics for the treatment of coronavirus infections are not available. Moreover, the pace of drug development and registration for human use is generally incompatible with strategies to combat emerging infectious diseases. Therefore, we have screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. If such compounds proved sufficiently potent, their efficacy might be directly assessed in MERS patients. We identified four compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibiting MERS-CoV replication in the low-micromolar range (50% effective concentrations [EC50s], 3 to 8 μM). Moreover, these compounds also inhibit the replication of SARS coronavirus and human coronavirus 229E. Although their protective activity (alone or in combination) remains to be assessed in animal models, our findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction may create a window during which to mount a protective immune response. PMID:24841269

  12. Identification of Tetraazacyclic Compounds as Novel Potent Inhibitors Antagonizing RORγt Activity and Suppressing Th17 Cell Differentiation

    PubMed Central

    Ding, Qingfeng; Zhao, Mei; Yu, Bolan; Bai, Chuan; Huang, Zhaofeng

    2015-01-01

    CD4+ T-helper cells that produce interleukin-17 (Th17 cells) are characterized as pathological T-helper cells in autoimmune diseases. Differentiation of human and mouse Th17 cells requires a key transcription regulator, retinoic acid receptor-related orphan receptor γt (RORγt), which is a potential therapeutic target for autoimmune diseases. To develop a therapeutic agent for Th17-mediated autoimmune diseases, we have established a high-throughput screening (HTS) assay for candidate screening, in which the luciferase activity in RORγt-LBD positive and negative Jurkat cells were analyzed to evaluate induction of RORγt activity by compounds. This technique was applied to screen a commercially-available drug-like chemical compound library (Enamine) which contains 20155 compounds. The screening identified 17 compounds that can inhibit RORγt function in the HTS screen system. Of these, three tetraazacyclic compounds can potently inhibit RORγt activity, and suppress Th17 differentiation and IL-17 production. These three candidate compounds could significantly attenuate the expression of the Il17a by 65%- 90%, and inhibit IL-17A secretion by 47%, 63%, and 74%, respectively. These compounds also exhibited a potent anti-RORγt activity, with EC50 values of 0.25 μM, 0.67 μM and 2.6 μM, respectively. Our data demonstrated the feasibility of targeting the RORγt to inhibit Th17 cell differentiation and function with these tetraazacyclic compounds, and the potential to improve the structure of these compounds for autoimmune diseases therapeutics. PMID:26368822

  13. Identifying active methane-oxidizers in thawed Arctic permafrost by proteomics

    NASA Astrophysics Data System (ADS)

    Lau, C. M.; Stackhouse, B. T.; Chourey, K.; Hettich, R. L.; Vishnivetskaya, T. A.; Pfiffner, S. M.; Layton, A. C.; Mykytczuk, N. C.; Whyte, L.; Onstott, T. C.

    2012-12-01

    The rate of CH4 release from thawing permafrost in the Arctic has been regarded as one of the determining factors on future global climate. It is uncertain how indigenous microorganisms would interact with such changing environmental conditions and hence their impact on the fate of carbon compounds that are sequestered in the cryosol. Multitudinous studies of pristine surface cryosol (top 5 cm) and microcosm experiments have provided growing evidence of effective methanotrophy. Cryosol samples corresponding to active layer were sampled from a sparsely vegetated, ice-wedge polygon at the McGill Arctic Research Station at Axel Heiberg Island, Nunavut, Canada (N79°24, W90°45) before the onset of annual thaw. Pyrosequencing of 16S rRNA gene indicated the occurrence of methanotroph-containing bacterial families as minor components (~5%) in pristine cryosol including Bradyrhizobiaceae, Methylobacteriaceae and Methylocystaceae within alpha-Proteobacteria, and Methylacidiphilaceae within Verrucomicrobia. The potential of methanotrophy is supported by preliminary analysis of metagenome data, which indicated putative methane monooxygenase gene sequences relating to Bradyrhizobium sp. and Pseudonocardia sp. are present. Proteome profiling in general yielded minute traces of proteins, which likely hints at dormant nature of the soil microbial consortia. The lack of specific protein database for permafrost posted additional challenge to protein identification. Only 35 proteins could be identified in the pristine cryosol and of which 60% belonged to Shewanella sp. Most of the identified proteins are known to be involved in energy metabolism or post-translational modification of proteins. Microcosms amended with sodium acetate exhibited a net methane consumption of ~65 ngC-CH4 per gram (fresh weight) of soil over 16 days of aerobic incubation at room temperature. The pH in microcosm materials remained acidic (decreased from initial 4.7 to 4.5). Protein extraction and

  14. Gene expression profiling in Ishikawa cells: A fingerprint for estrogen active compounds

    SciTech Connect

    Boehme, Kathleen; Simon, Stephanie

    2009-04-01

    Several anthropogenous and naturally occurring substances, referred to as estrogen active compounds (EACs), are able to interfere with hormone and in particular estrogen receptor signaling. EACs can either cause adverse health effects in humans and wildlife populations or have beneficial effects on estrogen-dependent diseases. The aim of this study was to examine global gene expression profiles in estrogen receptor (ER)-proficient Ishikawa plus and ER-deficient Ishikawa minus endometrial cancer cells treated with selected well-known EACs (Diethylstilbestrol, Genistein, Zearalenone, Resveratrol, Bisphenol A and o,p'-DDT). We also investigated the effect of the pure antiestrogen ICI 182,780 (ICI) on the expression patterns caused by these compounds. Transcript levels were quantified 24 h after compound treatment using Illumina BeadChip Arrays. We identified 87 genes with similar expression changes in response to all EAC treatments in Ishikawa plus. ICI lowered the magnitude or reversed the expression of these genes, indicating ER dependent regulation. Apart from estrogenic gene regulation, Bisphenol A, o,p'-DDT, Zearalenone, Genistein and Resveratrol displayed similarities to ICI in their expression patterns, suggesting mixed estrogenic/antiestrogenic properties. In particular, the predominant antiestrogenic expression response of Resveratrol could be clearly distinguished from the other test compounds, indicating a distinct mechanism of action. Divergent gene expression patterns of the phytoestrogens, as well as weaker estrogenic gene expression regulation determined for the anthropogenous chemicals Bisphenol A and o,p'-DDT, warrants a careful assessment of potential detrimental and/or beneficial effects of EACs. The characteristic expression fingerprints and the identified subset of putative marker genes can be used for screening chemicals with an unknown mode of action and for predicting their potential to exert endocrine disrupting effects.

  15. Phenolic Compounds from the Flowers of Bombax malabaricum and Their Antioxidant and Antiviral Activities.

    PubMed

    Zhang, Yu-Bo; Wu, Peng; Zhang, Xiao-Li; Xia, Chao; Li, Guo-Qiang; Ye, Wen-Cai; Wang, Guo-Cai; Li, Yao-Lan

    2015-01-01

    Three new phenolic compounds 1-3 and twenty known ones 4-23 were isolated from the flowers of Bombax malabaricum. Their chemical structures were elucidated by spectroscopic analyses (IR, ESI-MS, HR-ESI-MS, 1D- and 2D-NMR) and chemical reactions. The antioxidant capacities of the isolated compounds were tested using FRAP and DPPH radical-scavenging assays, and compounds 4, 6, 8, 12, as well as the new compound 2, exhibited stronger antioxidant activities than ascorbic acid. Furthermore, all of compounds were tested for their antiviral activities against RSV by the CPE reduction assay and plaque reduction assay. Compounds 4, 10, 12 possess in vitro antiviral activities, and compound 10 exhibits potent anti-RSV effects, comparable to the positive control ribavirin. PMID:26556329

  16. Identifying the Main Driver of Active Region Outflows

    NASA Astrophysics Data System (ADS)

    Baker, D.; van Driel-Gesztelyi, L.; Mandrini, C. H.; Démoulin, P.; Murray, M. J.

    2012-08-01

    Hinode's EUV Imaging Spectrometer (EIS) has discovered ubiquitous outflows of a few to 50 km s-1 from active regions (ARs). The characteristics of these outflows are very curious in that they are most prominent at the AR boundary and appear over monopolar magnetic areas. They are linked to strong non-thermal line broadening and are stronger in hotter EUV lines. The outflows persist for at least several days. Whereas red-shifted down flows observed in AR closed loops are well understood, to date there is no general consensus for the mechanism(s) driving blue-shifted AR-related outflows. We use Hinode EIS and X-Ray Telescope observations of AR 10942 coupled with magnetic modeling to demonstrate for the first time that the outflows originate from specific locations of the magnetic topology where field lines display strong gradients of magnetic connectivity, namely quasi-separatrix layers (QSLs), or in the limit of infinitely thin QSLs, separatrices. The strongest AR outflows were found to be in the vicinity of QSL sections located over areas of strong magnetic field. We argue that magnetic reconnection at QSLs, separating closed field lines of the AR and either large-scale externally connected or ‘open’ field lines, is a viable mechanism for driving AR outflows which are potentially sources of the slow solar wind. In fact, magnetic reconnection along QSLs (including separatricies) is the first theory to explain the most puzzling characteristics of the outflows, namely their occurrence over monopolar areas at the periphery of ARs and their longevity.

  17. Synthesis and antiplatelet activity of antithrombotic thiourea compounds: biological and structure-activity relationship studies.

    PubMed

    Lourenço, André Luiz; Saito, Max Seidy; Dorneles, Luís Eduardo Gomes; Viana, Gil Mendes; Sathler, Plínio Cunha; Aguiar, Lúcia Cruz de Sequeira; de Pádula, Marcelo; Domingos, Thaisa Francielle Souza; Fraga, Aline Guerra Manssour; Rodrigues, Carlos Rangel; de Sousa, Valeria Pereira; Castro, Helena Carla; Cabral, Lucio Mendes

    2015-01-01

    The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N'-disubstituted thioureas derivatives using in vitro and in silico approaches. New designed compounds inhibit the arachidonic acid pathway in human platelets. The most active thioureas (compounds 3d, 3i, 3m and 3p) displayed IC50 values ranging from 29 to 84 µM with direct influence over in vitro PGE2 and TXA2 formation. In silico evaluation of these compounds suggests that direct blockage of the tyrosyl-radical at the COX-1 active site is achieved by strong hydrophobic contacts as well as electrostatic interactions. A low toxicity profile of this series was observed through hemolytic, genotoxic and mutagenic assays. The most active thioureas were able to reduce both PGE2 and TXB2 production in human platelets, suggesting a direct inhibition of COX-1. These results reinforce their promising profile as lead antiplatelet agents for further in vivo experimental investigations. PMID:25903367

  18. Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity.

    PubMed

    Sola, Irene; Castellà, Sílvia; Viayna, Elisabet; Galdeano, Carles; Taylor, Martin C; Gbedema, Stephen Y; Pérez, Belén; Clos, M Victòria; Jones, Deuan C; Fairlamb, Alan H; Wright, Colin W; Kelly, John M; Muñoz-Torrero, Diego

    2015-08-15

    Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity. PMID:25678015

  19. Compounds extracted from feverfew that have anti-secretory activity contain an alpha-methylene butyrolactone unit.

    PubMed

    Groenewegen, W A; Knight, D W; Heptinstall, S

    1986-09-01

    Extracts of feverfew inhibit secretion of granular contents from platelets and neutrophils and this may be relevant to the therapeutic value of feverfew in migraine and other conditions. In this investigation we fractionated an extract of feverfew and obtained eleven fractions with antisecretory activity. The activity. The active fractions, together with two fractions that were devoid of anti-secretory activity, were examined using 1H NMR and infrared spectroscopy. All the active fractions (but neither of the inactive fractions) contained compounds with an alpha-methylene butyrolactone unit. Five compounds that contain this unit were identified as parthenolide, 3-beta-hydroxyparthenolide, secotanapartholide A, canin and artecanin, all of which are sesquiterpene lactones. It is very likely that these and other sesquiterpene lactones that contain an alpha-methylene butyrolactone unit are responsible for the anti-secretory activity in extracts of feverfew. PMID:2877077

  20. Low cost whole-organism screening of compounds for anthelmintic activity.

    PubMed

    Preston, Sarah; Jabbar, Abdul; Nowell, Cameron; Joachim, Anja; Ruttkowski, Bärbel; Baell, Jonathan; Cardno, Tony; Korhonen, Pasi K; Piedrafita, David; Ansell, Brendan R E; Jex, Aaron R; Hofmann, Andreas; Gasser, Robin B

    2015-04-01

    Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors (GlaxoSmithKline, USA; code: PKIS2) for activity against H. contortus by measuring the inhibition of larval motility using an automated image analysis system. We identified two chemicals within the compound classes biphenyl amides and pyrazolo[1,5-α]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14-47 μM. Given that these inhibitors were designed as anti-inflammatory drugs for use in humans and fit the Lipinski rule-of-five (including bioavailability), they show promise for hit-to-lead optimisation and repurposing for use against parasitic nematodes. The screening assay established here has significant advantages over conventional methods, particularly in terms of ease of use, throughput, time and cost. Although not yet fully automated, the current assay is readily suited to the screening of hundreds to thousands of compounds for subsequent hit-to-lead optimisation. The current assay is highly adaptable to many parasites of socioeconomic importance, including those causing neglected tropical diseases. This aspect is of major relevance, given the urgent need to deliver the goals of the London Declaration (http://unitingtocombatntds.org/resource/london-declaration) through the rapid and efficient repurposing of compounds in public-private partnerships. PMID:25746136

  1. HPLC-Analysis of Polyphenolic Compounds in Gardenia jasminoides and Determination of Antioxidant Activity by Using Free Radical Scavenging Assays

    PubMed Central

    Uddin, Riaz; Saha, Moni Rani; Subhan, Nusrat; Hossain, Hemayet; Jahan, Ismet Ara; Akter, Raushanara; Alam, Ashraful

    2014-01-01

    Purpose: Gardenia jasminoides is a traditional medicinal plant rich in anti-inflammatory flavonoids and phenolic compounds and used for the treatment of inflammatory diseases and pain. In this present study, antioxidant potential of Gardenia jasminoides leaves extract was evaluated by using various antioxidant assays. Methods: Various antioxidant assays such as 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, reducing power and total antioxidant capacity expressed as equivalent to ascorbic acid were employed. Moreover, phenolic compounds were detected by high-performance liquid chromatography (HPLC) coupled with diode-array detection. Results: The methanol extract showed significant free radical scavenging activities in DPPH radical scavenging antioxidant assays compared to the reference antioxidant ascorbic acid. Total antioxidant activity was increased in a dose dependent manner. The extract also showed strong reducing power. The total phenolic content was determined as 190.97 mg/g of gallic acid equivalent. HPLC coupled with diode-array detection was used to identify and quantify the phenolic compounds in the extracts. Gallic acid, (+)-catechin, rutin hydrate and quercetin have been identified in the plant extracts. Among the phenolic compounds, catechin and rutin hydrate are present predominantly in the extract. The accuracy and precision of the presented method were corroborated by low intra- and inter-day variations in quantitative results in leaves extract. Conclusion: These results suggest that phenolic compounds and flavonoids might contribute to high antioxidant activities of Gardenia jasminoides leaves. PMID:24754012

  2. Syntheses, biological activities and SAR studies of novel carboxamide compounds containing piperazine and arylsulfonyl moieties.

    PubMed

    Wang, Bao-Lei; Shi, Yan-Xia; Zhang, Shu-Jun; Ma, Yi; Wang, Hong-Xue; Zhang, Li-Yuan; Wei, Wei; Liu, Xing-Hai; Li, Yong-Hong; Li, Zheng-Ming; Li, Bao-Ju

    2016-07-19

    A series of novel carboxamide compounds 19a-19j, 20a-20j and 22a-22d containing piperazine and arylsulfonyl moieties have been synthesized. The bioassay results showed that some compounds exhibited favorable herbicidal activities against dicotyledonous plants and many of them possessed excellent antifungal activities. Among 24 novel compounds, some showed superiority over the commercial fungicides Chlorothalonil, Dimethomorph, Thiophanate-methyl, Iprodione, and Zhongshengmycin at 500 mg/L concentration. Some compounds also exhibited high KARI inhibitory activity at 100 μg/mL concentration and could be used as new KARI lead inhibitors for further studies. Moreover, SAR of these new compounds were comprehensively investigated using different computational methods in which 3D-QSAR model obtained provided useful information for further structural optimization for the discovery of new fungicides. The results of this research will contribute to explore comprehensive biological activities of piperazine-containing compounds in different areas of chemistry. PMID:27092414

  3. Antihyperlipidemic activity of sesquiterpene lactones and related compounds.

    PubMed

    Hall, I H; Lee, K H; Starnes, C O; Muraoka, O; Sumida, Y; Waddell, T G

    1980-06-01

    Some naturally occurring pseudoguaianolides and germacranolides as well as synthetic related compounds were observed to be antihyperlipidemic agents in mice. Several of these compounds at a dose of 20 mg/kg/day resulted in lowering of serum cholesterol by approximately 30% and of serum triglycerides by approximately 25%. Thiol-bearing enzymes of lipid synthesis, i.e., acetyl-CoA, citrate-lyase, acetyl-CoA synthetase, and beta-hydroxy-beta-methylglutaryl-CoA reductase, were inhibited by these agents in vitro, supporting the premise that these agents alkylate thiol nucleophiles by a Michael-type addition. The alpha-methylene-gamma-lactone moiety, the beta-unsubstituted cyclopentenone ring, and the alpha-epoxycyclopentanone system of these compounds appeared to be responsible for the lowering of serum lipids. PMID:7205585

  4. Production of antioomycete compounds active against the phytopathogens Phytophthora sojae and Aphanomyces cochlioides by clavicipitoid entomopathogenic fungi.

    PubMed

    Putri, Sastia Prama; Ishido, Kei-Ichi; Kinoshita, Hiroshi; Kitani, Shigeru; Ihara, Fumio; Sakihama, Yasuko; Igarashi, Yasuhiro; Nihira, Takuya

    2014-05-01

    A total of 412 strains belonging to 14 genera of clavicipitoid entomopathogenic fungi (EPF) were screened for activities against two economically important plant pathogenic oomycetes, Phytophthora sojae and Aphanomyces cochlioides. To identify the antioomycete compounds produced by EPF, the extracts of 13 highly active EPF strains were characterized in detail by high performance liquid chromatography with diode array detection and high-resolution mass spectrometric detection and antioomycete assay. The antioomycete activity of several Metarhizium extracts was associated with previously isolated aurovertins, fungerin, N-(methyl-3-oxodec-6-enoyl)-2-pyrroline, and N-(methyl-3-oxodecanoyl)-2-pyrroline. The depsipeptide beauvericin was confirmed to be one of the active principles of three strains of Isaria tenuipes, which strongly inhibited mycelial growth of both P. sojae and A. cochlioides. Two known bioactive metabolites, paecilosetin and aranorosinol A, together with a novel and potent antioomycete compound, farinomalein, were isolated from the extracts of Isaria farinosa and all compounds were confirmed to have antioomycete activity. Identification of 8 antioomycete compounds from 13 clavicipitioid EPF demonstrated a new potential use of EPF as a source of compounds for the control of soil-borne plant pathogenic oomycetes. PMID:24268864

  5. Hyphenated Analytical Methods in Determination of Biologically Active Compounds in Hen's Eggs.

    PubMed

    Walczak, Justyna; Bocian, Szymon; Trziszka, Tadeusz; Buszewski, Bogusław

    2016-05-01

    Hen's egg is a complete material needed for the development of the embryo; it is an important source of nutraceutical compounds, such as protein, fats, vitamins, trace metals, and minerals. Moreover, avian egg contains biologically active compounds that exhibit antibacterial and antimicrobial activities as well as antitumor, antiviral, antioxidant, immunomodulating, and therapeutic properties. Eggs are mostly very good sources of valuable, easily digestible proteins. This review focuses on the biologically active compounds from hen's egg and applications of these compounds in medicine and the pharmaceutical industry. Additionally, it gives an overview of the hyphenated separation techniques, including sample preparation, analysis, and identification, used in the proteomics and lipidomics analysis. PMID:26186292

  6. Design, synthesis and anticancer activity of novel hybrid compounds between benzofuran and N-aryl piperazine.

    PubMed

    Mao, Ze-Wei; Zheng, Xi; Lin, Yu-Ping; Hu, Chun-Yan; Wang, Xiu-Li; Wan, Chun-Ping; Rao, Gao-Xiong

    2016-08-01

    A series of novel hybrid compounds between benzofuran and N-aryl piperazine have been designed and prepared. These derivatives were evaluated for their in vitro anti-tumor activity against a panel of human tumor cell lines by MTT assay. The results demonstrated that amide derivatives were more bioactive than sulfonamide compounds in general, and that chloro or trifluoromethyl substituent was vital for modulating cytotoxic activity. In particular, compound 13 was found to be the most potent compound against 4 strains human tumor cell lines, and exhibited cytotoxic activity selectively against Hela (0.03μM). PMID:27371110

  7. The influence of interactions among phenolic compounds on the antiradical activity of chokeberries (Aronia melanocarpa).

    PubMed

    Jakobek, Lidija; Seruga, Marijan; Krivak, Petra

    2011-06-01

    In the present work, interactions between phenolic compounds from chokeberries and their influence on the antiradical activity was studied. Three fractions were isolated from chokeberries containing different classes of phenolic compounds. The first fraction contained a major part of phenolic acids and flavonols, the second anthocyanins, and the third insoluble phenols and proanthocyanidins. The phenolic compound content was determined using high-performance liquid chromatography, and the antiradical activity using the DPPH test. In order to evaluate the effects of interactions between phenolic compounds on the antiradical activity, the antiradical activity of individual phenolic fractions was compared with that obtained by mixing phenolic fractions. Phenolic mixtures showed the decrease in the antiradical activity in comparison with the individual phenolic fractions. These results suggest the existence of complex interactions among phenolic compounds that caused the decrease of the antiradical activity. Interactions among chokeberry phenols promoted a negative synergism. PMID:21214419

  8. Cytotoxic activity of the novel heterocyclic compound G-11 is primarily mediated through intrinsic apoptotic pathway.

    PubMed

    Saleh, Ayman M; Aziz, Mohammad A; Abdou, Ibrahim M; Taha, Mutasem O; Al-Qudah, Mahmoud A; Abadleh, Mohammed M; Aljada, Ahmad; Rizvi, Syed A

    2016-07-01

    Natural and chemically synthesized heterocyclic compounds have been explored for their potential use as anticancer agents. We had synthesized non-natural heterocyclic analogs and evaluated their anti-tumor activity by measuring effect on cell proliferation and induction of apoptosis in different cell lines. Previously, we identified a pyrazole-containing compound (G-11) showing cytotoxic effect towards leukemia and lymphoma cell lines. In this study, we further investigated the mechanistic aspects of anticancer properties of G-11 in HL-60 cell line. We demonstrated that cytotoxic effect of G-11 is mediated by caspase-dependent apoptosis. However, the involvement of mitochondrial dysfunction induced by G-11 was independent of caspases. G-11 triggered generation of ROS, caused disruption of mitochondrial transmembrane potential, increased release of cytochrome c to the cytosol, and altered the expression of Bcl-2 and Bax proteins. These results suggest significant involvement of intrinsic apoptotic pathway. This study comprehensively details the possible mechanisms of action of a novel heterocyclic compound which could find its potential use as an anticancer agent. PMID:27154302

  9. Volatile flavor compounds, total polyphenolic contents and antioxidant activities of a China gingko wine.

    PubMed

    Wang, Xu; Xie, Kelin; Zhuang, Haining; Ye, Ran; Fang, Zhongxiang; Feng, Tao

    2015-09-01

    The volatile compounds in gingko wine, a novel functional wine, were extracted by head-space solid phase micro-extraction (SPME) and analyzed by gas chromatography-mass spectrometry (GC-MS) coupled with odor activity value (OAV) and relative odor contribution (ROC) analyses. In addition, the total polyphenolic content of gingko wine was determined using the Folin-Ciocalteu reagent, and its antioxidant capacity was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. Fifty-eight compounds were tentatively identified, including 13 esters, 10 alcohols, 11 acids, 12 carbonyl compounds, 2 lactones, 2 phenols, and 8 hydrocarbons. Ethyl hexanoate, ethyl pentanoate, nonanal, ethyl butyrate and ethyl heptanoate were the major contributors to the gingko wine aroma based on the results of OAV and ROC. The total phenols content of the gingko wine was 456 mg/L gallic acid equivalents, and its antioxidant capacity was higher than those of typical Chinese liquors analyzed in this paper. PMID:25842306

  10. Inhibition of soluble epoxide hydrolase activity by compounds isolated from the aerial parts of Glycosmis stenocarpa.

    PubMed

    Kim, Jang Hoon; Morgan, Abubaker M A; Tai, Bui Huu; Van, Doan Thi; Cuong, Nguyen Manh; Kim, Young Ho

    2016-08-01

    The aim of this study is to search for soluble epoxide hydrolase (sEH) inhibitors from natural plants, bioassay-guided fractionation of lipophilic n-hexane and chloroform layers of an extract of the aerial parts of Glycosmis stenocarpa led to the isolation of 12 compounds (1-12) including murrayafoline-A (1), isomahanine (2), bisisomahanine (3), saropeptate (4), (24 S)-ergost-4-en-3,6-dione (5), stigmasta-4-en-3,6-dion (6), stigmast-4-en-3-one (7), β-sitosterol (8), 24-methylpollinastanol (9), trans-phytol (10), neosarmentol III (11) and (+)-epiloliolide (12). Their structures were elucidated on the basis of spectroscopic data. Among them, neosarmentol III (11) was isolated from nature for the first time. All the isolated compounds were evaluated for their inhibitory activity against sEH. Among isolated carbazole-type compounds, isomahanine (2) and bisisomahanine (3) were identified as a potent inhibitor of sEH, with IC50 values of 22.5 ± 1.7 and 7.7 ± 1.2 µM, respectively. Moreover, the inhibitory action of 2 and 3 represented mixed-type enzyme inhibition. PMID:26444316

  11. Structural alerts for predicting clastogenic activity of pro-oxidant flavonoid compounds: quantitative structure-activity relationship study.

    PubMed

    Yordi, Estela Guardado; Pérez, Enrique Molina; Matos, Maria Joao; Villares, Eugenio Uriarte

    2012-02-01

    Flavonoids have been reported to exert multiple biological effects that include acting as pro-oxidants at very high doses. The authors determined a structural alert to identify the clastogenic activity of a series of flavonoids with pro-oxidant activity. The methodology was based on a quantitative structure-activity relationship (QSAR) study. Specifically, the authors developed a virtual screening method for a clastogenic model using the topological substructural molecular design (TOPS-MODE) approach. It represents a useful platform for the automatic generation of structural alerts, based on the calculation of spectral moments of molecular bond matrices appropriately weighted, taking into account the hydrophobic, electronic, and steric molecular features. Therefore, it was possible to establish the structural criteria for maximal clastogenicity of pro-oxidant flavonoids: the presence of a 3-hydroxyl group and a 4-carbonyl group in ring C, the maximal number of hydroxyl groups in ring B, the presence of methoxyl and phenyl groups, the absence of a 2,3-double bond in ring C, and the presence of 5,7 hydroxyl groups in ring A. The presented clastogenic model may be useful for screening new pro-oxidant compounds. This alert could help in the design of new and efficient flavonoids, which could be used as bioactive compounds in nutraceuticals and functional food. PMID:21940715

  12. Methanobactin: a copper binding compound having antibiotic and antioxidant activity isolated from methanotrophic bacteria

    DOEpatents

    DiSpirito, Alan A.; Zahn, James A.; Graham, David W.; Kim, Hyung J.; Alterman, Michail; Larive, Cynthia

    2007-04-03

    A means and method for treating bacterial infection, providing antioxidant activity, and chelating copper using a copper binding compound produced by methanotrophic bacteria is described. The compound, known as methanobactin, is the first of a new class of antibiotics having gram-positive activity. Methanobactin has been sequenced, and its structural formula determined.

  13. Evaluation of Natural Compounds for Antimicrobial Activity in the Introductory Microbiology Laboratory.

    ERIC Educational Resources Information Center

    Finer, Kim R.

    1997-01-01

    Presents an experiment that provides students with an opportunity to investigate folk medicine and herbal cures and their accompanying claims. Involves isolating some active compounds from plant materials and demonstrating their antibacterial activity. (JRH)

  14. A Survey of Marine Natural Compounds and Their Derivatives with Anti-cancer Activity Reported in 2012.

    PubMed

    Sawadogo, Wamtinga Richard; Boly, Rainatou; Cerella, Claudia; Teiten, Marie Hélène; Dicato, Mario; Diederich, Marc

    2015-01-01

    Although considerable effort and progress has been made in the search for new anticancer drugs and treatments in the last several decades, cancer remains a major public health problem and one of the major causes of death worldwide. Many sources, including plants, animals, and minerals, are of interest in cancer research because of the possibility of identifying novel molecular therapeutics. Moreover, structure-activity-relationship (SAR) investigations have become a common way to develop naturally derived or semi-synthetic molecular analogues with improved efficacy and decreased toxicity. In 2012, approximately 138 molecules from marine sources, including isolated compounds and their associated analogues, were shown to be promising anticancer drugs. Among these, 62% are novel compounds. In this report, we review the marine compounds identified in 2012 that may serve as novel anticancer drugs. PMID:25903364

  15. A novel approach for identification of biologically active phenolic compounds in complex matrices using hybrid quadrupole-orbitrap mass spectrometer: A promising tool for testing antimicrobial activity of hops.

    PubMed

    Dušek, Martin; Jandovská, Vladimíra; Čermák, Pavel; Mikyška, Alexandr; Olšovská, Jana

    2016-08-15

    The phenolic compounds, secondary metabolites of hops represent a large family of compounds that could be subsequently divided into smaller groups based on the similarities between their chemical structures. The antibacterial, antifungal and antiviral properties of hops are well known, but there is a lack of information about antimicrobial activities of individual hop compounds. This study was carried out with an objective to identify compounds present in hops that have potential antibacterial activity. In the first stage of experiment, the active compounds with potential anti-microbial activity had to be extracted from hop cones. Therefore, minced hop cones were applied on solid growth medium inoculated with Staphylococcus aureus. The active substances that migrated into the medium created an inhibition zone. In the second stage of experiment, the inhibition zones were cut out from Petri dishes, active compounds were extracted from these zones and consequently analyzed using LC-HRMS. These complex assays were developed and optimized. The data were acquired by using a quadrupole-orbitrap hybrid mass spectrometer by targeted-MS2 experiment in both ionization modes. The MS method has been developed as a screening method with a subsequent fragmentation of compound of interest on the base of inclusion mass list. The unknown compounds extracted from inhibition zones have been identified either by searching against a database or their structure has been elucidated on the basis of their fragmentation spectra. On the basis of this experiment the list of active compounds with potential anti-microbial activities was enhanced. PMID:27260455

  16. The removal of endocrine disrupting compounds, pharmaceutically activated compounds and cyanobacterial toxins during drinking water preparation using activated carbon--a review.

    PubMed

    Delgado, Luis F; Charles, Philippe; Glucina, Karl; Morlay, Catherine

    2012-10-01

    This paper provides a review of recent scientific research on the removal by activated carbon (AC) in drinking water (DW) treatment of 1) two classes of currently unregulated trace level contaminants with potential chronic toxicity-pharmaceutically activate compounds (PhACs) and endocrine disrupting compounds (EDCs); 2) cyanobacterial toxins (CyBTs), which are a group of highly toxic and regulated compounds (as microcystin-LR); and 3) the above mentioned compounds by the hybrid system powdered AC/membrane filtration. The influence of solute and AC properties, as well as the competitive effect from background natural organic matter on the adsorption of such trace contaminants, are also considered. In addition, a number of adsorption isotherm parameters reported for PhACs, EDCs and CyBTs are presented herein. AC adsorption has proven to be an effective removal process for such trace contaminants without generating transformation products. This process appears to be a crucial step in order to minimize PhACs, EDCs and CyBTs in finished DW, hence calling for further studies on AC adsorption removal of these compounds. Finally, a priority chart of PhACs and EDCs warranting further study for the removal by AC adsorption is proposed based on the compounds' structural characteristics and their low removal by AC compared to the other compounds. PMID:22885596

  17. Antibacterial activity of extracellular compounds produced by a Pseudomonas strain against methicillin-resistant Staphylococcus aureus (MRSA) strains

    PubMed Central

    2013-01-01

    Background The emergence of multidrug-resistant bacteria is a world health problem. Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains, is one of the most important human pathogens associated with hospital and community-acquired infections. The aim of this work was to evaluate the antibacterial activity of a Pseudomonas aeruginosa-derived compound against MRSA strains. Methods Thirty clinical MRSA strains were isolated, and three standard MRSA strains were evaluated. The extracellular compounds were purified by vacuum liquid chromatography. Evaluation of antibacterial activity was performed by agar diffusion technique, determination of the minimal inhibitory concentration, curve of growth and viability and scanning electron microscopy. Interaction of an extracellular compound with silver nanoparticle was studied to evaluate antibacterial effect. Results The F3 (ethyl acetate) and F3d (dichloromethane- ethyl acetate) fractions demonstrated antibacterial activity against the MRSA strains. Phenazine-1-carboxamide was identified and purified from the F3d fraction and demonstrated slight antibacterial activity against MRSA, and synergic effect when combined with silver nanoparticles produced by Fusarium oxysporum. Organohalogen compound was purified from this fraction showing high antibacterial effect. Using scanning electron microscopy, we show that the F3d fraction caused morphological changes to the cell wall of the MRSA strains. Conclusions These results suggest that P. aeruginosa-produced compounds such as phenazines have inhibitory effects against MRSA and may be a good alternative treatment to control infections caused by MRSA. PMID:23773484

  18. An in silico study on antidiabetic activity of bioactive compounds in Euphorbia thymifolia Linn.

    PubMed

    Nguyen Vo, T Hoang; Tran, Ngan; Nguyen, Dat; Le, Ly

    2016-01-01

    Herbal medicines have become strongly preferred treatment to reduce the negative impacts of diabetes mellitus (DM) and its severe complications due to lesser side effects and low cost. Recently, strong anti-hyperglycemic effect of Euphorbia thymifolia Linn. (E. thymifolia) on mice models has reported but the action mechanism of its bioactive compounds has remained unknown. This study aimed to evaluate molecular interactions existing between various bioactive compounds in E. thymifolia and targeted proteins related to Type 2 DM. This process involved the molecular docking of 3D structures of those substances into 4 targeted proteins: 11-β hydroxysteroid dehydrogenase type 1, glutamine: fructose-6-phosphate amidotransferase, protein-tyrosine phosphatase 1B and mono-ADP-ribosyltransferase sirtuin-6. In the next step, LigandScout was applied to evaluate the bonds formed between 20 ligands and the binding sites of each targeted proteins. The results identified seven bioactive compounds with high binding affinity (<-8.0 kcal/mol) to all 4 targeted proteins including β-amyrine, taraxerol, 1-O-galloyl-β-d-glucose, corilagin, cosmosiin, quercetin-3-galactoside and quercitrin. The pharmacophore features were also explained in 2D figures which indicated hydrophobic interactions, hydrogen bond acceptors and hydrogen bond donors forming between carbonyl oxygen molecules of those ligands and active site residues of 4 targeted protein.Graphical abstract Euphorbia thymifolia Linn. is a small prostrate herbaceous annual weed that can positively impact on reducing hyperglycemic effect. In order to clearly understand about molecular level of the its bioactive compounds, in silico approach is performed. PMID:27588252

  19. Structural characterisation and antioxidant activity evaluation of phenolic compounds from cold-pressed Perilla frutescens var. arguta seed flour.

    PubMed

    Zhou, Xiao-Jing; Yan, Lin-Lin; Yin, Pei-Pei; Shi, Ling-Ling; Zhang, Jing-Hua; Liu, Yu-Jun; Ma, Chao

    2014-12-01

    A total of 11 phenolic compounds, as well as sucrose (12) and tryptophan (13), were isolated from cold-pressed Perilla frutescens var. arguta seed flour using column chromatography, and their chemical structures were identified as 3'-dehydroxyl-rosmarinic acid-3-o-glucoside (1), rosmarinic acid-3-o-glucoside (2), rosmarinic acid (3), rosmarinic acid methyl ester (4), luteolin (5), luteolin-5-o-glucoside (6), apigenin (7), caffeic acid (8), caffeic acid-3-o-glucoside (9), vanillic acid (10) and cimidahurinine (11) using NMR and time-of-flight mass spectrometry. Of these components, compound 1 is novel, and this is the first report of compounds 10 and 11 in perilla seeds. HPLC quantification combined with antioxidant activity evaluation revealed that rosmarinic acid and rosmarinic acid-3-o-glucoside were the dominant phenolic antioxidants with strong antioxidant activities. PMID:24996318

  20. Isolation and identification of active compounds from Drimys winteri barks.

    PubMed

    Cechinel Filho, V; Schlemper, V; Santos, A R; Pinheiro, T R; Yunes, R A; Mendes, G L; Calixto, J B; Delle Monache, F

    1998-10-01

    The barks of Drimys winteri are used in folk medicine as a remedy to treat several diseases, including dolorous processes. Previous pre-clinical experiments carried out in our laboratories revealed that the hydroalcoholic extract of this plant showed anti-allergenic, anti-inflammatory and antinociceptive properties. Such promising results led us to determine the analgesic compounds present in D. winteri. Through conventional chromatographic procedures with fractions of CH2Cl2 and EtOAc obtained from methanolic extract, it was found that polygodial (1), 1-beta-(p-methoxycynnamyl) polygodial (2), taxifolin (3) and astilbin (4), are the main components of these fractions. Compounds 1 and 2 exhibited marked antinociceptive action by intraperitoneal and oral routes against acetic acid-induced abdominal constrictions in mice, suggesting that they are responsible, at least partially, for the antinociceptive effects of this plant. In addition, both compounds were notably more potent than aspirin and acetaminophen, two well-known drugs used here as comparison. PMID:9849632

  1. Bioactive compounds and antioxidant activity analysis of Malaysian pineapple cultivars

    NASA Astrophysics Data System (ADS)

    Chiet, Chong Hang; Zulkifli, Razauden Mohamed; Hidayat, Topik; Yaakob, Harisun

    2014-03-01

    Pineapple industry is one of the important agricultural sectors in Malaysia with 76 cultivars planted throughout the country. This study aims to generate useful nutritional information as well as evaluating antioxidant properties of different pineapple commercial cultivars in Malaysia. The bioactive compound content and antioxidant capacity of `Josapine', `Morris' and `Sarawak' pineapple (Ananas comosus) were studied. The pineapple varieties were collected at commercial maturity stage (20-40% yellowish of fruit peel) and the edible portion of the fruit was used as sample for evaluation. The bioactive compound of the fruit extracts were evaluated by total phenolic and tannin content assay while the antioxidant capacity was determined by ferric reducing antioxidant power (FRAP). From the results obtained, total phenolic and tannin content was highest for `Josapine' followed by `Morris' and `Sarawak'. With respect to FRAP, `Josapine' showed highest reducing capacity, followed by `Morris' and then `Sarawak' having the least value. The bioactive compounds content are positively correlated with the antioxidant capacities of the pineapple extracts. This result indicates that the total phenolics and tannin content present in the pineapples may contribute to the antioxidant capacity of the pineapples.

  2. Radiosensitization of Escherichia coli and Salmonella typhi in presence of active compounds

    NASA Astrophysics Data System (ADS)

    Lacroix, M.; Chiasson, F.; Borsa, J.; Ouattara, B.

    2004-09-01

    The radiosensitization of Escherichia coli and Salmonella typhi in ground beef was evaluated in the presence of 18 active compounds. Medium fat ground beef (23% fat) was inoculated with E. coli or S. typhi and each active compound was added separately at various concentrations. For E. coli, the most efficient compounds were trans-cinnamaldehyde, thymol and thyme. For S. typhi, the most efficient compounds was trans-cinnamaldehyde, carvacrol and thymol. The addition of tetrasodium pyrophosphate, carvacrol and ascorbic acid had no effect on the irradiation sensitivity of E. coli. For S. typhi, only ascorbic acid had no effect.

  3. Odor-active compounds in cooked rice cultivars from Camargue (France) analyzed by GC-O and GC-MS.

    PubMed

    Maraval, Isabelle; Mestres, Christian; Pernin, Karine; Ribeyre, Fabienne; Boulanger, Renaud; Guichard, Elisabeth; Gunata, Ziya

    2008-07-01

    Volatile compounds of cooked rice from scented (Aychade, Fidji) and nonscented (Ruille) cultivars grown in the Camargue area in France were compared to that of a marketed Asian scented one (Thai) by gas chromatography-olfactometry (GC-O) and gas chromatography-mass spectrometry (GC-MS). GC-O analyses of the organic extracts resulted in the perception of 40 odorous compounds. Only two compounds, oct-1-en-3-one and 2-acetyl-1-pyrroline, were almost always perceived. Hierarchical cluster analysis showed that most of the difference between rice odors was linked to quantitative differences with only 11 compounds being specific to some of the rice. Sixty compounds were identified and quantified by GC-MS, including a few new odor-active components. Principal component analysis enabled us to differentiate scented cultivars from a nonscented one, and scented rice cultivars from Camargue from a Thai sample. Calculated odor-active values evidenced that the Thai sample odor differed from that of scented Camargue cultivars because of the degradation of lipids and of cinnamic acid compounds. PMID:18547050

  4. Discovery of a Novel Compound with Anti-Venezuelan Equine Encephalitis Virus Activity That Targets the Nonstructural Protein 2

    PubMed Central

    Chung, Dong-Hoon; Jonsson, Colleen B.; Tower, Nichole A.; Chu, Yong-Kyu; Sahin, Ergin; Golden, Jennifer E.; Noah, James W.; Schroeder, Chad E.; Sotsky, Julie B.; Sosa, Melinda I.; Cramer, Daniel E.; McKellip, Sara N.; Rasmussen, Lynn; White, E. Lucile; Schmaljohn, Connie S.; Julander, Justin G.; Smith, Jeffrey M.; Filone, Claire Marie; Connor, John H.; Sakurai, Yasuteru; Davey, Robert A.

    2014-01-01

    Alphaviruses present serious health threats as emerging and re-emerging viruses. Venezuelan equine encephalitis virus (VEEV), a New World alphavirus, can cause encephalitis in humans and horses, but there are no therapeutics for treatment. To date, compounds reported as anti-VEEV or anti-alphavirus inhibitors have shown moderate activity. To discover new classes of anti-VEEV inhibitors with novel viral targets, we used a high-throughput screen based on the measurement of cell protection from live VEEV TC-83-induced cytopathic effect to screen a 340,000 compound library. Of those, we identified five novel anti-VEEV compounds and chose a quinazolinone compound, CID15997213 (IC50 = 0.84 µM), for further characterization. The antiviral effect of CID15997213 was alphavirus-specific, inhibiting VEEV and Western equine encephalitis virus, but not Eastern equine encephalitis virus. In vitro assays confirmed inhibition of viral RNA, protein, and progeny synthesis. No antiviral activity was detected against a select group of RNA viruses. We found mutations conferring the resistance to the compound in the N-terminal domain of nsP2 and confirmed the target residues using a reverse genetic approach. Time of addition studies showed that the compound inhibits the middle stage of replication when viral genome replication is most active. In mice, the compound showed complete protection from lethal VEEV disease at 50 mg/kg/day. Collectively, these results reveal a potent anti-VEEV compound that uniquely targets the viral nsP2 N-terminal domain. While the function of nsP2 has yet to be characterized, our studies suggest that the protein might play a critical role in viral replication, and further, may represent an innovative opportunity to develop therapeutic interventions for alphavirus infection. PMID:24967809

  5. Biologically active vitamin B12 compounds in foods for preventing deficiency among vegetarians and elderly subjects.

    PubMed

    Watanabe, Fumio; Yabuta, Yukinori; Tanioka, Yuri; Bito, Tomohiro

    2013-07-17

    The usual dietary sources of vitamin B12 are animal-source based foods, including meat, milk, eggs, fish, and shellfish, although a few plant-based foods such as certain types of dried lavers (nori) and mushrooms contain substantial and considerable amounts of vitamin B12, respectively. Unexpectedly, detailed characterization of vitamin B12 compounds in foods reveals the presence of various corrinoids that are inactive in humans. The majority of edible blue-green algae (cyanobacteria) and certain edible shellfish predominately contain an inactive corrinoid known as pseudovitamin B12. Various factors affect the bioactivity of vitamin B12 in foods. For example, vitamin B12 is partially degraded and loses its biological activity during cooking and storage of foods. The intrinsic factor-mediated gastrointestinal absorption system in humans has evolved to selectively absorb active vitamin B12 from naturally occurring vitamin B12 compounds, including its degradation products and inactive corrinoids that are present in daily meal foods. The objective of this review is to present up-to-date information on various factors that can affect the bioactivity of vitamin B12 in foods. To prevent vitamin B12 deficiency in high-risk populations such as vegetarians and elderly subjects, it is necessary to identify plant-source foods that contain high levels of bioactive vitamin B12 and, in conjunction, to prepare the use of crystalline vitamin B12-fortified foods. PMID:23782218

  6. Integrated compound profiling screens identify the mitochondrial electron transport chain as the molecular target of the natural products manassantin, sesquicillin, and arctigenin.

    PubMed

    Lai, Kevin; Selinger, Douglas W; Solomon, Jonathan M; Wu, Hua; Schmitt, Esther; Serluca, Fabrizio C; Curtis, Daniel; Benson, John D

    2013-01-18

    Phenotypic compound screens can be used to identify novel targets in signaling pathways and disease processes, but the usefulness of these screens depends on the ability to quickly determine the target and mechanism of action of the molecules identified as hits. One fast route to discovering the mechanism of action of a compound is to profile its properties and to match this profile with those of compounds of known mechanism of action. In this work, the Novartis collection of over 12,000 pure natural products was screened for effects on early zebrafish development. The largest phenotypic class of hits, which caused developmental arrest without necrosis, contained known electron transport chain inhibitors and many compounds of unknown mechanism of action. High-throughput transcriptional profiling revealed that these compounds are mechanistically related to one another. Metabolic and biochemical assays confirmed that all of the molecules that induced developmental arrest without necrosis inhibited the electron transport chain. These experiments demonstrate that the electron transport chain is the target of the natural products manassantin, sesquicillin, and arctigenin. The overlap between the zebrafish and transcriptional profiling screens was not perfect, indicating that multiple profiling screens are necessary to fully characterize molecules of unknown function. Together, zebrafish screening and transcriptional profiling represent sensitive and scalable approaches for identifying bioactive compounds and elucidating their mechanism of action. PMID:23138533

  7. Asymmetric bioreduction of activated alkenes to industrially relevant optically active compounds

    PubMed Central

    Winkler, Christoph K.; Tasnádi, Gábor; Clay, Dorina; Hall, Mélanie; Faber, Kurt

    2012-01-01

    Ene-reductases from the ‘Old Yellow Enzyme’ family of flavoproteins catalyze the asymmetric reduction of various α,β-unsaturated compounds at the expense of a nicotinamide cofactor. They have been applied to the synthesis of valuable enantiopure products, including chiral building blocks with broad industrial applications, terpenoids, amino acid derivatives and fragrances. The combination of these highly stereoselective biocatalysts with a cofactor recycling system has allowed the development of cost-effective methods for the generation of optically active molecules, which is strengthened by the availability of stereo-complementary enzyme homologues. PMID:22498437

  8. Larvicidal activity of medicinal plant extracts and lignan identified in Phryma leptostachya var. asiatica roots against housefly (Musca domestica L.).

    PubMed

    Seo, Seon-Mi; Park, Il-Kwon

    2012-05-01

    Medicinal plant extracts from 27 plant species in 20 families were tested for their larvicidal activity against housefly, Musca domestica (L.). Responses varied with plant material and concentration. Among plant species tested, Phryma leptostachya var. asiatica showed 100% larvicidal activity against M. domestica at 10 mg/g concentration. Larvicidal activities of Atractylodes japonica, Saussurea lappa, Asiasarum sieboldi, and Gleditsia japonica var. koraiensis were 89.3%, 85.3%, 93.3%, and 96.6% at 10 mg/g concentration, respectively. Extracts of Prunus persica, Curcuma longa, and Paeonia moutan produced moderate activity. Larvicidal activity of other plant extracts was less than 50%. Among test plant species, P. leptostachya var. asiatica showed the most potent larvicidal activity. The active constituent of P. leptostachya var. asiatica roots was identified as the leptostachyol acetate by spectroscopic analysis. The LC(50) values of leptostachyol acetate against M. domestica larvae were 0.039 mg/g. Naturally occurring medicinal plant extracts and P. leptostachya var. asiatica root-derived compounds merit further study as potential housefly larval control agents or lead compounds. PMID:22065063

  9. Anti-inflammatory and anticancer activities of extracts and compounds from the mushroom Inonotus obliquus.

    PubMed

    Ma, Lishuai; Chen, Haixia; Dong, Peng; Lu, Xueming

    2013-08-15

    Mushroom Inonotus obliquus (I. obliquus) has been used as functional food and traditional Chinese herbs for long time. An efficient method for bioassay-guided preparative isolation was used for identifying the anti-inflammatory and anticancer constituents in I. obliquus. The petroleum ether and ethyl acetate fractions were found to have significant inhibition effects on NO production and NF-κB luciferase activity in macrophage RAW 264.7 cells and cytotoxicity against human prostatic carcinoma cell PC3 and breast carcinoma cell MDA-MB-231. Six main constituents were isolated from these two fractions and they were identified as lanosterol (1), 3β-hydroxy-8,24-dien-21-al (2), ergosterol (3), inotodiol (4), ergosterol peroxide (5) and trametenolic acid (6). Compound ergosterol, ergosterol peroxide and trametenolic acid showed anti-inflammatory activities and ergosterol peroxide and trametenolic acid showed obviously cytotoxicity on human prostatic carcinoma cell PC3 and breast carcinoma MDA-MB-231 cell. The results obtained in this work might contribute to understanding the biological activity of mushroom I. obliquus for food and drug application. PMID:23561137

  10. Isolation of Bioactive Compounds That Relate to the Anti-Platelet Activity of Cymbopogon ambiguus

    PubMed Central

    Grice, I. Darren; Rogers, Kelly L.; Griffiths, Lyn R.

    2011-01-01

    Infusions and decoctions of Cymbopogon ambiguus have been used traditionally in Australia for the treatment of headache, chest infections and muscle cramps. The aim of the present study was to screen and identify bioactive compounds from C. ambiguus that could explain this plant's anti-headache activity. A dichloromethane extract of C. ambiguus was identified as having activity in adenosine-diphosphate-induced human platelet aggregation and serotonin-release inhibition bioassays. Subsequent fractionation of this extract led to the isolation of four phenylpropenoids, eugenol, elemicin, eugenol methylether and trans-isoelemicin. While both eugenol and elemicin exhibited dose-dependent inhibition of ADP-induced human platelet serotonin release, only eugenol displayed potent inhibitory activity with an IC50 value of 46.6 μM, in comparison to aspirin, with an IC50 value of 46.1 μM. These findings provide evidence to support the therapeutic efficacy of C. ambiguus in the non-conventional treatment of headache and inflammatory conditions. PMID:20047890

  11. Identifying unknown minerals and compounds from X-ray diffraction patterns using the Johnson and Vand FORTRAN 4 computer program

    NASA Technical Reports Server (NTRS)

    Kyte, F. T.

    1976-01-01

    Automated computer identification of minerals and compounds from unknown samples is provided along with detailed instructions and worked examples for use in graduate level courses in mineralogy and X-ray analysis applications.

  12. Multiple microbial activities for volatile organic compounds reduction by biofiltration.

    PubMed

    Civilini, Marcello

    2006-07-01

    In the northeast of Italy, high volatile organic carbon (VOC) emissions originate from small-medium companies producing furniture. In these conditions it is difficult to propose a single, efficient, and economic system to reduce pollution. Among the various choices, the biofiltration method could be a good solution, because microbial populations possess multiple VOC degradation potentials used to oxidize these compounds to CO2. Starting from the air emissions of a typical industrial wood-painting plant, a series of experiments studied in vitro microbial degradation of each individual VOC. Isolated strains were then added to a laboratory-scale biofiltration apparatus filled with an organic matrix, and the different VOC behavior demonstrated the potential of single and/or synergic microbial removal actions. When a single substrate was fed, the removal efficiency of a Pseudomonas aeruginosa inoculated reactor was 1.1, 1.17, and 0.33 g m(-3) hr(-1), respectively, for xylene, toluene, and ethoxy propyl acetate. A VOC mixture composed of butyl acetate, ethyl acetate, diacetin alcohol, ethoxy propanol acetate, methyl ethyl ketone, methyl isobutyl ketone, toluene, and xylene was then fed into a 2-m(3) reactor treating 100 m3 hr(-1) of contaminated air. The reactor was filled with the same mixture of organic matrix, enriched with all of the isolated strains together. During reactor study, different VOC loading rates were used, and the behavior was evaluated continuously. After a short acclimation period, the removal efficiency was > 65% at VOC load of 150-200 g m(-3) hr(-1). Quantification of removal efficiencies and VOC speciation confirmed the relationship among removal efficiencies, compound biodegradability, and the dynamic transport of each mixture component within the organic matrix. Samples of the fixed bed were withdrawn at different intervals and the heterogeneous microbial community evaluated for both total and differential compound counts. PMID:16878585

  13. Review on Natural Coumarin Lead Compounds for Their Pharmacological Activity

    PubMed Central

    Venugopala, K. N.; Rashmi, V.; Odhav, B.

    2013-01-01

    Coumarin (2H-1-benzopyran-2-one) is a plant-derived natural product known for its pharmacological properties such as anti-inflammatory, anticoagulant, antibacterial, antifungal, antiviral, anticancer, antihypertensive, antitubercular, anticonvulsant, antiadipogenic, antihyperglycemic, antioxidant, and neuroprotective properties. Dietary exposure to benzopyrones is significant as these compounds are found in vegetables, fruits, seeds, nuts, coffee, tea, and wine. In view of the established low toxicity, relative cheapness, presence in the diet, and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further. PMID:23586066

  14. Rapid screening and quantitative determination of bioactive compounds from fruit extracts of Myristica species and their in vitro antiproliferative activity.

    PubMed

    Pandey, Renu; Mahar, Rohit; Hasanain, Mohammad; Shukla, Sanjeev K; Sarkar, Jayanta; Rameshkumar, K B; Kumar, Brijesh

    2016-11-15

    Efficient and sensitive LC-MS/MS methods have been developed for the rapid screening and determination of bioactive compounds in different fruit parts of four Myristica species, viz., Myristica beddomeii, Myristica fragrans, Myristica fatua and Myristica malabarica. Twenty-one compounds were identified and characterized on the basis of their accurate mass and MS/MS fragmentation pattern using HPLC-QTOF-MS/MS and NMR analysis. Quantitative determination of five major bioactive compounds was performed using multiple-reaction monitoring mode with continuous polarity switching by UHPLC-QqQLIT-MS/MS. Moreover, in vitro antiproliferative activity of these Myristica species was evaluated against five human cancer cell lines A549, DLD-1, DU145, FaDu and MCF-7 using SRB assay. Seventeen phytoconstituents were identified and reported for the first time from M. beddomeii and sixteen from M. fatua. Quantification result showed highest total content of five major bioactive compounds in mace of M. fragrans. Evaluation of in vitro antiproliferative activity revealed potent activity in all investigated species except M. fragrans. PMID:27283658

  15. Detection of retinoic acid receptor agonistic activity and identification of causative compounds in municipal wastewater treatment plants in Japan.

    PubMed

    Sawada, Kazuko; Inoue, Daisuke; Wada, Yuichiro; Sei, Kazunari; Nakanishi, Tsuyoshi; Ike, Michihiko

    2012-02-01

    Retinoic acid (RA) receptor (RAR) agonists are potential toxicants that can cause teratogenesis in vertebrates. To determine the occurrence of RAR agonists in municipal wastewater treatment plants (WWTPs), we examined the RARα agonistic activities of influent and effluent samples from several municipal WWTPs in Osaka, Japan, using a yeast two-hybrid assay. Significant RARα agonistic activity was detected in all the influent samples investigated, suggesting that municipal wastewater consistently contains RAR agonists. Fractionations using high-performance liquid chromatography, directed by the bioassay, found several bioactive peaks from influent samples. The RAR agonists, all-trans RA (atRA), 13-cis RA (13cRA), 4-oxo-atRA, and 4-oxo-13cRA, possibly arising from human urine, were identified by liquid chromatography ion trap time-of-flight mass spectrometry. Quantification of the identified compounds in municipal WWTPs confirmed that they were responsible for the majority of RARα agonistic activity in WWTP influents, and also revealed they were readily removed from wastewater by activated sludge treatment. Simultaneous measurement of the RARα agonistic activity revealed that although total activity typically declined concomitant with the reduction of the four identified compounds, it remained high after the decline of RAs and 4-oxo-RAs in one WWTP, suggesting the occurrence of unidentified RAR agonists during the activated sludge treatment. PMID:22095885

  16. Thiazole compounds with activity against Cryptococcus gattii and Cryptococcus neoformans in vitro.

    PubMed

    Pereira de Sá, Nívea; Lino, Cleudiomar Inácio; Fonseca, Nayara Cristina; Borelli, Beatriz Martins; Ramos, Jonas Pereira; Souza-Fagundes, Elaine Maria; Rosa, Carlos Augusto; Santos, Daniel Assis; Barbosa de Oliveira, Renata; Johann, Susana

    2015-09-18

    Human cryptococcosis can occur as a primary or opportunistic infection and develop as an acute, subacute, or chronic, systemic infection involving different host organs. We evaluated the antifungal activity of thirteen compounds against Cryptococcus gattii and Cryptococcus neoformans in vitro, by assessing the toxicity of the compounds showing the greatest antifungal activity in VERO cells and murine macrophages. From these results, four compounds were considered promising for further studies because they displayed low cytotoxicity and significant antifungal activity. The heterocyclic compounds 1b, 1c, 1d, and 1m have antifungal activity levels between that of amphotericin B and fluconazole in vitro. The death curve of Cryptococcus spp. treated with these four compounds was similar to the curve obtained for amphotericin B, in that we observed a significant reduction in cell viability within the first 24 h of treatment. Additionally, we found that there was no effect when these compounds were combined with amphotericin and fluconazole, except for 1c, which antagonized the effect of amphotericin B against C. gattii, also reflected in the reduction of the post-antifungal effect (PAFE); however, this interaction did not alter the ergosterol content. The results shown in this paper reveal the discovery of novel thiazole compounds, which are easy to synthesize, and with potentially exhibit antifungal activity, and display low cytotoxicity in normal mammalian cells. These compounds can be used as prototypes for the design of new antifungal drugs against C. gattii and C. neoformans. PMID:26276437

  17. Bioactive compounds from Bauhinia purpurea possessing antimalarial, antimycobacterial, antifungal, anti-inflammatory, and cytotoxic activities.

    PubMed

    Boonphong, Surat; Puangsombat, Pakawan; Baramee, Apiwat; Mahidol, Chulabhorn; Ruchirawat, Somsak; Kittakoop, Prasat

    2007-05-01

    Eleven new secondary metabolites (1-11), together with two known flavanones (12 and 13) and five known bibenzyls (14-18), were isolated from the root extract of Bauhinia purpurea. New compounds include eight dihydrodibenzoxepins (1-8), a dihydrobenzofuran (9), a novel spirochromane-2,1'-hexenedione (10), and a new bibenzyl (11). Antimycobacterial, antimalarial, antifungal, cytotoxic, and anti-inflammatory activities of the isolated compounds are reported, and biosynthetic pathways of these compounds are also discussed. PMID:17480099

  18. A high throughput drug screen based on fluorescence resonance energy transfer (FRET) for anticancer activity of compounds from herbal medicine

    PubMed Central

    Tian, H; Ip, L; Luo, H; Chang, D C; Luo, K Q

    2006-01-01

    Background and purpose: We report the development of a very efficient cell-based high throughput screening (HTS) method, which utilizes a novel bio-sensor that selectively detects apoptosis based on the fluorescence resonance energy transfer (FRET) technique. Experimental approach: We generated a stable HeLa cell line expressing a FRET-based bio-sensor protein. When cells undergo apoptosis, they activate a protease called ‘caspase-3'. Activation of this enzyme will cleave our sensor protein and cause its fluorescence emission to shift from a wavelength of 535 nm (green) to 486 nm (blue). A decrease in the green/blue emission ratio thus gives a direct indication of apoptosis. The sensor cells are grown in 96-well plates. After addition of different chemical compounds to each well, a fluorescence profile can be measured at various time-points using a fluorescent plate reader. Compounds that can trigger apoptosis are potential candidates as anti-cancer drugs. Key results: This novel cell-based HTS method is highly effective in identifying anti-cancer compounds. It was very sensitive in detecting apoptosis induced by various known anti-cancer drugs. Further, this system detects apoptosis, but not necrosis, and is thus more useful than the conventional cell viability assays, such as those using MTT. Finally, we used this system to screen compounds, isolated from two plants used in Chinese medicine, and identified several effective compounds for inducing apoptosis. Conclusions and Implications: This FRET-based HTS method is a powerful tool for identifying anti-cancer compounds and can serve as a highly efficient platform for drug discovery. PMID:17179946

  19. Inhibitory effects of Tyrphostin AG-related compounds on oxidative stress-sensitive transient receptor potential channel activation.

    PubMed

    Toda, Takahiro; Yamamoto, Shinichiro; Yonezawa, Ryo; Mori, Yasuo; Shimizu, Shunichi

    2016-09-01

    Some transient receptor potential (TRP) proteins including TRPA1, TPRM2 and TRPV1 are oxidative stress-sensitive Ca(2+)-permeable channels. Ca(2+) signaling via these TRP channels activated by oxidative stress has been implicated in the aggravation of various inflammatory diseases and pain sensation. We recently reported that Tyrphostin AG490 exerted inhibitory effects on H2O2-induced TRPM2 activation by scavenging the hydroxyl radical. In order to identify stronger inhibitors of oxidative stress-sensitive TRP channels than AG490, we examined the inhibitory effects of Tyrphostin AG-related compounds on H2O2-induced TRP channel activation in human embryonic kidney 293 cells expressing TRP channels. AG555 and AG556 blocked the activation of TRPM2 by H2O2 more strongly than AG490. Regarding TRPV1 and TRPA1, none of the three compounds tested affected H2O2-induced TRPV1 activation; however, AG555 and AG556 reduced H2O2-induced TRPA1 activation more than AG490. Thus, we herein identified AG555 and AG556 as new compounds that exert stronger inhibitory effects on H2O2-induced TRPM2 and TRPA1 activation than AG490. Edaravone, a hydroxyl radical scavenger used in the treatment of cerebral hemorrhage and cerebral infarction, did not affect H2O2-induced TRPM2 or TRPA1 activation. AG555 and AG556 may be useful seed compounds as therapeutic agents for several TRP-related diseases associated with oxidative stress. PMID:27238971

  20. In vitro neuroprotective activities of compounds from Angelica shikokiana Makino.

    PubMed

    Mira, Amira; Yamashita, Shuntaro; Katakura, Yoshinori; Shimizu, Kuniyoshi

    2015-01-01

    Angelica shikokiana is widely marketed in Japan as a dietary food supplement. With a focus on neurodegenerative conditions such as Alzheimer's disease, the aerial part was extracted and through bio-guided fractionation, fifteen compounds [α-glutinol, β-amyrin, kaempferol, luteolin, quercetin, kaempferol-3-O-glucoside, kaempferol-3-O-rutinoside, methyl chlorogenate, chlorogenic acid, hyuganin E, 5-(hydroxymethyl)-2-furaldehyde, β-sitosterol-3-O-glucoside, adenosine (isolated for the first time from A. shikokiana), isoepoxypteryxin and isopteryxin] were isolated. Isolated compounds were evaluated for in vitro neuroprotection using acetylcholine esterase inhibitory, protection against hydrogen peroxide and amyloid β peptide (Aβ25-35)-induced neurotoxicity in neuro-2A cells, scavenging of hydroxyl radicals and intracellular reactive oxygen species and thioflavin T assays. Quercetin showed the strongest AChE inhibition (IC50 value = 35.5 µM) through binding to His-440 and Tyr-70 residues at the catalytic and anionic sites of acetylcholine esterase, respectively. Chlorogenic acid, its methyl ester, quercetin and luteolin could significantly protect neuro-2A cells against H2O2-induced neurotoxicity and scavenge hydroxyl radical and intracellular reactive oxygen species. Kaempferol-3-O-rutinoiside, hyuganin E and isoepoxypteryxin significantly decreased Aβ25-35-induced neurotoxicity and Th-T fluorescence. To the best of our knowledge, this is the first report about neuroprotection of hyuganin E and isoepoxypteryxin against Aβ25-35-induced neurotoxicity. PMID:25786165

  1. Volatile Organic Compounds Identified in Post-Flight Air Analysis of the Multipurpose Logistics Module from International Space Station

    NASA Astrophysics Data System (ADS)

    Peterson, B.; Wheeler, R.

    Bioregenerative systems involve storing and processing waste along with atmospheric management. The MPLM, Multipurpose Logistics Module, is a reusable logistics carrier and primary delivery system used to resupply the International Space Station (ISS) and return Station cargo that requires a pressurized environment. The cylindrical module is approximately 6.4 meters long, 4.6 meters in diameter, and weighs almost 4,082kg. The module provides storage and additional workspace for up to two astronauts when docked to the ISS. It can carry up to 9,072 kg of supplies, science experiments, spare parts and other logistical components for ISS. There is concern for a potentially hazardous condition caused by contamination of the atmosphere in the MPLM upon return from orbit. This would be largely due to unforeseen spills or container leakage. This has led to the need for special care in handling the returned module prior to processing the module for its next flight. Prior to opening the MPLM, atmospheric samples are analyzed for trace volatile organic compounds, VOC's. It is noted that our analyses also reflect the atmosphere in the ISS on that day of closure. With the re turn of STS-108, 12th ISS Flight (UF1), the analysis showed 24 PPM of methane. This corresponds to the high levels on space station during a time period when the air filtration system was shut off. Chemical characterization of atmospheres on the ISS and MPLM provide useful information for concerns with plant growth experiments on ISS. Work with closed plant growth chambers show potential for VOC's to accumulate to toxic levels for plants. The ethylene levels for 4 MPLM analyses over the course on one year were measured at, 0.070, 0.017, 0.012 and 0.007 PPM. Phytochemical such as ethylene are detected with natural plant physiological events such as flowering and as a result of plant damage or from decaying food. A build up of VOC's may contribute to phytotoxic effects for the plant growth experiments or

  2. Comparison of predicted and derived measures of volatile organic compounds inside four relocatable classrooms due to identified interior finish sources

    SciTech Connect

    Hodgson, Alfred T.; Shendell, Derek G.; Fisk, William J.; Apte, Michael G.

    2003-06-01

    Indoor exposures to toxic and odorous volatile organic compounds (VOCs) are of general concern. Recently, VOCs in portable or relocatable classrooms (RCs) have received particular attention. However, very little was known about indoor environmental quality (IEQ) and the sources, composition, and indoor concentrations of VOCs in RCs. This project task focused on developing and demonstrating a process for selecting interior finish materials for RCs that have relatively low impacts with respect to their emissions of toxic and odorous VOCs. This task was part of a larger project to demonstrate the potential for simultaneous improvements in IEQ and energy efficiency in four new RCs equipped both with a continuously ventilating advanced heating, ventilating, and air conditioning system (HVAC) and a standard HVAC system. These HVACs were operated on alternate weeks. One RC per pair was constructed with standard interior finish materials, and the other included alternate interior materials identified in our prior laboratory study to have low VOC emissions. The RCs were sited in side-by-side pairs at two elementary schools in distinct northern California climate zones. Classroom VOC emission rates (mg hr{sup -1}) and concentrations were predicted based on VOC emission factors ({micro}g m{sup -2} hr{sup -1}) measured for individual materials in the laboratory, the quantities of installed materials and design ventilation rates. Predicted emission rates were compared to values derived from classroom measurements of VOC concentrations and ventilation rates made at pre-occupancy, eight weeks, and 27 weeks. Predicted concentrations were compared to measured integrated VOC indoor minus outdoor concentrations during school hours in the fall cooling season with the advanced HVAC operated. These measured concentrations also were compared between standard and material-modified RCs. Our combined laboratory and field process proved effective by correctly predicting that IEQ impacts of

  3. Antibacterial active compounds from Hypericum ascyron L. induce bacterial cell death through apoptosis pathway.

    PubMed

    Li, Xiu-Mei; Luo, Xue-Gang; Si, Chuan-Ling; Wang, Nan; Zhou, Hao; He, Jun-Fang; Zhang, Tong-Cun

    2015-01-01

    Hypericum ascyron L. has been used as a traditional medicine for the treatment of wounds, swelling, headache, nausea and abscesses in China for thousands of years. However, modern pharmacological studies are still necessary to provide a scientific basis to substantiate their traditional use. In this study, the mechanism underlying the antimicrobial effect of the antibacterial activity compounds from H. ascyron L. was investigated. Bioguided fractionation of the extract from H. ascyron L. afforded antibacterial activity fraction 8. The results of cup plate analysis and MTT assay showed that the MIC and MBC of fraction 8 is 5 mg/mL. Furthermore, using Annexin V-FITC/PI, TUNEL labeling and DNA gel electrophoresis, we found that cell death with apoptosis features similar to those in eucaryon could be induced in bacteria strains after exposure to the antibacterial activity compounds from H. ascyron L. at moderate concentration. In addition, we further found fraction 8 could disrupt the cell membrane potential indicate that fraction 8 exerts pro-apoptotic effects through a membrane-mediated apoptosis pathway. Finally, quercetin and kaempferol 3-O-β-(2″-acetyl)-galactopyranoside, were identified from fraction 8 by means of Mass spectrometry and Nuclear magnetic resonance. To our best knowledge, this study is the first to show that Kaempferol 3-O-β-(2″-acetyl)-galactopyranoside coupled with quercetin had significant antibacterial activity via apoptosis pathway, and it is also the first report that Kaempferol 3-O-β-(2″-acetyl)-galactopyranoside was found in clusiacea. Our data might provide a rational base for the use of H. ascyron L. in clinical, and throw light on the development of novel antibacterial drugs. PMID:25916905

  4. Active compounds from a diverse library of triazolothiadiazole and triazolothiadiazine scaffolds: synthesis, crystal structure determination, cytotoxicity, cholinesterase inhibitory activity, and binding mode analysis.

    PubMed

    Khan, Imtiaz; Ibrar, Aliya; Zaib, Sumera; Ahmad, Sarfraz; Furtmann, Norbert; Hameed, Shahid; Simpson, Jim; Bajorath, Jürgen; Iqbal, Jamshed

    2014-11-01

    In an effort to identify novel cholinesterase candidates for the treatment of Alzheimer's disease (AD), a diverse array of potentially bioactive compounds including triazolothiadiazoles (4a-h and 5a-f) and triazolothiadiazines (6a-h) was obtained in good yields through the cyclocondensation reaction of 4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol (3) with various substituted aryl/heteroaryl/aryloxy acids and phenacyl bromides, respectively. The structures of newly prepared compounds were confirmed by IR, (1)H and (13)C NMR spectroscopy and, in case of 4a, by single crystal X-ray diffraction analysis. The purity of the synthesized compounds was ascertained by elemental analysis. The newly synthesized conjugated heterocycles were screened for cholinesterase inhibitory activity against electric eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE). Among the evaluated hybrids, several compounds were identified as potent inhibitors. Compounds 5b and 5d were most active with an IC50 value of 3.09 ± 0.154 and 11.3 ± 0.267 μM, respectively, against acetylcholinesterase, whereas 5b, 6a and 6g were most potent against butyrylcholinesterase, with an IC50 of 0.585 ± 0.154, 0.781 ± 0.213, and 1.09 ± 0.156 μM, respectively, compared to neostigmine and donepezil as standard drugs. The synthesized heteroaromatic compounds were also tested for their cytotoxic potential against lung carcinoma (H157) and vero cell lines. Among them, compound 6h exhibited highest antiproliferative activity against H157 cell lines, with IC50 value of 0.96 ± 0.43 μM at 1mM concentration as compared to vincristine (IC50=1.03 ± 0.04 μM), standard drug used in this study. PMID:25257911

  5. Derivatives of Procaspase-Activating Compound 1 (PAC-1) and Anticancer Activities

    PubMed Central

    Roth, Howard S.; Hergenrother, Paul J.

    2016-01-01

    PAC-1 induces the activation of procaspase-3 in vitro and in cell culture by chelation of inhibitory labile zinc ions via its ortho-hydroxy-N-acylhydrazone moiety. First reported in 2006, PAC-1 has shown promise in cell culture and animal models of cancer, and a Phase I clinical trial in cancer patients began in March 2015 (NCT02355535). Because of the considerable interest in this compound and a well-defined structure-activity relationship, over 1000 PAC-1 derivatives have been synthesized in an effort to vary pharmacological properties such as potency and pharmacokinetics. This article provides a comprehensive examination of all PAC-1 derivatives reported to date. A survey of PAC-1 derivative libraries is provided, with an in-depth discussion of four derivatives on which extensive studies have been performed. PMID:26630918

  6. Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities.

    PubMed

    Roth, Howard S; Hergenrother, Paul J

    2016-01-01

    PAC-1 induces the activation of procaspase-3 in vitro and in cell culture by chelation of inhibitory labile zinc ions via its ortho-hydroxy-N-acylhydrazone moiety. First reported in 2006, PAC-1 has shown promise in cell culture and animal models of cancer, and a Phase I clinical trial in cancer patients began in March 2015 (NCT02355535). Because of the considerable interest in this compound and a well-defined structure-activity relationship, over 1000 PAC-1 derivatives have been synthesized in an effort to vary pharmacological properties such as potency and pharmacokinetics. This article provides a comprehensive examination of all PAC-1 derivatives reported to date. A survey of PAC-1 derivative libraries is provided, with an indepth discussion of four derivatives on which extensive studies have been performed. PMID:26630918

  7. Antimicrobial activities against periodontopathic bacteria of Pittosporum tobira and its active compound.

    PubMed

    Oh, Jung-Hyun; Jeong, Yong Joon; Koo, Hyun Jung; Park, Dae Won; Kang, Se Chan; Khoa, Hoang Viet Bach; Le, Le Ba; Cho, Joon Hyeong; Lee, Jin-Yong

    2014-01-01

    The study of medicinal plants for treatment of periodontitis is of great value to establish their efficacy as sources of new antimicrobial drugs. Five hundred and fifty eight Korean local plant extracts were screened for antibacterial activity against representative periodontopathic bacteria such as Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum. Among the various medicinal plants, the alcohol extract of Pittosporum tobira, which significantly exhibited antibacterial effect for all tested strains, showed the highest activity in the antimicrobial assays. NMR analyses revealed that R1-barrigenol, a triterpene sapogenin, was the most effective compound in P. tobira. These results demonstrated that P. tobira possesses antimicrobial properties and would be beneficial for the prevention and treatment of periodontitis. PMID:24662076

  8. Synthesis, antimicrobial activity of Schiff base compounds of cinnamaldehyde and amino acids.

    PubMed

    Wang, Hui; Yuan, Haijian; Li, Shujun; Li, Zhuo; Jiang, Mingyue

    2016-02-01

    The purpose of this study was to synthesize hydrophilic cinnamaldehyde Schiff base compounds and investigate those bioactivity. A total of 24 Schiff base compounds were synthesized using a simple approach with 3 cinnamaldehyde derivates and 8 amino acids as raw materials. The structures of synthesized compounds were confirmed using FTIR, (1)HNMR, HRMS purity and melting point. The antimicrobial activities of new compounds were evaluated with fluconazole and ciprofloxacin as the control against Aspergillus niger, Penicillium citrinum, Escherichia coli and Staphylococcus aureus. Findings show that major compounds exhibited significant bioactivity. Results from the structure-activity relationship suggest that both -p-Cl on benzene ring of cinnamaldehyde and the number of -COOK of amino acid salts significantly contributed to antimicrobial activity. PMID:26774583

  9. [Importance of estrogens and estrogen-active compounds for udder health in cattle. A review].

    PubMed

    Zdunczyk, S; Zerbe, H; Hoedemaker, M

    2003-11-01

    High oestrogen concentrations in blood or high intake of oestrogen-active compounds with forage can be associated with an enhanced occurrence of udder diseases. Mean somatic cell count (MSCC) can increase and milk yield can decrease. Subclinically infected udder quarters can develop clinical mastitis and the rate of new infections can be high. This review describes concentrations of oestrogens in peripheral blood plasma in cattle and occurrence of oestrogen-active compounds in forage. Relationships between oestrogens or oestrogen-active compounds and udder health are presented. The possible mechanisms of enhanced susceptibility of the udder to infection under the influence of oestrogens are discussed. PMID:14679840

  10. Quantitative High-Throughput Screening Identifies 8-Hydroxyquinolines as Cell-Active Histone Demethylase Inhibitors

    PubMed Central

    Kawamura, Akane; Rose, Nathan R.; Ng, Stanley S.; Quinn, Amy M.; Rai, Ganesha; Mott, Bryan T.; Beswick, Paul; Klose, Robert J.; Oppermann, Udo; Jadhav, Ajit; Heightman, Tom D.; Maloney, David J.; Schofield, Christopher J.; Simeonov, Anton

    2010-01-01

    Background Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. Nε-Methylation of lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. Nε-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors. Principal Findings High-throughput screening of a ∼236,000-member collection of diverse molecules arrayed as dilution series was used to identify inhibitors of the JMJD2 (KDM4) family of 2-oxoglutarate-dependent histone demethylases. Initial screening hits were prioritized by a combination of cheminformatics, counterscreening using a coupled assay enzyme, and orthogonal confirmatory detection of inhibition by mass spectrometric assays. Follow-up studies were carried out on one of the series identified, 8-hydroxyquinolines, which were shown by crystallographic analyses to inhibit by binding to the active site Fe(II) and to modulate demethylation at the H3K9 locus in a cell-based assay. Conclusions These studies demonstrate that diverse compound screening can yield novel inhibitors of 2OG dependent histone demethylases and provide starting points for the development of potent and selective agents to interrogate epigenetic regulation. PMID:21124847

  11. Case study: Comparison of biological active compounds in milk from organic and conventional dairy herds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Conflicting reports of the quantities of biologically active compounds present in milk from organic grass-fed and conventional herds show that more research is required, especially as these compounds are linked to human health benefits and can improve the health value consumers place on dairy produc...

  12. 6-azacytidine--compound with wide spectrum of antiviral activity.

    PubMed

    Alexeeva, I; Dyachenko, N; Nosach, L; Zhovnovataya, V; Rybalko, S; Lozitskaya, R; Fedchuk, A; Lozitsky, V; Gridina, T; Shalamay, A; Palchikovskaja, L; Povnitsa, O

    2001-01-01

    6-azacytidine demonstrates activity against adenoviruses types 1, 2, 5. It inhibit synthesis of viral DNA and proteins. 6-AC shows antiherpetic and antiinfluenza action during experimental infection in mice. 6-AC is prospective for drug development as an antiviral substance with a wide spectrum of activity. PMID:11562975

  13. Identification of Trypanocidal Activity for Known Clinical Compounds Using a New Trypanosoma cruzi Hit-Discovery Screening Cascade.

    PubMed

    De Rycker, Manu; Thomas, John; Riley, Jennifer; Brough, Stephen J; Miles, Tim J; Gray, David W

    2016-04-01

    Chagas disease is a significant health problem in Latin America and the available treatments have significant issues in terms of toxicity and efficacy. There is thus an urgent need to develop new treatments either via a repurposing strategy or through the development of new chemical entities. A key first step is the identification of compounds with anti-Trypanosoma cruzi activity from compound libraries. Here we describe a hit discovery screening cascade designed to specifically identify hits that have the appropriate anti-parasitic properties to warrant further development. The cascade consists of a primary imaging-based assay followed by newly developed and appropriately scaled secondary assays to predict the cidality and rate-of-kill of the compounds. Finally, we incorporated a cytochrome P450 CYP51 biochemical assay to remove compounds that owe their phenotypic response to inhibition of this enzyme. We report the use of the cascade in profiling two small libraries containing clinically tested compounds and identify Clemastine, Azelastine, Ifenprodil, Ziprasidone and Clofibrate as molecules having appropriate profiles. Analysis of clinical derived pharmacokinetic and toxicity data indicates that none of these are appropriate for repurposing but they may represent suitable start points for further optimisation for the treatment of Chagas disease. PMID:27082760

  14. Identification of Trypanocidal Activity for Known Clinical Compounds Using a New Trypanosoma cruzi Hit-Discovery Screening Cascade

    PubMed Central

    De Rycker, Manu; Thomas, John; Riley, Jennifer; Brough, Stephen J.; Miles, Tim J.; Gray, David W.

    2016-01-01

    Chagas disease is a significant health problem in Latin America and the available treatments have significant issues in terms of toxicity and efficacy. There is thus an urgent need to develop new treatments either via a repurposing strategy or through the development of new chemical entities. A key first step is the identification of compounds with anti-Trypanosoma cruzi activity from compound libraries. Here we describe a hit discovery screening cascade designed to specifically identify hits that have the appropriate anti-parasitic properties to warrant further development. The cascade consists of a primary imaging-based assay followed by newly developed and appropriately scaled secondary assays to predict the cidality and rate-of-kill of the compounds. Finally, we incorporated a cytochrome P450 CYP51 biochemical assay to remove compounds that owe their phenotypic response to inhibition of this enzyme. We report the use of the cascade in profiling two small libraries containing clinically tested compounds and identify Clemastine, Azelastine, Ifenprodil, Ziprasidone and Clofibrate as molecules having appropriate profiles. Analysis of clinical derived pharmacokinetic and toxicity data indicates that none of these are appropriate for repurposing but they may represent suitable start points for further optimisation for the treatment of Chagas disease. PMID:27082760

  15. Antiproliferative activity of Saponaria vaccaria constituents and related compounds.

    PubMed

    Balsevich, J John; Ramirez-Erosa, Irving; Hickie, Robert A; Dunlop, Donna M; Bishop, Greg G; Deibert, Leah K

    2012-01-01

    Total methanolic extracts of Saponaria vaccaria seed derived from several varieties, as well as various purified components obtained through successive chromatographic separations of total extracts were evaluated for their growth inhibitory activity in WiDr (colon), MDA-MB-231 (breast), NCI-417 (lung) and PC-3 (prostate) human cancer cells as well as the non-tumorigenic fibroblast BJ (CRL-2522) cell line using MTT colorimetric assay. Purified bisdesmosidic saponins segetoside H and I were further examined using microscopy and apoptosis assays. Bisdesmosidic saponins exhibited dose-dependent growth inhibitory and selective apoptosis-inducing activity. Growth inhibitory effects were particularly strong in a breast (MDA-MB-231) and a prostate (PC-3) cancer cell line. Total extracts exhibited a different preference being most active against a colon cancer cell line (WiDr). In a comparison of varieties, all of the total seed extracts exhibited similar dose-dependent activities, but with some variation in potency. Monodesmosidic saponins vaccarosides A and B, phenolic vaccarin, and cyclopeptide segetalin A, co-occurring seed substituents, did not exhibit activity. The non-tumorigenic fibroblast cell line BJ (CRL 2522) was growth inhibited but did not undergo apoptosis when treated with bisdesmosidic saponins at low micromolar concentrations. Saponin-rich extracts from Kochia scoparia seed and Chenopodium quinoa were also evaluated alongside Saponaria saponins but did not exhibit activity. Closely related Quillaja saponins exhibited activity but were less potent. PMID:22056663

  16. Green alga Ulva pertusa--a new source of bioactive compounds with antialgal activity.

    PubMed

    Ying-ying, Sun; Hui, Wang; Gan-lin, Guo; Yin-fang, Pu; Bin-lun, Yan; Chang-hai, Wang

    2015-07-01

    We tested the effects of solvent fractions (FA, FB, FC, and FD), which partitioned by liquid-liquid extraction from the methanol extract of Ulva pertusa, on the growth of red tide microalgae (Karenia mikimitoi, Skeletonema costatum, Alexandrium tamarense, Heterosigma akashiwo, Prorocentrum donghaiense), and FA, FB, and FC exhibited significantly antialgal activity. The chemical constituent analysis showed the existence of bioactive compounds such as phenols and alkaloids. Further, four solvent fractions were applied to silica gel column and repeated preparative TLC to produce 13 samples and their purity qualified as thin-layer chromatographic grade. Among these purified samples, FA111, FB411, FC411, FD111, and FD211 exhibited stronger antialgal activity. Furthermore, their functional groups were analyzed by colorimetric methods and UV spectra data. FD111 and FD211 were temptatively identified as alkaloids; the others were initially identified as phenolic acids. This is a preliminary study and the structure identification of these purified samples requires further investigation. While concentration of these purified samples in this algae was very small, they showed excellent effects against red tide microalgae. PMID:25724801

  17. Update on project determining biologically active compounds in milk

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The added health value of raw and pasteurized milk from organic and grass-fed herds is strongly debated because of limited, and often conflicting, scientific data. The Dairy & Functional Foods Research Unit, USDA-ARS-NAA, Wyndmoor, PA has an ongoing project to identify and compare the levels of bio...

  18. Using Indices of Fidelity to Intervention Core Components to Identify Program Active Ingredients

    ERIC Educational Resources Information Center

    Abry, Tashia; Hulleman, Chris S.; Rimm-Kaufman, Sara E.

    2015-01-01

    Identifying the active ingredients of an intervention--intervention-specific components serving as key levers of change--is crucial for unpacking the intervention black box. Measures of intervention fidelity can be used to identify specific active ingredients, yet such applications are rare. We illustrate how fidelity measures can be used to…

  19. A modified reverse one-hybrid screen identifies transcriptional activation in Phyochrome-Interacting Factor 3

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Transcriptional activation domains (TAD) are difficult to predict and identify, since they are not conserved and have little consensus. Here, we describe a yeast-based screening method that is able to identify individual amino acid residues involved in transcriptional activation in a high throughput...

  20. Use of component analyses to identify active variables in treatment packages for children with feeding disorders.

    PubMed Central

    Cooper, L J; Wacker, D P; McComas, J J; Brown, K; Peck, S M; Richman, D; Drew, J; Frischmeyer, P; Millard, T

    1995-01-01

    We evaluated the separate components in treatment packages for food refusal of 4 young children. First, treatment packages were implemented until food acceptance improved. Next, a component analysis was conducted within a multielement or reversal design to identify the active components that facilitated food acceptance. The results indicated that escape extinction was always identified as an active variable when assessed; however, other variables, including positive reinforcement and noncontingent play, were also identified as active variables for 2 of the children. The results suggest that the component analysis was useful for identifying variables that affected food acceptance. PMID:7601802

  1. Plant compounds enhance the assay sensitivity for detection of active Bacillus cereus toxin.

    PubMed

    Rasooly, Reuven; Hernlem, Bradley; He, Xiaohua; Friedman, Mendel

    2015-03-01

    Bacillus cereus is an important food pathogen, producing emetic and diarrheal syndromes, the latter mediated by enterotoxins. The ability to sensitively trace and identify this active toxin is important for food safety. This study evaluated a nonradioactive, sensitive, in vitro cell-based assay, based on B. cereus toxin inhibition of green fluorescent protein (GFP) synthesis in transduced monkey kidney Vero cells, combined with plant extracts or plant compounds that reduce viable count of B. cereus in food. The assay exhibited a dose dependent GFP inhibition response with ~25% inhibition at 50 ng/mL toxin evaluated in culture media or soy milk, rice milk or infant formula, products associated with food poisonings outbreak. The plant extracts of green tea or bitter almond and the plant compounds epicatechin or carvacrol were found to amplify the assay response to ~90% inhibition at the 50 ng/mL toxin concentration greatly increasing the sensitivity of this assay. Additional studies showed that the test formulations also inhibited the growth of the B. cereus bacteria, likely through cell membrane disruption. The results suggest that the improved highly sensitive assay for the toxin and the rapid inactivation of the pathogen producing the toxin have the potential to enhance food safety. PMID:25767986

  2. Plant Compounds Enhance the Assay Sensitivity for Detection of Active Bacillus cereus Toxin

    PubMed Central

    Rasooly, Reuven; Hernlem, Bradley; He, Xiaohua; Friedman, Mendel

    2015-01-01

    Bacillus cereus is an important food pathogen, producing emetic and diarrheal syndromes, the latter mediated by enterotoxins. The ability to sensitively trace and identify this active toxin is important for food safety. This study evaluated a nonradioactive, sensitive, in vitro cell-based assay, based on B. cereus toxin inhibition of green fluorescent protein (GFP) synthesis in transduced monkey kidney Vero cells, combined with plant extracts or plant compounds that reduce viable count of B. cereus in food. The assay exhibited a dose dependent GFP inhibition response with ~25% inhibition at 50 ng/mL toxin evaluated in culture media or soy milk, rice milk or infant formula, products associated with food poisonings outbreak. The plant extracts of green tea or bitter almond and the plant compounds epicatechin or carvacrol were found to amplify the assay response to ~90% inhibition at the 50 ng/mL toxin concentration greatly increasing the sensitivity of this assay. Additional studies showed that the test formulations also inhibited the growth of the B. cereus bacteria, likely through cell membrane disruption. The results suggest that the improved highly sensitive assay for the toxin and the rapid inactivation of the pathogen producing the toxin have the potential to enhance food safety. PMID:25767986

  3. Identification of three novel natural product compounds that activate PXR and CAR and inhibit inflammation

    PubMed Central

    Kittayaruksakul, Suticha; Zhao, Wenchen; Xu, Meishu; Ren, Songrong; Lu, Jing; Wang, Ju; Downes, Michael; Evans, Ronald M.; Venkataramanan, Raman; Chatsudthipong, Varanuj; Xie, Wen

    2013-01-01

    The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been known to play a role in xenobiotic metabolism by regulating the expression of drug-metabolizing enzymes and transporters. In addition, PXR agonists were found to exert therapeutic effects through multiple mechanisms, such as detoxification of bile acids and inhibition of inflammation. In this study, we first investigated the effects of three natural product compounds, carapin, santonin and isokobusone, on the activity of PXR and CAR. These compounds activated both PXR and CAR in transient transfection and luciferase reporter gene assays. Mutagenesis studies showed that two amino acid residues, Phe305 of the rodent PXR and Leu308 of the human PXR, are critical for the recognition of these compounds by PXR. Importantly, the activation of PXR and CAR by these compounds induced the expression of drug-metabolizing enzymes in primary human and mouse hepatocytes. Furthermore, activation of PXR by these compounds inhibited the expression of inflammatory mediators in response to lipopolysaccharide (LPS). The effects of these natural compounds on drug metabolism and inflammation were abolished in PXR−/− hepatocytes. These natural compounds can be explored for their potential in the treatment of diseases where the PXR activation has been shown to be beneficial, such as inflammatory bowel disease, cholestasis, and hyperbilirubinemia. PMID:23896737

  4. Compound K Attenuates the Development of Atherosclerosis in ApoE−/− Mice via LXRα Activation

    PubMed Central

    Zhou, Li; Zheng, Yu; Li, Zhuoying; Bao, Lingxia; Dou, Yin; Tang, Yuan; Zhang, Jianxiang; Zhou, Jianzhi; Liu, Ya; Jia, Yi; Li, Xiaohui

    2016-01-01

    Background: Atherosclerosis is a fundamental pathological process responded to some serious cardiovascular events. Although the cholesterol-lowering drugs are widely prescribed for atherosclerosis therapy, it is still the leading cause of death in the developed world. Here we measured the effects of compound K in atherosclerosis formation and investigated the probably mechanisms of the anti-antherosclerosis roles of compound K. Methods: We treated the atherosclerotic model animals (apoE−/− mice on western diet) with compound K and measured the size of atherosclerotic lesions, inflammatory cytokine levels and serum lipid profile. Peritoneal macrophages were collected in vitro for the foam cell and inflammasome experiments. Results: Our results show that treatment with compound K dose-dependently attenuates the formation of atherosclerotic plaques by 55% through activation of reverse cholesterol transport pathway, reduction of systemic inflammatory cytokines and inhibition of local inflammasome activity. Compound K increases the cholesterol efflux of macrophage-derived foam cells, and reduces the inflammasome activity in cholesterol crystal stimulated macrophages. The activation of LXRα may contribute to the athero-protective effects of compound K. Conclusion: These observations provide evidence for an athero-protective effect of compound K via LXRα activation, and support its further evaluation as a potential effective modulator for the prevention and treatment of atherosclerosis. PMID:27399689

  5. Synergistic anti-Campylobacter jejuni activity of fluoroquinolone and macrolide antibiotics with phenolic compounds

    PubMed Central

    Oh, Euna; Jeon, Byeonghwa

    2015-01-01

    The increasing resistance of Campylobacter to clinically important antibiotics, such as fluoroquinolones and macrolides, is a serious public health problem. The objective of this study is to investigate synergistic anti-Campylobacter jejuni activity of fluoroquinolones and macrolides in combination with phenolic compounds. Synergistic antimicrobial activity was measured by performing a checkerboard assay with ciprofloxacin and erythromycin in the presence of 21 phenolic compounds. Membrane permeability changes in C. jejuni by phenolic compounds were determined by measuring the level of intracellular uptake of 1-N-phenylnaphthylamine (NPN). Antibiotic accumulation assays were performed to evaluate the level of ciprofloxacin accumulation in C. jejuni. Six phenolic compounds, including p-coumaric acid, sinapic acid, caffeic acid, vanillic acid, gallic acid, and taxifolin, significantly increased the susceptibility to ciprofloxacin and erythromycin in several human and poultry isolates. The synergistic antimicrobial effect was also observed in ciprofloxacin- and erythromycin-resistant C. jejuni strains. The phenolic compounds also substantially increased membrane permeability and antibiotic accumulation in C. jejuni. Interestingly, some phenolic compounds, such as gallic acid and taxifolin, significantly reduced the expression of the CmeABC multidrug efflux pump. Phenolic compounds increased the NPN accumulation in the cmeB mutant, indicating phenolic compounds may affect the membrane permeability. In this study, we successfully demonstrated that combinational treatment of C. jejuni with antibiotics and phenolic compounds synergistically inhibits C. jejuni by impacting both antimicrobial influx and efflux. PMID:26528273

  6. Isolation and Chemical Structural Characterisation of a Compound with Antioxidant Activity from the Roots of Senna italica

    PubMed Central

    Mokgotho, Matlou Phineas; Gololo, Stanley Sechene; Masoko, Peter; Shai, Leshwene Jeremiah; Bagla, Victor Patrick; Eloff, Jacobus Nicolaas

    2013-01-01

    Senna italica, a member of the Fabaceae family (subfamily Caesalpiniaceae), is widely used in South African traditional medicine to treat a number of disease conditions. Aqueous extracts of the plant are mainly used to treat sexually transmitted infections and intestinal complications. The roots of S. italica were ground to a fine powder and sequentially extracted with n-hexane, dichloromethane, acetone, and methanol using serial exhaustive extraction (SEE) method. Thin layer chromatography was used to analyse the phytochemical composition of the extracts and DPPH radical scavenging method to detect the presence of antioxidant compounds. The bioassay guided fractionation of the acetone fraction afforded an antioxidant compound with free radical scavenging activity. The isolated compound was subsequently identified as 3,4′,5-trihydroxystilbene (resveratrol). This study represents the first report of the stilbene resveratrol in S. italica. PMID:23843877

  7. Bioactivity-guided fractionation and analysis of compounds with anti-influenza virus activity from Gardenia jasminoides Ellis.

    PubMed

    Yang, Quanjun; Wu, Bin; Shi, Yujing; Du, Xiaowei; Fan, Mingsong; Sun, Zhaolin; Cui, Xiaolan; Huang, Chenggang

    2012-01-01

    Bioassay-guided fractionation of extracts from Fructus Gardeniae led to analysis of its bioactive natural products. After infection by influenza virus strain A/FM/1/47-MA in vivo, antiviral activity of the extracts were investigated. The target fraction was orally administered to rats and blood was collected. High-performance liquid chromatography coupled with photo diode array detector and electrospray ion trap multiple-stage tandem mass spectrometry was applied to screen the compounds absorbed into the blood. A structural characterization based on the retention time, ultraviolet spectra, parent ions and fragmentation ions was performed. Thirteen compounds were confirmed or tentatively identified. This provides an accurate profile of the composition of bioactive compounds responsible for the anti-influenza properties. PMID:22297738

  8. Identification of aroma active compounds of cereal coffee brew and its roasted ingredients.

    PubMed

    Majcher, Małgorzata A; Klensporf-Pawlik, Dorota; Dziadas, Mariusz; Jeleń, Henryk H

    2013-03-20

    Cereal coffee is a coffee substitute made mainly from roasted cereals such as barley and rye (60-70%), chicory (15-20%), and sugar beets (6-10%). It is perceived by consumers as a healthy, caffeine free, non-irritating beverage suitable for those who cannot drink regular coffee made from coffee beans. In presented studies, typical Polish cereal coffee brew has been subjected to the key odorants analysis with the application of gas chromatography-olfactometry (GC-O) and aroma extract dilution analysis (AEDA). In the analyzed cereal coffee extract, 30 aroma-active volatiles have been identified with FD factors ranging from 16 to 4096. This approach was also used for characterization of key odorants in ingredients used for the cereal coffee production. Comparing the main odors detected in GC-O analysis of roasted cereals brew to the odor notes of cereal coffee brew, it was evident that the aroma of cereal coffee brew is mainly influenced by roasted barley. Flavor compound identification and quantitation has been performed with application of comprehensive multidimentional gas chromatography and time-of-flight mass spectrometry (GCxGC-ToFMS). The results of the quantitative measurements followed by calculation of the odor activity values (OAV) revealed 17 aroma active compounds of the cereal coffee brew with OAV ranging from 12.5 and 2000. The most potent odorant was 2-furfurylthiol followed by the 3-mercapto-3-methylbutyl formate, 3-isobutyl-2-methoxypyrazine and 2-ethyl-3,5-dimethylpyrazine, 2-thenylthiol, 2,3-butanedione, 2-methoxy phenol and 2-methoxy-4-vinyl phenol, 3(sec-butyl)-2-methoxypyrazine, 2-acetyl-1-pyrroline, 3-(methylthio)-propanal, 2,3-pentanedione, 4-hydroxy-2,5-dimethyl-3-(2H)-furanone, (E,E)-2,4-decadienal, (Z)-4-heptenal, phenylacetaldehyde, and 1-octen-3-one. PMID:23414530

  9. Phenolic compounds and antioxidant activity of red wine made from grapes treated with different fungicides.

    PubMed

    Mulero, J; Martínez, G; Oliva, J; Cermeño, S; Cayuela, J M; Zafrilla, P; Martínez-Cachá, A; Barba, A

    2015-08-01

    The effect of treating grapes with six fungicides, applied under critical agricultural practices (CAP) on levels of phenolic compounds and antioxidant activity of red wines of Monastrell variety was studied. Vinifications were performed through addition of active dry yeast (ADY). Measurement of phenolic compounds was made with HPLC-DAD. Determination of antioxidant activity was through reaction of the wine sample with the DPPH radical. The wine prepared from grapes treated with quinoxyfen shows a greater increase of phenolic compounds than the control wine. In contrast, the wine obtained from grapes treated with trifloxystrobin showed lower total concentration of phenolic compounds, including stilbenes, whilst treatments with kresoxim-methyl, fluquinconazole, and famoxadone slightly reduced their content. Hence, the use of these last four fungicides could cause a decrease in possible health benefits to consumers. Antioxidant activity hardly varied in the assays with quinoxyfen, fluquinconazole and famoxadone, and decreased in the other wines. PMID:25766797

  10. Protective Effects of Chinese Herbal Medicine Rhizoma drynariae in Rats After Traumatic Brain Injury and Identification of Active Compound.

    PubMed

    Wang, Wenzhu; Li, Haigang; Yu, Jintao; Hong, Michael; Zhou, Jing; Zhu, Lin; Wang, Yang; Luo, Min; Xia, Zian; Yang, Zeng-Jin; Tang, Tao; Ren, Ping; Huang, Xi; Wang, Jian

    2016-09-01

    Traumatic brain injury (TBI) is a leading cause of death and disability in the USA. Effective therapeutic strategies for TBI are needed, and increasing attention is turning toward traditional herbal medicine. Rhizoma drynariae is a traditional Chinese medicine that has immunomodulatory and anti-inflammatory effects. Here, using the controlled cortical impact model of TBI in rats, we examined whether oral administration of R. drynariae can reduce TBI-induced brain injury in rats. We also identified the likely active compound among its four major phytochemicals in decoction. We found that post-treatment with R. drynariae decreased brain lesion volume, improved neurologic and cognitive function, and reduced anxiety- and depression-like behaviors. These changes were accompanied by reduced blood levels of IL-6 and increased IL-10. R. drynariae treatment also reversed the TBI-induced decrease in blood monocyte numbers and percentage of blood CD3 and CD4 T lymphocytes while inhibiting microglial/macrophage activation. Furthermore, by using ultra performance liquid chromatography and comparing retention times with authentic standards, we identified eriodictyol as the putative active compound of R. drynariae extract in the blood of rats with TBI. These novel findings indicate that the traditional Chinese herbal medicine R. drynariae protects brain against TBI-induced brain injury, possibly via immune-promoting, anti-inflammatory, and neuroprotective effects. Eriodictyol could be its active compound. PMID:26334614

  11. Iron-Targeting Antitumor Activity of Gallium Compounds and Novel Insights Into Triapine®-Metal Complexes

    PubMed Central

    Antholine, William E.

    2013-01-01

    Abstract Significance: Despite advances made in the treatment of cancer, a significant number of patients succumb to this disease every year. Hence, there is a great need to develop new anticancer agents. Recent Advances: Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that gallium compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer gallium compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin's lymphoma, while the thiosemicarbazone Triapine® has demonstrated activity against other tumors. Critical Issues: Novel gallium compounds with greater cytotoxicity and a broader spectrum of antineoplastic activity than gallium nitrate should continue to be developed. Future Directions: The antineoplastic activity and toxicity of the existing novel gallium compounds and thiosemicarbazone-metal complexes should be tested in animal tumor models and advanced to Phase I and II clinical trials. Future research should identify biologic markers that predict tumor sensitivity to gallium compounds. This will help direct gallium-based therapy to cancer patients who are most likely to benefit from it. Antioxid. Redox Signal. 00, 000–000. PMID:22900955

  12. A Quantum Chemical and Statistical Study of Cytotoxic Activity of Compounds Isolated from Curcuma zedoaria.

    PubMed

    Hamdi, Omer Abdalla Ahmed; Anouar, El Hassane; Shilpi, Jamil A; Trabolsy, Zuhra Bashir Khalifa Al; Zain, Sharifuddin Bin Md; Zakaria, Nur Shahidatul Shida; Zulkefeli, Mohd; Weber, Jean-Frédéric F; Malek, Sri Nurestri A; Rahman, Syarifah Nur Syed Abdul; Awang, Khalijah

    2015-01-01

    A series of 21 compounds isolated from Curcuma zedoaria was subjected to cytotoxicity test against MCF7; Ca Ski; PC3 and HT-29 cancer cell lines; and a normal HUVEC cell line. To rationalize the structure-activity relationships of the isolated compounds; a set of electronic; steric and hydrophobic descriptors were calculated using density functional theory (DFT) method. Statistical analyses were carried out using simple and multiple linear regressions (SLR; MLR); principal component analysis (PCA); and hierarchical cluster analysis (HCA). SLR analyses showed that the cytotoxicity of the isolated compounds against a given cell line depend on certain descriptors; and the corresponding correlation coefficients (R2) vary from 0%-55%. MLR results revealed that the best models can be achieved with a limited number of specific descriptors applicable for compounds having a similar basic skeleton. Based on PCA; HCA and MLR analyses; active compounds were classified into subgroups; which was in agreement with the cell based cytotoxicity assay. PMID:25923077

  13. Extraction, chemical characterization and biological activity determination of broccoli health promoting compounds.

    PubMed

    Ares, Ana M; Nozal, María J; Bernal, José

    2013-10-25

    Broccoli (Brassica oleracea L. var. Italica) contains substantial amount of health-promoting compounds such as vitamins, glucosinolates, phenolic compounds, and dietary essential minerals; thus, it benefits health beyond providing just basic nutrition, and consumption of broccoli has been increasing over the years. This review gives an overview on the extraction and separation techniques, as well as the biological activity of some of the above mentioned compounds which have been published in the period January 2008 to January 2013. The work has been distributed according to the different families of health promoting compounds discussing the extraction procedures and the analytical techniques employed for their characterization. Finally, information about the different biological activities of these compounds has been also provided. PMID:23899380

  14. Isolation and characterization of phenolic compounds and anthocyanins from Murta (Ugni molinae Turcz.) fruits. Assessment of antioxidant and antibacterial activity.

    PubMed

    Junqueira-Gonçalves, Maria Paula; Yáñez, Lina; Morales, Carolina; Navarro, Muriel; A Contreras, Rodrigo; Zúñiga, Gustavo E

    2015-01-01

    Berry fruit consumption has become important in the promotion of human health, mainly due to their phenolic compounds, which have been associated with protection against different pathologies, as well as antimicrobial and other biological activities. Consequently, there has been a growing interest in identifying natural antioxidants and antimicrobials from these plants. This study aimed to characterize the phenolic chemical composition and anthocyanin profile of murta (Ugni molinae Turcz.) fruit, and to evaluate the antioxidant and antimicrobial activity of its extracts (ethanolic and methanolic). LC/MS of the ethanolic extracts showed the presence of three major compounds: caffeic acid 3-glu, quercetin-3-glu and quercetin, while in the methanolic acid extract they were cyanidin-3-glucoside, pelargonidin-3-arabinose and delphinidin-3-glucoside. The antioxidant activity of ethanolic extracts (DPPH· and ORAC assays) was higher than that of methanol acid extracts or purified anthocynins. Furthermore, the methanol acid extract showed an inhibitory activity against the bacteria E. coli and S. typhi similar to that of standard antibiotics. The results suggest that the antioxidant activity of the ethanolic extract is regulated by the high content of phenolic compounds and the fruit's characteristic color is due to the content of pelargonidin-3-arabinose and delphinidin-3-glucoside. The obtained results demonstrated the appreciable antioxidant and antibacterial activities, providing opportunities to explore murta extracts as biopreservatives. PMID:25838172

  15. Molecular modeling and snake venom phospholipase A2 inhibition by phenolic compounds: Structure-activity relationship.

    PubMed

    Alam, Md Iqbal; Alam, Mohammed A; Alam, Ozair; Nargotra, Amit; Taneja, Subhash Chandra; Koul, Surrinder

    2016-05-23

    In our earlier study, we have reported that a phenolic compound 2-hydroxy-4-methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 (2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4-methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20, 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads. PMID:26986086

  16. Prediction of compounds in different local structure-activity relationship environments using emerging chemical patterns.

    PubMed

    Namasivayam, Vigneshwaran; Gupta-Ostermann, Disha; Balfer, Jenny; Heikamp, Kathrin; Bajorath, Jürgen

    2014-05-27

    Active compounds can participate in different local structure-activity relationship (SAR) environments and introduce different degrees of local SAR discontinuity, depending on their structural and potency relationships in data sets. Such SAR features have thus far mostly been analyzed using descriptive approaches, in particular, on the basis of activity landscape modeling. However, compounds in different local SAR environments have not yet been predicted. Herein, we adapt the emerging chemical patterns (ECP) method, a machine learning approach for compound classification, to systematically predict compounds with different local SAR characteristics. ECP analysis is shown to accurately assign many compounds to different local SAR environments across a variety of activity classes covering the entire range of observed local SARs. Control calculations using random forests and multiclass support vector machines were carried out and a variety of statistical performance measures were applied. In all instances, ECP calculations yielded comparable or better performance than controls. The approach presented herein can be applied to predict compounds that complement local SARs or prioritize compounds with different SAR characteristics. PMID:24803014

  17. Antithrombotic Activity of a New Hypoglycemic Compound Limiglidole in Mouse Model of Cell Thrombosis.

    PubMed

    Kucheryavenko, A F; Spasov, A A; Smirnov, A V

    2015-05-01

    Antithrombotic activity of hypoglycemic compound limiglidole that exhibits antiplatelet activity 2-fold exceeded activity of antiplatelet agent acetylsalicylic acid in the mouse model of systemic collagen-epinephrine thrombosis. Limiglidole signifi cantly reduced the relative and mean area of blood clots in the sections of mouse lungs. PMID:26033587

  18. Anti depressant activity of Mamsyadi Kwatha: An Ayurvedic compound formulation.

    PubMed

    Shreevathsa, M; Ravishankar, B; Dwivedi, Rambabu

    2013-01-01

    Depression is a psychiatric condition in which there is loss of interest in all pleasurable outlets, viz. food, sex, work, friends, hobbies and entertainment. The prevalence rate of the disease is 6-8% in women and 3-5% in men. Ayurveda, the science of life, provides systematic management principles for depression. Mamsyadi Kwatha is one such formulation stated by Yadavji Trikamji Acharya in Siddha Yoga Sangraha and Bheshaja Samhita, which is said to be effective in psychiatric conditions. The ingredients are Jatamansi (Nardostachys jatamansi), Ashwagandh (Withania somnifera) and Parasika Yavani (Hyocymus niger) in an 8:4:1 ratio, respectively. The test drug was subjected for antidepressant activity in experimental models. The models selected for anti depressant activity were behavioral despair test, anti-reserpine test and Chronic Fatigue Syndrome (CFS) test in albino mice. The test formulation showed significant inhibition of behavioural despair (P < 0.05), weak to moderate anti-reserpine activity - ptosis (P < 0.001), catatonia (P < 0.01), sedation (P < 0.01) and moderate effect in CFS test (P < 0.050). These effects clearly show that Mamsyadi Kwatha has an anti-depressant activity. PMID:24049416

  19. Solubilities of biologically active phenolic compounds: measurements and modeling.

    PubMed

    Queimada, António J; Mota, Fátima L; Pinho, Simão P; Macedo, Eugénia A

    2009-03-19

    Aqueous solubilities of natural phenolic compounds from different families (hydroxyphenyl, polyphenol, hydroxybenzoic, and phenylpropenoic) were experimentally obtained. Measurements were performed on tyrosol and ellagic, protocatechuic, syringic, and o-coumaric acids, at five different temperatures (from 288.2 to 323.2 K), using the standard shake-flask method, followed by compositional analysis using UV spectrophotometry. To verify the accuracy of the spectrophotometric method, some data points were measured by gravimetry, and in general, the values obtained with the two methods are in good agreement (deviations lower than 11%). To adequately understand the solubilization process, melting properties of the pure phenolics were obtained by differential scanning calorimetry (DSC), and apparent acid dissociation constants were measured by potentiometry titration. The aqueous solubilities followed the expected general exponential trend. The melting temperatures did not follow the same solubility tendency, and for tyrosol and ellagic acid, not only the size and extent of hydrogen bonding, but also the energy associated with their crystal structures, determine the solubility. For these binary systems, acid dissociation is not important. Approaches for modeling the measured data were evaluated. These included an excess Gibbs energy equation, the modified UNIQUAC model, and the cubic-plus-association (CPA) equation of state. Particularly for the CPA approach, a new methodology that explicitly takes into account the number and nature of the associating sites and the prediction of the pure-component parameters from molecular structure is proposed. The results indicate that these are appropriate tools for representing the water solubilities of these molecules. PMID:19243119

  20. Analysis of coenzyme A activated compounds in actinomycetes.

    PubMed

    Cabruja, Matías; Lyonnet, Bernardo Bazet; Millán, Gustavo; Gramajo, Hugo; Gago, Gabriela

    2016-08-01

    Acyl-CoAs are crucial compounds involved in essential metabolic pathways such as the Krebs cycle and lipid, carbohydrate, and amino acid metabolisms, and they are also key signal molecules involved in the transcriptional regulation of lipid biosynthesis in many organisms. In this study, we took advantage of the high selectivity of mass spectrometry and developed an ion-pairing reverse-phase high-pressure liquid chromatography electrospray ionization high-resolution mass spectrometry (IP-RP-HPLC/ESI-HRMS) method to carry on a comprehensive analytical determination of the wide range of fatty acyl-CoAs present in actinomycetes. The advantage of using a QTOF spectrometer resides in the excellent mass accuracy over a wide dynamic range and measurements of the true isotope pattern that can be used for molecular formula elucidation of unknown analytes. As a proof of concept, we used this assay to determine the composition of the fatty acyl-CoA pools in Mycobacterium, Streptomyces, and Corynebacterium species, revealing an extraordinary difference in fatty acyl-CoA amounts and species distribution between the three genera and between the two species of mycobacteria analyzed, including the presence of different chain-length carboxy-acyl-CoAs, key substrates of mycolic acid biosynthesis. The method was also used to analyze the impact of two fatty acid synthase inhibitors on the acyl-CoA profile of Mycobacterium smegmatis, which showed some unexpected low levels of C24 acyl-CoAs in the isoniazid-treated cells. This robust, sensitive, and reliable method should be broadly applicable in the studies of the wide range of bacteria metabolisms in which acyl-CoA molecules participate. PMID:27270600

  1. Repellent activity of constituents identified in Foeniculum vulgare fruit against Aedes aegypti (Diptera: Culicidae).

    PubMed

    Kim, Do-Hyoung; Kim, Soon-Il; Chang, Kyu-Sik; Ahn, Young-Joon

    2002-11-20

    The repellent activity of materials derived from the methanol extract of fruits from Foeniculum vulgareagainst hungry Aedes aegypti females was examined using skin and patch tests and compared with that of the commercial N,N-diethyl-m-toluamide (deet) and (Z)-9-octadecenoic acid. The biologically active constituents of the Foeniculum fruits were characterized as (+)-fenchone and (E)-9-octadecenoic acid by spectroscopic analyses. Responses varied according to compound, dose, and exposure time. In a skin test with female mosquitoes, at a dose of 0.4 mg/cm(2), (+)-fenchone and (Z)-9-octadecenoic acid exhibited moderate repellent activity at 30 min after treatment, whereas deet provided >1 h of protection against adult mosquitoes at 0.2 mg/cm(2). (Z)-9-Octadecenoic acid was a more potent repellent agent than (E)-9-octadecenoic acid. (+)-Fenchone and (E)-9-octadecenoic acid merit further study as potential mosquito repellent agents or as lead compounds. PMID:12428949

  2. Establishment and Validation of Whole-Cell Based Fluorescence Assays to Identify Anti-Mycobacterial Compounds Using the Acanthamoeba castellanii - Mycobacterium marinum Host-Pathogen System

    PubMed Central

    Kicka, Sébastien; Trofimov, Valentin; Harrison, Christopher; Ouertatani-Sakouhi, Hajer; McKinney, John; Scapozza, Leonardo; Hilbi, Hubert; Cosson, Pierre; Soldati, Thierry

    2014-01-01

    Tuberculosis is considered to be one of the world’s deadliest disease with 2 million deaths each year. The need for new antitubercular drugs is further exacerbated by the emergence of drug-resistance strains. Despite multiple recent efforts, the majority of the hits discovered by traditional target-based screening showed low efficiency in vivo. Therefore, there is heightened demand for whole-cell based approaches directly using host-pathogen systems. The phenotypic host-pathogen assay described here is based on the monitoring of GFP-expressing Mycobacterium marinum during infection of the amoeba Acanthamoeba castellanii. The assay showed straight-forward medium-throughput scalability, robustness and ease of manipulation, demonstrating its qualities as an efficient compound screening system. Validation with a series of known antitubercular compounds highlighted the advantages of the assay in comparison to previously published macrophage-Mycobacterium tuberculosis-based screening systems. Combination with secondary growth assays based on either GFP-expressing D. discoideum or M. marinum allowed us to further fine-tune compound characterization by distinguishing and quantifying growth inhibition, cytotoxic properties and antibiotic activities of the compounds. The simple and relatively low cost system described here is most suitable to detect anti-infective compounds, whether they present antibiotic activities or not, in which case they might exert anti-virulence or host defense boosting activities, both of which are largely overlooked by classical screening approaches. PMID:24498207

  3. Phenolic compounds and antioxidant activity of olive leaf extracts.

    PubMed

    Kontogianni, Vassiliki G; Gerothanassis, Ioannis P

    2012-01-01

    The total phenolic content and antioxidant activities of olive leaf extracts were determined. Plant material was extracted with methanol and fractionated with solvents of increasing polarity, giving certain extracts. The qualitative changes in the composition of the extracts were determined after the storage of leaves for 22 h at 37°C, before the extraction. Total polyphenol contents in extracts were determined by the Folin-Ciocalteu procedure. They were also analysed by liquid chromatography-mass spectrometry. Their antioxidant activities were evaluated using the diphenyl picrylhydrazyl method and the β-carotene linoleate model assay. Moreover, the effects of different crude olive leaf extracts on the oxidative stability of sunflower oil at 40°C and sunflower oil-in-water emulsions (10% o/w) at 37°C, at a final concentration of crude extract 200 mg kg(-1) oil, were tested and compared with butylated hydroxyl toluene. PMID:22060136

  4. Persistence of biologically active compounds in soil: Final report

    SciTech Connect

    Williams, S.E.

    1987-02-01

    This document describes the long-term effects of soil-applied oil shale process water on the VA fungi and Rhizobium bacteria in a native soil. Techniques include assessing the VA fungal activity at field treatment plots and using treated field soils in a bioassay to determine VA infection and Rhizobium-nodulation potentials four years after process water application. 52 refs., 32 figs., 2 tabs.

  5. Screening SIRT1 Activators from Medicinal Plants as Bioactive Compounds against Oxidative Damage in Mitochondrial Function

    PubMed Central

    Wang, Yi; Liang, Xinying; Chen, Yaqi; Zhao, Xiaoping

    2016-01-01

    Sirtuin type 1 (SIRT1) belongs to the family of NAD+ dependent histone deacetylases and plays a critical role in cellular metabolism and response to oxidative stress. Traditional Chinese medicines (TCMs), as an important part of natural products, have been reported to exert protective effect against oxidative stress in mitochondria. In this study, we screened SIRT1 activators from TCMs and investigated their activities against mitochondrial damage. 19 activators were found in total by in vitro SIRT1 activity assay. Among those active compounds, four compounds, ginsenoside Rb2, ginsenoside F1, ginsenoside Rc, and schisandrin A, were further studied to validate the SIRT1-activation effects by liquid chromatography-mass spectrometry and confirm their activities against oxidative damage in H9c2 cardiomyocytes exposed to tert-butyl hydroperoxide (t-BHP). The results showed that those compounds enhanced the deacetylated activity of SIRT1, increased ATP content, and inhibited intracellular ROS formation as well as regulating the activity of Mn-SOD. These SIRT1 activators also showed moderate protective effects on mitochondrial function in t-BHP cells by recovering oxygen consumption and increasing mitochondrial DNA content. Our results suggested that those compounds from TCMs attenuated oxidative stress-induced mitochondrial damage in cardiomyocytes through activation of SIRT1. PMID:26981165

  6. Solubility Prediction of Active Pharmaceutical Compounds with the UNIFAC Model

    NASA Astrophysics Data System (ADS)

    Nouar, Abderrahim; Benmessaoud, Ibtissem; Koutchoukali, Ouahiba; Koutchoukali, Mohamed Salah

    2016-03-01

    The crystallization from solution of an active pharmaceutical ingredient requires the knowledge of the solubility in the entire temperature range investigated during the process. However, during the development of a new active ingredient, these data are missing. Its experimental determination is possible, but tedious. UNIFAC Group contribution method Fredenslund et al. (Vapor-liquid equilibria using UNIFAC: a group contribution method, 1977; AIChE J 21:1086, 1975) can be used to predict this physical property. Several modifications on this model have been proposed since its development in 1977, modified UNIFAC of Dortmund Weidlich et al. (Ind Eng Chem Res 26:1372, 1987), Gmehling et al. (Ind Eng Chem Res 32:178, 1993), Pharma-modified UNIFAC Diedrichs et al. (Evaluation und Erweiterung thermodynamischer Modelle zur Vorhersage von Wirkstofflöslichkeiten, PhD Thesis, 2010), KT-UNIFAC Kang et al. (Ind Eng Chem Res 41:3260, 2002), ldots In this study, we used UNIFAC model by considering the linear temperature dependence of interaction parameters as in Pharma-modified UNIFAC and structural groups as defined by KT-UNIFAC first-order model. More than 100 binary datasets were involved in the estimation of interaction parameters. These new parameters were then used to calculate activity coefficient and solubility of some molecules in various solvents at different temperatures. The model gives better results than those from the original UNIFAC and shows good agreement between the experimental solubility and the calculated one.

  7. Global emissions and models of photochemically active compounds

    SciTech Connect

    Penner, J.E.; Atherton, C.S.; Graedel, T.E.

    1993-05-20

    Anthropogenic emissions from industrial activity, fossil fuel combustion, and biomass burning are now known to be large enough (relative to natural sources) to perturb the chemistry of vast regions of the troposphere. A goal of the IGAC Global Emissions Inventory Activity (GEIA) is to provide authoritative and reliable emissions inventories on a 1{degree} {times} 1{degree} grid. When combined with atmospheric photochemical models, these high quality emissions inventories may be used to predict the concentrations of major photochemical products. Comparison of model results with measurements of pertinent species allows us to understand whether there are major shortcomings in our understanding of tropospheric photochemistry, the budgets and transport of trace species, and their effects in the atmosphere. Through this activity, we are building the capability to make confident predictions of the future consequences of anthropogenic emissions. This paper compares IGAC recommended emissions inventories for reactive nitrogen and sulfur dioxide to those that have been in use previously. We also present results from the three-dimensional LLNL atmospheric chemistry model that show how emissions of anthropogenic nitrogen oxides might potentially affect tropospheric ozone and OH concentrations and how emissions of anthropogenic sulfur increase sulfate aerosol loadings.

  8. Wild Bitter Melon Leaf Extract Inhibits Porphyromonas gingivalis-Induced Inflammation: Identification of Active Compounds through Bioassay-Guided Isolation.

    PubMed

    Tsai, Tzung-Hsun; Huang, Wen-Cheng; Ying, How-Ting; Kuo, Yueh-Hsiung; Shen, Chien-Chang; Lin, Yin-Ku; Tsai, Po-Jung

    2016-01-01

    Porphyromonas gingivalis has been identified as one of the major periodontal pathogens. Activity-directed fractionation and purification processes were employed to identify the anti-inflammatory active compounds using heat-killed P. gingivalis-stimulated human monocytic THP-1 cells in vitro. Five major fractions were collected from the ethanol/ethyl acetate extract of wild bitter melon (Momordica charantia Linn. var. abbreviata Ser.) leaves and evaluated for their anti-inflammatory activity against P. gingivalis. Among the test fractions, Fraction 5 effectively decreased heat-killed P. gingivalis-induced interleukin (IL)-8 and was subjected to separation and purification by using chromatographic techniques. Two cucurbitane triterpenoids were isolated from the active fraction and identified as 5β,19-epoxycucurbita-6,23-diene-3β,19,25-triol (1) and 3β,7β,25-trihydroxycucurbita-5,23-dien-19-al (2) by comparing spectral data. Treatments of both compounds in vitro potently suppressed P. gingivalis-induced IL-8, IL-6, and IL-1β levels and the activation of mitogen-activated protein kinase (MAPK) in THP-1 cells. Both compounds effectively inhibited the mRNA levels of IL-6, tumor necrosis factor (TNF)-α, and cyclooxygenase (COX)-2 in P. gingivalis-stimulated gingival tissue of mice. These findings imply that 5β,19-epoxycucurbita-6,23-diene-3β,19,25-triol and 3β,7β,25-trihydroxycucurbita-5,23-dien-19-al could be used for the development of novel therapeutic approaches against P. gingivalis infections. PMID:27058519

  9. Soymilk phenolic compounds, isoflavones and antioxidant activity as affected by in vitro gastrointestinal digestion.

    PubMed

    Rodríguez-Roque, María Janeth; Rojas-Graü, María Alejandra; Elez-Martínez, Pedro; Martín-Belloso, Olga

    2013-01-01

    The aim of this research was to evaluate changes in the phenolic compounds, isoflavones and antioxidant activity of soymilk following in vitro gastrointestinal digestion (including dialysis). Gastric digestion significantly influenced the release of bioactive substances from the soymilk matrix, increasing the concentration of total phenolic components (35% as the sum of individuals and 14% by Folin-Ciocalteu [F-C] method), total isoflavone content (22%) and total antioxidant activity (76%). The concentration of all those compounds was reduced significantly in the duodenal fraction in comparison to gastric digestion and their lowest concentration was observed in the dialysed fraction, where phenolic acids were not detected. The bioaccessibility of soymilk phenolic compounds was 15% as the sum of individuals and 20% by F-C assay; isoflavones 36% and constituents with antioxidant activity 27%. Results suggest that most of these compounds were sufficiently available to be absorbed and could contribute health benefits. PMID:23017414

  10. Activity of compound G2 isolated from alfalfa roots against medically important yeasts.

    PubMed Central

    Polacheck, I; Zehavi, U; Naim, M; Levy, M; Evron, R

    1986-01-01

    An antimycotic agent was isolated from roots of alfalfa and further purified to yield a nonhemolytic, homogeneous compound (G2). This compound contained considerable activity against 10 medically important yeasts. MICs obtained by both agar and broth dilution methods ranged from 3 to 15 micrograms/ml. Compound G2 was fungicidal at a relatively low concentration for nine different species of yeasts tested (minimum fungicidal concentrations ranged between 6 and 24 micrograms/ml). The considerable stability of compound G2 and its strong inhibitory and fungicidal activity against a broad range of yeasts suggest that after further development it might be useful as an active agent in the treatment of mycotic infections. PMID:3767342

  11. Leishmanicidal and cholinesterase inhibiting activities of phenolic compounds from Allanblackia monticola and Symphonia globulifera.

    PubMed

    Lenta, Bruno Ndjakou; Vonthron-Sénécheau, Catherine; Weniger, Bernard; Devkota, Krishna Prasad; Ngoupayo, Joseph; Kaiser, Marcel; Naz, Qamar; Choudhary, Muhammad Iqbal; Tsamo, Etienne; Sewald, Norbert

    2007-01-01

    In a preliminary antiprotozoal screening of several Clusiaceae species, the methanolic extracts of Allanblackia monticola and Symphonia globulifera showed high in vitro leishmanicidal activity. Further bioguided phytochemical investigation led to the isolation of four benzophenones: guttiferone A (1), garcinol (2), cambogin (3) and guttiferone F (4), along with three xanthones: allanxanthone A (5), xanthone V1 (6) and globulixanthone C (7) as active constituents. Compounds 1 and 6 were isolated from S. globulifera leaves, while compounds 2-5 were obtained from A. monticola fruits. Guttiferone A (1) and F (4) showed particulary strong leishmanicidal activity in vitro, with IC50 values (0.2 microM and 0.16 microM, respectively) comparable to that of the reference compound, miltefosine (0.46 microM). Although the leishmanicidal activity is promising, the cytotoxicity profile of these compounds prevent at this state further in vivo biological evaluation. In addition, all the isolated compounds were tested in vitro for their anticholinesterase properties. The four benzophenones showed potent anticholinesterase properties towards acetylcholinesterase (AChE) and butylcholinesterase (AChE). For AChE, the IC50 value (0.66 microM) of garcinol (2) was almost equal to that of the reference compound galanthamine (0.50 microM). Furthermore, guttiferone A (1) and guttiferone F (4) (IC50 = 2.77 and 3.50 microM, respectively) were more active than galanthamine (IC50 = 8.5) against BChE. PMID:17960072

  12. Analyzing compound activity records and promiscuity degrees in light of publication statistics

    PubMed Central

    Hu, Ye; Bajorath, Jürgen

    2016-01-01

    For the generation of contemporary databases of bioactive compounds, activity information is usually extracted from the scientific literature. However, when activity data are analyzed, source publications are typically no longer taken into consideration. Therefore, compound activity data selected from ChEMBL were traced back to thousands of original publications, activity records including compound, assay, and target information were systematically generated, and their distributions across the literature were determined. In addition, publications were categorized on the basis of activity records. Furthermore, compound promiscuity, defined as the ability of small molecules to specifically interact with multiple target proteins, was analyzed in light of publication statistics, thus adding another layer of information to promiscuity assessment. It was shown that the degree of compound promiscuity was not influenced by increasing numbers of source publications. Rather, most non-promiscuous as well as promiscuous compounds, regardless of their degree of promiscuity, originated from single publications, which emerged as a characteristic feature of the medicinal chemistry literature. PMID:27347396

  13. High Throughput Screening for Compounds That Alter Muscle Cell Glycosylation Identifies New Role for N-Glycans in Regulating Sarcolemmal Protein Abundance and Laminin Binding*

    PubMed Central

    Cabrera, Paula V.; Pang, Mabel; Marshall, Jamie L.; Kung, Raymond; Nelson, Stanley F.; Stalnaker, Stephanie H.; Wells, Lance; Crosbie-Watson, Rachelle H.; Baum, Linda G.

    2012-01-01

    Duchenne muscular dystrophy is an X-linked disorder characterized by loss of dystrophin, a cytoskeletal protein that connects the actin cytoskeleton in skeletal muscle cells to extracellular matrix. Dystrophin binds to the cytoplasmic domain of the transmembrane glycoprotein β-dystroglycan (β-DG), which associates with cell surface α-dystroglycan (α-DG) that binds laminin in the extracellular matrix. β-DG can also associate with utrophin, and this differential association correlates with specific glycosylation changes on α-DG. Genetic modification of α-DG glycosylation can promote utrophin binding and rescue dystrophic phenotypes in mouse dystrophy models. We used high throughput screening with the plant lectin Wisteria floribunda agglutinin (WFA) to identify compounds that altered muscle cell surface glycosylation, with the goal of finding compounds that increase abundance of α-DG and associated sarcolemmal glycoproteins, increase utrophin usage, and increase laminin binding. We identified one compound, lobeline, from the Prestwick library of Food and Drug Administration-approved compounds that fulfilled these criteria, increasing WFA binding to C2C12 cells and to primary muscle cells from wild type and mdx mice. WFA binding and enhancement by lobeline required complex N-glycans but not O-mannose glycans that bind laminin. However, inhibiting complex N-glycan processing reduced laminin binding to muscle cell glycoproteins, although O-mannosylation was intact. Glycan analysis demonstrated a general increase in N-glycans on lobeline-treated cells rather than specific alterations in cell surface glycosylation, consistent with increased abundance of multiple sarcolemmal glycoproteins. This demonstrates the feasibility of high throughput screening with plant lectins to identify compounds that alter muscle cell glycosylation and identifies a novel role for N-glycans in regulating muscle cell function. PMID:22570487

  14. Bioassay-guided isolation and identification of active compounds from Fructus Arctii against Dactylogyrus intermedius (Monogenea) in goldfish (Carassius auratus).

    PubMed

    Wang, Gao-xue; Han, Jing; Feng, Ting-ting; Li, Fu-yuan; Zhu, Bin

    2009-12-01

    Dactylogyrus intermedius is a significant monogenean parasite on the gills of cyprinid fishes and can cause serious problem in fish aquaculture. In the present study, bioassay-guided fractionation was employed to identify the active compounds from Fructus Arctii against D. intermedius. Five solvents (petroleum ether, chloroform, ethyl acetate, ethanol, and water) were applied for the extraction of Fructus Arctii. Among them, only the chloroform extract exhibited promising anthelmintic efficacy and therefore, subjected to the further isolation and purification using various chromatographic techniques. Two compounds showing potent activity were obtained and identified by spectral data (infrared, nuclear magnetic resonance, and mass spectrometry) as: arctigenin (1) and arctiin (2). They were found to be significantly effective against D. intermedius with median effective concentration (EC(50)) values of 0.62 and 3.55 mg L(-1), respectively. Arctigenin exhibited higher activity as compared with the positive control mebendazole with an EC(50) value of 1.25 mg L(-1). The 48-h acute toxicity tests (LC(50)) of arctigenin and arctiin were found to be 8.47 and 14.14 mg L(-1) for goldfish, respectively. These results provided evidence that the studied plant extract, as well as the isolated compounds, might be potential sources of new antiparasitic drug for the control of Dactylogyrus. PMID:19859737

  15. Selection of desorbing solvents for organic compounds from active carbon tubes.

    PubMed

    Matsumura, Y

    1996-01-01

    To ensure the effective performance of active carbon tubes for working environment measurements, suitable desorbing solvents were selected for 46 kinds of organic compounds by the phase equilibrium method. The criteria for suitable desorbing solvents in this study was desorption of the objective compounds from active carbon at efficiencies greater than 90% and to give good separation between its own peak and that of the objective compound on a gas chromatogram. For most non-polar or hydrophobic compounds, carbon disulfide was a versatile and effective solvent. But for polar and hydrophilic compounds like alcohol, N,N-dimethylformamide and dimethylsulfoxide were good desorbing solvents if their peaks did not overlap with those of the objective compounds. Mixtures of lower molecular weight alcohols with carbon disulfide or dichloromethane could be alternative solvents for hydrophilic compounds as well. A thermodynamic parameter of the solute-solvent system, i.e., the mixing energy derived from the solubility parameter, gave a rough indication of the effectiveness of solvents but it could not be used as a critical indicator for the efficient desorbing solvents for organic vapors collected on active carbon. PMID:8768662

  16. Antioxidant activity and phytochemical compounds of snake fruit (Salacca Zalacca)

    NASA Astrophysics Data System (ADS)

    Suica-Bunghez, I. R.; Teodorescu, S.; Dulama, I. D.; Voinea, O. C.; imionescu, S.; Ion, R. M.

    2016-06-01

    Snake fruit (Salacca zalacca) is a palm tree species, which is found in Malaysia and Indonesia. This study was conducted to investigate and compare the composition, total phenolic, flavonoid, tanins and monoterpenoids contents in the core and shell fruits. Concentration values of extracts were obtained from standard curves obtained. Antioxidant activity was determined using DPPH method. For all methods it was used the UV-VIS Specord M40, using different wavelength. The infrared spectral analysis was carried out to caracterized the type of functional group existent in snake fruit parts (shell and core).

  17. Activated phosphors having matrices of yttrium-transition metal compound

    DOEpatents

    De Kalb, E.L.; Fassel, V.A.

    1975-07-01

    A method is described for preparing a phosphor composition containing a lanthanide activator element with a host matrix having a transition element as a major component. The host matrix is composed of certain rare earth phosphates or vanadates such as YPO$sub 4$ with a portion of the rare earth replaced with one or more of the transition elements. On x-ray or other electromagnetic excitation, trace lanthanide impurities or additives within the phosphor are spectrometrically determined from their characteristic luminescence. (auth)

  18. [The influence of compound aITEL1296 on telomerase activity and the growth of cancer cells].

    PubMed

    Kovalenko, N A; Zhdanov, D D; Bibikova, M V; Gotovtseva, V Iu

    2011-01-01

    Telomerase is a ribonucleoprotein that synthesizes telomeric repeats and identified as a promising target for anticancer therapy. Here we describe a new compound aITEL1296 as a potent telomerase inhibitor. Its inhibitory activity was a bit higher (IC50 = 0,19 +/- 0,02 ng/ml) than that of BIBR1532, one of the most potent telomerase inhibitors known to date. Besides telomerase inhibition aITEL1296 activated apoptotic mechanisms and effectively suppressed proliferation of tumor cell lines (GI50 = 5,0 +/- 0,2 ng/ml for most sensitive cell line LnCap) but not normal fibroblast cell line. PMID:22629600

  19. Steroid-Derived Naphthoquinoline Asphaltene Model Compounds: Hydriodic Acid Is the Active Catalyst in I2-Promoted Multicomponent Cyclocondensation Reactions.

    PubMed

    Schulze, Matthias; Scott, David E; Scherer, Alexander; Hampel, Frank; Hamilton, Robin J; Gray, Murray R; Tykwinski, Rik R; Stryker, Jeffrey M

    2015-12-01

    A multicomponent cyclocondensation reaction between 2-aminoanthracene, aromatic aldehydes, and 5-α-cholestan-3-one has been used to synthesize model asphaltene compounds. The active catalyst for this reaction has been identified as hydriodic acid, which is formed in situ from the reaction of iodine with water, while iodine is not a catalyst under anhydrous conditions. The products, which contain a tetrahydro[4]helicene moiety, are optically active, and the stereochemical characteristics have been examined by VT-NMR and VT-CD spectroscopies, as well as X-ray crystallography. PMID:26584791

  20. Elucidation of the Mode of Action of a New Antibacterial Compound Active against Staphylococcus aureus and Pseudomonas aeruginosa.

    PubMed

    Gerits, Evelien; Blommaert, Eline; Lippell, Anna; O'Neill, Alex J; Weytjens, Bram; De Maeyer, Dries; Fierro, Ana Carolina; Marchal, Kathleen; Marchand, Arnaud; Chaltin, Patrick; Spincemaille, Pieter; De Brucker, Katrijn; Thevissen, Karin; Cammue, Bruno P A; Swings, Toon; Liebens, Veerle; Fauvart, Maarten; Verstraeten, Natalie; Michiels, Jan

    2016-01-01

    Nosocomial and community-acquired infections caused by multidrug resistant bacteria represent a major human health problem. Thus, there is an urgent need for the development of antibiotics with new modes of action. In this study, we investigated the antibacterial characteristics and mode of action of a new antimicrobial compound, SPI031 (N-alkylated 3, 6-dihalogenocarbazol 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol), which was previously identified in our group. This compound exhibits broad-spectrum antibacterial activity, including activity against the human pathogens Staphylococcus aureus and Pseudomonas aeruginosa. We found that SPI031 has rapid bactericidal activity (7-log reduction within 30 min at 4x MIC) and that the frequency of resistance development against SPI031 is low. To elucidate the mode of action of SPI031, we performed a macromolecular synthesis assay, which showed that SPI031 causes non-specific inhibition of macromolecular biosynthesis pathways. Liposome leakage and membrane permeability studies revealed that SPI031 rapidly exerts membrane damage, which is likely the primary cause of its antibacterial activity. These findings were supported by a mutational analysis of SPI031-resistant mutants, a transcriptome analysis and the identification of transposon mutants with altered sensitivity to the compound. In conclusion, our results show that SPI031 exerts its antimicrobial activity by causing membrane damage, making it an interesting starting point for the development of new antibacterial therapies. PMID:27167126

  1. Elucidation of the Mode of Action of a New Antibacterial Compound Active against Staphylococcus aureus and Pseudomonas aeruginosa

    PubMed Central

    Gerits, Evelien; Blommaert, Eline; Lippell, Anna; O’Neill, Alex J.; Weytjens, Bram; De Maeyer, Dries; Fierro, Ana Carolina; Marchal, Kathleen; Marchand, Arnaud; Chaltin, Patrick; Spincemaille, Pieter; De Brucker, Katrijn; Thevissen, Karin; Cammue, Bruno P. A.; Swings, Toon; Liebens, Veerle; Fauvart, Maarten; Verstraeten, Natalie; Michiels, Jan

    2016-01-01

    Nosocomial and community-acquired infections caused by multidrug resistant bacteria represent a major human health problem. Thus, there is an urgent need for the development of antibiotics with new modes of action. In this study, we investigated the antibacterial characteristics and mode of action of a new antimicrobial compound, SPI031 (N-alkylated 3, 6-dihalogenocarbazol 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol), which was previously identified in our group. This compound exhibits broad-spectrum antibacterial activity, including activity against the human pathogens Staphylococcus aureus and Pseudomonas aeruginosa. We found that SPI031 has rapid bactericidal activity (7-log reduction within 30 min at 4x MIC) and that the frequency of resistance development against SPI031 is low. To elucidate the mode of action of SPI031, we performed a macromolecular synthesis assay, which showed that SPI031 causes non-specific inhibition of macromolecular biosynthesis pathways. Liposome leakage and membrane permeability studies revealed that SPI031 rapidly exerts membrane damage, which is likely the primary cause of its antibacterial activity. These findings were supported by a mutational analysis of SPI031-resistant mutants, a transcriptome analysis and the identification of transposon mutants with altered sensitivity to the compound. In conclusion, our results show that SPI031 exerts its antimicrobial activity by causing membrane damage, making it an interesting starting point for the development of new antibacterial therapies. PMID:27167126

  2. Oxidation of pharmaceutically active compounds by a ligninolytic fungal peroxidase.

    PubMed

    Eibes, Gemma; Debernardi, Gianfranco; Feijoo, Gumersindo; Moreira, M Teresa; Lema, Juan M

    2011-06-01

    Pharmaceuticals are an important group of emerging pollutants with increasing interest due to their rising consumption and the evidence for ecotoxicological effects associated to trace amounts in aquatic environments. In this paper, we assessed the potential degradation of a series of pharmaceuticals: antibiotics (sulfamethoxazole), antidepressives (citalopram hydrobromide and fluoxetine hydrochloride), antiepileptics (carbamazepine), anti-inflammatory drugs (diclofenac and naproxen) and estrogen hormones (estrone, 17β-estradiol, 17α-ethinylestradiol) by means of a versatile peroxidase (VP) from the ligninolytic fungus Bjerkandera adusta. The effects of the reaction conditions: VP activity, organic acid concentration and H(2)O(2) addition rate, on the kinetics of the VP based oxidation system were evaluated. Diclofenac and estrogens were completely degraded after only 5-25 min even with a very low VP activity (10 U l(-1)). High degradation percentages (80%) were achieved for sulfamethoxazole and naproxen. Low or undetectable removal yields were observed for citalopram (up to 18%), fluoxetine (lower than 10%) and carbamazepine (not degraded). PMID:20972884

  3. Procaspase-3 Activation as an Anti-Cancer Strategy: Structure-Activity Relationship of Procaspase-Activating Compound 1 (PAC-1) and its Cellular Co-Localization with Caspase-3

    PubMed Central

    Peterson, Quinn P.; Hsu, Danny C.; Goode, David R.; Novotny, Chris J.; Totten, Ryan K.; Hergenrother, Paul J.

    2009-01-01

    A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivatives where key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently-labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc. PMID:19708658

  4. Active Compounds of Rhubarb Root and Rhizome in Animal Model Experiments of Focal Cerebral Ischemia

    PubMed Central

    Liu, Ai-ju; Song, Liang; Li, Yan; Zhang, Xiao-guang; Chen, Zi-xian; Huang, Li-bo; Zhang, Hong-feng; Zheng, Guo-qing

    2015-01-01

    Rhubarb root and rhizome (RRR) has been clinically used for stroke at least 2000 years and is still used in modern times in both China and elsewhere worldwide. The objective of present study was to evaluate the efficacy of active compounds of RRR (ACRRR) for experimental ischemic stroke. Studies of ACRRR in animal models of ischemic stroke were identified from 5 databases until April 2014. Study quality for each included article was evaluated according to the CAMARADES 10-item checklist. Outcome measures were neurological deficit score and infarct size. All the data were analyzed using RevMan 5.1 software. As a result, 20 studies were identified describing procedures involving 577 animals. The quality score of studies ranges from 2 to 6, and the median was 3.4. Six studies showed significant effects of ACRRR for improving infarct size compared with model group (P < 0.01). Six studies indicated significant effects of ACRRR for improving the neurological deficit scores according to Zea longa criterion or eight-point criterion (P < 0.01). In conclusion, these findings demonstrated a possible efficacy of ACRRR that have potential neuroprotective effect for experimental ischemic stroke. However, these apparently positive findings should be interpreted with caution because of the methodological flaws. PMID:26495006

  5. Anti-Prion Activity of a Panel of Aromatic Chemical Compounds: In Vitro and In Silico Approaches

    PubMed Central

    Ferreira, Natalia C.; Marques, Icaro A.; Conceição, Wesley A.; Macedo, Bruno; Machado, Clarice S.; Mascarello, Alessandra; Chiaradia-Delatorre, Louise Domeneghini; Yunes, Rosendo Augusto; Nunes, Ricardo José; Hughson, Andrew G.; Raymond, Lynne D.; Pascutti, Pedro G.; Caughey, Byron; Cordeiro, Yraima

    2014-01-01

    The prion protein (PrP) is implicated in the Transmissible Spongiform Encephalopathies (TSEs), which comprise a group of fatal neurodegenerative diseases affecting humans and other mammals. Conversion of cellular PrP (PrPC) into the scrapie form (PrPSc) is the hallmark of TSEs. Once formed, PrPSc aggregates and catalyzes PrPC misfolding into new PrPSc molecules. Although many compounds have been shown to inhibit the conversion process, so far there is no effective therapy for TSEs. Besides, most of the previously evaluated compounds failed in vivo due to poor pharmacokinetic profiles. In this work we propose a combined in vitro/in silico approach to screen for active anti-prion compounds presenting acceptable drugability and pharmacokinetic parameters. A diverse panel of aromatic compounds was screened in neuroblastoma cells persistently infected with PrPSc (ScN2a) for their ability to inhibit PK-resistant PrP (PrPRes) accumulation. From ∼200 compounds, 47 were effective in decreasing the accumulation of PrPRes in ScN2a cells. Pharmacokinetic and physicochemical properties were predicted in silico, allowing us to obtain estimates of relative blood brain barrier permeation and mutagenicity. MTT reduction assays showed that most of the active compounds were non cytotoxic. Compounds that cleared PrPRes from ScN2a cells, were non-toxic in the MTT assay, and presented a good pharmacokinetic profile were investigated for their ability to inhibit aggregation of an amyloidogenic PrP peptide fragment (PrP109–149). Molecular docking results provided structural models and binding affinities for the interaction between PrP and the most promising compounds. In summary, using this combined in vitro/in silico approach we have identified new small organic anti-scrapie compounds that decrease the accumulation of PrPRes in ScN2a cells, inhibit the aggregation of a PrP peptide, and possess pharmacokinetic characteristics that support their drugability. These compounds are

  6. Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds.

    PubMed

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-05-01

    Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria. PMID:26953199

  7. Competitive adsorption of furfural and phenolic compounds onto activated carbon in fixed bed column.

    PubMed

    Sulaymon, Abbas H; Ahmed, Kawther W

    2008-01-15

    For a multicomponent competitive adsorption of furfural and phenolic compounds, a mathematical model was builtto describe the mass transfer kinetics in a fixed bed column with activated carbon. The effects of competitive adsorption equilibrium constant, axial dispersion, external mass transfer, and intraparticle diffusion resistance on the breakthrough curve were studied for weakly adsorbed compound (furfural) and strongly adsorbed compounds (parachlorophenol and phenol). Experiments were carried out to remove the furfural and phenolic compound from aqueous solution. The equilibrium data and intraparticle diffusion coefficients obtained from separate experiments in a batch adsorber, by fitting the experimental data with theoretical model. The results show that the mathematical model includes external mass transfer and pore diffusion using nonlinear isotherms and provides a good description of the adsorption process for furfural and phenolic compounds in a fixed bed adsorber. PMID:18284136

  8. Leishmanicidal and cytotoxic activities of extracts and naturally-occurring compounds from two Lauraceae species.

    PubMed

    Sánchez-Suárez, Jeysson; Coy-Barrera, Ericsson; Cuca, Luis Enrique; Delgado, Gabriela

    2011-02-01

    The in vitro leishmanicidal effects of ethanolic extracts and fifteen naturally-occurring compounds (five lignans, eight neolignans, a diterpene and a dihydrochalcone), obtained from Pleurothyrium cinereum and Ocotea macrophylla, were evaluated on promastigotes of Leishmania panamensis and L. braziliensis. In addition, in order to determine the selective action on Leishmania species as a safety principle, in vitro cytotoxicity on J774 cells was also evaluated for test compounds and extracts. One extract and seven compounds showed activity against Leishmania parasites at different levels. Dihydroflavokawin B (8) was found to be the most potent antileishmanial compound on both parasites, whilst (+)-otobaphenol (14), was found to be the most selective compound on L. panamensis. PMID:21425681

  9. Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation.

    PubMed

    Zhang, Yi-Ze; Chen, Xi; Fan, Xing-Xing; He, Jian-Xing; Huang, Jun; Xiao, Da-Kai; Zhou, Yan-Ling; Zheng, Sen-You; Xu, Jia-Hui; Yao, Xiao-Jun; Liu, Liang; Leung, Elaine Lai-Han

    2016-01-01

    Non-small-cell lung cancer (NSCLC) dominates over 85% of all lung cancer cases. Epidermal growth factor receptor (EGFR) activating mutation is a common situation in NSCLC. In the clinic, molecular-targeting with Gefitinib as a tyrosine kinase inhibitor (TKI) for EGFR downstream signaling is initially effective. However, drug resistance frequently happens due to additional mutation on EGFR, such as substitution from threonine to methionine at amino acid position 790 (T790M). In this study, we screened a traditional Chinese medicine (TCM) compound library consisting of 800 single compounds in TKI-resistance NSCLC H1975 cells, which contains substitutions from leucine to arginine at amino acid 858 (L858R) and T790M mutation on EGFR. Attractively, among these compounds there are 24 compounds CC50 of which was less than 2.5 μM were identified. We have further investigated the mechanism of the most effective one, Digitoxin. It showed a significantly cytotoxic effect in H1975 cells by causing G2 phase arrest, also remarkably activated 5' adenosine monophosphate-activated protein kinase (AMPK). Moreover, we first proved that Digitoxin suppressed microtubule formation through decreasing α-tubulin. Therefore, it confirmed that Digitoxin effectively depressed the growth of TKI-resistance NSCLC H1975 cells by inhibiting microtubule polymerization and inducing cell cycle arrest. PMID:26999101

  10. Angiotensin-converting enzyme inhibitory effects by plant phenolic compounds: a study of structure activity relationships.

    PubMed

    Al Shukor, Nadin; Van Camp, John; Gonzales, Gerard Bryan; Staljanssens, Dorien; Struijs, Karin; Zotti, Moises J; Raes, Katleen; Smagghe, Guy

    2013-12-01

    In this study, 22 phenolic compounds were investigated to inhibit the angiotensin-converting enzyme (ACE). Tannic acid showed the highest activity (IC50 = 230 μM). The IC50 values obtained for phenolic acids and flavonoids ranged between 0.41 and 9.3 mM. QSAR analysis confirmed that the numbers of hydroxyl groups on the benzene ring play an important role for activity of phenolic compounds and that substitution of hydroxyl groups by methoxy groups decreased activity. Docking studies indicated that phenolic acids and flavonoids inhibit ACE via interaction with the zinc ion and this interaction is stabilized by other interactions with amino acids in the active site. Other compounds, such as resveratrol and pyrogallol, may inhibit ACE via interactions with amino acids at the active site, thereby blocking the catalytic activity of ACE. These structure-function relationships are useful for designing new ACE inhibitors and potential blood-pressure-lowering compounds based on phenolic compounds. PMID:24219111

  11. Identification of an orally available compound with potent and broad FLT3 inhibition activity.

    PubMed

    Chen, Y; Guo, Y; Zhao, W; Tina Ho, W-T; Fu, X; Zhao, Z J

    2016-06-01

    FLT3 internal tandem duplication (FLT3-ITD) is an activating mutation found in 20-30% of patients with acute myeloid leukemia (AML), which makes FLT3 an attractive target for the treatment of AML. Although FLT3-mutant patients respond to current FLT3 inhibitors, relapse usually happens because of the acquisition of resistant secondary mutations at the FLT3 catalytic domain, which is mainly on D835. In the search for compounds with broad FLT3 inhibition activities, we screened a kinase inhibitor library by using our unique FLT3 substrate and identified JAK3 inhibitor VI (designated JI6 hereafter) as a novel FLT3 inhibitor, which selectively targets FLT3 D835 mutants as well as FLT3-ITD. JI6 effectively inhibited FLT3-ITD-containing MV4-11 cells and HCD-57 cells transformed with FLT3-ITD and D835 mutants. Furthermore, administration of JI6 effectively targeted FLT3 signaling in vivo and suppressed the myeloproliferative phenotypes in FLT3-ITD knock-in mice, and significantly prolonged the survival of immunodeficient mice implanted with the transformed HCD-57 cells. Therefore, JI6 is a promising candidate for the development of next-generation anti-AML drugs. PMID:26411368

  12. Identification of an orally available compound with potent and broad FLT3 inhibition activity

    PubMed Central

    Chen, Yun; Guo, Yao; Zhao, Wanke; Tina Ho, Wan-Ting; Fu, Xueqi; Joe Zhao, Zhizhuang

    2015-01-01

    FLT3 internal tandem duplication (FLT3-ITD) is an activating mutation found in 20%-30% of patients with acute myeloid leukemia (AML), which makes FLT3 an attractive target for the treatment of AML. Although FLT3-mutant patients respond to current FLT3 inhibitors, relapse usually happens due to the acquisition of resistant secondary mutations at the FLT3 catalytic domain, which is mainly on D835. In the search for compounds with broad FLT3 inhibition activities, we screened a kinase inhibitor library by using our unique FLT3 substrate and identified JAK3 inhibitor VI (designated JI6 hereafter) as a novel FLT3 inhibitor, which selectively targets FLT3 D835 mutants as well as FLT3-ITD. JI6 effectively inhibited FLT3-ITD-containing MV4-11 cells and HCD-57 cells transformed with FLT3-ITD and D835 mutants. Furthermore, administration of JI6 effectively targeted FLT3 signaling in vivo and suppressed the myeloproliferative phenotypes in FLT3-ITD knock-in mice and significantly prolonged the survival of immunodeficient mice implanted with the transformed HCD-57 cells. Therefore, JI6 is a promising candidate for development of next generation anti-AML drugs. PMID:26411368

  13. Evaluation of anxiolytic activity of compound Valeriana jatamansi Jones in mice

    PubMed Central

    2012-01-01

    Background Compound Valeriana jatamansi Jones is a formula for treating anxiety-related diseases in the clinic, which is composed of Valeriana jatamansi Rhizoma et Radix, Ziziphi Spinosae Semen, Albiziae Cortex and Junci Medulla. The purpose of this study was to explore the anxiolytic properties of this compound in mice. Methods Male ICR mice were treated with compound Valerianae Jatamansi Jones (1.2 g/kg, 2.4 g/kg, 4.8 g/kg), saline, diazepam (2 mg/kg) orally for 10 days and then exposed to elevated maze-plus (EPM) and light–dark box (LDB). The effects of the compound on spontaneous activity were evaluated by locomotor activity test. We further investigated the mechanism of action underlying the anxiolytic-like effect of compound by pre-treating animals with antagonists of benzodiazepine (flumazenil, 3mg/kg) prior to evaluation using EPM and LDB. Results Compound Valerianae Jatamansi Jones (2.4, 4.8 g/kg, p.o.) significantly increased entries (P<0.05) into and time spent (P<0.05) on the open arms of the EPM, and number of transitions (P<0.05) and time spent (P<0.05) in the light compartment of the LDB. However, the anxiolytic-like effects of compound were significantly reduced by pre-treatment with flumazenil (P>0.05). In addition, compound Valerianae Jatamansi Jones treatment didn’t affect the spontaneous activity in mice (P> 0.05). Conclusions The present study supports the hypothesis that compound Valeriana jatamansi Jones exert anxiolytic action but no sedative effects in mice and that this effect might be mediated by benzodiazepine receptors. PMID:23171285

  14. Fate of alkylphenolic compounds during activated sludge treatment: impact of loading and organic composition.

    PubMed

    McAdam, Ewan J; Bagnall, John P; Soares, Ana; Koh, Yoong K K; Chiu, Tze Y; Scrimshaw, Mark D; Lester, John N; Cartmell, Elise

    2011-01-01

    The impact of loading and organic composition on the fate of alkylphenolic compounds in the activated sludge plant (ASP) has been studied. Three ASP designs comprising carbonaceous, carbonaceous/nitrification, and carbonaceous/nitrification/denitrification treatment were examined to demonstrate the impact of increasing levels of process complexity and to incorporate a spectrum of loading conditions. Based on mass balance, overall biodegradation efficiencies for nonylphenol ethoxylates (NPEOs), short chain carboxylates (NP(1-3)EC) and nonylphenol (NP) were 37%, 59%, and 27% for the carbonaceous, carbonaceous/nitrification, and carbonaceous/nitrification/denitrification ASP, respectively. The presence of a rich community of ammonia oxidizing bacteria does not necessarily facilitate effective alkylphenolic compound degradation. However, a clear correlation between alkylphenolic compound loading and long chain ethoxylate compound biodegradation was determined at the three ASPs, indicating that at higher initial alkylphenolic compound concentrations (or load), greater ethoxylate biotransformation can occur. In addition, the impact of settled sewage organic composition on alkylphenolic compound removal was evaluated. A correlation between the ratio of chemical oxygen demand (COD) to alkylphenolic compound concentration and biomass activity was determined, demonstrating the inhibiting effect of bulk organic matter on alkylphenol polyethoxylate transformation activity. At all three ASPs the biodegradation pathway proposed involves the preferential biodegradation of the amphiphilic ethoxylated compounds, after which the preferential attack of the lipophilic akylphenol moiety occurs. The extent of ethoxylate biodegradation is driven by the initial alkylphenolic compound concentration and the proportion of COD constituted by the alkylphenol polyethoxylates (APEOs) and their metabolites relative to the bulk organic concentration of the sewage composed of proteins, acids, fats

  15. Functional Brain Activation Differences in Stuttering Identified with a Rapid fMRI Sequence

    ERIC Educational Resources Information Center

    Loucks, Torrey; Kraft, Shelly Jo; Choo, Ai Leen; Sharma, Harish; Ambrose, Nicoline G.

    2011-01-01

    The purpose of this study was to investigate whether brain activity related to the presence of stuttering can be identified with rapid functional MRI (fMRI) sequences that involved overt and covert speech processing tasks. The long-term goal is to develop sensitive fMRI approaches with developmentally appropriate tasks to identify deviant speech…

  16. Relationship between electronic properties and drug activity of seven quinoxaline compounds: A DFT study

    NASA Astrophysics Data System (ADS)

    Behzadi, Hadi; Roonasi, Payman; Assle taghipour, Khatoon; van der Spoel, David; Manzetti, Sergio

    2015-07-01

    The quantum chemical calculations at the DFT/B3LYP level of theory were carried out on seven quinoxaline compounds, which have been synthesized as anti-Mycobacterium tuberculosis agents. Three conformers were optimized for each compound and the lowest energy structure was found and used in further calculations. The electronic properties including EHOMO, ELUMO and related parameters as well as electron density around oxygen and nitrogen atoms were calculated for each compound. The relationship between the calculated electronic parameters and biological activity of the studied compounds were investigated. Six similar quinoxaline derivatives with possible more drug activity were suggested based on the calculated electronic descriptors. A mechanism was proposed and discussed based on the calculated electronic parameters and bond dissociation energies.

  17. Phenolic compounds from sugarcane molasses possessing antibacterial activity against cariogenic bacteria.

    PubMed

    Takara, Kensaku; Ushijima, Kenji; Wada, Koji; Iwasaki, Hironori; Yamashita, Masatsugu

    2007-01-01

    During the course of our research into the use of cane by-products from sugar manufacturing, we have studied the isolation and structural determination of bioactive compounds present in sugarcane molasses. In this study, dehydrodiconiferylalcohol-9'-O-beta-D-glucopyranoside (1) and isoorientin-7, 3'-O-dimethyl ether (2) were isolated as antibacterial active compounds against cariogenic bacteria. Their structures were elucidated by (1)H-NMR, (13)C-NMR and ESI-MS. The activities of these isolated compounds against Streptococcus mutans and Streptococcus sobrinus were assessed by a minimum inhibitory concentration (MIC) test. The MICs of compounds 1 and 2 against both S. mutans and S. sobrinus were >4 mg/mL and 4 mg/mL, respectively. PMID:17938552

  18. Anti-inflammatory and antioxidant activities of phenolic compounds from Desmodium caudatum leaves and stems.

    PubMed

    Li, Wei; Sun, Ya Nan; Yan, Xi Tao; Yang, Seo Young; Kim, Sohyun; Chae, Doobyeong; Hyun, Jin Won; Kang, Hee Kyoung; Koh, Young-Sang; Kim, Young Ho

    2014-06-01

    Four flavanonols (1-4), one xanthone (5), and three flavonoid glycosides (6-8), were isolated from the leaves and stems of Desmodium caudatum. Their structures were elucidated by comparing spectroscopic data with reported values. The anti-inflammatory activity of the isolated compounds was investigated in lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells. Among them, compounds 1 and 2 exhibited inhibitory effects on LPS-induced IL-6, IL-12 p40, and TNF-α production with IC50 values ranging from 6.0 to 29.4 μM. Compound 5 exhibited 1,1-diphenyl-2-picrylhydrazyl radical and intracellular reactive oxygen species scavenging activity in human HaCaT keratinocytes. These results warrant further studies of the potential anti-inflammatory and antioxidant benefits of compounds from D. caudatum. PMID:24026429

  19. 3-Arylidene-N-hydroxyoxindoles: A New Class of Compounds Endowed with Antitumor Activity.

    PubMed

    Musso, Loana; Cincinelli, Raffaella; Zuco, Valentina; De Cesare, Michelandrea; Zunino, Franco; Fallacara, Anna Lucia; Botta, Maurizio; Dallavalle, Sabrina

    2016-08-19

    A series of compounds containing the N-hydroxyoxindole scaffold were synthesized and evaluated for antitumor activity. The compounds showed potent antiproliferative activity against the wild-type p53 IGROV-1 ovarian carcinoma cell line and considerably lower efficacy against the mutant IGROV-1/Pt1 subline that lacks p53 function. The differential response of ovarian carcinoma cells depending on p53 status was also reflected in the varied susceptibility to apoptosis of the treated cell lines. These results support a role for the p53 transcription factor as a determinant of cytotoxicity. The therapeutic potential of the most promising compound of the series was evaluated in the treatment of an IGROV-1 xenograft growing as ascitic tumor in mice. Using intraperitoneal administration, daily treatment with the compound for four weeks produced a significant delay in the onset of ascites. PMID:27311681

  20. Multivariate analysis of PRISMA optimized TLC image for predicting antioxidant activity and identification of contributing compounds from Pereskia bleo.

    PubMed

    Sharif, K M; Rahman, M M; Azmir, J; Khatib, A; Sabina, E; Shamsudin, S H; Zaidul, I S M

    2015-12-01

    Multivariate analysis of thin-layer chromatography (TLC) images was modeled to predict antioxidant activity of Pereskia bleo leaves and to identify the contributing compounds of the activity. TLC was developed in optimized mobile phase using the 'PRISMA' optimization method and the image was then converted to wavelet signals and imported for multivariate analysis. An orthogonal partial least square (OPLS) model was developed consisting of a wavelet-converted TLC image and 2,2-diphynyl-picrylhydrazyl free radical scavenging activity of 24 different preparations of P. bleo as the x- and y-variables, respectively. The quality of the constructed OPLS model (1 + 1 + 0) with one predictive and one orthogonal component was evaluated by internal and external validity tests. The validated model was then used to identify the contributing spot from the TLC plate that was then analyzed by GC-MS after trimethylsilyl derivatization. Glycerol and amine compounds were mainly found to contribute to the antioxidant activity of the sample. An alternative method to predict the antioxidant activity of a new sample of P. bleo leaves has been developed. PMID:26033701

  1. RP-HPLC-DAD analysis of phenolic compounds in pomace extracts from five grape cultivars: Evaluation of their antioxidant, antiradical and antifungal activities in orange and apple juices.

    PubMed

    Sagdic, Osman; Ozturk, Ismet; Ozkan, Gulcan; Yetim, Hasan; Ekici, Lutfiye; Yilmaz, Mustafa Tahsin

    2011-06-15

    Phenolic compounds, related to antioxidative and antifungal properties of ethanolic extracts from five commercial grape cultivars (three red and two white) grown in Turkey were determined. A reversed-phase high performance liquid chromatography (RP-HPLC) procedure was developed, and a total 18 different phenolic compounds were identified. Total phenolic contents of the extracts were determined using Folin-Ciocalteau method. Antioxidant activities of the extracts were evaluated by using DPPH radical scavenging and phosphomolybdenum methods. All extracts exhibited strong antioxidant and antiradical activity. Phenolic compounds and antioxidant activities of the extracts were variety dependent. Antifungal activities of the pomaces and extracts were screened by both in vitro agar-well diffusion assay and antifungal activity in apple and orange juices in situ using Zygosaccharomyces rouxii and Z. bailii. Antifungal activities revealed that the pomaces and extracts of Gamay and Kalecik karasi could be more effective antifungal agents than those of Emir, Narince and Okuzgozu grape cultivars. PMID:25213954

  2. SYNTHESIS AND IN VITRO ANTIMICROBIAL ACTIVITY OF NOVEL SERIES OF 3,5-DIACETYLPYRIDINE COMPOUNDS.

    PubMed

    Morsy, Eman M H; Kotb, Eman R; Soliman, Hanan A; Sayyed, Hayam H; Abdelwahed, Nayira A M

    2015-01-01

    Bis diacetylpyridine derivative (1) was prepared and reacted with different halo-compounds, namely: epichlorohydrine and dichloroethyl ethyl ether to give 2a,b, respectively, and reacted with morpholine and piperidine to afford Mannich products 3a,b, successively. Compound 4 was synthesized by reaction of 1 with potassium thiocyanate. Reaction of 4 with 4-chlorobenzaldehyde, glucose and phthalic or maleic anhydrides produced 5, 6 and 7a,b. Compound 1 reacted with 4-chlorobenzaldehyde to give bisanylmethylene derivative 8. Also some new compounds 9-11 were prepared from the reaction of compound 8 with nucleophiles, namely: hydrazine hydrate, thiosemicarbazide and hydroxylamine via Michael condensation reaction. On the other hand, compound 8 was reacted with cyclohexanone and cyclopentanone to give 12a,b. The structures of newly synthesized products have been deduced on the basis of elemental analysis and spectral data. Some synthesized compounds were screened for their antimicrobial evaluation. Among the assayed compounds, derivatives 3b and 12a showed the highest antimicrobial activities. PMID:26642655

  3. SYNTHESIS AND BIOLOGICAL ACTIVITY OF SULFUR COMPOUNDS SHOWING STRUCTURAL ANALOGY WITH COMBRETASTATIN A-4

    PubMed Central

    dos Santos, Edson dos A.; Prado, Paulo C.; de Carvalho, Wanderley R.; de Lima, Ricardo V.; Beatriz e, Adilson; de Lima, Dênis P.; Hamel, Ernest; Dyba, Marzena A.; Albuquerque, Sergio

    2013-01-01

    We extended our previous exploration of sulfur bridges as bioisosteric replacements for atoms forming the bridge between the aromatic rings of combretastatin A-4. Employing coupling reactions between 5-iodo-1,2,3-trimethoxybenzene and substituted thiols, followed by oxidation to sulfones with m-CPBA, different locations for attaching the sulfur atom to ring A through the synthesis of nine compounds were examined. Antitubulin activity was performed with electrophoretically homogenous bovine brain tubulin, and activity occurred with the 1,2,3-trimethoxy-4-[(4-methoxyphenyl)thio]benzene (12), while the other compounds were inactive. The compounds were also tested for leishmanicidal activity using promastigote forms of Leishmania braziliensis (MHOM/BR175/M2904), and the greatest activity was observed with 1,2,3-trimethoxy-4-(phenylthio)benzene (10) and 1,2,3-trimethoxy-4-[(4-methoxyphenyl) sulfinyl]benzene (15). PMID:23766547

  4. THE SEARCH OF COMPOUNDS WITH ANTIAGGREGATION ACTIVITY AMONG S-ESTERS OF THIOSULFONIC ACIDS.

    PubMed

    Halenova, T I; Nikolaeva, I V; Nakonechna, A V; Bolibrukh, K B; Monka, N Y; Lubenets, V I; Savchuk, O M; Novikov, V P; Ostapchenko, L I

    2015-01-01

    According to the current understanding, the hyperactivation of platelets may lead to increased intravascular coagulation and thrombosis. Today a relevant issue is the search for new anti-thrombotic agents that are able to modulate the activity of platelet receptors, thus, influence the processes of activation and aggregation of platelets. The aim of this study was to investigate the effects of newly synthesized thiosulfonate derivatives on platelet aggregation. The activity of the compounds was tested in vitro using platelet-rich plasma. As a result of the screening test, structural formulas of four agents with high antiaggregative activity were established. These compounds inhibited ADP- and collagen-induced platelet aggregation in a dose-dependent manner. Two of these compounds were shown to be more effective inhibitors of aggregation induced by ADP (IC50 - 8-10 μM), as well as collagen (IC50 - 1.5-2.0 μM). PMID:26717599

  5. [Antibacterial activity of polyphenolic compounds isolated from plants of Geraniaceae and Rosaceae families].

    PubMed

    Nikitina, V S; Kuz'mina, L Iu; Melent'ev, A I; Shendel', G V

    2007-01-01

    Polyphenolic compounds present in extracts of plants belonging to the families Geraniaceae (blood-red cranesbill, wood cranesbill, meadow cranesbill, and alfilaria) and Rosaceae (red raspberry, European dewberry, and tormentil) have been tested for their activity against gram-positive and gram-negative bacteria of the genera Azotobacter, Bacillus, and Pseudomonas. The bacteriostatic activity exhibited some species-related features and depended on the polarity of the extracting agent. The bacteriostatic activity of plant-derived phenolic compounds correlated with their antioxidant potential. The plants of the families Geraniaceae and Rosaceae offer promise as a source of raw material for isolation of polyphenolic compounds exhibiting bactericidal activity, including against opportunistic pathogens (B. cereus, E. coli, P. aeruginosa, and S. aureus strains). PMID:18173115

  6. Synthesis and biological activities of certain mesoionic sydnone compounds containing chalcone moiety.

    PubMed

    Deshpande, Shreenivas R; Pai, K Vasantakumar

    2010-06-01

    In order to have antibacterial, analgesic and anti-inflammatory activity in the same molecule, 4-[1-oxo-3- (substituted aryl)-2-propenyl]-3-(4-chlorophenyl) sydnones were synthesized by condensing 4-acetyl-3-(4-chlorophenyl)sydnone with various substituted aryl aldehydes and characterized by spectral studies; 4-acetyl-3-(4-chlorophenyl)sydnone itself, was prepared by acetylation of 3-(4-chlorophenyl) sydnone. The newly synthesized compounds were evaluated for antibacterial and anti-inflammatory activities by cup plate and carrageenan induced rat paw edema methods respectively. Some of the compounds showed promising antibacterial and anti-inflammatory activities. PMID:24825982

  7. SYNTHESIS AND BIOLOGICAL ACTIVITIES OF CERTAIN MESOIONIC SYDNONE COMPOUNDS CONTAINING CHALCONE MOIETY

    PubMed Central

    Deshpande, Shreenivas R.; Pai, K. Vasantakumar

    2010-01-01

    In order to have antibacterial, analgesic and anti-inflammatory activity in the same molecule, 4-[1-oxo-3- (substituted aryl)-2-propenyl]-3-(4-chlorophenyl) sydnones were synthesized by condensing 4-acetyl-3-(4-chlorophenyl)sydnone with various substituted aryl aldehydes and characterized by spectral studies; 4-acetyl-3-(4-chlorophenyl)sydnone itself, was prepared by acetylation of 3-(4-chlorophenyl) sydnone. The newly synthesized compounds were evaluated for antibacterial and anti-inflammatory activities by cup plate and carrageenan induced rat paw edema methods respectively. Some of the compounds showed promising antibacterial and anti-inflammatory activities PMID:24825982

  8. Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro▿

    PubMed Central

    Caffrey, Conor R.; Steverding, Dietmar; Swenerton, Ryan K.; Kelly, Ben; Walshe, Deirdre; Debnath, Anjan; Zhou, Yuan-Min; Doyle, Patricia S.; Fafarman, Aaron T.; Zorn, Julie A.; Land, Kirkwood M.; Beauchene, Jessica; Schreiber, Kimberly; Moll, Heidrun; Ponte-Sucre, Alicia; Schirmeister, Tanja; Saravanamuthu, Ahilan; Fairlamb, Alan H.; Cohen, Fred E.; McKerrow, James H.; Weisman, Jennifer L.; May, Barnaby C. H.

    2007-01-01

    Parasitic diseases are of enormous public health significance in developing countries—a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 Å. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC50) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC50 values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent

  9. Lignans, bacteriocides and organochlorine compounds activate the human pregnane X receptor (PXR)

    SciTech Connect

    Jacobs, Miriam N. . E-mail: miriam.jacobs@jrc.it; Nolan, Gail T.; Hood, Steven R.

    2005-12-01

    The pregnane X receptor (PXR) mediates the induction of enzymes involved in steroid metabolism and xenobiotic detoxification. The receptor is expressed in liver and intestinal tissues and is activated by a wide range of compounds. The ability of a diverse range of dietary compounds to activate PXR-mediated transcription was assayed in HuH7 cells following transient transfection with human PXR (hPXR). The compounds investigated included phytochemicals such as lignans and phytoestrogens, organochlorine dietary contaminants such as polychlorinated biphenyls (PCBs) and triclosan and selected steroid, drug and herbal compounds. The hPXR activation at the top concentrations tested (10 {mu}M) relative to the positive control 10 {mu}M rifampicin ranged from 1.3% (trans-resveratrol) to 152% (ICI 182780). Hydroxylated compounds were marginally more potent than the parent compounds (tamoxifen activation was 74.6% whereas 4 hydroxytamoxifen activation was 84.2%) or significantly greater (vitamin D{sub 3} activation was 1.6%, while hydroxylated vitamin D{sub 3} activation was 55.6%). Enterolactone, the metabolite of common dietary lignans, was a medium activator of PXR (35.6%), compared to the lower activation of a parent lignan, secoisolariciresinol (20%). Two non-hydroxylated PCB congeners (PCB 118 and 153), which present a larger fraction of the PCB contamination of fatty foods, activated hPXR by 26.6% and 17%, respectively. The pesticide trans-nonachlor activation was 53.8%, while the widely used bacteriocide triclosan was a medium activator of hPXR at 46.2%. The responsiveness of PXR to activation by lignan metabolites suggests that dietary intake of these compounds may affect the metabolism of drugs that are CYP3A substrates. Additionally, the evidence that organochlorine chemicals, particularly the ubiquitous triclosan, activate hPXR suggests that these environmental chemicals may, in part, exhibit their endocrine disruptor activities by altering PXR-regulated steroid

  10. Anti-Campylobacter Activities and Resistance Mechanisms of Natural Phenolic Compounds in Campylobacter

    PubMed Central

    Klančnik, Anja; Možina, Sonja Smole; Zhang, Qijing

    2012-01-01

    Background Campylobacter is a major foodborne pathogen and alternative antimicrobials are needed to prevent or decrease Campylobacter contamination in foods or food producing animals. The objectives of this study are to define the anti-Campylobacter activities of natural phenolic compounds of plant origin and to determine the roles of bacterial drug efflux systems in the resistance to these natural phenolics in Campylobacter jejuni. Methodology/Principal Findings Anti-Campylobacter activities were evaluated by an MIC assay using microdilution coupled with ATP measurement. Mutants of the cmeB and cmeF efflux genes and the cmeR transcriptional repressor gene were compared with the wild-type strain for their susceptibilities to phenolics in the absence and presence of efflux-pump inhibitors (EPIs). The phenolic compounds produced significant, but variable activities against both antibiotic-susceptible and antibiotic resistant Campylobacter. The highest anti-Campylobacter activity was seen with carnosic and rosmarinic acids in their pure forms or in enriched plant extracts. Inactivation of cmeB rendered C. jejuni significantly more susceptible to the phenolic compounds, while mutation of cmeF or cmeR only produced a moderate effect on the MICs. Consistent with the results from the efflux pump mutants, EPIs, especially phenylalanine-arginine β-naphthylamide and NMP, significantly reduced the MICs of the tested phenolic compounds. Further reduction of MICs by the EPIs was also observed in the cmeB and cmeF mutants, suggesting that other efflux systems are also involved in Campylobacter resistance to phenolic compounds. Conclusion/Significance Natural phenolic compounds of plant origin have good anti-Campylobacter activities and can be further developed for potential use in controlling Campylobacter. The drug efflux systems in Campylobacter contribute significantly to its resistance to the phenolics and EPIs potentiate the anti-Campylobacter activities of plant phenolic

  11. Enhanced photo-activated luminescence for screening polychlorobiphenyls (PCBs) and other related chlorinated compounds

    DOEpatents

    Vo-Dinh, T.

    1994-06-07

    The presence of polychlorinated biphenyls and other chlorinated compounds in a sample is determined by treating the sample with a photo-activator and then exposing the treated sample to a UV light source. The UV light produces a photo-product complex, which is subsequently excited with UV light to cause luminescence of the complex. The luminescence is detected and characteristics of the luminescence spectra are used to determine the presence of chlorinated compounds and also the quantity of the chlorine in the compounds. 14 figs.

  12. Enhanced photo-activated luminescence for screening polychlorobiphenyls (PCBs) and other related chlorinated compounds

    DOEpatents

    Vo-Dinh, Tuan

    1994-01-01

    The presence of polychlorinated biphenyls and other chlorinated compounds in a sample is determined by treating the sample with a photo-activator and then exposing the treated sample to a UV light source. The UV light produces a photo-product complex, which is subsequently excited with UV light to cause luminescence of the complex. The luminescence is detected and characteristics of the luminescence spectra are used to determine the presence of chlorinated compounds and also the quantity of the chlorine in the compounds

  13. Enhanced photo-activated luminescence for screening polychlorobiphenyls (PCBs) and other related chlorinated compounds

    DOEpatents

    Tuan Vodinh.

    1993-12-21

    The presence of polychlorinated biphenyls and other chlorinated compounds in a sample is determined by treating the sample with a photo-activator and then exposing the treated sample to a UV light source. The UV light produces a photo-product complex, which is subsequently excited with UV light to cause luminescence of the complex. The luminescence is detected and characteristics of the luminescence spectra are used to determine the presence of chlorinated compounds and also the quantity of the chlorine in the compounds. 14 figures.

  14. Enhanced photo-activated luminescence for screening polychlorobiphenyls (PCBs) and other related chlorinated compounds

    DOEpatents

    Vo-Dinh, Tuan

    1993-01-01

    The presence of polychlorinated biphenyls and other chlorinated compounds in a sample is determined by treating the sample with a photo-activator and then exposing the treated sample to a UV light source. The UV light produces a photo-product complex, which is subsequently excited with UV light to cause luminescence of the complex. The luminescence is detected and characteristics of the luminescence spectra are used to determine the presence of chlorinated compounds and also the quantity of the chlorine in the compounds.

  15. Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics.

    PubMed

    Roth, Howard S; Botham, Rachel C; Schmid, Steven C; Fan, Timothy M; Dirikolu, Levent; Hergenrother, Paul J

    2015-05-14

    Procaspase-activating compound 1 (PAC-1) is an o-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues were designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater area under the curve values for each of the four compounds, suggesting them as promising candidates for further development. PMID:25856364

  16. Supercritical CO2 extraction of functional compounds from Spirulina and their biological activity.

    PubMed

    K G, Mallikarjun Gouda; K, Udaya Sankar; R, Sarada; G A, Ravishankar

    2015-06-01

    Supercritical carbon dioxide (SCCO2) extraction and fractionation of Spirulina platensis was carried out to obtain functional compounds with antioxidant, antimicrobial and enzyme inhibitory activities. Extraction of SCCO2 was carried out using 200 g of Spirulina powder at 40 ºC under 120 bar pressure with CO2 flow rate of 1.2 kg h(-1). SCCO2 fraction obtained was further treated with hexane and ethyl acetate to identify its components. Individual components were identified by comparing mass spectra of samples with standard data and retention indices (RI) of C5-C20 n-alkanes mixture using the kovat index formula. The phenolic and flavonoid content of the SCCO2 extract was found to be 0.34 ± 0.01 g/100 g and 0.12 ± 0.01 g/100 g respectively. The SCCO2 extract had antioxidant activity with IC50 value of 109.6 ± 3.0 μg mL(-1) for DPPH (2,2-Diphenyl-1-picryl hydrazyl radical), IC50 value of 81.66 ± 2.5 μg mL(-1) for reducing power and IC50 value of 112.70 ± 0.8 μg mL(-1) for hydroxyl radical scavenging activity. Further, antioxidant activity study on oxidative induced DNA damage was analysed to elucidate the positive role of SCCO2 extract. SCCO2 extracts showed high antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus FRI 722 and Bacillus cereus F 4810) compared to that of Gram negative bacteria (Escherichia coli MTCC 108 and Yersinia enterocolitica MTCC 859). The SCCO2 extract exhibited inhibitory activity on both Angiotensin-1 converting enzyme and α-glucosidase with IC50 values of 274 ± 1.0 μg mL(-1) and 307 ± 2.0 μg mL(-1) respectively. PMID:26028745

  17. Antifungal activity of extracts and select compounds in heartwood of seven western conifers toward Phytophthora ramorum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Individual compounds and ethyl acetate extracts from heartwood of seven conifer species were tested for fungicidal activity against Phytophthora ramorum. Extracts from incense and western red cedar exhibited the strongest activity (EC50 589 and 646 ppm, respectively), yellow-cedar, western juniper,...

  18. Inhibition of guinea pig aldehyde oxidase activity by different flavonoid compounds: An in vitro study.

    PubMed

    Siah, Maryam; Farzaei, Mohammad Hosein; Ashrafi-Kooshk, Mohammad Reza; Adibi, Hadi; Arab, Seyed Shahriar; Rashidi, Mohammad Reza; Khodarahmi, Reza

    2016-02-01

    Aldehyde oxidase (AO), a cytosolic molybdenum-containing hydroxylase, is predominantly active in liver and other tissues of mammalian species and involved in the metabolism of extensive range of aldehydes and nitrogen-containing compounds. A wide range of natural components including polyphenols are able to interfere with AO-catalyzed reactions. Polyphenols and flavonoids are one of the extensive secondary plant metabolites ubiquitously present in plants considered an important part of the human diet. The aim of the present study was to investigate inhibitory effect of selected phenolic compounds from three subclasses of aurone, flavanone and phenolic lactone compounds on the activity of AO, spectrophotometrically. AO enzyme was partially purified from liver of guinea pig. Then, inhibitory effects of 10 flavonoid compounds including 8 derivatives of 2-benzylidenebenzofuran-3(2H)-ones, as well as naringenin and ellagic acid on the activity of aldehyde oxidase were assessed compared with the specific inhibitor of AO, menadione. Among the phenolic compounds with inhibitory effects on the enzyme, ellagic acid (IC50=14.47 μM) was the most potent agent with higher inhibitory action than menadione (IC50=31.84 μM). The mechanisms by which flavonoid compounds inhibit AO activity have been also determined. The inhibitory process of the assessed compounds occurs via either a non-competitive or mixed mode. Although flavonoid compounds extensively present in the nature, mainly in dietary regimen, aurones with promising biological properties are not widely distributed in nature, so synthesis of aurone derivatives is of great importance. Additionally, aurones seem to provide a promising scaffold in medicinal chemistry for the skeleton of new developing drugs, so the results of the current study can be valuable in order to better understanding drug-food as well as drug-drug interaction and also appears to be worthwhile in drug development strategies. PMID:26722818

  19. Responses of mixtures of polyhalogenated aromatic compounds or single compounds in the CALUX-assay a novel species-specific bioassay for Ah-receptor active compounds

    SciTech Connect

    Murk, A.J.; Aarts, J.M.M.J.G.; Jonas, A.; Brouwer, A.; Denison, M.S.

    1995-12-31

    Polyhalogenated aromatic hydrocarbons (PHAHs) elicit a number of common toxic responses, including reproductive toxicity, teratogenicity, impairment of immune responses, alterations in vitamin A and thyroid hormone metabolism and carcinogenesis. The toxic effects however are highly dependent on the animal species used, The most toxic PHAHs are approximate isostereomeres of 2,3,7,8 tetrachlorinated dibenzo-p-dioxin (TCDD) and share a common mechanism of action mediated by the aryl hydrocarbon receptor (AhR). Based on the common receptor mediated mechanism, the toxic equivalency factor concept was developed, in which the potency of each individual congener is expressed relative to TCDD, thus allowing hazard and risk assessment for mixtures of PHAHs. A number of recombinant cell lines were developed, including hepalclc7 mouse and H4IIE rat hepatoma cell lines, with AhR-mediated firefly (Photinus pyralis) luciferase gene expression. The response in this so-called CALUX (chemical activated luciferase expression) assay is additive for polychlorinated dibenzofurans (PCDFs) and PCDDS, but for polychlorinated biphenyls (PCBs) both synergistic and antagonistic interactions have been demonstrated, which are partially species-dependent. Also some structurally related compounds, like polybrominated diphenyl ether, pentachlorinated phenol, benzo(a)pyrene, pyrene, tetrachlorobenzyltoluene (Ugilec 141) and mixtures of polychlorinated terphenyls have been tested in the CALUX assay. The responses of these compounds were sometimes agonistic, but also antagonistic and synergistic effects on the TCDO response were observed.

  20. Bioactive compounds and antioxidant activity of Rosa canina L. biotypes from spontaneous flora of Transylvania

    PubMed Central

    2013-01-01

    Background The theoretical, but especially the practical values of identifying the biochemical compounds from the Rosa canina L. fruits are of present interest, this aspect being illustrated by the numerous researches. It was reported that the Rosa canina L. fruit, with its high ascorbic acid, phenolics and flavonoids contents, have antioxidant, antimutagenic and anticarcinogenic effects. This study was performed on order to evaluate the amount of the main phytochemicals (vitamin C, total polyphenols, and total flavonoids) content and their antioxidant activity. Results The results obtained revealed that the average amounts of vitamin C within the studied genotypes were: 360.22 mg/100 g frozen pulp (var. transitoria f. ramosissima, altitude 1250 m) and 112.20 mg/100 g frozen pulp (var. assiensis, altitude 440 m), giving a good correlation between the vitamin C content of the rosehip and the altitude. The total polyphenols content varied from 575 mg/100 g frozen pulp (var. transitoria f. ramosissima) to 326 mg/100 g frozen pulp (var. lutetiana f. fallens). The total flavonoids content showed the highest value for var. assiensis variant 163.3 mg/100 g frozen pulp and the lowest value attributed to var. transitoria f. montivaga 101.3 mg/100 g frozen pulp. The antioxidant activity of eight rose hip extracts from wild Transylvania populations was investigated through DPPH method. The antioxidant activity revealed a good correlation only with vitamin C content and total polyphenols. Conclusion Eight Rose hip fruit species were compared taking into consideration the ascorbic acid, total polyphenols, total flavonoids contents and their antioxidant activity. Based on these results, two of the rosehip genotypes that were analysed could be of perspective for these species’ amelioration, due to their content of phytochemicals mentioned above. These varieties are var. transitoria f. ramosissima (Bistrita-Nasaud, Agiesel) and var. transitoria f. montivaga (Bistrita

  1. Multifunctional activity of polyphenolic compounds associated with a potential for Alzheimer's disease therapy from Ecklonia cava.

    PubMed

    Choi, Byoung Wook; Lee, Hye Sook; Shin, Hyeon-Cheol; Lee, Bong Ho

    2015-04-01

    Five polyphenols were isolated and purified from a brown alga Ecklonia cava. These compounds showed diverse biological activities such as antioxidative, antiinflammatory, and enzyme inhibitory activities. This led us to investigate the potential of these compounds as Alzheimer's disease drugs. All of the compounds showed moderate acetylcholinesterase inhibitory activity in a micromolar range (IC50 from 16.0 to 96.3 μM). For butyrylcholinesterase, a new target for the treatment of Alzheimer's disease, phlorofucofuroeckol-A (PFF-A), showed a particularly potent inhibitory activity (IC50 0.95 μM), which is over 100-fold greater than for acetylcholinesterase. These compounds inhibited glycogen synthase kinase 3 beta, which is related to the formation of hyperphosphorylated tau and generation Aβ. Bieckol and PFF-A inhibited amyloid precursor protein biosynthesis. PFF-A also showed very strong β-secretase inhibitory activity with IC50 of submicromole. These results render these compounds as interesting potential drug candidates for Alzheimer's disease. PMID:25640212

  2. Omega-pyridiniumalkylethers of steroidal phenols: new compounds with potent antibacterial and antiproliferative activities.

    PubMed

    Lange, C; Holzhey, N; Schönecker, B; Beckert, R; Möllmann, U; Dahse, H-M

    2004-06-15

    Novel omega-pyridiniumalkylethers of two steroidal phenols were synthesized as compounds with potential antimicrobial activity. 3-Hydroxy-estra-1,3,5(10)-triene-17-one and 1-hydroxy-4-methyl-estra-1,3,5(10)-triene-17-one were reacted with omega,omega'-dibromoalkanes to omega-bromoalkoxy-estra-1,3,5(10)-trienes followed by reaction with pyridine to obtain the desired steroidal omega-pyridiniumalkoxy compounds as bromides. Their antimicrobial activity against strains of multiresistant Staphylococcus aureus (MRSA), a vancomycin resistant Enterococcus faecalis and fast growing mycobacteria depends clearly on the length of the alkyl chain. A strong broadband activity has been found for the compounds with eight or 10 C-atoms; in some cases better than ciprofloxacin or cetylpyridinium salts. In addition, the antiproliferative and cytotoxic activity depends on the chain length, too. The differentiation between antibacterial and cytotoxic activity is better for the steroid hybrid molecules than the cetylpyridinium salts. These new compounds can serve as lead compounds for further optimization. PMID:15158804

  3. Hammerhead ribozyme activity and oligonucleotide duplex stability in mixed solutions of water and organic compounds

    PubMed Central

    Nakano, Shu-ichi; Kitagawa, Yuichi; Miyoshi, Daisuke; Sugimoto, Naoki

    2014-01-01

    Nucleic acids are useful for biomedical targeting and sensing applications in which the molecular environment is different from that of a dilute aqueous solution. In this study, the influence of various types of mixed solutions of water and water-soluble organic compounds on RNA was investigated by measuring the catalytic activity of the hammerhead ribozyme and the thermodynamic stability of an oligonucleotide duplex. The compounds with a net neutral charge, such as poly(ethylene glycol), small primary alcohols, amide compounds, and aprotic solvent molecules, added at high concentrations changed the ribozyme-catalyzed RNA cleavage rate, with the magnitude of the effect dependent on the NaCl concentration. These compounds also changed the thermodynamic stability of RNA base pairs of an oligonucleotide duplex and its dependence on the NaCl concentration. Specific interactions with RNA molecules and reduced water activity could account for the inhibiting effects on the ribozyme catalysis and destabilizing effects on the duplex stability. The salt concentration dependence data correlated with the dielectric constant, but not with water activity, viscosity, and the size of organic compounds. This observation suggests the significance of the dielectric constant effects on the RNA reactions under molecular crowding conditions created by organic compounds. PMID:25161873

  4. 6-shogaol, a major compound in ginger, induces aryl hydrocarbon receptor-mediated transcriptional activity and gene expression.

    PubMed

    Yoshida, Kazutaka; Satsu, Hideo; Mikubo, Ayano; Ogiwara, Haru; Yakabe, Takafumi; Inakuma, Takahiro; Shimizu, Makoto

    2014-06-18

    Xenobiotics are usually detoxified by drug-metabolizing enzymes and excreted from the body. The expression of many of drug-metabolizing enzymes is regulated by the aryl hydrocarbon receptor (AHR). Some substances in vegetables have the potential to be AHR ligands. To search for vegetable components that exhibit AHR-mediated transcriptional activity, we assessed the activity of vegetable extracts and identified the active compounds using the previously established stable AHR-responsive HepG2 cell line. Among the hot water extracts of vegetables, the highest activity was found in ginger. The ethyl acetate fraction of the ginger hot water extract remarkably induced AHR-mediated transcriptional activity, and the major active compound was found to be 6-shogaol. Subsequently, the mRNA levels of AHR-targeting drug-metabolizing enzymes (CYP1A1, UGT1A1, and ABCG 2) and the protein level of CYP1A1 in HepG2 cells were shown to be increased by 6-shogaol. This is the first report that 6-shogaol can regulate the expression of detoxification enzymes by AHR activation. PMID:24857157

  5. Pupicidal and repellent activities of Pogostemon cablin essential oil chemical compounds against medically important human vector mosquitoes

    PubMed Central

    Gokulakrishnan, J; Kuppusamy, Elumalai; Shanmugam, Dhanasekaran; Appavu, Anandan; Kaliyamoorthi, Krishnappa

    2013-01-01

    Objective To determine the repellent and pupicidal activities of Pogostemon cablin (P. cablin) chemical compositions were assayed for their toxicity against selected important vector mosquitoes, viz., Aedes aegypti (Ae. aegypti), Anopheles stephensi (An. stephensi) and Culex quinquefasciatus (Cx. quinquefasciatus) (Diptera: Culicidae). Methods The plants dry aerial parts were subjected to hydrodistillation using a modified Clevenger-type apparatus. The composition of the essential oil was analyzed by Gas Chromatography (GC) and GC mass spectrophotometry. Evaluation was carried out in a net cage (45 cm×30 cm×45 cm) containing 100 blood starved female mosquitoes and were assayed in the laboratory condition by using the protocol of WHO 2010. The repellent activity of P. cablin chemical compositions at concentration of 2mg/cm2were applied on skin of fore arm in man and exposed against adult female mosquitoes. The pupicidal activity was determined against selected important vector mosquitoes to concentration of 100 mg/L and mortality of each pupa was recorded after 24 h of exposure to the compounds. Results Chemical constituents of 15 compounds were identified in the oil of P.cablin compounds representing to 98.96%. The major components in essential oil were â-patchoulene, á-guaiene, ã-patchoulene, á-bulnesene and patchouli alcohol. The repellent activity of patchouli alcohol compound was found to be most effective for repellent activity and 2 mg/cm2 concentration provided 100% protection up to 280 min against Ae. aegypti, An. stephensi and Cx. quinquefasciatus, respectively. Similarly, pupae exposed to 100 mg/L concentrations of P. cablin chemical compositions. Among five compounds tested patchouli alcoholwas found to be most effective for pupicidal activity provided 28.44, 26.28 and 25.36 against Ae.aegypti, An.stephensi and Cx. quinquefasciatus, respectively. The percent adult emergence was inversely proportional to the concentration of compounds and directly

  6. Identifying Facilitators and Barriers to Physical Activity for Adults with Down Syndrome

    ERIC Educational Resources Information Center

    Mahy, J.; Shields, N.; Taylor, N. F.; Dodd, K. J.

    2010-01-01

    Background: Adults with Down syndrome are typically sedentary, and many do not participate in the recommended levels of physical activity per week. The aim of this study was to identify the facilitators and barriers to physical activity for this group. Method: Semi-structured interviews were conducted to elicit the views of adults with Down…

  7. Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites.

    PubMed

    Fernández, Mariana; Arce, Esteban Rodríguez; Sarniguet, Cynthia; Morais, Tânia S; Tomaz, Ana Isabel; Azar, Claudio Olea; Figueroa, Roberto; Diego Maya, J; Medeiros, Andrea; Comini, Marcelo; Helena Garcia, M; Otero, Lucía; Gambino, Dinorah

    2015-12-01

    Searching for new prospective antitrypanosomal agents, three novel Ru(II)-cyclopentadienyl compounds, [Ru(η(5)-C5H5)(PPh3)L], with HL=bioactive 5-nitrofuryl containing thiosemicarbazones were synthesized and characterized in the solid state and in solution. The compounds were evaluated in vitro on the blood circulating trypomastigote form of Trypanosoma cruzi (Dm28c strain), the infective form of Trypanosoma brucei brucei (strain 427) and on J774 murine macrophages and human-derived EA.hy926 endothelial cells. The compounds were active against both parasites with IC50 values in the micromolar or submicromolar range. Interestingly, they are much more active on T. cruzi than previously developed Ru(II) classical and organometallic compounds with the same bioactive ligands. The new compounds showed moderate to very good selectivity towards the parasites in respect to mammalian cells. The global results point at [RuCp(PPh3)L2] (L2=N-methyl derivative of 5-nitrofuryl containing thiosemicarbazone and Cp=cyclopentadienyl) as the most promising compound for further developments (IC50T. cruzi=0.41μM; IC50T. brucei brucei=3.5μM). Moreover, this compound shows excellent selectivity towards T. cruzi (SI>49) and good selectivity towards T. brucei brucei (SI>6). In order to get insight into the mechanism of antiparasitic action, the intracellular free radical production capacity of the new compounds was assessed by ESR. DMPO (5,5-dimethyl-1-pirroline-N-oxide) spin adducts related to the bioreduction of the complexes and to redox cycling processes were characterized. In addition, DNA competitive binding studies with ethidium bromide by fluorescence measurements showed that the compounds interact with this biomolecule. PMID:26275470

  8. Quantum chemical and statistical study of megazol-derived compounds with trypanocidal activity

    NASA Astrophysics Data System (ADS)

    Rosselli, F. P.; Albuquerque, C. N.; da Silva, A. B. F.

    In this work we performed a structure-activity relationship (SAR) study with the aim to correlate molecular properties of the megazol compound and 10 of its analogs with the biological activity against Trypanosoma cruzi (trypanocidal or antichagasic activity) presented by these molecules. The biological activity indication was obtained from in vitro tests and the molecular properties (variables or descriptors) were obtained from the optimized chemical structures by using the PM3 semiempirical method. It was calculated ˜80 molecular properties selected among steric, constitutional, electronic, and lipophilicity properties. In order to reduce dimensionality and investigate which subset of variables (descriptors) would be more effective in classifying the compounds studied, according to their degree of trypanocidal activity, we employed statistical methodologies (pattern recognition and classification techniques) such as principal component analysis (PCA), hierarchical cluster analysis (HCA), K-nearest neighbor (KNN), and discriminant function analysis (DFA). These methods showed that the descriptors molecular mass (MM), energy of the second lowest unoccupied molecular orbital (LUMO+1), charge on the first nitrogen at substituent 2 (qN'), dihedral angles (D1 and D2), bond length between atom C4 and its substituent (L4), Moriguchi octanol-partition coefficient (MLogP), and length-to-breadth ratio (L/Bw) were the variables responsible for the separation between active and inactive compounds against T. cruzi. Afterwards, the PCA, KNN, and DFA models built in this work were used to perform trypanocidal activity predictions for eight new megazol analog compounds.

  9. Structural activity of bovidic acid and related compounds as feeding deterrents against Aedes aegypti.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    5-(1-hydroxynonyl)-2-tetrahydrofuranpentanoic acid (18-Bovidic acid), a compound recently identified as a mosquito deterrent from the hair of gaur, has been evaluated for its efficacy compared to known synthetic repellents. In the present study we have evaluated analogs of Bovidic acid, related hydr...

  10. A high-content, multiplexed screen in human breast cancer cells identifies profilin-1 inducers with anti-migratory activities.

    PubMed

    Joy, Marion E; Vollmer, Laura L; Hulkower, Keren; Stern, Andrew M; Peterson, Cameron K; Boltz, R C Dutch; Roy, Partha; Vogt, Andreas

    2014-01-01

    Profilin-1 (Pfn-1) is a ubiquitously expressed actin-binding protein that is essential for normal cell proliferation and migration. In breast cancer and several other adenocarcinomas, Pfn-1 expression is downregulated when compared to normal tissues. Previous studies from our laboratory have shown that genetically modulating Pfn-1 expression significantly impacts proliferation, migration, and invasion of breast cancer cells in vitro, and mammary tumor growth, dissemination, and metastatic colonization in vivo. Therefore, small molecules that can modulate Pfn-1 expression could have therapeutic potential in the treatment of metastatic breast cancer. The overall goal of this study was to perform a multiplexed phenotypic screen to identify compounds that inhibit cell motility through upregulation of Pfn-1. Screening of a test cassette of 1280 compounds with known biological activities on an Oris™ Pro 384 cell migration platform identified several agents that increased Pfn-1 expression greater than two-fold over vehicle controls and exerted anti-migratory effects in the absence of overt cytotoxicity in MDA-MB-231 human breast cancer cells. Concentration-response confirmation and orthogonal follow-up assays identified two bona fide inducers of Pfn-1, purvalanol and tyrphostin A9, that confirmed in single-cell motility assays and Western blot analyses. SiRNA-mediated knockdown of Pfn-1 abrogated the inhibitory effect of tyrphostin A9 on cell migration, suggesting Pfn-1 is mechanistically linked to tyrphostin A9's anti-migratory activity. The data illustrate the utility of the high-content cell motility assay to discover novel targeted anti-migratory agents by integrating functional phenotypic analyses with target-specific readouts in a single assay platform. PMID:24520372

  11. Exploiting uncertainty measures in compounds activity prediction using support vector machines.

    PubMed

    Smusz, Sabina; Czarnecki, Wojciech Marian; Warszycki, Dawid; Bojarski, Andrzej J

    2015-01-01

    The great majority of molecular modeling tasks require the construction of a model that is then used to evaluate new compounds. Although various types of these models exist, at some stage, they all use knowledge about the activity of a given group of compounds, and the performance of the models is dependent on the quality of these data. Biological experiments verifying the activity of chemical compounds are often not reproducible; hence, databases containing these results often possess various activity records for a given molecule. In this study, we developed a method that incorporates the uncertainty of biological tests in machine-learning-based experiments using the Support Vector Machine as a classification model. We show that the developed methodology improves the classification effectiveness in the tested conditions. PMID:25466199

  12. Sorghum flour fractions: correlations among polysaccharides, phenolic compounds, antioxidant activity and glycemic index.

    PubMed

    Moraes, Érica Aguiar; Marineli, Rafaela da Silva; Lenquiste, Sabrina Alves; Steel, Caroline Joy; de Menezes, Cícero Beserra; Queiroz, Valéria Aparecida Vieira; Maróstica Júnior, Mário Roberto

    2015-08-01

    Nutrients composition, phenolic compounds, antioxidant activity and estimated glycemic index (EGI) were evaluated in sorghum bran (SB) and decorticated sorghum flour (DSF), obtained by a rice-polisher, as well as whole sorghum flour (WSF). Correlation between EGI and the studied parameters were determined. SB presented the highest protein, lipid, ash, β-glucan, total and insoluble dietary fiber contents; and the lowest non-resistant and total starch contents. The highest carbohydrate and resistant starch contents were in DSF and WSF, respectively. Phenolic compounds and antioxidant activities were concentrated in SB. The EGI values were: DSF 84.5 ± 0.41; WSF 77.2 ± 0.33; and SB 60.3 ± 0.78. Phenolic compounds, specific flavonoids and antioxidant activities, as well as total, insoluble and soluble dietary fiber and β-glucans of sorghum flour samples were all negatively correlated to EGI. RS content was not correlated to EGI. PMID:25766808

  13. Inhibition of gastric H+, K(+)-ATPase activity by compounds from medicinal plants.

    PubMed

    Freitas, Cristina Setim; Baggio, Cristiane Hatsuko; Mayer, Bárbara; dos Santos, Ana Cristina; Twardowschy, André; Santos, Cid Aimbiré de Moraes; Marques, Maria Consuelo Andrade

    2011-09-01

    H+, K(+)-ATPase enzyme is a therapeutic target for the treatment of gastric disturbances. Several medicinal plants and isolated compounds inhibit the acid gastric secretion through interaction with the proton pump. In order to add new properties to some natural constituents, five compounds, a benzylated derivative of vincoside, a diterpene (abietic acid) and three alkaloids (cephaeline, vinblastine and vindoline), were tested for their activities on gastric H+, K(+)-ATPase isolated from rabbit stomach. All the compounds inhibited H+, K(+)-ATPase activity with varied potency. The IC50 value for benzylvincoside was 121 (50-293) microM, and for abietic acid 177 (148-211) microM. The alkaloids cephaeline, vinblastine and vindoline inhibited the H+, K(+)-ATPase activity with IC50 values of 194, 761 and 846 microM, respectively. The results suggest that benzylvincoside, abietic acid and cephaeline can be important sources for the development of anti-secretor agents. PMID:21941891

  14. Developmental toxicity of thyroid-active compounds in a zebrafish embryotoxicity test.

    PubMed

    Jomaa, Barae; Hermsen, Sanne A B; Kessels, Maurijn Y; van den Berg, Johannes H J; Peijnenburg, Ad A C M; Aarts, Jac M M J G; Piersma, Aldert H; Rietjens, Ivonne M C M

    2014-01-01

    Zebrafish embryos were exposed to concentration ranges of selected thyroid-active model compounds in order to assess the applicability of zebrafish-based developmental scoring systems withinan alternative testing strategy to detect the developmental toxicity ofthyroid-active compounds. Model compounds tested included triiodothyronine (T3), propylthiouracil (PTU), methimazole (MMI), sodium perchlorate (NaClO4) and amiodarone hydrochloride (AMI), selected to represent different modes of action affecting thyroid activity. Tested time windows included 48-120 hours post fertilization (hpf), 0-72 hpf and 0-120 hpf. All tested compounds resulted in developmental changes, with T3 being the most potent. The developmental parameters affected included reflective iridophores, beat and glide swimming, inflated swim bladders, as well as resorbed yolk sacs. These effects are only evident by 120 hpf and therefore an existing General Morphology Score (GMS) system was extended to create a General Developmental Score(GDS) that extends beyond the 72 hpfscoring limit of GMS and includes additional parameters that are affected by exposure to model thyroid-active compounds. Moreover, the GDS is cumulative as it includes not only the scoring of developmental morphologies but also integrates developmental dysmorphologies. Exposures from 48-120 hpf did not provide additional information to exposures from 0-120 hpf. The results indicate that the zebrafish GDS can detect the developmental toxicity of thyroid toxicants and may be of use in an integrated testing strategy to reduce, refine and in certain cases replace animal testing. PMID:24793664

  15. Prenylated polyphenolic compounds from Glycyrrhiza iconica and their antimicrobial and antioxidant activities.

    PubMed

    Kırmızıbekmez, Hasan; Uysal, Görkem Berk; Masullo, Milena; Demirci, Fatih; Bağcı, Yavuz; Kan, Yüksel; Piacente, Sonia

    2015-06-01

    A new prenylated isoflavan, iconisoflavan (1), and a new prenylated isoflav-3-ene, iconisoflaven (2) were isolated from the roots of Glycyrrhiza iconica together with four known ones namely (3S)-licoricidin (3), licorisoflavan A (4), topazolin (5) and glycycoumarin (6). The structures were elucidated on the basis of extensive spectroscopic analysis including 1D and 2D NMR as well as HR-MS. Furthermore, the absolute configurations of compounds 1, 3 and 4 were established by electronic circular dichroism (ECD). All the isolated compounds (1-6) were evaluated for their in vitro antimicrobial activities against five pathogenic bacteria and one yeast (Candida albicans) using an in vitro microdilution method. Compounds 1 and 3-5 displayed significant activity against Salmonella typhimurium ATCC 13311 with MIC values ranging from 2 to 8 μg/mL. Additionally, all compounds were screened for their in vitro free radical scavenging activities using an in vitro microdilution DPPH assay spectrofotometrically. The tested compounds exhibited IC50 values in the range of 0.18-0.56 mg/mL, suggesting an activity comparable with that of ascorbic acid (IC50: 0.07 mg/mL). To the best of our knowledge, the present study constitutes the first phytochemical and bioactivity investigation on G. iconica. PMID:25963162

  16. Feasibility studies on newly identified LiCrP2O7 compound for lithium insertion behavior

    NASA Astrophysics Data System (ADS)

    Gangulibabu; Bhuvaneswari, D.; Kalaiselvi, N.

    2009-08-01

    A new category of lithium intercalating cathode candidates, namely LiCrP2O7, was synthesized at 800°C using a citric acid assisted modified (CAM) sol-gel method and examined for possible lithium insertion behavior. The formation of a phase pure and monoclinic LiCrP2O7 compound with finer crystallite size was confirmed from the X-ray diffraction patterns. The presence of nano-sized particles as observed from a transmittance electron microscope image of LiCrP2O7 and the presence of a preferred local cation environment, evidenced from Fourier transform infra-red and 7Li nuclear magnetic resonance studies, are the added advantages of the present study. Further, cyclic voltametry study performed on 2016 coin cells consisting of the synthesized LiCrP2O7 cathode revealed an excellent cycling reversibility and structural stability. Hence, CAM sol-gel synthesized LiCrP2O7 is found to possess desirable physical as well as electrochemical properties, leading one to consider the same as a possible lithium intercalating cathode material.

  17. Nitrogen K-edge XANES - an overview of reference compounds used to identify unknown organic nitrogen in environmental samples.

    PubMed

    Leinweber, Peter; Kruse, Jens; Walley, Fran L; Gillespie, Adam; Eckhardt, Kai Uwe; Blyth, Robert I R; Regier, Tom

    2007-11-01

    The chemical nature of soil organic nitrogen (N) is still poorly understood and one-third to one-half of it is typically classified as ;unknown N'. Nitrogen K-edge XANES spectroscopy has been used to develop a systematic overview on spectral features of all major N functions in soil and environmental samples. The absolute calibration of the photon energy was completed using the 1s --> pi* transitions of pure gas-phase N(2). On this basis a library of spectral features is provided for mineral N, nitro N, amino acids, peptides, and substituted pyrroles, pyridines, imidazoles, pyrazoles, pyrazines, pyrimidines and purine bases. Although N XANES was previously considered ;non-destructive', effects of radiation damage were shown for two compound classes and an approach was proposed to minimize it. This new evidence is integrated into a proposal for the evaluation spectra from environmental samples with unknown composition. Thus a basis is laid to develop N K-edge XANES as a complementary standard research method to study the molecular composition and ecological functions of ;unknown N' in soil and the environment. PMID:17960033

  18. Synthesis, characterization, investigation of biological activity and theoretical studies of hydrazone compounds containing choloroacetyl group

    NASA Astrophysics Data System (ADS)

    Cukurovali, Alaaddin; Yilmaz, Engin

    2014-10-01

    In this study, three new hydrazide-hydrazone derivative compounds which contain choloroacetyl group have been synthesized and characterized. In the characterization, spectral techniques such as IR, 1H NMR, 13C NMR and UV-Vis spectroscopy techniques were used. Antibacterial effects of the synthesized compounds were investigated against Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853. In the theoretical calculations Gaussian 09 software was used with the DFT/6-311+(d,p) basis set. Experimental X-ray analysis of compounds has not been studied. Theoretical bond lengths of synthesized compounds were compared with experimental bond lengths of a similar compound. Theoretical and experimental bond lengths are in good agreement with R2: 0.896, 0.899 and 0.900 for compounds 1, 2, and 3, respectively. For antibacterial activity, the most effective one was found to be N‧-(4-bromobenzylidene)-2-chloro-N-(4-(3-methyl-3-phenylcyclobutyl)-thiazol-2-yl) acetohydrazide against P.aeroginaosa ATTC 27853, among the studied compounds.

  19. Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity

    PubMed Central

    dos Santos, Edson dos A.; Hamel, Ernest; Bai, Ruoli; Burnett, James C.; Tozatti, Camila Santos Suniga; Bogo, Danielle; Perdomo, Renata T.; Antunes, Alexandra M. M.; Marques, M. Matilde; Matos, Maria de F. C.; de Lima, Dênis P.

    2013-01-01

    We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site. PMID:23810282

  20. Phytogrowth-inhibitory activities of 2-thiophenecarboxylic acid and its related compounds.

    PubMed

    Inamori, Y; Muro, C; Funakoshi, Y; Usami, Y; Tsujibo, H; Numata, A

    1994-01-01

    2-Thiophenecarboxylic acid (I) exhibited growth-inhibitory activity in five kinds of plants. In particular, I strongly inhibited the growth of the roots of Lactuca sativa L. var. longifolia LAM and Echinochloa utilis OHWI et YABUNO, even at the low concentration of 5.0 x 10(-3) M. Furthermore, all of the I-related compounds (II-V and VII-X) except for VI, showed more or less obvious inhibitory activity on the seeds of Sesamum indicum L. Compounds VII-X, in which the carboxyl group of I was replaced by acetic acid, propionic acid, butyric acid and acrylic acid, and exhibited more potent phytogrowth-inhibitory activity than I. Among these compounds, 2-thiophenebutyric acid (IX) showed the strongest activity. Esterification of the carboxyl group in I increased the inhibitory activity relative to that of I, while amidation and reduction of this group markedly decreased its inhibitory activity. The radicles of the plants treated with each of the compounds except for VI showed negative geotropism, even though germination occurred. PMID:8148810

  1. A High-content screen identifies compounds promoting the neuronal differentiation and the midbrain dopamine neuron specification of human neural progenitor cells.

    PubMed

    Rhim, Ji Heon; Luo, Xiangjian; Xu, Xiaoyun; Gao, Dongbing; Zhou, Tieling; Li, Fuhai; Qin, Lidong; Wang, Ping; Xia, Xiaofeng; Wong, Stephen T C

    2015-01-01

    Small molecule compounds promoting the neuronal differentiation of stem/progenitor cells are of pivotal importance to regenerative medicine. We carried out a high-content screen to systematically characterize known bioactive compounds, on their effects on the neuronal differentiation and the midbrain dopamine (mDA) neuron specification of neural progenitor cells (NPCs) derived from the ventral mesencephalon of human fetal brain. Among the promoting compounds three major pharmacological classes were identified including the statins, TGF-βRI inhibitors, and GSK-3 inhibitors. The function of each class was also shown to be distinct, either to promote both the neuronal differentiation and mDA neuron specification, or selectively the latter, or promote the former but suppress the latter. We then carried out initial investigation on the possible mechanisms underlying, and demonstrated their applications on NPCs derived from human pluripotent stem cells (PSCs). Our study revealed the potential of several small molecule compounds for use in the directed differentiation of human NPCs. The screening result also provided insight into the signaling network regulating the differentiation of human NPCs. PMID:26542303

  2. A High-content screen identifies compounds promoting the neuronal differentiation and the midbrain dopamine neuron specification of human neural progenitor cells

    PubMed Central

    Rhim, Ji heon; Luo, Xiangjian; Xu, Xiaoyun; Gao, Dongbing; Zhou, Tieling; Li, Fuhai; Qin, Lidong; Wang, Ping; Xia, Xiaofeng; Wong, Stephen T. C.

    2015-01-01

    Small molecule compounds promoting the neuronal differentiation of stem/progenitor cells are of pivotal importance to regenerative medicine. We carried out a high-content screen to systematically characterize known bioactive compounds, on their effects on the neuronal differentiation and the midbrain dopamine (mDA) neuron specification of neural progenitor cells (NPCs) derived from the ventral mesencephalon of human fetal brain. Among the promoting compounds three major pharmacological classes were identified including the statins, TGF-βRI inhibitors, and GSK-3 inhibitors. The function of each class was also shown to be distinct, either to promote both the neuronal differentiation and mDA neuron specification, or selectively the latter, or promote the former but suppress the latter. We then carried out initial investigation on the possible mechanisms underlying, and demonstrated their applications on NPCs derived from human pluripotent stem cells (PSCs). Our study revealed the potential of several small molecule compounds for use in the directed differentiation of human NPCs. The screening result also provided insight into the signaling network regulating the differentiation of human NPCs. PMID:26542303

  3. Novel anti-Cryptosporidium activity of known drugs identified by high-throughput screening against parasite fatty acyl-CoA binding protein (ACBP)

    PubMed Central

    Fritzler, Jason M.; Zhu, Guan

    2012-01-01

    Background Cryptosporidium parvum causes an opportunistic infection in AIDS patients, and no effective treatments are yet available. This parasite possesses a single fatty acyl-CoA binding protein (CpACBP1) that is localized to the unique parasitophorous vacuole membrane (PVM). The major goal of this study was to identify inhibitors from known drugs against CpACBP1 as potential new anti-Cryptosporidium agents. Methods A fluorescence assay was developed to detect CpACBP1 activity and to identify inhibitors by screening known drugs. Efficacies of top CpACBP1 inhibitors against Cryptosporidium growth in vitro were evaluated using a quantitative RT–PCR assay. Results Nitrobenzoxadiazole-labelled palmitoyl-CoA significantly increased the fluorescent emission upon binding to CpACBP1 (excitation/emission 460/538 nm), which was quantified to determine the CpACBP1 activity and binding kinetics. The fluorescence assay was used to screen a collection of 1040 compounds containing mostly known drugs, and identified the 28 most active compounds that could inhibit CpACBP1 activity with sub-micromolar IC50 values. Among them, four compounds displayed efficacies against parasite growth in vitro with low micromolar IC50 values. The effective compounds were broxyquinoline (IC50 64.9 μM), cloxyquin (IC50 25.1 μM), cloxacillin sodium (IC50 36.2 μM) and sodium dehydrocholate (IC50 53.2 μM). Conclusions The fluorescence ACBP assay can be effectively used to screen known drugs or other compound libraries. Novel anti-Cryptosporidium activity was observed in four top CpACBP1 inhibitors, which may be further investigated for their potential to be repurposed to treat cryptosporidiosis and to serve as leads for drug development. PMID:22167242

  4. A High-Throughput Cell-Based Screen Identified a 2-[(E)-2-Phenylvinyl]-8-Quinolinol Core Structure That Activates p53.

    PubMed

    Bechill, John; Zhong, Rong; Zhang, Chen; Solomaha, Elena; Spiotto, Michael T

    2016-01-01

    p53 function is frequently inhibited in cancer either through mutations or by increased degradation via MDM2 and/or E6AP E3-ubiquitin ligases. Most agents that restore p53 expression act by binding MDM2 or E6AP to prevent p53 degradation. However, fewer compounds directly bind to and activate p53. Here, we identified compounds that shared a core structure that bound p53, caused nuclear localization of p53 and caused cell death. To identify these compounds, we developed a novel cell-based screen to redirect p53 degradation to the Skip-Cullin-F-box (SCF) ubiquitin ligase complex in cells expressing high levels of p53. In a multiplexed assay, we coupled p53 targeted degradation with Rb1 targeted degradation in order to identify compounds that prevented p53 degradation while not inhibiting degradation through the SCF complex or other proteolytic machinery. High-throughput screening identified several leads that shared a common 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that stabilized p53. Surface plasmon resonance analysis indicated that these compounds bound p53 with a KD of 200 ± 52 nM. Furthermore, these compounds increased p53 nuclear localization and transcription of the p53 target genes PUMA, BAX, p21 and FAS in cancer cells. Although p53-null cells had a 2.5±0.5-fold greater viability compared to p53 wild type cells after treatment with core compounds, loss of p53 did not completely rescue cell viability suggesting that compounds may target both p53-dependent and p53-independent pathways to inhibit cell proliferation. Thus, we present a novel, cell-based high-throughput screen to identify a 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that bound to p53 and increased p53 activity in cancer cells. These compounds may serve as anti-neoplastic agents in part by targeting p53 as well as other potential pathways. PMID:27124407

  5. A High-Throughput Cell-Based Screen Identified a 2-[(E)-2-Phenylvinyl]-8-Quinolinol Core Structure That Activates p53

    PubMed Central

    Bechill, John; Zhong, Rong; Zhang, Chen; Solomaha, Elena

    2016-01-01

    p53 function is frequently inhibited in cancer either through mutations or by increased degradation via MDM2 and/or E6AP E3-ubiquitin ligases. Most agents that restore p53 expression act by binding MDM2 or E6AP to prevent p53 degradation. However, fewer compounds directly bind to and activate p53. Here, we identified compounds that shared a core structure that bound p53, caused nuclear localization of p53 and caused cell death. To identify these compounds, we developed a novel cell-based screen to redirect p53 degradation to the Skip-Cullin-F-box (SCF) ubiquitin ligase complex in cells expressing high levels of p53. In a multiplexed assay, we coupled p53 targeted degradation with Rb1 targeted degradation in order to identify compounds that prevented p53 degradation while not inhibiting degradation through the SCF complex or other proteolytic machinery. High-throughput screening identified several leads that shared a common 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that stabilized p53. Surface plasmon resonance analysis indicated that these compounds bound p53 with a KD of 200 ± 52 nM. Furthermore, these compounds increased p53 nuclear localization and transcription of the p53 target genes PUMA, BAX, p21 and FAS in cancer cells. Although p53-null cells had a 2.5±0.5-fold greater viability compared to p53 wild type cells after treatment with core compounds, loss of p53 did not completely rescue cell viability suggesting that compounds may target both p53-dependent and p53-independent pathways to inhibit cell proliferation. Thus, we present a novel, cell-based high-throughput screen to identify a 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that bound to p53 and increased p53 activity in cancer cells. These compounds may serve as anti-neoplastic agents in part by targeting p53 as well as other potential pathways. PMID:27124407

  6. X-ray and DFT Study of Glaucocalyxin A Compound with Cytotoxic Activity

    NASA Astrophysics Data System (ADS)

    Wang, Fu-dong; Wang, Tao; Wu, An-an; Ding, Lan; Wang, Han-qing

    2009-06-01

    The title compound glaucocalyxin A (1) (7α, 14β-dihydroxy-ent-kaur-16-en-3,15-dione) isolated from the leaves of isodon excisoides was characterized by IR, 1H NMR, 13C NMR, 1H-1H COSY, HMQC, HMBC, and EIMS, and its crystal structure was determined by single-crystal X-ray diffraction. The X-ray crystal structure revealed that the molecular backbone of the chosen crystal is a tetracyclic system, including three six-membered rings and a five-membered ring, and the three six-membered rings are in a chair-like conformation. The five-membered ring adopts a twisted envelope-like conformation, and its geometrical parameters were compared with theoretical calculations at the B3LYP and HF level of theory. The molecules form extensive networks through the intra- and intermolecular hydrogen bonds. The experimental NMR data were interpreted with the aid of magnetic shielding constant calculations, by means of the GIAO (gauge-lncluding atomic orbitals) method. Calculated and experimental results were compared with a satisfactory level of agreement. Molecular electrostatic potential map was used in an attempt to identify key features of the diterpenoid glaucocalyxin A that is necessary for its activity. Calculations of molecular electrostatic potential and stabilization energies suggest that the protonation of glaucocalyxin A will be able to occur on carbonyl oxygen atoms.

  7. Seasonal variation of pharmaceutically active compounds in surface (Tagus River) and tap water (Central Spain).

    PubMed

    Valcárcel, Y; Alonso, S González; Rodríguez-Gil, J L; Castaño, A; Montero, J C; Criado-Alvarez, J J; Mirón, I J; Catalá, M

    2013-03-01

    Numerous studies have shown the presence of pharmaceutically active compounds (PhACs) in different environmental compartments, for example, in surface water or wastewater ranging from nanograms per litre to micrograms per litre. Likewise, some recent studies have pointed to seasonal variability, thus indicating that PhAcs concentrations in the aquatic environment may depend on the time of year. This work intended to find out (1) whether Tagus fluvial and drinking water were polluted with different groups of PhACs and (2) if their concentrations differed between winter and summer seasons. From the 58 substances analysed, 41 were found belonging to the main therapeutic groups. Statistical differences were seen for antibacterials, antidepressants, anxiolytics, antiepileptics, and cardiovascular drugs, with higher concentrations being detected in winter than in summer. These results might indicate that the PhACs analysed in this study undergo lower environmental degradation in winter than in summer. In order to confirm these initial results, a continuous monitoring should be performed especially on those PhACs that either because of an elevated consumption or an intrinsic chemical persistence are poorly degraded during winter months due to low temperatures and solar irradiation. It is especially important to identify which of these specific PhACs are in order to recommend their substitution by equally effective and safe substances but also environmentally friendly. PMID:22847337

  8. A Rapid Screening Analysis of Antioxidant Compounds in Native Australian Food Plants Using Multiplexed Detection with Active Flow Technology Columns.

    PubMed

    Rupesinghe, Emmanuel Janaka Rochana; Jones, Andrew; Shalliker, Ross Andrew; Pravadali-Cekic, Sercan

    2016-01-01

    Conventional techniques for identifying antioxidant and phenolic compounds in native Australian food plants are laborious and time-consuming. Here, we present a multiplexed detection technique that reduces analysis time without compromising separation performance. This technique is achieved using Active Flow Technology-Parallel Segmented Flow (AFT-PSF) columns. Extracts from cinnamon myrtle (Backhousia myrtifolia) and lemon myrtle (Backhousia citriodora) leaves were analysed via multiplexed detection using an AFT-PSF column with underivatised UV-VIS, mass spectroscopy (MS), and the 2,2-diphenyl-1-picrylhydrazyl (DPPH(•)) derivatisation for antioxidants as detection methods. A number of antioxidant compounds were detected in the extracts of each leaf extract. PMID:26805792

  9. High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome.

    PubMed

    Kaufmann, Markus; Schuffenhauer, Ansgar; Fruh, Isabelle; Klein, Jessica; Thiemeyer, Anke; Rigo, Pierre; Gomez-Mancilla, Baltazar; Heidinger-Millot, Valerie; Bouwmeester, Tewis; Schopfer, Ulrich; Mueller, Matthias; Fodor, Barna D; Cobos-Correa, Amanda

    2015-10-01

    Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and it is caused in most of cases by epigenetic silencing of the Fmr1 gene. Today, no specific therapy exists for FXS, and current treatments are only directed to improve behavioral symptoms. Neuronal progenitors derived from FXS patient induced pluripotent stem cells (iPSCs) represent a unique model to study the disease and develop assays for large-scale drug discovery screens since they conserve the Fmr1 gene silenced within the disease context. We have established a high-content imaging assay to run a large-scale phenotypic screen aimed to identify compounds that reactivate the silenced Fmr1 gene. A set of 50,000 compounds was tested, including modulators of several epigenetic targets. We describe an integrated drug discovery model comprising iPSC generation, culture scale-up, and quality control and screening with a very sensitive high-content imaging assay assisted by single-cell image analysis and multiparametric data analysis based on machine learning algorithms. The screening identified several compounds that induced a weak expression of fragile X mental retardation protein (FMRP) and thus sets the basis for further large-scale screens to find candidate drugs or targets tackling the underlying mechanism of FXS with potential for therapeutic intervention. PMID:26024946

  10. Antimicrobial activities of the methanol extract and compounds from the twigs of Dorstenia mannii (Moraceae)

    PubMed Central

    2012-01-01

    Background Dorstenia mannii (Moraceae) is a medicinal herb used traditionally for the treatment of many diseases. In the present study, the methanol extract of D. mannii and nine of its isolated compounds, namely dorsmanin A (1), B (2), C (3), D (4), E (6), F (7), G (8) dorsmanin I (9) and 6,8-diprenyleriodictyol (5), were tested for their antimicrobial activities against yeast, Mycobacteria and Gram-negative bacteria. Methods The microplate alamar blue assay (MABA) and the broth microdilution method were used to determine the minimal inhibitory concentration (MIC) and minimal microbicidal concentration (MMC) of the above extract and compounds on a panel of bacterial species. Results The results of the MIC determinations demonstrated that the methanol extract as well as compounds 3 and 8 were able to prevent the growth of all the fourteen studied microorganisms within the concentration range of 4 to 1024 μg/ml. The lowest MIC value for the methanol extract (64 μg/ml) was obtained on Candida albicans. The lowest value for individual compounds (4 μg/ml) was recorded with compounds 3 on Pseudomonas aeruginosa PA01 and 7 on Eschericia coli ATCC strain. The MIC values recorded with compounds 3 on P. aeruginosa PA01, 6 on C. albicans,7 on P. aeruginosa PA01 and K. pneumoniae ATCC strain and C. albicans,and 8 on P. aeruginosa PA01, PA124, P. stuartii, M. tuberculosis MTCS1 were lower than or equal to those of the reference drugs. MMC values not greater than 1024 μg/ml were recorded on all studied microorganisms with compounds 3 and 8. Conclusion The overall results of the present investigation provided evidence that the crude extract of D. mannii as well as some of its compounds such compounds 3 and 8 could be a potential source of natural antimicrobial products. PMID:22747736

  11. Antifungal, antioxidant and larvicidal activities of compounds isolated from the heartwood of Mansonia gagei.

    PubMed

    Tiew, P; Ioset, J R; Kokpol, U; Chavasiri, W; Hostettmann, K

    2003-02-01

    Eleven compounds isolated from the heartwood of Mansonia gagei were tested for their antifungal activities against Cladosporium cucumerinum and Candida albicans, as well as for their larvicidal activities against Aedes aegypti and radical scavenging properties in a DPPH assay. Mansonone C (4) was found to be the most interesting compound with antifungal activities against Cladosporium cucumerinum and Candida albicans as well as for its larvicidal properties against Aedes aegypti. Mansonone E (5) was active against Cladosporium cucumerinum and Candida albicans. Two coumarin derivatives, mansorin A (1) and mansorin B (2) were also found to be active against Cladosporium cucumerinum, while mansonone N (9) was the only isolated product to show radical scavenging properties. PMID:12601687

  12. Active Compounds Against Anopheles minimus Carboxypeptidase B for Malaria Transmission-Blocking Strategy.

    PubMed

    Mongkol, Watcharakorn; Arunyawat, Uraiwan; Surat, Wunrada; Kubera, Anchanee

    2015-11-01

    Malaria transmission-blocking compounds have been studied to block the transmission of malaria parasites, especially the drug-resistant Plasmodium. Carboxypeptidase B (CPB) in the midgut of Anopheline mosquitoes has been demonstrated to be essential for the sexual development of Plasmodium in the mosquito. Thus, the CPB is a potential tar