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Sample records for alkaloid camptothecin cpt

  1. A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin

    PubMed Central

    Schoemaker, N E; van Kesteren, C; Rosing, H; Jansen, S; Swart, M; Lieverst, J; Fraier, D; Breda, M; Pellizzoni, C; Spinelli, R; Porro, M Grazia; Beijnen, J H; Schellens, J H M; ten Bokkel Huinink, WW

    2002-01-01

    Polymeric drug conjugates are a new and experimental class of drug delivery systems with pharmacokinetic promises. The antineoplastic drug camptothecin was linked to a water-soluble polymeric backbone (MAG-CPT) and administrated as a 30 min infusion over 3 consecutive days every 4 weeks to patients with malignant solid tumours. The objectives of our study were to determine the maximal tolerated dose, the dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document anti-tumour activity. The starting dose was 17 mg m−2 day−1. Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m−2 day−1 and dose-limiting toxicities consisted of cumulative bladder toxicity. MAG-CPT and free camptothecin were accumulated during days 1–3 and considerable amounts of MAG-CPT could still be retrieved in plasma and urine after 4–5 weeks. The half-lives of bound and free camptothecin were equal indicating that the kinetics of free camptothecin were release rate dependent. In summary, the pharmacokinetics of camptothecin were dramatically changed, showing controlled prolonged exposure of camptothecin. Haematological toxicity was relatively mild, but serious bladder toxicity was encountered which is typical for camptothecin and was found dose limiting. British Journal of Cancer (2002) 21, 608–614. doi:10.1038/sj.bjc.6600516 www.bjcancer.com © 2002 Cancer Research UK PMID:12237769

  2. A Novel Preparation Method for Camptothecin (CPT) Loaded Folic Acid Conjugated Dextran Tumor-Targeted Nanoparticles

    PubMed Central

    Zu, Yuangang; Wang, Dan; Zhao, Xiuhua; Jiang, Ru; Zhang, Qi; Zhao, Dongmei; Li, Yong; Zu, Baishi; Sun, Zhiqiang

    2011-01-01

    In this study, folic-dextran-camptothecin (Fa-DEX-CPT) tumor-targeted nanoparticles were produced with a supercritical antisolvent (SAS) technique by using dimethyl sulfoxide (DMSO) as a solvent and carbon dioxide as an antisolvent. A factorial design was used to reveal the effect of various process parameters on the mean particle size (MPS) and morphology of the particles formed. Under the optimum operation conditions, Fa-DEX-CPT nanoparticles with a MPS of 182.21 nm were obtained. Drug encapsulation efficiency and loading efficiency were 62.13% and 36.12%, respectively. It was found that the concentrations of the camptothecin (CPT) and dextran solution had a major influence upon morphology and shape of the final product. In addition, the samples were characterized by Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) with the purpose of developing a suitable targeted drug delivery system for cancer chemotherapy. PMID:21845075

  3. The inhibitory effects of camptothecin (CPT) and its derivatives on the substrate uptakes mediated by human solute carrier transporters (SLCs).

    PubMed

    Zheng, Jian; Chan, Ting; Zhu, Ling; Yan, Xiufeng; Cao, Zhisong; Wang, Yang; Zhou, Fanfan

    2016-09-01

    1. Camptothecin (CPT) and its derivatives are potent candidate compounds in treating cancers. However, their clinical applications are largely restricted by severe toxicities. 2. The solute carrier transporters (SLCs), particularly the organic anion transporting polypeptides and organic anion/cation transporters (OATs/OCTs) are widely expressed in human key organs and responsible for the cellular influx of many substances including endogenous substrates and many clinically important drugs. Drug-drug interactions through SLCs often result in unsatisfied therapeutic outcomes and/or unexpected toxicities. 3. This study investigated the inhibitory effects of CPT and its eight derivatives on the cellular uptake of specific substrates mediated by the essential SLCs in over-expressing Human embryonic kidney 293 cells. 4. Our data revealed that CPT, 10-hydroxycamptothecin (HCPT), 10-methoxycamptothecin (MCPT) and 9-nitrocamptothecin (9NC) significantly inhibit the uptake activity of OAT3. 9NC also inhibited the substrate transport mediated by OAT1. The substrate uptakes of OAT1, OCTN1 and OCTN2 were significantly decreased in the presence of CZ112, while CPT-11 potently down-regulated the transport activity of OCT1 and OCT3. 5. In summary, our study demonstrated that CPT and its eight derivatives selectively inhibit the substrate uptakes mediated by the essential SLCs. This information contributes to understanding the localized toxicity of CPTs and provides novel molecular targets for the therapeutic optimization of CPTs in the future.

  4. Metabolite Diversity in Alkaloid Biosynthesis: A Multilane (Diastereomer) Highway for Camptothecin Synthesis in Camptotheca acuminata.

    PubMed

    Sadre, Radin; Magallanes-Lundback, Maria; Pradhan, Sujana; Salim, Vonny; Mesberg, Alex; Jones, A Daniel; DellaPenna, Dean

    2016-08-01

    Camptothecin is a monoterpene indole alkaloid (MIA) used to produce semisynthetic antitumor drugs. We investigated camptothecin synthesis in Camptotheca acuminata by combining transcriptome and expression data with reverse genetics, biochemistry, and metabolite profiling. RNAi silencing of enzymes required for the indole and seco-iridoid (monoterpene) components identified transcriptional crosstalk coordinating their synthesis in roots. Metabolite profiling and labeling studies of wild-type and RNAi lines identified plausible intermediates for missing pathway steps and demonstrated nearly all camptothecin pathway intermediates are present as multiple isomers. Unlike previously characterized MIA-producing plants, C. acuminata does not synthesize 3-α(S)-strictosidine as its central MIA intermediate and instead uses an alternative seco-iridoid pathway that produces multiple isomers of strictosidinic acid. NMR analysis demonstrated that the two major strictosidinic acid isomers are (R) and (S) diastereomers at their glucosylated C21 positions. The presence of multiple diastereomers throughout the pathway is consistent with their use in synthesis before finally being resolved to a single camptothecin isomer after deglucosylation, much as a multilane highway allows parallel tracks to converge at a common destination. A model "diastereomer" pathway for camptothecin biosynthesis in C. acuminata is proposed that fundamentally differs from previously studied MIA pathways. PMID:27432874

  5. Metabolite fingerprinting of Camptotheca acuminata and the HPLC-ESI-MS/MS analysis of camptothecin and related alkaloids.

    PubMed

    Montoro, Paola; Maldini, Mariateresa; Piacente, Sonia; Macchia, Mario; Pizza, Cosimo

    2010-01-20

    The major phytochemical constituents, namely, alkaloids, flavonoids and ellagic acid derivatives, of leaves of Camptotheca acuminata were identified using high performance liquid chromatography (HPLC) coupled with electrospray mass spectrometry (ESI-MS) in extracts of plants cultivated in Italy and collected at different growth stages. Alkaloids related to camptothecin were identified and quantified by HPLC coupled with ESI-tandem mass spectrometry (MS/MS) employing, respectively, an ion trap and a triple quadrupole mass analyser. The fragmentation patterns of alkaloids related to camptothecin were analysed and a specific Multiple Reaction Monitoring HPLC-MS/MS method was developed for the quantitative determination of these constituents. The described method provides high sensitivity and specificity for the characterisation and quantitative determination of the alkaloids in C. acuminata.

  6. Perspectives on Biologically Active Camptothecin Derivatives

    PubMed Central

    Liu, Ying-Qian; Li, Wen-Qun; Morris-Natschke, Susan L.; Qian, Keduo; Yang, Liu; Zhu, Gao-Xiang; Wu, Xiao-Bing; Chen, An-Liang; Zhang, Shao-Yong; Song, Zi-Long; Lee, Kuo-Hsiung

    2015-01-01

    Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects. PMID:25808858

  7. Efficacy of camptothecin and polymer-conjugated camptothecin in tumor spheroids and solid tumors.

    PubMed

    Ying, Victoria; Haverstick, Kraig; Page, Rodney L; Saltzman, W Mark

    2007-01-01

    Camptothecin (CPT) is an anti-cancer drug with low solubility in aqueous solutions, which limits its efficacy during chemotherapy. To bypass this problem, CPT was conjugated to poly(ethylene glycol) (PEG) to make CPT more hydrophilic: CM-PEG-CPT (carboxylmethylpoly(ethlyene glycol)-camptothecin), CM-PEG-GLY-CPT (carboxylmethyl-poly(ethlyene glycol)-glycine-camptothecin) and CM-PEG-SAR-CPT (carboxylmethyl-poly(ethlyene glycol)-sarcosine camptothecin) were synthesized. These conjugates differed in the amino-acid linker, which altered the hydrolysis rate of CPT from CPT-PEG. We tested the hypothesis that CPT conjugates were more effective than unconjugated CPT in effectiveness upon direct delivery to solid tumors using two systems: in vitro tumor spheroids suspended in collagen gels and in vivo solid tumors in rats. CPT was effective in spheroids, but not in flank tumors. However, when CPT was conjugated, there was improvement in the treatment of spheroids and, to a lesser extent, tumors in rats. There was no difference in therapeutic effects among the various conjugates. We conclude that conjugation of CPT to PEG enhances CPT solubility and improves effectiveness of delivery to tumors.

  8. Compound Specific Extraction of Camptothecin from Nothapodytes nimmoniana and Piperine from Piper nigrum Using Accelerated Solvent Extractor.

    PubMed

    Upadhya, Vinayak; Pai, Sandeep R; Sharma, Ajay K; Hegde, Harsha V; Kholkute, Sanjiva D; Joshi, Rajesh K

    2014-01-01

    Effects of varying temperatures with constant pressure of solvent on extraction efficiency of two chemically different alkaloids were studied. Camptothecin (CPT) from stem of Nothapodytes nimmoniana (Grah.) Mabb. and piperine from the fruits of Piper nigrum L. were extracted using Accelerated Solvent Extractor (ASE). Three cycles of extraction for a particular sample cell at a given temperature assured complete extraction. CPT and piperine were determined and quantified by using a simple and efficient UFLC-PDA (245 and 343 nm) method. Temperature increased efficiency of extraction to yield higher amount of CPT, whereas temperature had diminutive effect on yield of piperine. Maximum yield for CPT was achieved at 80°C and for piperine at 40°C. Thus, the study determines compound specific extraction of CPT from N. nimmoniana and piperine from P. nigrum using ASE method. The present study indicates the use of this method for simple, fast, and accurate extraction of the compound of interest.

  9. In Vitro and In Vivo Therapeutic Evaluation of Camptothecin-Encapsulated β-Cyclodextrin Nanosponges in Prostate Cancer.

    PubMed

    Gigliotti, Casimiro Luca; Minelli, Rosalba; Cavalli, Roberta; Occhipinti, Sergio; Barrera, Giuseppina; Pizzimenti, Stefania; Cappellano, Giuseppe; Boggio, Elena; Conti, Laura; Fantozzi, Roberto; Giovarelli, Mirella; Trotta, Francesco; Dianzani, Umberto; Dianzani, Chiara

    2016-01-01

    Camptothecin (CPT), a pentacyclic alkaloid, is an inhibitor of DNA Topoisomerase-I and shows a wide spectrum of anti-cancer activities. The use of CPT has been hampered by poor aqueous solubility and a high degradation rate. Previously, it has been reported that CPT encapsulated in β-cyclodextrin-nanosponges (CN-CPT) overcomes these disadvantages and improves the CPT's inhibitory effect on DU145 prostate tumor cell lines, and PC-3 growth in vitro. This work extends these observations by showing that CN-CPT significantly inhibits the adhesion and migration of these tumor cells and their STAT3 phosphorylation. The anti-adhesive effect is exerted also in human endothelial cells, in which CN-CPT also inhibits the angiogenic activity as assessed by the tubulogenesis and sprouting assays. Finally, CN-CPT substantially delays the growth of PC-3 cell engraftment in SCID mice in vivo without apparent toxic effects. These results support the use of β-cyclodextrin nanosponge nanotechnology as a potential nanocarrier for delivery of anticancer drugs in the treatment of prostate cancers. PMID:27301177

  10. Co-overexpression of geraniol-10-hydroxylase and strictosidine synthase improves anti-cancer drug camptothecin accumulation in Ophiorrhiza pumila

    PubMed Central

    Cui, Lijie; Ni, Xiaoling; Ji, Qian; Teng, Xiaojuan; Yang, Yanru; Wu, Chao; Zekria, David; Zhang, Dasheng; Kai, Guoyin

    2015-01-01

    Camptothecin (CPT) belongs to a group of monoterpenoidindole alkaloids (TIAs) and its derivatives such as irinothecan and topothecan have been widely used worldwide for the treatment of cancer, giving rise to rapidly increasing market demands. Genes from Catharanthus roseus encoding strictosidine synthase (STR) and geraniol 10-hydroxylase (G10H), were separately and simultaneously introduced into Ophiorrhiza pumila hairy roots. Overexpression of individual G10H (G lines) significantly improved CPT production with respect to non-transgenic hairy root cultures (NC line) and single STR overexpressing lines (S lines), indicating that G10H plays a more important role in stimulating CPT accumulation than STR in O. pumila. Furthermore, co-overexpression of G10H and STR genes (SG Lines) caused a 56% increase on the yields of CPT compared to NC line and single gene transgenic lines, showed that simultaneous introduction of G10H and STR can produce a synergistic effect on CPT biosynthesis in O. pumila. The MTT assay results indicated that CPT extracted from different lines showed similar anti-tumor activity, suggesting that transgenic O. pumila hairy root lines could be an alternative approach to obtain CPT. To our knowledge, this is the first report on the enhancement of CPT production in O. pumila employing a metabolic engineering strategy. PMID:25648209

  11. In Vitro and In Vivo Therapeutic Evaluation of Camptothecin-Encapsulated β-Cyclodextrin Nanosponges in Prostate Cancer.

    PubMed

    Gigliotti, Casimiro Luca; Minelli, Rosalba; Cavalli, Roberta; Occhipinti, Sergio; Barrera, Giuseppina; Pizzimenti, Stefania; Cappellano, Giuseppe; Boggio, Elena; Conti, Laura; Fantozzi, Roberto; Giovarelli, Mirella; Trotta, Francesco; Dianzani, Umberto; Dianzani, Chiara

    2016-01-01

    Camptothecin (CPT), a pentacyclic alkaloid, is an inhibitor of DNA Topoisomerase-I and shows a wide spectrum of anti-cancer activities. The use of CPT has been hampered by poor aqueous solubility and a high degradation rate. Previously, it has been reported that CPT encapsulated in β-cyclodextrin-nanosponges (CN-CPT) overcomes these disadvantages and improves the CPT's inhibitory effect on DU145 prostate tumor cell lines, and PC-3 growth in vitro. This work extends these observations by showing that CN-CPT significantly inhibits the adhesion and migration of these tumor cells and their STAT3 phosphorylation. The anti-adhesive effect is exerted also in human endothelial cells, in which CN-CPT also inhibits the angiogenic activity as assessed by the tubulogenesis and sprouting assays. Finally, CN-CPT substantially delays the growth of PC-3 cell engraftment in SCID mice in vivo without apparent toxic effects. These results support the use of β-cyclodextrin nanosponge nanotechnology as a potential nanocarrier for delivery of anticancer drugs in the treatment of prostate cancers.

  12. Multiple shoot cultures of Ophiorrhiza rugosa var. decumbens Deb and Mondal--a viable renewable source for the continuous production of bioactive Camptotheca alkaloids apart from stems of the parent plant of Nothapodytes foetida (Wight) Sleumer.

    PubMed

    Gopalakrishnan, Roja; Shankar, Bhavani

    2014-02-15

    Camptotheca alkaloids were isolated from multiple shoot cultures of O. decumbens (0.056% dry weight) and stems of N. foetida. The cytotoxicity of the extracts and products were tested in a panel of five cell lines. Crude extract from O. decumbens (Cr-Od) and N. foetida (Cr-Nf) showed more potent cytotoxic activity as compared to the isolated camptothecin from O. decumbens (CPT-Od) and N. foetida (CPT-Nf). CPT isolated from shoot cultures contained biological activity suggesting the possibility of using this system of O. decumbens as a renewable source for the production of camptotheca alkaloids. 9-Methoxy camptothecin (9-mCPT), isolated from N. foetida, was a very effective cytotoxic agent as compared to Cr-Nf or CPT-Nf. The IC50 of 9-mCPT was 0.84, 0.32, and 0.35 μg/ml for A549, MCF7 and Jurkat cell lines and >3 μg/ml for U937. Viability assays using MTT dye were further confirmed by assessing extent of apoptosis in these cells. These findings suggest that shoot cultures of O. decumbens offer a rich alternative plant source for the anticancer compound, CPT and 9-mCPT is a more potent compound in N. foetida as compared to CPT.

  13. Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors.

    PubMed

    Tomicic, Maja T; Kaina, Bernd

    2013-01-01

    Topoisomerase I (TOP1) inhibitors applied in cancer therapy such as topotecan and irinotecan are derivatives of the natural alkaloid camptothecin (CPT). The mechanism of CPT poisoning of TOP1 rests on inhibition of the re-ligation function of the enzyme resulting in the stabilization of the TOP1-cleavable complex. In the presence of CPTs this enzyme-DNA complex impairs transcription and DNA replication, resulting in fork stalling and the formation of DNA double-strand breaks (DSB) in proliferating cells. As with most chemotherapeutics, intrinsic and acquired drug resistance represents a hurdle that limits the success of CPT therapy. Preclinical data indicate that resistance to CPT-based drugs might be caused by factors such as (a) poor drug accumulation in the tumor, (b) high rate of drug efflux, (c) mutations in TOP1 leading to failure in CPT docking, or (d) altered signaling triggered by the drug-TOP1-DNA complex, (e) expression of DNA repair proteins, and (f) failure to activate cell death pathways. This review will focus on the issues (d-f). We discuss degradation of TOP1 as part of the repair pathway in the processing of TOP1 associated DNA damage, give a summary of proteins involved in repair of CPT-induced replication mediated DSB, and highlight the role of p53 and inhibitors of apoptosis proteins (IAPs), particularly XIAP and survivin, in cancer cell resistance to CPT-like chemotherapeutics.

  14. Experimental and theoretical spectroscopic and structural study of A-ring substituted camptothecins

    NASA Astrophysics Data System (ADS)

    Ivanova, Bojidarka B.; Spiteller, Michael

    2012-03-01

    The molecular architecture design and physical properties of seven camptothecin (CPT) alkaloids, structurally related to irinotecan (CPT-11), substituted with the cyclic bulk N-aliphatic substituents at A-ring as well as their different protonated forms were studied. The correlation between the molecular geometry and physical properties of the neutral lactone form and different possible cationic forms was elucidated, using the electronic absorptions (EAs), circular dichroic (CD) and Raman spectroscopy within the far-IR region as well as electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry and nuclear magnetic resonance methods. The electronic structures, and properties of the neutral CPTs, their mono- and diprotonated forms as well as molecular ion fragments, obtained by the mass spectrometric data are predicted theoretically using the DFT method.

  15. Transcriptome analysis of stem wood of Nothapodytes nimmoniana (Graham) Mabb. identifies genes associated with biosynthesis of camptothecin, an anti-carcinogenic molecule.

    PubMed

    Manjunatha, B L; Singh, H R; Ravikanth, G; Nataraja, Karaba N; Shankar, Ravi; Kumar, Sanjay; Shaanker, R Uma

    2016-03-01

    Camptothecin (CPT), a monoterpene indole alkaloid, is a potent inhibitor of DNA topoisomerase I and has applications in treating ovarian, small lung and refractory ovarian cancers. Stem wood tissue of Nothapodytes nimmoniana (Graham) Mabb. (family Icacinaceae) is one of the richest sources of CPT. Since there is no genomic or transcriptome data available for the species, the present work sequenced and analysed transcriptome of stem wood tissue on an Illumina platform. From a total of 77,55,978 reads, 9,187 transcripts were assembled with an average length of 255 bp. Functional annotation and categorization of these assembled transcripts unraveled the transcriptome architecture and also a total of 13 genes associated with CPT biosynthetic pathway were identified in the stem wood tissue. Four genes of the pathway were cloned to full length by RACE to validate the transcriptome data. Expression analysis of 13 genes associated with CPT biosynthetic pathway in 11 different tissues vis-a-vis CPT content analysis suggested an important role of NnPG10H, NnPSLS and NnPSTR genes in the biosynthesis of CPT. These results indicated that CPT might be synthesized in the leaves and then perhaps exported to stem wood tissue for storage. PMID:26949094

  16. Production of camptothecin in cultures of Chonemorpha grandiflora

    PubMed Central

    Kulkarni, A. V.; Patwardhan, A. A.; Lele, U.; Malpathak, N. P.

    2010-01-01

    Background: Chonemorpha grandiflora (Syn. Chonemorpha fragrans (Apocynaceae) is an endangered medicinal plant. It is used in different preparations, such as sudarsanasavam and kumaryasavam used in Kerala Ayurvedic system. C. grandiflora is used for the treatment of fever and stomach disorders. Phytochemical investigations have revealed the presence of steroidal alkaloids, such as chonemorphine and funtumafrine in C. grandiflora. Camptothecin, a well-known anticancer alkaloid has been detected in ethanolic extracts of stem with bark and callus cultures derived from C. grandiflora. Methods: Callus cultures of C. grandiflora were raised on Murashige and Skoog’s medium supplemented with 2, 4-D. Stem with bark and callus were used for phytochemical analysis mainly the alkaloids. Detection and identification of camptothecin was carried out using thin-layer chromatography (TLC), high-performance thin-layer chromatography, (HPTLC) and high-performance liquid chromatography (HPLC). Results: An important anticancer alkaloid, camptothecin was detected in ethanolic extracts of stem with bark and callus cultures of C. grandiflora. camptothecin content was 0.013 mg/g in stem with bark and 0.003 mg/g in callus. Conclusion: This is the first report on in vivo and in vitro production of camptothecin in C. grandiflora. Camptothecin is known to occur only in six plant sources so, alternative sources for camptothecin are needed. Thus of C. grandiflora could be a new promising alternative source of camptothecin. PMID:21589755

  17. The self-assembling camptothecin-tocopherol prodrug: An effective approach for formulating camptothecin.

    PubMed

    Lu, Jianqin; Liu, Chuang; Wang, Pengcheng; Ghazwani, Mohammed; Xu, Jieni; Huang, Yixian; Ma, Xiaochao; Zhang, Peijun; Li, Song

    2015-09-01

    Camptothecin (CPT) is a potent antitumor agent and functions via inhibiting the activity of topoisomerase I during DNA replication. However, the clinical application of CPT has been greatly hindered by its extremely poor solubility, the instability of its active lactone ring in blood stream, as well as the non-specific toxicity to normal tissues. In addition, most of the formulations developed so far are not applicable for formulating CPT. In this study, two novel CPT prodrugs were developed by conjugating CPT to α-tocopherol via a carbonate ester bond (CPT-VE) or disulfide linkage (CPT-S-S-VE). Both CPT prodrugs were able to self-assemble into nanofibers with the facilitation of a PEG5K-Fmoc-VE2-based nanomicellar carrier. Both prodrug nanoassemblies exhibited excellent stability. Fluorescence quenching, UV absorbance, and FT-IR studies demonstrated strong interactions between carrier and prodrugs, including hydrophobic interaction, π-π stacking, as well as hydrogen bonding. NMR studies suggested that prodrugs were successfully incorporated into PEG5K-Fmoc-VE2 during self-assembly process. In vitro, PEG5K-Fmoc-VE2/CPT-S-S-VE presented significantly higher level of cytotoxicity on tumor cells compared to PEG5K-Fmoc-VE2/CPT-VE. Biodistribution study showed that CPT-S-S-VE formulated in PEG5K-Fmoc-VE2 micelles was effectively converted to parent CPT following delivery to tumor tissues. Finally, PEG5K-Fmoc-VE2/CPT-S-S-VE nanofibers showed superior tumor growth inhibition in an aggressive murine breast cancer model (4T1.2).

  18. The Self-Assembling Camptothecin-Tocopherol Prodrug: An Effective Approach for Formulating Camptothecin

    PubMed Central

    Lu, Jianqin; Liu, Chuang; Wang, Pengcheng; Ghazwani, Mohammed; Xu, Jieni; Huang, Yixian; Ma, Xiaochao; Zhang, Peijun; Li, Song

    2015-01-01

    Camptothecin (CPT) is a potent antitumor agent and functions via inhibiting the activity of topoisomerase I during DNA replication. However, the clinical application of CPT has been greatly hindered by its extremely poor solubility, the instability of its active lactone ring in blood stream, as well as the non-specific toxicity to normal tissues. In addition, most of the formulations developed so far are not applicable for formulating CPT. In this study, two novel CPT prodrugs were developed by conjugating CPT to α-tocopherol via a carbonate ester bond (CPT-VE) or disulfide linkage (CPT-S-S-VE). Both CPT prodrugs were able to self-assemble into nanofibers with the facilitation of a PEG5K-Fmoc-VE2-based nanomicellar carrier. Both prodrug nanoassemblies exhibited excellent stability. Fluorescence quenching, UV absorbance, and FT-IR studies demonstrated strong interactions between carrier and prodrugs, including hydrophobic interaction, π-π stacking, as well as hydrogen bonding. NMR studies suggested that prodrugs were successfully incorporated into PEG5K-Fmoc-VE2 during self-assembly process. In vitro, PEG5K-Fmoc-VE2/CPT-S-S-VE presented significantly higher level of cytotoxicity on tumor cells compared to PEG5K-Fmoc-VE2/CPT-VE. Biodistribution study showed that CPT-S-S-VE formulated in PEG5K-Fmoc-VE2 micelles was effectively converted to parent CPT following delivery to tumor tissues. Finally, PEG5K-Fmoc-VE2/CPT-S-S-VE nanofibers showed superior tumor growth inhibition in an aggressive murine breast cancer model (4T1.2). PMID:26057133

  19. Single and combined supplementation of glutamine and n-3 polyunsaturated fatty acids on host tolerance and tumour response to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11)/5-fluorouracil chemotherapy in rats bearing Ward colon tumour.

    PubMed

    Xue, Hongyu; Le Roy, Séverine; Sawyer, Michael B; Field, Catherine J; Dieleman, Levinus A; Baracos, Vickie E

    2009-08-01

    Prior reports suggest that during irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin; CPT-11) chemotherapy in laboratory rats, the anti-tumour efficacy and diarrhoea toxicity could be modulated by n-3 PUFA and glutamine, respectively. We further examined how these two dietary elements, when provided individually and in combination, would affect the efficacy of a cyclical regimen of CPT-11/5-fluorouracil (5-FU), an accepted combination regimen for colorectal cancer. Prior to initiating chemotherapy, diets enriched either with glutamine (2 %, w/w total diet) or n-3 PUFA (0.88 %, w/w total diet) alone, inhibited Ward colon tumour growth (P < 0.05). These diets also completely or partially normalized the changes in peripheral leucocyte counts associated with the tumour-bearing state (e.g. neutrophil proportion/concentration and lymphocyte proportion). During chemotherapy, either glutamine- or n-3 PUFA-enriched diet enhanced tumour chemo-sensitivity, and reduced body weight loss, anorexia and muscle wasting (v. animals fed control diet, P < 0.05). Surprisingly, providing both glutamine and n-3 PUFA together did not confer a greater benefit on tumour inhibition either in the presence or absence of chemotherapy; individual benefits associated with single treatments, particularly in respect to host nutritional status (i.e. body weight, food intake and muscle weight) and immune (peripheral leucocyte counts) features were instead partially or completely lost when these two nutrients were combined. These results draw into question the common assumption that there are additive or synergistic benefits of combinations of nutrients, which are beneficial on an individual basis, and suggest that co-supplementation with glutamine and n-3 PUFA is not indicated during chemotherapy with CPT-11 and 5-FU.

  20. Chemical modification of antitumor alkaloids, 20(S)-camptothecin and 7-ethylcamptothecin: reaction of the E-lactone ring portion with hydrazine hydrate.

    PubMed

    Yaegashi, T; Sawada, S; Furuta, T; Yokokura, T; Yamaguchi, K; Miyasaka, T

    1993-05-01

    The structure of the N-amino pyridone (4a) obtained by the reaction of camptothecin (1a) with hydrazine was determined by X-ray crystallography. A mixture of 7-ethylcamptothecin (1b) and hydrazine hydrate was stirred at room temperature, and the hydrazide (2b) was isolated as its diacetate 2c. Treatment of the 17-O-acetyl amide (5a) with hydrazine gave 1b (74% yield) and the N-amino lactam 6 (11% yield). Compounds with bulky acyl groups, 5c--e, gave 6 in modest yields. The N-amino lactam 6 was smoothly dehydrated into the pyridone 4d by refluxing in hydrazine hydrate. PMID:8339343

  1. Efficient and chemoselective N-acylation of 10-amino-7-ethyl camptothecin with poly(ethylene glycol).

    PubMed

    Guiotto, Andrea; Canevari, Mirta; Orsolini, Piero; Lavanchy, Olivier; Deuschel, Christine; Kaneda, Norimasa; Kurita, Akinobu; Matsuzaki, Takeshi; Yaegashi, Takeshi; Sawada, Seigo; Veronese, Francesco M

    2004-04-01

    A new poly(ethylene glycol) (PEG) conjugate of 10-amino-7-ethyl camptothecin, a potent antitumor analogue of camptothecin, has been synthesized and preliminary in vivo tests have been performed. Successful chemoselective N-acylation of 10-amino-7-ethyl camptothecin was accomplished using phenyl dichlorophosphate, a coupling reagent used in esterification of alcohols, while other coupling methods failed, due to the low nucleophilicity of the amino group in position 10. The conjugate was tested against P388 murine leukemia cell lines and resulted equipotent to CPT-11, a camptothecin analogue already in clinical use.

  2. Preparation, formula optimization and antitumor actions of mannitol coupling camptothecin nanoparticles.

    PubMed

    Wang, Zhichao; Li, Qingyong; Zhao, Xiuhua; Sun, Baihe; Zhu, Qiaochu; Gao, Wenqing; Hua, Changlong

    2014-04-25

    The purpose of this work is to prepare a formulation using mannitol coupling Camptothecin (CPT) nanoparticles (CPT-NPs) to circumvent the difficult solubilization practice based on central composite experimental statistical design. CPT-NPs were prepared with a high-pressure homogenization technique method. The independent variables considered for the optimization of CPT-NPs were percentage of CPT in raw material (CPT and mannitol), concentration of CPT in working liquid, cycles numbers and homogenizer pressure for drug loading efficiency, particle size and polydispersity index. Analysis of variance (ANOVA) statistical test was used to assess the optimization. The optimized CPT-NPs showed an appropriate drug loading efficiency (18.09 ± 2.13%), a homogeneous particle size (165.33 ± 37.23 nm) and a low polydispersity index (0.29 ± 0.01). The CPT-NPs group show higher inhibition ratio (79.95%) of H22 tumor growth in vivo compared with TPT and CPT at the same dose. Changes in mice body weight demonstrate CPT-NPs have the lower toxicity. The results of biodistribution studies indicated the obviously superiority of CPT-NPs in increasing the accumulation of CPT within tumor. Overall, CPT-NPs under optimum conditions are considered to be potentially feasible to overcome formulation challenges for drug delivery.

  3. Camptothecine encapsulated composite drug delivery system for colorectal peritoneal carcinomatosis therapy: biodegradable microsphere in thermosensitive hydrogel.

    PubMed

    Liu, Lei; Wu, Qinjie; Ma, Xuelei; Xiong, Dake; Gong, Changyang; Qian, Zhiyong; Zhao, Xia; Wei, Yuquan

    2013-06-01

    In this work, we developed a biodegradable and injectable composite drug delivery system (DDS), camptothecine (CPT) loaded polymeric microsphere in thermosensitive hydrogel, for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administrated to form microsphere or thermosensitive hydrogel, respectively. Therefore, the composite DDS was composed of CPT loaded microsphere (CPT-MS) and thermosensitive hydrogel. CPT-MS was prepared by CPT and PCEC copolymer (Mn=31,600) using an oil-in-water emulsion solvent evaporation method. Besides, biodegradable and injectable thermosensitive PCEC hydrogel (Mn=3150) with lower sol-gel transition temperature at around body temperature was also prepared. The CPT-MS in thermosensitive hydrogel (CPT-MS/hydrogel) composite is a free-flowing sol at ambient temperature and instantly converts into a non-flowing gel at body temperature. Furthermore, cytotoxicity assay indicated that both microsphere and hydrogel were biocompatible with very low cytotoxicity. In vitro release profile demonstrated a significant difference between rapid release of free CPT and much slower and sustained release of CPT-MS/hydrogel. In addition, intraperitoneal administration of CPT-MS/hydrogel could effectively suppress growth and metastasis of CT26 peritoneal carcinomatosis in vivo, and prolonged the survival of tumor bearing mice. Compared with CPT-MS or free CPT, CPT-MS/hydrogel induced a stronger anti-tumor effect by increasing apoptosis of tumor cells and inhibiting microvessel density of tumor tissue. Besides, side effects of CPT were also alleviated in CPT-MS/hydrogel-treated mice. Thus, our results suggested that CPT-MS/hydrogel may have great potential applications in clinic.

  4. Camptothecin blocks memory of conditioned avoidance in the goldfish.

    PubMed

    Neale, J H; Klinger, P D; Agranoff, B W

    1973-03-23

    Intracranial injection of 10 to 75 micrograms of camptothecin, a plant alkaloid that blocks RNA synthesis in eucaryotic cells, blocks incorporation of tritiated uridine into RNA in the goldfish brain. Injection of 10 to 50 micrograms of the drug within 1.5 hours of training results in greatly diminished memory, tested 1 week later. Injection of the drug 5 or 24 hours after training produces no measurable effect on retention of the learned response.

  5. Supramolecular assembly and antitumor activity of multiwalled carbon nanotube-camptothecin complexes.

    PubMed

    Tian, Zhong; Yin, Min; Ma, Hongmei; Zhu, Longzhang; Shen, Hebei; Jia, Nengqin

    2011-02-01

    The novel supramolecular complexes were prepared with a water-insoluble anticancer drug camptothecin (CPT) loading onto functionalized multiwalled carbon nanotubes via pi-stacking, in order to improve their solubility and antitumor activity. The multiwalled carbon nanotubes were firstly coated with the tri-block copolymer (Pluronic P123) to render high aqueous solubility. The copolymer-coated multiwalled carbon nanotubes can effectively form non-covalent supramolecular complexes with camptothecin. The supramolecular assembly of the complexes (f-MWNTs-CPT) were systematically characterized by transmission electron microscopy (TEM), UV-vis spectrophotometry (UV), fluorescence spectrophotometry, atomic force microscopy (AFM) and electrochemical impedance spectroscopy (EIS). Furthermore, in vitro cytotoxicity studies of f-MWNTs-CPT supramolecular complexes using the MTT assay exhibit enhanced antitumor activity, suggesting that the functionalized multiwalled carbon nanotubes can facilitate intracellular delivery of anticancer drug and improve drug activity.

  6. Activation of camptothecin derivatives by conjugation to triple helix-forming oligonucleotides.

    PubMed

    Arimondo, Paola B; Laco, Gary S; Thomas, Craig J; Halby, Ludovic; Pez, Didier; Schmitt, Philippe; Boutorine, Alexandre; Garestier, Thérèse; Pommier, Yves; Hecht, Sidney M; Sun, Jian-Sheng; Bailly, Christian

    2005-03-22

    Topoisomerase I (topo I) is a ubiquitous DNA-cleaving enzyme and an important therapeutic target in cancer chemotherapy. Camptothecins (CPTs) reversibly trap topo I in covalent complex with DNA but exhibit limited sequence preference. The utilization of conjugates such as triplex-forming oligonucleotides (TFOs) to target a medicinal agent (like CPT) to a specific genetic sequence and orientation within the DNA has been accomplished successfully. In this study, different attachment points of the TFO to CPT (including positions 7, 9, 10, and 12) were investigated and our findings confirmed and extended previous conclusions. Interestingly, the conjugates induced specific DNA cleavage by topo I at the triplex site even when poorly active or inactive CPT derivatives were used. This suggests that the positioning of the drug in the cleavage complex by the sequence-specific DNA ligand is able to stabilize the ternary complex, even when important interactions between topo I and CPT are disrupted. Finally, certain TFO-CPT conjugates were able to induce sequence-specific DNA cleavage with the topo I mutants R364H and N722S that are resistant to camptothecin. The TFO-CPT conjugates are thus valuable tools to study the interactions involved in the formation of the ternary complex and also to enlarge the family of compounds that poison topo I. The fact that an inactive CPT analogue can act as a topo I poison when appropriately coupled to a TFO provides a new perspective at the level of drug design. PMID:15766244

  7. Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer.

    PubMed

    Shamanna, Raghavendra A; Lu, Huiming; Croteau, Deborah L; Arora, Arvind; Agarwal, Devika; Ball, Graham; Aleskandarany, Mohammed A; Ellis, Ian O; Pommier, Yves; Madhusudan, Srinivasan; Bohr, Vilhelm A

    2016-03-22

    Werner syndrome protein (WRN) is a RecQ helicase that participates in DNA repair, genome stability and cellular senescence. The five human RecQ helicases, RECQL1, Bloom, WRN, RECQL4 and RECQL5 play critical roles in DNA repair and cell survival after treatment with the anticancer drug camptothecin (CPT). CPT derivatives are widely used in cancer chemotherapy to inhibit topoisomerase I and generate DNA double-strand breaks during replication. Here we studied the effects of CPT on the stability and expression dynamics of human RecQ helicases. In the cells treated with CPT, we observed distinct effects on WRN compared to other human RecQ helicases. CPT altered the cellular localization of WRN and induced its degradation by a ubiquitin-mediated proteasome pathway. WRN knockdown cells as well as CPT treated cells became senescent and stained positive for senescence-associated β-galactosidase at a higher frequency compared to control cells. However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells. Approximately 5-23% of breast cancer tumors are known to respond to CPT-based chemotherapy. Interestingly, we found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT. The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells. In a large clinical cohort of breast cancer patients, we find that WRN and topoisomerase I expression correlate with an aggressive tumor phenotype and poor prognosis. Our novel observations suggest that WRN abundance along with CPT-induced degradation could be a promising strategy for personalizing CPT-based cancer chemotherapeutic regimens.

  8. Camptothecins guanine interactions: mechanism of charge transfer reaction upon photoactivation

    NASA Astrophysics Data System (ADS)

    Steenkeste, K.; Guiot, E.; Tfibel, F.; Pernot, P.; Mérola, F.; Georges, P.; Fontaine-Aupart, M. P.

    2002-01-01

    The potent activity exhibited by the antitumoral camptothecin (CPT) and its analog irinotecan (CPT-11) is known to be related to a close contact between the drug and the nucleic acid base guanine. This specificity of interaction between these two chromophores was examined by following changes in the photophysical properties of the drug using steady-state as well as time-resolved absorption and fluorescence methods. The observed effects on absorption, fluorescence emission and singlet excited state lifetimes give evidence for the occurrence of a stacking complex formation restricted to the quinoline part of CPT or CPT-11 and the guanine base but also with the adenine base. The triplet excited state properties of the drugs have been also characterized in absence and in presence of guanosine monophosphate and reveal the occurrence of an electron transfer from the guanine base to the drug. Support for this conclusion was obtained from the studies of a set of biological targets of various oxido-reduction potentials, adenosine monophosphate, cytidine, cytosine, tryptophan, tyrosine and phenylalanine. This finding gives an interpretation of the CPT-induced guanine photolesions previously reported in the literature. These data taken together are discussed in connection with the drug activity. The stacking complex CPT/guanine is necessary but not sufficient to explain the role of the chirality and of the lactone structure in the function of the drug. A stereospecific interaction with the enzyme topoisomerase I seems necessary to stabilize the stacking complex. The first experiments using time-resolved fluorescence by two-photon excitation confirms that CPT does not bind to the isolated enzyme.

  9. Pulmonary targeting microparticulate camptothecin delivery system: anti-cancer evaluation in a rat orthotopic lung cancer model

    PubMed Central

    Chao, Piyun; Deshmukh, Manjeet; Kutscher, Hilliard L.; Gao, Dayuan; Sundara Rajan, Sujata; Hu, Peidi; Laskin, Debra L.; Stein, Stanley; Sinko, Patrick J.

    2013-01-01

    Large (>6 µm) rigid microparticles (MPs) become passively entrapped within the lungs following intravenous injection making them an attractive and highly efficient alternative to inhalation for pulmonary delivery. In the current studies, PEGylated 6 μm polystyrene MPs with multiple copies of the norvaline (Nva) α-amino acid prodrug of camptothecin (CPT) were prepared. Surface morphology was characterized using a scanning electron microscope (SEM). CPT was released from the CPT-Nva-MPs over 24 hours in rat plasma at 37°C. In vivo CPT plasma concentrations were low (~1 ng/mL or less) and constant over a period of 4 days after a single intravenous injection of CPT-Nva-MPs as compared to high but short-lived systemic exposures after an IV injection of free CPT. This suggests that sustained local CPT concentrations were achieved in the lung after administration of the MP delivery system. Anti-cancer efficacy was evaluated in an orthotopic lung cancer animal model and compared to a bolus injection of CPT. Animals receiving either free CPT (2 mg/kg) or CPT-Nva-MPs (0.22 mg/kg CPT, 100 mg/kg MPs) were found to have statistically significant smaller areas of lung cancer (P<0.05, P<0.01, respectively) than untreated animals. In addition, 40% of the animals receiving CPT-Nva-MPs were found to be free of cancer. The CPT dose using targeted MPs was ten fold lower than after IV injection of free CPT but was more effective in reducing the amount of cancerous areas. In conclusion, CPT-Nva-MPs were able to achieve effective local lung and low systemic CPT concentrations at a dose that was ten times lower than systemically administered CPT resulting in a significant improvement in anticancer efficacy in an orthotopic rat model of lung cancer. PMID:19966540

  10. Assessment of the chemotherapeutic potential of a new camptothecin derivative, ZBH-1205.

    PubMed

    Wu, Di; Shi, Weiguo; Zhao, Jing; Wei, Zhengren; Chen, Zhijia; Zhao, Dawei; Lan, Shijie; Tai, Jiandong; Zhong, Bohua; Yu, Hong

    2016-08-15

    CPT-11 (irinotecan) is a derivative of camptothecin which is a natural product derived from the Chinese tree Camptotheca acuminta and widely used in antitumor therapy. Here, the in vitro anti-tumor activity and associated mechanisms of a novel derivative of camptothecin, ZBH-1205, were investigated in a panel of 9 human tumor cell lines, as well as in HEK 293 and SK-OV-3/DPP, a multi-drug resistant (MDR) cell line, and compared to CPT-11 and 7-ethyl-10-hydroxy-camptothecin (SN38). Comparisons between the different compounds were made on the basis of IC50 values as determined by the MTT assay, and flow cytometry was used to evaluate cell cycle progression, apoptosis, and the levels of pro- and active caspase-3 among different treatment groups. Interaction between the molecules and topoisomerase-1 (Topo-1)-DNA complexes was detected by a DNA relaxation assay. Our results demonstrated that IC50 values for ZBH-1205 ranged from 0.0009 μmol/L to 2.5671 μmol/L, which were consistently lower than IC50 values of CPT-11 or SN38 in the panel of cell lines, including SK-OV-3/DPP. Furthermore, ZBH-1205 was more effective than CPT-11 or SN38 at stabilizing Topo-1-DNA complexes and inducing tumor cell apoptosis. Therefore, ZBH-1205 is a promising chemotherapeutic agent to be further assessed in large-scale clinical trials. PMID:27302903

  11. MWNT-hybrided supramolecular hydrogel for hydrophobic camptothecin delivery.

    PubMed

    Mu, Shansong; Liang, Yuanyuan; Chen, Shuaijun; Zhang, Liming; Liu, Tao

    2015-05-01

    To encapsulate the hydrophobic camptothecin (CPT) into hydrogel matrix with a high loading amount, a supramolecular hydrogel hybrided with multi-walled carbon nanotubes (MWNTs) was developed by the host-guest interactions and used for loading and delivering CPT. Firstly, carboxylated MWNTs were modified by polyethylene glycol monomethyl ether (MPEG), which resulted in the water-dispersed MPEG-MWNTs. Then α-cyclodextrin (α-CD) was mixed with MPEG-MWNTs and the hybrid supramolecular hydrogel was fabricated by the inclusion interactions between α-CD and MPEG. The used MPEG not only dispersed MWNTs in aqueous solution, but also functioned as hydrogel matrix by interacting with α-CD. The gelation time for the sol-gel transition and rheological properties of the resultant hydrogels were studied. Due to the excellent application of MWNTs in drug delivery, hydrophobic CPT could be loaded into the hydrogel matrix by a higher amount compared with micelles. By in vitro release and cell viability tests, it was found that the encapsulated CPT could exhibit a controlled and sustained release behavior as well as sustained antitumor efficacy.

  12. Inhibitory Effect of Camptothecin against Rice Bacterial Brown Stripe Pathogen Acidovorax avenae subsp. avenae RS-2.

    PubMed

    Dong, Qiaolin; Luo, Ju; Qiu, Wen; Cai, Li; Anjum, Syed Ishtiaq; Li, Bin; Hou, Mingsheng; Xie, Guanlin; Sun, Guochang

    2016-01-01

    Camptothecin (CPT) has anticancer, antiviral, and antifungal properties. However, there is a dearth of information about antibacterial activity of CPT. Therefore, in this study, we investigated the inhibitory effect of CPT on Acidovorax avenae subsp. avenae strain RS-2, the pathogen of rice bacterial brown stripe, by measuring cell growth, DNA damage, cell membrane integrity, the expression of secretion systems, and topoisomerase-related genes, as well as the secretion of effector protein Hcp. Results indicated that CPT solutions at 0.05, 0.25, and 0.50 mg/mL inhibited the growth of strain RS-2 in vitro, while the inhibitory efficiency increased with an increase in CPT concentration, pH, and incubation time. Furthermore, CPT treatment affected bacterial growth and replication by causing membrane damage, which was evidenced by transmission electron microscopic observation and live/dead cell staining. In addition, quantitative real-time PCR analysis indicated that CPT treatment caused differential expression of eight secretion system-related genes and one topoisomerase-related gene, while the up-regulated expression of hcp could be justified by the increased secretion of Hcp based on the ELISA test. Overall, this study indicated that CPT has the potential to control the bacterial brown stripe pathogen of rice. PMID:27472315

  13. Induction of oncogene addiction shift to NF-{kappa}B by camptothecin in solid tumor cells

    SciTech Connect

    Togano, Tomiteru; Sasaki, Masataka; Watanabe, Mariko; Nakashima, Makoto; Tsuruo, Takashi; Umezawa, Kazuo; Higashihara, Masaaki; Watanabe, Toshiki; Horie, Ryouichi

    2009-12-04

    The biological basis of the resistance of solid tumor cells to chemotherapy is not well understood. While addressing this problem, we found that gastric cancer cell line St-4/CPT, lung cancer cell line A549/CPT, and colon cancer cell line HT-29/CPT, all of which are resistant to camptothecin (CPT), showed strong and constitutive nuclear factor (NF)-{kappa}B activity driven by I{kappa}B kinase compared with their parental cell lines St-4, A549, and HT-29. A new NF-{kappa}B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced viability and induced apoptosis in St-4/CPT, A549/CPT, and HT-29/CPT cell lines, while their parental cell lines were resistant to DHMEQ. The results in this study present an example of the shift in signals that support the survival of solid tumor cells to NF-{kappa}B during the acquisition of resistance to CPT. The results also indicate that solid tumor cells that become resistant to chemotherapy may be more easily treated by NF-{kappa}B inhibitors.

  14. On the CPT theorem

    NASA Astrophysics Data System (ADS)

    Greaves, Hilary; Thomas, Teruji

    2014-02-01

    We provide a careful development and rigorous proof of the CPT theorem within the framework of mainstream (Lagrangian) quantum field theory. This is in contrast to the usual rigorous proofs in purely axiomatic frameworks, and non-rigorous proof-sketches in the mainstream approach. We construct the CPT transformation for a general field directly, without appealing to the enumerative classification of representations, and in a manner that is clearly related to the requirements of our proof. Our approach applies equally in Minkowski spacetimes of any dimension at least three, and is in principle neutral between classical and quantum field theories: the quantum CPT theorem has a natural classical analogue. The key mathematical tool is that of complexification; this tool is central to the existing axiomatic proofs, but plays no overt role in the usual mainstream approaches to CPT.

  15. Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells.

    PubMed

    Su, Hao; Zhang, Pengcheng; Cheetham, Andrew G; Koo, Jin Mo; Lin, Ran; Masood, Asad; Schiapparelli, Paula; Quiñones-Hinojosa, Alfredo; Cui, Honggang

    2016-01-01

    Chemical modification of small molecule hydrophobic drugs is a clinically proven strategy to devise prodrugs with enhanced treatment efficacy. While this prodrug strategy improves the parent drug's water solubility and pharmacokinetic profile, it typically compromises the drug's potency against cancer cells due to the retarded drug release rate and reduced cellular uptake efficiency. Here we report on the supramolecular design of self-assembling prodrugs (SAPD) with much improved water solubility while maintaining high potency against cancer cells. We found that camptothecin (CPT) prodrugs created by conjugating two CPT molecules onto a hydrophilic segment can associate into filamentous nanostructures in water. Our results suggest that these SAPD exhibit much greater efficacy against primary brain cancer cells relative to that of irinotecan, a clinically used CPT prodrug. We believe these findings open a new avenue for rational design of supramolecular prodrugs for cancer treatment. PMID:27217839

  16. Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells

    PubMed Central

    Su, Hao; Zhang, Pengcheng; Cheetham, Andrew G; Koo, Jin Mo; Lin, Ran; Masood, Asad; Schiapparelli, Paula; Quiñones-Hinojosa, Alfredo; Cui, Honggang

    2016-01-01

    Chemical modification of small molecule hydrophobic drugs is a clinically proven strategy to devise prodrugs with enhanced treatment efficacy. While this prodrug strategy improves the parent drug's water solubility and pharmacokinetic profile, it typically compromises the drug's potency against cancer cells due to the retarded drug release rate and reduced cellular uptake efficiency. Here we report on the supramolecular design of self-assembling prodrugs (SAPD) with much improved water solubility while maintaining high potency against cancer cells. We found that camptothecin (CPT) prodrugs created by conjugating two CPT molecules onto a hydrophilic segment can associate into filamentous nanostructures in water. Our results suggest that these SAPD exhibit much greater efficacy against primary brain cancer cells relative to that of irinotecan, a clinically used CPT prodrug. We believe these findings open a new avenue for rational design of supramolecular prodrugs for cancer treatment. PMID:27217839

  17. Micropropagation and hairy root culture of Ophiorrhiza alata Craib for camptothecin production.

    PubMed

    Ya-ut, Pornwilai; Chareonsap, Piyarat; Sukrong, Suchada

    2011-12-01

    An efficient system was developed for the in vitro micropropagation and hairy root culture of Ophiorrhiza alata Craib for camptothecin (CPT) production. Shoot multiplication on leaf and node explants from germinated seeds of O. alata was successful on half-strength Murashige and Skoog medium supplemented with varying amounts of kinetin and α-naphthaleneacetic acid. Node explants grown in vitro were successfully infected by Agrobacterium rhizogenes TISTR 1450 for the establishment of hairy root culture. The amount of CPT in various parts of O. alata was analyzed by HPLC. The accumulation of CPT in transformed hairy roots was twice that in soil-grown plants (785 ± 52 and 388 ± 32 μg/g dry wt, respectively). In the presence of a polystyrene resin (Diaion HP-20) that absorbed CPT, the CPT content in the culture media increased sevenfold compared with controls (1,036 and 151 μg per 250 ml medium, respectively). These results enable the feasible production of CPT of O. alata by means of a cell culture strategy. These measures can help safeguard the plant from extinction.

  18. Synthesis, biological activities, and quantitative structure-activity relationship (QSAR) study of novel camptothecin analogues.

    PubMed

    Wu, Dan; Zhang, Shao-Yong; Liu, Ying-Qian; Wu, Xiao-Bing; Zhu, Gao-Xiang; Zhang, Yan; Wei, Wei; Liu, Huan-Xiang; Chen, An-Liang

    2015-05-13

    In continuation of our program aimed at the development of natural product-based pesticidal agents, three series of novel camptothecin derivatives were designed, synthesized, and evaluated for their biological activities against T. Cinnabarinus, B. brassicae, and B. xylophilus. All of the derivatives showed good-to-excellent activity against three insect species tested, with LC50 values ranging from 0.00761 to 0.35496 mmol/L. Remarkably, all of the compounds were more potent than CPT against T. Cinnabarinus, and compounds 4d and 4c displayed superior activity (LC50 0.00761 mmol/L and 0.00942 mmol/L, respectively) compared with CPT (LC50 0.19719 mmol/L) against T. Cinnabarinus. Based on the observed bioactivities, preliminary structure-activity relationship (SAR) correlations were also discussed. Furthermore, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) was built. The model gave statistically significant results with the cross-validated q2 values of 0.580 and correlation coefficient r2 of 0.991 and  of 0.993. The QSAR analysis indicated that the size of the substituents play an important in the activity of 7-modified camptothecin derivatives. These findings will pave the way for further design, structural optimization, and development of camptothecin-derived compounds as pesticidal agents.

  19. Ab initio study on the noncovalent adsorption of camptothecin anticancer drug onto graphene, defect modified graphene and graphene oxide.

    PubMed

    Saikia, Nabanita; Deka, Ramesh C

    2013-09-01

    The application of graphene and related nanomaterials like boron nitride (BN) nanosheets, BN-graphene hybrid nanomaterials, and graphene oxide (GO) for adsorption of anticancer chemotherapeutic camptothecin (CPT) along with the effect on electronic properties prior to functionalization and after functionalization has been reported using density functional theory (DFT) calculations. The inclusion of dispersion correction to DFT is instrumental in accounting for van der Waals π-π stacking between CPT and the nanomaterial. The adsorption of CPT exhibits significant strain within the nanosheets and noncovalent adsorption of CPT is thermodynamically favoured onto the nanosheets. In case of GO, surface incorporation of functional groups result in significant crumpling along the basal plane and the interaction is basically mediated by H-bonding rather than π-π stacking. Docking studies predict the plausible binding of CPT, CPT functionalized graphene and GO with topoisomerase I (top 1) signifying that CPT interacts through π stacking with AT and GC base pairs of DNA and in presence of nano support, DNA bases preferentially gets bound to the basal plane of graphene and GO rather than the edges. At a theoretical level of understanding, our studies point out the noncovalent interaction of CPT with graphene based nanomaterials and GO for loading and delivery of anticancer chemotherapeutic along with active binding to Top1 protein. PMID:24132695

  20. Ab initio study on the noncovalent adsorption of camptothecin anticancer drug onto graphene, defect modified graphene and graphene oxide.

    PubMed

    Saikia, Nabanita; Deka, Ramesh C

    2013-09-01

    The application of graphene and related nanomaterials like boron nitride (BN) nanosheets, BN-graphene hybrid nanomaterials, and graphene oxide (GO) for adsorption of anticancer chemotherapeutic camptothecin (CPT) along with the effect on electronic properties prior to functionalization and after functionalization has been reported using density functional theory (DFT) calculations. The inclusion of dispersion correction to DFT is instrumental in accounting for van der Waals π-π stacking between CPT and the nanomaterial. The adsorption of CPT exhibits significant strain within the nanosheets and noncovalent adsorption of CPT is thermodynamically favoured onto the nanosheets. In case of GO, surface incorporation of functional groups result in significant crumpling along the basal plane and the interaction is basically mediated by H-bonding rather than π-π stacking. Docking studies predict the plausible binding of CPT, CPT functionalized graphene and GO with topoisomerase I (top 1) signifying that CPT interacts through π stacking with AT and GC base pairs of DNA and in presence of nano support, DNA bases preferentially gets bound to the basal plane of graphene and GO rather than the edges. At a theoretical level of understanding, our studies point out the noncovalent interaction of CPT with graphene based nanomaterials and GO for loading and delivery of anticancer chemotherapeutic along with active binding to Top1 protein.

  1. CPT-hole closure

    USGS Publications Warehouse

    Noce, T.E.; Holzer, T.L.

    2003-01-01

    The long-term stability of deep holes 1.75 inches. (4.4 cm) in diameter by 98.4 feet (30 m) created by cone penetration testing (CPT) was monitored at a site in California underlain by Holocene and Pleistocene age alluvial fan deposits. Portions of the holes remained open both below and above the 28.6-foot (8.7 m)-deep water table for approximately three years, when the experiment was terminated. Hole closure appears to be a very slow process that may take decades in the stiff soils studied here. Other experience suggests holes in softer soils may also remain open. Thus, despite their small diameter, CPT holes may remain open for years and provide paths for rapid migration of contaminants. The observations confirm the need to grout holes created by CPT soundings as well as other direct-push techniques in areas where protection of shallow ground water is important.

  2. Poly(ω-pentadecalactone-co-butylene-co-succinate) Nanoparticles as Biodegradable Carriers for Camptothecin Delivery

    PubMed Central

    Liu, Jie; Jiang, Zhaozhong; Zhang, Shengmin; Saltzman, W. Mark

    2009-01-01

    In this study, we show that degradable particles of a hydrophobic polymer can effectively deliver drugs to tumors after i.v. administration. Free-standing nanoparticles with diameters of 100–300 nm were successfully fabricated from highly hydrophobic, biodegradable poly(ω-pentadecalactone- co-butylene-co-succinate) (PPBS) copolyesters. PPBS copolymers with various compositions (20–80 mol% PDL unit contents) were synthesized via copolymerization of ω-pentadecalactone (PDL), diethyl succinate (DES), and 1,4-butanediol (BD) using Candida antarctica lipase B (CALB) as the catalyst. Camptothecin (CPT, 12–22%) was loaded into PPBS nanoparticles with high encapsulation efficiency (up to 96%) using a modified oil-in-water single emulsion technique. The CPT-loaded nanoparticles had a zeta potential of about −10 mV. PPBS particles were non toxic in cell culture. Upon encapsulation, the active lactone form of CPT was remarkably stabilized and no lactone-to-carboxylate structural conversion was observed for CPT-loaded PPBS nanoparticles incubated in both phosphate-buffered saline (PBS, pH = 7.4) and DMEM medium for at least 24 hr. In PBS at 37 °C, CPT-loaded PPBS nanoparticles showed a low burst CPT release (20–30%) within the first 24 hrs followed by a sustained, essentially complete, release of the remaining drug over the subsequent 40 days. Compared to free CPT, CPT-loaded PPBS nanoparticles showed a significant enhancement of cellular uptake, higher cytotoxicity against Lewis lung carcinoma and 9L cell lines in vitro, a longer circulation time, and substantially better antitumor efficacy in vivo. These results demonstrate the potential of PPBS nanoparticles as long-term stable and effective drug delivery systems in cancer therapy. PMID:19632718

  3. ''CPT Theorem'' for Accelerators

    SciTech Connect

    Vladimir Shiltsev

    2004-08-05

    In this paper we attempt to reveal common features in evolution of various colliders' luminosity over commissioning periods. A simplified formula, ''CPT theorem'' or CP = T, is proposed which relates the time needed for commissioning T, the ''complexity'' of the machine C and performance increase goal P.

  4. Micropropagation and production of Camptothecin from in vitro plants of Ophiorrhiza rugosa var. decumbens.

    PubMed

    Roja, G

    2008-01-01

    Camptothecin and its derivatives are used as anticancer alkaloids. At present, they are obtained by the extraction from the Chinese tree Camptotheca acuminata and the indigenous tree Nothapodytes foetida. Identification of alternate species of plants like Ophiorrhiza species and development of tissue culture methods may be a suitable alternative for large-scale micropropagation as well as for the production of camptothecin. Plantlets were successfully regenerated from shoot cultures of Ophiorrhiza rugosa initiated from axillary meristems on medium containing benzyladenine (BA) (4.0 mg L(-1)) + alpha-naphthalene acetic acid (NAA) (0.05 mg L(-1)). Rooting was initiated in half concentration of Murashige and Skoog's (MS) basal medium devoid of growth hormones. Tissue culture derived plants of O. rugosa were similar to the normal plants in their morphological characteristics and chemical constitution. Ten O. rugosa plants that were obtained through micropropagation showed when analysed a higher alkaloid content compared to the normal plant. Chemical analysis of the different organs of the tissue culture plant of O. rugosa established in soil indicated 0.002% dry weight of camptothecin in the roots, 0.011% dry weight in the stems, 0.090% dry weight in the leaves and 0.015% in the floral parts.

  5. Poly(ADP-ribose) polymers regulate DNA topoisomerase I (Top1) nuclear dynamics and camptothecin sensitivity in living cells

    PubMed Central

    Das, Subhendu K.; Rehman, Ishita; Ghosh, Arijit; Sengupta, Souvik; Majumdar, Papiya; Jana, Biman; Das, Benu Brata

    2016-01-01

    Topoisomerase 1 (Top1) is essential for removing the DNA supercoiling generated during replication and transcription. Anticancer drugs like camptothecin (CPT) and its clinical derivatives exert their cytotoxicity by reversibly trapping Top1 in covalent complexes on the DNA (Top1cc). Poly(ADP-ribose) polymerase (PARP) catalyses the addition of ADP-ribose polymers (PAR) onto itself and Top1. PARP inhibitors enhance the cytotoxicity of CPT in the clinical trials. However, the molecular mechanism by which PARylation regulates Top1 nuclear dynamics is not fully understood. Using live-cell imaging of enhanced green fluorescence tagged-human Top1, we show that PARP inhibitors (Veliparib, ABT-888) delocalize Top1 from the nucleolus to the nucleoplasm, which is independent of Top1–PARP1 interaction. Using fluorescence recovery after photobleaching and subsequent fitting of the data employing kinetic modelling we demonstrate that ABT-888 markedly increase CPT-induced bound/immobile fraction of Top1 (Top1cc) across the nuclear genome, suggesting Top1-PARylation counteracts CPT-induced stabilization of Top1cc. We further show Trp205 and Asn722 of Top1 are critical for subnuclear dynamics. Top1 mutant (N722S) was restricted to the nucleolus in the presence of CPT due to its deficiency in the accumulation of CPT-induced Top1-PARylation and Top1cc formation. This work identifies ADP-ribose polymers as key determinant for regulating Top1 subnuclear dynamics. PMID:27466387

  6. Poly(ADP-ribose) polymers regulate DNA topoisomerase I (Top1) nuclear dynamics and camptothecin sensitivity in living cells.

    PubMed

    Das, Subhendu K; Rehman, Ishita; Ghosh, Arijit; Sengupta, Souvik; Majumdar, Papiya; Jana, Biman; Das, Benu Brata

    2016-09-30

    Topoisomerase 1 (Top1) is essential for removing the DNA supercoiling generated during replication and transcription. Anticancer drugs like camptothecin (CPT) and its clinical derivatives exert their cytotoxicity by reversibly trapping Top1 in covalent complexes on the DNA (Top1cc). Poly(ADP-ribose) polymerase (PARP) catalyses the addition of ADP-ribose polymers (PAR) onto itself and Top1. PARP inhibitors enhance the cytotoxicity of CPT in the clinical trials. However, the molecular mechanism by which PARylation regulates Top1 nuclear dynamics is not fully understood. Using live-cell imaging of enhanced green fluorescence tagged-human Top1, we show that PARP inhibitors (Veliparib, ABT-888) delocalize Top1 from the nucleolus to the nucleoplasm, which is independent of Top1-PARP1 interaction. Using fluorescence recovery after photobleaching and subsequent fitting of the data employing kinetic modelling we demonstrate that ABT-888 markedly increase CPT-induced bound/immobile fraction of Top1 (Top1cc) across the nuclear genome, suggesting Top1-PARylation counteracts CPT-induced stabilization of Top1cc. We further show Trp205 and Asn722 of Top1 are critical for subnuclear dynamics. Top1 mutant (N722S) was restricted to the nucleolus in the presence of CPT due to its deficiency in the accumulation of CPT-induced Top1-PARylation and Top1cc formation. This work identifies ADP-ribose polymers as key determinant for regulating Top1 subnuclear dynamics.

  7. Polymeric phosphorylcholine-camptothecin conjugates prepared by controlled free radical polymerization and click chemistry.

    PubMed

    Chen, Xiangji; McRae, Samantha; Parelkar, Sangram; Emrick, Todd

    2009-12-01

    Novel polymer-drug conjugates, consisting of zwitterionic poly(methacryloyloxyethyl phosphorylcholine) (polyMPC) as the polymer component, and camptothecin (CPT) as the drug, were prepared by two methods. In one case, CPT was transformed by acylation into a functional initiator for copper catalyzed atom transfer radical polymerization (ATRP), and polyMPC was grown from this therapeutic initiator. In the other case, a one-pot ATRP-"click" conjugation strategy was employed to synthesize novel polyMPC structures containing multiple copies of the drug pendant to the zwitterionic polymer chain. The latter method allows polyMPC-graft-CPT conjugates to be prepared with a high weight percent drug loading (up to 14% CPT) with excellent solubility in pure water (>250 mg/mL). The linkage chemistry chosen between the polyMPC backbone and the pendant drugs proved critically important for assuring drug release within a time frame reasonable to consider these structures as a platform for injectable cancer therapeutics. Liberation of the drug from the polymer backbone was monitored by high-performance liquid chromatography, using size-exclusion and reverse-phase columns, and the toxicity of the polymer-drug conjugates was examined in cell culture against breast (MCF7), ovarian (OVCAR-3), and colorectal (COLO 205) cancer cell lines.

  8. Targeting of Topoisomerase I for Prognoses and Therapeutics of Camptothecin-Resistant Ovarian Cancer

    PubMed Central

    Tsai, Hsiang-Ping; An, Herng-Wei; Lee, Chi-Ming; Wu, Jen-Chine; Chen, Chien-Shu; Huang, Shih-Hao; Hwang, Jaulang; Cheng, Kur-Ta; Leiw, Phui-Ly; Chen, Chi-Long; Lin, Chun-Mao

    2015-01-01

    DNA topoisomerase I (TOP1) levels of several human neoplasms are higher than those of normal tissues. TOP1 inhibitors are widely used in treating conventional therapy-resistant ovarian cancers. However, patients may develop resistance to TOP1 inhibitors, hampering chemotherapy success. In this study, we examined the mechanisms associated with the development of camptothecin (CPT) resistance in ovarian cancers and identified evodiamine (EVO), a natural product with TOP1 inhibiting activity that overcomes the resistance. The correlations among TOP1 levels, cancer staging, and overall survival (OS) were analyzed. The effect of EVO on CPT-resistant ovarian cancer was evaluated in vitro and in vivo. TOP1 was associated with poor prognosis in ovarian cancers (p = 0.024). EVO induced apoptosis that was detected using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The tumor size decreased significantly in the EVO treatment group compared with the control group (p < 0.01) in a xenograft mouse model. Effects of drugs targeting TOP1 for prognosis and therapy in CPT-resistant ovarian cancer are anticipated. EVO with TOP1 can be developed as an antiproliferative agent for overcoming CPT resistance in ovarian cancers. PMID:26207989

  9. Physicochemical characterization of camptothecin membrane binding properties and polymeric microsphere formulations

    NASA Astrophysics Data System (ADS)

    Selvi, Bilge

    In an effort to design novel formulation strategies to optimize the antitumor activity of camptothecin (CPT), the physicochemical and membrane binding properties of the drug, were investigated by various techniques in acidic and physiological pH. The intrinsic solubility of the CPT-lactone free base was determined to be 3.44 muM and 5.11 muM at 22°C and 37°C, respectively. The equilibrium solubility of the drug was found to increase with increasing temperature and decreasing pH. The enhanced solubility of the drug at very low pH is attributed to the protonation of the nitrogen atom in the ring B and the increased solvency of the highly acidic media. The logarithmic value of the intrinsic partition coefficient P of the free base CPT-lactone form was estimated to be 1.65, characteristic of a molecule suitable for oral absorption. The association constants Kf of the drug for bilayers composed of the zwitterionic 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and the negatively-charged 1,2-dioleoyl-sn-glycero-3-phospho- rac-(1-glycerol) (DOPG) were studied at acidic pH by fluorescence anisotropy and determined to be 35.4 +/- 4.5 M-1 and 93.1 +/- 11.0 M-1 for DOPC and DOPG, respectively, indicating a tendency of CPT to preferentially bind to negatively charged membranes. The energy of activation for the hydrolysis of CPT at physiological pH was found to be 114.3 +/- 33.4 kj/mole. The calculated t½ of the reaction at pH 7.2 at temperatures 25°C and 10°C was found to be 0.07 days and 5.12 days, respectively, whereas the time required for 1% of CPT-lactone to hydrolyze to CPT-carboxylate (t99%) was determined to be 1.8 hours, thus offering enough time to safely handle CPT-lactone at low temperatures. The preformulation results indicated that at highly acidic media CPT is positively charged and exists at its stable lactone form of increased solubility and has a capacity to bind to negatively charged membranes. Taking advantage of the increased stability of CPT in

  10. Restoration of camptothecine production in attenuated endophytic fungus on re-inoculation into host plant and treatment with DNA methyltransferase inhibitor.

    PubMed

    Vasanthakumari, M M; Jadhav, S S; Sachin, Naik; Vinod, G; Shweta, Singh; Manjunatha, B L; Kumara, P Mohana; Ravikanth, G; Nataraja, Karaba N; Uma Shaanker, R

    2015-10-01

    Fungal endophytes inhabit living tissues of plants without any apparent symptoms and in many cases are known to produce secondary metabolites similar to those produced by their respective host plants. However on sub-culture, the endophytic fungi gradually attenuate their ability to produce the metabolites. Attenuation has been a major constraint in realizing the potential of endophytic fungi as an alternative source of plant secondary metabolites. In this study, we report attempts to restore camptothecine (CPT) production in attenuated endophytic fungi isolated from CPT producing plants, Nothapodytes nimmoniana and Miquelia dentata when they are passed through their host plant or plants that produce CPT and when treated with a DNA methyl transferase inhibitor. Attenuated endophytic fungi that traversed through their host tissue or plants capable of synthesizing CPT, produced significantly higher CPT compared to the attenuated fungi. Attenuated fungus cultured in the presence of 5-azacytidine, a DNA methyltransferase inhibitor, had an enhanced CPT content compared to untreated attenuated fungus. These results indicate that the attenuation of CPT production in endophytic fungi could in principle be reversed by eliciting some signals from plant tissue, most likely that which prevents the methylation or silencing of the genes responsible for CPT biosynthesis.

  11. Alkaloids Isolated from Natural Herbs as the Anticancer Agents

    PubMed Central

    Lu, Jin-Jian; Bao, Jiao-Lin; Chen, Xiu-Ping; Huang, Min; Wang, Yi-Tao

    2012-01-01

    Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation and antimetastasis effects on various types of cancers both in vitro and in vivo. Alkaloids, such as camptothecin and vinblastine, have already been successfully developed into anticancer drugs. This paper focuses on the naturally derived alkaloids with prospective anticancer properties, such as berberine, evodiamine, matrine, piperine, sanguinarine, and tetrandrine, and summarizes the mechanisms of action of these compounds. Based on the information in the literature that is summarized in this paper, the use of alkaloids as anticancer agents is very promising, but more research and clinical trials are necessary before final recommendations on specific alkaloids can be made. PMID:22988474

  12. In situ DOX-calcium phosphate mineralized CPT-amphiphilic gelatin nanoparticle for intracellular controlled sequential release of multiple drugs.

    PubMed

    Li, Wei-Ming; Su, Chia-Wei; Chen, Yu-Wei; Chen, San-Yuan

    2015-03-01

    A co-delivery strategy has been developed to achieve the synergistic effect of a hydrophobic drug (camptothecin, CPT) and a hydrophilic drug (doxorubicin, DOX) by utilizing the unique structure of amphiphilic gelatin/camptothecin @calcium phosphate-doxorubicin (AG/CPT@CaP-DOX) nanoparticles as a carriers in order to replace double emulsions while preserving the advantages of inorganic materials. The hydrophobic agent (CPT) was encapsulated via emulsion with an amphiphilic gelatin core, and subsequently mineralized by CaP-hydrophilic drug (DOX) through precipitation to form a CaP shell on the CPT-AG amphiphilic gelatin core so that drug molecules with different characteristics (i.e. hydrophobic and hydrophilic) can be encapsulated in different regions to avoid their interaction. The existence of the CaP shell can protect the DOX against free release and cause an increased transfer of DOX across membranes, overcoming multidrug resistance. Release studies from core-shell carriers showed the possibility of achieving sequential release of more than one type of drug by controlling the pH-sensitive CaP shell and degradable AG core. The highly pH-responsive behavior of the carrier can modulate the dual-drug-release of DOX/CPT, specifically in acidic intracellular pH environments. The AG/CPT@CaP-DOX nanoparticles also exhibited higher drug efficiencies against MCF-7/ADR cells than MCF-7 cells, thanks to a synergistic cell cycle arrest/apoptosis-inducing effect between CPT and DOX. As such, this core-shell system can serve as a general platform for the localized, controlled, sequential delivery of multiple drugs to treat several diseases, especially for multidrug-resistant cancer cells.

  13. Topoisomerase I inhibitor, camptothecin, induces apoptogenic signaling in human embryonic stem cells.

    PubMed

    García, Carolina Paola; Videla Richardson, Guillermo Agustín; Romorini, Leonardo; Miriuka, Santiago Gabriel; Sevlever, Gustavo Emilio; Scassa, María Elida

    2014-03-01

    Embryonic stem cells (ESCs) need to maintain their genomic integrity in response to DNA damage to safeguard the integrity of the organism. DNA double strand breaks (DSBs) are one of the most lethal forms of DNA damage and, if not repaired correctly, they can lead to cell death, genomic instability and cancer. How human ESCs (hESCs) maintain genomic integrity in response to agents that cause DSBs is relatively unclear. In the present study we aim to determine the hESC response to the DSB inducing agent camptothecin (CPT). We find that hESCs are hypersensitive to CPT, as evidenced by high levels of apoptosis. CPT treatment leads to DNA-damage sensor kinase (ATM and DNA-PKcs) phosphorylation on serine 1981 and serine 2056, respectively. Activation of ATM and DNA-PKcs was followed by histone H2AX phosphorylation on Ser 139, a sensitive reporter of DNA damage. Nuclear accumulation and ATM-dependent phosphorylation of p53 on serine 15 were also observed. Remarkably, hESC viability was further decreased when ATM or DNA-PKcs kinase activity was impaired by the use of specific inhibitors. The hypersensitivity to CPT treatment was markedly reduced by blocking p53 translocation to mitochondria with pifithrin-μ. Importantly, programmed cell death was achieved in the absence of the cyclin dependent kinase inhibitor, p21(Waf1), a bona fide p53 target gene. Conversely, differentiated hESCs were no longer highly sensitive to CPT. This attenuated apoptotic response was accompanied by changes in cell cycle profile and by the presence of p21(Waf1). The results presented here suggest that p53 has a key involvement in preventing the propagation of damaged hESCs when genome is threatened. As a whole, our findings support the concept that the phenomenon of apoptosis is a prominent player in normal embryonic development.

  14. Hypersensitivity of Cockayne's syndrome cells to camptothecin is associated with the generation of abnormally high levels of double strand breaks in nascent DNA.

    PubMed

    Squires, S; Ryan, A J; Strutt, H L; Johnson, R T

    1993-05-01

    We report that fibroblasts from individuals with Cockayne's Syndrome (CS), an autosomal recessive disease exhibiting hypersensitivity to UV, are also hypersensitive to the killing action of camptothecin (CPT). In normal and CS cell lines the level of the protein-linked single strand DNA breaks (SSBs) induced by equal doses of CPT is similar, and these DNA breaks disappear within minutes of the removal of CPT. Thus, the toxicity of CPT does not correlate with the primary DNA lesions induced by the drug, and the hypersensitivity of CS cells cannot be explained by excessive topoisomerase I activity or by a defect in the enzyme ligation step. We have reported that CPT toxicity in normal cells is closely associated with the generation of double-strand DNA breaks (DSBs), predominantly at sites of DNA replication. The hypersensitivity of CS cells to CPT correlates closely with the much higher level of DSBs in nascent DNA than in normal cells. These DSBs are long-lived in all cells, but in CS many more (about 10-fold) remain 24 h after CPT removal and are presumably responsible for the higher frequency of chromosome aberrations in these cells. In CS as in normal cells aphidicolin prevents the generation of replication-related DSBs, suggesting that the movement of the DNA polymerase is necessary for the induction by CPT of the cytotoxic DSBs. Resistance to CPT and UV is restored to wild type in proliferating hybrids constructed between CS lines from two different complementation groups as is the abundance of replication-related DSBs. On the basis of this complementation we conclude that the UV and CPT sensitivities are distinct phenotypic traits arising from mutations in the CS A and B genes. PMID:7683249

  15. Camptothecin Enhances Cell Death Induced by (177)Lu-EDTMP in Osteosarcoma Cells.

    PubMed

    Kumar, Chandan; Vats, Kusum; Lohar, Sharad P; Korde, Aruna; Samuel, Grace

    2014-10-01

    Lutetium-177 is an assured therapeutic radionuclide with favorable half-life and suitable β(-) energy. Radiolabeled (177)Lu-EDTMP (Ethylenediamine tetramethylene phosphonic acid) is by and large used for bone pain palliation in cancer patients. In vitro cell studies are carried out in osteosarcoma cells MG-63 to evaluate the combined effect of anticancer drug camptothecin (CPT) and (177)Lu-EDTMP. Two concentrations of (177)Lu-EDTMP (3.7 and 37 MBq) were incubated with MG63 cell line for 48 hours with and without pretreatment of CPT (10 nM) for 1 hour. After completion of incubation, the cells were harvested and cellular toxicity was estimated by LDH, MTT, and trypan blue dye. Apoptotic DNA fragmentation was estimated by ELISA kit. The expression of proteins such as bcl2, PARP, and MAPK (mitogen-activated protein kinase) that were related to apoptotic signaling pathways was assessed by western blotting. The results indicated that cellular toxicity and apoptosis were relatively higher in MG63 cells that were treated with CPT prior to treating with (177)Lu-EDTMP in comparison with the corresponding individual controls.

  16. Camptothecin inhibits platelet-derived growth factor-BB-induced proliferation of rat aortic vascular smooth muscle cells through inhibition of PI3K/Akt signaling pathway

    SciTech Connect

    Park, Eun-Seok; Kang, Shin-il; Yoo, Kyu-dong; Lee, Mi-Yea; Yoo, Hwan-Soo; Hong, Jin-Tae; Shin, Hwa-Sup; Kim, Bokyung; Yun, Yeo-Pyo

    2013-04-15

    The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial wall is a major cause of vascular disorders such as atherosclerosis and restenosis after angioplasty. In this study, we investigated not only the inhibitory effects of camptothecin (CPT) on PDGF-BB-induced VSMC proliferation, but also its molecular mechanism of this inhibition. CPT significantly inhibited proliferation with IC50 value of 0.58 μM and the DNA synthesis of PDGF-BB-stimulated VSMCs in a dose-dependent manner (0.5–2 μM ) without any cytotoxicity. CPT induced the cell cycle arrest at G0/G1 phase. Also, CPT decreased the expressions of G0/G1-specific regulatory proteins including cyclin-dependent kinase (CDK)2, cyclin D1 and PCNA in PDGF-BB-stimulated VSMCs. Pre-incubation of VSMCs with CPT significantly inhibited PDGF-BB-induced Akt activation, whereas CPT did not affect PDGF-receptor beta phosphorylation, extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and phospholipase C (PLC)-γ1 phosphorylation in PDGF-BB signaling pathway. Our data showed that CPT pre-treatment inhibited VSMC proliferation, and that the inhibitory effect of CPT was enhanced by LY294002, a PI3K inhibitor, on PDGF-BB-induced VSMC proliferation. In addition, inhibiting the PI3K/Akt pathway by LY294002 significantly enhanced the suppression of PCNA expression and Akt activation by CPT. These results suggest that the anti-proliferative activity of CPT is mediated in part by downregulating the PI3K/Akt signaling pathway. - Highlights: ► CPT inhibits proliferation of PDGF-BB-induced VSMC without cytotoxicity. ► CPT arrests the cell cycle in G0/G1 phase by downregulation of cyclin D1 and CDK2. ► CPT significantly attenuates Akt phosphorylation in PDGF-BB signaling pathway. ► LY294002 enhanced the inhibitory effect of CPT on VSMC proliferation. ► Thus, CPT is mediated by downregulating the PI3K/Akt signaling pathway.

  17. Design and synthesis of novel PEG-conjugated 20(S)-camptothecin sulfonylamidine derivatives with potent in vitro antitumor activity via Cu-catalyzed three-component reaction.

    PubMed

    Song, Zi-Long; Chen, Hai-Le; Wang, Yu-Han; Goto, Masuo; Gao, Wen-Jing; Cheng, Pi-Le; Morris-Natschke, Susan L; Liu, Ying-Qian; Zhu, Gao-Xiang; Wang, Mei-Juan; Lee, Kuo-Hsiung

    2015-07-01

    In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel structurally diverse PEG-based 20(S)-CPT sulfonylamidine derivatives were designed, synthesized via a Cu-multicomponent reaction (MCR), and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Significantly, these derivatives exhibited comparable cytotoxicity against KBvin, while irinotecan was less active against this cell line. With a concise efficient synthesis and potent cytotoxic profiles, especially significant activity towards KBvin, these compounds merit further development as a new generation of CPT-derived PEG-conjugated drug candidates.

  18. Fluorescence detection of the anticancer drug topotecan and related camptothecins in plasma and whole blood by two-photon excitation

    NASA Astrophysics Data System (ADS)

    Burke, Thomas G.; Malak, Henryk M.; Gryczynski, Ignacy; Lakowicz, Joseph R.

    1997-05-01

    Recent FDA-approval of topotecan (9-dimethylaminomethyl-10- hydroxycamptothecin) and camptosar (CPT-11) along with the accelerated clinical development of related camptothecin drugs provides new hope for the successful treatment of human cancer, including neoplasms for which no effective treatments currently exist. Current clinical efforts worldwide are aimed at optimizing the therapeutic efficacies of the camptothecins, with the major focus on the determination of the most effective dosing schedules. To this end, technological advances which provide a direct and rapid means of measuring plasma drug levels (i.e. such that correlations between plasma drug levels and clinical responses can be sought) would be of great utility. Here we report on the direct fluorescence detection of topotecan and SN-38 in human plasma and topotecan in whole blood at micro molar levels using two-photon excitation at 730 or 820 nm. Topotecan was detected at concentrations as low as 0.05 and 1 (mu) M in plasma and whole blood, respectively. Since skin, blood and other tissues are translucent at long wavelengths, our results suggest the attractive possibility of homogeneous or noninvasive clinical sensing of camptothecins in situ using two-photon excitation.

  19. DNA structural alterations induced by bis-netropsins modulate human DNA topoisomerase I cleavage activity and poisoning by camptothecin.

    PubMed

    Sukhanova, Alyona; Grokhovsky, Sergei; Ermishov, Michael; Mochalov, Konstantin; Zhuze, Alexei; Oleinikov, Vladimir; Nabiev, Igor

    2002-07-01

    Bis-netropsins (bis-Nts) are efficient catalytic inhibitors of human DNA topoisomerase I (top I). These DNA minor groove binders are considered to serve as suppressors of top I-linked DNA breaks, which is generally believed to be related to their affinity to DNA. In this study, it was found that bis-Nts exhibit sequence-specificity of suppression of the strong top I-specific DNA cleavage sites and that this sequence-specificity is determined by differential ligand-induced structural alterations of DNA. Raman scattering analysis of bis-Nts interactions with double-stranded oligonucleotides, each containing the site of specific affinity to one of bis-Nts and a distinctly located top I degenerate consensus, demonstrated that bis-Nts induce not only structural changes in duplex DNA at their loading position, but also conformational changes in a distant top I-specific DNA cleavage site. The ability to alter the DNA structure correlates with the anti-top I inhibitory activities of the ligands. In addition, DNA structural alterations induced by bis-Nts were shown to be responsible for modulation of the camptothecin (CPT)-mediated DNA cleavage by top I. This effect is expressed in the bis-Nts-induced enhancement of some of the CPT-dependent DNA cleavage sites as well as in the CPT-induced enhancement of some of the top I-specific DNA cleavage sites suppressed by bis-Nts in the absence of CPT. PMID:12106608

  20. Nitric Oxide Down-Regulates Topoisomerase I and Induces Camptothecin Resistance in Human Breast MCF-7 Tumor Cells

    PubMed Central

    Kumari, Amrita; Tokar, Erik J.; Waalkes, Michael P.; Bortner, Carl D.; Williams, Jason; Ehrenshaft, Marilyn; Mason, Ronald P.; Sinha, Birandra K.

    2015-01-01

    Camptothecin (CPT), a topoisomerase I poison, is an important drug for the treatment of solid tumors in the clinic. Nitric oxide (·NO), a physiological signaling molecule, is involved in many cellular functions, including cell proliferation, survival and death. We have previously shown that ·NO plays a significant role in the detoxification of etoposide (VP-16), a topoisomerase II poison in vitro and in human melanoma cells. ·NO/·NO-derived species are reported to modulate activity of several important cellular proteins. As topoisomerases contain a number of free sulfhydryl groups which may be targets of ·NO/·NO-derived species, we have investigated the roles of ·NO/·NO-derived species in the stability and activity of topo I. Here we show that ·NO/·NO-derived species induces a significant down-regulation of topoisomerase I protein via the ubiquitin/26S proteasome pathway in human colon (HT-29) and breast (MCF-7) cancer cell lines. Importantly, ·NO treatment induced a significant resistance to CPT only in MCF-7 cells. This resistance to CPT did not result from loss of topoisomerase I activity as there were no differences in topoisomerase I-induced DNA cleavage in vitro or in tumor cells, but resulted from the stabilization/induction of bcl2 protein. This up-regulation of bcl2 protein in MCF-7 cells was wtp53 dependent as pifithrine-α, a small molecule inhibitor of wtp53 function, completely reversed CPT resistance, suggesting that wtp53 and bcl2 proteins played important roles in CPT resistance. Because tumors in vivo are heterogeneous and contaminated by infiltrating macrophages, ·NO-induced down-regulation of topoisomerase I protein combined with bcl2 protein stabilization could render certain tumors highly resistant to CPT and drugs derived from it in the clinic. PMID:26540186

  1. Worldline CPT and massless supermultiplets

    NASA Astrophysics Data System (ADS)

    Arvanitakis, Alex S.; Mezincescu, Luca; Townsend, Paul K.

    2016-09-01

    The action for a massless particle in 4D Minkowski space-time has a worldline-time reversing symmetry corresponding to CPT invariance of the quantum theory. The analogous symmetry of the 𝒩-extended superparticle is shown to be anomalous when 𝒩 is odd; in the supertwistor formalism this is because a CPT-violating worldline-Chern-Simons term is needed to preserve the chiral U(1) gauge invariance. This accords with the fact that no massless 𝒩 = 1 super-Poincaré irrep is CPT-self-conjugate. There is a CPT self-conjugate supermultiplet when 𝒩 is even, but it has 2𝒩+1 states when 1 2𝒩 is odd (e.g. the 𝒩 = 2 hypermultiplet) in contrast to just 2𝒩 when 1 2𝒩 is even (e.g. the 𝒩 = 4 Maxwell supermultiplet). This is shown to follow from a Kramers degeneracy of the superparticle state space when 1 2𝒩 is odd.

  2. CPT Word Processing Instructional Materials.

    ERIC Educational Resources Information Center

    Slaymaker, Josephine; Eakman, Donna

    A project to develop a student word processing manual was developed by using input from: (1) information specialists, employees, and educators; and (2) students using the manual. These instructional materials provide workbook assignments and reading for an individualized unit on CPT word processing to be used by 30 to 40 high school students per…

  3. CPT violation implies violation of Lorentz invariance.

    PubMed

    Greenberg, O W

    2002-12-01

    A interacting theory that violates CPT invariance necessarily violates Lorentz invariance. On the other hand, CPT invariance is not sufficient for out-of-cone Lorentz invariance. Theories that violate CPT by having different particle and antiparticle masses must be nonlocal. PMID:12484997

  4. CPT violation and B-meson oscillations

    SciTech Connect

    Kostelecky, V. Alan; Van Kooten, Richard J.

    2010-11-15

    Recent evidence for anomalous CP violation in B-meson oscillations can be interpreted as resulting from CPT violation. This yields the first sensitivity to CPT violation in the B{sub s}{sup 0} system, with the relevant coefficient for CPT violation constrained at the level of parts in 10{sup 12}.

  5. CPT violation implies violation of Lorentz invariance.

    PubMed

    Greenberg, O W

    2002-12-01

    A interacting theory that violates CPT invariance necessarily violates Lorentz invariance. On the other hand, CPT invariance is not sufficient for out-of-cone Lorentz invariance. Theories that violate CPT by having different particle and antiparticle masses must be nonlocal.

  6. Isoeugenol is a selective potentiator of camptothecin cytotoxicity in vertebrate cells lacking TDP1

    PubMed Central

    Elsayed, Waheba; El-Shafie, Lamia; Hassan, Mohamed K.; Farag, Mohamed A.; El-Khamisy, Sherif F.

    2016-01-01

    Camptothecin (CPT), a topoisomerase I (TOP1) inhibitor, exhibits anti-tumor activity against a wide range of tumors. Redundancy of TOP1-mediated repair mechanisms is a major challenge facing the efficiency of TOP1-targetting therapies. This study aims to uncover new TOP1 targeting approaches utilising a selection of natural compounds in the presence or absence of tyrosyl DNA phosphodiesterase I (TDP1); a key TOP1-mediated protein-linked DNA break (PDB) repair enzyme. We identify, isoeugenol, a phenolic ether found in plant essential oils, as a potentiator of CPT cytotoxicity in Tdp1 deficient but not proficient cells. Consistent with our cellular data, isoeugenol did not inhibit Tdp1 enzymatic activity in vitro nor it sensitized cells to the PARP1 inhibitor olaparib. However, biochemical analyses suggest that isoeugenol inhibits TDP2 catalytic activity; a pathway that can compensate for the absence of TDP1. Consistent with this, isoeugenol exacerbated etoposide-induced cytotoxicity, which generates TOP2-mediated PDBs for which TDP2 is required for processing. Together, these findings identify isoeugenol as a potential lead compound for developing TDP2 inhibitors and encourage structure-activity relationship studies to shed more light on its utility in drug discovery programs. PMID:27220325

  7. N+CPT clock resonance

    SciTech Connect

    Crescimanno, M.; Hohensee, M.

    2008-12-15

    In a typical compact atomic time standard a current modulated semiconductor laser is used to create the optical fields that interrogate the atomic hyperfine transition. A pair of optical sidebands created by modulating the diode laser become the coherent population trapping (CPT) fields. At the same time, other pairs of optical sidebands may contribute to other multiphoton resonances, such as three-photon N-resonance [Phys. Rev. A 65, 043817 (2002)]. We analyze the resulting joint CPT and N-resonance (hereafter N+CPT) analytically and numerically. Analytically we solve a four-level quantum optics model for this joint resonance and perturbatively include the leading ac Stark effects from the five largest optical fields in the laser's modulation comb. Numerically we use a truncated Floquet solving routine that first symbolically develops the optical Bloch equations to a prescribed order of perturbation theory before evaluating. This numerical approach has, as input, the complete physical details of the first two excited-state manifolds of {sup 87}Rb. We test these theoretical approaches with experiments by characterizing the optimal clock operating regimes.

  8. A Series of α-Amino Acid Ester Prodrugs of Camptothecin: In vitro Hydrolysis and A549 Human Lung Carcinoma Cell Cytotoxicity

    PubMed Central

    Deshmukh, Manjeet; Chao, Piyun; Kutscher, Hilliard L.; Gao, Dayuan; Sinko, Patrick J.

    2013-01-01

    The objective of the present study was to identify a camptothecin (CPT) prodrug with optimal release and cytotoxicity properties for immobilization on a passively targeted microparticle delivery system. A series of α-amino acid ester prodrugs of CPT were synthesized, characterized and evaluated. Four CPT prodrugs were synthesized with increasing aliphatic chain length (glycine (Gly) (2a), alanine (Ala) (2b), aminobutyric acid (Abu) (2c) and norvaline (Nva) (2d)). Prodrug reconversion was studied at pH 6.6, 7.0 and 7.4 corresponding to tumor, lung and extracellular/physiological pH, respectively. Cytotoxicity was evaluated in A549 human lung carcinoma cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The hydrolytic reconversion rate to parent CPT increased with decreasing side chain length as well as increasing pH. The Hill slope of 2d was significantly less than CPT and the other prodrugs tested, indicating a higher cell death rate at lower concentrations. These results suggest that 2d is the best candidate for a passively targeted sustained release lung delivery system. PMID:20063889

  9. Complete regression of xenografted human carcinomas by camptothecin analogue-carboxymethyl dextran conjugate (T-0128).

    PubMed

    Okuno, S; Harada, M; Yano, T; Yano, S; Kiuchi, S; Tsuda, N; Sakamura, Y; Imai, J; Kawaguchi, T; Tsujihara, K

    2000-06-01

    Clinically available camptothecins (CPTs), such as irinotecan (CPT-11) and topotecan, represent one of the most promising classes of antitumor agents, despite their toxicity. To improve their pharmacological profiles, a new macromolecular prodrug, denoted T-0128, was synthesized. This prodrug is a novel CPT analogue (T-2513)-carboxymethyl (CM) dextran conjugate via a triglycine spacer, with a molecular weight of Mr 130,000. This study was designed to test the concept that the rational design of a CPT-polymer conjugate would increase the efficacy of the parent drug. The in vivo antitumor study against Walker-256 carcinoma demonstrated that T-0128 was 10 times as active as T-2513, supporting this concept. Additionally, comparative efficacy studies of T-0128, T-2513, CPT-11, and topotecan were performed using a panel of human tumor xenografts in nude mice, showing the advantage of T-0128 over these CPTs. The maximal tolerated doses (MTDs) of T-0128, T-2513, and CPT-11 were comparable. Even a single i.v. injection of T-0128 at 6 mg/kg (based on the amount of T-2513 bound to CM dextran) induced complete regression of MX-1 mammary carcinoma. T-0128 at 10 mg/kg weekly for 3 weeks (one-tenth of its MTD) cured LX-1 lung carcinoma. Also, T-0128 below its MTD consistently cured or regressed St-4 gastric and HT-29 colorectal tumor xenografts that are highly refractory to CPTs. These demonstrate the broad range of therapeutic doses achieved with T-0128. Pharmacokinetic studies were performed to correlate the efficacy results obtained for T-0128 with plasma and tissue drug concentrations using Walker-256 tumor-bearing rats. Results showed that after i.v. administration of T-0128, the conjugate continued to circulate at a high concentration for an extended period, resulting in tumor accumulation. In the tumor, the sustained release of T-2513 occurred. In contrast, T-2513 disappeared rapidly from the body. The significant increases in the amount and exposure time of released T

  10. Near-Infrared Light Triggered ROS-activated Theranostic Platform based on Ce6-CPT-UCNPs for Simultaneous Fluorescence Imaging and Chemo-Photodynamic Combined Therapy.

    PubMed

    Yue, Caixia; Zhang, Chunlei; Alfranca, Gabriel; Yang, Yao; Jiang, Xinquan; Yang, Yuming; Pan, Fei; de la Fuente, Jesús M; Cui, Daxiang

    2016-01-01

    Many drug controlled release methods have been integrated in multifunctional nanoparticles, such as pH-, redox-, temperature-, enzyme-, and light-responsive release. However, few report is associated with the ROS responsive drug controlled release. Herein, a thioketal linker-based ROS responsive drug (camptothecin conjugated with thioketal linker, abbreviated as TL-CPT) was prepared and the thioketal linker could be cleaved by ROS(reactive oxygen species). To achieve cancer simultaneous optical imaging, photodynamic therapy and chemotherapy, the photosensitizer Chlorin e6(Ce6), TL-CPT and carboxyl-mPEG were loaded on the upconversion nanoparticles (UCNPs), which were named as Ce6-CPT-UCNPs. Under 980 nm laser irradiation, Ce6-CPT-UCNPs emitted a narrow emission band at 645-675 nm which was overlapped with Ce6 absorption peak. Ce6 absorbed the light to produce ROS, which was used for photodynamic therapy and to cleave the thioketal linker in Ce6-CPT-UCNPs to release camptothecin for chemotherapy. Meanwhile, Ce6 absorbed the light, was used for near-infrared fluorescence imaging. The in vivo biodistribution studies showed that the prepared nanoparticles had high orthotopic lung cancer targeting efficiency. The in vivo therapeutic results demonstrated that NCI-H460 lung cancers could be completely eliminated by combining chemo- and photodynamic therapy under 980 nm laser irradiation. The prepared multifunctional Ce6-CPT-UCNPs have great potential in applications such as cancer targeted fluorescent imaging, simultaneous ROS activated chemo- and photodynamic therapy in near future.

  11. Near-Infrared Light Triggered ROS-activated Theranostic Platform based on Ce6-CPT-UCNPs for Simultaneous Fluorescence Imaging and Chemo-Photodynamic Combined Therapy

    PubMed Central

    Yue, Caixia; Zhang, Chunlei; Alfranca, Gabriel; Yang, Yao; Jiang, Xinquan; Yang, Yuming; Pan, Fei; de la Fuente, Jesús M.; Cui, Daxiang

    2016-01-01

    Many drug controlled release methods have been integrated in multifunctional nanoparticles, such as pH-, redox-, temperature-, enzyme-, and light-responsive release. However, few report is associated with the ROS responsive drug controlled release. Herein, a thioketal linker-based ROS responsive drug (camptothecin conjugated with thioketal linker, abbreviated as TL-CPT) was prepared and the thioketal linker could be cleaved by ROS(reactive oxygen species). To achieve cancer simultaneous optical imaging, photodynamic therapy and chemotherapy, the photosensitizer Chlorin e6(Ce6), TL-CPT and carboxyl-mPEG were loaded on the upconversion nanoparticles (UCNPs), which were named as Ce6-CPT-UCNPs. Under 980 nm laser irradiation, Ce6-CPT-UCNPs emitted a narrow emission band at 645-675 nm which was overlapped with Ce6 absorption peak. Ce6 absorbed the light to produce ROS, which was used for photodynamic therapy and to cleave the thioketal linker in Ce6-CPT-UCNPs to release camptothecin for chemotherapy. Meanwhile, Ce6 absorbed the light, was used for near-infrared fluorescence imaging. The in vivo biodistribution studies showed that the prepared nanoparticles had high orthotopic lung cancer targeting efficiency. The in vivo therapeutic results demonstrated that NCI-H460 lung cancers could be completely eliminated by combining chemo- and photodynamic therapy under 980 nm laser irradiation. The prepared multifunctional Ce6-CPT-UCNPs have great potential in applications such as cancer targeted fluorescent imaging, simultaneous ROS activated chemo- and photodynamic therapy in near future. PMID:26941840

  12. Synthesis and Self-Assembly of a Mikto-Arm Star Dual Drug Amphiphile Containing both Paclitaxel and Camptothecin

    PubMed Central

    Cheetham, A.G.; Zhang, P.; Lin, Y.-A.; Lin, R.; Cui, H.

    2014-01-01

    Self-assembly of anticancer therapeutics into discrete nanostructures provides an innovative way to develop a self-delivering nanomedicine with a high, quantitative drug loading. We report here the synthesis and assembly of a mikto-arm star dual drug amphiphile (DA) containing both a bulky paclitaxel (PTX) and a planar camptothecin (CPT). The two anti-cancer drugs of interest were stochastically conjugated to a β-sheet forming peptide (Sup35) and under physiologically-relevant conditions the dual DA could spontaneously associate into supramolecular filaments with a fixed 41% total drug loading (29% PTX and 12% CPT). Transmission electron microscopy imaging and circular dichroism spectroscopy studies reveal that the bulkiness of the PTX, as well as the π-π interaction preference between the CPT units, has a significant impact on the assembly kinetics, molecular level packing, and nanostructure morphology and stability. We found that the DA containing two PTX units assembled into non-filamentous micelle-like structures, in contrast to the filamentous structures formed by the hetero dual DA and the DA containing two CPTs. The hetero dual DA was found to effectively release the two anticancer agents, exhibiting superior cytotoxicity against PTX-resistant cervical cancer cells. The presented work offers a potential method to generate well-defined entwined filamentous nanostructures and provides the basis for a future combination therapy platform. PMID:25667746

  13. Decreased cyclin B1 expression contributes to G2 delay in human brain tumor cells after treatment with camptothecin.

    PubMed Central

    Janss, A. J.; Maity, A.; Tang, C. B.; Muschel, R. J.; McKenna, W. G.; Sutton, L.; Phillips, P. C.

    2001-01-01

    DNA damage produces delayed mitosis (G2/M delay) in proliferating cells, and shortening the delay sensitizes human malignant glioma and medulloblastoma cells to cytotoxic chemotherapy. Although activation of the cyclin-dependent kinase CDC2 mediates G2/M transition in all tumor cells studied to date, regulation of CDC2 varies between tumor types. Persistent hyperphosphorylation of kinase and reduced cyclin expression have been implicated as mediators of treatment-induced G2 delay in different tumor models. To evaluate regulation of G2/M transition in human brain tumors, we studied the expression and/or activity of CDC2 kinase and cyclins A and B1 in U-251 MG and DAOY medulloblastoma cells after their treatment with camptothecin (CPT). Synchronized cells were treated during S phase, then harvested at predetermined intervals for evaluation of cell cycle kinetics, kinase activity mRNA, and protein expression. CPT produced G2 delay associated with decreased CDC2 kinase activity and cyclin B1 expression. Kinase activity was associated with CDC2 bound to cyclin B1, not cyclin A, in both cell lines. Cyclin A mRNA and protein expression were reduced after CPT treatment; however, decreased protein expression was short lived and moderate in the glioma and primitive neuroectodermal tumor/medulloblastoma cells, respectively. We conclude that G2 delay is a common response of brain tumor cells to chemotherapy with topoisomerase I inhibitors and that a mechanism of this delay may be reduced expression of cyclin B1. PMID:11305412

  14. Neutrino experiments: Hierarchy, CP, CPT

    NASA Astrophysics Data System (ADS)

    Gupta, Manmohan; Randhawa, Monika; Singh, Mandip

    2016-07-01

    We present an overview of our recent investigations regarding the prospects of ongoing neutrino experiments as well as future experiments in determining few of the most important unknowns in the field of neutrino physics, specifically the neutrino mass ordering and leptonic CP-violation phase. The effect of matter oscillations on the neutrino oscillation probabilities has been exploited in resolving the degeneracy between the neutrino mass ordering and the CP violation phase in the leptonic sector. Further, we estimate the extent of extrinsic CP and CPT violation in the experiments with superbeams as well as neutrino factories.

  15. CPT-Odd resonances in neutrino oscillations

    PubMed

    Barger; Pakvasa; Weiler; Whisnant

    2000-12-11

    We consider the consequences for future neutrino factory experiments of small CPT-odd interactions in neutrino oscillations. The nu(&mgr;)-->nu(&mgr;) and nu;(&mgr;)-->nu;(&mgr;) survival probabilities at a baseline L = 732 km can test for CPT-odd contributions at orders of magnitude better sensitivity than present neutrino sector limits. Interference between the CPT-violating interaction and CPT-even mass terms in the Lagrangian can lead to a resonant enhancement of the oscillation amplitude. For oscillations in matter, a simultaneous enhancement of both neutrino and antineutrino oscillation amplitudes is possible.

  16. Effects of antidepressants on DSP4/CPT-induced DNA damage response in neuroblastoma SH-SY5Y cells

    PubMed Central

    Wang, Yan; Hilton, Benjamin A.; Cui, Kui; Zhu, Meng-Yang

    2015-01-01

    DNA damage is a form of cell stress and injury. Increased systemic DNA damage is related to the pathogenic development of neurodegenerative diseases. Depression occurs in a relatively high percentage of patients suffering from degenerative diseases, for whom antidepressants are often used to relieve depressive symptoms. However, few studies have attempted to elucidate why different groups of antidepressants have similar effects on relieving symptoms of depression. Previously, we demonstrated that neurotoxins N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)- and camptothecin (CPT)-induced the DNA damage response in SH-SY5Y cells, and DSP4 caused cell cycle arrest which was predominately in the S-phase. The present study shows that CPT treatment also resulted in similar cell cycle arrest. Some classic antidepressants could reduce the DNA damage response induced by DSP4 or CPT in SH-SY5Y cells. Cell viability examination demonstrated that both DSP4 and CPT caused cell death, which was prevented by spontaneous administration of some tested antidepressants. Flow cytometric analysis demonstrated that a majority of the tested antidepressants protect cells from being arrested in S-phase. These results suggest that blocking the DNA damage response may be an important pharmacologic characteristic of antidepressants. Exploring the underlying mechanisms may allow for advances in the effort to improve therapeutic strategies for depression appearing in degenerative and psychiatric diseases. PMID:26038195

  17. Probing CPT violation in B systems

    SciTech Connect

    Kundu, Anirban; Patra, Sunando Kumar; Nandi, Soumitra

    2010-04-01

    We discuss how a possible violation of the combined symmetry CPT in the B meson system can be investigated at the LHC. We show how a tagged and an untagged analysis of the decay modes of both B{sub d} and B{sub s} mesons can lead not only to a possible detection of a CPT-violating new physics but also to an understanding of its precise nature. The implication of CPT violation to a large mixing phase in the B{sub s} system is also discussed.

  18. Testing CPT Invariance with Antiprotonic Helium Atoms

    SciTech Connect

    Horvath, Dezso

    2008-08-08

    The structure of matter is related to symmetries at every level of study. CPT symmetry is one of the most important laws of field theory: it states the invariance of physical properties when one simultaneously changes the signs of the charge and of the spatial and time coordinates of free elementary particles. Although in general opinion CPT symmetry is not violated in Nature, there are theoretical attempts to develop CPT-violating models. The Antiproton Decelerator at CERN has been built to test CPT invariance. The ASACUSA experiment compares the properties of particles and antiparticles by studying the antiprotonic helium atom via laser spectroscopy and measuring the mass, charge and magnetic moment of the antiproton as compared to those of the proton.

  19. Fabrication and optimization of camptothecin loaded Eudragit S 100 nanoparticles by Taguchi L4 orthogonal array design

    PubMed Central

    Mahalingam, Manikandan; Krishnamoorthy, Kannan

    2015-01-01

    Introduction: The objective of this investigation was to design and optimize the experimental conditions for the fabrication of camptothecin (CPT) loaded Eudragit S 100. Nanoparticles, and to understand the effect of various process parameters on the average particles size, particle size uniformity and surface area of the prepared polymeric nanoparticles using Taguchi design. Materials and Methods: CPT loaded Eudragit S 100 nanoparticles were prepared by nanoprecipitation method and characterized by particles size analyzer. Taguchi orthogonal array design was implemented to study the influence of seven independent variables on three dependent variables. Eight experimental trials involving seven independent variables at higher and lower levels were generated by design expert. Results: Factorial design result has shown that (a) except, β-cyclodextrin concentration all other parameters do not significantly influenced the average particle size (R1); (b) except, sonication duration and aqueous phase volume, all other process parameters significantly influence the particle size uniformity; (c) all the process parameters does not significantly influence the surface area. Conclusion: The R1, particle size uniformity and surface area of the prepared drug-loaded polymeric nanoparticles were found to be 120 nm, 0.237 and 55.7 m2 /g and the results were good correlated with the data generated by the Taguchi design method. PMID:26258056

  20. CPT violation and particle-antiparticle asymmetry in cosmology

    SciTech Connect

    Dolgov, A. D.

    2010-04-15

    General features of generation of the cosmological charge asymmetry in CPT noninvariant world are discussed. If the effects of CPT violationmanifest themselves only inmass differences of particles and antiparticles, the baryon asymmetry of the Universe hardly can be explained solely by breaking of CPT invariance. However, CPT noninvariant theories may lead to a new effect of distorting the usual equilibrium distributions. If this takes place, CPT violation may explain the baryon asymmetry of the Universe.

  1. Distinct CPT-induced deaths in lung cancer cells caused by clathrin-mediated internalization of CP micelles

    NASA Astrophysics Data System (ADS)

    Liu, Yu-Sheng; Cheng, Ru-You; Lo, Yu-Lun; Hsu, Chin; Chen, Su-Hwei; Chiu, Chien-Chih; Wang, Li-Fang

    2016-02-01

    We previously synthesized a chondroitin sulfate-graft-poly(ε-caprolactone) copolymer (H-CP) with a high content of poly(ε-caprolactone) (18.7 mol%), which self-assembled in water into a rod-like micelle to encapsulate hydrophobic camptothecin (CPT) in the core (micelle/CPT) for tumor-targeted drug delivery. As a result of the recognition of the micelle by CD44, the micelle/CPT entered CRL-5802 cells efficiently and released CPT efficaciously, resulting in higher tumor suppression than commercial CPT-11. In this study, H1299 cells were found to have a higher CD44 expression than CRL-5802 cells. However, the lower CD44-expressing CRL-5802 cells had a higher percentage of cell death and higher cellular uptake of the micelle/CPT than the higher CD44-expressing H1299 cells. Examination of the internalization pathway of the micelle/CPT in the presence of different endocytic chemical inhibitors showed that the CRL-5802 cells involved clathrin-mediated endocytosis, which was not found in the H1299 cells. Analysis of the cell cycle of the two cell lines exposed to the micelle/CPT revealed that the CRL-5802 cells arrested mainly in the S phase and the H1299 cells arrested mainly in the G2-M phase. A consistent result was also found in the evaluation of γ-H2AX expression, which was about three-fold higher in the CRL-5802 cells than in the H1299 cells. A near-infrared dye, IR780, was encapsulated into the micelle to observe the in vivo biodistribution of the micelle/IR780 in tumor-bearing mice. The CRL-5802 tumor showed a higher fluorescence intensity than the H1299 tumor at any tracing time after 1 h. Thus we tentatively concluded that CRL-5802 cells utilized the clathrin-mediated internalization pathway and arrested in the S phase on exposure to the micelle/CPT; all are possible reasons for the better therapeutic outcome in CRL-5802 cells than in H1299 cells.We previously synthesized a chondroitin sulfate-graft-poly(ε-caprolactone) copolymer (H-CP) with a high content of

  2. Impediments to enhancement of CPT-11 anticancer activity by E. coli directed beta-glucuronidase therapy.

    PubMed

    Hsieh, Yuan-Ting; Chen, Kai-Chuan; Cheng, Chiu-Min; Cheng, Tian-Lu; Tao, Mi-Hua; Roffler, Steve R

    2015-01-01

    CPT-11 is a camptothecin analog used for the clinical treatment of colorectal adenocarcinoma. CPT-11 is converted into the therapeutic anti-cancer agent SN-38 by liver enzymes and can be further metabolized to a non-toxic glucuronide SN-38G, resulting in low SN-38 but high SN-38G concentrations in the circulation. We previously demonstrated that adenoviral expression of membrane-anchored beta-glucuronidase could promote conversion of SN-38G to SN-38 in tumors and increase the anticancer activity of CPT-11. Here, we identified impediments to effective tumor therapy with E. coli that were engineered to constitutively express highly active E. coli beta-glucuronidase intracellularly to enhance the anticancer activity of CPT-11. The engineered bacteria, E. coli (lux/βG), could hydrolyze SN-38G to SN-38, increased the sensitivity of cultured tumor cells to SN-38G by about 100 fold and selectively accumulated in tumors. However, E. coli (lux/βG) did not more effectively increase CPT-11 anticancer activity in human tumor xenografts as compared to non-engineered E. coli. SN-38G conversion to SN-38 by E. coli (lux/βG) appeared to be limited by slow uptake into bacteria as well as by segregation of E. coli in necrotic regions of tumors that may be relatively inaccessible to systemically-administered drug molecules. Studies using a fluorescent glucuronide probe showed that significantly greater glucuronide hydrolysis could be achieved in mice pretreated with E. coli (lux/βG) by direct intratumoral injection of the glucuronide probe or by intratumoral lysis of bacteria to release intracellular beta-glucuronidase. Our study suggests that the distribution of beta-glucuronidase, and possibly other therapeutic proteins, in the tumor microenvironment might be an important barrier for effective bacterial-based tumor therapy. Expression of secreted therapeutic proteins or induction of therapeutic protein release from bacteria might therefore be a promising strategy to enhance anti

  3. Impediments to Enhancement of CPT-11 Anticancer Activity by E. coli Directed Beta-Glucuronidase Therapy

    PubMed Central

    Hsieh, Yuan-Ting; Chen, Kai-Chuan; Cheng, Chiu-Min; Cheng, Tian-Lu; Tao, Mi-Hua; Roffler, Steve R.

    2015-01-01

    CPT-11 is a camptothecin analog used for the clinical treatment of colorectal adenocarcinoma. CPT-11 is converted into the therapeutic anti-cancer agent SN-38 by liver enzymes and can be further metabolized to a non-toxic glucuronide SN-38G, resulting in low SN-38 but high SN-38G concentrations in the circulation. We previously demonstrated that adenoviral expression of membrane-anchored beta-glucuronidase could promote conversion of SN-38G to SN-38 in tumors and increase the anticancer activity of CPT-11. Here, we identified impediments to effective tumor therapy with E. coli that were engineered to constitutively express highly active E. coli beta-glucuronidase intracellularly to enhance the anticancer activity of CPT-11. The engineered bacteria, E. coli (lux/βG), could hydrolyze SN-38G to SN-38, increased the sensitivity of cultured tumor cells to SN-38G by about 100 fold and selectively accumulated in tumors. However, E. coli (lux/βG) did not more effectively increase CPT-11 anticancer activity in human tumor xenografts as compared to non-engineered E. coli. SN-38G conversion to SN-38 by E. coli (lux/βG) appeared to be limited by slow uptake into bacteria as well as by segregation of E. coli in necrotic regions of tumors that may be relatively inaccessible to systemically-administered drug molecules. Studies using a fluorescent glucuronide probe showed that significantly greater glucuronide hydrolysis could be achieved in mice pretreated with E. coli (lux/βG) by direct intratumoral injection of the glucuronide probe or by intratumoral lysis of bacteria to release intracellular beta-glucuronidase. Our study suggests that the distribution of beta-glucuronidase, and possibly other therapeutic proteins, in the tumor microenvironment might be an important barrier for effective bacterial-based tumor therapy. Expression of secreted therapeutic proteins or induction of therapeutic protein release from bacteria might therefore be a promising strategy to enhance anti

  4. 15-Deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} enhanced the anti-tumor activity of camptothecin against renal cell carcinoma independently of topoisomerase-II and PPAR{gamma} pathways

    SciTech Connect

    Yamamoto, Yasuhiro; Fujita, Megumi; Koma, Hiromi; Yamamori, Motohiro; Nakamura, Tsutomu; Okamura, Noboru; Yagami, Tatsurou

    2011-07-08

    Highlights: {yields} A topoisomerase-I inhibitor, camptothecin, exhibited synergistically toxicity with 15d-PGJ{sub 2}. {yields} The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. {yields} A PPAR{gamma} antagonist did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. {yields} The treatment of camptothecin combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. -- Abstract: Renal cell carcinoma (RCC) is chemoresistant cancer. Although several clinical trials were conducted to explore effective medications, the chemoresistance of RCC has not yet been conquered. An endogenous ligand for peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}), 15-deoxy-{Delta}{sup 12,14}-prostaglandin J{sub 2} (15d-PGJ{sub 2}), induces apoptosis in RCC. Here, we examined synergistic effects of several carcinostatics on the anti-tumor activity of 15d-PGJ{sub 2} in Caki-2 cell line by MTT assay. A topoisomerase-I inhibitor, camptothecin (CPT), exhibited synergistically toxicity with 15d-PGJ{sub 2}, but neither 5-fluorouracil nor cisplatin did. The combination of 15d-PGJ{sub 2} and a topoisomerase-II inhibitor, doxorubicine, did not cause synergistic cell growth inhibition. The synergistic effect of topoisomerase-I and II inhibitors was not also detected. A PPAR{gamma} antagonist, GW9662, did not prevent Caki-2 from undergoing 15d-PGJ{sub 2}-induced cytotoxicity. The treatment of CPT combined with 15d-PGJ{sub 2} activated caspase-3 more than the separate treatment. These results suggest that 15d-PGJ{sub 2} exhibited the anti-tumor activity synergistically with CPT independent of topoisomerase-II and PPAR{gamma}.

  5. Controlled release camptothecin tablets based on pluronic and poly(acrylic acid) copolymer. Effect of fabrication technique on drug stability, tablet structure, and release mode.

    PubMed

    Bromberg, Lev; Hatton, T Alan; Barreiro-Iglesias, Rafael; Alvarez-Lorenzo, Carmen; Concheiro, Angel

    2007-06-01

    Poly(ethylene oxide)-b-poly(propylene oxide)-b-(polyethylene oxide)-g-poly(acrylic acid), a graft-comb copolymer of Pluronic 127 and poly(acrylic acid) (Pluronic-PAA), was explored as an excipient for tablet dosage form of camptothecin (CPT). The tablets were prepared by either direct compression of the drug-polymer physical blend, suspension in ethanol followed by evaporation, or compression after kneading and characterized with respect to their physical structures, drug stability, and release behavior. Porosity and water uptake rate were strongly dependent on the fabrication procedure, ranking in the order: direct compression of physical blend > compression after suspension/evaporation in ethanol > compression after kneading. Tablets prepared by compression of physical blends swelled in water with a rapid surface gel layer formation that impeded swelling and disintegration of the tablets core. These tablets were able to sustain the CPT release for a period of time longer than those observed with the tablets made by either suspension/evaporation or kneading, which disintegrated within a few minutes. Despite the tablet disintegration, the CPT release was impeded for at least 6 hr, which was attributed to the ability of the Pluronic-PAA copolymers to form micellar aggregates at the hydrated surface of the particles. Physical mixing did not alter the fraction of CPT being in the pharmaceutically active lactone form, whilst the preparation of the tablets by the other two methods caused a significant reduction in the lactone form content. Tablets prepared from the physical blends demonstrated CPT release rates increasing with the pH due to the PAA ionization leading to the increase in the rate and extent of the tablet swelling. The results obtained demonstrate the potential of the Pluronic-PAA copolymers for the oral administration of chemotherapeutic agents. PMID:17613025

  6. Alkaloids from Delphinium pentagynum.

    PubMed

    Díaz, Jesús G; Ruiz, Juan García; Herz, Werner

    2004-07-01

    Aerial parts of a collection of Delphinium pentagynum Lam. from Niebla, Southern Spain, furnished one diterpene alkaloid, 2-dehydrodeacetylheterophylloidine, two norditerpene alkaloids, 14-demethyl-14-isobutyrylanhweidelphinine and 14-demethyl-14-acetylanhweidelphinine, the known alkaloids 14-deacetylnudicauline, methyllycaconitine, 14-deacetyl-14-isobutyrylnudicauline, 14-acetylbrowniine, browniine, delcosine, lycoctonine, 18-methoxygadesine, neoline, karakoline and the aporphine alkaloid magnoflorine. Structures of the alkaloids were established by MS, 1D and 2-D NMR techniques.

  7. Layer-by-layer nanoencapsulation of camptothecin with improved activity.

    PubMed

    Parekh, Gaurav; Pattekari, Pravin; Joshi, Chaitanya; Shutava, Tatsiana; DeCoster, Mark; Levchenko, Tatyana; Torchilin, Vladimir; Lvov, Yuri

    2014-04-25

    160 nm nanocapsules containing up to 60% of camptothecin in the core and 7-8 polyelectrolyte bilayers in the shell were produced by washless layer-by-layer assembly of heparin and block-copolymer of poly-l-lysine and polyethylene glycol. The outer surface of the nanocapsules was additionally modified with polyethylene glycol of 5 kDa or 20 kDa molecular weight to attain protein resistant properties, colloidal stability in serum and prolonged release of the drug from the capsules. An advantage of the LbL coated capsules is the preservation of camptothecin lactone form with the shell assembly starting at acidic pH and improved chemical stability of encapsulated drug at neutral and basic pH, especially in the presence of albumin that makes such formulation more active than free camptothecin. LbL nanocapsules preserve the camptothecin lactone form at pH 7.4 resulting in triple activity of the drug toward CRL2303 glioblastoma cell. PMID:24508806

  8. Layer-by-layer nanoencapsulation of camptothecin with improved activity

    PubMed Central

    Parekh, Gaurav; Pattekari, Pravin; Joshi, Chaitanya; Shutava, Tatsiana; DeCoster, Mark; Levchenko, Tatyana; Torchilin, Vladimir; Lvov, Yuri

    2014-01-01

    160 nm nanocapsules containing up to 60% of camptothecin in the core and 7–8 polyelectrolyte bilayers in the shell were produced by washless layer-by-layer assembly of heparin and block-copolymer of poly-L-lysine and polyethylene glycol. The outer surface of the nanocapsules was additionally modified with polyethylene glycol of 5 kDa or 20 kDa molecular weight to attain protein resistant properties, colloidal stability in serum and prolonged release of the drug from the capsules. An advantage of the LbL coated capsules is the preservation of camptothecin lactone form with the shell assembly starting at acidic pH and improved chemical stability of encapsulated drug at neutral and basic pH, especially in the presence of albumin that makes such formulation more active than free camptothecin. LbL nanocapsules preserve the camptothecin lactone form at pH 7.4 resulting in triple activity of the drug toward CRL2303 glioblastoma cell. PMID:24508806

  9. Double-modulation CPT cesium compact clock

    NASA Astrophysics Data System (ADS)

    Yun, Peter; Mejri, Sinda; Tricot, Francois; Abdel Hafiz, Moustafa; Boudot, Rodolphe; de Clercq, Emeric; Guérandel, Stéphane

    2016-06-01

    Double-modulation coherent population trapping (CPT) is based on a synchronous modulation of Raman phase and laser polarization, which allows the atomic population to accumulate in a common dark state. The high contrast signal obtained on the clock transition with a relative compact and robust laser system is interesting as basis of a high performance microwave clock. Here we study the parameters of a double-modulation CPT Cs clock working in cw mode. The optimal polarization modulation frequency and cell temperature for maximum contrast of clock transition are investigated. The parameters of the detection are also studied. With the optimal parameters, we observe a CPT signal with contrast of 10% and linewidth of 492 Hz, which is well suited for implementing a cw atomic clock.

  10. Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients.

    PubMed

    Takeda, Y; Kobayashi, K; Akiyama, Y; Soma, T; Handa, S; Kudoh, S; Kudo, K

    2001-04-15

    It has been reported that 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have absorption characteristics of weakly basic drugs, suggesting that alkalization of the intestinal lumen might reduce reabsorption and its attendant side effects. Furthermore, stasis of stools containing these compounds is thought to induce damage to the intestinal mucosa. The prevention of CPT-11-induced side effects by oral alkalization (OA) combined with control of defecation (CD) was estimated in a case-control study of lung cancer patients. Coinciding with day 1 of CPT-11 infusion and for 4 days thereafter, OA and CD were practiced utilizing orally administered sodium bicarbonate, magnesium oxide, basic water and ursodeoxycholic acid. OA involved the daily use of all four therapeutics, and CD required doses of up to 4.0 g/day of magnesium oxide and 2 L/day of excess basic water. From three ongoing prospective phase I/II studies, we selected 37 consecutive patients who were treated with CPT-11 in combination with cisplatin in the presence of OA and CD (group B). Thirty-two control subjects who were matched to the background characteristics of the case patients were treated with the same regimen in the absence of OA and CD (group A). Toxicities induced by the CPT-11/cisplatin combination were evaluated and analyzed in group A and group B in a case-control format. The use of OA and CD resulted in significantly higher stool pH (p < 0.0001), while reducing the incidence of delayed diarrhea (> or = grade 2: group A 32.3% versus group B 9.4%; p = 0.005), nausea (p = 0.0001), vomiting (p = 0.001) and myelotoxicity, especially granulocytopenia (p = 0.03) and lymphocytopenia (p = 0.034). In addition, dose intensification was well tolerated in patients receiving OA and CD, allowing dose escalation from 35.6 +/- 6.0 to 39.9 +/- 5.6 mg/m(2)/week (p < 0.001). Tumor response rates for non-small cell lung

  11. Theoretical Studies of Lorentz and CPT Symmetry

    NASA Technical Reports Server (NTRS)

    Kostelecky, V. Alan

    2005-01-01

    The fundamental symmetries studied here are Lorentz and CPT invariance, which form a cornerstone of the relativistic quantum theories used in modern descriptions of nature. The results obtained during the reporting period focus on the idea, originally suggested by the P.I. and his group in the late 1980s, that observable CPT and Lorentz violation in nature might emerge from the qualitatively new physics expected to hold at the Planck scale. What follows is a summary of results obtained during the period of this grant.

  12. CPT Results from KTeV

    SciTech Connect

    Hogan Nguyen

    2002-01-14

    I present several preliminary measurements from KTeV of the fundamental neutral K parameters, and their implications for CPT violation. A new limit is given on the sidereal time dependence of {phi}{sub +-}. The results are based on data collected in 1996-97.

  13. Effects of cannabinoid receptor 1 (brain) on lipid accumulation by transcriptional control of CPT1A and CPT1B.

    PubMed

    Zhang, Y-F; Yuan, Z-Q; Song, D-G; Zhou, X-H; Wang, Y-Z

    2014-02-01

    CB1 (also known as CNR1), a main receptor for cannabinoids acting at PPARs, can enhance fat deposition. Carnitine palmitoyltransferase-1 (CPT1), an enzyme responsible for the transport of long-chain fatty acids for β-oxidation, is closely related to fat deposition. Whether CB1 can regulate intramuscular adipocytes lipid accumulation through regulation of CPT1 is unclear. Based on the investigation of tissue- and breed-specific CPT1A and CPT1B mRNA expression levels in Jinhua and Landrace pigs, we studied the effects of CB1 on lipid accumulation and CPT1B expression by treating porcine intramuscular adipocytes with CB1 antagonist Δ9-THC and antagonist SR141716. Results showed that muscle CPT1 mRNA was expressed at higher levels in the longissimus dorsi and subcutaneous fat. Liver CPT1A mRNA expression levels were higher in the pancreas, duodenum and liver. Compared with Landrace pigs, CPT1A and CPT1B in the longissimus dorsi of Jinhua pigs were significantly higher and positively correlated with intramuscular fat content. However, for subcutaneous fat, CPT1 levels were significantly lower and negatively correlated with body fat percentage. Δ9-THC significantly increased CB1 mRNA levels and lipid accumulation but decreased CPT1A and CPT1B mRNA levels. Conversely, SR141716 reduced CB1 mRNA levels but increased CPT1A and CPT1B mRNA levels, resulting in decreased lipid accumulation. The CPT1 antagonist etomoxir did not affect CB1 expression, suggesting that CB1 is likely upstream of CPT1A and CPT1B. Meanwhile, PPARA expression was greatly decreased when CPT1A and CPT1B were inhibited and enhanced when CPT1A and CPT1B were activated. Taken together, these data indicate that CB1 can affect intramuscular fat deposition by regulating both CPT1A and CPT1B mRNA expression, with the PPARA signal pathway likely playing a major role in this process. PMID:23914904

  14. High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation

    SciTech Connect

    Akao, Yukihiro . E-mail: yakao@giib.or.jp; Banno, Yoshiko; Nakagawa, Yoshihito; Hasegawa, Nobuko; Kim, Tack-Joong; Murate, Takashi; Igarashi, Yasuyuki; Nozawa, Yoshinori

    2006-04-21

    Although most of pharmacological therapies for cancer utilize the apoptotic machinery of the cells, the available anti-cancer drugs are limited due to the ability of prostate cancer cells to escape from the anti-cancer drug-induced apoptosis. A human prostate cancer cell line PC3 is resistant to camptothecin (CPT). To elucidate the mechanism of this resistance, we have examined the involvement of sphingosine kinase (SPHK) and sphingosine 1-phosphate (S1P) receptor in CPT-resistant PC3 and -sensitive LNCaP cells. PC3 cells exhibited higher activity accompanied with higher expression levels of protein and mRNA of SPHK1, and also elevated expression of S1P receptors, S1P{sub 1} and S1P{sub 3}, as compared with those of LNCaP cells. The knockdown of SPHK1 by small interfering RNA and inhibition of S1P receptor signaling by pertussis toxin in PC3 cells induced significant inhibition of cell growth, suggesting implication of SPHK1 and S1P receptors in cell proliferation in PC3 cells. Furthermore, the treatment of PC3 cells with CPT was found to induce up-regulation of the SPHK1/S1P signaling by induction of both SPHK1 enzyme and S1P{sub 1}/S1P{sub 3} receptors. These findings strongly suggest that high expression and up-regulation of SPHK1 and S1P receptors protect PC3 cells from the apoptosis induced by CPT.

  15. New cancer-treatment model of photodynamic therapy combined with a type I topoisomerase inhibitor, CPT-11, against HeLa cell tumors in nude mice used by OPO parametric tunable laser

    NASA Astrophysics Data System (ADS)

    Yoshida, Takato O.; Matsuzawa, Eiji; Matsuo, Tetsumichi; Koide, Yukio; Terakawa, Susumu; Yokokura, Teruo; Hirano, Toru

    1995-03-01

    A new cancer-treatment model, photodynamic therapy (PDT) combined with a type I topoisomerase inhibitor, camptothecin derivative (CPT-11), against HeLa cell tumors in BALB/c nude mice has been developed using a wide-band tunable coherent light source operated on optical parametric oscillation (OPO parametric tunable laser). The Photosan-3 PDT and CPT-11 combined therapy was remarkably effective, that is the inhibition rate (I.R.) 40 - 80%, as compared to PDT only in vivo. The analysis of HpD (Photosan-3) and CPT-11 effects on cultured HeLa cells in vitro has been studied by a video-enhanced contrast differential interference contrast microscope (VEC-DIC). Photosan-3 with 600 nm light killed cells by mitochondrial damage within 50 min, but not with 700 nm light. CPT-11 with 700 - 400 nm light killed cells within 50 min after nucleolus damage appeared after around 30 min. The localization of CPT-11 in cells was observed as fluorescence images in the nucleus, particularly the nucleoral area produced clear images using an Argus 100.

  16. Exploiting plant alkaloids.

    PubMed

    Schläger, Sabrina; Dräger, Birgit

    2016-02-01

    Alkaloid-containing plants have been used for medicine since ancient times. Modern pharmaceuticals still rely on alkaloid extraction from plants, some of which grow slowly, are difficult to cultivate and produce low alkaloid yields. Microbial cells as alternative alkaloid production systems are emerging. Before industrial application of genetically engineered bacteria and yeasts, several steps have to be taken. Original alkaloid-forming enzymes have to be elucidated from plants. Their activity in the heterologous host cells, however, may be low. The exchange of individual plant enzymes for alternative catalysts with better performance and optimal fermentation parameters appear promising. The overall aim is enhancement and stabilization of alkaloid yields from microbes in order to replace the tedious extraction of low alkaloid concentrations from intact plants.

  17. Exploiting plant alkaloids.

    PubMed

    Schläger, Sabrina; Dräger, Birgit

    2016-02-01

    Alkaloid-containing plants have been used for medicine since ancient times. Modern pharmaceuticals still rely on alkaloid extraction from plants, some of which grow slowly, are difficult to cultivate and produce low alkaloid yields. Microbial cells as alternative alkaloid production systems are emerging. Before industrial application of genetically engineered bacteria and yeasts, several steps have to be taken. Original alkaloid-forming enzymes have to be elucidated from plants. Their activity in the heterologous host cells, however, may be low. The exchange of individual plant enzymes for alternative catalysts with better performance and optimal fermentation parameters appear promising. The overall aim is enhancement and stabilization of alkaloid yields from microbes in order to replace the tedious extraction of low alkaloid concentrations from intact plants. PMID:26748036

  18. Lorentz and CPT tests involving antiprotons

    NASA Astrophysics Data System (ADS)

    Lehnert, Ralf

    2005-10-01

    Perhaps the largest gap in our understanding of nature at the smallest scales is a consistent quantum theory underlying the Standard Model and General Relativity. Substantial theoretical research has been performed in this context, but observational efforts are hampered by the expected Planck suppression of deviations from conventional physics. However, a variety of candidate models predict minute violations of both Lorentz and CPT invariance. Such effects open a promising avenue for experimental research in this field because these symmetries are amenable to Planck-precision tests. The low-energy signatures of Lorentz and CPT breaking are described by an effective field theory called the Standard-Model Extension (SME). In addition to the body of established physics (i.e., the Standard Model and General Relativity), this framework incorporates all Lorentz- and CPT-violating corrections compatible with key principles of physics. To date, the SME has provided the basis for the analysis of numerous tests of Lorentz and CPT symmetry involving protons, neutrons, electrons, muons, and photons. Discovery potential exists in neutrino physics. A particularly promising class of Planck-scale tests involve matter-antimatter comparisons at low temperatures. SME predictions for transition frequencies in such systems include both matter-antimatter differences and sidereal variations. For example, in hydrogen-antihydrogen spectroscopy, leading-order effects in a 1S-2S transition as well as in a 1S Zeeman transition could exist that can be employed to obtain clean constraints. Similarly, tight bounds can be obtained from Penning-trap experiments involving antiprotons.

  19. Lorentz and CPT tests involving antiprotons

    SciTech Connect

    Lehnert, Ralf

    2005-10-19

    Perhaps the largest gap in our understanding of nature at the smallest scales is a consistent quantum theory underlying the Standard Model and General Relativity. Substantial theoretical research has been performed in this context, but observational efforts are hampered by the expected Planck suppression of deviations from conventional physics. However, a variety of candidate models predict minute violations of both Lorentz and CPT invariance. Such effects open a promising avenue for experimental research in this field because these symmetries are amenable to Planck-precision tests.The low-energy signatures of Lorentz and CPT breaking are described by an effective field theory called the Standard-Model Extension (SME). In addition to the body of established physics (i.e., the Standard Model and General Relativity), this framework incorporates all Lorentz- and CPT-violating corrections compatible with key principles of physics. To date, the SME has provided the basis for the analysis of numerous tests of Lorentz and CPT symmetry involving protons, neutrons, electrons, muons, and photons. Discovery potential exists in neutrino physics.A particularly promising class of Planck-scale tests involve matter-antimatter comparisons at low temperatures. SME predictions for transition frequencies in such systems include both matter-antimatter differences and sidereal variations. For example, in hydrogen-antihydrogen spectroscopy, leading-order effects in a 1S-2S transition as well as in a 1S Zeeman transition could exist that can be employed to obtain clean constraints. Similarly, tight bounds can be obtained from Penning-trap experiments involving antiprotons.

  20. The Changing Face of Healthcare: 2016 CPT Changes and Beyond.

    PubMed

    Thelian, Jacqueline

    2016-01-01

    This article reviews the changes to CPT 2016, with emphasis on the way CPT services will be provided in the future. Some of the newer codes are designed for reimbursable services provided by the medical clinical staff. In addition to the CPT changes, there are changes to the Medicare fee-for service Physician Fee Schedule. Review of these changes provides the reader with a snapshot of how healthcare will be provided and reimbursed in the future. PMID:27249875

  1. Gravity, CPT, and the standard-model extension

    NASA Astrophysics Data System (ADS)

    Tasson, Jay D.

    2015-08-01

    Exotic atoms provide unique opportunities to search for new physics. The search for CPT and Lorentz violation in the context of the general field-theory based framework of the gravitational Standard-Model Extension (SME) is one such opportunity. This work summarizes the implications of Lorentz and CPT violation for gravitational experiments with antiatoms and atoms containing higher-generation matter as well as recent nongravitational proposals to test CPT and Lorentz symmetry with muons and muonic systems.

  2. Two Faces of Alkaloids

    NASA Astrophysics Data System (ADS)

    Dostál, Jirí

    2000-08-01

    Alkaloids can occur in two forms, denoted as ammonium salts and free bases. These forms differ substantially in their properties and in some cases in their structures. The article discusses and compares the salts and free bases of six well-known alkaloids: nicotine, morphine, cocaine, sanguinarine, allocryptopine, and magnoflorine. Relevance for the biological and medical uses of these compounds is emphasized.

  3. The discovery of alkaloids.

    PubMed

    Hosztafi, S

    1997-07-01

    This paper presents the history of the discovery of the first alkaloids. Isolation of alkaloids is connected with the study of the active principles of medicines of plant origin, for example opium and cinchona bark. Sertürner described morphine as a plant alkali and claimed that it was capable of neutralizing free acids yielding salts. The recognition of alkaloids as a new class of compounds was an important step at that time because of the dogmatic denial of the possible existence of plant bases. Isolation of alkaloids is a significant event from the point of view of chemistry, physiology and medicine. The discovery caused essential conceptual changes in chemistry. Priority claims with reference to the discovery of the alkaloids are also reviewed.

  4. RKIP phosphorylation and STAT3 activation is inhibited by oxaliplatin and camptothecin and are associated with poor prognosis in stage II colon cancer patients

    PubMed Central

    2013-01-01

    Background A major obstacle in treating colorectal cancer (CRC) is the acquired resistance to chemotherapeutic agents. An important protein in the regulation of cancer cell death and clinical outcome is Raf kinase inhibitor protein (RKIP). In contrast, activated signal transducer and activator of transcription 3 (STAT3) is a protein that promotes tumor cell survival by inhibiting apoptosis and has an important role in cancer progression in many of cancer types. The aim of this study was to evaluate the regulation of RKIP and STAT3 after treatment with clinically relevant chemotherapeutic agents (camptothecin (CPT) and oxaliplatin (OXP)) and the cytokine interleukin-6 (IL-6) in HCT116 colon cancer cells as well as evaluate the association between RKIP and STAT3 with clinical outcome of Stage II colon cancer patients. Methods HCT-116 colon cancer cells were treated with CPT, OXP, and IL-6 separately or in combination in a time and dose-dependent manner and examined for phosphorylated and non-phosphorylated RKIP and STAT3 via Western blot analysis. STAT3 transcriptional activity was measured via a luciferase reporter assay in HCT116 cells treated with CPT, IL-6 or transfected with JAK 1, 2 separately or in combination. We extended these observations and determined STAT3 and RKIP/ pRKIP in tumor microarrays (TMA) in stage II colon cancer patients. Results We demonstrate IL-6-mediated activation of STAT3 occurs in conjunction with the phosphorylation of RKIP in vitro in human colon cancer cells. OXP and CPT block IL-6 mediated STAT3 activation and RKIP phosphorylation via the inhibition of the interaction of STAT3 with gp130. We determined that STAT3 and nuclear pRKIP are significantly associated with poor patient prognosis in stage II colon cancer patients. Conclusions In the analysis of tumor samples from stage II colon cancer patients and the human colon carcinoma cell line HCT116, pRKIP and STAT3, 2 proteins potentially involved in the resistance to conventional

  5. [Alkaloids of Annonaceae. XXIX. Alkaloids of Annona muricata].

    PubMed

    Leboeuf, M; Legueut, C; Cavé, A; Desconclois, J F; Forgacs, P; Jacquemin, H

    1981-05-01

    From leaves, root - and stem - barks of Annona muricata L., seven isoquinoline alkaloids have been isolated: reticuline (main alkaloid), coclaurine, coreximine, atherosperminine, stepharine. Anomurine and anomuricine, two minor alkaloids, are new tetrahydrobenzylisoquinolines, with 5, 6, 7 substituted ring A. The phytochemical significance of these alkaloids is discussed.

  6. LSND, SN1987A, and CPT violation

    SciTech Connect

    Murayama, Hitoshi; Yanagida, T.

    2000-10-17

    We point out that neutrino events observed at Kamiokande andIMB from SN1987A disfavor the neutrino oscillation parameters preferredby the LSND experiment. For Delta m2>0 (the light side), theelectron neutrinos from the neutronization burst would be lost, while thefirst event at Kamiokande is quite likely to be due to an electronneutrino. For Delta m2<0 (the dark side), the average energy of thedominantly bar nu e events is already lower than the theoreticalexpectations, which would get aggravated by a complete conversion frombar nu mu to bar nu e. If taken seriously, the LSND data are disfavoredindependent of the existence of a sterile neutrino. A possible remedy isCPT violation, which allows different mass spectra for neutrinos andanti-neutrinos and hence can accommodate atmospheric, solar and LSND datawithout a sterile neutrino. If this is the case, Mini-BooNE must run inbar nu rather than the planned nu mode to test the LSND signal. Wespeculate on a possible origin of CPT violation.

  7. Semisynthesis, cytotoxic activity, and oral availability of new lipophilic 9-substituted camptothecin derivatives.

    PubMed

    Rodriguez-Berna, Guillermo; Cabañas, Maria Jose Díaz; Mangas-Sanjuán, Victor; Gonzalez-Alvarez, Marta; Gonzalez-Alvarez, Isabel; Abasolo, Ibane; Schwartz, Simó; Bermejo, Marival; Corma, Avelino

    2013-07-11

    Despite that 9-substituted camptothecins are promising candidates in cancer therapy, the limited accessibility to this position has reduced the studies of these derivatives to a few standard modifications. We report herein a novel semisynthetic route based on the Tscherniac-Einhorn reaction to synthesize new lipophilic camptothecin derivatives with amidomethyl and imidomethyl substitutions in position 9. Compounds were evaluated for their antiproliferative activity, topoisomerase I inhibition, and oral availability. Preliminary data demonstrated that bulky imidomethyl modification is an appropriate lipophilic substitution for an effective oral administration relative to topotecan. In addition, this general procedure paves the way for obtaining new camptothecin derivatives.

  8. Semisynthesis, Cytotoxic Activity, and Oral Availability of New Lipophilic 9-Substituted Camptothecin Derivatives

    PubMed Central

    2013-01-01

    Despite that 9-substituted camptothecins are promising candidates in cancer therapy, the limited accessibility to this position has reduced the studies of these derivatives to a few standard modifications. We report herein a novel semisynthetic route based on the Tscherniac–Einhorn reaction to synthesize new lipophilic camptothecin derivatives with amidomethyl and imidomethyl substitutions in position 9. Compounds were evaluated for their antiproliferative activity, topoisomerase I inhibition, and oral availability. Preliminary data demonstrated that bulky imidomethyl modification is an appropriate lipophilic substitution for an effective oral administration relative to topotecan. In addition, this general procedure paves the way for obtaining new camptothecin derivatives. PMID:24900725

  9. CPT Violation: What and where to look for

    SciTech Connect

    Mavromatos, Nick E.

    2005-10-26

    In this review I classify the possible ways of CPT violation, and I describe briefly their phenomenology, in both terrestrial and astrophysical experiments, including antimatter factories, neutral mesons and neutrinos, and discuss the various sensitivities. I also pay attention to disentangling genuine quantum-gravity induced CPT violation from 'fake' violation due to ordinary matter effects. A particularly interesting situation arises when the breaking of CPT invariance is through unitarity violations, in the sense of the matter theory being viewed as an effective field theory, entangled with decoherening quantum gravity 'environments'. In such a case the quantum mechanical CPT operator is ill defined due to another mathematical theorem, and one has novel effects associated with CPT Violating modifications of Einstein-Podolsky-Rosen type correlations of entangled meson states in B and {phi} meson factories.

  10. McGee Ranch CPT investigation

    SciTech Connect

    Cassem, B.R.

    1993-06-15

    Applied Research Associated, Inc. (ARA), under contract to Argonne National Laboratory to perform work for Westinghouse Hanford Company (WHC), conducted Peizo Cone Penetration (P-CPT) Tests as part of an investigation of the fine-textured soils at the McGee Ranch Site. The purpose of the investigation was to characterize a potential borrow area for fine-textured soil materials that would be used to construct multi-layer closure covers on the Hanford Site. As part of the investigation, WHC conducted non auger-drill borings on the site during September 1992. ARA`s objective was to characterize the soils at the McGee Ranch site using the cone penetrometer and compare the findings with the lithologic characterization obtained from geologic boring logs. This report documents ARA`s site investigation efforts, test techniques, and analysis of the data for field work conducted April 14 and 15, 1993.

  11. Cosmological CPT violation and CMB polarization measurements

    NASA Astrophysics Data System (ADS)

    Xia, Jun-Qing

    2012-01-01

    In this paper we study the possibility of testing Charge-Parity-Time Reversal (CPT) symmetry with cosmic microwave background (CMB) experiments. We consider two kinds of Chern-Simons (CS) term, electromagnetic CS term and gravitational CS term, and study their effects on the CMB polarization power spectra in detail. By combining current CMB polarization measurements, the seven-year WMAP, BOOMERanG 2003 and BICEP observations, we obtain a tight constraint on the rotation angle Δα = -2.28±1.02 deg (1 σ), indicating a 2.2 σ detection of the CPT violation. Here, we particularly take the systematic errors of CMB measurements into account. After adding the QUaD polarization data, the constraint becomes -1.34 < Δα < 0.82 deg at 95% confidence level. When comparing with the effect of electromagnetic CS term, the gravitational CS term could only generate TB and EB power spectra with much smaller amplitude. Therefore, the induced parameter epsilon can not be constrained from the current polarization data. Furthermore, we study the capabilities of future CMB measurements, Planck and CMBPol, on the constraints of Δα and epsilon. We find that the constraint of Δα can be significantly improved by a factor of 15. Therefore, if this rotation angle effect can not be taken into account properly, the constraints of cosmological parameters will be biased obviously. For the gravitational CS term, the future Planck data still can not constrain epsilon very well, if the primordial tensor perturbations are small, r < 0.1. We need the more accurate CMBPol experiment to give better constraint on epsilon.

  12. Dimeric Cinchona alkaloids.

    PubMed

    Boratyński, Przemysław J

    2015-05-01

    Nature is full of dimeric alkaloids of various types from many plant families, some of them with interesting biological properties. However, dimeric Cinchona alkaloids were not isolated from any species but were products of designed partial chemical synthesis. Although the Cinchona bark is amongst the sources of oldest efficient medicines, the synthetic dimers found most use in the field of asymmetric synthesis. Prominent examples include the Sharpless dihydroxylation and aminohydroxylation ligands, and dimeric phase transfer catalysts. In this article the syntheses of Cinchona alkaloid dimers and oligomers are reviewed, and their structure and applications are outlined. Various synthetic routes exploit reactivity of the alkaloids at the central 9-hydroxyl group, quinuclidine, and quinoline rings, as well as 3-vinyl group. This availability of reactive sites, in combination with a plethora of linker molecules, contributes to the diversity of the products obtained.

  13. Occurrence of halogenated alkaloids.

    PubMed

    Gribble, Gordon W

    2012-01-01

    Once considered to be isolation artifacts or chemical "mistakes" of nature, the number of naturally occurring organohalogen compounds has grown from a dozen in 1954 to >5000 today. Of these, at least 25% are halogenated alkaloids. This is not surprising since nitrogen-containing pyrroles, indoles, carbolines, tryptamines, tyrosines, and tyramines are excellent platforms for biohalogenation, particularly in the marine environment where both chloride and bromide are plentiful for biooxidation and subsequent incorporation into these electron-rich substrates. This review presents the occurrence of all halogenated alkaloids, with the exception of marine bromotyrosines where coverage begins where it left off in volume 61 of The Alkaloids. Whereas the biological activity of these extraordinary compounds is briefly cited for some examples, a future volume of The Alkaloids will present full coverage of this topic and will also include selected syntheses of halogenated alkaloids. Natural organohalogens of all types, especially marine and terrestrial halogenated alkaloids, comprise a rapidly expanding class of natural products, in many cases expressing powerful biological activity. This enormous proliferation has several origins: (1) a revitalization of natural product research in a search for new drugs, (2) improved compound characterization methods (multidimensional NMR, high-resolution mass spectrometry), (3) specific enzyme-based and other biological assays, (4) sophisticated collection methods (SCUBA and remote submersibles for deep ocean marine collections), (5) new separation and purification techniques (HPLC and countercurrent separation), (6) a greater appreciation of traditional folk medicine and ethobotany, and (7) marine bacteria and fungi as novel sources of natural products. Halogenated alkaloids are truly omnipresent in the environment. Indeed, one compound, Q1 (234), is ubiquitous in the marine food web and is found in the Inuit from their diet of whale

  14. Marine Indole Alkaloids

    PubMed Central

    Netz, Natalie; Opatz, Till

    2015-01-01

    Marine indole alkaloids comprise a large and steadily growing group of secondary metabolites. Their diverse biological activities make many compounds of this class attractive starting points for pharmaceutical development. Several marine-derived indoles were found to possess cytotoxic, antineoplastic, antibacterial and antimicrobial activities, in addition to the action on human enzymes and receptors. The newly isolated indole alkaloids of marine origin since the last comprehensive review in 2003 are reported, and biological aspects will be discussed. PMID:26287214

  15. Sarpagine and related alkaloids

    PubMed Central

    Namjoshi, Ojas A.; Cook, James M.

    2016-01-01

    The sarpagine-related macroline and ajmaline alkaloids share a common biosynthetic origin, and bear important structural similarities, as expected. These indole alkaloids are widely dispersed in 25 plant genera, principally in the Apocynaceae family. Very diverse and interesting biological properties have been reported for this group of natural products. Isolation of new sarpagine-related alkaloids as well as the asymmetric synthesis of these structurally complex molecules are of paramount importance to the synthetic and medicinal chemists. A total of 115 newly isolated sarpagine-related macroline and ajmaline alkaloids, along with their physicochemical properties have been included in this chapter. A general and efficient strategy for the synthesis of these monomeric alkaloids, as well as bisindoles has been presented, which involves application of the asymmetric Pictet–Spengler reaction (>98% ee) as a key step because of the ease of scale up of the tetracyclic template. Also included in this chapter are the syntheses of the sarpagine-related alkaloids, published since the year 2000. PMID:26827883

  16. Sarpagine and Related Alkaloids.

    PubMed

    Namjoshi, Ojas A; Cook, James M

    2016-01-01

    The sarpagine-related macroline and ajmaline alkaloids share a common biosynthetic origin, and bear important structural similarities, as expected. These indole alkaloids are widely dispersed in 25 plant genera, principally in the family Apocynaceae. Very diverse and interesting biological properties have been reported for this group of natural products. Isolation of new sarpagine-related alkaloids and the asymmetric synthesis of these structurally complex molecules are of paramount importance to the synthetic and medicinal chemists. A total of 115 newly isolated sarpagine-related macroline and ajmaline alkaloids, along with their physicochemical properties have been included in this chapter. A general and efficient strategy for the synthesis of these monomeric alkaloids, as well as bisindoles, has been presented, which involves application of the asymmetric Pictet-Spengler reaction (>98% ee) as a key step because of the ease of scale up of the tetracyclic template. Also included in this chapter are the syntheses of the sarpagine-related alkaloids, published since 2000. PMID:26827883

  17. Formation of nanoparticles by cooperative inclusion between (S)-camptothecin-modified dextrans and β-cyclodextrin polymers.

    PubMed

    Nielsen, Thorbjørn Terndrup; Amiel, Catherine; Duroux, Laurent; Larsen, Kim Lambertsen; Städe, Lars Wagner; Wimmer, Reinhard; Wintgens, Véronique

    2015-01-01

    Novel (S)-camptothecin-dextran polymers were obtained by "click" grafting of azide-modified (S)-camptothecin and alkyne-modified dextrans. Two series based on 10 kDa and 70 kDa dextrans were prepared with a degree of substitution of (S)-camptothecin between 3.1 and 10.2%. The binding properties with β-cyclodextrin and β-cyclodextrin polymers were measured by isothermal titration calorimetry and fluorescence spectroscopy, showing no binding with β-cyclodextrin but high binding with β-cyclodextrin polymers. In aqueous solution nanoparticles were formed from association between the (S)-camptothecin-dextran polymers and the β-cyclodextrin polymers.

  18. Lorentz- and CPT-violating signals in Penning traps

    NASA Astrophysics Data System (ADS)

    Ding, Yunhua; Kostelecký, Alan

    2016-05-01

    CPT and Lorentz symmetries are fundamental properties of the Standard Model. However, violation of these symmetries is possible in an underlying unified theory such as strings. This talk will focus on possible experimental effects for Lorentz and CPT violations. In particular, observable signals in measurements of anomaly and cyclotron frequencies of particles and antiparticles in a Penning trap will be discussed. New constraints from existing data will be presented and prospective sensitivities in future experiments will be outlined.

  19. DEVELOPMENT OF A WIRELINE CPT SYSTEM FOR MULTIPLE TOOL USAGE

    SciTech Connect

    Stephen P. Farrington; Martin L. Gildea; J. Christopher Bianchi

    1999-08-01

    The first phase of development of a wireline cone penetrometer system for multiple tool usage was completed under DOE award number DE-AR26-98FT40366. Cone penetrometer technology (CPT) has received widespread interest and is becoming more commonplace as a tool for environmental site characterization activities at several Department of Energy (DOE) facilities. Although CPT already offers many benefits for site characterization, the wireline system can improve CPT technology by offering greater utility and increased cost savings. Currently the use of multiple CPT tools during a site characterization (i.e. piezometric cone, chemical sensors, core sampler, grouting tool) must be accomplished by withdrawing the entire penetrometer rod string to change tools. This results in multiple penetrations being required to collect the data and samples that may be required during characterization of a site, and to subsequently seal the resulting holes with grout. The wireline CPT system allows multiple CPT tools to be interchanged during a single penetration, without withdrawing the CPT rod string from the ground. The goal of the project is to develop and demonstrate a system by which various tools can be placed at the tip of the rod string depending on the type of information or sample desired. Under the base contract, an interchangeable piezocone and grouting tool was designed, fabricated, and evaluated. The results of the evaluation indicate that success criteria for the base contract were achieved. In addition, the wireline piezocone tool was validated against ASTM standard cones, the depth capability of the system was found to compare favorably with that of conventional CPT, and the reliability and survivability of the system were demonstrated.

  20. Biosynthesis of Fungal Indole Alkaloids

    PubMed Central

    Xu, Wei; Gavia, Diego J.; Tang, Yi

    2014-01-01

    This review provides a summary of recent research advances in elucidating the biosynthesis of fungal indole alkaloids. Different strategies used to incorporate and derivatize the indole/indoline moieties in various families of fungal indole alkaloids will be discussed, including tryptophan-containing nonribosomal peptides and polyketide-nonribosomal peptide hybrids; and alkaloids derived from other indole building blocks. This review also includes discussion regarding the downstream modifications that generate chemical and structural diversity among indole alkaloids. PMID:25180619

  1. Crystal Structure of Rat Carnitine Palmitoyltransferase II (CPT-II)

    SciTech Connect

    Hsiao,Y.; Jogl, G.; Esser, V.; Tong, L.

    2006-01-01

    Carnitine palmitoyltransferase II (CPT-II) has a crucial role in the {beta}-oxidation of long-chain fatty acids in mitochondria. We report here the crystal structure of rat CPT-II at 1.9 Angstroms resolution. The overall structure shares strong similarity to those of short- and medium-chain carnitine acyltransferases, although detailed structural differences in the active site region have a significant impact on the substrate selectivity of CPT-II. Three aliphatic chains, possibly from a detergent that is used for the crystallization, were found in the structure. Two of them are located in the carnitine and CoA binding sites, respectively. The third aliphatic chain may mimic the long-chain acyl group in the substrate of CPT-II. The binding site for this aliphatic chain does not exist in the short- and medium-chain carnitine acyltransferases, due to conformational differences among the enzymes. A unique insert in CPT-II is positioned on the surface of the enzyme, with a highly hydrophobic surface. It is likely that this surface patch mediates the association of CPT-II with the inner membrane of the mitochondria.

  2. Poly(amido amine) dendrimers as absorption enhancers for oral delivery of camptothecin.

    PubMed

    Sadekar, S; Thiagarajan, G; Bartlett, K; Hubbard, D; Ray, A; McGill, L D; Ghandehari, H

    2013-11-01

    Oral delivery of camptothecin has a treatment advantage but is limited by low bioavailability and gastrointestinal toxicity. Poly(amido amine) or PAMAM dendrimers have shown promise as intestinal penetration enhancers, drug solubilizers and drug carriers for oral delivery in vitro and in situ. There have been very limited studies in vivo to evaluate PAMAM dendrimers for oral drug delivery. In this study, camptothecin (5 mg/kg) was formulated and co-delivered with cationic, amine-terminated PAMAM dendrimer generation 4.0 (G4.0) (100 and 300 mg/kg) and anionic, carboxylate-terminated PAMAM generation 3.5 (G3.5) (300 and 1000 mg/kg) in CD-1 mice. Camptothecin associated to a higher extent with G4.0 than G3.5 in the formulation, attributed to an electrostatic interaction on the surface of G4.0. Both PAMAM G4.0 and G3.5 increased camptothecin solubilization in simulated gastric fluid and caused a 2-3 fold increase in oral absorption of camptothecin when delivered at 2 h. PAMAM G4.0 and G3.5 did not increase mannitol transport suggesting that the oral absorption of camptothecin was not due to tight junction modulation. Histologic observations of the epithelial layer of small intestinal segments of the gastrointestinal tract (GIT) at 4 h post dosing supported no evidence of toxicity at the evaluated doses of PAMAM dendrimers. This study demonstrates that both cationic (G.4) and anionic (G3.5) PAMAM dendrimers were effective in enhancing the oral absorption of camptothecin. Results suggest that drug inclusion in PAMAM interior controlled solubilization in simulated gastric and intestinal fluids, and increased oral bioavailability.

  3. Analysis of Ergot Alkaloids

    PubMed Central

    Crews, Colin

    2015-01-01

    The principles and application of established and newer methods for the quantitative and semi-quantitative determination of ergot alkaloids in food, feed, plant materials and animal tissues are reviewed. The techniques of sampling, extraction, clean-up, detection, quantification and validation are described. The major procedures for ergot alkaloid analysis comprise liquid chromatography with tandem mass spectrometry (LC-MS/MS) and liquid chromatography with fluorescence detection (LC-FLD). Other methods based on immunoassays are under development and variations of these and minor techniques are available for specific purposes. PMID:26046699

  4. PP2A-B56ϵ complex is involved in dephosphorylation of γ-H2AX in the repair process of CPT-induced DNA double-strand breaks.

    PubMed

    Li, Xiuying; Nan, Anuo; Xiao, Ying; Chen, Yongzhong; Lai, Yandong

    2015-05-01

    Phosphorylation of histone H2AX (γ-H2AX) in response to DNA double-strand breaks (DSBs) should be eliminated from the sites of DNA damage to fulfill the DNA repair and release cells from the growth arrest. Previous study showed that protein phosphatase 2A (PP2A) interact with γ-H2AX that lead to the dephosphorylation of γ-H2AX. Here, we examined the effects of suppression of PP2A regulatory subunits on dephosphorylation of γ-H2AX in human embryonic kidney epithelial cells (HEK) treated by topoisomerase I inhibitor camptothecin (CPT). We found that cells with suppression of B55α or B56ϵ were more sensitive to DNA damage agents. Suppression of B56ϵ led to persistence of γ-H2AX, resulting in prolonged DSBs repair and increased chromatin instability measured by comet assay. In addition, the deficiency of B56ϵ impaired the cell cycle regulation and the DNA repair pathway of homologous recombination (HR). Notably, we detected that PP2A B56ϵ subunit was involved directly in dephosphorylation of γ-H2AX and translocated from cytoplasm to nucleus upon the treatment of CPT. Our findings demonstrate that PP2A holoenzyme containing B56ϵ is responsible for the dephosphorylation of γ-H2AX and regulation of DNA repair of DSBs induced by CPT.

  5. Hydrogen and antihydrogen spectroscopy for studies of CPT and Lorentz symmetry

    SciTech Connect

    Bluhm, Robert; Kostelecky, V. Alan; Russell, Neil

    1999-01-15

    A theoretical study of possible signals for CPT and Lorentz violation arising in hydrogen and antihydrogen spectroscopy is described. The analysis uses a CPT- and Lorentz-violating extension of quantum electrodynamics, obtained from a general Lorentz-violating extension of the minimal standard model with both CPT-even and CPT-odd terms. Certain 1S-2S transitions and hyperfine Zeeman lines exhibit effects at leading order in small CPT-violating couplings.

  6. Hydrogen and antihydrogen spectroscopy for studies of CPT and Lorentz symmetry

    SciTech Connect

    Bluhm, R.; Kostelecky, V.A.; Russell, N.

    1999-01-01

    A theoretical study of possible signals for CPT and Lorentz violation arising in hydrogen and antihydrogen spectroscopy is described. The analysis uses a CPT- and Lorentz-violating extension of quantum electrodynamics, obtained from a general Lorentz-violating extension of the minimal standard model with both CPT-even and CPT-odd terms. Certain 1S-2S transitions and hyperfine Zeeman lines exhibit effects at leading order in small CPT-violating couplings. {copyright} {ital 1999 American Institute of Physics.}

  7. 10-Boronic acid substituted camptothecin as prodrug of SN-38.

    PubMed

    Wang, Lei; Xie, Shao; Ma, Longjun; Chen, Yi; Lu, Wei

    2016-06-30

    Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon-boron bond to the SN-38. Prodrug B1 selectively activated by H2O2, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H2O2. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.0 mg/kg in a xenograft model using human brain star glioblastoma cell lines U87MG. PMID:27060760

  8. The Securinega alkaloids.

    PubMed

    Chirkin, Eqor; Atkatlian, William; Porée, François-Hugues

    2015-01-01

    Securinega alkaloids represent a family of plant secondary metabolites known for 50 years. Securinine (1), the most abundant and studied alkaloid of this series was isolated by Russian researchers in 1956. In the following years, French and Japanese scientists reported other Securinega compounds and extensive work was done to elucidate their intriguing structures. The homogeneity of this family relies mainly on its tetracyclic chemical backbone, which features a butenolide moiety (cycle D) and an azabicyclo[3.2.1]octane ring system (rings B and C). Interestingly, after a period of latency of 20 years, the Securinega topic reemerged as a prolific source of new natural structures and to date more than 50 compounds have been identified and characterized. The oligomeric subgroup gathering dimeric, trimeric, and tetrameric units is of particular interest. The unprecedented structure of the Securinega alkaloids was the subject of extensive synthetic efforts culminating in several efficient and elegant total syntheses. The botanical distribution of these alkaloids seems limited to the Securinega, Flueggea, Margaritaria, and Breynia genera (Phyllanthaceae). However, only a limited number of plant species have been considered for their alkaloid contents, and additional phytochemical as well as genetic studies are needed. Concerning the biosynthesis, experiments carried out with radiolabelled aminoacids allowed to identify lysine and tyrosine as the precursors of the piperidine ring A and the CD rings of securinine (1), respectively. Besides, plausible biosynthetic pathways were proposed for virosaine A (38) and B (39), flueggine A (46), and also the different oligomers flueggenine A-D (48-51), fluevirosinine A (56), and flueggedine (20). The case of nirurine (45) and secu'amamine (37) remains elusive and additional studies seem necessary to understand their mode of production. The scope of biological of activities of the Securinega alkaloids was mainly centered on the CNS

  9. The Securinega alkaloids.

    PubMed

    Chirkin, Eqor; Atkatlian, William; Porée, François-Hugues

    2015-01-01

    Securinega alkaloids represent a family of plant secondary metabolites known for 50 years. Securinine (1), the most abundant and studied alkaloid of this series was isolated by Russian researchers in 1956. In the following years, French and Japanese scientists reported other Securinega compounds and extensive work was done to elucidate their intriguing structures. The homogeneity of this family relies mainly on its tetracyclic chemical backbone, which features a butenolide moiety (cycle D) and an azabicyclo[3.2.1]octane ring system (rings B and C). Interestingly, after a period of latency of 20 years, the Securinega topic reemerged as a prolific source of new natural structures and to date more than 50 compounds have been identified and characterized. The oligomeric subgroup gathering dimeric, trimeric, and tetrameric units is of particular interest. The unprecedented structure of the Securinega alkaloids was the subject of extensive synthetic efforts culminating in several efficient and elegant total syntheses. The botanical distribution of these alkaloids seems limited to the Securinega, Flueggea, Margaritaria, and Breynia genera (Phyllanthaceae). However, only a limited number of plant species have been considered for their alkaloid contents, and additional phytochemical as well as genetic studies are needed. Concerning the biosynthesis, experiments carried out with radiolabelled aminoacids allowed to identify lysine and tyrosine as the precursors of the piperidine ring A and the CD rings of securinine (1), respectively. Besides, plausible biosynthetic pathways were proposed for virosaine A (38) and B (39), flueggine A (46), and also the different oligomers flueggenine A-D (48-51), fluevirosinine A (56), and flueggedine (20). The case of nirurine (45) and secu'amamine (37) remains elusive and additional studies seem necessary to understand their mode of production. The scope of biological of activities of the Securinega alkaloids was mainly centered on the CNS

  10. Simple Indolizidine and Quinolizidine Alkaloids.

    PubMed

    Michael, Joseph P

    2016-01-01

    This review of simple indolizidine and quinolizidine alkaloids (i.e., those in which the parent bicyclic systems are in general not embedded in polycyclic arrays) is an update of the previous coverage in Volume 55 of this series (2001). The present survey covers the literature from mid-1999 to the end of 2013; and in addition to aspects of the isolation, characterization, and biological activity of the alkaloids, much emphasis is placed on their total synthesis. A brief introduction to the topic is followed by an overview of relevant alkaloids from fungal and microbial sources, among them slaframine, cyclizidine, Steptomyces metabolites, and the pantocins. The important iminosugar alkaloids lentiginosine, steviamine, swainsonine, castanospermine, and related hydroxyindolizidines are dealt with in the subsequent section. The fourth and fifth sections cover metabolites from terrestrial plants. Pertinent plant alkaloids bearing alkyl, functionalized alkyl or alkenyl substituents include dendroprimine, anibamine, simple alkaloids belonging to the genera Prosopis, Elaeocarpus, Lycopodium, and Poranthera, and bicyclic alkaloids of the lupin family. Plant alkaloids bearing aryl or heteroaryl substituents include ipalbidine and analogs, secophenanthroindolizidine and secophenanthroquinolizidine alkaloids (among them septicine, julandine, and analogs), ficuseptine, lasubines, and other simple quinolizidines of the Lythraceae, the simple furyl-substituted Nuphar alkaloids, and a mixed quinolizidine-quinazoline alkaloid. The penultimate section of the review deals with the sizable group of simple indolizidine and quinolizidine alkaloids isolated from, or detected in, ants, mites, and terrestrial amphibians, and includes an overview of the "dietary hypothesis" for the origin of the amphibian metabolites. The final section surveys relevant alkaloids from marine sources, and includes clathryimines and analogs, stellettamides, the clavepictines and pictamine, and bis

  11. Simple Indolizidine and Quinolizidine Alkaloids.

    PubMed

    Michael, Joseph P

    2016-01-01

    This review of simple indolizidine and quinolizidine alkaloids (i.e., those in which the parent bicyclic systems are in general not embedded in polycyclic arrays) is an update of the previous coverage in Volume 55 of this series (2001). The present survey covers the literature from mid-1999 to the end of 2013; and in addition to aspects of the isolation, characterization, and biological activity of the alkaloids, much emphasis is placed on their total synthesis. A brief introduction to the topic is followed by an overview of relevant alkaloids from fungal and microbial sources, among them slaframine, cyclizidine, Steptomyces metabolites, and the pantocins. The important iminosugar alkaloids lentiginosine, steviamine, swainsonine, castanospermine, and related hydroxyindolizidines are dealt with in the subsequent section. The fourth and fifth sections cover metabolites from terrestrial plants. Pertinent plant alkaloids bearing alkyl, functionalized alkyl or alkenyl substituents include dendroprimine, anibamine, simple alkaloids belonging to the genera Prosopis, Elaeocarpus, Lycopodium, and Poranthera, and bicyclic alkaloids of the lupin family. Plant alkaloids bearing aryl or heteroaryl substituents include ipalbidine and analogs, secophenanthroindolizidine and secophenanthroquinolizidine alkaloids (among them septicine, julandine, and analogs), ficuseptine, lasubines, and other simple quinolizidines of the Lythraceae, the simple furyl-substituted Nuphar alkaloids, and a mixed quinolizidine-quinazoline alkaloid. The penultimate section of the review deals with the sizable group of simple indolizidine and quinolizidine alkaloids isolated from, or detected in, ants, mites, and terrestrial amphibians, and includes an overview of the "dietary hypothesis" for the origin of the amphibian metabolites. The final section surveys relevant alkaloids from marine sources, and includes clathryimines and analogs, stellettamides, the clavepictines and pictamine, and bis

  12. Pyrenacantha volubilis Wight, (Icacinaceae) a rich source of camptothecine and its derivatives, from the Coromandel Coast forests of India.

    PubMed

    Suma, Hirenallur Kumarappa; Kumar, Vadlapudi; Senthilkumar, Umapathy; Kumara, Patel Mohana; Ravikanth, Gudasalamani; Santhoshkumar, Thankayyan Retnabai; Shaanker, Ramanan Uma

    2014-09-01

    Camptothecine, a potent eukaryotic topoisomerase inhibitor, is an important anticancer compound. The global demand for this compound was estimated to be $1 billion in 2003 and is only further expected to increase. Partly to meet the expected increase in demand, in the recent past, several efforts have been made to discover newer and alternative plant and fungal sources of camptothecine. In this study we report a rich source of camptothecine and its natural derivatives, Pyrenacantha volubilis (Icacinaceae) from the eastern coast of peninsular India. Camptothecine and its derivatives were analyzed using high performance liquid chromatography (HPLC) coupled with electrospray mass spectrometry (ESI-MS) in all plant parts such as twigs, leaves, roots, seedling, ripened whole fruit, fruit coat, seed coat and cotyledons. Cotyledons and ripened whole fruits contained the highest amount of camptothecine (1.35% and 0.60% dry weight respectively). LC-MS and ESI-MS/MS analyses revealed besides camptothecine, other derivatives and precursors such as 10-hydroxycamptothecine, 9-methoxycamptothecine, 20-deoxycamptothecine, deoxypumiloside, strictosidine and strictosamide. Pure camptothecine was isolated from fruits and structurally confirmed using NMR. Seed extracts were found to be effective against breast cancer, ovarian, colon and carcinoma cell lines (with IC50 values of 4.0 μg/mL, 6.5 μg/mL, 25.0 μg/mL and 25.0 μg/mL respectively). We discuss the results in the context of exploring alternative sources of camptothecine. PMID:24882065

  13. [Kinetics of the lactone-carboxylate transition of hybrid camptothecin-netropsin molecules].

    PubMed

    Oleĭnikov, V A; Ustinova, O A; Mochalov, K E; Ermishov, M A; Grokhovskiĭ, S L; Zhuze, A L; Sukhanova, A V; Nabiev, I R

    2003-01-01

    The kinetics of the hydrolysis of the lactone ring of a hybrid molecule containing the molecules of the antitumor drug camptothecin and a derivative of the antibiotic netropsines, which is highly affine and specific to the DNA A-T sequences was investigated. It was shown that intramolecular interaction significantly slows down the rate of hydrolysis but does not change the equilibrium ratio of concentrations of the lactone and carboxylate forms of the camptothecin fragment of the hybrid molecule, which corresponds to the pH value. The use of intramolecular interaction for controlling the kinetics of the lactone/carboxylate transition makes it possible to create the drugs of the camptothecin family, which preserve the biologically active lactone form under the physiological conditions for a longer time and, therefore, are more effective as anticancer agents. PMID:12815854

  14. Fluorescence detection of camptothecin anticancer drugs by two-photon excitation

    NASA Astrophysics Data System (ADS)

    Burke, Thomas G.; Malak, Magda; Bom, David; Curran, Dennis P.; Malak, Henryk M.; Gryczynski, Ignacy; Lakowicz, Joseph R.

    1998-04-01

    Hycamtin is a camptothecin anticancer analogue containing a dimethylaminomethyl substituent at position 9 and a hydroxy functionality at position 10. Using an excitation wavelength of 800 nm we have compared the two-photon cross sections and excited-state lifetimes from several camptothecins in phosphate buffered saline solution with and without the presence of human serum albumin (HSA). Drug and HSA concentrations of 10 (mu) M and 46 (mu) M were employed in our studies. In phosphate buffered saline solution containing HSA the following excited-state lifetimes (ns) and two- photon cross-sections (10-50 cm4 s/photon), respectively, were determined: hycamtin (4.3 nm, 36); camptothecin (1.3 ns, 1); 7-t-butyldimethylsilyl-10- hydroxycamptothecin (1.7 ns, 3.7); 7-t-butyldimethylsilyl- camptothecin (1.9 ns, 1.9); 7-trimethylsilyl-10- aminocamptothecin (6.3 ns; 35); and 7-trimethylsilyl-10- hydroxycamptothecin (1.8 ns; 2.2). Our results indicate that Hycamtin exhibits a high cross-section relative to the parent camptothecin molecule and represents one of the best camptothecin analogues to detect using two-photon excitation. Hycamtin was detected at concentrations as low as 0.05 (mu) M and 1 (mu) M in plasma and whole blood, respectively. The newly synthesized analogue 7- trimethylsilyl-10-aminocamptothecin was found to display similar lifetime and two-photon cross section values relative to Hycamtin. Thus, fluorescence detection with two- photon excitation may prove to be of advantage in the development of this promising new experimental therapeutic.

  15. Search for CPT-odd decays of positronium

    SciTech Connect

    Vetter, Paul A.; Freedman, Stuart J.

    2003-07-11

    We have limited a CPT-violating correlation in annihilationsof polarized ortho-positronium. We searched for an asymmetry in thetriple correlations dot k1 cross k2, where k1 and k2 are the two largestphoton momenta, and s is the spin of the positronium. Using theGammasphere array of Compton-suppressed high-purity germanium detectors,we detected 2.65e7 events of ortho-Ps annihila tion. The amplitude of aCPT-violating asymmetry in the data set is found to be 0.0026 plus orminus 0.0031, a factor of 6 smaller than previousexperiments.

  16. Quinolizidine alkaloids from Lupinus lanatus

    NASA Astrophysics Data System (ADS)

    Neto, Alexandre T.; Oliveira, Carolina Q.; Ilha, Vinicius; Pedroso, Marcelo; Burrow, Robert A.; Dalcol, Ionara I.; Morel, Ademir F.

    2011-10-01

    In this study, one new quinolizidine alkaloid, lanatine A ( 1), together with three other known alkaloids, 13-α- trans-cinnamoyloxylupanine ( 2), 13-α-hydroxylupanine ( 3), and (-)-multiflorine ( 4) were isolated from the aerial parts of Lupinus lanatus (Fabaceae). The structures of alkaloids 1- 4 were elucidated by spectroscopic data analysis. The stereochemistry of 1 was determined by single crystal X-ray analysis. Bayesian statistical analysis of the Bijvoet differences suggests the absolute stereochemistry of 1. In addition, the antimicrobial potential of alkaloids 1- 4 is also reported.

  17. Neutron-antineutron transition as a test-bed for dynamical CPT violations

    NASA Astrophysics Data System (ADS)

    Addazi, Andrea

    2016-05-01

    We show a simple mechanism for a dynamical CPT violation in the neutron sector. In particular, we show a CPT-violating see-saw mechanism, generating a Majorana mass and a CPT-violating mass for the neutron. CPT-violating see-saw involves a sterile partner of the neutron, living in a hidden sector, in which CPT is spontaneously broken. In particular, neutrons (antineutrons) can communicate with the hidden sector through nonperturbative quantum gravity effects called exotic instantons. Exotic instantons dynamically break R-parity, generating one effective vertex between the neutron and its sterile partner. In this way, we show how a small CPT-violating mass term for the neutron is naturally generated. This model can be tested in the next generation of experiments in neutron-antineutron physics. This strongly motivates researches of CPT-violating effects in neutron-antineutron physics as a test-bed for dynamical CPT-violations in SM.

  18. Camptothecin sensitizes androgen-independent prostate cancer cells to anti-Fas-induced apoptosis

    PubMed Central

    Costa-Pereira, A P; Cotter, T G

    1999-01-01

    Despite expressing both Fas and Fas ligand, DU145 and LNCaP prostate cancer cells were resistant to anti-Fas-induced cell death. Resistance to Fas-mediated cytotoxicity could be overcome in DU145, but not in LNCaP, cells by pretreating cells with sublethal doses of cytotoxic drugs, such as camptothecin. Activated caspases were shown to be required for this cytotoxicity. Indeed, poly(ADP-Ribose) polymerase was shown to be proteolytically cleaved in cells treated with camptothecin plus anti-Fas, but not in cells treated with anti-Fas only. Moreover, pretreatment of cells with ZVAD completely blocked camptothecin-mediated Fas-induced apoptosis. Sensitization of cells to Fas-induced cell death did not involve up-regulation of Fas or FasL, and it was independent of alterations in the cell cycle. Reactive oxygen intermediates (ROI) have been shown to be important mediators of drug-induced apoptosis. Here, we demonstrate that treatment of DU145 cells with camptothecin, anti-Fas, or both, did not alter the intracellular levels of peroxide or superoxide anion. © 1999 Cancer Research Campaign PMID:10408840

  19. CPT and Lorentz Tests in Hydrogen and Antihydrogen

    SciTech Connect

    Bluhm, R.; Kostelecky, V.A.; Russell, N.

    1999-03-01

    Signals for CPT and Lorentz violation at the Planck scale may arise in hydrogen and antihydrogen spectroscopy. We show that certain 1S-2S and hyperfine transitions can exhibit theoretically detectable effects unsuppressed by any power of the fine-structure constant. {copyright} {ital 1999} {ital The American Physical Society}

  20. Antihydrogen for tests of CPT and Lorentz invariance

    SciTech Connect

    Holzscheiter, Michael H.

    1999-01-15

    Antihydrogen atoms, produced near rest, trapped in a magnetic well, and cooled to the lowest possible temperature (kinetic energy) could provide an extremely powerful tool for the search of violations of CPT and Lorentz invarianz. We describe our plans to form a significant number of cold antihydrogen atoms for comparative precision spectroscopy of hydrogen and antihydrogen.

  1. Antihydrogen for tests of CPT and Lorentz invariance

    SciTech Connect

    ATHENA collaboration

    1999-01-01

    Antihydrogen atoms, produced near rest, trapped in a magnetic well, and cooled to the lowest possible temperature (kinetic energy) could provide an extremely powerful tool for the search of violations of CPT and Lorentz invarianz. We describe our plans to form a significant number of cold antihydrogen atoms for comparative precision spectroscopy of hydrogen and antihydrogen. {copyright} {ital 1999 American Institute of Physics.}

  2. TOMOGRAPHIC SITE CHARACTERIZATION USING CPT, ERT, AND GPR

    SciTech Connect

    Rexford M. Morey; Susanne M. Conklin; Stephen P. Farrington, P.E.; James D. Shinn II, P.E.

    1999-07-01

    The US Department of Energy (DOE) is responsible for the cleanup of inactive DOE sites and for bringing DOE sites and facilities into compliance with federal, state, and local laws and regulations. The DOE's Office of Environmental Management (EM) needs advanced technologies that can make environmental restoration and waste management operations more efficient and less costly. These techniques are required to better characterize the physical, hydrogeological, and chemical properties of the subsurface while minimizing and optimizing the use of boreholes and monitoring wells. Today the cone penetrometer technique (CPT) is demonstrating the value of a minimally invasive deployment system for site characterization. Applied Research Associates, Inc. is developing two new sensor packages for site characterization and monitoring. The two new methods are: (1) Electrical Resistivity Tomography (ERT); and (2) Ground Penetrating Radar (GPR) Tomography. These sensor systems are now integrated with the CPT. The results of this program now make it possible to install ERT and GPR units by CPT methods and thereby reduce installation costs and total costs for ERT and GPR surveys. These two techniques can complement each other in regions of low resistivity where ERT is more effective and regions of high resistivity where GPR is more effective. The results show that CPT-installed GeoWells can be used for both ERT and GPR borehole tomographic subsurface imaging. These two imaging techniques can be used for environmental site characterization and monitoring have numerous and diverse applications within site cleanup and waste management operations.

  3. Lorentz and CPT Tests with Spin-Polarized Solids

    SciTech Connect

    Bluhm, Robert; Kostelecky, V. Alan

    2000-02-14

    Experiments using macroscopic samples of spin-polarized matter offer exceptional sensitivity to Lorentz and CPT violation in the electron sector. Data from existing experiments with a spin-polarized torsion pendulum provide sensitivity in this sector rivaling that of all other existing experiments and could reveal spontaneous violation of Lorentz symmetry at the Planck scale. (c) 2000 The American Physical Society.

  4. The Veratrum and Solanum alkaloids.

    PubMed

    Heretsch, Philipp; Giannis, Athanassios

    2015-01-01

    This survey on steroidal alkaloids of the Veratrum and Solanum family isolated between 1974 and 2014 includes 187 compounds and 197 references. New developments in the chemistry and biology of this family of natural products with a special focus on the medicinal relevance of the jervanine alkaloid cyclopamine are discussed. PMID:25845062

  5. Automatic alkaloid removal system.

    PubMed

    Yahaya, Muhammad Rizuwan; Hj Razali, Mohd Hudzari; Abu Bakar, Che Abdullah; Ismail, Wan Ishak Wan; Muda, Wan Musa Wan; Mat, Nashriyah; Zakaria, Abd

    2014-01-01

    This alkaloid automated removal machine was developed at Instrumentation Laboratory, Universiti Sultan Zainal Abidin Malaysia that purposely for removing the alkaloid toxicity from Dioscorea hispida (DH) tuber. It is a poisonous plant where scientific study has shown that its tubers contain toxic alkaloid constituents, dioscorine. The tubers can only be consumed after it poisonous is removed. In this experiment, the tubers are needed to blend as powder form before inserting into machine basket. The user is need to push the START button on machine controller for switching the water pump ON by then creating turbulence wave of water in machine tank. The water will stop automatically by triggering the outlet solenoid valve. The powders of tubers are washed for 10 minutes while 1 liter of contaminated water due toxin mixture is flowing out. At this time, the controller will automatically triggered inlet solenoid valve and the new water will flow in machine tank until achieve the desire level that which determined by ultra sonic sensor. This process will repeated for 7 h and the positive result is achieved and shows it significant according to the several parameters of biological character ofpH, temperature, dissolve oxygen, turbidity, conductivity and fish survival rate or time. From that parameter, it also shows the positive result which is near or same with control water and assuming was made that the toxin is fully removed when the pH of DH powder is near with control water. For control water, the pH is about 5.3 while water from this experiment process is 6.0 and before run the machine the pH of contaminated water is about 3.8 which are too acid. This automated machine can save time for removing toxicity from DH compared with a traditional method while less observation of the user. PMID:24783795

  6. Alkaloids from Galanthus nivalis.

    PubMed

    Berkov, Strahil; Codina, Carles; Viladomat, Francesc; Bastida, Jaume

    2007-07-01

    Phytochemical studies on Galanthus nivalis of Bulgarian origin resulted in the isolation of five compounds: 11-O-(3'-hydroxybutanoyl)hamayne, 3,11-O-(3',3''-dihydroxybutanoyl)hamayne, 3-O-(2''-butenoyl)-11-O-(3'-hydroxybutanoyl)hamayne, 3,11,3''-O-(3',3'',3'''-trihydroxybutanoyl)hamayne, and 2-O-(3'-acetoxybutanoyl)lycorine, together with five known alkaloids: ungeremine, lycorine, tazettine, hamayne, and ismine. Their structures were determined by (1)H and (13)C NMR spectroscopy and two-dimensional (1)H-(1)H and (1)H-(13)C chemical shift correlation experiments.

  7. Omnibus experiment: CPT and CP violation with sterile neutrinos

    NASA Astrophysics Data System (ADS)

    Loo, K. K.; Novikov, N. Yu; Smirnov, M. V.; Trzaska, W. H.; Wurm, M.

    2016-05-01

    We propose to probe both the CPT and CP violation together with the search for sterile neutrinos in one do-it-all experiment. This omnibus experiment would utilize neutrino oscillometry with large scintillator detectors like LENA, JUNO or RENO-50 and manmade radioactive sources similar to the ones used by the GALLEX experiment. Our calculations indicate that such an experiment is realistic and could be performed in parallel to the main research plan for JUNO, LENA, or RENO-50. Assuming as the starting point the values of the oscillation parameters indicated by the current global fit (in 3 active + 1 sterile scenario) and requiring at least 5 sigma confidence level, we estimate that with the proposed experiment we would be able to detect CPT mass anomalies of the order of 1% or larger.

  8. Tests of CP and CPT with polarized positronium

    SciTech Connect

    Skalsey, M. )

    1992-08-20

    This paper reports on two experiments, using polarization techniques with triplet positronium (ps), that have searched for violations of initially the CPT and, most recently, the CP symmetries. Angular correlations between the Ps spin (S) and the momenta of the decay [lambda]-rays ([vert bar]k[sub 1][vert bar] [gt] [vert bar]k[sub 2][vert bar] [gt] [vert bar]k[sub 3][vert bar]) were measured: C[sub n](S [center dot] K[sub 1] [times] k[sub 2]) CPT-test, C[sub CP](S [center dot] k[sub 1])(S [center dot] k[sub 1] [times] k[sub 2]) CP-test.

  9. CPT symmetry and antimatter gravity in general relativity

    NASA Astrophysics Data System (ADS)

    Villata, M.

    2011-04-01

    The gravitational behavior of antimatter is still unknown. While we may be confident that antimatter is self-attractive, the interaction between matter and antimatter might be either attractive or repulsive. We investigate this issue on theoretical grounds. Starting from the CPT invariance of physical laws, we transform matter into antimatter in the equations of both electrodynamics and gravitation. In the former case, the result is the well-known change of sign of the electric charge. In the latter, we find that the gravitational interaction between matter and antimatter is a mutual repulsion, i.e. antigravity appears as a prediction of general relativity when CPT is applied. This result supports cosmological models attempting to explain the Universe accelerated expansion in terms of a matter-antimatter repulsive interaction.

  10. Tests of Lorentz and CPT symmetry with hadrons and nuclei

    NASA Astrophysics Data System (ADS)

    Noordmans, J. P.; de Vries, J.; Timmermans, R. G. E.

    2016-08-01

    We explore the breaking of Lorentz and CPT invariance in strong interactions at low energy in the framework of chiral perturbation theory. Starting from the set of Lorentz-violating operators of mass-dimension five with quark and gluon fields, we construct the effective chiral Lagrangian with hadronic and electromagnetic interactions induced by these operators. We develop the power-counting scheme and discuss loop diagrams and the one-pion-exchange nucleon-nucleon potential. The effective chiral Lagrangian is the basis for calculations of low-energy observables with hadronic degrees of freedom. As examples, we consider clock-comparison experiments with nuclei and spin-precession experiments with nucleons in storage rings. We derive strict limits on the dimension-five tensors that quantify Lorentz and CPT violation.

  11. Effect of precursors feeding and media manipulation on production of novel anticancer pro-drug camptothecin from endophytic fungus.

    PubMed

    Amna, Touseef; Amina, Musarat; Sharma, P R; Puri, S C; Al-Youssef, Hanan M; Al-Taweel, Areej M; Qazi, G N

    2012-10-01

    We have established methodology for the isolation and characterization of a novel endophytic fungus from the inner bark of medicinal plant Nothapodytes foetida, which produced camptothecin in Sabouraud broth (SB) under shake flask conditions. Camptothecin and its related compounds are at present obtained by extraction from intact plants, but fungal endopytes may be an alternative source of production. In present study we have observed the effect of different nutrient combinations and precursors (tryptophan, tryptamine, geraniol, citral, mevalonic acid and leucine) on the accumulation of camptothecin by endophytic fungus Entrophospora infrequens. The precursors were fed either alone or in combinations (tryptophan and geraniol, tryptophan and citral, tryptophan and mevalonic acid, tryptophan and leucine). The highest camptothecin content was observed in the range of 503 ± 25µg/100g dry cell mass in Sabouraud medium. Camptothecin content in the medium was increased by 2.5 folds by the presence of tryptophan and leucine whereas the production with trytophan was also significantly different from other treatments. Furthermore, the effect of fungal camptothecin on the morphology of human cancer cell lines was also studied. The treated cells showed reduction in size, condensation of nucleus and the protoplasmic extensions were reduced. All these characteristics are found in apoptotic cells. PMID:24031979

  12. Tomographic Site Characterization Using CPT, ERT, and GPR

    SciTech Connect

    Rexford M. Morey

    1997-05-23

    The U.S. Department of Energy (DOE) is responsible for the cleanup of inactive DOE sites and for bringing DOE sites and facilities into compliance with federal, state and local laws and regulations. The DOE's Office of Environmental Management (EM) needs advanced technologies that can make environmental restoration and waste management operations more efficient and less costly. These techniques are required to better characterize the physical, hydrogeological, and chemical properties of the subsurface while minimizing and optimizing the use of boreholes and monitoring wells. Today the cone penetrometer technique (CPT) is demonstrating the value of a minimally invasive deployment system fix site characterization. Applied Research Associates is developing two new sensor packages for site characterization and monitoring. The two new methods are: . Electrical Resistivity Tomography (ERT) and . Ground Penetrating Radar (GPR) Tomography. These sensor systems are now integrated with the Cone Penetrometer Technique (CPT). The results of this program now make it possible to install ERT and GPR units by CPT methods and thereby reduce installation costs and total costs for ERT and GPR surveys. These two techniques can complement each other in regions of low resistivity where ERT is more effective and regions of high resistivity where GPR is more effective. The results show that CPT-installed GeoWells can be used in both ERT and GPR borehole tomographic subsurface imaging. These two imaging techniques can be used for environmental site characterization and environmental remediation monitoring. Technologies used for site characterization and monitoring have numerous and diverse applications within site clean-up and waste management operations.

  13. Checking T and CPT violation with sterile neutrino

    NASA Astrophysics Data System (ADS)

    Pant, Yogita; Diwakar, Sujata; Singh, Jyotsna; Singh, R. B.

    2016-08-01

    Post LSND results, sterile neutrinos have drawn attention and motivated the high energy physics, astronomy and cosmology to probe physics beyond the standard model considering minimal 3 + 1 (3 active and 1 sterile) to 3 + N neutrino schemes. The analytical equations for neutrino conversion probabilities are developed in this work for 3 + 1 neutrino scheme. Here, we have tried to explore the possible signals of T and CPT violations with four flavor neutrino scheme at neutrino factory. Values of sterile parameters considered in this analysis are taken from two different types of neutrino experiments viz. long baseline experiments and reactor+atmospheric experiments. In this work golden and discovery channels are selected for the investigation of T violation. While observing T violation we stipulate that neutrino factory working at 50 GeV energy has the potential to observe the signatures of T violation through discovery channel if sterile parameter values are equal to that taken from reactor+atmospheric experiments. The ability of neutrino factory for constraining CPT violation is enhanced with increase in energy for normal neutrino mass hierarchy (NH). Neutrino factory with the exposure time of 500 kt-yr will be able to capture CPT violation with δc31 ≥ 3.6 ×10-23 GeV at 3σ level for NH and for IH with δc31 ≥ 4 ×10-23 GeV at 3σ level.

  14. Purine alkaloids in Paullinia.

    PubMed

    Weckerle, Caroline S; Stutz, Michael A; Baumann, Thomas W

    2003-10-01

    Among the few purine alkaloid-containing genera consumed as stimulants, Paullinia is the least investigated with respect to both chemotaxonomy and within-the-plant allocation of caffeine and its allies. Since purine alkaloids (PuA) have been proved to be valuable marker compounds in chemotaxonomy, 34 species of Paullinia and related genera were screened for them, but only one, P. pachycarpa, was positive in addition to the already known P. cupana and P. yoco. The PuA allocation in P. pachycarpa was examined and found to be restricted to theobromine in the stem, leaves and flowers. Moreover, the theobromine concentration in the stem cortex increased significantly towards the base of the plant. Since the stem cortex of P. yoco is traditionally used by the natives of Colombia and Ecuador to prepare a caffeine-rich beverage, we suspected that within the genus Paullinia the PuA are preferentially allocated to the older parts of the stem and not to young shoots like e.g., in the coffee plant (Coffea spp.). Indeed, the axis (greenhouse) of P. cupana (guaraná), known for its caffeine-rich seeds, exhibited a basipetal PuA gradient (0.005-0.145%). Moreover, the analysis of young cortex samples (herbarium) and of one piece of old stem (museum collection) revealed the same for P. yoco, even though we found much less (0.5 vs 2.5%) caffeine in the old cortex as compared to the only two analyses in 1926 of similar material. However, this discrepancy may be explained by the high variability of the PuA pattern we detected among yoco, the diversity of which the Indians take advantage.

  15. Activity of weekly irinotecan (CPT-11) in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes.

    PubMed

    Sánchez, Rosa; Esteban, Emilio; Palacio, Isabel; Fernández, Yolanda; Muñiz, Isabel; Vieitez, Jose M; Fra, Joaquin; Blay, Pilar; Villanueva, Noemí; Uña, Esther; Mareque, Beatriz; Estrada, Enrique; Buesa, Jose M; Lacave, Angel J

    2003-11-01

    Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is active in the treatment of non-small cell lung cancer (NSCLC). In this report we describe our experience with this drug when used as a single agent in patients with advanced NSCLC refractory to chemotherapy with platinum and taxanes. Nineteen NSCLC patients (thirteen males and six females; 53% adenocarcinoma and 26% squamous cell carcinoma) with a median age of 52 years (range 34-71) and a Karnofsky performance status of 60% (60-80%) were included in the study. At baseline, the patients had a median of two disease sites and had been treated with a median of two prior regimens. Irinotecan was given at a dose of 100 mg/m(2) i.v.) weekly for 4 weeks followed by 1 week of rest. A total of 123 weekly infusions were administered, and each patient received a median of 4 weeks of treatment (range 1-32). All patients were evaluated by intention-to-treat analysis for efficacy and safety. Main toxicities reported were grade 3 neutropenia (10% of patients), diarrhea (10% of patients), and grade 4 thrombocytopenia (5% of patients). The overall clinical response rate was 16% (95% CI: 8-24) with three partial responses and 9 (47%) patients with stable disease. The median time to progression and the median survival time were 7 and 15 weeks, respectively. In conclusion, weekly irinotecan showed antitumoral activity and minimum toxicity in NSCLC patients refractory to platinum and taxanes.

  16. Biosynthetic Pathways of Ergot Alkaloids

    PubMed Central

    Gerhards, Nina; Neubauer, Lisa; Tudzynski, Paul; Li, Shu-Ming

    2014-01-01

    Ergot alkaloids are nitrogen-containing natural products belonging to indole alkaloids. The best known producers are fungi of the phylum Ascomycota, e.g., Claviceps, Epichloë, Penicillium and Aspergillus species. According to their structures, ergot alkaloids can be divided into three groups: clavines, lysergic acid amides and peptides (ergopeptines). All of them share the first biosynthetic steps, which lead to the formation of the tetracyclic ergoline ring system (except the simplest, tricyclic compound: chanoclavine). Different modifications on the ergoline ring by specific enzymes result in an abundance of bioactive natural products, which are used as pharmaceutical drugs or precursors thereof. From the 1950s through to recent years, most of the biosynthetic pathways have been elucidated. Gene clusters from several ergot alkaloid producers have been identified by genome mining and the functions of many of those genes have been demonstrated by knock-out experiments or biochemical investigations of the overproduced enzymes. PMID:25513893

  17. [Taxotere (docetaxel) and CPT 11 (irinotecan): phase I trials].

    PubMed

    Couteau, C; Yakendji, K; Terret, C; Goncalves, E; Armand, J P

    1996-01-01

    Two new drugs from two new chemotherapy compound families were developed concomitantly: Taxoter (docetaxel), a taxane derivate and CPT 11 (irinotecan) a topoisomerase inhibitor. Six phase I trials of Taxoter were performed. The limiting toxicity is neutropenia. The recommended dosage for phase II trial is 100 mg/m2 administered in 1 hour perfusion, every 21 days. Neutropenic fever is unfrequent. Other toxicities are mucositis, skin toxicity, hypersensibility reaction, weight gain and oedema. None of these toxicities were limiting. Six phase I studies were conducted to determine the maximum tolerated dose of CPT 11 (irinotecan). Two different schedules were studied: the weekly 30-90 minutes infusion and an infusion administered every three weeks in one day or daily over three or five consecutive days. The limiting toxicity of the weekly schedule is diarrhea. Therefore the recommended dosage is 100-150 mg/m2/week. While dose limiting toxicities in the three week schedule are diarrhea as well as neutropenia. The recommended dose is 350 mg/m2. Since diarrhea appeared to be the major problem in achieving high dose intensity with CPT 11, a dose escalation trial with drug support against diarrhea was performed. A recommended dosage of 500 mg/m2 is therefore described. These two drugs are under evaluation in a large spectrum of tumors. Their original mechanism of action suggests interesting therapeutic properties. Clinical studies in combination with other drugs are in progress to define the role of topoisomerase I inhibitors and taxane in cancer therapy. PMID:8672854

  18. TESTING CPT SYMMETRY WITH CURRENT AND FUTURE CMB MEASUREMENTS

    SciTech Connect

    Li, Si-Yu; Zhang, Xinmin; Xia, Jun-Qing; Li, Hong; Li, Mingzhe

    2015-02-01

    In this paper, we use the current and future cosmic microwave background (CMB) experiments to test the Charge-Parity-Time Reversal (CPT) symmetry. We consider a CPT-violating interaction in the photon sector L{sub cs}∼p{sub μ}A{sub ν} F-tilde {sup μν}, which gives rise to a rotation of the polarization vectors of the propagating CMB photons. By combining the 9 yr WMAP, BOOMERanG 2003, and BICEP1 observations, we obtain the current constraint on the isotropic rotation angle α-bar =−2.12±1.14 (1σ), indicating that the significance of the CPT violation is about 2σ. Here, we particularly take the systematic errors of CMB measurements into account. Then, we study the effects of the anisotropies of the rotation angle [Δα( n-hat )] on the CMB polarization power spectra in detail. Due to the small effects, the current CMB polarization data cannot constrain the related parameters very well. We obtain the 95% C.L. upper limit of the variance of the anisotropies of the rotation angle C {sup α}(0) < 0.035 from all of the CMB data sets. More interestingly, including the anisotropies of rotation angle could lower the best-fit value of r and relax the tension on the constraints of r between BICEP2 and Planck. Finally, we investigate the capabilities of future Planck polarization measurements on α-bar and Δα( n-hat ). Benefited from the high precision of Planck data, the constraints of the rotation angle can be significantly improved.

  19. Decoherence induced CPT violation and entangled neutral mesons

    SciTech Connect

    Bernabeu, J.; Mavromatos, Nick E.; Sarkar, Sarben

    2006-08-15

    We discuss two classes of semimicroscopic theoretical models of stochastic spacetime foam in quantum gravity and the associated effects on entangled states of neutral mesons, signalling an intrinsic breakdown of CPT invariance. One class of models deals with a specific model of foam, initially constructed in the context of noncritical (Liouville) string theory, but viewed here in the more general context of effective quantum-gravity models. The relevant Hamiltonian perturbation, describing the interaction of the meson with the foam medium, consists of off-diagonal stochastic metric fluctuations, connecting distinct mass eigenstates (or the appropriate generalization thereof in the case of K-mesons), and it is proportional to the relevant momentum transfer (along the direction of motion of the meson pair). There are two kinds of CPT-violating effects in this case, which can be experimentally disentangled: one (termed '{omega}-effect') is associated with the failure of the indistinguishability between the neutral meson and its antiparticle, and affects certain symmetry properties of the initial state of the two-meson system; the second effect is generated by the time evolution of the system in the medium of the spacetime foam, and can result in time-dependent contributions of the {omega}-effect type in the time profile of the two-meson state. Estimates of both effects are given, which show that, at least in certain models, such effects are not far from the sensitivity of experimental facilities available currently or in the near future. The other class of quantum-gravity models involves a medium of gravitational fluctuations which behaves like a 'thermal bath'. In this model both of the above-mentioned intrinsic CPT violation effects are not valid.

  20. Searches for Lorentz and CPT Violation with Fermions in Penning Traps

    NASA Astrophysics Data System (ADS)

    Ding, Yunhua; Kostelecký, V. Alan

    2015-04-01

    A theoretical analysis is performed of the prospects for detecting Lorentz and CPT violation in Penning-trap experiments with trapped particles and antiparticles. Using the general effective field theory called the Standard-Model Extension, we study signals in anomaly and cyclotron frequencies arising from Lorentz- and CPT-violating operators of arbitrary mass dimensions. Constraints on coefficients for Lorentz and CPT violation are extracted from existing data, and sensitivities attainable in forthcoming Penning-trap experiments are discussed.

  1. The Carnitine Palmitoyl Transferase (CPT) System and Possible Relevance for Neuropsychiatric and Neurological Conditions.

    PubMed

    Virmani, Ashraf; Pinto, Luigi; Bauermann, Otto; Zerelli, Saf; Diedenhofen, Andreas; Binienda, Zbigniew K; Ali, Syed F; van der Leij, Feike R

    2015-10-01

    The carnitine palmitoyl transferase (CPT) system is a multiprotein complex with catalytic activity localized within a core represented by CPT1 and CPT2 in the outer and inner membrane of the mitochondria, respectively. Two proteins, the acyl-CoA synthase and a translocase also form part of this system. This system is crucial for the mitochondrial beta-oxidation of long-chain fatty acids. CPT1 has two well-known isoforms, CPT1a and CPT1b. CPT1a is the hepatic isoform and CPT1b is typically muscular; both are normally utilized by the organism for metabolic processes throughout the body. There is a strong evidence for their involvement in various disease states, e.g., metabolic syndrome, cardiovascular diseases, and in diabetes mellitus type 2. Recently, a new, third isoform of CPT was described, CPT1c. This is a neuronal isoform and is prevalently localized in brain regions such as hypothalamus, amygdala, and hippocampus. These brain regions play an important role in control of food intake and neuropsychiatric and neurological diseases. CPT activity has been implicated in several neurological and social diseases mainly related to the alteration of insulin equilibrium in the brain. These pathologies include Parkinson's disease, Alzheimer's disease, and schizophrenia. Evolution of both Parkinson's disease and Alzheimer's disease is in some way linked to brain insulin and related metabolic dysfunctions with putative links also with the diabetes type 2. Studies show that in the CNS, CPT1c affects ceramide levels, endocannabionoids, and oxidative processes and may play an important role in various brain functions such as learning. PMID:26041663

  2. Rubitecan: 9-NC, 9-Nitro-20(S)-camptothecin, 9-nitro-camptothecin, 9-nitrocamptothecin, RFS 2000, RFS2000.

    PubMed

    2004-01-01

    Rubitecan [Orathecin, 9-nitrocamptothecin, 9NC, RFS 2000] is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree, which is native to China. Rubitecan is an oral compound being developed for the treatment of pancreatic cancer and other solid tumours by SuperGen. One of the major benefits of rubitecan is that it can be administered in an outpatient setting, so patients can be treated in their homes. Rubitecan was isolated by the Stehlin Foundation in the US. SuperGen is currently awaiting regulatory approval in the US and the EU for rubitecan in the treatment of pancreatic cancer. At the BIO-2004 conference, SuperGen announced it is seeking a partner for rubitecan for territories outside the US. SuperGen acquired exclusive worldwide rights to rubitecan from the Stehlin Foundation in 1997 except in Mexico, Canada, Spain, Japan, the UK, France, Italy and Germany. SuperGen has also received approval from the US FDA to use its own manufactured rubitecan in clinical trials. SuperGen and the Stehlin Foundation have an 8-year research agreement that secures global rights to other camptothecins and additional anticancer compounds for the former. In December 1999, SuperGen and Abbott signed a worldwide sales and marketing agreement for rubitecan. Under the terms of the agreement, Abbott had exclusive distribution and promotion rights for rubitecan outside the US, and co-promotion rights with SuperGen within the US. In return, Abbott made an initial equity investment in SuperGen. SuperGen and Abbott Laboratories ended their collaboration agreement in February 2002 by mutual consent with SuperGen stating that the dissolution of the agreement was based on commercial motivation rather than anything to do with rubitecan's safety or efficacy. Abbott no longer has rights or obligations to purchase shares of SuperGen stock or an option to purchase up to 49% of the company. For its part, SuperGen will no longer receive milestone payments

  3. Prospects of CPT tests using antiprotonic helium and antihydrogen

    SciTech Connect

    Hayano, Ryugo S.

    2005-10-19

    Testing CPT to the highest possible precision using the laser spectroscopy of antiprotonic helium atoms (a neutral three-body system consisting of an antiproton, a helium nucleus and an electron) is the current goal of ASACUSA collaboration at CERN AD. The present status and future prospects are discussed in the first half of the talk. Our program will be extended in the future to include the microwave spectroscopy of ground-state hyperfine splitting of antihydrogen. The physics motivations and possible measurement schemes are presented in the second half.

  4. Tests of CPT, Lorentz invariance and the WEP with antihydrogen

    SciTech Connect

    Holzscheiter, M.H.; ATHENA Collaboration

    1999-03-01

    Antihydrogen atoms, produced near rest, trapped in a magnetic well, and cooled to the lowest possible temperature (kinetic energy) could provide an extremely powerful tool for the search of violations of CPT and Lorentz invariance. Equally well, such a system could be used for searches of violations of the Weak Equivalence Principle (WEP) at high precision. The author describes his plans to form a significant number of cold, trapped antihydrogen atoms for comparative precision spectroscopy of hydrogen and antihydrogen and comment on possible first experiments.

  5. The Chemistry of the Akuammiline Alkaloids.

    PubMed

    Adams, Gregory L; Smith, Amos B

    2016-01-01

    An update on the literature covering the akuammiline family of alkaloids is presented. This chapter begins with a summary of new akuammiline alkaloids reported since 2000 and is followed by an overview of new reported bioactivities of akuammiline alkaloids since 2000. The remainder of the chapter comprises a comprehensive review of the synthetic chemistry that has been reported in the last 50 years concerning akuammiline alkaloids and their structural motifs.

  6. CPT conservation and atmospheric neutrinos in the MINOS far detector

    SciTech Connect

    Becker, Bernard Raymond

    2006-02-01

    The MINOS Far Detector is a 5400 ton iron calorimeter located at the Soudan state park in Soudan Minnesota. The MINOS far detector can observe atmospheric neutrinos and separate charge current νμ and $\\bar{v}$μ interactions by using a 1.4 T magnetic field to identify the charge of the produced muon. The CPT theorem requires that neutrinos and anti-neutrinos oscillate in the same way. In a fiducial exposure of 5.0 kilo-ton years a total of 41 candidate neutrino events are observed with an expectation of 53.1 ± 7.6(system.) ± 7.2(stat.) unoscillated events or 31.6 ± 4.7(system.) ± 5.6(stat.) events with Δm2 = 2.4 x 10-3 eV2, sin2(2θ) = 1.0 as oscillation parameters. These include 28 events which can have there charge identified with high confidence. These 28 events consist of 18 events consistent with being produced by νμ and 10 events being consistent with being produced by $\\bar{v}$μ. No evidence of CPT violation is observed.

  7. 27 CFR 21.99 - Brucine alkaloid.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Brucine alkaloid. 21.99... Brucine alkaloid. (a) Identification test. Add a few drops of concentrated nitric acid to about 10 mg of brucine alkaloid. A vivid red color is produced. Dilute the red solution with a few drops of water and...

  8. 27 CFR 21.99 - Brucine alkaloid.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false Brucine alkaloid. 21.99... Brucine alkaloid. (a) Identification test. Add a few drops of concentrated nitric acid to about 10 mg of brucine alkaloid. A vivid red color is produced. Dilute the red solution with a few drops of water and...

  9. 27 CFR 21.99 - Brucine alkaloid.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Brucine alkaloid. 21.99... Brucine alkaloid. (a) Identification test. Add a few drops of concentrated nitric acid to about 10 mg of brucine alkaloid. A vivid red color is produced. Dilute the red solution with a few drops of water and...

  10. 27 CFR 21.99 - Brucine alkaloid.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Brucine alkaloid. 21.99... Brucine alkaloid. (a) Identification test. Add a few drops of concentrated nitric acid to about 10 mg of brucine alkaloid. A vivid red color is produced. Dilute the red solution with a few drops of water and...

  11. AMPAR interacting protein CPT1C enhances surface expression of GluA1-containing receptors

    PubMed Central

    Gratacòs-Batlle, Esther; Yefimenko, Natalia; Cascos-García, Helena; Soto, David

    2015-01-01

    AMPARs mediate the vast majority of fast excitatory synaptic transmission in the brain and their biophysical and trafficking properties depend on their subunit composition and on several posttranscriptional and posttranslational modifications. Additionally, in the brain AMPARs associate with auxiliary subunits, which modify the properties of the receptors. Despite the abundance of AMPAR partners, recent proteomic studies have revealed even more interacting proteins that could potentially be involved in AMPAR regulation. Amongst these, carnitine palmitoyltransferase 1C (CPT1C) has been demonstrated to form an integral part of native AMPAR complexes in brain tissue extracts. Thus, we aimed to investigate whether CPT1C might be able to modulate AMPAR function. Firstly, we confirmed that CPT1C is an interacting protein of AMPARs in heterologous expression systems. Secondly, CPT1C enhanced whole-cell currents of GluA1 homomeric and GluA1/GluA2 heteromeric receptors. However, CPT1C does not alter the biophysical properties of AMPARs and co-localization experiments revealed that AMPARs and CPT1C are not associated at the plasma membrane despite a strong level of co-localization at the intracellular level. We established that increased surface GluA1 receptor number was responsible for the enhanced AMPAR mediated currents in the presence of CPT1C. Additionally, we revealed that the palmitoylable residue C585 of GluA1 is important in the enhancement of AMPAR trafficking to the cell surface by CPT1C. Nevertheless, despite its potential as a depalmitoylating enzyme, CPT1C does not affect the palmitoylation state of GluA1. To sum up, this work suggests that CPT1C plays a role as a novel regulator of AMPAR surface expression in neurons. Fine modulation of AMPAR membrane trafficking is fundamental in normal synaptic activity and in plasticity processes and CPT1C is therefore a putative candidate to regulate neuronal AMPAR physiology. PMID:25698923

  12. Preclinical development of camptothecin derivatives and clinical trials in pediatric oncology.

    PubMed

    Vassal, G; Pondarré, C; Boland, I; Cappelli, C; Santos, A; Thomas, C; Lucchi, E; Imadalou, K; Pein, F; Morizet, J; Gouyette, A

    1998-03-01

    Although the prognosis of childhood cancers has dramatically improved over the last three decades, new active drugs are needed. Camptothecins represent a very attractive new class of anticancer drugs to develop in paediatric oncology. The preclinical and clinical development of two of these DNA-topoisomerase I inhibitors, i.e. topotecan and irinotecan, is ongoing in paediatric malignancies. Here we review the currently available results of this evaluation. Topotecan proved to be active against several paediatric tumour xenografts. In paediatric phase I studies exploring several administration schedules, myelosuppression was dose-limiting. The preliminary results of topotecan evaluation in phase II study showed antitumour activity in neuroblastoma (response rate: 15% at relapse and 37% in newly diagnosed patients with disseminated disease) and in metastatic rhabdomyosarcoma (40% in untreated patients). Topotecan-containing drug combinations are currently investigated. Irinotecan displayed a broad spectrum of activity in paediatric solid tumour xenografts, including rhabdo-myosarcoma, neuroblastoma, peripheral primitive neuroectodermal tumour, medulloblastoma, ependymoma, malignant glioma and juvenile colon cancer. For several of these histology types, tumour-free survivors have been observed among animals bearing an advanced-stage tumour at time of treatment. The clinical evaluation of irinotecan in children is ongoing. Irinotecan undergoes a complex in vivo biotransformation involving several enzyme systems, such as carboxylesterase, UDPGT and cytochrome P450, in children as well as in adults. Preclinical studies of both drugs have shown that their activity was schedule-dependent. The optimal schedule of administration is an issue that needs to be addressed in children. In conclusion, the preliminary results of the paediatric evaluation of camptothecin derivatives show very encouraging results in childhood malignancies. The potential place of camptothecins in the

  13. Suzuki coupling based synthesis and in vitro cytotoxic evaluation of 7-heteroaryl-substituted camptothecin analogs.

    PubMed

    Wang, Lei; Huang, Ying; Zhang, Jie; Tong, Linjiang; Chen, Yi; Lu, Wei; Huang, Qingqing

    2014-03-15

    In an effort to discover potent antitumor agents, a series of novel C-7-heteroaryl-substituted camptothecin derivatives were designed and synthesized via microwave-promoted Suzuki coupling reaction. These analogs were then assessed for cytotoxicity against three human tumor cell lines, A549, HCT116, HT-29, and inhibitory effects on topoisomerase I. All of the new compounds showed potent inhibition of human tumor cell growth, among which compound 10a showed higher cytotoxic activity than that of SN-38. Furthermore, this series of compounds retained or enhanced Topo I inhibition. PMID:24529870

  14. The alkaloid profiles of Lupinus sulphureus.

    PubMed

    Cook, Daniel; Lee, Stephen T; Gardner, Dale R; Pfister, James A; Welch, Kevin D; Green, Benedict T; Davis, T Zane; Panter, Kip E

    2009-02-25

    Lupines are common plants on the rangelands in the western United States. Lupines contain alkaloids that can be toxic and teratogenic causing congenital birth defects (crooked calf disease). One such lupine, Lupinus sulphureus, occurs in parts of Oregon, Washington, and British Columbia. Specimens of L. sulphureus from field collections and herbaria were evaluated taxonomically and by chemical means. A total of seven distinct alkaloid profiles and the individual alkaloids associated with each profile were identified. Each alkaloid profile was unique in its geographical distribution and its potential risk to livestock. In conclusion, taxonomic classification is not sufficient to determine risk, as chemical characterization of the alkaloids must also be performed.

  15. The invariance of classical electromagnetism under Charge-conjugation, Parity and Time-reversal (CPT) transformations

    NASA Technical Reports Server (NTRS)

    Norbury, John W.

    1989-01-01

    The invariance of classical electromagnetism under charge-conjugation, parity, and time-reversal (CPT) is studied by considering the motion of a charged particle in electric and magnetic fields. Upon applying CPT transformations to various physical quantities and noting that the motion still behaves physically demonstrates invariance.

  16. Structural and quantitative analysis of Equisetum alkaloids.

    PubMed

    Cramer, Luise; Ernst, Ludger; Lubienski, Marcus; Papke, Uli; Schiebel, Hans-Martin; Jerz, Gerold; Beuerle, Till

    2015-08-01

    Equisetum palustre L. is known for its toxicity for livestock. Several studies in the past addressed the isolation and identification of the responsible alkaloids. So far, palustrine (1) and N(5)-formylpalustrine (2) are known alkaloids of E. palustre. A HPLC-ESI-MS/MS method in combination with simple sample work-up was developed to identify and quantitate Equisetum alkaloids. Besides the two known alkaloids six related alkaloids were detected in different Equisetum samples. The structure of the alkaloid palustridiene (3) was derived by comprehensive 1D and 2D NMR experiments. N(5)-Acetylpalustrine (4) was also thoroughly characterized by NMR for the first time. The structure of N(5)-formylpalustridiene (5) is proposed based on mass spectrometry results. Twenty-two E. palustre samples were screened by a HPLC-ESI-MS/MS method after development of a simple sample work-up and in most cases the set of all eight alkaloids were detected in all parts of the plant. A high variability of the alkaloid content and distribution was found depending on plant organ, plant origin and season ranging from 88 to 597mg/kg dried weight. However, palustrine (1) and the alkaloid palustridiene (3) always represented the main alkaloids. For the first time, a comprehensive identification, quantitation and distribution of Equisetum alkaloids was achieved.

  17. Monoterpene alkaloids from Argylia radiata.

    PubMed

    Bianco, Armandodoriano; Bonadies, Francesco; Cianciolo, Valeria; Melchioni, Cristiana; Ramunno, Alessia; Dezzi, Sandro; Nicoletti, Marcello; Serafini, Mauro; Ballero, Mauro

    2002-04-01

    Argylia radiata (L.) D. Don (Bignoniaceae) represents an important source of secondary metabolites, largely unexplored. The paper presents the isolation from the plant root of two new monoterpene alkaloids, 10-acetoxy-actinidine and 4-nor-7,8-dehydro-10-hydroxy-skytanthine, whose structures were elucidated by Mass spectrometry and 1H-NMR data.

  18. Indole alkaloids from Antirhea lucida.

    PubMed

    Weniger, B; Rafik, W; Bastida, J; Quirion, J C; Anton, R

    1995-12-01

    A new indole alkaloid, N,N-methyl-3'-indolylmethyl-5-methoxytryptamine, as well as the known gramine, N,N-dimethyltryptamine and 6-methoxy-2-methyl-1,2,3,4-tetrahydro-beta-carboline were isolated from the roots of Antirhea lucida (Sw.) Hook (Rubiaceae). Their structures were established by spectroscopic methods.

  19. Quaternary alkaloids of tinospora species.

    PubMed

    Bisset, N G; Nwaiwu, J

    1983-08-01

    The occurrence of quaternary alkaloids in TINOSPORA (and PARABAENA) species (Menispermaceae) has been studied. The main components were generally the protoberberine bases berberine and palmatine, with jatrorrhizine an occasional minor constituent, and the aporphine base magnoflorine. Choline was also often present. Only magnoflorine was detected in the PARABAENA material examined. PMID:17404996

  20. Nonlinear modes of the tensor Dirac equation and CPT violation

    NASA Technical Reports Server (NTRS)

    Reifler, Frank J.; Morris, Randall D.

    1993-01-01

    Recently, it has been shown that Dirac's bispinor equation can be expressed, in an equivalent tensor form, as a constrained Yang-Mills equation in the limit of an infinitely large coupling constant. It was also shown that the free tensor Dirac equation is a completely integrable Hamiltonian system with Lie algebra type Poisson brackets, from which Fermi quantization can be derived directly without using bispinors. The Yang-Mills equation for a finite coupling constant is investigated. It is shown that the nonlinear Yang-Mills equation has exact plane wave solutions in one-to-one correspondence with the plane wave solutions of Dirac's bispinor equation. The theory of nonlinear dispersive waves is applied to establish the existence of wave packets. The CPT violation of these nonlinear wave packets, which could lead to new observable effects consistent with current experimental bounds, is investigated.

  1. Simultaneously improving the sensitivity and absolute accuracy of CPT magnetometer.

    PubMed

    Liang, Shang-Qing; Yang, Guo-Qing; Xu, Yun-Fei; Lin, Qiang; Liu, Zhi-Heng; Chen, Zheng-Xiang

    2014-03-24

    A new method to improve the sensitivity and absolute accuracy simultaneously for coherent population trapping (CPT) magnetometer based on the differential detection method is presented. Two modulated optical beams with orthogonal circular polarizations are applied, in one of which two magnetic resonances are excited simultaneously by modulating a 3.4GHz microwave with Larmor frequency. When a microwave frequency shift is introduced, the difference in the power transmitted through the cell in each beam shows a low noise resonance. The sensitivity of 2pT/Hz @ 10Hz is achieved. Meanwhile, the absolute accuracy of ± 0.5nT within the magnetic field ranging from 20000nT to 100000nT is realized.

  2. Lethal carnitine palmitoyltransferase (CPT) II deficiency in newborns: A molecular-genetic study

    SciTech Connect

    Taroni, F.; Gellera, C.; Cavadini, P.

    1994-09-01

    Classically, CPT II deficiency presents in young adults with recurrent episodes of paroxysmal myoglobinuria triggered by prolonged exercise, cold, or fever. More severe forms of CPT II deficiency have recently been observed in children and newborns. Here, were present biochemical and molecular studies of lethal neonatal CPT II deficiency in a premature Haitian infant of nonconsanguineous parents. He presented at birth with severe respiratory distress, cardiac arrhythmia and heart failure. His condition worsened and he died on the 4th day of life. Postmortem examination showed hypertrophied, dilated heart, and lipid storage in liver, heart and kidney. An older sibling had died unexpectantly at 4 days of age with postmortem evidence of fatty infiltration of liver, kidney, heart and muscle. Biochemical study of cultured fibroblasts demonstrated dramatic reduction of palmitate oxidation (to < 3%) and very low residual CPT II activity ({le}15%). No CPT II protein was detected by Western blot analysis of fibroblasts. However, immunoprecitation of cells pulse-labeled with L-[{sup 35}S] methionine demonstrated normal amounts of newly synthesized CPT II, thus suggesting altered stability of the enzyme. To identify the molecular defect in his patient, individual CPT II exons were amplified by genomic PCR and directly sequenced. A missense mutation was found in exon 4, resulting in the nonconservative amino acid substitution at codon 227 (Pro227Leu). SSCP analysis of a genomic PCR fragment encompassing the mutation demonstrated that the patient was homozygous and the parents were heterozygous for this mutation. The mutation was detected neither in a large number of controls nor in other CPT II deficient patients. Finally, CPT II activity in COS-1 cells transfected with mutated CPT II cDNA was <8% than that in cells transfected with wild-type cDNA, thus demonstrating the pathogenic role of this mutation.

  3. How Trypanosoma cruzi handles cell cycle arrest promoted by camptothecin, a topoisomerase I inhibitor.

    PubMed

    Zuma, Aline Araujo; Mendes, Isabela Cecília; Reignault, Lissa Catherine; Elias, Maria Carolina; de Souza, Wanderley; Machado, Carlos Renato; Motta, Maria Cristina M

    2014-02-01

    The protozoan Trypanosoma cruzi is the etiological agent of Chagas disease, which affects approximately 8 million people in Latin America. This parasite contains a single nucleus and a kinetoplast, which harbors the mitochondrial DNA (kDNA). DNA topoisomerases act during replication, transcription and repair and modulate DNA topology by reverting supercoiling in the DNA double-strand. In this work, we evaluated the effects promoted by camptothecin, a topoisomerase I inhibitor that promotes protozoan proliferation impairment, cell cycle arrest, ultrastructure alterations and DNA lesions in epimastigotes of T. cruzi. The results showed that inhibition of cell proliferation was reversible only at the lowest drug concentration (1μM) used. The unpacking of nuclear heterochromatin and mitochondrion swelling were the main ultrastructural modifications observed. Inhibition of parasite proliferation also led to cell cycle arrest, which was most likely caused by nuclear DNA lesions. Following camptothecin treatment, some of the cells restored their DNA, whereas others entered early apoptosis but did not progress to late apoptosis, indicating that the protozoa stay alive in a "senescence-like" state. This programmed cell death may be associated with a decrease in mitochondrial membrane potential and an increase in the production of reactive oxygen species. Taken together, these results indicate that the inhibition of T. cruzi proliferation is related to events capable of affecting cell cycle, DNA organization and mitochondrial activity. PMID:24530483

  4. Reprint of: Effect of fermentation parameters, elicitors and precursors on camptothecin production from the endophyte Fusarium solani.

    PubMed

    Venugopalan, Aarthi; Potunuru, Uma Rani; Dixit, Madhulika; Srivastava, Smita

    2016-08-01

    Volumetric productivity of camptothecin from the suspension culture of the endophyte Fusarium solani was enhanced up to ∼152 fold (from 0.19μgl(-1)d(-1) to 28.9μgl(-1)d(-1)) under optimized fermentation conditions including initial pH (6.0), temperature (32°C) and agitation speed (80rpm) with (5% (v/v)) ethanol as medium component. Among various elicitors and precursors studied, tryptamine (0.5mM) as precursor and bovine serum albumin (BSA) (0.075mM) as an elicitor added on day 6 of the cultivation period resulted in maximum enhancement of camptothecin concentration (up to 4.5 and 3.4-fold, respectively). These leads provide immense scope for further enhancement in camptothecin productivity at bioreactor level. The cytotoxicity analysis of the crude camptothecin extract from the fungal biomass revealed its high effectiveness against colon and mammary gland cancer cell lines. PMID:27189536

  5. Antifeedant C20 diterpene alkaloids.

    PubMed

    González-Coloma, Azucena; Reina, Matías; Guadaño, Ana; Martínez-Díaz, Rafael; Díaz, Jesús G; García-Rodriguez, Juan; Alva, Allenger; Grandez, Maritza

    2004-09-01

    We have tested the insect antifeedant and toxic activity of 21 C20 diterpenoid alkaloids on Spodoptera littoralis and Leptinotarsa decemlineata. The antifeedant effects of the test compounds were structure- and species-dependent. The most active antifeedants to L. decemlineata and S. littoralis were the rearranged form of hetisine (20; EC50 = 1.7 microg/cm2) and 19-oxodihydroatisine (9; EC50 = 0.1 microg/cm2), resp. Glandulosine (8) moderately affected orally injected S. littoralis larvae. A few compounds (13-oxocardiopetamine (4), 9, and atisinium chloride (13)) had cytotoxic effects to insect-derived Sf9 cells with varying degrees of selectivity with respect to mammalian CHO cells. Compounds 4 and 15,22-O-diacetyl-19-oxodihydroatisine (10) increased Trypanosoma cruzi mortality. Our results support the plant protective role of C20 diterpenoid alkaloids and open a new field for parasite control strategies.

  6. Computational Study of Anticancer Drug Resistance Caused by 10 Topisomerase I Mutations, Including 7 Camptothecin Analogs and Lucanthone.

    PubMed

    Mulholland, Kelly; Wu, Chun

    2016-09-26

    Although Camptothecin and its analogs as Topoisomerase I poisons can effectively treat cancers, serious drug resistance has been identified for this class of drugs. Recent computational studies have indicated that the mutations near the active binding site of the drug can significantly weaken the drug binding and cause drug resistance. However, only Topotecan and three mutations have been previously analyzed. Here we present a comprehensive binding study of 10 Topoisomerase I mutants (N722S, N722A, D533G, D533N, G503S, G717V, T729A, F361S, G363C, and R364H) and 8 poisons including 7 Camptothecin analogs as well as a new generation Topoisomerase I drug, Lucanthone. Utilizing Glide docking followed by MMGBSA calculations, we determined the binding energy for each complex. We examine the relative binding energy changes with reference to the wild type, which are linked to the degree of drug resistance. On this set of mutant complexes, Topotecan and Camptothecin showed much smaller binding energies than a set of new Camptothecin derivatives (Lurtotecan, SN38, Gimatecan, Exatecan, and Belotecan) currently under clinical trials. We observed that Lucanthone exhibited comparable results to Topotecan and Camptothecin, indicating that it may serve as a promising candidate for future studies as a Topoisomerase I poison. Our docked results on Topotecan were also validated by a set of molecular dynamics simulations. In addition to a good agreement on the MMGBSA binding energy change, our simulation data also shows there is larger conformation fluctuation upon the mutations. These results may be utilized to further advancements of Topoisomerase I drugs that are resistant to mutations.

  7. Spin-polarized dark state free CPT state preparation with co-propagating left and right circularly polarized lasers.

    PubMed

    Zhang, Yi; Qu, Suping; Gu, Sihong

    2012-03-12

    We have developed and experimentally studied a coherent population trapping (CPT) state preparation scheme for atomic clock application with co-propagating left and right circularly polarized lasers. With realization of constructive interference and spin-polarized dark state free in CPT state preparation, we have obtained CPT resonance signal 3 times larger than that of the conventional scheme used in atomic clock. Polarization fluctuations and CPT signal sensitivity to laser power behaviors are both improved with the scheme. Our study reveals that it is a promising candidate for both normal-size and chip-scale CPT atomic clocks. PMID:22418521

  8. Stereoselective synthesis of (+)-loline alkaloid skeleton.

    PubMed

    Miller, Kelsey E; Wright, Anthony J; Olesen, Margaret K; Hovey, M Todd; Scheerer, Jonathan R

    2015-02-01

    The loline alkaloids present a compact polycyclic pyrrolizidine skeleton and contain a strained five-membered ethereal bridge, structural features that have proven challenging for synthetic chemists to incorporate since the discovery of this natural product family more than 100 years ago. These alkaloids are produced by mutualistic fungal symbionts (endophytes) living on certain species of pasture grasses and protect the host plant from insect herbivory. The asymmetric total synthesis of loline alkaloids is reported and extends our first-generation (racemic) synthesis of this alkaloid family. Key to the synthesis is a diastereoselective tethered aminohydroxylation of a homoallylic carbamate function and a Petasis Borono-Mannich addition.

  9. Six new alkaloids from Melodinus henryi.

    PubMed

    Ma, Ke; Wang, Jun-Song; Luo, Jun; Kong, Ling-Yi

    2015-01-01

    A total of six new alkaloids, melodinhenines A-F (1-6), were isolated from Melodinus henryi. Melodinhenines A and B are new eburnan-vindolinine-type bisindole alkaloids and melodinhenines C-F are new quinolinic melodinus alkaloids. Their structures were elucidated through extensive spectroscopic methods including 2D NMR and HRESIMS analyses. The absolute configuration of 1 and 2 was determined using ECD exciton chirality method. To the best of our knowledge, this is the first report on the determination of the absolute configuration of eburnan-vindolinine-type bisindole alkaloid using this method.

  10. Tests of CP and CPT symmetry with positronium

    SciTech Connect

    Namba, T.; Kobayashi, T.; Nishihara, K.; Yamazaki, T.; Asai, S.

    2008-08-08

    The 3{gamma} decay of spin-aligned triplet positronium can be used to test CP (C = charge conjugation, and P = parity operation) invariance in the lepton sector. The angular correlation (s-circumflex {center_dot}k-circumflex {sub 1})(s-circumflex {center_dot}k-circumflex {sub 1}xk-circumflex {sub 2}) is used for this test, where s is the positronium spin and |k{sub 1}|>|k{sub 2}|>|k{sub 3}| are the {gamma} momenta.We designed a new detector to test this symmetry at the 10{sup -3} level. This detector consists of a magnet, a {beta}{sup +} tagging and o-Ps creation system, {gamma}-ray detectors, and a turntable. The detector construction is almost finished and data acquisition will begin in this spring.With a similar detector, the CPT (T = time reversal) symmetry can be also tested. In this case, the angular correlation (s-circumflex {center_dot}k-circumflex {sub 1}xk-circumflex {sub 2}) is used. This test will be started after the CP test is finished.

  11. Search for Violation of CPT and Lorentz Invariance in Bs(0) Meson Oscillations.

    PubMed

    Abazov, V M; Abbott, B; Acharya, B S; Adams, M; Adams, T; Agnew, J P; Alexeev, G D; Alkhazov, G; Alton, A; Askew, A; Atkins, S; Augsten, K; Avila, C; Badaud, F; Bagby, L; Baldin, B; Bandurin, D V; Banerjee, S; Barberis, E; Baringer, P; Bartlett, J F; Bassler, U; Bazterra, V; Bean, A; Begalli, M; Bellantoni, L; Beri, S B; Bernardi, G; Bernhard, R; Bertram, I; Besançon, M; Beuselinck, R; Bhat, P C; Bhatia, S; Bhatnagar, V; Blazey, G; Blessing, S; Bloom, K; Boehnlein, A; Boline, D; Boos, E E; Borissov, G; Borysova, M; Brandt, A; Brandt, O; Brock, R; Bross, A; Brown, D; Bu, X B; Buehler, M; Buescher, V; Bunichev, V; Burdin, S; Buszello, C P; Camacho-Pérez, E; Casey, B C K; Castilla-Valdez, H; Caughron, S; Chakrabarti, S; Chan, K M; Chandra, A; Chapon, E; Chen, G; Cho, S W; Choi, S; Choudhary, B; Cihangir, S; Claes, D; Clutter, J; Cooke, M; Cooper, W E; Corcoran, M; Couderc, F; Cousinou, M-C; Cuth, J; Cutts, D; Das, A; Davies, G; de Jong, S J; De La Cruz-Burelo, E; Déliot, F; Demina, R; Denisov, D; Denisov, S P; Desai, S; Deterre, C; DeVaughan, K; Diehl, H T; Diesburg, M; Ding, P F; Dominguez, A; Dubey, A; Dudko, L V; Duperrin, A; Dutt, S; Eads, M; Edmunds, D; Ellison, J; Elvira, V D; Enari, Y; Evans, H; Evdokimov, A; Evdokimov, V N; Fauré, A; Feng, L; Ferbel, T; Fiedler, F; Filthaut, F; Fisher, W; Fisk, H E; Fortner, M; Fox, H; Fuess, S; Garbincius, P H; Garcia-Bellido, A; García-González, J A; Gavrilov, V; Geng, W; Gerber, C E; Gershtein, Y; Ginther, G; Gogota, O; Golovanov, G; Grannis, P D; Greder, S; Greenlee, H; Grenier, G; Gris, Ph; Grivaz, J-F; Grohsjean, A; Grünendahl, S; Grünewald, M W; Guillemin, T; Gutierrez, G; Gutierrez, P; Haley, J; Han, L; Harder, K; Harel, A; Hauptman, J M; Hays, J; Head, T; Hebbeker, T; Hedin, D; Hegab, H; Heinson, A P; Heintz, U; Hensel, C; Heredia-De La Cruz, I; Herner, K; Hesketh, G; Hildreth, M D; Hirosky, R; Hoang, T; Hobbs, J D; Hoeneisen, B; Hogan, J; Hohlfeld, M; Holzbauer, J L; Howley, I; Hubacek, Z; Hynek, V; Iashvili, I; Ilchenko, Y; Illingworth, R; Ito, A S; Jabeen, S; Jaffré, M; Jayasinghe, A; Jeong, M S; Jesik, R; Jiang, P; Johns, K; Johnson, E; Johnson, M; Jonckheere, A; Jonsson, P; Joshi, J; Jung, A W; Juste, A; Kajfasz, E; Karmanov, D; Katsanos, I; Kaur, M; Kehoe, R; Kermiche, S; Khalatyan, N; Khanov, A; Kharchilava, A; Kharzheev, Y N; Kiselevich, I; Kohli, J M; Kozelov, A V; Kraus, J; Kumar, A; Kupco, A; Kurča, T; Kuzmin, V A; Lammers, S; Lebrun, P; Lee, H S; Lee, S W; Lee, W M; Lei, X; Lellouch, J; Li, D; Li, H; Li, L; Li, Q Z; Lim, J K; Lincoln, D; Linnemann, J; Lipaev, V V; Lipton, R; Liu, H; Liu, Y; Lobodenko, A; Lokajicek, M; Lopes de Sa, R; Luna-Garcia, R; Lyon, A L; Maciel, A K A; Madar, R; Magaña-Villalba, R; Malik, S; Malyshev, V L; Mansour, J; Martínez-Ortega, J; McCarthy, R; McGivern, C L; Meijer, M M; Melnitchouk, A; Menezes, D; Mercadante, P G; Merkin, M; Meyer, A; Meyer, J; Miconi, F; Mondal, N K; Mulhearn, M; Nagy, E; Narain, M; Nayyar, R; Neal, H A; Negret, J P; Neustroev, P; Nguyen, H T; Nunnemann, T; Orduna, J; Osman, N; Osta, J; Pal, A; Parashar, N; Parihar, V; Park, S K; Partridge, R; Parua, N; Patwa, A; Penning, B; Perfilov, M; Peters, Y; Petridis, K; Petrillo, G; Pétroff, P; Pleier, M-A; Podstavkov, V M; Popov, A V; Prewitt, M; Price, D; Prokopenko, N; Qian, J; Quadt, A; Quinn, B; Ratoff, P N; Razumov, I; Ripp-Baudot, I; Rizatdinova, F; Rominsky, M; Ross, A; Royon, C; Rubinov, P; Ruchti, R; Sajot, G; Sánchez-Hernández, A; Sanders, M P; Santos, A S; Savage, G; Savitskyi, M; Sawyer, L; Scanlon, T; Schamberger, R D; Scheglov, Y; Schellman, H; Schott, M; Schwanenberger, C; Schwienhorst, R; Sekaric, J; Severini, H; Shabalina, E; Shary, V; Shaw, S; Shchukin, A A; Simak, V; Skubic, P; Slattery, P; Smirnov, D; Snow, G R; Snow, J; Snyder, S; Söldner-Rembold, S; Sonnenschein, L; Soustruznik, K; Stark, J; Stoyanova, D A; Strauss, M; Suter, L; Svoisky, P; Titov, M; Tokmenin, V V; Tsai, Y-T; Tsybychev, D; Tuchming, B; Tully, C; Uvarov, L; Uvarov, S; Uzunyan, S; Van Kooten, R; van Leeuwen, W M; Varelas, N; Varnes, E W; Vasilyev, I A; Verkheev, A Y; Vertogradov, L S; Verzocchi, M; Vesterinen, M; Vilanova, D; Vokac, P; Wahl, H D; Wang, M H L S; Warchol, J; Watts, G; Wayne, M; Weichert, J; Welty-Rieger, L; Williams, M R J; Wilson, G W; Wobisch, M; Wood, D R; Wyatt, T R; Xie, Y; Yamada, R; Yang, S; Yasuda, T; Yatsunenko, Y A; Ye, W; Ye, Z; Yin, H; Yip, K; Youn, S W; Yu, J M; Zennamo, J; Zhao, T G; Zhou, B; Zhu, J; Zielinski, M; Zieminska, D; Zivkovic, L

    2015-10-16

    We present the first search for CPT-violating effects in the mixing of Bs(0) mesons using the full Run II data set with an integrated luminosity of 10.4  fb(-1) of proton-antiproton collisions collected using the D0 detector at the Fermilab Tevatron Collider. We measure the CPT-violating asymmetry in the decay Bs(0)→μ(±)Ds(±) as a function of celestial direction and sidereal phase. We find no evidence for CPT-violating effects and place limits on the direction and magnitude of flavor-dependent CPT- and Lorentz-invariance violating coupling coefficients. We find 95% confidence intervals of Δa⊥<1.2×10(-12)  GeV and (-0.8<ΔaT-0.396ΔaZ<3.9)×10(-13)  GeV. PMID:26550864

  12. FL118, a novel camptothecin analogue, overcomes irinotecan and topotecan resistance in human tumor xenograft models

    PubMed Central

    Ling, Xiang; Liu, Xiaojun; Zhong, Kai; Smith, Nicholas; Prey, Joshua; Li, Fengzhi

    2015-01-01

    Irinotecan and topotecan are the only camptothecin analogues approved by the FDA for cancer treatment. However, inherent and/or acquired irinotecan and topotecan resistance is a challenging issue in clinical practice. In this report, we showed that FL118, a novel camptothecin analogue, effectively obliterated human xenograft tumors that acquire irinotecan and topotecan resistance. Consistent with this finding, Pharmacokinetics studies indicated that FL118 rapidly clears from circulation, while effectively accumulating in tumors with a long elimination half-life. Consistent with our previous studies on irinotecan, FL118 exhibited ≥25 fold more effectiveness than topotecan at inhibiting cancer cell growth and colony formation; we further showed that although topotecan can inhibit the expression of survivin, Mcl-1, XIAP or cIAP2, its effectiveness is about 10-100 fold weaker than FL118. Lastly, in contrast to both SN-38 (active metabolite of irinotecan) and topotecan are substrates of the efflux pump proteins P-gp/MDR1 and ABCG2/BCRP, FL118 is not a substrate of P-gp and ABCG2. Consistently, sildenafil, a multiple efflux pump inhibitor, sensitized SN-38 much more than these of the ABCG2-selective inhibitor KO143 in growth inhibition of SW620 and HCT-8 cells. In contrast, both inhibitors showed no effect on FL118 efficacy. Given that both P-gp and ABCG2 express in SW620 and HCT-8 cells and FL118 is not a substrate for P-gp and ABCG2, this suggests that FL118 appears to bypass multiple efflux pump protein-induced resistance, which may contribute to FL118 overcoming irinotecan and topotecan resistance in vivo. These new findings provide renewed perspectives for further development of FL118 for clinical applications. PMID:26692923

  13. Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives.

    PubMed

    Song, Zi-Long; Wang, Mei-Juan; Li, Lanlan; Wu, Dan; Wang, Yu-Han; Yan, Li-Ting; Morris-Natschke, Susan L; Liu, Ying-Qian; Zhao, Yong-Long; Wang, Chih-Ya; Liu, Huanxiang; Goto, Masuo; Liu, Heng; Zhu, Gao-Xiang; Lee, Kuo-Hsiung

    2016-06-10

    In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π-π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.

  14. Influence of the prodrugs 5-fluorocytosine and CPT-11 on ovarian cancer cells using genetically engineered stem cells: tumor-tropic potential and inhibition of ovarian cancer cell growth.

    PubMed

    Kim, Ki-Yon; Kim, Seung U; Leung, Peter C K; Jeung, Eui-Bae; Choi, Kyung-Chul

    2010-04-01

    Recent studies have shown that genetically engineered stem cells (GESTECs) to produce suicide enzymes that convert non-toxic prodrugs to toxic metabolites selectively migrate toward tumor sites and reduce tumor growth. In the present study, we evaluated whether these GESTECs were capable of migrating to human ovarian cancer cells and examined the potential therapeutic efficacy of the gene-directed enzyme prodrug therapy against ovarian cancer cells in vitro. The expression of cytosine deaminase (CD) or carboxyl esterase (CE) mRNA of GESTECs was confirmed by RT-PCR. A modified transwell migration assay was performed to determine the migratory capacity of GESTECs to ovarian cancer cells. GESTECs (HB1.F3.CD or HB1.F3.CE cells) engineered to express a suicide gene (CD or CE) selectively migrated toward ovarian cancer cells. A [(3)H] thymidine incorporation assay was conducted to measure the proliferative index. Treatment of human epithelial ovarian cancer cell line (SKOV-3, an ovarian adenocarcinoma derived from the ascites of an ovarian cancer patient) with the prodrugs 5-fluorocytosine (5-FC) or camptothecin-11 (CPT-11) in the presence of HB1.F3.CD or HB1.F3.CE cells resulted in the inhibition of ovarian cancer cell growth. Based on the data presented herein, we suggest that GESTECs expressing CD/CE may have a potent advantage to selectively treat ovarian cancers.

  15. Intraspecific variability in the alkaloid metabolism of Galanthus elwesii.

    PubMed

    Berkov, Strahil; Sidjimova, Borjana; Evstatieva, Luba; Popov, Simeon

    2004-03-01

    Alkaloid pattern of individuals from 16 Bulgarian Galanthus elwesii populations was investigated by GC/MS and TLC. Twenty-one Amaryllidaceae alkaloids were detected and 14 of them were identified. Crinane type alkaloids, haemanthamine or crinine, dominated alkaloid metabolism in most of the populations. With exception of one population, where the separate individuals showed variable alkaloid profiles (dominated by crinine or haemanthamine) the individuals of the rest of populations have identical and characteristic alkaloid profiles. Some populations showed remarkable differences in respect to their alkaloid pattern-type of biosynthesis, main alkaloids and number of alkaloids. Populations dominated by galanthamine type alkaloids were found as well. These data demonstrate that like the morphological features, the alkaloid metabolism of G. elwesii is also variable.

  16. Preliminary numerical modeling results - cone penetrometer (CPT) tip used as an electrode

    SciTech Connect

    Ramirez, A L

    2006-12-19

    Figure 1 shows the resistivity models considered in this study; log10 of the resistivity is shown. The graph on the upper left hand side shows a hypothetical resisitivity well log measured along a well in the upper layered model; 10% Gaussian noise has been added to the well log data. The lower model is identical to the upper one except for one square area located within the second deepest layer. Figure 2 shows the electrode configurations considered. The ''reference'' case (upper frame) considers point electrodes located along the surface and along a vertical borehole. The ''CPT electrode'' case (middle frame) assumes that the CPT tip serves as an electrode that is electrically connected to the push rod; the surface electrodes are used in conjuction with the moving CPT electrode. The ''isolated CPT electrode'' case assumes that the electrode at the CPT tip is electrically isolated from the pushrod. Note that the separate CPT push rods in the middle and lower frames are shown separated to clarify the figure; in reality, there is only one pushrod that is changing length as the probe advances. Figure 3 shows three pole-pole measurement schemes were considered; in all cases, the ''get lost'' electrodes were the leftmost and rightmost surface electrodes. The top frame shows the reference scheme where all surface and borehole electrodes can be used. The middle frame shows two possible configurations available when a CPT mounted electrode is used. Note that only one of the four poles can be located along the borehole at any given time; electrode combinations such as the one depicted in blue (upper frame) are not possible in this case. The bottom frame shows a sample configuration where only the surface electrodes are used. Figure 4 shows the results obtained for the various measurement schemes. The white lines show the outline of the true model (shown in Figure 1, upper frame). The starting initial model for these inversions is based on the electrical resistivity log

  17. Alkaloids of Nelumbo lutea (Wild.) pers. (Nymphaeaceae)

    PubMed

    Zelenski, S G

    1977-11-01

    A phytochemical investigation of an alcoholic extract of the petioles of Nelumbo lutea resulted in the identification of the alkaloids N-methylasimilobine, anonaine, and roemerine. The alkaloids nuciferine, armepavine, N-nornuciferine, and N-norarmepavine, previously previously reported in the whole plant, were also identified.

  18. Halogenated Indole Alkaloids from Marine Invertebrates

    PubMed Central

    Pauletti, Patrícia Mendonça; Cintra, Lucas Silva; Braguine, Caio Guedes; da Silva Filho, Ademar Alves; Silva, Márcio Luís Andrade e; Cunha, Wilson Roberto; Januário, Ana Helena

    2010-01-01

    This review discusses the isolation, structural elucidation, and biological activities of halogenated indole alkaloids obtained from marine invertebrates. Meridianins and related compounds (variolins, psammopemmins, and aplicyanins), as well as aplysinopsins and leptoclinidamines, are focused on. A compilation of the 13C-NMR spectral data of these selected natural indole alkaloids is also provided. PMID:20559487

  19. Phenylalkylamine alkaloids from Stapelia hirsuta L.

    PubMed

    Shabana, Marwan; Gonaid, Mariam; Salama, Maha Mahmoud; Abdel-Sattar, Essam

    2006-07-10

    Four alkaloids of the phenethylamine derivatives have been isolated from the n-butanol fraction of the aerial parts of Stapelia hirsuta L. The structures of the isolated alkaloids were determined as N-acetyl hordenine (a new natural compound), hordenine, candicine and hordenine-1-O-beta-D-glucoside, in addition to luteolin-7-O-beta-D-glucopyranoside. PMID:16753902

  20. In vivo Cytotoxicity Studies of Amaryllidaceae Alkaloids.

    PubMed

    Nair, Jerald J; Bastida, Jaume; van Staden, Johannes

    2016-01-01

    The plant family Amaryllidaceae is recognizable for its esthetic floral characteristics, its widespread usage in traditional medicine as well as its unique alkaloid principles. Few alkaloid-producing families rival the Amaryllidaceae in terms of the diversity of its structures as well as their wide applicability on the biological landscape. In particular, cytotoxic effects have come to be a dominant theme in the biological properties of Amaryllidacea alkaloids. To this extent, a significant number of structures have been subjected to in vitro studies in numerous cell lines from which several targets have been identified as promising chemotherapeutics. By contrast, in vivo models of study involving these alkaloids have been carried out to a lesser extent and should prove crucial in the continued development of a clinical target such as pancratistatin. This survey examines the cytotoxic effects of Amaryllidaceae alkaloids in vivo and contrasts these against the corresponding in vitro effects.

  1. In vitro ruminal metabolism of larkspur alkaloids.

    PubMed

    Siemion, R S; Raisbeck, M F; Waggoner, J W; Tidwell, M A; Sanchez, D A

    1992-06-01

    Larkspur (Delphinium sp) poisoning of range cattle is a serious, recurring problem in the western United States. Numerous stratagems have been recommended to ameliorate larkspur intoxication, but none are completely effective. Previous studies in this laboratory indicated bovine ruminal microflora are capable of chemically modifying Delphinium alkaloids. Research reported herein was undertaken to further evaluate whether differences in ovine and bovine rumen metabolism might explain differences in susceptibility to larkspur intoxication and whether existing metabolic activity can be enhanced by sustained exposure to Delphinium alkaloids. Comparison of ovine and bovine rumen metabolism of Delphinium geyeri alkaloids in vitro failed to demonstrate differences in the rate of alkaloid metabolism. Rumen liquor collected sequentially from a fistulated cow dosed with dried Delphinium geyeri did not vary in ability to metabolize larkspur alkaloids.

  2. Carnitine Palmitoyltransferase-1b (CPT1b) Deficiency Aggravates Pressure-Overload-Induced Cardiac Hypertrophy due to Lipotoxicity

    PubMed Central

    He, Lan; Kim, Teayoun; Long, Qinqiang; Liu, Jian; Wang, Peiyong; Zhou, Yiqun; Ding, Yishu; Prasain, Jeevan; Wood, Philip A.; Yang, Qinglin

    2012-01-01

    Background Carnitine palmitoyltransferase 1(CPT1) is a rate-limiting step of mitochondrial β-oxidation by controlling the mitochondrial uptake of long-chain acyl-CoAs. The muscle isoform, CPT1b, is the predominant isoform expressed in the heart. It has been suggested that inhibiting CPT-1 activity by specific CPT-1 inhibitors exerts protective effects against cardiac hypertrophy and heart failure. However, clinical and animal studies have shown mixed results, thereby posting concerns on the safety of this class of drugs. Preclinical studies using genetically modified animal models should provide a better understanding of targeting CPT1 in order to evaluate it as a safe and effective therapeutic approach. Methods and Results Heterozygous CPT1b knockout mice (CPT1b+/−) were subjected to transverse aorta constriction (TAC)-induced pressure-overload. These mice showed overtly normal cardiac structure/function under the basal condition. Under a severe pressure-overload condition induced by two weeks of transverse aorta constriction (TAC), CPT1b+/− mice were susceptible to premature death with congestive heart failure. Under a milder pressure-overload condition, CPT1b+/− mice exhibited exacerbated cardiac hypertrophy and remodeling compared with that in wild-type littermates. There were more pronounced impairments of cardiac contraction with greater eccentric cardiac hypertrophy in CPT1b+/− than in controlled mice. Moreover, the CPT1b+/− heart exhibited exacerbated mitochondrial abnormalities and myocardial lipid accumulation with elevated triglycerides and ceramide content, leading to greater cardiomyocytes apoptosis. Conclusions We conclude that CPT1b deficiency can cause lipotoxicity in the heart under pathological stress, leading to exacerbation of cardiac pathology. Therefore, caution should be applied in the clinical use of CPT-1 inhibitors. PMID:22932257

  3. Expression of a cDNA isolated from rat brown adipose tissue and heart identifies the product as the muscle isoform of carnitine palmitoyltransferase I (M-CPT I). M-CPT I is the predominant CPT I isoform expressed in both white (epididymal) and brown adipocytes.

    PubMed

    Esser, V; Brown, N F; Cowan, A T; Foster, D W; McGarry, J D

    1996-03-22

    We set out to determine if the cDNA encoding a carnitine palmitoyltransferase (CPT)-like protein recently isolated from rat brown adipose tissue (BAT) by Yamazaki et al. (Yamazaki, N., Shinohara, Y., Shima, A., and Terada, H. (1995) FEBS Lett. 363, 41-45) actually encodes the muscle isoform of mitochondrial CPT I (M-CPT I). To this end, a cDNA essentially identical to the original BAT clone was isolated from a rat heart library. When expressed in COS cells, the novel cDNA and our previously described cDNA for rat liver CPT I (L-CPT I) gave rise to products with the same kinetic characteristics (sensitivity to malonyl-CoA and Km for carnitine) as CPT I in skeletal muscle and liver mitochondria, respectively. When labeled with [3H]etomoxir, recombinant L-CPT I and putative M-CPT I, although having approximately the same predicated masses (88.2 kDa), migrated differently on SDS gels, as did CPT I from liver and muscle mitochondria. The same was true for the products of in vitro transcription and translation of the L-CPT I and putative M-CPT I cDNAs. We conclude that the BAT cDNA does in fact encode M-CPT I. Northern blots using L- and M-CPT I cDNA probes revealed the presence of L-CPT I mRNA in liver and heart and its absence from skeletal muscle and BAT. M-CPT I mRNA, which was absent from liver, was readily detected in skeletal muscle and was particularly strong in heart and BAT. Whereas the signal for L-CPT I was more abundant than that for M-CPT I in RNA isolated from whole epididymal fat pad, this was reversed in purified adipocytes from this source. These findings, coupled with the kinetic properties and migration profiles on SDS gels of CPT I in brown and white adipocytes, indicate that the muscle form of the enzyme is the dominant, if not exclusive, species in both cell types.

  4. Formation of nanoparticles by cooperative inclusion between (S)-camptothecin-modified dextrans and β-cyclodextrin polymers

    PubMed Central

    Amiel, Catherine; Duroux, Laurent; Larsen, Kim Lambertsen; Städe, Lars Wagner; Wimmer, Reinhard; Wintgens, Véronique

    2015-01-01

    Summary Novel (S)-camptothecin–dextran polymers were obtained by “click” grafting of azide-modified (S)-camptothecin and alkyne-modified dextrans. Two series based on 10 kDa and 70 kDa dextrans were prepared with a degree of substitution of (S)-camptothecin between 3.1 and 10.2%. The binding properties with β-cyclodextrin and β-cyclodextrin polymers were measured by isothermal titration calorimetry and fluorescence spectroscopy, showing no binding with β-cyclodextrin but high binding with β-cyclodextrin polymers. In aqueous solution nanoparticles were formed from association between the (S)-camptothecin–dextran polymers and the β-cyclodextrin polymers. PMID:25670998

  5. Molecular Cloning, Heterologous Expression, and Functional Characterization of an NADPH-Cytochrome P450 Reductase Gene from Camptotheca acuminata, a Camptothecin-Producing Plant

    PubMed Central

    Chen, Fei; Yang, Yun; Yang, Lixia; Zhang, Guolin; Luo, Yinggang

    2015-01-01

    Camptothecin (CAM), a complex pentacyclic pyrroloqinoline alkaloid, is the starting material for CAM-type drugs that are well-known antitumor plant drugs. Although many chemical and biological research efforts have been performed to produce CAM, a few attempts have been made to uncover the enzymatic mechanism involved in the biosynthesis of CAM. Enzyme-catalyzed oxidoreduction reactions are ubiquitously presented in living organisms, especially in the biosynthetic pathway of most secondary metabolites such as CAM. Due to a lack of its reduction partner, most catalytic oxidation steps involved in the biosynthesis of CAM have not been established. In the present study, an NADPH-cytochrome P450 reductase (CPR) encoding gene CamCPR was cloned from Camptotheca acuminata, a CAM-producing plant. The full length of CamCPR cDNA contained an open reading frame of 2127-bp nucleotides, corresponding to 708-amino acid residues. CamCPR showed 70 ~ 85% identities to other characterized plant CPRs and it was categorized to the group II of CPRs on the basis of the results of multiple sequence alignment of the N-terminal hydrophobic regions. The intact and truncate CamCPRs with N- or C-terminal His6-tag were heterologously overexpressed in Escherichia coli. The recombinant enzymes showed NADPH-dependent reductase activity toward a chemical substrate ferricyanide and a protein substrate cytochrome c. The N-terminal His6-tagged CamCPR showed 18- ~ 30-fold reduction activity higher than the C-terminal His6-tagged CamCPR, which supported a reported conclusion, i.e., the last C-terminal tryptophan of CPRs plays an important role in the discrimination between NADPH and NADH. Co-expression of CamCPR and a P450 monooxygenase, CYP73A25, a cinnamate 4-hydroxylase from cotton, and the following catalytic formation of p-coumaric acid suggested that CamCPR transforms electrons from NADPH to the heme center of P450 to support its oxidation reaction. Quantitative real-time PCR analysis showed that

  6. CPT-based probabilistic and deterministic assessment of in situ seismic soil liquefaction potential

    USGS Publications Warehouse

    Moss, R.E.S.; Seed, R.B.; Kayen, R.E.; Stewart, J.P.; Der Kiureghian, A.; Cetin, K.O.

    2006-01-01

    This paper presents a complete methodology for both probabilistic and deterministic assessment of seismic soil liquefaction triggering potential based on the cone penetration test (CPT). A comprehensive worldwide set of CPT-based liquefaction field case histories were compiled and back analyzed, and the data then used to develop probabilistic triggering correlations. Issues investigated in this study include improved normalization of CPT resistance measurements for the influence of effective overburden stress, and adjustment to CPT tip resistance for the potential influence of "thin" liquefiable layers. The effects of soil type and soil character (i.e., "fines" adjustment) for the new correlations are based on a combination of CPT tip and sleeve resistance. To quantify probability for performancebased engineering applications, Bayesian "regression" methods were used, and the uncertainties of all variables comprising both the seismic demand and the liquefaction resistance were estimated and included in the analysis. The resulting correlations were developed using a Bayesian framework and are presented in both probabilistic and deterministic formats. The results are compared to previous probabilistic and deterministic correlations. ?? 2006 ASCE.

  7. Polycyclic Guanidine Alkaloids from Poecilosclerida Marine Sponges

    PubMed Central

    Sfecci, Estelle; Lacour, Thierry; Amade, Philippe; Mehiri, Mohamed

    2016-01-01

    Sessile marine sponges provide an abundance of unique and diversified scaffolds. In particular, marine guanidine alkaloids display a very wide range of biological applications. A large number of cyclic guanidine alkaloids, including crambines, crambescins, crambescidins, batzelladines or netamins have been isolated from Poecilosclerida marine sponges. In this review, we will explore the chemodiversity of tri- and pentacyclic guanidine alkaloids. NMR and MS data tools will also be provided, and an overview of the wide range of bioactivities of crambescidins and batzelladines derivatives will be given. PMID:27070629

  8. Marine Pyridoacridine Alkaloids: Biosynthesis and Biological Activities.

    PubMed

    Ibrahim, Sabrin R M; Mohamed, Gamal A

    2016-01-01

    Pyridoacridines are a class of strictly marine-derived alkaloids that constitute one of the largest chemical families of marine alkaloids. During the last few years, both natural pyridoacridines and their analogues have constituted excellent targets for synthetic works. They have been the subject of intense study due to their significant biological activities; cytotoxic, antibacterial, antifungal, antiviral, insecticidal, anti-HIV, and anti-parasitic activities. In the present review, 95 pyridoacridine alkaloids isolated from marine organisms are discussed in term of their occurrence, biosynthesis, biological activities, and structural assignment.

  9. Capacitive power transfer (CPT) system design using a class E resonant converter circuit

    NASA Astrophysics Data System (ADS)

    Kh., Kamarudin; Saat, Shakir; Yusmarnita, Y.; Ramli. M., S.; Sufiah, A. W. Siti

    2016-02-01

    This paper presents a Capacitive Power Transfer (CPT) system design using a Class E resonant converter circuit. The Class E resonant converter circuit is used to produce a high frequency of alternate current. The purpose of this circuit is to transfer the power via capacitive coupling efficiently. A major advantage of Class E resonant converter circuit is low switching losses. To be specifically, the performance of CPT system at 1MHz of operating frequency and 12V of DC supply voltage is analyzed through experimental works. Finally, a prototype of a CPT system is successfully developed which produced 2mW output power through a capacitive plate size is 12cm × 12cm at 0.1cm of air gap distance.

  10. D0 Evidence for CP Violation and Implication for CPT Violation in B-Meson Mixing

    SciTech Connect

    Kooten, R.Van; /Indiana U.

    2010-08-01

    A D0 analysis measuring the charge asymmetry A{sub sl}{sup b} of like-sign dimuon events due to semileptonic b-hadron decays at the Fermilab Tevatron Collider is described. It differs by 3.2 standard deviations from the Standard Model prediction to provide first evidence of CPT-invariant anomalous CP violation in the mixing of neutral B mesons, and is compared to the CP-violating phase obtained from a D0 analysis of the time-dependent decay angles in B{sub s}{sup 0} {yields} J/{psi}{phi}. If CPT violation is allowed, the dimuon asymmetry also yields the first sensitivity to CPT violation in the B{sub s}{sup 0} system.

  11. Search for Violation of $CPT$ and Lorentz Invariance in $${B_s^0}$$ Meson Oscillations

    DOE PAGES

    Abazov, Victor Mukhamedovich

    2015-06-12

    We present the first search for CPT-violating effects in the mixing of B0s mesons using the full Run II data set with an integrated luminosity of 10.4 fb-1 of proton-antiproton collisions collected using the D0 detector at the Fermilab Tevatron Collider. We measure the CPT-violating asymmetry in the decay B0s → µ±D±s as a function of celestial direction and sidereal phase. We find no evidence for CPT-violating effects and place limits on the direction and magnitude of flavor-dependent CPTand Lorentz-invariance violating coupling coefficients. We find 95% confidence intervals of Δa⊥ < 1.2 × 10-12 GeV and (-0.8 < ΔaT -more » 0.396ΔaZ < 3.9) × 10-13 GeV.« less

  12. Synthetic Cytotoxicity: Digenic Interactions with TEL1/ATM Mutations Reveal Sensitivity to Low Doses of Camptothecin

    PubMed Central

    Li, Xuesong; O’Neil, Nigel J.; Moshgabadi, Noushin; Hieter, Philip

    2014-01-01

    Many tumors contain mutations that confer defects in the DNA-damage response and genome stability. DNA-damaging agents are powerful therapeutic tools that can differentially kill cells with an impaired DNA-damage response. The response to DNA damage is complex and composed of a network of coordinated pathways, often with a degree of redundancy. Tumor-specific somatic mutations in DNA-damage response genes could be exploited by inhibiting the function of a second gene product to increase the sensitivity of tumor cells to a sublethal concentration of a DNA-damaging therapeutic agent, resulting in a class of conditional synthetic lethality we call synthetic cytotoxicity. We used the Saccharomyces cerevisiae nonessential gene-deletion collection to screen for synthetic cytotoxic interactions with camptothecin, a topoisomerase I inhibitor, and a null mutation in TEL1, the S. cerevisiae ortholog of the mammalian tumor-suppressor gene, ATM. We found and validated 14 synthetic cytotoxic interactions that define at least five epistasis groups. One class of synthetic cytotoxic interaction was due to telomere defects. We also found that at least one synthetic cytotoxic interaction was conserved in Caenorhabditis elegans. We have demonstrated that synthetic cytotoxicity could be a useful strategy for expanding the sensitivity of certain tumors to DNA-damaging therapeutics. PMID:24653001

  13. New polymorphs of 9-nitro-camptothecin prepared using a supercritical anti-solvent process.

    PubMed

    Huang, Yinxia; Wang, Hongdi; Liu, Guijin; Jiang, Yanbin

    2015-12-30

    Recrystallization and micronization of 9-nitro-camptothecin (9-NC) has been investigated using the supercritical anti-solvent (SAS) technology in this study. Five operating factors, i.e., the type of organic solvent, the concentration of 9-NC in the solution, the flow rate of 9-NC solution, the precipitation pressure and the temperature, were optimized using a selected OA16 (4(5)) orthogonal array design and a series of characterizations were performed for all samples. The results showed that the processed 9-NC particles exhibited smaller particle size and narrower particle size distribution as compared with 9-NC raw material (Form I), and the optimum micronization conditions for preparing 9-NC with minimum particle size were determined by variance analysis, where the solvent plays the most important role in the formation and transformation of polymorphs. Three new polymorphic forms (Form II, III and IV) of 9-NC, which present different physicochemical properties, were generated after the SAS process. The predicted structures of the 9-NC crystals, which were consistent with the experiments, were performed from their experimental XRD data by the direct space approach using the Reflex module of Materials Studio. Meanwhile, the optimal sample (Form III) was proved to have higher cytotoxicity against the cancer cells, which suggested the therapeutic efficacy of 9-NC is polymorph-dependent.

  14. Encapsulation of 10-hydroxy camptothecin in supramolecular hydrogel as an injectable drug delivery system.

    PubMed

    Li, Ruixin; Shu, Chang; Wang, Wei; Wang, Xiaoliang; Li, Hui; Xu, Danke; Zhong, Wenying

    2015-07-01

    10-Hydroxy camptothecin (HCPT) has been proven to be a cell cycle-specific chemotherapeutic agent, which is a necessary choice to inhibit tumor residue growth and prevent tumor metastasis after surgery. But it suffers from light decomposition, poor solubility, relatively low bioavailability, and some side effects, which are the major obstacles toward its clinical use. Integration of hydrophobic HCPT with hydrophilic hydrogel is a facile approach to change the disadvantageous situation of HCPT. In this study, a novel supramolecular hydrogelator with improved synthetic strategy was triggered by chemical hydrolysis, and then self-assembled to hydrogel. Taking advantage of the high-equilibrium solubility of HCPT in hydrogelator solution, this hydrogel was utilized to load HCPT via encapsulation as an effective carrier. HCPT hydrogels were characterized by several techniques including transmission electronic microscopy, rheology, and UV spectroscopy. In vitro release experiment indicated HCPT hydrogel could maintain long term and sustained release of HCPT at high accumulated rate. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay showed that HCPT hydrogel had an optimized anticancer efficacy. Besides, with prominent physical properties of carrier, HCPT hydrogel possessed satisfactory stability, syringeability, and recoverability, demonstrating itself as a potential localized injectable drug delivery system.

  15. Thermosensitive PNIPAM-b-HTPB block copolymer micelles: molecular architectures and camptothecin drug release.

    PubMed

    Luo, Yan-Ling; Yang, Xiao-Li; Xu, Feng; Chen, Ya-Shao; Zhang, Bin

    2014-02-01

    Two kinds of thermo-sensitive poly(N-isoproplacrylamide) (PNIPAM) block copolymers, AB4 four-armed star multiblock and linear triblock copolymers, were synthesized by ATRP with hydroxyl-terminated polybutadiene (HTPB) as central blocks, and characterization was performed by (1)H NMR, FT-IR and SEC. The multiblock copolymers could spontaneously assemble into more regular spherical core-shell nanoscale micelles than the linear triblock copolymer. The physicochemical properties were detected by a surface tension technique, nano particle analyzer, TEM, DLS and UV-vis measurements. The multiblock copolymer micelles had lower critical micelle concentration than the linear counterpart, TEM size from 100 to 120 nm and the hydrodynamic diameters below 150 nm. The micelles exhibited thermo-dependent size change, with low critical solution temperature about 33-35 °C. The characteristic parameters were affected by the composition ratios, length of PNIPAM blocks and molecular architectures. The camptothecin release demonstrated that the drug release was thermo-responsive, accompanied by the temperature-induced structural changes of the micelles. MTT assays were performed to evaluate the biocompatibility or cytotoxicity of the prepared copolymer micelles. PMID:24184534

  16. Effects of camptothecin derivatives and topoisomerase dual inhibitors on Trypanosoma cruzi growth and ultrastructure

    PubMed Central

    2014-01-01

    Background Trypanosoma cruzi is the etiological agent of Chagas’ disease that is an endemic disease in Latin America and affects about 8 million people. This parasite belongs to the Trypanosomatidae family which contains a single mitochondrion with an enlarged region, named kinetoplast that harbors the mitochondrial DNA (kDNA). The kinetoplast and the nucleus present a great variety of essential enzymes involved in DNA replication and topology, including DNA topoisomerases. Such enzymes are considered to be promising molecular targets for cancer treatment and for antiparasitic chemotherapy. In this work, the proliferation and ultrastructure of T. cruzi epimastigotes were evaluated after treatment with eukaryotic topoisomerase I inhibitors, such as topotecan and irinotecan, as well as with dual inhibitors (compounds that block eukaryotic topoisomerase I and topoisomerase II activities), such as baicalein, luteolin and evodiamine. Previous studies have shown that such inhibitors were able to block the growth of tumor cells, however most of them have never been tested on trypanosomatids. Results Considering the effects of topoisomerase I inhibitors, our results showed that topotecan decreased cell proliferation and caused unpacking of nuclear heterochromatin, however none of these alterations were observed after treatment with irinotecan. The dual inhibitors baicalein and evodiamine decreased cell growth; however the nuclear and kinetoplast ultrastructures were not affected. Conclusions Taken together, our data showed that camptothecin is more efficient than its derivatives in decreasing T. cruzi proliferation. Furthermore, we conclude that drugs pertaining to a certain class of topoisomerase inhibitors may present different efficiencies as chemotherapeutical agents. PMID:24917086

  17. Piperidine alkaloids: Human and food animal teratogens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Piperidine alkaloids are acutely toxic to adult livestock species and produce musculoskeletal deformities in neonatal animals. These teratogenic effects include multiple congenital contracture (MCC) deformities and cleft palate in cattle, pigs, sheep, and goats. Poisonous plants containing teratogen...

  18. Anxiolytic Activity of Diterpene Alkaloid Songorine.

    PubMed

    Nesterova, Yu V; Povet'eva, T N; Suslov, N I; Shults, E E; Ziuz'kov, G N; Aksinenko, S G; Afanas'eva, O G; Krapivin, A V; Kharina, T G

    2015-09-01

    Antianxiety action of diterpene alkaloid songorine was studied using Vogel conflict test. Songorine in a dose of 0.25 mg/kg demonstrated high anxiolytic activity comparable to that of phenazepam and produced no sedative effect.

  19. Anxiolytic Activity of Diterpene Alkaloid Songorine.

    PubMed

    Nesterova, Yu V; Povet'eva, T N; Suslov, N I; Shults, E E; Ziuz'kov, G N; Aksinenko, S G; Afanas'eva, O G; Krapivin, A V; Kharina, T G

    2015-09-01

    Antianxiety action of diterpene alkaloid songorine was studied using Vogel conflict test. Songorine in a dose of 0.25 mg/kg demonstrated high anxiolytic activity comparable to that of phenazepam and produced no sedative effect. PMID:26468026

  20. New furocarbazole alkaloids from Lonicera quinquelocularis.

    PubMed

    Khan, Dilfaraz; Khan, Shafiullah; Badshah, Syed; Ali, Hazrat; Ullah, Hamid; Muhammad, Zia; Woodward, Simon

    2016-01-01

    Two new furocarbazole alkaloids, 3-formyl-6,7-dimethoxy-furo[1,2]carbazole (1) and methyl-6,7-dimethoxy-furo[1,2]carbazole-3-carboxylate (2), along with two known carbazole alkaloids, 3-formyl-2-hydroxy-7-methoxycarbazole (3) and methyl 2,7-dimethoxycarbazole-3-carboxylate (4) were isolated from the ethyl acetate soluble fraction of Lonicera quinquelocularis. Their structures were established on the basis of spectroscopic analysis.

  1. Total Synthesis of the Akuammiline Alkaloid Picrinine

    PubMed Central

    2015-01-01

    We report the first total synthesis of the complex akuammiline alkaloid picrinine, which was first isolated nearly five decades ago. Our synthetic approach features a concise assembly of the [3.3.1]-azabicyclic core, a key Fischer indolization reaction to forge the natural product’s carbon framework, and a series of delicate late-stage transformations to complete the synthesis. Our synthesis of picrinine also constitutes a formal synthesis of the related polycyclic alkaloid strictamine. PMID:24597784

  2. Camptothecin-Loaded Liposomes with α-Melanocyte-Stimulating Hormone Enhance Cytotoxicity Toward and Cellular Uptake by Melanomas: An Application of Nanomedicine on Natural Product

    PubMed Central

    Lin, Chih-Hung; Al-Suwayeh, Saleh A.; Hung, Chih-Feng; Chen, Chih-Chieh; Fang, Jia-You

    2013-01-01

    In this study, we attempted to develop functional liposomes loaded with camptothecin and attached to α-melanocyte-stimulating hormone (α-MSH) to target melanoma cells. The liposomes were mainly composed of phosphatidylcholine, cholesterol, and stearylamine, and were characterized by the vesicle size, zeta potential, camptothecin encapsulation efficiency, and release behavior. Results revealed that α-MSH liposomes possessed an average size of approximately 250 nm with a surface charge of 60 mV. Camptothecin was successfully entrapped by the targeted liposomes with an encapsulation percentage of nearly 95%. The liposomes provided sustained and controlled camptothecin release. Non-targeted liposomes with the drug exerted superior cytotoxicity against melanomas compared to the free control. Cell viability was reduced from 48% to 32% compared to conventional liposomes. Peptide ligand conjugation further promoted cytotoxicity to 18% viability, which was a 2.7-fold decrease versus the free control. According to the images of fluorescence microscopy, α-MSH liposomes exhibited greater cell endocytosis than did non-targeted liposomes and the free control. α-MSH liposomes were predominantly internalized in the cytoplasm. These findings demonstrate that α-MSH liposomes could enhance the anti-melanoma activity of camptothecin owing to their targeting ability and controlled drug delivery. PMID:24716164

  3. Novel type of CPT violation for correlated Einstein-Podolsky-Rosen states of neutral mesons.

    PubMed

    Bernabéu, J; Mavromatos, N; Papavassiliou, J

    2004-04-01

    We discuss modifications to the concept of an "antiparticle," induced by a breakdown of the CPT symmetry at a fundamental level, realized within an extended class of quantum gravity models. The resulting loss of particle-antiparticle identity in the neutral-meson system induces a breaking of the Einstein-Podolsky-Rosen correlation imposed by Bose statistics. This is parametrized by a complex parameter associated with the contamination by the "wrong symmetry" state. The physical consequences are studied, and novel observables of CPT violation in phi factories are proposed. PMID:15089595

  4. A Search for Lorentz Invariance and CPT Violation with the MINOS Far Detector

    SciTech Connect

    Adamson, P.; Auty, D.J.; Ayres, D.S.; Backhouse, C.; Barr, G.; Barrett, W.L.; Bishai, M.; Blake, A.; Bock, G.J.; Boehnlein, D.J.; Bogert, D.; /Fermilab /Indiana U.

    2010-07-01

    We searched for a sidereal modulation in the MINOS far detector neutrino rate. Such a signal would be a consequence of Lorentz and CPT violation as described by the Standard-Model Extension framework. It also would be the first detection of a perturbative effect to conventional neutrino mass oscillations. We found no evidence for this sidereal signature and the upper limits placed on the magnitudes of the Lorentz and CPT violating coefficients describing the theory are an improvement by factors of 20-510 over the current best limits found using the MINOS near detector.

  5. Search for Lorentz invariance and CPT violation with the MINOS far detector.

    PubMed

    Adamson, P; Auty, D J; Ayres, D S; Backhouse, C; Barr, G; Barrett, W L; Bishai, M; Blake, A; Bock, G J; Boehnlein, D J; Bogert, D; Bower, C; Budd, S; Cavanaugh, S; Cherdack, D; Childress, S; Choudhary, B C; Coelho, J A B; Cobb, J H; Coleman, S J; Corwin, L; Cravens, J P; Cronin-Hennessy, D; Danko, I Z; de Jong, J K; Devenish, N E; Diwan, M V; Dorman, M; Escobar, C O; Evans, J J; Falk, E; Feldman, G J; Frohne, M V; Gallagher, H R; Gomes, R A; Goodman, M C; Gouffon, P; Gran, R; Grant, N; Grzelak, K; Habig, A; Harris, D; Harris, P G; Hartnell, J; Hatcher, R; Himmel, A; Holin, A; Huang, X; Hylen, J; Ilic, J; Irwin, G M; Isvan, Z; Jaffe, D E; James, C; Jensen, D; Kafka, T; Kasahara, S M S; Koizumi, G; Kopp, S; Kordosky, M; Krahn, Z; Kreymer, A; Lang, K; Lefeuvre, G; Ling, J; Litchfield, P J; Loiacono, L; Lucas, P; Mann, W A; Marshak, M L; Mayer, N; McGowan, A M; Mehdiyev, R; Meier, J R; Messier, M D; Michael, D G; Miller, J L; Miller, W H; Mishra, S R; Mitchell, J; Moore, C D; Mualem, L; Mufson, S; Musser, J; Naples, D; Nelson, J K; Newman, H B; Nichol, R J; Oliver, W P; Orchanian, M; Paley, J; Patterson, R B; Patzak, T; Pawloski, G; Pearce, G F; Pittam, R; Plunkett, R K; Ratchford, J; Raufer, T M; Rebel, B; Rodrigues, P A; Rosenfeld, C; Rubin, H A; Ryabov, V A; Sanchez, M C; Saoulidou, N; Schneps, J; Schreiner, P; Semenov, V K; Shanahan, P; Smart, W; Sousa, A; Strait, M; Tagg, N; Talaga, R L; Thomas, J; Thomson, M A; Tinti, G; Toner, R; Tzanakos, G; Urheim, J; Vahle, P; Viren, B; Weber, A; Webb, R C; White, C; Whitehead, L; Wojcicki, S G; Wright, D M; Yang, T; Zois, M; Zwaska, R

    2010-10-01

    We searched for a sidereal modulation in the MINOS far detector neutrino rate. Such a signal would be a consequence of Lorentz and CPT violation as described by the standard-model extension framework. It also would be the first detection of a perturbative effect to conventional neutrino mass oscillations. We found no evidence for this sidereal signature, and the upper limits placed on the magnitudes of the Lorentz and CPT violating coefficients describing the theory are an improvement by factors of 20-510 over the current best limits found by using the MINOS near detector.

  6. Novel type of CPT violation for correlated Einstein-Podolsky-Rosen states of neutral mesons.

    PubMed

    Bernabéu, J; Mavromatos, N; Papavassiliou, J

    2004-04-01

    We discuss modifications to the concept of an "antiparticle," induced by a breakdown of the CPT symmetry at a fundamental level, realized within an extended class of quantum gravity models. The resulting loss of particle-antiparticle identity in the neutral-meson system induces a breaking of the Einstein-Podolsky-Rosen correlation imposed by Bose statistics. This is parametrized by a complex parameter associated with the contamination by the "wrong symmetry" state. The physical consequences are studied, and novel observables of CPT violation in phi factories are proposed.

  7. Bioactive indole alkaloids isolated from Alstonia angustifolia

    PubMed Central

    Pan, Li; Terrazas, César; Muñoz Acuña, Ulyana; Ninh, Tran Ngoc; Chai, Heebyung; Carcache de Blanco, Esperanza J.; Soejarto, Djaja D.; Satoskar, Abhay R.

    2014-01-01

    Bioassay-guided fractionation was conducted on a CHCl3-soluble extract of the stem bark of Alstonia angustifolia (Apocynaceae) collected in Vietnam using the HT-29 human colon cancer cell line, and led to the isolation of a new sarpagine-type indole alkaloid (1), together with nine known alkaloids, including four macroline-derived alkaloids (2–5), a sarpagine-type alkaloid (6), and four macroline-pleiocarpamine bisindole alkaloids (7–10). The structure of the new compound (1) was determined on the basis of spectroscopic data interpretation. Compounds 1–10 were evaluated in vitro for their NF-κB (p65) inhibitory activity against the Hela cells in an ELISA assay. The new sarpagine alkaloid, N(4)-methyltalpinine (1), was found to show significant NF-κB inhibitory activity (ED50 = 1.2 µM). Furthermore, all the isolates (1–10) were evaluated in vitro for their antileishmanial activity, and compounds (1–4, 6 and 8–10) exhibited leishmaniacidal activity against promastigotes of Leishmania mexicana. PMID:25584095

  8. Rhabdomyolysis and Cardiomyopathy in a 20-Year-Old Patient with CPT II Deficiency

    PubMed Central

    Vavlukis, M.; Eftimov, A.; Zafirovska, P.; Caparovska, E.; Pocesta, B.; Kedev, S.; Dimovski, A. J.

    2014-01-01

    Aim. To raise the awareness of adult-onset carnitite palmitoyltransferase II deficiency (CPT II) by describing clinical, biochemical, and genetic features of the disease occurring in early adulthood. Method. Review of the case characteristics and literature review. Results. We report on a 20-year-old man presenting with dyspnea, fatigue, fever, and myoglobinuria. This was the second episode with such symptoms (the previous one being three years earlier). The symptoms occurred after intense physical work, followed by a viral infection resulting in fever treated with NSAIDs. Massive rhabdomyolysis was diagnosed, resulting in acute renal failure necessitating plasmapheresis and hemodialysis, acute hepatic lesion, and respiratory insufficiency. Additionally, our patient had cardiomyopathy with volume overload. After a detailed workup, CPT II deficiency was suspected. We did a sequencing analysis for exons 1, 3, and 4 of the CPT II gene and found that the patient was homozygote for Ser 113 Leu mutation in exon 3 of the CPT II gene. The patient recovery was complete except for the cardiomiopathy with mildly impaired systolic function. Conclusion. Whenever a patient suffers recurrent episodes of myalgia, followed by myoglobinuria due to rhabdomyolysis, we should always consider the possibility of this rare condition. The definitive diagnose of this condition is achieved by genetic testing. PMID:24563797

  9. Bound on Lorentz and CPT Violating Boost Effects for the Neutron

    NASA Technical Reports Server (NTRS)

    Walsworth, Ronald

    2003-01-01

    A search for a sidereal annual variation in the frequency difference between co-located Xe-129 and He-3 Zeeman masers sets a limit of approximately 10(exp -27) GeV on the coupling of the neutron to the time component of a possible background Lorentz and CPT violating tensor field.

  10. Therapeutic Targeting of CPT-11 Induced Diarrhea: A Case for Prophylaxis

    PubMed Central

    Swami, Umang; Goel, Sanjay; Mani, Sridhar

    2014-01-01

    CPT-11 (irinotecan), a DNA topoisomerase I inhibitor is one of the main treatments for colorectal cancer. The main dose limiting toxicities are neutropenia and late onset diarrhea. Though neutropenia is manageable, CPT-11 induced diarrhea is frequently severe, resulting in hospitalizations, dose reductions or omissions leading to ineffective treatment administration. Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT-11 induced late onset diarrhea. It is predicted that prophylaxis of CPT-11 induced diarrhea will reduce sub-therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates. This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity. Covered topics include schedule/dose modification, intestinal alkalization, structural/chemical modification, genetic testing, anti-diarrheal therapies, transporter (ABCB1, ABCC2, BCRP2) inhibitors, enzyme (β-glucuronidase, UGT1A1, CYP3A4, carboxylesterase, COX-2) inducers and inhibitors, probiotics, antibiotics, adsorbing agents, cytokine and growth factor activators and inhibitors and other miscellaneous agents. PMID:23597015

  11. Order of Conners' CPT-II Administration within a Cognitive Test Battery Influences ADHD Indices

    ERIC Educational Resources Information Center

    Erdodi, Laszlo A.; Lajiness-O'Neill, Renee; Saules, Karen K.

    2010-01-01

    Objective: To study the effect of administration sequence on Conner's continuous performance test (CPT-II) scores in clients requesting psychological assessment. It was hypothesized that when administered at the end rather than beginning of a test battery, the test scores will show higher symptom severity. If present, order effects may cause the…

  12. Maps and documentation of seismic CPT soundings in the central, eastern, and western United States

    USGS Publications Warehouse

    Holzer, Thomas L.; Noce, Thomas E.; Bennett, Michael J.

    2010-01-01

    Nine hundred twenty seven seismic cone penetration tests (CPT) in a variety of geologic deposits and geographic locations were conducted by the U.S. Geological Survey (USGS) primarily between 1998 and 2008 for the purpose of collecting penetration test data to evaluate the liquefaction potential of different types of surficial geologic deposits (table 1). The evaluation is described in Holzer and others (in press). This open-file report summarizes the seismic CPT and geotechnical data that were collected for the evaluation, outlines the general conditions under which the data were acquired, and briefly describes the geographic location of each study area and local geologic conditions. This report also describes the field methods used to obtain the seismic CPT data and summarizes the results of shear-wave velocities measurements at 2-m intervals in each sounding. Although the average depth of the 927 soundings was 18.5 m, we estimated a time-averaged shear-wave velocity to depths of 20 m and 30 m, VS20 and VS30, respectively, for soundings deeper than 10 m and 20 m. Soil sampling also was selectively conducted in many of the study areas at representative seismic CPT soundings. These data are described and laboratory analyses of geotechnical properties of these samples are summarized in table 2.

  13. Augmenting CPT to Improve Sleep Impairment in PTSD: A Randomized Clinical Trial

    PubMed Central

    Galovski, Tara E.; Mott, Juliette; Blain, Leah M.; Elwood, Lisa; Gloth, Chelsea; Fletcher, Thomas

    2015-01-01

    Objective Despite the success of empirically supported treatments for posttraumatic stress disorder (PTSD), sleep impairment frequently remains refractory following treatment for PTSD. This single-site, randomized controlled trial examined the effectiveness of sleep-directed hypnosis as a complement to an empirically supported psychotherapy for PTSD (cognitive processing therapy; CPT). Method Participants completed either 3 weeks of hypnosis (n = 52) or a symptom monitoring control condition (n = 56) before beginning standard CPT. Multilevel modeling was used to investigate differential patterns of change to determine whether hypnosis resulted in improvements in sleep, PTSD, and depression. An intervening variable approach was then used to determine whether improvements in sleep achieved during hypnosis augmented change in PTSD and depression during CPT. Results After the initial phase of treatment (hypnosis or symptom monitoring), the hypnosis condition showed significantly greater improvement than the control condition in sleep and depression, but not PTSD. After CPT, both conditions demonstrated significant improvement in sleep and PTSD; however, the hypnosis condition demonstrated greater improvement in depressive symptoms. As sleep improved, there were corresponding improvements in PTSD and depression, with a stronger relationship between sleep and PTSD. Conclusion Hypnosis was effective in improving sleep impairment, but those improvements did not augment gains in PTSD recovery during the trauma-focused intervention. Public Health Significance: This study suggests that hypnosis may be a viable treatment option in a stepped-care approach for treating sleep impairment in individuals suffering from PTSD. PMID:26689303

  14. CPT-cGMP Is A New Ligand of Epithelial Sodium Channels.

    PubMed

    Ji, Hong-Long; Nie, Hong-Guang; Chang, Yongchang; Lian, Qizhou; Liu, Shan-Lu

    2016-01-01

    Epithelial sodium channels (ENaC) are localized at the apical membrane of the epithelium, and are responsible for salt and fluid reabsorption. Renal ENaC takes up salt, thereby controlling salt content in serum. Loss-of-function ENaC mutations lead to low blood pressure due to salt-wasting, while gain-of-function mutations cause impaired sodium excretion and subsequent hypertension as well as hypokalemia. ENaC activity is regulated by intracellular and extracellular signals, including hormones, neurotransmitters, protein kinases, and small compounds. Cyclic nucleotides are broadly involved in stimulating protein kinase A and protein kinase G signaling pathways, and, surprisingly, also appear to have a role in regulating ENaC. Increasing evidence suggests that the cGMP analog, CPT-cGMP, activates αβγ-ENaC activity reversibly through an extracellular pathway in a dose-dependent manner. Furthermore, the parachlorophenylthio moiety and ribose 2'-hydroxy group of CPT-cGMP are essential for facilitating the opening of ENaC channels by this compound. Serving as an extracellular ligand, CPT-cGMP eliminates sodium self-inhibition, which is a novel mechanism for stimulating salt reabsorption in parallel to the traditional NO/cGMP/PKG signal pathway. In conclusion, ENaC may be a druggable target for CPT-cGMP, leading to treatments for kidney malfunctions in salt reabsorption. PMID:27019621

  15. Coexistence of VHL Disease and CPT2 Deficiency: A Case Report

    PubMed Central

    Ferrara, Alfonso Massimiliano; Sciacco, Monica; Zovato, Stefania; Rizzati, Silvia; Colombo, Irene; Boaretto, Francesca; Moggio, Maurizio; Opocher, Giuseppe

    2016-01-01

    von Hippel-Lindau (VHL) disease is an inherited syndrome manifesting with benign and malignant tumors. Deficiency of carnitine palmitoyltransferase type II (CPT2) is a disorder of lipid metabolism that, in the muscle form, manifests with recurrent attacks of myalgias often associated with myoglobinuria. Rhabdomyolytic episodes may be complicated by life-threatening events, including acute renal failure (ARF). We report on a male patient who was tested, at 10 years of age, for VHL disease because of family history of VHL. He was diagnosed with VHL but without VHL-related manifestation at the time of diagnosis. During childhood, the patient was hospitalized several times for diffuse muscular pain, muscle weakness, and dark urine. These recurrent attacks of rhabdomyolysis were never accompanied by ARF. The patient was found to be homozygous for the mutation p.S113L of the CPT2 gene. To the best of our knowledge, this is the first report of the coexistence of VHL disease and CPT2 deficiency in the same individual. Based on findings from animal models, the case illustrates that mutations in the VHL gene might protect against renal damage caused by CPT2 gene mutations. PMID:27034144

  16. Hemlock alkaloids from Socrates to poison aloes.

    PubMed

    Reynolds, Tom

    2005-06-01

    Hemlock (Conium maculatum L. Umbelliferae) has long been known as a poisonous plant. Toxicity is due to a group of piperidine alkaloids of which the representative members are coniine and gamma-coniceine. The latter is the more toxic and is the first formed biosynthetically. Its levels in relation to coniine vary widely according to environmental conditions and to provenance of the plants. Surprisingly, these piperidine alkaloids have turned up in quite unrelated species in the monocotyledons as well as the dicotyledons. Aloes, for instance, important medicinal plants, are not regarded as poisonous although some species are very bitter. Nevertheless a small number of mostly local species contain the alkaloids, especially gamma-coniceine and there have been records of human poisoning. The compounds are recognized by their characteristic mousy smell. Both acute and chronic symptoms have been described. The compounds are neurotoxins and death results from respiratory failure, recalling the effects of curare. Chronic non-lethal ingestion by pregnant livestock leads to foetal malformation. Both acute and chronic toxicity are seen with stock in damp meadows and have been recorded as problems especially in North America. The alkaloids derive biosynthetically from acetate units via the polyketide pathway in contrast to other piperidine alkaloids which derive from lysine.

  17. Benzylisoquinoline alkaloid biosynthesis in opium poppy.

    PubMed

    Beaudoin, Guillaume A W; Facchini, Peter J

    2014-07-01

    Opium poppy (Papaver somniferum) is one of the world's oldest medicinal plants and remains the only commercial source for the narcotic analgesics morphine, codeine and semi-synthetic derivatives such as oxycodone and naltrexone. The plant also produces several other benzylisoquinoline alkaloids with potent pharmacological properties including the vasodilator papaverine, the cough suppressant and potential anticancer drug noscapine and the antimicrobial agent sanguinarine. Opium poppy has served as a model system to investigate the biosynthesis of benzylisoquinoline alkaloids in plants. The application of biochemical and functional genomics has resulted in a recent surge in the discovery of biosynthetic genes involved in the formation of major benzylisoquinoline alkaloids in opium poppy. The availability of extensive biochemical genetic tools and information pertaining to benzylisoquinoline alkaloid metabolism is facilitating the study of a wide range of phenomena including the structural biology of novel catalysts, the genomic organization of biosynthetic genes, the cellular and sub-cellular localization of biosynthetic enzymes and a variety of biotechnological applications. In this review, we highlight recent developments and summarize the frontiers of knowledge regarding the biochemistry, cellular biology and biotechnology of benzylisoquinoline alkaloid biosynthesis in opium poppy.

  18. The alkaloids of the madangamine group.

    PubMed

    Amat, Mercedes; Pérez, Maria; Ballette, Roberto; Proto, Stefano; Bosch, Joan

    2015-01-01

    This chapter is focused on madangamines, a small group of complex diamine alkaloids isolated from marine sponges of the order Haplosclerida, and covers their isolation, characterization, biogenesis, biological activity, and synthesis. Structurally, madangamines are pentacyclic alkaloids with an unprecedented skeletal type, characterized by a common diazatricyclic core and two peripheral macrocyclic rings. The isolation of these alkaloids from Xestospongia ingens (madangamines A-E) and Pachychalina alcaloidifera (madangamine F) is described in detail. Physical and complete spectroscopic 1H and 13C NMR data are included. The proposed biogenesis of madangamines from ammonia, a functionalized three-carbon unit, and saturated or unsaturated linear long-chain dialdehydes, via partially reduced bis-alkylpyridine macrocycles, is discussed. The synthesis of alkaloids of the madangamine group has been little explored, with only one total synthesis reported so far, that of (+)-madangamine D. This review also describes several model synthetic approaches to the diazatricyclic ABC core of these alkaloids, as well as model studies on the construction of the (Z,Z)-unsaturated 11-membered E macrocycle common to madangamines A-E, the 13- and 14-membered D rings of madangamines C-E, and the all-cis-triunsaturated 15-membered D ring of madangamine A. Some members of this group have shown significant in vitro cytotoxicity against a number of cancer cell lines.

  19. Benzylisoquinoline alkaloid biosynthesis in opium poppy.

    PubMed

    Beaudoin, Guillaume A W; Facchini, Peter J

    2014-07-01

    Opium poppy (Papaver somniferum) is one of the world's oldest medicinal plants and remains the only commercial source for the narcotic analgesics morphine, codeine and semi-synthetic derivatives such as oxycodone and naltrexone. The plant also produces several other benzylisoquinoline alkaloids with potent pharmacological properties including the vasodilator papaverine, the cough suppressant and potential anticancer drug noscapine and the antimicrobial agent sanguinarine. Opium poppy has served as a model system to investigate the biosynthesis of benzylisoquinoline alkaloids in plants. The application of biochemical and functional genomics has resulted in a recent surge in the discovery of biosynthetic genes involved in the formation of major benzylisoquinoline alkaloids in opium poppy. The availability of extensive biochemical genetic tools and information pertaining to benzylisoquinoline alkaloid metabolism is facilitating the study of a wide range of phenomena including the structural biology of novel catalysts, the genomic organization of biosynthetic genes, the cellular and sub-cellular localization of biosynthetic enzymes and a variety of biotechnological applications. In this review, we highlight recent developments and summarize the frontiers of knowledge regarding the biochemistry, cellular biology and biotechnology of benzylisoquinoline alkaloid biosynthesis in opium poppy. PMID:24671624

  20. Actions of Piperidine Alkaloid Teratogens at Fetal Nicotinic Acetylcholine Receptors.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Teratogenic alkaloids are found in many species of plants including Conium maculatum L., Nicotiana glauca, Nicotiana tabaccum, and multiple Lupinus spp. Fetal musculoskeletal defects produced by alkaloids from these plants include arthrogyropisis, scoliosis, torticollis, kyposis, lordosis, and clef...

  1. Biological activity of alkaloids from Solanum dulcamara L.

    PubMed

    Kumar, Padma; Sharma, Bindu; Bakshi, Nidhi

    2009-01-01

    Alkaloids are well known for their antimicrobial activity. Though all natural alkaloids come from plants, not all plants produce alkaloids. Plants of the Solanaceae family are known for their high alkaloid content. Alkaloids are found in all plant parts like roots, stems, leaves, flowers, fruits and seeds. In the present study, those plant parts of Solanum dulcamara were selected which have been reported to produce a high content of a specific alkaloid: solanine (from unripe fruits), solasodine (from flowers) and beta-solamarine (from roots). These alkaloids were extracted from various parts of S. dulcamara by well-established methods and were screened for their antibacterial activity. Human pathogenic bacteria, viz., Enterobacter aerogenes, Escherichia coli, Staphylococcus aureus, were selected for the study. All three alkaloids inhibited the growth of E. coli and S. aureus. However, no significant activity was observed against E. aerogenes. Minimum inhibitory concentration and minimum bactericidal concentration were also evaluated.

  2. The Double-Bond Configuration of Corynanthean Alkaloids and Its Impact on Monoterpenoid Indole Alkaloid Biosynthesis.

    PubMed

    Eckermann, Ruben; Gaich, Tanja

    2016-04-11

    Experimental evidence is provided for the coherence of the double-bond geometry and the occurrence of "secondary cyclizations" in the biosynthesis of monoterpenoid indole alkaloids. Biosynthetically, akuammiline, C-mavacurine, and Strychnos alkaloids are proposed to be derived from the corynanthean alkaloid geissoschizine, a key intermediate in the biosynthetic pathway of these monoterpenoid indole alkaloids. This process occurs by so-called "secondary cyclizations" from geissoschizine or its derivatives. Although corynanthean alkaloids like geissoschizine incorporate E or Z double bonds located at C19-C20, the alkaloids downstream in the biosynthesis exclusively exhibit the E double bond. This study shows that secondary cyclizations preferentially occur with the E isomer of geissoschizine or its derivatives. This is attributed to the flexibility of the quinolizidine system of the corynanthean alkaloids, which can adopt a cis or trans conformation. For the secondary cyclization to take place, the cis-quinolizidine conformation is required. Experimental evidence supports the hypothesis that the E double bond of geissoschizine induces the cis conformation, whereas the Z double bond induces the trans conformation, which prohibits secondary cyclization of the Z compounds.

  3. Simulation of the type of coralin alkaloid-DNA binding

    NASA Astrophysics Data System (ADS)

    Kulikov, K. G.; Koshlan, T. V.

    2015-05-01

    Interaction between a synthesized coralin protoberberine alkaloid and the DNA double helix of the calf's thymus in a salt solution is studied by optical absorption spectroscopy and spectropolarimetry. The dependence of the spectral characteristics of the alkaloid on a ratio between the DNA base pair concentration and the alkaloid molecule concentration is considered. The parameters of bonds between the coralin alkaloid and the DNA double helix are determined using modified McGhee-von Hippel equations.

  4. Rotational Investigation of Tropane Alkaloids

    NASA Astrophysics Data System (ADS)

    Cocinero, Emilio J.; Lesarri, Alberto; Ecija, Patricia; Grabow, Jens-Uwe; Fernández, Jose A.; Castano, Fernando

    2010-06-01

    We report an investigation of the rotational spectrum of several tropane alkaloids using the new Balle-Flygare-type FT-MW spectrometer built at the University of the Basque Country. The initial work focused on the azabicycles of tropinone, scopine and scopoline, vaporized using heating methods. For tropinone the spectrum confirmed the presence of equatorial and axial conformers originated by the inversion of the N-methyl group, with the tropane motif adopting a distorted chair configuration. The determination of substitution and effective structures for the two conformers included the 13C, 15N and 18O isotopomers observed in natural abundance. The structures revealed the flexibility and structural changes associated to the N-methyl inversion, mostly a flattening at the nitrogen atom and a simultaneous rising of the carbonyl group in the axial form. The investigation of scopine gave an intense spectrum, but it was inconsistent with the structural models expected for this molecule. The carrier of the new spectrum was later identified as scopoline, generated in situ by an intramolecular reaction at the moderate temperatures of the nozzle. A single conformation was detected for scopoline, with an ether bridge seriously distorting the tropane motif. E. J. Cocinero, A. Lesarri, P. écija, J.-U. Grabow, J. A. Fernández, F. Castaño, in publication, 2010 E. J. Cocinero, A. Lesarri, P. Écija, J.-U. Grabow, J. A. Fernández, F. Castaño, Phys. Chem. Chem. Phys.,in press, 2010

  5. An efficient synthesis of loline alkaloids

    NASA Astrophysics Data System (ADS)

    Cakmak, Mesut; Mayer, Peter; Trauner, Dirk

    2011-07-01

    Loline (1) is a small alkaloid that, in spite of its simple-looking structure, has posed surprising challenges to synthetic chemists. It has been known for more than a century and has been the subject of extensive biological investigations, but only two total syntheses have been achieved to date. Here, we report an asymmetric total synthesis of loline that, with less then ten steps, is remarkably short. Our synthesis incorporates a Sharpless epoxidation, a Grubbs olefin metathesis and an unprecedented transannular aminobromination, which converts an eight-membered cyclic carbamate into a bromopyrrolizidine. The synthesis is marked by a high degree of chemo- and stereoselectivity and gives access to several members of the loline alkaloid family. It delivers sufficient material to support a programme aimed at studying the complex interactions between plants, fungi, insects and bacteria brokered by loline alkaloids.

  6. Ether bridge formation in loline alkaloid biosynthesis

    PubMed Central

    Pan, Juan; Bhardwaj, Minakshi; Faulkner, Jerome R.; Nagabhyru, Padmaja; Charlton, Nikki D.; Higashi, Richard M.; Miller, Anne-Frances; Young, Carolyn A.; Grossman, Robert B.; Schardl, Christopher L.

    2014-01-01

    Lolines are potent insecticidal agents produced by endophytic fungi of cool-season grasses. These alkaloids are composed of a pyrrolizidine ring system and an uncommon ether bridge linking carbons 2 and 7. Previous results indicated that 1-aminopyrrolizidine was a pathway intermediate. We used RNA interference to knock down expression of lolO, resulting in the accumulation of a novel alkaloid identified as exo-1-acetamidopyrrolizidine based on high-resolution MS and NMR. Genomes of endophytes differing in alkaloid profiles were sequenced, revealing that those with mutated lolO accumulated exo-1-acetamidopyrrolizidine but no lolines. Heterologous expression of wild-type lolO complemented a lolO mutant, resulting in the production of N-acetylnorloline. These results indicated that the non-heme iron oxygenase, LolO, is required for ether bridge formation, probably through oxidation of exo-1-acetamidopyrrolizidine. PMID:24374065

  7. Alkaloid profiles of Mimosa tenuiflora and associated methods of analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The alkaloid contents of the leaves and seeds of M. tenuiflora collected from northeastern Brazil were studied. Alkaloids were isolated by classical acid/base extraction procedures and by cation exchange solid phase extraction. The crude alkaloid fractions were then analysed by thin layer chromatogr...

  8. 21 CFR 119.1 - Dietary supplements containing ephedrine alkaloids.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 2 2012-04-01 2012-04-01 false Dietary supplements containing ephedrine alkaloids... UNREASONABLE RISK § 119.1 Dietary supplements containing ephedrine alkaloids. Dietary supplements containing ephedrine alkaloids present an unreasonable risk of illness or injury under conditions of use recommended...

  9. 21 CFR 119.1 - Dietary supplements containing ephedrine alkaloids.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Dietary supplements containing ephedrine alkaloids... UNREASONABLE RISK § 119.1 Dietary supplements containing ephedrine alkaloids. Dietary supplements containing ephedrine alkaloids present an unreasonable risk of illness or injury under conditions of use recommended...

  10. 21 CFR 119.1 - Dietary supplements containing ephedrine alkaloids.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 2 2011-04-01 2011-04-01 false Dietary supplements containing ephedrine alkaloids... UNREASONABLE RISK § 119.1 Dietary supplements containing ephedrine alkaloids. Dietary supplements containing ephedrine alkaloids present an unreasonable risk of illness or injury under conditions of use recommended...

  11. 21 CFR 119.1 - Dietary supplements containing ephedrine alkaloids.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 2 2014-04-01 2014-04-01 false Dietary supplements containing ephedrine alkaloids... UNREASONABLE RISK § 119.1 Dietary supplements containing ephedrine alkaloids. Dietary supplements containing ephedrine alkaloids present an unreasonable risk of illness or injury under conditions of use recommended...

  12. 21 CFR 119.1 - Dietary supplements containing ephedrine alkaloids.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 2 2013-04-01 2013-04-01 false Dietary supplements containing ephedrine alkaloids... UNREASONABLE RISK § 119.1 Dietary supplements containing ephedrine alkaloids. Dietary supplements containing ephedrine alkaloids present an unreasonable risk of illness or injury under conditions of use recommended...

  13. Production, detection, and purification of clavine-type ergot alkaloids.

    PubMed

    Wallwey, Christiane; Li, Shu-Ming

    2012-01-01

    Ergot alkaloids are indole derivatives with diverse structures and biological activities. This chapter describes the procedure from fungal cultivation to purified ergot alkaloids, as exemplified by fumigaclavine A in Penicillium commune. Furthermore, useful notes for working with purified ergot alkaloids are given. PMID:23065612

  14. Pancratium canariense as an important source of amaryllidaceae alkaloids.

    PubMed

    Cedrón, Juan C; Oberti, Juan C; Estévez-Braun, Ana; Ravelo, Angel G; Del Arco-Aguilar, Marcelino; López, Matías

    2009-01-01

    Four new alkaloids (1-4) have been isolated from a methanolic extract of bulbs of Pancratium canariense, together with 12 known alkaloids (5-16). The structures of the new alkaloids were determined by extensive 1D and 2D NMR spectroscopic studies and X-ray diffraction.

  15. Carnitine palmitoyl transferase-1A (CPT1A): a new tumor specific target in human breast cancer.

    PubMed

    Pucci, Sabina; Zonetti, Maria Josè; Fisco, Tommaso; Polidoro, Chiara; Bocchinfuso, Gianfranco; Palleschi, Antonio; Novelli, Giuseppe; Spagnoli, Luigi G; Mazzarelli, Paola

    2016-04-12

    Transcriptional mechanisms epigenetically-regulated in tumoral tissues point out new targets for anti-cancer therapies. Carnitine palmitoyl transferase I (CPT1) is the rate-limiting enzyme in the transport of long-chain fatty acids for β-oxidation. Here we identified the tumor specific nuclear CPT1A as a product of the transcript variant 2, that doesn't retain the classical transferase activity and is strongly involved in the epigenetic regulation of cancer pro-survival, cell death escaping and tumor invasion pathways. The knockdown of CPT1A variant 2 by small interfering RNAs (siRNAs), was sufficient to induce apoptosis in MCF-7, SK-BR3 and MDA-MB-231 breast cancer cells. The cell death triggered by CPT1A silencing correlated with reduction of HDAC activity and histone hyperacetylation. Docking experiments and molecular dynamics simulations confirmed an high binding affinity of the variant 2 for HDAC1. The CPT1A silenced cells showed an up-regulated transcription of pro-apoptotic genes (BAD, CASP9, COL18A1) and down-modulation of invasion and metastasis related-genes (TIMP-1, PDGF-A, SERPINB2). These findings provide evidence of the CPT1 variant 2 involvement in breast cancer survival, cell death escape and invasion. Thus, we propose nuclear CPT1A as a striking tumor specific target for anticancer therapeutics, more selective and effective as compared with the well-known HDAC inhibitors.

  16. Carnitine palmitoyl transferase-1A (CPT1A): a new tumor specific target in human breast cancer

    PubMed Central

    Zonetti, Maria Josè; Fisco, Tommaso; Polidoro, Chiara; Bocchinfuso, Gianfranco; Palleschi, Antonio; Novelli, Giuseppe; Spagnoli, Luigi G.

    2016-01-01

    Transcriptional mechanisms epigenetically-regulated in tumoral tissues point out new targets for anti-cancer therapies. Carnitine palmitoyl transferase I (CPT1) is the rate-limiting enzyme in the transport of long-chain fatty acids for β-oxidation. Here we identified the tumor specific nuclear CPT1A as a product of the transcript variant 2, that doesn't retain the classical transferase activity and is strongly involved in the epigenetic regulation of cancer pro-survival, cell death escaping and tumor invasion pathways. The knockdown of CPT1A variant 2 by small interfering RNAs (siRNAs), was sufficient to induce apoptosis in MCF-7, SK-BR3 and MDA-MB-231 breast cancer cells. The cell death triggered by CPT1A silencing correlated with reduction of HDAC activity and histone hyperacetylation. Docking experiments and molecular dynamics simulations confirmed an high binding affinity of the variant 2 for HDAC1. The CPT1A silenced cells showed an up-regulated transcription of pro-apoptotic genes (BAD, CASP9, COL18A1) and down-modulation of invasion and metastasis related-genes (TIMP-1, PDGF-A, SERPINB2). These findings provide evidence of the CPT1 variant 2 involvement in breast cancer survival, cell death escape and invasion. Thus, we propose nuclear CPT1A as a striking tumor specific target for anticancer therapeutics, more selective and effective as compared with the well-known HDAC inhibitors. PMID:26799588

  17. Design, Synthesis, and Biological Evaluations of Tumor-Targeting Dual-Warhead Conjugates for a Taxoid–Camptothecin Combination Chemotherapy

    PubMed Central

    2015-01-01

    Novel tumor-targeting dual-warhead conjugates, 2 (DW-1) and 3 (DW-2), which consist of a next-generation taxoid, 1 (SB-T-1214), and camptothecin as two warheads, self-immolative disulfide linkers for drug release, biotin as the tumor-targeting moiety, and 1,3,5-triazine as the tripod splitter module, were designed and synthesized. The potency of 2 was evaluated against MX-1, MCF-7, ID8, L1210FR (BR+, biotin receptor overexpressed) and WI38 (BR–, normal) cell lines in the absence and presence of glutathione (GSH), which is an endogenous thiol that triggers drug release inside the cancer cells. With the GSH and resuspension protocol, 2 exhibited IC50 values of 3.22–9.80 nM against all BR+ cancer cell lines, and 705 nM against WI38. Thus, there was a two orders of magnitude higher selectivity to cancer cells. Also, a clear cooperative effect was observed for the taxoid–camptothecin combination when two drugs were delivered to the cancer cells specifically in the form of a dual-warhead conjugate. PMID:24901491

  18. Effects of camptothecin, etoposide and Ca2+ on caspase-3 activity and myofibrillar disruption of chicken during postmortem ageing.

    PubMed

    Chen, Lin; Feng, Xian Chao; Lu, Feng; Xu, Xing Lian; Zhou, Guang Hong; Li, Qing Yun; Guo, Xiang Ying

    2011-03-01

    Recently, a novel consideration has focused on the potential relationship of apoptosis and the protease caspases and the underlying mechanism for meat postmortem tenderization. In this study, apoptosis inducers, camptothecin and etoposide as well as Ca(2+) were used to treat chicken muscle immediately after slaughter and follow the changes in caspase-3 activities and changes in the myofibrillar structures during 7 days of ageing. All three treatments resulted in significantly higher caspase-3 activities during storage (p<0.05), with the natural substrates, whereas Western blotting analysis of the α-spectrin cleavage product, 120 kDa peptide (SBDP 120), showed that Ca(2+) was more effective than either camptothecin or etopside, and all were most active up to day 3 (p<0.01). According to SDS-PAGE, each treatment enhanced the accumulation of the 30 kD Troponin-T degradation product, especially during the first 3 days (p<0.05), and this was supported by the degradation of myofibrils observed by electron microscopy (TEM). TEM images showed the treatments resulted in enlargement of the I-bands and shrinkage of A-bands; however Z-lines were only slightly affected, even at day 7. The findings revealed that the three apoptosis inducers could increase myofibrillar dissociation and proteolysis during the first 3 days of chicken meat ageing. Because of the high activity of caspase-3 during the early postmortem period, it is possible that caspase-3 contributes to the conversion of muscle into meat.

  19. Development of transcriptomic resources for interrogating the biosynthesis of monoterpene indole alkaloids in medicinal plant species.

    PubMed

    Góngora-Castillo, Elsa; Childs, Kevin L; Fedewa, Greg; Hamilton, John P; Liscombe, David K; Magallanes-Lundback, Maria; Mandadi, Kranthi K; Nims, Ezekiel; Runguphan, Weerawat; Vaillancourt, Brieanne; Varbanova-Herde, Marina; Dellapenna, Dean; McKnight, Thomas D; O'Connor, Sarah; Buell, C Robin

    2012-01-01

    The natural diversity of plant metabolism has long been a source for human medicines. One group of plant-derived compounds, the monoterpene indole alkaloids (MIAs), includes well-documented therapeutic agents used in the treatment of cancer (vinblastine, vincristine, camptothecin), hypertension (reserpine, ajmalicine), malaria (quinine), and as analgesics (7-hydroxymitragynine). Our understanding of the biochemical pathways that synthesize these commercially relevant compounds is incomplete due in part to a lack of molecular, genetic, and genomic resources for the identification of the genes involved in these specialized metabolic pathways. To address these limitations, we generated large-scale transcriptome sequence and expression profiles for three species of Asterids that produce medicinally important MIAs: Camptotheca acuminata, Catharanthus roseus, and Rauvolfia serpentina. Using next generation sequencing technology, we sampled the transcriptomes of these species across a diverse set of developmental tissues, and in the case of C. roseus, in cultured cells and roots following elicitor treatment. Through an iterative assembly process, we generated robust transcriptome assemblies for all three species with a substantial number of the assembled transcripts being full or near-full length. The majority of transcripts had a related sequence in either UniRef100, the Arabidopsis thaliana predicted proteome, or the Pfam protein domain database; however, we also identified transcripts that lacked similarity with entries in either database and thereby lack a known function. Representation of known genes within the MIA biosynthetic pathway was robust. As a diverse set of tissues and treatments were surveyed, expression abundances of transcripts in the three species could be estimated to reveal transcripts associated with development and response to elicitor treatment. Together, these transcriptomes and expression abundance matrices provide a rich resource for

  20. Evaporative light scattering detection of pyrrolizidine alkaloids.

    PubMed

    Schaneberg, Brian T; Molyneux, Russell J; Khan, Ikhlas A

    2004-01-01

    A reverse-phase high-performance liquid chromatography method utilizing evaporative light scattering detection (ELSD) has been developed for the simultaneous detection of hepatotoxic pyrrolizidine alkaloids with and without chromophores, namely, riddelliine, riddelliine N-oxide, senecionine, senecionine N-oxide, seneciphylline, retrorsine, integerrimine, lasiocarpine and heliotrine. Pyrrolizidine alkaloids were detected in five plant extracts (Senecio spartioides, S. douglasii var. longilobus, S. jacobaea, S. intergerrimus var. exaltatus and Symphytum officinale). The detection of heliotrine (which does not contain a chromophore) was much improved by ELSD compared with photodiode array detection. PMID:14979525

  1. Antitussive indole alkaloids from Kopsia hainanensis.

    PubMed

    Tan, Min-Jia; Yin, Chun; Tang, Chun-Ping; Ke, Chang-Qiang; Lin, Ge; Ye, Yang

    2011-06-01

    Three new indole alkaloids, named kopsihainins A-C (1-3), and two known compounds, kopsinine (4) and methyl demethoxycarbonylchanofruticosinate (5), were isolated from the stems of Kopsia hainanensis. Their structures were determined using extensive spectroscopic methods. The two main constituents 4 and 5 exhibited significant antitussive activity in a citric acid induced guinea pig cough model. The antitussive effect of 4 was demonstrated to interact with the δ-opioid receptor. This is the first report of antitussive effects of aspidofractinine type and chanofruticosinate type alkaloids.

  2. The expanding universe of alkaloid biosynthesis.

    PubMed

    De Luca, V; Laflamme, P

    2001-06-01

    Characterization of many of the major gene families responsible for the generation of central intermediates and for their decoration, together with the development of large genomics and proteomics databases, has revolutionized our capability to identify exotic and interesting natural-product pathways. Over the next few years, these tools will facilitate dramatic advances in our knowledge of the biosynthesis of alkaloids, which will far surpass that which we have learned in the past 50 years. These tools will also be exploited for the rapid characterization of regulatory genes, which control the development of specialized cell factories for alkaloid biosynthesis.

  3. Antimicrobial hasubanalactam alkaloid from Stephania glabra.

    PubMed

    Semwal, Deepak Kumar; Rawat, Usha

    2009-03-01

    A novel hasubanalactam alkaloid, named glabradine, has been isolated from the tubers of Stephania glabra, together with three known quaternary protoberberine alkaloids, palmatine, dehydrocorydalmine and stepharanine. The structure of glabradine was assigned as 7-O-demethyl-N,O-dimethyloxostephinine, by means of rigorous spectroscopic analysis including 2 D NMR measurements. It was evaluated for antimicrobial activity against Staphylococcus aureus, S. mutans, Microsporum gypseum, M. canis and Trichophyton rubrum and displayed potent antimicrobial activity superior to those of novobiocin and erythromycin used as positive controls. PMID:19148860

  4. Resistance to irinotecan (CPT-11) activates epidermal growth factor receptor/nuclear factor kappa B and increases cellular metastasis and autophagy in LoVo colon cancer cells.

    PubMed

    Chen, Ming-Cheng; Lee, Nien-Hung; Ho, Tsung-Jung; Hsu, Hsi-Hsien; Kuo, Chia-Hua; Kuo, Wei-Wen; Lin, Yueh-Min; Tsai, Fuu-Jen; Tsai, Chang-Hai; Huang, Chih-Yang

    2014-07-10

    Chemotherapy is usually applied to treat colon cancer but leads to chemoresistance, and increased metastasis and invasion. The main focus of this study is to observe effects of resistance to irinotecan (CPT-11) on metastasis, invasion and autophagy in CPT-11 resistant (CPT-11-R) LoVo colon cancer cells. CPT-11, a topoisomerase I inhibitor and a first-line chemotherapeutic drug, is used to treat colon cancer. CPT-11-R cells were constructed in a step-wise fashion with increasing CPT-11 doses. The CPT-11-R strain had a significantly lower expression of Wnt/β-catenin pathway, but induced an EGFR/IKKα/β/NF-κB pathway with elevated cell cycle, metastasis and basal autophagy.

  5. A high-performance frequency stability compact CPT clock based on a Cs-Ne microcell.

    PubMed

    Boudot, Rodolphe; Liu, Xiaochi; Abbé, Philippe; Chutani, Ravinder; Passilly, Nicolas; Galliou, Serge; Gorecki, Christophe; Giordano, Vincent

    2012-11-01

    This paper reports on a compact table-top Cs clock based on coherent population trapping (CPT) with advanced frequency stability performance. The heart of the clock is a single buffer gas Cs-Ne microfabricated cell. Using a distributed feedback (DFB) laser resonant with the Cs D1 line, the contrast of the CPT signal is found to be maximized around 80°C, a value for which the temperature dependence of the Cs clock frequency is canceled. Advanced techniques are implemented to actively stabilize the clock operation on a zero-light-shift point. The clock frequency stability is measured to be 3.8 × 10(-11) at 1 s and well below 10(-11) until 50,000 s. These results demonstrate the possibility to develop high-performance chip-scale atomic clocks using vapor cells containing a single buffer gas. PMID:23192824

  6. Testing Lorentz invariance and CPT conservation with NuMI neutrinos in the MINOS near detector.

    PubMed

    Adamson, P; Andreopoulos, C; Arms, K E; Armstrong, R; Auty, D J; Ayres, D S; Baller, B; Barr, G; Barrett, W L; Becker, B R; Belias, A; Bernstein, R H; Bhattacharya, D; Bishai, M; Blake, A; Bock, G J; Boehm, J; Boehnlein, D J; Bogert, D; Bower, C; Buckley-Geer, E; Cavanaugh, S; Chapman, J D; Cherdack, D; Childress, S; Choudhary, B C; Coleman, S J; Culling, A J; de Jong, J K; Diwan, M V; Dorman, M; Dytman, S A; Escobar, C O; Evans, J J; Falk Harris, E; Feldman, G J; Frohne, M V; Gallagher, H R; Goodman, M C; Gouffon, P; Gran, R; Grashorn, E W; Grossman, N; Grzelak, K; Habig, A; Harris, D; Harris, P G; Hartnell, J; Hatcher, R; Heller, K; Himmel, A; Holin, A; Hylen, J; Irwin, G M; Ishitsuka, M; Jaffe, D E; James, C; Jensen, D; Kafka, T; Kasahara, S M S; Kim, J J; Koizumi, G; Kopp, S; Kordosky, M; Koskinen, D J; Kreymer, A; Kumaratunga, S; Lang, K; Ling, J; Litchfield, P J; Litchfield, R P; Loiacono, L; Lucas, P; Ma, J; Mann, W A; Marshak, M L; Marshall, J S; Mayer, N; McGowan, A M; Meier, J R; Messier, M D; Metelko, C J; Michael, D G; Miller, J L; Miller, W H; Mishra, S R; Moore, C D; Morfín, J; Mualem, L; Mufson, S; Murgia, S; Musser, J; Naples, D; Nelson, J K; Newman, H B; Nichol, R J; Nicholls, T C; Ochoa-Ricoux, J P; Oliver, W P; Ospanov, R; Paley, J; Paolone, V; Para, A; Patzak, T; Pavlović, Z; Pawloski, G; Pearce, G F; Peck, C W; Petyt, D A; Pittam, R; Plunkett, R K; Rahaman, A; Rameika, R A; Raufer, T M; Rebel, B; Reichenbacher, J; Rodrigues, P A; Rosenfeld, C; Rubin, H A; Sanchez, M C; Saoulidou, N; Schneps, J; Schreiner, P; Shanahan, P; Smart, W; Sousa, A; Speakman, B; Stamoulis, P; Strait, M; Tagg, N; Talaga, R L; Tavera, M A; Thomas, J; Thompson, J; Thomson, M A; Thron, J L; Tinti, G; Tzanakos, G; Urheim, J; Vahle, P; Viren, B; Watabe, M; Weber, A; Webb, R C; Wehmann, A; West, N; White, C; Wojcicki, S G; Yang, T; Zois, M; Zhang, K; Zwaska, R

    2008-10-10

    A search for a sidereal modulation in the MINOS near detector neutrino data was performed. If present, this signature could be a consequence of Lorentz and CPT violation as predicted by the effective field theory called the standard-model extension. No evidence for a sidereal signal in the data set was found, implying that there is no significant change in neutrino propagation that depends on the direction of the neutrino beam in a sun-centered inertial frame. Upper limits on the magnitudes of the Lorentz and CPT violating terms in the standard-model extension lie between 10(-4) and 10(-2) of the maximum expected, assuming a suppression of these signatures by a factor of 10(-17).

  7. Therapeutic Potential of Steroidal Alkaloids in Cancer and Other Diseases.

    PubMed

    Jiang, Qi-Wei; Chen, Mei-Wan; Cheng, Ke-Jun; Yu, Pei-Zhong; Wei, Xing; Shi, Zhi

    2016-01-01

    Steroidal alkaloids are a class of secondary metabolites isolated from plants, amphibians, and marine invertebrates. Evidence accumulated in the recent two decades demonstrates that steroidal alkaloids have a wide range of bioactivities including anticancer, antimicrobial, anti-inflammatory, antinociceptive, etc., suggesting their great potential for application. It is therefore necessary to comprehensively summarize the bioactivities, especially anticancer activities and mechanisms of steroidal alkaloids. Here we systematically highlight the anticancer profiles both in vitro and in vivo of steroidal alkaloids such as dendrogenin, solanidine, solasodine, tomatidine, cyclopamine, and their derivatives. Furthermore, other bioactivities of steroidal alkaloids are also discussed. The integrated molecular mechanisms in this review can increase our understanding on the utilization of steroidal alkaloids and contribute to the development of new drug candidates. Although the therapeutic potentials of steroidal alkaloids look promising in the preclinical and clinical studies, further pharmacokinetic and clinical studies are mandated to define their efficacy and safety in cancer and other diseases.

  8. Alkaloid diversity in Galanthus elwesii and Galanthus nivalis.

    PubMed

    Berkov, Strahil; Bastida, Jaume; Sidjimova, Borjana; Viladomat, Francesc; Codina, Carles

    2011-01-01

    Seventy alkaloids of galanthamine, lycorine, homolycorine, tazettine, haemanthamine, narciclasine, and tyramine types were detected by GC/MS in 25 Galanthus elwesii and seven Galanthus nivalis populations, collected from different locations in Bulgaria. Intraspecies diversity in the alkaloid profiles regarding the main alkaloid types (chemotypes) was observed. Tyramine-type protoalkaloids (namely, hordenine and its derivatives) were dominant in 19 populations of G. elwesii. In other populations of G. elwesii, the plants accumulated mainly homolycorine-, lycorine-, and galanthamine-type alkaloids. The alkaloid profiles of G. nivalis were dominated by narciclasine-, galanthamine-, lycorine-, haemanthamine-, or tazettine-type compounds. Geographical distribution of chemotypes indicated a relationship between populations, since adjacent populations often displayed similar alkaloid profiles. The results from year-to-year sampling and transplantation experiments imply genetic determination of alkaloid synthesis in the two studied species of Galanthus.

  9. Apoptosis-Inducing Effects of Amaryllidaceae Alkaloids.

    PubMed

    Nair, Jerald J; van Staden, Johannes; Bastida, Jaume

    2016-01-01

    The Amaryllidaceae occupies a privileged status amongst medicinal plants in having delivered the Alzheimer's drug galanthamine to the clinical market. Following its resounding success, there have been several positive indicators for the emergence of an anticancer drug from the family due to the potent antiproliferative activities manifested by several of its alkaloid constituents. Of these, the phenanthridones such as pancratistatin hold most promise as potential chemotherapeutics having succumbed to various phases of clinical trials. Other cytotoxic targets of the Amaryllidaceae are to be found within the lycorane and crinane groups, as exemplified by crinine and lycorine. Although the molecular targets of these alkaloids still remain elusive, much effort has gone into understanding their mode of action in cancer cells. Recent findings have shown that the apoptotic pathway may be a key factor in cancer cell death instigated by Amaryllidaceae alkaloids. As such, this review seeks to: (a) examine the apoptotic effects of Amaryllidaceae alkaloids in cancer cells; (b) explore the molecular basis to these effects; and (c) provide a pharmacophoric rationale in support of these activities.

  10. Highly selective hydroformylation of the cinchona alkaloids.

    PubMed

    Lambers, Marielle; Beijer, Felix H; Padron, José M; Toth, Imre; de Vries, Johannes G

    2002-07-12

    The four naturally occurring cinchona alkaloids were subjected to hydroformylation to create an extra functional group that allows immobilization. Cinchonidine, quinine, and quinidine, could be hydroformylated with virtually complete terminal selectivity, using a rhodium/tetraphosphite catalyst. The cinchonidine aldehyde was reduced to the alcohol and subjected to reductive amination with benzylamine.

  11. Chinchona alkaloid from Dendrosenecio kilimanjari subsp. cottonii.

    PubMed

    Were, O; Benn, M; Munavu, R

    1997-02-01

    Investigation of the Tanzanian Dendrosenecio kilimanjari subsp. cottonii resulted in the isolation of the cinchona alkaloid, cinchonidine. Conversion of cinchonidine to deoxy-cinchonidine was achieved in high yield using zinc dust in aqueous sulphuric acid. This illustrates the first reduction of a quinoline system using these reagents.

  12. No contact terms for the magnetic field in Lorentz- and CPT-violating electrodynamics

    NASA Astrophysics Data System (ADS)

    Schober, Karl; Altschul, Brett

    2016-09-01

    In a Lorentz- and CPT-violating modification of electrodynamics, the fields of a moving charge are known to have unusual singularities. This raises the question of whether the singular behavior may include δ-function contact terms, similar to those that appear in the fields of idealized dipoles. However, by calculating the magnetic field of an infinite straight wire in this theory, we demonstrate that there are no such contact terms in the magnetic field of a moving point charge.

  13. Methylation at CPT1A locus is associated with lipoprotein subfraction profiles[S

    PubMed Central

    Frazier-Wood, Alexis C.; Aslibekyan, Stella; Absher, Devin M.; Hopkins, Paul N.; Sha, Jin; Tsai, Michael Y.; Tiwari, Hemant K.; Waite, Lindsay L.; Zhi, Degui; Arnett, Donna K.

    2014-01-01

    Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the first systematic screen of the genome to determine associations between methylation status at ∼470,000 cytosine-guanine dinucleotide (CpG) sites in CD4+ T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identified two CpGs, both in the carnitine palmitoyltransferase-1A (CPT1A) gene, which reached significant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases (P < 1.1 × 10−7 in the discovery phase, P < .004 in the replication phase, and P < 1.1 × 10−12 in the full sample). CPT1A is regulated by PPARα, a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this gene in metabolic dysfunction. PMID:24711635

  14. Search for Violations of Lorentz Invariance and CPT Symmetry in B_{(s)}^{0} Mixing.

    PubMed

    Aaij, R; Abellán Beteta, C; Adeva, B; Adinolfi, M; Ajaltouni, Z; Akar, S; Albrecht, J; Alessio, F; Alexander, M; Ali, S; Alkhazov, G; Alvarez Cartelle, P; Alves, A A; Amato, S; Amerio, S; Amhis, Y; An, L; Anderlini, L; Andreassi, G; Andreotti, M; Andrews, J E; Appleby, R B; Aquines Gutierrez, O; Archilli, F; d'Argent, P; Artamonov, A; Artuso, M; Aslanides, E; Auriemma, G; Baalouch, M; Bachmann, S; Back, J J; Badalov, A; Baesso, C; Baker, S; Baldini, W; Barlow, R J; Barschel, C; Barsuk, S; Barter, W; Batozskaya, V; Battista, V; Bay, A; Beaucourt, L; Beddow, J; Bedeschi, F; Bediaga, I; Bel, L J; Bellee, V; Belloli, N; Belyaev, I; Ben-Haim, E; Bencivenni, G; Benson, S; Benton, J; Berezhnoy, A; Bernet, R; Bertolin, A; Betti, F; Bettler, M-O; van Beuzekom, M; Bifani, S; Billoir, P; Bird, T; Birnkraut, A; Bizzeti, A; Blake, T; Blanc, F; Blouw, J; Blusk, S; Bocci, V; Bondar, A; Bondar, N; Bonivento, W; Borgheresi, A; Borghi, S; Borisyak, M; Borsato, M; Boubdir, M; Bowcock, T J V; Bowen, E; Bozzi, C; Braun, S; Britsch, M; Britton, T; Brodzicka, J; Buchanan, E; Burr, C; Bursche, A; Buytaert, J; Cadeddu, S; Calabrese, R; Calvi, M; Calvo Gomez, M; Campana, P; Campora Perez, D; Capriotti, L; Carbone, A; Carboni, G; Cardinale, R; Cardini, A; Carniti, P; Carson, L; Carvalho Akiba, K; Casse, G; Cassina, L; Castillo Garcia, L; Cattaneo, M; Cauet, Ch; Cavallero, G; Cenci, R; Charles, M; Charpentier, Ph; Chatzikonstantinidis, G; Chefdeville, M; Chen, S; Cheung, S-F; Chrzaszcz, M; Cid Vidal, X; Ciezarek, G; Clarke, P E L; Clemencic, M; Cliff, H V; Closier, J; Coco, V; Cogan, J; Cogneras, E; Cogoni, V; Cojocariu, L; Collazuol, G; Collins, P; Comerma-Montells, A; Contu, A; Cook, A; Coombes, M; Coquereau, S; Corti, G; Corvo, M; Couturier, B; Cowan, G A; Craik, D C; Crocombe, A; Cruz Torres, M; Cunliffe, S; Currie, R; D'Ambrosio, C; Dall'Occo, E; Dalseno, J; David, P N Y; Davis, A; De Aguiar Francisco, O; De Bruyn, K; De Capua, S; De Cian, M; De Miranda, J M; De Paula, L; De Simone, P; Dean, C-T; Decamp, D; Deckenhoff, M; Del Buono, L; Déléage, N; Demmer, M; Derkach, D; Deschamps, O; Dettori, F; Dey, B; Di Canto, A; Di Ruscio, F; Dijkstra, H; Dordei, F; Dorigo, M; Dosil Suárez, A; Dovbnya, A; Dreimanis, K; Dufour, L; Dujany, G; Dungs, K; Durante, P; Dzhelyadin, R; Dziurda, A; Dzyuba, A; Easo, S; Egede, U; Egorychev, V; Eidelman, S; Eisenhardt, S; Eitschberger, U; Ekelhof, R; Eklund, L; El Rifai, I; Elsasser, Ch; Ely, S; Esen, S; Evans, H M; Evans, T; Falabella, A; Färber, C; Farley, N; Farry, S; Fay, R; Fazzini, D; Ferguson, D; Fernandez Albor, V; Ferrari, F; Ferreira Rodrigues, F; Ferro-Luzzi, M; Filippov, S; Fiore, M; Fiorini, M; Firlej, M; Fitzpatrick, C; Fiutowski, T; Fleuret, F; Fohl, K; Fontana, M; Fontanelli, F; Forshaw, D C; Forty, R; Frank, M; Frei, C; Frosini, M; Fu, J; Furfaro, E; Gallas Torreira, A; Galli, D; Gallorini, S; Gambetta, S; Gandelman, M; Gandini, P; Gao, Y; García Pardiñas, J; Garra Tico, J; Garrido, L; Garsed, P J; Gascon, D; Gaspar, C; Gavardi, L; Gazzoni, G; Gerick, D; Gersabeck, E; Gersabeck, M; Gershon, T; Ghez, Ph; Gianì, S; Gibson, V; Girard, O G; Giubega, L; Gligorov, V V; Göbel, C; Golubkov, D; Golutvin, A; Gomes, A; Gotti, C; Grabalosa Gándara, M; Graciani Diaz, R; Granado Cardoso, L A; Graugés, E; Graverini, E; Graziani, G; Grecu, A; Griffith, P; Grillo, L; Grünberg, O; Gushchin, E; Guz, Yu; Gys, T; Hadavizadeh, T; Hadjivasiliou, C; Haefeli, G; Haen, C; Haines, S C; Hall, S; Hamilton, B; Han, X; Hansmann-Menzemer, S; Harnew, N; Harnew, S T; Harrison, J; He, J; Head, T; Heister, A; Hennessy, K; Henrard, P; Henry, L; Hernando Morata, J A; van Herwijnen, E; Heß, M; Hicheur, A; Hill, D; Hoballah, M; Hombach, C; Hongming, L; Hulsbergen, W; Humair, T; Hushchyn, M; Hussain, N; Hutchcroft, D; Idzik, M; Ilten, P; Jacobsson, R; Jaeger, A; Jalocha, J; Jans, E; Jawahery, A; John, M; Johnson, D; Jones, C R; Joram, C; Jost, B; Jurik, N; Kandybei, S; Kanso, W; Karacson, M; Karbach, T M; Karodia, S; Kecke, M; Kelsey, M; Kenyon, I R; Kenzie, M; Ketel, T; Khairullin, E; Khanji, B; Khurewathanakul, C; Kirn, T; Klaver, S; Klimaszewski, K; Kolpin, M; Komarov, I; Koopman, R F; Koppenburg, P; Kozeiha, M; Kravchuk, L; Kreplin, K; Kreps, M; Krokovny, P; Kruse, F; Krzemien, W; Kucewicz, W; Kucharczyk, M; Kudryavtsev, V; Kuonen, A K; Kurek, K; Kvaratskheliya, T; Lacarrere, D; Lafferty, G; Lai, A; Lambert, D; Lanfranchi, G; Langenbruch, C; Langhans, B; Latham, T; Lazzeroni, C; Le Gac, R; van Leerdam, J; Lees, J-P; Lefèvre, R; Leflat, A; Lefrançois, J; Lemos Cid, E; Leroy, O; Lesiak, T; Leverington, B; Li, Y; Likhomanenko, T; Lindner, R; Linn, C; Lionetto, F; Liu, B; Liu, X; Loh, D; Longstaff, I; Lopes, J H; Lucchesi, D; Lucio Martinez, M; Luo, H; Lupato, A; Luppi, E; Lupton, O; Lusardi, N; Lusiani, A; Lyu, X; Machefert, F; Maciuc, F; Maev, O; Maguire, K; Malde, S; Malinin, A; Manca, G; Mancinelli, G; Manning, P; Mapelli, A; Maratas, J; Marchand, J F; Marconi, U; Marin Benito, C; Marino, P; Marks, J; Martellotti, G; Martin, M; Martinelli, M; Martinez Santos, D; Martinez Vidal, F; Martins Tostes, D; Massacrier, L M; Massafferri, A; Matev, R; Mathad, A; Mathe, Z; Matteuzzi, C; Mauri, A; Maurin, B; Mazurov, A; McCann, M; McCarthy, J; McNab, A; McNulty, R; Meadows, B; Meier, F; Meissner, M; Melnychuk, D; Merk, M; Merli, A; Michielin, E; Milanes, D A; Minard, M-N; Mitzel, D S; Molina Rodriguez, J; Monroy, I A; Monteil, S; Morandin, M; Morawski, P; Mordà, A; Morello, M J; Moron, J; Morris, A B; Mountain, R; Muheim, F; Müller, D; Müller, J; Müller, K; Müller, V; Mussini, M; Muster, B; Naik, P; Nakada, T; Nandakumar, R; Nandi, A; Nasteva, I; Needham, M; Neri, N; Neubert, S; Neufeld, N; Neuner, M; Nguyen, A D; Nguyen-Mau, C; Niess, V; Nieswand, S; Niet, R; Nikitin, N; Nikodem, T; Novoselov, A; O'Hanlon, D P; Oblakowska-Mucha, A; Obraztsov, V; Ogilvy, S; Okhrimenko, O; Oldeman, R; Onderwater, C J G; Osorio Rodrigues, B; Otalora Goicochea, J M; Otto, A; Owen, P; Oyanguren, A; Palano, A; Palombo, F; Palutan, M; Panman, J; Papanestis, A; Pappagallo, M; Pappalardo, L L; Pappenheimer, C; Parker, W; Parkes, C; Passaleva, G; Patel, G D; Patel, M; Patrignani, C; Pearce, A; Pellegrino, A; Penso, G; Pepe Altarelli, M; Perazzini, S; Perret, P; Pescatore, L; Petridis, K; Petrolini, A; Petruzzo, M; Picatoste Olloqui, E; Pietrzyk, B; Pikies, M; Pinci, D; Pistone, A; Piucci, A; Playfer, S; Plo Casasus, M; Poikela, T; Polci, F; Poluektov, A; Polyakov, I; Polycarpo, E; Popov, A; Popov, D; Popovici, B; Potterat, C; Price, E; Price, J D; Prisciandaro, J; Pritchard, A; Prouve, C; Pugatch, V; Puig Navarro, A; Punzi, G; Qian, W; Quagliani, R; Rachwal, B; Rademacker, J H; Rama, M; Ramos Pernas, M; Rangel, M S; Raniuk, I; Raven, G; Redi, F; Reichert, S; Dos Reis, A C; Renaudin, V; Ricciardi, S; Richards, S; Rihl, M; Rinnert, K; Rives Molina, V; Robbe, P; Rodrigues, A B; Rodrigues, E; Rodriguez Lopez, J A; Rodriguez Perez, P; Rogozhnikov, A; Roiser, S; Romanovsky, V; Romero Vidal, A; Ronayne, J W; Rotondo, M; Ruf, T; Ruiz Valls, P; Saborido Silva, J J; Sagidova, N; Saitta, B; Salustino Guimaraes, V; Sanchez Mayordomo, C; Sanmartin Sedes, B; Santacesaria, R; Santamarina Rios, C; Santimaria, M; Santovetti, E; Sarti, A; Satriano, C; Satta, A; Saunders, D M; Savrina, D; Schael, S; Schiller, M; Schindler, H; Schlupp, M; Schmelling, M; Schmelzer, T; Schmidt, B; Schneider, O; Schopper, A; Schubiger, M; Schune, M-H; Schwemmer, R; Sciascia, B; Sciubba, A; Semennikov, A; Sergi, A; Serra, N; Serrano, J; Sestini, L; Seyfert, P; Shapkin, M; Shapoval, I; Shcheglov, Y; Shears, T; Shekhtman, L; Shevchenko, V; Shires, A; Siddi, B G; Silva Coutinho, R; Silva de Oliveira, L; Simi, G; Sirendi, M; Skidmore, N; Skwarnicki, T; Smith, E; Smith, I T; Smith, J; Smith, M; Snoek, H; Sokoloff, M D; Soler, F J P; Soomro, F; Souza, D; Souza De Paula, B; Spaan, B; Spradlin, P; Sridharan, S; Stagni, F; Stahl, M; Stahl, S; Stefkova, S; Steinkamp, O; Stenyakin, O; Stevenson, S; Stoica, S; Stone, S; Storaci, B; Stracka, S; Straticiuc, M; Straumann, U; Sun, L; Sutcliffe, W; Swientek, K; Swientek, S; Syropoulos, V; Szczekowski, M; Szumlak, T; T'Jampens, S; Tayduganov, A; Tekampe, T; Tellarini, G; Teubert, F; Thomas, C; Thomas, E; van Tilburg, J; Tisserand, V; Tobin, M; Tolk, S; Tomassetti, L; Tonelli, D; Topp-Joergensen, S; Tournefier, E; Tourneur, S; Trabelsi, K; Traill, M; Tran, M T; Tresch, M; Trisovic, A; Tsaregorodtsev, A; Tsopelas, P; Tuning, N; Ukleja, A; Ustyuzhanin, A; Uwer, U; Vacca, C; Vagnoni, V; Valat, S; Valenti, G; Vallier, A; Vazquez Gomez, R; Vazquez Regueiro, P; Vázquez Sierra, C; Vecchi, S; van Veghel, M; Velthuis, J J; Veltri, M; Veneziano, G; Vesterinen, M; Viaud, B; Vieira, D; Vieites Diaz, M; Vilasis-Cardona, X; Volkov, V; Vollhardt, A; Voong, D; Vorobyev, A; Vorobyev, V; Voß, C; de Vries, J A; Waldi, R; Wallace, C; Wallace, R; Walsh, J; Wang, J; Ward, D R; Watson, N K; Websdale, D; Weiden, A; Whitehead, M; Wicht, J; Wilkinson, G; Wilkinson, M; Williams, M; Williams, M P; Williams, M; Williams, T; Wilson, F F; Wimberley, J; Wishahi, J; Wislicki, W; Witek, M; Wormser, G; Wotton, S A; Wraight, K; Wright, S; Wyllie, K; Xie, Y; Xu, Z; Yang, Z; Yin, H; Yu, J; Yuan, X; Yushchenko, O; Zangoli, M; Zavertyaev, M; Zhang, L; Zhang, Y; Zhelezov, A; Zheng, Y; Zhokhov, A; Zhong, L; Zhukov, V; Zucchelli, S

    2016-06-17

    Violations of CPT symmetry and Lorentz invariance are searched for by studying interference effects in B^{0} mixing and in B_{s}^{0} mixing. Samples of B^{0}→J/ψK_{S}^{0} and B_{s}^{0}→J/ψK^{+}K^{-} decays are recorded by the LHCb detector in proton-proton collisions at center-of-mass energies of 7 and 8 TeV, corresponding to an integrated luminosity of 3  fb^{-1}. No periodic variations of the particle-antiparticle mass differences are found, consistent with Lorentz invariance and CPT symmetry. Results are expressed in terms of the standard model extension parameter Δa_{μ} with precisions of O(10^{-15}) and O(10^{-14})  GeV for the B^{0} and B_{s}^{0} systems, respectively. With no assumption on Lorentz (non)invariance, the CPT-violating parameter z in the B_{s}^{0} system is measured for the first time and found to be Re(z)=-0.022±0.033±0.005 and Im(z)=0.004±0.011±0.002, where the first uncertainties are statistical and the second systematic. PMID:27367382

  15. Stray magnetic field influence on the CPT resonance in a coated Rb vacuum cell

    NASA Astrophysics Data System (ADS)

    Taskova, E.; Alipieva, E.; Todorov, G.

    2016-03-01

    Interaction of a resonant laser beam with an atomic absorption medium creates population redistribution and interference between atomic levels. This anisotropy of the medium is experimentally observed as coherent population trapping (CPT) or electromagnetically induced transparency (EIT). Due to the small sub-natural width of the CPT and EIT resonances, they find wide applications in metrology, quantum optics, atom cooling. A non-compensated stray magnetic field (SMF) can change the shape and sign of the resonance or destroy it completely. In this work, we present an experimental and theoretical investigation of the influence of a stray magnetic field on the CPT resonances obtained on Zeeman sublevels of the D1 line of 87Rb in a paraffin-coated vacuum cell. The role is clarified of the polarization moments with different rank in creating the integral registered fluorescent signal in the presence of a stray magnetic field. It is shown that a transverse magnetic field plays an important role in changing the shape of the signal.

  16. Search for Violation of CPT and Lorentz Invariance in B-s(0) Meson Oscillations

    SciTech Connect

    Abazov, V. M.

    2015-10-14

    We present the first search for CPT-violating effects in the mixing of B0s mesons using the full Run II data set with an integrated luminosity of 10.4 fb-1 of proton-antiproton collisions collected using the D0 detector at the Fermilab Tevatron Collider. We measure the CPT-violating asymmetry in the decay B0s → µ±D±s as a function of celestial direction and sidereal phase. We find no evidence for CPT-violating effects and place limits on the direction and magnitude of flavor-dependent CPTand Lorentz-invariance violating coupling coefficients. We find 95% confidence intervals of Δa⊥ < 1.2 × 10-12 GeV and (-0.8 < ΔaT - 0.396ΔaZ < 3.9) × 10-13 GeV.

  17. Search for Violations of Lorentz Invariance and CPT Symmetry in B_{(s)}^{0} Mixing.

    PubMed

    Aaij, R; Abellán Beteta, C; Adeva, B; Adinolfi, M; Ajaltouni, Z; Akar, S; Albrecht, J; Alessio, F; Alexander, M; Ali, S; Alkhazov, G; Alvarez Cartelle, P; Alves, A A; Amato, S; Amerio, S; Amhis, Y; An, L; Anderlini, L; Andreassi, G; Andreotti, M; Andrews, J E; Appleby, R B; Aquines Gutierrez, O; Archilli, F; d'Argent, P; Artamonov, A; Artuso, M; Aslanides, E; Auriemma, G; Baalouch, M; Bachmann, S; Back, J J; Badalov, A; Baesso, C; Baker, S; Baldini, W; Barlow, R J; Barschel, C; Barsuk, S; Barter, W; Batozskaya, V; Battista, V; Bay, A; Beaucourt, L; Beddow, J; Bedeschi, F; Bediaga, I; Bel, L J; Bellee, V; Belloli, N; Belyaev, I; Ben-Haim, E; Bencivenni, G; Benson, S; Benton, J; Berezhnoy, A; Bernet, R; Bertolin, A; Betti, F; Bettler, M-O; van Beuzekom, M; Bifani, S; Billoir, P; Bird, T; Birnkraut, A; Bizzeti, A; Blake, T; Blanc, F; Blouw, J; Blusk, S; Bocci, V; Bondar, A; Bondar, N; Bonivento, W; Borgheresi, A; Borghi, S; Borisyak, M; Borsato, M; Boubdir, M; Bowcock, T J V; Bowen, E; Bozzi, C; Braun, S; Britsch, M; Britton, T; Brodzicka, J; Buchanan, E; Burr, C; Bursche, A; Buytaert, J; Cadeddu, S; Calabrese, R; Calvi, M; Calvo Gomez, M; Campana, P; Campora Perez, D; Capriotti, L; Carbone, A; Carboni, G; Cardinale, R; Cardini, A; Carniti, P; Carson, L; Carvalho Akiba, K; Casse, G; Cassina, L; Castillo Garcia, L; Cattaneo, M; Cauet, Ch; Cavallero, G; Cenci, R; Charles, M; Charpentier, Ph; Chatzikonstantinidis, G; Chefdeville, M; Chen, S; Cheung, S-F; Chrzaszcz, M; Cid Vidal, X; Ciezarek, G; Clarke, P E L; Clemencic, M; Cliff, H V; Closier, J; Coco, V; Cogan, J; Cogneras, E; Cogoni, V; Cojocariu, L; Collazuol, G; Collins, P; Comerma-Montells, A; Contu, A; Cook, A; Coombes, M; Coquereau, S; Corti, G; Corvo, M; Couturier, B; Cowan, G A; Craik, D C; Crocombe, A; Cruz Torres, M; Cunliffe, S; Currie, R; D'Ambrosio, C; Dall'Occo, E; Dalseno, J; David, P N Y; Davis, A; De Aguiar Francisco, O; De Bruyn, K; De Capua, S; De Cian, M; De Miranda, J M; De Paula, L; De Simone, P; Dean, C-T; Decamp, D; Deckenhoff, M; Del Buono, L; Déléage, N; Demmer, M; Derkach, D; Deschamps, O; Dettori, F; Dey, B; Di Canto, A; Di Ruscio, F; Dijkstra, H; Dordei, F; Dorigo, M; Dosil Suárez, A; Dovbnya, A; Dreimanis, K; Dufour, L; Dujany, G; Dungs, K; Durante, P; Dzhelyadin, R; Dziurda, A; Dzyuba, A; Easo, S; Egede, U; Egorychev, V; Eidelman, S; Eisenhardt, S; Eitschberger, U; Ekelhof, R; Eklund, L; El Rifai, I; Elsasser, Ch; Ely, S; Esen, S; Evans, H M; Evans, T; Falabella, A; Färber, C; Farley, N; Farry, S; Fay, R; Fazzini, D; Ferguson, D; Fernandez Albor, V; Ferrari, F; Ferreira Rodrigues, F; Ferro-Luzzi, M; Filippov, S; Fiore, M; Fiorini, M; Firlej, M; Fitzpatrick, C; Fiutowski, T; Fleuret, F; Fohl, K; Fontana, M; Fontanelli, F; Forshaw, D C; Forty, R; Frank, M; Frei, C; Frosini, M; Fu, J; Furfaro, E; Gallas Torreira, A; Galli, D; Gallorini, S; Gambetta, S; Gandelman, M; Gandini, P; Gao, Y; García Pardiñas, J; Garra Tico, J; Garrido, L; Garsed, P J; Gascon, D; Gaspar, C; Gavardi, L; Gazzoni, G; Gerick, D; Gersabeck, E; Gersabeck, M; Gershon, T; Ghez, Ph; Gianì, S; Gibson, V; Girard, O G; Giubega, L; Gligorov, V V; Göbel, C; Golubkov, D; Golutvin, A; Gomes, A; Gotti, C; Grabalosa Gándara, M; Graciani Diaz, R; Granado Cardoso, L A; Graugés, E; Graverini, E; Graziani, G; Grecu, A; Griffith, P; Grillo, L; Grünberg, O; Gushchin, E; Guz, Yu; Gys, T; Hadavizadeh, T; Hadjivasiliou, C; Haefeli, G; Haen, C; Haines, S C; Hall, S; Hamilton, B; Han, X; Hansmann-Menzemer, S; Harnew, N; Harnew, S T; Harrison, J; He, J; Head, T; Heister, A; Hennessy, K; Henrard, P; Henry, L; Hernando Morata, J A; van Herwijnen, E; Heß, M; Hicheur, A; Hill, D; Hoballah, M; Hombach, C; Hongming, L; Hulsbergen, W; Humair, T; Hushchyn, M; Hussain, N; Hutchcroft, D; Idzik, M; Ilten, P; Jacobsson, R; Jaeger, A; Jalocha, J; Jans, E; Jawahery, A; John, M; Johnson, D; Jones, C R; Joram, C; Jost, B; Jurik, N; Kandybei, S; Kanso, W; Karacson, M; Karbach, T M; Karodia, S; Kecke, M; Kelsey, M; Kenyon, I R; Kenzie, M; Ketel, T; Khairullin, E; Khanji, B; Khurewathanakul, C; Kirn, T; Klaver, S; Klimaszewski, K; Kolpin, M; Komarov, I; Koopman, R F; Koppenburg, P; Kozeiha, M; Kravchuk, L; Kreplin, K; Kreps, M; Krokovny, P; Kruse, F; Krzemien, W; Kucewicz, W; Kucharczyk, M; Kudryavtsev, V; Kuonen, A K; Kurek, K; Kvaratskheliya, T; Lacarrere, D; Lafferty, G; Lai, A; Lambert, D; Lanfranchi, G; Langenbruch, C; Langhans, B; Latham, T; Lazzeroni, C; Le Gac, R; van Leerdam, J; Lees, J-P; Lefèvre, R; Leflat, A; Lefrançois, J; Lemos Cid, E; Leroy, O; Lesiak, T; Leverington, B; Li, Y; Likhomanenko, T; Lindner, R; Linn, C; Lionetto, F; Liu, B; Liu, X; Loh, D; Longstaff, I; Lopes, J H; Lucchesi, D; Lucio Martinez, M; Luo, H; Lupato, A; Luppi, E; Lupton, O; Lusardi, N; Lusiani, A; Lyu, X; Machefert, F; Maciuc, F; Maev, O; Maguire, K; Malde, S; Malinin, A; Manca, G; Mancinelli, G; Manning, P; Mapelli, A; Maratas, J; Marchand, J F; Marconi, U; Marin Benito, C; Marino, P; Marks, J; Martellotti, G; Martin, M; Martinelli, M; Martinez Santos, D; Martinez Vidal, F; Martins Tostes, D; Massacrier, L M; Massafferri, A; Matev, R; Mathad, A; Mathe, Z; Matteuzzi, C; Mauri, A; Maurin, B; Mazurov, A; McCann, M; McCarthy, J; McNab, A; McNulty, R; Meadows, B; Meier, F; Meissner, M; Melnychuk, D; Merk, M; Merli, A; Michielin, E; Milanes, D A; Minard, M-N; Mitzel, D S; Molina Rodriguez, J; Monroy, I A; Monteil, S; Morandin, M; Morawski, P; Mordà, A; Morello, M J; Moron, J; Morris, A B; Mountain, R; Muheim, F; Müller, D; Müller, J; Müller, K; Müller, V; Mussini, M; Muster, B; Naik, P; Nakada, T; Nandakumar, R; Nandi, A; Nasteva, I; Needham, M; Neri, N; Neubert, S; Neufeld, N; Neuner, M; Nguyen, A D; Nguyen-Mau, C; Niess, V; Nieswand, S; Niet, R; Nikitin, N; Nikodem, T; Novoselov, A; O'Hanlon, D P; Oblakowska-Mucha, A; Obraztsov, V; Ogilvy, S; Okhrimenko, O; Oldeman, R; Onderwater, C J G; Osorio Rodrigues, B; Otalora Goicochea, J M; Otto, A; Owen, P; Oyanguren, A; Palano, A; Palombo, F; Palutan, M; Panman, J; Papanestis, A; Pappagallo, M; Pappalardo, L L; Pappenheimer, C; Parker, W; Parkes, C; Passaleva, G; Patel, G D; Patel, M; Patrignani, C; Pearce, A; Pellegrino, A; Penso, G; Pepe Altarelli, M; Perazzini, S; Perret, P; Pescatore, L; Petridis, K; Petrolini, A; Petruzzo, M; Picatoste Olloqui, E; Pietrzyk, B; Pikies, M; Pinci, D; Pistone, A; Piucci, A; Playfer, S; Plo Casasus, M; Poikela, T; Polci, F; Poluektov, A; Polyakov, I; Polycarpo, E; Popov, A; Popov, D; Popovici, B; Potterat, C; Price, E; Price, J D; Prisciandaro, J; Pritchard, A; Prouve, C; Pugatch, V; Puig Navarro, A; Punzi, G; Qian, W; Quagliani, R; Rachwal, B; Rademacker, J H; Rama, M; Ramos Pernas, M; Rangel, M S; Raniuk, I; Raven, G; Redi, F; Reichert, S; Dos Reis, A C; Renaudin, V; Ricciardi, S; Richards, S; Rihl, M; Rinnert, K; Rives Molina, V; Robbe, P; Rodrigues, A B; Rodrigues, E; Rodriguez Lopez, J A; Rodriguez Perez, P; Rogozhnikov, A; Roiser, S; Romanovsky, V; Romero Vidal, A; Ronayne, J W; Rotondo, M; Ruf, T; Ruiz Valls, P; Saborido Silva, J J; Sagidova, N; Saitta, B; Salustino Guimaraes, V; Sanchez Mayordomo, C; Sanmartin Sedes, B; Santacesaria, R; Santamarina Rios, C; Santimaria, M; Santovetti, E; Sarti, A; Satriano, C; Satta, A; Saunders, D M; Savrina, D; Schael, S; Schiller, M; Schindler, H; Schlupp, M; Schmelling, M; Schmelzer, T; Schmidt, B; Schneider, O; Schopper, A; Schubiger, M; Schune, M-H; Schwemmer, R; Sciascia, B; Sciubba, A; Semennikov, A; Sergi, A; Serra, N; Serrano, J; Sestini, L; Seyfert, P; Shapkin, M; Shapoval, I; Shcheglov, Y; Shears, T; Shekhtman, L; Shevchenko, V; Shires, A; Siddi, B G; Silva Coutinho, R; Silva de Oliveira, L; Simi, G; Sirendi, M; Skidmore, N; Skwarnicki, T; Smith, E; Smith, I T; Smith, J; Smith, M; Snoek, H; Sokoloff, M D; Soler, F J P; Soomro, F; Souza, D; Souza De Paula, B; Spaan, B; Spradlin, P; Sridharan, S; Stagni, F; Stahl, M; Stahl, S; Stefkova, S; Steinkamp, O; Stenyakin, O; Stevenson, S; Stoica, S; Stone, S; Storaci, B; Stracka, S; Straticiuc, M; Straumann, U; Sun, L; Sutcliffe, W; Swientek, K; Swientek, S; Syropoulos, V; Szczekowski, M; Szumlak, T; T'Jampens, S; Tayduganov, A; Tekampe, T; Tellarini, G; Teubert, F; Thomas, C; Thomas, E; van Tilburg, J; Tisserand, V; Tobin, M; Tolk, S; Tomassetti, L; Tonelli, D; Topp-Joergensen, S; Tournefier, E; Tourneur, S; Trabelsi, K; Traill, M; Tran, M T; Tresch, M; Trisovic, A; Tsaregorodtsev, A; Tsopelas, P; Tuning, N; Ukleja, A; Ustyuzhanin, A; Uwer, U; Vacca, C; Vagnoni, V; Valat, S; Valenti, G; Vallier, A; Vazquez Gomez, R; Vazquez Regueiro, P; Vázquez Sierra, C; Vecchi, S; van Veghel, M; Velthuis, J J; Veltri, M; Veneziano, G; Vesterinen, M; Viaud, B; Vieira, D; Vieites Diaz, M; Vilasis-Cardona, X; Volkov, V; Vollhardt, A; Voong, D; Vorobyev, A; Vorobyev, V; Voß, C; de Vries, J A; Waldi, R; Wallace, C; Wallace, R; Walsh, J; Wang, J; Ward, D R; Watson, N K; Websdale, D; Weiden, A; Whitehead, M; Wicht, J; Wilkinson, G; Wilkinson, M; Williams, M; Williams, M P; Williams, M; Williams, T; Wilson, F F; Wimberley, J; Wishahi, J; Wislicki, W; Witek, M; Wormser, G; Wotton, S A; Wraight, K; Wright, S; Wyllie, K; Xie, Y; Xu, Z; Yang, Z; Yin, H; Yu, J; Yuan, X; Yushchenko, O; Zangoli, M; Zavertyaev, M; Zhang, L; Zhang, Y; Zhelezov, A; Zheng, Y; Zhokhov, A; Zhong, L; Zhukov, V; Zucchelli, S

    2016-06-17

    Violations of CPT symmetry and Lorentz invariance are searched for by studying interference effects in B^{0} mixing and in B_{s}^{0} mixing. Samples of B^{0}→J/ψK_{S}^{0} and B_{s}^{0}→J/ψK^{+}K^{-} decays are recorded by the LHCb detector in proton-proton collisions at center-of-mass energies of 7 and 8 TeV, corresponding to an integrated luminosity of 3  fb^{-1}. No periodic variations of the particle-antiparticle mass differences are found, consistent with Lorentz invariance and CPT symmetry. Results are expressed in terms of the standard model extension parameter Δa_{μ} with precisions of O(10^{-15}) and O(10^{-14})  GeV for the B^{0} and B_{s}^{0} systems, respectively. With no assumption on Lorentz (non)invariance, the CPT-violating parameter z in the B_{s}^{0} system is measured for the first time and found to be Re(z)=-0.022±0.033±0.005 and Im(z)=0.004±0.011±0.002, where the first uncertainties are statistical and the second systematic.

  18. Search for Violation of $CPT$ and Lorentz Invariance in ${B_s^0}$ Meson Oscillations

    SciTech Connect

    Abazov, Victor Mukhamedovich

    2015-06-12

    We present the first search for CPT-violating effects in the mixing of B0s mesons using the full Run II data set with an integrated luminosity of 10.4 fb-1 of proton-antiproton collisions collected using the D0 detector at the Fermilab Tevatron Collider. We measure the CPT-violating asymmetry in the decay B0s → µ±D±s as a function of celestial direction and sidereal phase. We find no evidence for CPT-violating effects and place limits on the direction and magnitude of flavor-dependent CPTand Lorentz-invariance violating coupling coefficients. We find 95% confidence intervals of Δa⊥ < 1.2 × 10-12 GeV and (-0.8 < ΔaT - 0.396ΔaZ < 3.9) × 10-13 GeV.

  19. Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

    PubMed Central

    Bras-Gonçalves, R A; Rosty, C; Laurent-Puig, P; Soulié, P; Dutrillaux, B; Poupon, M-F

    2000-01-01

    Biological parameters influencing the response of human colorectal cancers (CRCs) to CPT-11, a topoisomerase 1 (top1) inhibitor, were investigated using a panel of nine CRCs xenografted into nude mice. CRC xenografts differed in their p53 status (wt or mut) and in their microsatellite instability phenotype (MSI+when altered). Five CRC xenografts were established from clinical samples. All five had a functional p53, two were MSI+and three were MSI–. Tumour-bearing nude mice were treated intraperitonealy (i.p.) with CPT-11. At 10 mg kg–1of CPT-11, four injections at 4-day intervals, four of the five xenografts responded to CPT-11 (growth delay of up to 10 days); the non-responder tumour was MSI−. At 40 mg kg−1of CPT-11, six injections at 4-day intervals, the five CRCs displayed variable but marked responses with complete regressions. In order to assess the role of p53 status in CPT-11 response, four CRC lines were used. HT29 cell line was MSI−/ Ala273-mutp53, its subclone HT29A3 being transfected by wtp53. LoVo cell line was MSI+/ wtp53, its subclone X17LoVo dominantly expressed Ala273-mutp53 after transfection. LoVo tumours (MSI+/ mutp53) were more sensitive than X17LoVo (MSI+/ mutp53. HT 29 tumours (MSI−Imutp53), were refractory to CPT-11 while HT29A3 tumours (MSI−/ wtp53) were sensitive, showing that wtp53 improves the drug-response in these MSI−tumours. Levels of mRNA expression of top1, fasR, TP53 and mdr1 were semi-quantified by reverse transcription polymerase chain reaction. None of these parameters correlated with CPT-11 response. Taken together, these observations indicate that MSI and p53 alterations could be associated with different CPT-11 sensitivities; MSI phenotype moderately influences the CPT-11 sensitivity, MSI+being more sensitive than MSI−CRC freshly obtained from patients, mutp53 status being associated with a poor response to CPT-11. © 2000 Cancer Research Campaign PMID:10732766

  20. Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline

    PubMed Central

    Liu, Pan-pan; Liu, Jinyun; Jiang, Wen-qi; Carew, Jennifer S.; Ogasawara, Marcia A.; Pelicano, Hélène; Croce, Carlo M.; Estrov, Zeev; Xu, Rui-hua; Keating, Michael J.; Huang, Peng

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western countries and is currently incurable due in part to difficulty in eliminating the leukemia cells protected by stromal microenvironment. Based on previous observations that CLL cells exhibit mitochondrial dysfunction and altered lipid metabolism and that carnitine palmitoyltransferases (CPT) play a major role in transporting fatty acid into mitochondria to support cancer cell metabolism, we tested several clinically relevant inhibitors of lipid metabolism for their ability to eliminate primary CLL cells. We discovered that Perhexiline, an anti-angina agent that inhibits CPT, was highly effective in killing CLL cells in stromal microenvironment at clinically achievable concentrations. These effective concentrations caused low toxicity to normal lymphocytes and normal stromal cells. Mechanistic study revealed that CLL cells expressed high levels of CPT1 and CPT2. Suppression of fatty acid transport into mitochondria by inhibiting CPT using Perhexiline resulted in a depletion of cardiolipin, a key component of mitochondrial membranes, and compromised mitochondrial integrity leading to rapid depolarization and massive CLL cell death. The therapeutic activity of Perhexiline was further demonstrated in vivo using a CLL transgenic mouse model. Perhexiline significantly prolonged the overall animal survival by only 4 drug injections. Our study suggests that targeting CPT using an anti-angina drug is able to effectively eliminate leukemia cells in vivo, and is a novel therapeutic strategy for potential clinical treatment of CLL. PMID:27065330

  1. Practical synthesis of (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin, a water-soluble analogue of camptothecin.

    PubMed

    Watanabe, Tatsuya; Tsuboi, Yasunori; Nomura, Sumihiro

    2013-03-01

    A robust, practical synthesis of (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin (T-2513, 5), which is a water-soluble analogue of camptothecin, has been developed. The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N-arylsulfonyl-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl-(S)-2-acyloxy-2-(6-cyano-5-oxo-1,2,3,5-tetrahydroindolizin-7-yl)butanoate (8k) in 93% yield and 87% de. Optically pure compound 8k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5. This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi-gram scale in 6.3% overall yield (16 steps). PMID:23281180

  2. Insecticidal Constituents and Activity of Alkaloids from Cynanchum mongolicum.

    PubMed

    Ge, Yang; Liu, Pingping; Yang, Rui; Zhang, Liu; Chen, Hongxing; Camara, Ibrahima; Liu, Yiqing; Shi, Wangpeng

    2015-09-21

    Based on MS and NMR data and bioassay-guided tracing, three insecticidal alkaloids I, II and III from Cynanchum mongolicum were identified to be antofine N-oxide, antofine and tylophorine. Alkaloid I was more toxic than alkaloids II and III, but they were less active against Spodoptera litura than total alkaloids. The contact toxicity from these alkaloids against the aphid Lipaphis erysimi was significant, as the 24 h-LC50 values of alkaloids I, II, III and total alkaloids were 292.48, 367.21, 487.791 and 163.52 mg/L, respectively. The development disruption of S. litura larvae was tested, the pupation and emergence rates of S. litura decreased and the acute mortality of S. litura increased significantly by day 3 after being injected in their body cavity with 10-40 mg/L of total alkaloid. The ecdysone titer of treated S. litura larvae and prepupae declined with increasing alkaloid concentration. The alkaloids of Cynanchum mongolicum are potential insect growth inhibitors.

  3. Aconitum lipo-alkaloids--semisynthetic products of the traditional medicine.

    PubMed

    Borcsa, Botond; Csupor, Dezso; Forgo, Peter; Widowitz, Ute; Bauer, Rudolf; Hohmann, Judit

    2011-04-01

    The term lipo-alkaloid is used for C19 aconitane alkaloids containing one or two long-chain fatty acid residues. Lipo-alkaloids are transesterified derivatives of the most toxic and highly effective diester-type diterpene alkaloids, such as aconitine, hypaconitine, mesaconitine. Lipo-alkaloids are native minor compounds of aconite drugs, but their amount significantly increases after traditional processing, which is a general method in the Far Eastern traditional medicinal systems. Analytical works demonstrated that cautious processing (usually boiling) of crude aconite roots decreases the amount of normal diterpene alkaloids and increases the concentration of lipo-alkaloids resulting in the reduction of toxicity of the drugs. Many papers reported that lipo-alkaloids occur as a complex mixture in the drugs, and the isolation of the individual components is extremely difficult. These compounds have been identified using highly sensitive analytical methods (HPLC-MS, NMR), and semisynthetic approaches have been developed to ensure lipo-alkaloids in pure form for pharmacological studies. This review summarizes the structure, chemistry, semisynthesis, analytics and bioactivities of lipo-alkaloids. On the basis of 32 references this is the first comprehensive study on this topic, covering the data of 173 compounds.

  4. Expression of the rat liver carnitine palmitoyltransferase I (CPT-Ialpha) gene is regulated by Sp1 and nuclear factor Y: chromosomal localization and promoter characterization.

    PubMed Central

    Steffen, M L; Harrison, W R; Elder, F F; Cook, G A; Park, E A

    1999-01-01

    Carnitine palmitoyltransferase (CPT)-I catalyses the transfer of long-chain fatty acids from CoA to carnitine for translocation across the mitochondrial inner membrane. Expression of the 'liver' isoform of the CPT-I gene (CPT-Ialpha) is subject to developmental, hormonal and tissue-specific regulation. To understand the basis for control of CPT-Ialpha gene expression, we have characterized the proximal promoter of the CPT-Ialpha gene. Here, we report the sequence of 6839 base pairs of the promoter and the localization of the rat CPT-Ialpha gene to region q43 on chromosome 1. Our studies show that the first 200 base pairs of the promoter are sufficient to drive transcription of the CPT-Ialpha gene. Within this region are two sites that bind both Sp1 and Sp3 transcription factors. In addition, nuclear factor Y (NF-Y) binds the proximal promoter. Mutation at the Sp1 or NF-Y sites severely decreases transcription from the CPT-Ialpha promoter. Other protein binding sites were identified within the first 200 base pairs of the promoter by DNase I footprinting, and these elements contribute to CPT-Ialpha gene expression. Our studies demonstrate that CPT-Ialpha is a TATA-less gene which utilizes NF-Y and Sp proteins to drive basal expression. PMID:10333485

  5. Total synthesis of the Daphniphyllum alkaloid daphenylline

    NASA Astrophysics Data System (ADS)

    Lu, Zhaoyong; Li, Yong; Deng, Jun; Li, Ang

    2013-08-01

    The Daphniphyllum alkaloids are a large class of natural products isolated from a genus of evergreen plants widely used in Chinese herbal medicine. They display a remarkable range of biological activities, including anticancer, antioxidant, and vasorelaxation properties as well as elevation of nerve growth factor. Daphenylline is a structurally unique member among the predominately aliphatic Daphniphyllum alkaloids, and contains a tetrasubstituted arene moiety mounted on a sterically compact hexacyclic scaffold. Herein, we describe the first total synthesis of daphenylline. A gold-catalysed 6-exo-dig cyclization reaction and a subsequent intramolecular Michael addition reaction, inspired by Dixon's seminal work, were exploited to construct the bridged 6,6,5-tricyclic motif of the natural product at an early stage, and the aromatic moiety was forged through a photoinduced olefin isomerization/6π-electrocyclization cascade followed by an oxidative aromatization process.

  6. Quinolizidine alkaloid biosynthesis: recent advances and future prospects

    PubMed Central

    Bunsupa, Somnuk; Yamazaki, Mami; Saito, Kazuki

    2012-01-01

    Lys-derived alkaloids, including piperidine, quinolizidine, indolizidine, and lycopodium alkaloids, are widely distributed throughout the plant kingdom. Several of these alkaloids have beneficial properties for humans and have been used in medicine. However, the molecular mechanisms underlying the biosynthesis of these alkaloids are not well understood. In the present article, we discuss recent advances in our understanding of Lys-derived alkaloids, especially the biochemistry, molecular biology, and biotechnology of quinolizidine alkaloid (QA) biosynthesis. We have also highlighted Lys decarboxylase (LDC), the enzyme that catalyzes the first committed step of QA biosynthesis and answers a longstanding question about the molecular entity of LDC activity in plants. Further prospects using current advanced technologies, such as next-generation sequencing, in medicinal plants have also been discussed. PMID:23112802

  7. Recent developments in the chemistry of quinazolinone alkaloids.

    PubMed

    Kshirsagar, U A

    2015-09-28

    Quinazolinones, an important class of fused heterocyclic alkaloids has attracted high attention in organic and medicinal chemistry due to their significant and wide range of biological activities. There are approximately 150 naturally occurring quinazolinone alkaloids known till 2005. Several new quinazolinone alkaloids (∼55) have been isolated in the last decade. Natural quinazolinones with exotic structural features and remarkable biological activities have incited a lot of activities in the synthetic community towards the development of new synthetic strategies and approaches for the total synthesis of quinazolinone alkaloids. This review is focused on these advances in the chemistry of quinazolinone alkaloids in the last decade. This article covers the newly isolated quinazolinone natural products with their biological activities and the recently reported total syntheses of quinazolinone alkaloids from 2006 to 2015.

  8. Natural alkaloids: basic aspects, biological roles, and future perspectives.

    PubMed

    Qiu, Shi; Sun, Hui; Zhang, Ai-Hua; Xu, Hong-Ying; Yan, Guang-Li; Han, Ying; Wang, Xi-Jun

    2014-06-01

    Natural products have gained popularity worldwide for promoting healthcare, as well as disease prevention. Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery. Several alkaloids isolated from natural herbs exhibit antiproliferation, antibacterial, antiviral, insecticidal, and antimetastatic effects on various types of cancers both in vitro and in vivo. This paper focuses on the naturally-derived alkaloids such as berberine, matrine, piperine, fritillarine, and rhynchophylline, etc., and summarizes the action mechanisms of these compounds. Based on the information in the literature that is summarized in this paper, the use of alkaloids as drugs is very promising, but more research and clinical trials are necessary before final recommendations on specific alkaloids can be made. Following this, it is hoped that as a result of this review, there will be a greater awareness of the excellent promise that natural alkaloids show for use in the therapy of diseases.

  9. Toxicosis by Plant Alkaloids in Humans and Animals in Colombia

    PubMed Central

    Diaz, Gonzalo J.

    2015-01-01

    Due to its tropical location, chains of mountains, inter-Andean valleys, Amazon basin area, eastern plains and shores on both the Atlantic and Pacific Oceans, Colombia has many ecosystems and the second largest plant biodiversity in the world. Many plant species, both native and naturalized, are currently recognized as toxic for both animals and humans, and some of them are known to cause their toxic effects due to their alkaloid content. Among these, there are plants containing the hepatotoxic pyrrolizidine alkaloids, neurotoxins such as the indolizidine alkaloid swainsonine and the piperidine alkaloids coniine and γ-coniceine and tropane alkaloids. Unfortunately, the research in toxic plants in Colombia is not nearly proportional to its plant biodiversity and the scientific information available is only very scarce. The present review aims at summarizing the scarce information about plant alkaloid toxicosis in animals and humans in Colombia. PMID:26690479

  10. Toxicosis by Plant Alkaloids in Humans and Animals in Colombia.

    PubMed

    Diaz, Gonzalo J

    2015-12-11

    Due to its tropical location, chains of mountains, inter-Andean valleys, Amazon basin area, eastern plains and shores on both the Atlantic and Pacific Oceans, Colombia has many ecosystems and the second largest plant biodiversity in the world. Many plant species, both native and naturalized, are currently recognized as toxic for both animals and humans, and some of them are known to cause their toxic effects due to their alkaloid content. Among these, there are plants containing the hepatotoxic pyrrolizidine alkaloids, neurotoxins such as the indolizidine alkaloid swainsonine and the piperidine alkaloids coniine and γ-coniceine and tropane alkaloids. Unfortunately, the research in toxic plants in Colombia is not nearly proportional to its plant biodiversity and the scientific information available is only very scarce. The present review aims at summarizing the scarce information about plant alkaloid toxicosis in animals and humans in Colombia.

  11. Histamine release inhibition activity of bisbenzylisoquinoline alkaloids.

    PubMed

    Nakamura, K; Tsuchiya, S; Sugimoto, Y; Sugimura, Y; Yamada, Y

    1992-12-01

    Eleven examples of bisbenzylisoquinoline alkaloids (head-to-head; 10, head-to-tail; 1) and one half molecule type (N-methylcoclaurine), were tested by in vitro histamine release inhibition assay. The order of the potency of the inhibitory effect was ranked thus: homoaromoline, aromoline, isotetrandrine, cepharanthine, fangchinoline, obaberine, and tetrandrine. The following substances, cepharanoline, berbamine, oxyacanthine, and cycleanine (head-to-tail structure) had no inhibitory effect. N-Methylcoclaurine showed an inhibitory effect comparable to that of fangchinoline. PMID:1484888

  12. Synthesis studies on the Melodinus alkaloid meloscine

    PubMed Central

    Feldman, Ken S.; Antoline, Joshua F.

    2012-01-01

    The pentacyclic Melodinus alkaloid (±)-meloscine was synthesized in 19 chemical steps from 2-bromobenzaldehyde through a route featuring an allenyl azide cyclization cascade to deliver the core azabicyclo[3.3.0]octane substructure. Peripheral functionalization of this core included a Tollens-type aldol condensation to set the quaternary center at C(20) and a diastereoselective ring closing metathesis to forge the tetrahydropyridine ring. PMID:23316092

  13. A new diketopiperazine alkaloid from Aspergillus oryzae.

    PubMed

    Shaaban, Mohamed; El-Metwally, Mohammad Magdy; Nasr, Hamdi

    2014-01-01

    Investigation of bioactive secondary metabolites from terrestrial Aspergillus oryzae sp. MMAO1 using M2 medium afforded a new diketopiperazine alkaloid, 7,9-dihydroxy-3-(1H-indol-3-ylmethyl)-8-methoxy-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione (1a), containing the unusual amino acid L-6,8-dihydroxy-7-methoxyphenylalanine. This was co-isolated with ditryptophenaline (2), cyclo-(Tryp,Tyr) (4), cyclo-(Pro,Val), α-cyclopiazonic acid (3), kojic acid and uridine. Re-cultivation of the fungal strain on Dox medium led to the production of bisdethio(bismethylthio)gliotoxin (5), pseurotin A (6) along with linoleic acid, α-cyclopiazonic acid (3) and kojic acid. The chemical structure of the new diketopiperazine alkaloid including the relative configuration was determined by 1D and 2D NMR spectroscopy and HR-ESI-MS spectrometry, and by comparison with the related literature. The new alkaloid (1a) showed no antimicrobial activity or cytotoxicity against brine shrimps.

  14. A new monoterpenoid oxindole alkaloid from Hamelia patens micropropagated plantlets.

    PubMed

    Paniagua-Vega, David; Cerda-García-Rojas, Carlos M; Ponce-Noyola, Teresa; Ramos-Valdivia, Ana C

    2012-11-01

    Chemical studies on Hamelia patens (Rubiaceae) micropropagated plantlets allowed production of a new monoterpenoid oxindole alkaloid, named (-)-hameline (7), together with eight known alkaloids, tetrahydroalstonine (1), aricine (2), pteropodine (3), isopteropodine (4), uncarine F (5), speciophylline (6), palmirine (8), and rumberine (9). The structure of the new alkaloid was assigned on the basis of 1D and 2D NMR spectroscopy, mass spectrometry, and molecular modeling.

  15. New Perspectives in the Chemistry of Marine Pyridoacridine Alkaloids

    PubMed Central

    Plodek, Alois; Bracher, Franz

    2016-01-01

    Secondary metabolites from marine organisms are a rich source of novel leads for drug development. Among these natural products, polycyclic aromatic alkaloids of the pyridoacridine type have attracted the highest attention as lead compounds for the development of novel anti-cancer and anti-infective drugs. Numerous sophisticated total syntheses of pyridoacridine alkaloids have been worked out, and many of them have also been extended to the synthesis of libraries of analogues of the alkaloids. This review summarizes the progress in the chemistry of pyridoacridine alkaloids that was made in the last one-and-a-half decades. PMID:26821033

  16. Plant alkaloids as drug leads for Alzheimer's disease.

    PubMed

    Ng, Yu Pong; Or, Terry Cho Tsun; Ip, Nancy Y

    2015-10-01

    Alzheimer's disease (AD) is a neurodegenerative illness associated with dementia and is most prevalent among the elderly population. Current medications can only treat symptoms. Alkaloids are structurally diverse and have been an important source of therapeutics for various brain disorders. Two US Food and Drug Administration (FDA)-approved acetylcholinesterase inhibitors for AD, galantamine and rivastigmine, are in fact alkaloids. In addition, clinical trials of four other extensively studied alkaloids-huperzine A, caffeine, nicotine, and indomethacin-have been conducted but do not convincingly demonstrate their clinical efficacy for AD. Interestingly, rhynchophylline, a known neuroprotective alkaloid, was recently discovered by in silico screening as an inhibitor of EphA4, a novel target for AD. Here, we review the pathophysiological mechanisms underlying AD, current treatment strategies, and therapeutic potential of several selected plant alkaloids in AD, highlighting their various drug targets and the key supportive preclinical and clinical studies. Future research should include more rigorous clinical studies of the most promising alkaloids, the further development of recently discovered candidate alkaloids, and the continual search for new alkaloids for relevant drug targets. It remains promising that an alkaloid drug candidate could significantly affect the progression of AD in addition to providing symptomatic relief.

  17. Evaluation of Biosynthetic Pathway and Engineered Biosynthesis of Alkaloids.

    PubMed

    Kishimoto, Shinji; Sato, Michio; Tsunematsu, Yuta; Watanabe, Kenji

    2016-01-01

    Varieties of alkaloids are known to be produced by various organisms, including bacteria, fungi and plants, as secondary metabolites that exhibit useful bioactivities. However, understanding of how those metabolites are biosynthesized still remains limited, because most of these compounds are isolated from plants and at a trace level of production. In this review, we focus on recent efforts in identifying the genes responsible for the biosynthesis of those nitrogen-containing natural products and elucidating the mechanisms involved in the biosynthetic processes. The alkaloids discussed in this review are ditryptophenaline (dimeric diketopiperazine alkaloid), saframycin (tetrahydroisoquinoline alkaloid), strictosidine (monoterpene indole alkaloid), ergotamine (ergot alkaloid) and opiates (benzylisoquinoline and morphinan alkaloid). This review also discusses the engineered biosynthesis of these compounds, primarily through heterologous reconstitution of target biosynthetic pathways in suitable hosts, such as Escherichia coli, Saccharomyces cerevisiae and Aspergillus nidulans. Those heterologous biosynthetic systems can be used to confirm the functions of the isolated genes, economically scale up the production of the alkaloids for commercial distributions and engineer the biosynthetic pathways to produce valuable analogs of the alkaloids. In particular, extensive involvement of oxidation reactions catalyzed by oxidoreductases, such as cytochrome P450s, during the secondary metabolite biosynthesis is discussed in details. PMID:27548127

  18. Plant alkaloids as drug leads for Alzheimer's disease.

    PubMed

    Ng, Yu Pong; Or, Terry Cho Tsun; Ip, Nancy Y

    2015-10-01

    Alzheimer's disease (AD) is a neurodegenerative illness associated with dementia and is most prevalent among the elderly population. Current medications can only treat symptoms. Alkaloids are structurally diverse and have been an important source of therapeutics for various brain disorders. Two US Food and Drug Administration (FDA)-approved acetylcholinesterase inhibitors for AD, galantamine and rivastigmine, are in fact alkaloids. In addition, clinical trials of four other extensively studied alkaloids-huperzine A, caffeine, nicotine, and indomethacin-have been conducted but do not convincingly demonstrate their clinical efficacy for AD. Interestingly, rhynchophylline, a known neuroprotective alkaloid, was recently discovered by in silico screening as an inhibitor of EphA4, a novel target for AD. Here, we review the pathophysiological mechanisms underlying AD, current treatment strategies, and therapeutic potential of several selected plant alkaloids in AD, highlighting their various drug targets and the key supportive preclinical and clinical studies. Future research should include more rigorous clinical studies of the most promising alkaloids, the further development of recently discovered candidate alkaloids, and the continual search for new alkaloids for relevant drug targets. It remains promising that an alkaloid drug candidate could significantly affect the progression of AD in addition to providing symptomatic relief. PMID:26220901

  19. Drug Delivery Systems and Combination Therapy by Using Vinca Alkaloids

    PubMed Central

    Lee, Chun-Ting; Huang, Yen-Wei; Yang, Chih-Hui; Huang, Keng-Shiang

    2015-01-01

    Developing new methods for chemotherapy drug delivery has become a topic of great concern. Vinca alkaloids are among the most widely used chemotherapy reagents for tumor therapy; however, their side effects are particularly problematic for many medical doctors. To reduce the toxicity and enhance the therapeutic efficiency of vinca alkaloids, many researchers have developed strategies such as using liposome-entrapped drugs, chemical- or peptide-modified drugs, polymeric packaging drugs, and chemotherapy drug combinations. This review mainly focuses on the development of a vinca alkaloid drug delivery system and the combination therapy. Five vinca alkaloids (eg, vincristine, vinblastine, vinorelbine, vindesine, and vinflunine) are reviewed. PMID:25877096

  20. Biosynthesis and Regulation of Bioprotective Alkaloids in the Gramineae Endophytic Fungi with Implications for Herbivores Deterrents.

    PubMed

    Luo, Hongping; Xie, Longxiang; Zeng, Jie; Xie, Jianping

    2015-12-01

    Four kinds of bioprotective alkaloids-peramine, loline, ergot alkaloid, indole-diterpenes, produced by grass-fungal endophyte symbioses, are deterrents or toxic to vertebrate and invertebrate herbivores. Ergot alkaloids have pharmacological properties and widely are used clinically. The regulation of alkaloids biosynthesis is under intensive study to improve the yield for better agricultural and medicinal application. In this paper, we summarize the structure, related genes, regulation, and toxicity of alkaloids. We focus on the biosynthesis and the regulation network of alkaloids.

  1. Dietary alkaloid sequestration in a poison frog: an experimental test of alkaloid uptake in Melanophryniscus stelzneri (Bufonidae).

    PubMed

    Hantak, Maggie M; Grant, Taran; Reinsch, Sherri; McGinnity, Dale; Loring, Marjorie; Toyooka, Naoki; Saporito, Ralph A

    2013-12-01

    Several lineages of brightly colored anurans independently evolved the ability to secrete alkaloid-containing defensive chemicals from granular glands in the skin. These species, collectively referred to as 'poison frogs,' form a polyphyletic assemblage that includes some species of Dendrobatidae, Mantellidae, Myobatrachidae, Bufonidae, and Eleutherodactylidae. The ability to sequester alkaloids from dietary arthropods has been demonstrated experimentally in most poison frog lineages but not in bufonid or eleutherodactylid poison frogs. As with other poison frogs, species of the genus Melanophryniscus (Bufonidae) consume large numbers of mites and ants, suggesting they might also sequester defensive alkaloids from dietary sources. To test this hypothesis, fruit flies dusted with alkaloid/nutritional supplement powder were fed to individual Melanophryniscus stelzneri in two experiments. In the first experiment, the alkaloids 5,8-disubstituted indolizidine 235B' and decahydroquinoline were administered to three individuals for 104 days. In the second experiment, the alkaloids 3,5-disubstituted indolizidine 239Q and decahydroquinoline were given to three frogs for 153 days. Control frogs were fed fruit flies dusted only with nutritional supplement. Gas chromatography/mass spectrometry analyses revealed that skin secretions of all experimental frogs contained alkaloids, whereas those of all control frogs lacked alkaloids. Uptake of decahydroquinoline was greater than uptake of 5,8-disubstituted indolizidine, and uptake of 3,5-disubstituted indolizidine was greater than uptake of decahydroquinoline, suggesting greater uptake efficiency of certain alkaloids. Frogs in the second experiment accumulated a greater amount of alkaloid, which corresponds to the longer duration and greater number of alkaloid-dusted fruit flies that were consumed. These findings provide the first experimental evidence that bufonid poison frogs sequester alkaloid-based defenses from dietary

  2. Ananas comosus L. Leaf Phenols and p-Coumaric Acid Regulate Liver Fat Metabolism by Upregulating CPT-1 Expression.

    PubMed

    Xie, Weidong; Zhang, Shaobo; Lei, Fan; Ouyang, Xiaoxi; Du, Lijun

    2014-01-01

    In this study, we aimed to investigate the effect and action mechanisms of pineapple leaf phenols (PLPs) on liver fat metabolism in high-fat diet-fed mice. Results show that PLP significantly reduced abdominal fat and liver lipid accumulation in high-fat diet-fed mice. The effects of PLP were comparable with those of FB. Furthermore, at the protein level, PLP upregulated the expression of carnitine palmitoyltransferase 1 (CPT-1), whereas FB had no effects on CPT-1 compared with the HFD controls. Regarding mRNA expression, PLP mainly promoted the expression of CPT-1, PGC1a, UCP-1, and AMPK in the mitochondria, whereas FB mostly enhanced the expression of Ech1, Acox1, Acaa1, and Ehhadh in peroxisomes. PLP seemed to enhance fat metabolism in the mitochondria, whereas FB mainly exerted the effect in peroxisomes. In addition, p-coumaric acid (CA), one of the main components from PLP, significantly inhibited fat accumulation in oleic acid-induced HepG2 cells. CA also significantly upregulated CPT-1 mRNA and protein expressions in HepG2 cells. We, firstly, found that PLP enhanced liver fat metabolism by upregulating CPT-1 expression in the mitochondria and might be promising in treatment of fatty liver diseases as alternative natural products. CA may be one of the active components of PLP.

  3. Heterologous expression of human carnitine palmitoyltransferase (CPT) II in yeast: A model for the molecular analysis of mitochondrial fatty acid oxidation defects

    SciTech Connect

    Cavadini, P.; Invernizzi, F.; Baratta, S.

    1994-09-01

    The CPT enzyme system, which is composed of two distinct mitochondrial membrane-bound proteins (CPT I and CPT II), provides the mechanism whereby long-chain fatty acids are transferred from the cytosol to the mitochondrial matrix to undergo {beta}-oxidation. Here, we report the development of an expression system for investigating genotype/phenotype correlations in CPT II deficiency and, potentially, other mitochondrial fatty acid oxidation defects. To explore yeast as an expression system, we introduced a cDNA encoding the entire human CPT II precursor into Saccharomyces cerevisiae. Expression was programmed by using an inducible galactose operon promoter (GAL1). Following induction, human CPT II was expressed at high levels, with activity 4- to 16-fold greater than in human fibroblasts. Levels of expression paralleled those of respiration, being higher in cells grown on a nonfermentable carbon source than in those grown on glucose. Immunoprecipitation of pulse-labeled transformed cells demonstrated that human CPT II expressed in yeast was targeted to mitochondria with correct proteolytic processing of its 25-residue mitochondrial leader sequence. Preliminary results on the expression of a number of mutant CPT II alleles associated with different clinical phenotypes demonstrated the value of this system for examining the functional consequences of disease-causing mutations and investigating genotype/phenotype correlations in patients with CPT II deficiency.

  4. CPT Test with (anti)proton Magnetic Moments Based on Quantum Logic Cooling and Readout

    NASA Astrophysics Data System (ADS)

    Niemann, M.; Paschke, A.-G.; Dubielzig, T.; Ulmer, S.; Ospelkaus, C.

    2014-01-01

    Dehmelt and VanDyck's famous 1987 measurement of the electron and positron g-factor is still the most precise g-factor comparison in the lepton sector, and a sensitive test of possible CPT violation. A complementary g-factor comparison between the proton and the antiproton is highly desirable to test CPT symmetry in the baryon sector. Current experiments, based on Dehmelt's continuous Stern-Gerlach effect and the double Penning-trap technique, are making rapid progress. They are, however, extremely difficult to carry out because ground state cooling using cryogenic techniques is virtually impossible for heavy baryons, and because the continous Stern-Gerlach effect scales as μ/m, where m is the mass of the particle and μ its magnetic moment. Both difficulties will ultimately limit the accuracy. We discuss experimental prospects of realizing an alternative approach to a g-factor comparison with single (anti)protons, based on quantum logic techniques proposed by Heinzen and Wineland and by Wineland et al. The basic idea is to cool, control and measure single (anti)protons through interaction with a well-controlled atomic ion.

  5. Feynman propagator for the nonbirefringent CPT-even electrodynamics of the standard model extension

    SciTech Connect

    Casana, Rodolfo; Ferreira, Manoel M. Jr.; Santos, Frederico E. P. dos; Gomes, Adalto R.

    2010-12-15

    The CPT-even gauge sector of the standard model extension is composed of 19 components comprised in the tensor (K{sub F}){sub {mu}{nu}{rho}{sigma}}, of which nine do not yield birefringence. In this work, we examine the Maxwell electrodynamics supplemented by these nine nonbirefringent CPT-even components in aspects related to the Feynman propagator and full consistency (stability, causality, unitarity). We adopt a prescription that parametrizes the nonbirefringent components in terms of a symmetric and traceless tensor, K{sub {mu}{nu}}, and second parametrization that writes K{sub {mu}{nu}} in terms of two arbitrary four-vectors, U{sub {mu}} and V{sub {nu}}. We then explicitly evaluate the gauge propagator of this electrodynamics in a tensor closed way. In the sequel, we show that this propagator and involved dispersion relations can be specialized for the parity-odd and parity-even sectors of the tensor (K{sub F}){sub {mu}{nu}{rho}{sigma}}. In this way, we reassess some results of the literature and derive some new outcomes showing that the parity-even anisotropic sector engenders a stable, noncausal and unitary electrodynamics.

  6. Test of CPT and Lorentz symmetry in entangled neutral kaons with the KLOE experiment

    NASA Astrophysics Data System (ADS)

    Babusci, D.; Balwierz-Pytko, I.; Bencivenni, G.; Bloise, C.; Bossi, F.; Branchini, P.; Budano, A.; Caldeira Balkeståhl, L.; Capon, G.; Ceradini, F.; Ciambrone, P.; Curciarello, F.; Czerwiński, E.; Danè, E.; De Leo, V.; De Lucia, E.; De Robertis, G.; De Santis, A.; De Simone, P.; Di Cicco, A.; Di Domenico, A.; Di Donato, C.; Di Salvo, R.; Domenici, D.; Erriquez, O.; Fanizzi, G.; Fantini, A.; Felici, G.; Fiore, S.; Franzini, P.; Gajos, A.; Gauzzi, P.; Giardina, G.; Giovannella, S.; Graziani, E.; Happacher, F.; Heijkenskjöld, L.; Höistad, B.; Jacewicz, M.; Johansson, T.; Kacprzak, K.; Kamińska, D.; Kupsc, A.; Lee-Franzini, J.; Loddo, F.; Loffredo, S.; Mandaglio, G.; Martemianov, M.; Martini, M.; Mascolo, M.; Messi, R.; Miscetti, S.; Morello, G.; Moricciani, D.; Moskal, P.; Nguyen, F.; Palladino, A.; Passeri, A.; Patera, V.; Prado Longhi, I.; Ranieri, A.; Santangelo, P.; Sarra, I.; Schioppa, M.; Sciascia, B.; Silarski, M.; Taccini, C.; Tortora, L.; Venanzoni, G.; Wiślicki, W.; Wolke, M.; Zdebik, J.

    2014-03-01

    Neutral kaon pairs produced in ϕ decays in anti-symmetric entangled state can be exploited to search for violation of CPT symmetry and Lorentz invariance. We present an analysis of the CP-violating process ϕ→KSKL→π+π-π+π- based on 1.7 fb of data collected by the KLOE experiment at the Frascati ϕ-factory DAΦNE. The data are used to perform a measurement of the CPT-violating parameters Δaμ for neutral kaons in the context of the Standard Model Extension framework. The parameters measured in the reference frame of the fixed stars are: Δa0=(-6.0±7.7stat±3.1syst)×10-18 GeV, ΔaX=(0.9±1.5stat±0.6syst)×10-18 GeV, ΔaY=(-2.0±1.5stat±0.5syst)×10-18 GeV, ΔaZ=(3.1±1.7stat±0.5syst)×10-18 GeV. These are presently the most precise measurements in the quark sector of the Standard Model Extension.

  7. Tall fescue seed extraction and partial purification of ergot alkaloids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many substances in the tall fescue/endophyte association (Schedonorus arundinaceus/Epichloë coenophiala) have biological activity. Of these compounds only the ergot alkaloids are known to have significant mammalian toxicity and the predominant ergot alkaloids are ergovaline and ergovalinine. Because...

  8. Cinchona alkaloids from Cinchona succirubra and Cinchona ledgeriana.

    PubMed

    Cheng, Gui-Guang; Cai, Xiang-Hai; Zhang, Bao-Hong; Li, Yan; Gu, Ji; Bao, Mei-Fen; Liu, Ya-Ping; Luo, Xiao-Dong

    2014-02-01

    Seven new cinchona alkaloids, cinchonanines A-G (1-7), and 29 known alkaloids were isolated from the barks of Cinchona surrirubra and C. ledgeriana collected from Yunnan Province in China. The new structures were elucidated by extensive spectroscopic analysis. All compounds were evaluated for their cytotoxicity against five human cancer cell lines. Compounds 2, 13, 14, and 15 showed moderate cytotoxicity.

  9. Effects of Ergot Alkaloids on Bovine Sperm Motility In Vitro

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ergot alkaloids are synthesized by endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum (Schreb.) S.J. Darbyshire). Our objective was to determine direct effects of ergot alkaloids (ergotamine, dihydroergotamine and ergonovine) on the motility of bovine spermatozoa in vit...

  10. A new alkaloid isolated from Abies webbiana leaf

    PubMed Central

    Ghosh, Ashoke K.; Sen, Debanjan; Bhattacharya, Sanjib

    2010-01-01

    A new alkaloid namely 1-(4’-methoxyphenyl)-aziridine was isolated from the leaf of Abies webbiana Lindl. (Pinaceae), grown in Sikkim Himalayan region of India. Its chemical structure was elucidated on the basis of elemental and spectral analyses. This is the first experimental report of the isolation of any alkaloid from A. webbiana. PMID:21808564

  11. Galanthindole: a new indole alkaloid from Galanthus plicatus ssp. byzantinus.

    PubMed

    Unver, Nehir; Kaya, G Irem; Werner, Christa; Verpoorte, Robert; Gözler, Belkis

    2003-09-01

    A new indole alkaloid, galanthindole, was isolated from Galanthus plicatus ssp. byzantinus (Amaryllidaceae), a plant native to northwestern Turkey. Incorporating a non-fused indole ring, galanthindole may represent the prototype of a new subgroup of the Amaryllidaceae alkaloids. Two other bases, (+)-11-hydroxyvittatine and hordenine, are also reported from the same plant.

  12. Identification of the quinolizidine alkaloids in Sophora leachiana

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sophora is a diverse genus representing herbs, shrubs, and trees that occurs throughout the world, primarily in the northern hemisphere. Sophora species contain a variety of quinolizidine alkaloids that are toxic and potentially teratogenic. However, there are no previous reports on the alkaloid c...

  13. Antiproliferative and Structure Activity Relationships of Amaryllidaceae Alkaloids.

    PubMed

    Cedrón, Juan C; Ravelo, Ángel G; León, Leticia G; Padrón, José M; Estévez-Braun, Ana

    2015-07-30

    The antiproliferative activity of a set of seven natural Amaryllidaceae alkaloids and 32 derivatives against four cancer cell lines (A2780, SW1573, T47-D and WiDr) was determined. The best antiproliferative activities were achieved with alkaloids derived from pancracine (2), haemanthamine (6) and haemantidine (7). For each skeleton, some structure-activity relationships were outlined.

  14. Alkaloids from Piper sarmentosum and Piper nigrum.

    PubMed

    Ee, G C L; Lim, C M; Lim, C K; Rahmani, M; Shaari, K; Bong, C F J

    2009-01-01

    Detailed chemical studies on the roots of Piper sarmentosum and Piper nigrum have resulted in several alkaloids. The roots of P. sarmentosum gave a new aromatic compound, 1-nitrosoimino-2,4,5-trimethoxybenzene (1). Piper nigrum roots gave pellitorine (2), (E)-1-[3',4'-(methylenedioxy)cinnamoyl]piperidine (3), 2,4-tetradecadienoic acid isobutyl amide (4), piperine (5), sylvamide (6), cepharadione A (7), piperolactam D (8) and paprazine (9). Structural elucidation of these compounds was achieved through NMR and MS techniques. Cytotoxic activity screening of the plant extracts indicated some activity.

  15. Estimation of total alkaloid in Chitrakadivati by UV-Spectrophotometer

    PubMed Central

    Ajanal, Manjunath; Gundkalle, Mahadev B.; Nayak, Shradda U.

    2012-01-01

    Background: Herbal formulation standardization by adopting newer technique is need of the hour in the field of Ayurvedic pharmaceutical industry. As very few reports exist. These kind of studies would certainly widen the herbal research area. Chitrakadivati is one such popular herbal formulation used in Ayurveda. Many of its ingredients are known for presence of alkaloids. Methodology: Presence of alkaloid was tested qualitatively by Dragondroff's method then subjected to quantitative estimation by UV-Spectrophotometer. This method is based on the reaction between alkaloid and bromocresol green (BCG). Results and Conclusion: Study discloses that out of 16 ingredients, 9 contain alkaloid. Chitrakadivati has shown 0.16% of concentration of alkaloid and which is significantly higher than it's individual ingredients. PMID:23661869

  16. Thermosensitive AB4 four-armed star PNIPAM-b-HTPB multiblock copolymer micelles for camptothecin drug release.

    PubMed

    Luo, Yan-Ling; Fu, Jing-Yu; Xu, Feng; Chen, Ya-Shao; Zhang, Bin

    2014-01-01

    Thermo-sensitive poly(N-isoproplacrylamide)m-block-hydroxyl-terminated polybutadiene-block-poly(N-isoproplacrylamide)m (PNIPAMm-b-HTPB-b-PNIPAMm, m = 1 or 2) block copolymers, AB4 four-armed star multiblock and linear triblock copolymers, were synthesized by ATRP with HTPB as central blocks, and characterization was performed by (1)H NMR, Fourier transform infrared, and size exclusion chromatography. The multiblock copolymers could spontaneously assemble into more regular spherical core-shell nanoscale micelles than the linear triblock copolymer. The physicochemical properties were detected by a surface tension, nanoparticle analyzer, transmission electron microscope (TEM), dynamic light scattering, and UV-vis measurements. The multiblock copolymer micelles had lower critical micelle concentration than the linear counterpart, TEM size from 100 to 120 nm, and the hydrodynamic diameters below 150 nm. The micelles exhibited thermo-dependent size change, with low critical solution temperature of about 33-35 °C. The characteristic parameters were affected by the composition ratios, length of PNIPAM blocks, and molecular architectures. The camptothecin release demonstrated that the drug release was thermo-responsive, accompanied by the temperature-induced structural changes of the micelles. MTT assays were performed to evaluate the biocompatibility or cytotoxicity of the prepared copolymer micelles. PMID:24236748

  17. Protein kinase C{eta} activates NF-{kappa}B in response to camptothecin-induced DNA damage

    SciTech Connect

    Raveh-Amit, Hadas; Hai, Naama; Rotem-Dai, Noa; Shahaf, Galit; Gopas, Jacob; Livneh, Etta

    2011-08-26

    Highlights: {yields} Protein kinase C-eta (PKC{eta}) is an upstream regulator of the NF-{kappa}B signaling pathway. {yields} PKC{eta} activates NF-{kappa}B in non-stressed conditions and in response to DNA damage. {yields} PKC{eta} regulates NF-{kappa}B by activating I{kappa}B kinase (IKK) and inducing I{kappa}B degradation. -- Abstract: The nuclear factor {kappa}B (NF-{kappa}B) family of transcription factors participates in the regulation of genes involved in innate- and adaptive-immune responses, cell death and inflammation. The involvement of the Protein kinase C (PKC) family in the regulation of NF-{kappa}B in inflammation and immune-related signaling has been extensively studied. However, not much is known on the role of PKC in NF-{kappa}B regulation in response to DNA damage. Here we demonstrate for the first time that PKC-eta (PKC{eta}) regulates NF-{kappa}B upstream signaling by activating the I{kappa}B kinase (IKK) and the degradation of I{kappa}B. Furthermore, PKC{eta} enhances the nuclear translocation and transactivation of NF-{kappa}B under non-stressed conditions and in response to the anticancer drug camptothecin. We and others have previously shown that PKC{eta} confers protection against DNA damage-induced apoptosis. Our present study suggests that PKC{eta} is involved in NF-{kappa}B signaling leading to drug resistance.

  18. Antifungal Quinoline Alkaloids from Waltheria indica.

    PubMed

    Cretton, Sylvian; Dorsaz, Stéphane; Azzollini, Antonio; Favre-Godal, Quentin; Marcourt, Laurence; Ebrahimi, Samad Nejad; Voinesco, Francine; Michellod, Emilie; Sanglard, Dominique; Gindro, Katia; Wolfender, Jean-Luc; Cuendet, Muriel; Christen, Philippe

    2016-02-26

    Chemical investigation of a dichloromethane extract of the aerial parts of Waltheria indica led to the isolation and characterization of five polyhydroxymethoxyflavonoids, namely, oxyanin A (1), vitexicarpin (3), chrysosplenol E (4), flindulatin (5), 5-hydroxy-3,7,4'-trimethoxyflavone (6), and six quinolone alkaloids, waltheriones M-Q (2, 7, 8, 10, 11) and 5(R)-vanessine (9). Among these, compounds 2, 7, 8, 10, and 11 have not yet been described in the literature. Their chemical structures were established by means of spectroscopic data interpretation including (1)H and (13)C, HSQC, HMBC, COSY, and NOESY NMR experiments and UV, IR, and HRESIMS. The absolute configurations of the compounds were established by ECD. The isolated constituents and 10 additional quinoline alkaloids previously isolated from the roots of the plant were evaluated for their in vitro antifungal activity against the human fungal pathogen Candida albicans, and 10 compounds (7, 9, 11-16, 18, 21) showed growth inhibitory activity on both planktonic cells and biofilms (MIC ≤ 32 μg/mL). Their spectrum of activity against other pathogenic Candida species and their cytotoxicity against human HeLa cells were also determined. In addition, the cytological effect of the antifungal isolated compounds on the ultrastructure of C. albicans was evaluated by transmission electron microscopy.

  19. Chirality and numbering of substituted tropane alkaloids.

    PubMed

    Humam, Munir; Shoul, Tarik; Jeannerat, Damien; Muñoz, Orlando; Christen, Philippe

    2011-08-25

    The strict application of IUPAC rules for the numbering of tropane alkaloids is not always applied by authors and there is hence a lot of confusion in the literature. In most cases, the notation of 3, 6/7-disubstituted derivatives has been chosen arbitrarily, based on NMR and MS data, without taking into account the absolute configuration of these two carbons. This paper discusses the problem and the relevance of CD and NMR to determine molecular configurations. We report on the use of (1)H-NMR anisochrony (Δδ) induced by the Mosher's chiral auxiliary reagents (R)-(-)- and (S)-(+)-α-methoxy-α-trifluoromethyl-phenylacetyl chlorides (MTPA-Cl), to determine the absolute configuration of (3R,6R)-3α-hydroxy-6β-senecioyloxytropane, a disubstituted tropane alkaloid isolated from the aerial parts of Schizanthus grahamii (Solanaceae). These analytical tools should help future works in correctly assigning the configuration of additional 3, 6/7 disubstituted tropane derivatives.

  20. CPT site characterization for seismic hazards in the New Madrid seismic zone

    USGS Publications Warehouse

    Liao, T.; Mayne, P.W.; Tuttle, M.P.; Schweig, E.S.; Van Arsdale, R.B.

    2002-01-01

    A series of cone penetration tests (CPTs) were conducted in the vicinity of the New Madrid seismic zone in central USA for quantifying seismic hazards, obtaining geotechnical soil properties, and conducting studies at liquefaction sites related to the 1811-1812 and prehistoric New Madrid earthquakes. The seismic piezocone provides four independent measurements for delineating the stratigraphy, liquefaction potential, and site amplification parameters. At the same location, two independent assessments of soil liquefaction susceptibility can be made using both the normalized tip resistance (qc1N) and shear wave velocity (Vs1). In lieu of traditional deterministic approaches, the CPT data can be processed using probability curves to assess the level and likelihood of future liquefaction occurrence. ?? 2002 Elsevier Science Ltd. All rights reserved.

  1. Constraints on CPT violation from Wilkinson Microwave Anisotropy Probe three year polarization data: A wavelet analysis

    SciTech Connect

    Cabella, Paolo; Silk, Joseph; Natoli, Paolo

    2007-12-15

    We perform a wavelet analysis of the temperature and polarization maps of the cosmic microwave background (CMB) delivered by the Wilkinson Microwave Anisotropy Probe experiment in search for a parity-violating signal. Such a signal could be seeded by new physics beyond the standard model, for which the Lorentz and CPT symmetries may not hold. Under these circumstances, the linear polarization direction of a CMB photon may get rotated during its cosmological journey, a phenomenon also called cosmological birefringence. Recently, Feng et al. have analyzed a subset of the Wilkinson Microwave Anisotropy Probe and BOOMERanG 2003 angular power spectra of the CMB, deriving a constraint that mildly favors a nonzero rotation. By using wavelet transforms we set a tighter limit on the CMB photon rotation angle {delta}{alpha}=-2.5{+-}3.0 ({delta}{alpha}=-2.5{+-}6.0) at the one (two) {sigma} level, consistent with a null detection.

  2. A unified classification model for modeling of seismic liquefaction potential of soil based on CPT.

    PubMed

    Samui, Pijush; Hariharan, R

    2015-07-01

    The evaluation of liquefaction potential of soil due to an earthquake is an important step in geosciences. This article examines the capability of Minimax Probability Machine (MPM) for the prediction of seismic liquefaction potential of soil based on the Cone Penetration Test (CPT) data. The dataset has been taken from Chi-Chi earthquake. MPM is developed based on the use of hyperplanes. It has been adopted as a classification tool. This article uses two models (MODEL I and MODEL II). MODEL I employs Cone Resistance (q c) and Cyclic Stress Ratio (CSR) as input variables. q c and Peak Ground Acceleration (PGA) have been taken as inputs for MODEL II. The developed MPM gives 100% accuracy. The results show that the developed MPM can predict liquefaction potential of soil based on q c and PGA. PMID:26199749

  3. Gravity-induced neutrino antineutrino oscillation: CPT and lepton number non-conservation under gravity

    NASA Astrophysics Data System (ADS)

    Mukhopadhyay, Banibrata

    2007-03-01

    We introduce a new effect in the neutrino oscillation phase which shows that the neutrino antineutrino oscillation is possible under gravity even if the rest masses of the corresponding eigenstates are the same. This is due to CPT violation, and is possible to demonstrate if the neutrino mass eigenstates are expressed as a combination of neutrino and antineutrino eigenstates, as of the neutral kaon system, with the plausible breaking of lepton number conservation. For Majorana neutrinos, this oscillation is expected to significantly affect the inner edge of neutrino-dominated accretion discs around compact objects by influencing the neutrino sphere which controls the accretion dynamics, and then the related type-II supernova evolution and the r-process nucleosynthesis. On the other hand, in the early universe, in the presence of various lepton number violating processes, this oscillation, we argue, might have led to neutrino asymmetry which resulted in baryogenesis from the B L symmetry by electro-weak sphaleron processes.

  4. A unified classification model for modeling of seismic liquefaction potential of soil based on CPT.

    PubMed

    Samui, Pijush; Hariharan, R

    2015-07-01

    The evaluation of liquefaction potential of soil due to an earthquake is an important step in geosciences. This article examines the capability of Minimax Probability Machine (MPM) for the prediction of seismic liquefaction potential of soil based on the Cone Penetration Test (CPT) data. The dataset has been taken from Chi-Chi earthquake. MPM is developed based on the use of hyperplanes. It has been adopted as a classification tool. This article uses two models (MODEL I and MODEL II). MODEL I employs Cone Resistance (q c) and Cyclic Stress Ratio (CSR) as input variables. q c and Peak Ground Acceleration (PGA) have been taken as inputs for MODEL II. The developed MPM gives 100% accuracy. The results show that the developed MPM can predict liquefaction potential of soil based on q c and PGA.

  5. Remarks on the Renormalization Properties of Lorentz- and CPT-Violating Quantum Electrodynamics

    NASA Astrophysics Data System (ADS)

    Santos, Tiago R. S.; Sobreiro, Rodrigo F.

    2016-08-01

    In this work, we employ algebraic renormalization technique to show the renormalizability to all orders in perturbation theory of the Lorentz- and CPT-violating QED. Essentially, we control the breaking terms by using a suitable set of external sources. Thus, with the symmetries restored, a perturbative treatment can be consistently employed. After showing the renormalizability, the external sources attain certain physical values, which allow the recovering of the starting physical action. The main result is that the original QED action presents the three usual independent renormalization parameters. The Lorentz-violating sector can be renormalized by 19 independent parameters. Moreover, vacuum divergences appear with extra independent renormalization. Remarkably, the bosonic odd sector (Chern-Simons-like term) does not renormalize and is not radiatively generated. One-loop computations are also presented and compared with the existing literature.

  6. Genuine T, CP, CPT asymmetry parameters for the entangled B d system

    NASA Astrophysics Data System (ADS)

    Bernabéu, José; Botella, Francisco J.; Nebot, Miguel

    2016-06-01

    The precise connection between the theoretical T, CP, CPT asymmetries, in terms of transition probabilities between the filtered neutral meson B d states, and the experimental asymmetries, in terms of the double decay rate intensities for Flavour-CP eigenstate decay products in a B-factory of entangled states, is established. This allows the identification of genuine Asymmetry Parameters in the time distribution of the asymmetries and their measurability by disentangling genuine and possible fake terms. We express the nine asymmetry parameters — three different observables for each one of the three symmetries — in terms of the ingredients of the Weisskopf-Wigner dynamical description of the entangled B d -meson states and we obtain a global fit to their values from the BaBar collaboration experimental results. The possible fake terms are all compatible with zero and the information content of the nine asymmetry parameters is indeed different. The non-vanishing [InlineMediaObject not available: see fulltext.] and [InlineMediaObject not available: see fulltext.] are impressive separate direct evidence of Time-Reversal-violation and CP-violation in these transitions and compatible with Standard Model expectations. An intriguing 2 σ effect for the Re( θ) parameter responsible of CPT-violation appears which, interpreted as an upper limit, leads to |{M}_{{overline{B}}^0{overline{B}}^0}-{M}_B{{{}{^0}}_B}{^0}|<4.0× 1{0}^{-5} eV at 95% C.L. for the diagonal flavour terms of the mass matrix. It contributes to the CP-violating [InlineMediaObject not available: see fulltext.] asymmetry parameter in an unorthodox manner — in its cos(Δ M t) time dependence —, and it is accessible in facilities with non-entangled B d 's, like the LHCb experiment.

  7. Decoherence and CPT Violation in a Stringy Model of Space-Time Foam

    NASA Astrophysics Data System (ADS)

    Mavromatos, Nick E.

    2010-07-01

    I discuss a model inspired from the string/brane framework, in which our Universe is represented (after perhaps appropriate compactification) as a three brane, propagating in a bulk space time punctured by D0-brane (D-particle) defects. As the D3-brane world moves in the bulk, the D-particles cross it, and from an effective observer on D3 the situation looks like a “space-time foam” with the defects “flashing” on and off (“D-particle foam”). The open strings, with their ends attached on the brane, which represent matter in this scenario, can interact with the D-particles on the D3-brane universe in a topologically non-trivial manner, involving splitting and capture of the strings by the D0-brane defects. Such processes are consistently described by logarithmic conformal field theories on the world-sheet of the strings. Physically, they result in effective decoherence of the string matter on the D3 brane, and as a result, of CPT Violation, but of a type that implies an ill-defined nature of the effective CPT operator. Due to electric charge conservation, only electrically neutral (string) matter can exhibit such interactions with the D-particle foam. This may have unique, experimentally detectable (in principle), consequences for electrically-neutral entangled quantum matter states on the brane world, in particular the modification of the pertinent Einstein-Podolsky-Rosen (EPR) Correlation in neutral mesons in an appropriate meson factory. For the simplest scenarios, the order of magnitude of such effects might lie within the sensitivity of upgraded φ-meson factories.

  8. IMPROVED DOWN-HOLE CPT TOOLS FOR THE DETECTION OF CHLORINATED SOLVENTS

    SciTech Connect

    Martin L. Gildea; Stephen P. Farrington, P.E.; Wesley L. Bratton, Ph.D., PE

    1998-09-01

    Conventional soil and groundwater sampling procedures present many opportunities for loss of volatile organic compounds (VOC) by exposing sample media to the atmosphere during transfers between sampling devices and containers, ultimately affecting the quality of the analytical results. Inaccurate characterization data often leads to improperly designed remedial systems that slow the clean-up process and increase the cost. For these reasons, in situ methods for sample extraction and real time analysis provide attractive alternatives to conventional sampling and analysis. Under funding from the U.S. Department of Energy's Federal Energy Technology Center (FETC), the investigators continued development of a system that combines High Speed Gas Chromatography techniques with Cone Penetration Testing to achieve near-real time analysis of soils and groundwater for chlorinated and aromatic hydrocarbon contamination (PCE, TCE, BTEX) during site characterization. The system combines three new CPT tools with an up-hole analyzer. The Dynamic Thermal Desorption (DTD) probe provides the up-hole analyzer with continuously sampled soil gas, enhancing detection limits by heating the soil matrix during penetration to thermally desorb volatile organic contaminants. The CPT In Situ Purge Probe (CISP) purges a water sample in situ, transferring the purge gas up-hole for analysis. Alternatively, soil gas or purge gas from the DTD probe or the CISP can be diverted to a Downhole Trap Module (DTM), which traps contaminants on conventional trap media for later analysis in a fixed laboratory. While the effectiveness of the CISP was hampered by the tendency of fine grained materials to clog its sample inlet filter, the DTD probe and the DTM were demonstrated to perform their intended functions well.

  9. MBL-II-141, a chromone derivative, enhances irinotecan (CPT-11) anticancer efficiency in ABCG2-positive xenografts

    PubMed Central

    Honorat, Mylène; Guitton, Jérôme; Gauthier, Charlotte; Bouard, Charlotte; Lecerf-Schmidt, Florine; Peres, Basile; Terreux, Raphaël; Gervot, Héloïse; Rioufol, Catherine; Boumendjel, Ahcène; Puisieux, Alain; Di Pietro, Attilio; Payen, Léa

    2014-01-01

    ABCG2 is responsible for the multidrug resistance (MDR) phenotype, and strongly modulates cancer outcomes. Its high expression at a number of physiological barriers, including blood-brain and intestinal barriers, impacts on drug pharmacokinetics parameters. We characterized MBL-II-141, a specific and potent ABCG2 inhibitor. Combination of 10 mg/kg MBL-II-141 with the anticancer agent CPT-11 completely blocked the growth of 90% freshly implanted ABCG2-positive tumors. Moreover, the same combination slowed the growth of already established tumors. As required for preclinical development, we defined the main pharmacokinetics parameters of MBL-II-141 and its influence on the kinetics of CPT-11 and its active metabolite SN-38 in mice. MBL-II-141 distribution into the brain occurred at a low, but detectable, level. Interestingly, preliminary data suggested that MBL-II-141 is well tolerated (at 50 mg/kg) and absorbed upon force-feeding. MBL-II-141 induced a potent sensitization of ABCG2-positive xenografts to CPT-11 through in vivo ABCG2 inhibition. MBL-II-141 strongly increased CPT-11 levels in the brain, and therefore would be a valuable agent to improve drug distribution into the brain to efficiently treat aggressive gliomas. Safety and other pharmacological data strongly support the reglementary preclinical development of MBL-II-141. PMID:25474134

  10. Humanized anti-hepatocyte growth factor (HGF) antibody suppresses innate irinotecan (CPT-11) resistance induced by fibroblast-derived HGF

    PubMed Central

    Kim, BoRa; Park, Byung Hee; Shin, Kum-Joo; Song, Seong-Won; Kim, Jung Ju; Kim, Hwan-Mook; Lee, Sang-Jin; Oh, Seung Hyun

    2015-01-01

    The growth factors derived from the microenvironment create an environment conducive to tumor growth and survival. HGF deprivation using neutralizing antibody enhanced chemosensitivity in colorectal cancer cells (CRC). We determined secreted HGF in fibroblast conditioned medium (CM). Combination treatment of anti-HGF antibody and irinotecan (CPT-11) directly enhanced CPT-11 sensitivity in CRC. We generated xenograft in NOD/SCID mice inoculating HCT-116 human colorectal cancer cells subcutaneously with or without fibroblast. We found that the combination of CPT-11 and anti-HGF antibody induced marked suppression of tumor development. These results suggest that HGF produced by fibroblast induce CPT-11 resistance, and that anti-HGF antibody abrogate such resistance in vivo. fibroblast-derived HGF is important determinant of chemoresistance. Anti-HGF monoclonal antibody treatment confirmed the importance of this growth factor for chemoresistance in CRC. These results present new options toward the early diagnosis of chemoresistance and suggest novel combinations of chemotherapy and anti-HGF agents to prevent or significantly delay the onset of therapy resistance. PMID:26090722

  11. Humanized anti-hepatocyte growth factor (HGF) antibody suppresses innate irinotecan (CPT-11) resistance induced by fibroblast-derived HGF.

    PubMed

    Woo, Jong Kyu; Kang, Ju-Hee; Kim, BoRa; Park, Byung Hee; Shin, Kum-Joo; Song, Seong-Won; Kim, Jung Ju; Kim, Hwan-Mook; Lee, Sang-Jin; Oh, Seung Hyun

    2015-09-15

    The growth factors derived from the microenvironment create an environment conducive to tumor growth and survival. HGF deprivation using neutralizing antibody enhanced chemosensitivity in colorectal cancer cells (CRC). We determined secreted HGF in fibroblast conditioned medium (CM). Combination treatment of anti-HGF antibody and irinotecan (CPT-11) directly enhanced CPT-11 sensitivity in CRC. We generated xenograft in NOD/SCID mice inoculating HCT-116 human colorectal cancer cells subcutaneously with or without fibroblast. We found that the combination of CPT-11 and anti-HGF antibody induced marked suppression of tumor development. These results suggest that HGF produced by fibroblast induce CPT-11 resistance, and that anti-HGF antibody abrogate such resistance in vivo. fibroblast-derived HGF is important determinant of chemoresistance. Anti-HGF monoclonal antibody treatment confirmed the importance of this growth factor for chemoresistance in CRC. These results present new options toward the early diagnosis of chemoresistance and suggest novel combinations of chemotherapy and anti-HGF agents to prevent or significantly delay the onset of therapy resistance.

  12. [Protective effects of d-chlorpheniramine maleate pre-treatment against acute side effects of Irinotecan(CPT- 11)].

    PubMed

    Misumi, Nobuhiro; Hiraike, Mikako; Nawata, Fusako; Hashimoto, Mirai; Tanigawa, Kayoko; Takase, Izumi; Nabeshima, Aya; Honda, Shinobu

    2011-07-01

    It is wellknown that cholinomimetic side effects, such as sedation, abdominal pain, nasal flow and watery eyes, may develop in patients in the early stage of Irinotecan (CPT-11) administration; however, there have been no investigations concerning methods for preventing the development of these side effects. To assess the protective effects of pre-treatment with d-CM on cholinomimetic side effects in the early stage after Irinotecan (CPT-11) administration, we prescribed d- Chlorpheniramine maleate (d-CM) to a group of patients prior to Irinotecan (CPT-11) administration. Twenty members from the group of non-d-CM-treated patients (n=39) and 4 members from the group of treated patients (n=20) complained of side effects. The pre-administration of d-CM significantly reduced the number of patients with side effects (p<0.05). The relative risk (RR) for the frequency of side effects was 0.39 (95% CI; 0.15-0.98), demonstrating that the frequency of side effects was significantly reduced. Based on theses findings, we concluded that the pre-administration of d-CM had protective effects against side effects that might develop in the early stage after Irinotecan (CPT-11) administration.

  13. Alternative mechanism of cholera toxin acquisition by Vibrio cholerae: generalized transduction of CTXPhi by bacteriophage CP-T1.

    PubMed

    Boyd, E F; Waldor, M K

    1999-11-01

    Horizontal transfer of genes encoding virulence factors has played a central role in the evolution of many pathogenic bacteria. The unexpected discovery that the genes encoding cholera toxin (ctxAB), the main cause of the profuse secretory diarrhea characteristic of cholera, are encoded on a novel filamentous phage named CTXPhi, has resulted in a renewed interest in the potential mechanisms of transfer of virulence genes among Vibrio cholerae. We describe here an alternative mechanism of cholera toxin gene transfer into nontoxigenic V. cholerae isolates, including strains that lack both the CTXPhi receptor, the toxin coregulated pilus (TCP), and attRS, the chromosomal attachment site for CTXPhi integration. A temperature-sensitive mutant of the V. cholerae generalized transducing bacteriophage CP-T1 (CP-T1ts) was used to transfer a genetically marked derivative of the CTX prophage into four nontoxigenic V. cholerae strains, including two V. cholerae vaccine strains. We demonstrate that CTXPhi transduced by CP-T1ts can replicate and integrate into these nontoxigenic V. cholerae strains with high efficiency. In fact, CP-T1ts transduces the CTX prophage preferentially when compared with other chromosomal markers. These results reveal a potential mechanism by which CTXPhi(+) V. cholerae strains that lack the TCP receptor may have arisen. Finally, these findings indicate an additional pathway for reversion of live-attenuated V. cholerae vaccine strains.

  14. Pyrrolizidine alkaloids of Echium vulgare honey found in pure pollen.

    PubMed

    Boppré, Michael; Colegate, Steven M; Edgar, John A

    2005-02-01

    The pyrrolizidine alkaloids previously identified in floral honey attributed to Echium vulgare (Boraginaceae) have been detected (8000-14 000 ppm) in pure pollen collected from the anthers of Echium vulgare. Pyrrolizidine alkaloids and/or their N-oxides were isolated from the aqueous acid extracts of pollen by use of strong cation-exchange, solid-phase extraction and identified by liquid chromatographic/mass spectrometric (LCMS) analysis. The pyrrolizidine alkaloids in the pollen are present mainly as the N-oxides. In addition to seven previously described pyrrolizidine alkaloids and/or their N-oxides (echimidine, acetylechimidine, uplandicine, 9-O-angelylretronecine, echiuplatine, leptanthine, and echimiplatine), one unidentified (echivulgarine), but previously found in honey, and two previously undescribed (vulgarine and 7-O-acetylvulgarine) pyrrolizidine alkaloids and/or their N-oxides were identified in the pollen. Tentative structures for these unidentified pyrrolizidine alkaloids are proposed on the basis of the mass spectrometric data and biogenetic considerations. The implications of these results for identifying the source and subsequent concentrations of pyrrolizidine alkaloids in honeys and commercial bee pollen are briefly discussed. PMID:15686407

  15. Cytotoxic and antimalarial bisbenzylisoquinoline alkaloids from Stephania erecta.

    PubMed

    Likhitwitayawuid, K; Angerhofer, C K; Cordell, G A; Pezzuto, J M; Ruangrungsi, N

    1993-01-01

    (+)-2-N-Methyltelobine [1], a new alkaloid, together with twelve known bisbenzylisoquinolines, was isolated from the tubers of Stephania erecta. The structure determination and the complete 1H- and unambiguous 13C-nmr assignments of 1 were obtained through extensive use of several 1D and 2D nmr techniques. All alkaloids inhibited the growth of cultured Plasmodium falciparum strains D-6 and W-2 and displayed nonselective cytotoxicity with a battery of cultured mammalian cells. These data were used for the calculation of selectivity indices. Relative to known antimalarial agents, these bisbenzylisoquinoline alkaloids do not appear to be promising clinical candidates at the present time. PMID:8450319

  16. γ-Lactam alkaloids from the flower buds of daylily.

    PubMed

    Matsumoto, Takahiro; Nakamura, Seikou; Nakashima, Souichi; Ohta, Tomoe; Yano, Mamiko; Tsujihata, Junichiro; Tsukioka, Junko; Ogawa, Keiko; Fukaya, Masashi; Yoshikawa, Masayuki; Matsuda, Hisashi

    2016-07-01

    Four new alkaloids, hemerocallisamines IV-VII, were isolated from the methanol extract of flower buds of daylily. The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. The absolute stereochemistry of the hemerocallisamines IV-VI was elucidated by the application of the modified Mosher's method, HPLC analysis, and optical rotation. In the present study, the isolated alkaloids significantly inhibited the aggregation of Aβ42 in vitro. This is the first report about bioactive alkaloids with a γ-lactam ring from daylily. In addition, isolated nucleosides showed accelerative effects on neurite outgrowth under the non-fasting condition. PMID:26849229

  17. γ-Lactam alkaloids from the flower buds of daylily.

    PubMed

    Matsumoto, Takahiro; Nakamura, Seikou; Nakashima, Souichi; Ohta, Tomoe; Yano, Mamiko; Tsujihata, Junichiro; Tsukioka, Junko; Ogawa, Keiko; Fukaya, Masashi; Yoshikawa, Masayuki; Matsuda, Hisashi

    2016-07-01

    Four new alkaloids, hemerocallisamines IV-VII, were isolated from the methanol extract of flower buds of daylily. The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. The absolute stereochemistry of the hemerocallisamines IV-VI was elucidated by the application of the modified Mosher's method, HPLC analysis, and optical rotation. In the present study, the isolated alkaloids significantly inhibited the aggregation of Aβ42 in vitro. This is the first report about bioactive alkaloids with a γ-lactam ring from daylily. In addition, isolated nucleosides showed accelerative effects on neurite outgrowth under the non-fasting condition.

  18. Indole Alkaloids from the Leaves of Nauclea officinalis.

    PubMed

    Fan, Long; Liao, Cheng-Hui; Kang, Qiang-Rong; Zheng, Kai; Jiang, Ying-Chun; He, Zhen-Dan

    2016-07-23

    Three new indole alkaloids, named naucleamide G (1), and nauclealomide B and C (5 and 6), were isolated from the n-BuOH-soluble fraction of an EtOH extract of the leaves of Nauclea officinalis, together with three known alkaloids, paratunamide C (2), paratunamide D (3) and paratunamide A (4). The structures with absolute configurations of the new compounds were identified on the basis of 1D and 2D NMR, HRESIMS, acid hydrolysis and quantum chemical circular dichroism (CD) calculation. According to the structures of isolated indole alkaloids, their plausible biosynthetic pathway was deduced.

  19. Cyclobutane-Containing Alkaloids: Origin, Synthesis, and Biological Activities

    PubMed Central

    Sergeiko, Anastasia; Poroikov, Vladimir V; Hanuš, Lumir O; Dembitsky, Valery M

    2008-01-01

    Present review describes research on novel natural cyclobutane-containing alkaloids isolated from terrestrial and marine species. More than 60 biological active compounds have been confirmed to have antimicrobial, antibacterial, antitumor, and other activities. The structures, synthesis, origins, and biological activities of a selection of cyclobutane-containing alkaloids are reviewed. With the computer program PASS some additional biological activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of cyclobutane-containing alkaloids as an important source of leads for drug discovery. PMID:19696873

  20. Photofragmentation mechanisms in protonated chiral cinchona alkaloids.

    PubMed

    Kumar, Sunil; Lucas, Bruno; Fayeton, Jacqueline; Scuderi, Debora; Alata, Ivan; Broquier, Michel; Barbu-Debus, Katia Le; Lepère, Valeria; Zehnacker, Anne

    2016-08-10

    The photo-stability of protonated cinchona alkaloids is studied in the gas phase by a multi-technique approach. A multi-coincidence technique is used to demonstrate that the dissociation is a direct process. Two dissociation channels are observed. They result from the C8-C9 cleavage, accompanied or not by hydrogen migration. The branching ratio between the two photo-fragments is different for the two pseudo-enantiomers quinine and quinidine. Mass spectrometry experiments coupling UV photo-dissociation of the reactants and structural characterization of the ionic photo-products by Infra-Red Multiple Photo-Dissociation (IRMPD) spectroscopy provide unambiguous information on their structure. In addition, quantum chemical calculations allow proposing a reactive scheme and discussing it in terms of the ground-state geometry of the reactant.

  1. Benhamycin, novel alkaloid from terrestrial Streptomyces sp.

    PubMed

    Shaaban, Mohamed; Abdel-Aziz, Mohamed S

    2007-11-01

    During our screening for bioactive natural compounds from microorganisms, a novel alkaloid has been isolated from a terrestrial Streptomyces sp. isolate NR12, and named as benhamycin (1). This was along with the known metabolites, uracil, thymine, p-hydroxybenzoic acid, 2'-deoxyuridin, tryptophol, indolyl-3-carboxylic acid, and indolyl-3-carbaldehyde. Chemical structure of the novel compound was determined by detailed analysis of its spectroscopic data (extensive NMR experiments, 1 & 2D, MS spectroscopy, and MS high resolution). Structurally, Benhamycin (1) is a pentacyclic aromatic compound bearing an acridine moiety lactamized with benzene. Biological studies showed that the strain extract was moderately active against Gram-positive, Gram-negative bacteria and fungi.

  2. Total Synthesis of Alkaloid 205B

    PubMed Central

    2015-01-01

    Concise and highly stereocontrolled total syntheses of racemic and enantiopure frog alkaloid 205B (1) were accomplished in 11 steps from 4-methoxypyridines 6 and 7 in overall yields of 8 and 8%, respectively. The assembly of the core of the natural product relies on a stereoselective Tsuji–Trost allylic amination reaction and a ring-closing metathesis. The synthesis features the use of an N-acylpyridinium salt reaction to introduce the first stereocenter and an unprecedented trifluoroacetic anhydride-mediated addition of an allylstannane to a vinylogous amide with complete facial selectivity. Deoxygenation of the C4 ketone proved difficult but was accomplished via a modified Barton–McCombie reaction in the presence of a catalytic amount of diphenyl diselenide. PMID:25180567

  3. Pyrrolidonyl and pyridyl alkaloids in Lymantria dispar.

    PubMed

    Deml, Reinhold

    2003-01-01

    The occurrence and metabolism of nicotine and related N-containing compounds in body fluids of the gipsy moth were addressed. Thin layer chromatographic studies clearly showed the simultaneous presence of GABA and 2-pyrrolidone but not of GABamide in the larval haemolymph and osmeterial secretion of Lymantria dispar as well as in the corresponding body fluids of the saturniids, Saturnia pavonia and Attacus atlas. Furthermore, feeding and injection experiments using alkylated precursors and combined gas chromatography/mass spectrometry gave evidence of the transformation of 2-pyrrolidone to nicotine and of nicotinic acid to nicotinamide in caterpillars of L. dispar. Based on these results, on the earlier described variation of the secondary-compound patterns of L. dispar during its development, and on literature data, metabolic pathways for the hitherto detected pyridyl and pyrrolidonyl alkaloids in Lymantriidae (and possibly Saturniidae) are proposed.

  4. Alkaloids from Spathelia excelsa: their chemosystematic significance.

    PubMed

    Lima, M da Paz; Rosas, Lisandra Vieira; da Silva, M Fátima das G F; Ferreira, A Gilberto; Fernandes, João B; Vieira, Paulo C

    2005-07-01

    The methanol extract from the leaves of Spathelia excelsa yielded six alkaloids: 2-(12-oxo-tridecanyl)-3-methoxy-4-quinolone, 2-(10-hydroxy-10-methyldodecanyl)-3-methoxy-4-quinolone, 2-(11-hydroxy-11-methyldodecanyl)-3-methoxy-4-quinolone, 2-(12-hydroxytridecanyl)-3-methoxy-4-quinolone, 7-hydroxy-2-(3-hydroxy-3-methylbutyl)-4-quinolone and 6-hydroxy-2-(3-hydroxy-3-methylbutyl)-4-quinolone, in addition to the known 3-O-beta-d-glucopiranosylsitosterol and (-)-epicatechin. The 2-alkyl-4(1H)-quinolones in S. excelsa display strong similarities with those in Dictyolomatoideae, which contains several 2-alkyl-4-quinolones. The data reported herein thus provide firm support for placing Spathelioideae close to or within the Dictyolomatoideae. PMID:16002107

  5. Treatment of Nonalcoholic Fatty Liver Disease with Total Alkaloids in Rubus aleaefolius Poir through Regulation of Fat Metabolism

    PubMed Central

    Li, Ying; Zhao, Jinyan; Zheng, Haiyin; Zhong, Xiaoyong; Zhou, Jianheng; Hong, Zhenfeng

    2014-01-01

    Total alkaloids in Rubus aleaefolius Poir (TARAP) is a folk medicinal herb that has been used clinically in China to treat nonalcoholic fatty liver disease (NAFLD) for many years. However, the mechanism of its anti-NAFLD effect is largely unknown. In this study, we developed a NAFLD rat model by supplying a modified high-fat diet (mHFD) ad libitum for 8 weeks and evaluated the therapeutic effect of TARAP in NAFLD rats as well as the underlying molecular mechanism. We found that TARAP could reduce the serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL-C) levels and increase the serum high-density lipoprotein (HDL-C) level in NAFLD rats. In addition, TARAP treatment reduced expression of fatty acid synthetase (FAS), and acetyl-CoA carboxylase (ACC) and upregulated the expression of carnitine palmitoyltransferase (CPT). Our results suggest that regulation of lipid metabolism may be a mechanism by which TARAP treats NAFLD. PMID:25404949

  6. Erythroidine alkaloids: a novel class of phytoestrogens.

    PubMed

    Djiogue, Sefirin; Halabalaki, Maria; Njamen, Dieudonné; Kretzschmar, Georg; Lambrinidis, George; Hoepping, Josephine; Raffaelli, Francesca M; Mikros, Emmanuel; Skaltsounis, Alexios-Leandros; Vollmer, Günter

    2014-07-01

    Erythrina poeppigiana is a medicinal plant which is widely used in Asia, Latin America, and Africa in traditional remedies for gynecological complications and maladies. In continuation of studies for the discovery of novel phytoestrogens, four erythroidine alkaloids, namely α-erythroidine, β-erythroidine, and their oxo-derivatives 8-oxo-α-erythroidine and 8-oxo-β-erythroidine, were isolated and structurally characterized from the methanolic extract of the stem bark of E. poeppigiana. Due to the high amounts of erythroidines in the extract and considering the widespread utilization of Erythrina preparations in traditional medicine, the exploration of their estrogenic properties was performed. The estrogenicity of the isolated erythroidines was assayed in various estrogen receptor-(ER)-dependent test systems, including receptor binding affinity, cell culture based ER-dependent reporter gene assays, and gene expression studies in cultured cells using reverse transcription polymerase chain reaction techniques. α-Erythroidine and β-erythroidine showed binding affinity values for ERα of 0.015 ± 0.010% and 0.005 ± 0.010%, respectively, whereas only β-erythroidine bound to ERβ (0.006 ± 0.010%). In reporter gene assays, both erythroidines exhibited a significant dose-dependent estrogenic stimulation of ER-dependent reporter gene activity in osteosarcoma cells detectable already at 10 nM. Results were confirmed in the MVLN cells, a bioluminescent variant of MCF-7 breast cancer cells. Further, α-erythroidine and β-erythroidine both induced the enhanced expression of the specific ERα-dependent genes trefoil factor-1 and serum/glucocorticoid regulated kinase 3 in MCF-7 cells, confirming estrogenicity. Additionally, using molecular docking simulations, a potential mode of binding on ERα, is proposed, supporting the experimental evidences. This is the first time that an estrogenic profile is reported for erythroidine alkaloids, potentially a new class of

  7. Activity of pyrrolizidine alkaloids against biofilm formation and Trichomonas vaginalis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Crotalaria genus belongs to the subfamily Papilionoideae comprising about 600 species spread throughout tropical, neotropical and subtropical regions. In this study, seeds of Crolatalaria pallida were used to the isolation of usaramine, a pyrrolizidine alkaloid. Thus, Pseudomonas aeruginosa and Stap...

  8. Microcalorimetry studies of the antimicrobial actions of Aconitum alkaloids.

    PubMed

    Shi, Yan-bin; Liu, Lian; Shao, Wei; Wei, Ting; Lin, Gui-mei

    2015-08-01

    The metabolic activity of organisms can be measured by recording the heat output using microcalorimetry. In this paper, the total alkaloids in the traditional Chinese medicine Radix Aconiti Lateralis were extracted and applied to Escherichia coli and Staphylococcus aureus. The effect of alkaloids on bacteria growth was studied by microcalorimetry. The power-time curves were plotted with a thermal activity monitor (TAM) air isothermal microcalorimeter and parameters such as growth rate constant (μ), peak-time (Tm), inhibitory ratio (I), and enhancement ratio (E) were calculated. The relationships between the concentration of Aconitum alkaloids and μ of E. coli or S. aureus were discussed. The results showed that Aconitum alkaloids had little effect on E. coli and had a potentially inhibitory effect on the growth of S. aureus.

  9. Crinine-type alkaloids from Hippeastrum aulicum and H. calyptratum.

    PubMed

    de Andrade, Jean Paulo; Guo, Ying; Font-Bardia, Mercè; Calvet, Teresa; Dutilh, Jullie; Viladomat, Francesc; Codina, Carles; Nair, Jerald J; Zuanazzi, Jose A Silveira; Bastida, Jaume

    2014-07-01

    An ongoing search for alkaloids in the Amaryllidaceae species using GC-MS resulted in the identification of two crinine-type alkaloids, aulicine (1) and 3-O-methyl-epimacowine, (2) from the indigenous Brazilian species Hippeastrum aulicum and Hippeastrum calyptratum, respectively. In addition, two alkaloids, 11-oxohaemanthamine (3) and 7-methoxy-O-methyllycorenine (4) were both isolated from H. aulicum. Furthermore, we provide here complete NMR spectroscopic data for the homolycorine analogues nerinine (5) and albomaculine (6). The absolute stereochemistry of the 5,10b-ethano bridge in the crinine variants was determined by circular dichroism and X-ray crystallographic analysis, thus presenting the first direct evidence for the presence of crinine-type alkaloids in the genus Hippeastrum.

  10. A new pyrrole alkaloid from seeds of Castanea sativa.

    PubMed

    Hiermann, Alois; Kedwani, Samir; Schramm, Hans Wolfgang; Seger, Christoph

    2002-02-01

    A new pyrrole alkaloid, methyl-(5-formyl-1H-pyrrole-2-yl)-4-hydroxybutyrate (1), was isolated from sweet chestnut seeds and its structure elucidated on the basis of data from NMR spectroscopy and by comparison with synthetic analogues.

  11. Crinine-type alkaloids from Hippeastrum aulicum and H. calyptratum.

    PubMed

    de Andrade, Jean Paulo; Guo, Ying; Font-Bardia, Mercè; Calvet, Teresa; Dutilh, Jullie; Viladomat, Francesc; Codina, Carles; Nair, Jerald J; Zuanazzi, Jose A Silveira; Bastida, Jaume

    2014-07-01

    An ongoing search for alkaloids in the Amaryllidaceae species using GC-MS resulted in the identification of two crinine-type alkaloids, aulicine (1) and 3-O-methyl-epimacowine, (2) from the indigenous Brazilian species Hippeastrum aulicum and Hippeastrum calyptratum, respectively. In addition, two alkaloids, 11-oxohaemanthamine (3) and 7-methoxy-O-methyllycorenine (4) were both isolated from H. aulicum. Furthermore, we provide here complete NMR spectroscopic data for the homolycorine analogues nerinine (5) and albomaculine (6). The absolute stereochemistry of the 5,10b-ethano bridge in the crinine variants was determined by circular dichroism and X-ray crystallographic analysis, thus presenting the first direct evidence for the presence of crinine-type alkaloids in the genus Hippeastrum. PMID:24768284

  12. Alkaloids with Different Carbon Units from Myrioneuron faberi.

    PubMed

    Cao, Ming-Ming; Zhang, Yu; Huang, Sheng-Dian; Di, Ying-Tong; Peng, Zong-Gen; Jiang, Jian-Dong; Yuan, Chun-Mao; Chen, Duo-Zhi; Li, Shun-Lin; He, Hong-Ping; Hao, Xiao-Jiang

    2015-11-25

    Three new Myrioneuron alkaloids, myrifamines A-C (1-3), with unique skeletons were isolated from Myrioneuron faberi. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction analysis, and the stereochemistry of the other two alkaloids was determined using a combination of ROESY experiments and calculated and experimental electronic circular dichroism spectra. Myrifamine C (3) is the first example of a symmetric dimer among the Myrioneuron alkaloids. Known alkaloids myrionamide (4) and schoberine (5) were also isolated, and experimental NMR and X-ray diffraction data suggest their structural revision. Compound 2 showed significant inhibitory activity toward the hepatitis C virus in vitro, with a therapeutic index (CC50/EC50) greater than 108.7.

  13. Arginine decarboxylase as the source of putrescine for tobacco alkaloids

    NASA Technical Reports Server (NTRS)

    Tiburcio, A. F.; Galston, A. W.

    1986-01-01

    The putrescine which forms a part of nicotine and other pyrrolidine alkaloids is generally assumed to arise through the action of ornithine decarboxylase (ODC). However, we have previously noted that changes in the activity of arginine decarboxylase (ADC), an alternate source of putrescine, parallel changes in tissue alkaloids, while changes in ODC activity do not. This led us to undertake experiments to permit discrimination between ADC and ODC as enzymatic sources of putrescine destined for alkaloids. Two kinds of evidence presented here support a major role for ADC in the generation of putrescine going into alkaloids: (a) A specific 'suicide inhibitor' of ADC effectively inhibits the biosynthesis of nicotine and nornicotine in tobacco callus, while the analogous inhibitor of ODC is less effective, and (b) the flow of 14C from uniformly labelled arginine into nicotine is much more efficient than that from ornithine.

  14. Marine bromopyrrole alkaloids: synthesis and diverse medicinal applications.

    PubMed

    Rane, Rajesh; Sahu, Niteshkumar; Shah, Chetan; Karpoormath, Rajshekhar

    2014-01-01

    Marine organisms have been found to be a very rich source of bioactive molecules. Among marine organisms, sponges have been proven to be excellent producers of secondary metabolites. More than 5,300 compounds have been isolated from sponges with around 200 new molecules reported each year. Bromopyrrole alkaloids constitute a family of exclusively marine alkaloids and represent a fascinating example of the large variety of compounds formed by marine sponges which exhibit different biological activities such as antifeedent, anti-biofilm, anticancer, antiinflammatory, antimicrobial, immunomodulatory, analgesic, antiserotonergic, antiangiogenic, antihistaminic, chitinase inhibitor and actimyosin ATPase activator. More than 140 derivatives with different structures and biological activities, have been isolated from more than 20 different sponges. Most of these alkaloids share a key building block, pyrrole-imidazole with oroidin being their underlying structural motif. In this review detailed account of isolation and medicinal application of marine bromopyrrole alkaloids and their synthetic derivatives are discussed. PMID:24359195

  15. Two new alkaloids from marine sponge Callyspongia sp.

    PubMed

    Yang, Bin; Tao, Huaming; Zhou, Xuefeng; Lin, Xiu-Ping; Liu, Yonghong

    2013-03-01

    Two new alkaloids, callylactam A (1) and callyimine A (4), along with three known ones (2, 3 and 5), were isolated from the marine sponge Callyspongia sp. The structures were determined on the basis of NMR and MS analysis.

  16. Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions.

    PubMed

    Tanriver, Gamze; Dedeoglu, Burcu; Catak, Saron; Aviyente, Viktorya

    2016-06-21

    Remarkable progress in the area of asymmetric organocatalysis has been achieved in the last decades. Cinchona alkaloids and their derivatives have emerged as powerful organocatalysts owing to their reactivities leading to high enantioselectivities. The widespread usage of cinchona alkaloids has been attributed to their nontoxicity, ease of use, stability, cost effectiveness, recyclability, and practical utilization in industry. The presence of tunable functional groups enables cinchona alkaloids to catalyze a broad range of reactions. Excellent experimental studies have extensively contributed to this field, and highly selective reactions were catalyzed by cinchona alkaloids and their derivatives. Computational modeling has helped elucidate the mechanistic aspects of cinchona alkaloid catalyzed reactions as well as the origins of the selectivity they induce. These studies have complemented experimental work for the design of more efficient catalysts. This Account presents recent computational studies on cinchona alkaloid catalyzed organic reactions and the theoretical rationalizations behind their effectiveness and ability to induce selectivity. Valuable efforts to investigate the mechanisms of reactions catalyzed by cinchona alkaloids and the key aspects of the catalytic activity of cinchona alkaloids in reactions ranging from pharmaceutical to industrial applications are summarized. Quantum mechanics, particularly density functional theory (DFT), and molecular mechanics, including ONIOM, were used to rationalize experimental findings by providing mechanistic insights into reaction mechanisms. B3LYP with modest basis sets has been used in most of the studies; nonetheless, the energetics have been corrected with higher basis sets as well as functionals parametrized to include dispersion M05-2X, M06-2X, and M06-L and functionals with dispersion corrections. Since cinchona alkaloids catalyze reactions by forming complexes with substrates via hydrogen bonds and long

  17. The effects of Aconitum alkaloids on the central nervous system.

    PubMed

    Ameri, A

    1998-10-01

    Preparations of Aconitum roots are employed in Chinese and Japanese medicine for analgesic, antirheumatic and neurological indications. The recent surge in use of phytomedicine derived from traditional Chinese medicine as well as increasing concerns about possible toxic effects of these compounds have inspired a great deal of research into the mechanisms by which certain Aconitum alkaloids may act on the central nervous system. The pharmacological effects of preparations of Aconitum roots are attributed to several diterpenoid alkaloids. The main alkaloid of these plants is aconitine, a highly toxic diterpenoid alkaloid which is known to suppress the inactivation of voltage-dependent Na+ channels by binding to neurotoxin binding site 2 of the alpha-subunit of the channel protein. In this article the pharmacology of several structurally related Aconitum alkaloids is highlighted and their therapeutic vs toxic potential is discussed. Neurochemical and neurophysiological studies will be reviewed with emphasis on the effects of the alkaloids in regions of the brain that have been implicated in pain transmission and generation of epileptic activity. Considering the chemical structure of the Aconitum alkaloids as well as their mechanism of action, a subdivision in three groups becomes obvious: the first group comprises such alkaloids which possess high toxicity due to two ester boundings at the diterpene skeleton. The members of this group activate voltage-dependent sodium channels already at resting potential and inhibit noradrenaline reuptake. Activation of sodium channels and in consequence excessive depolarization with final inexcitability and suppression of pain transmission account for their antinociceptive properties. The second group comprises less toxic monoesters which have been shown to possess strong antinociceptive, antiarrhythmic and antiepileptiform properties due to a blockade of the voltage-dependent sodium channel. Electrophysiological studies have

  18. Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions.

    PubMed

    Tanriver, Gamze; Dedeoglu, Burcu; Catak, Saron; Aviyente, Viktorya

    2016-06-21

    Remarkable progress in the area of asymmetric organocatalysis has been achieved in the last decades. Cinchona alkaloids and their derivatives have emerged as powerful organocatalysts owing to their reactivities leading to high enantioselectivities. The widespread usage of cinchona alkaloids has been attributed to their nontoxicity, ease of use, stability, cost effectiveness, recyclability, and practical utilization in industry. The presence of tunable functional groups enables cinchona alkaloids to catalyze a broad range of reactions. Excellent experimental studies have extensively contributed to this field, and highly selective reactions were catalyzed by cinchona alkaloids and their derivatives. Computational modeling has helped elucidate the mechanistic aspects of cinchona alkaloid catalyzed reactions as well as the origins of the selectivity they induce. These studies have complemented experimental work for the design of more efficient catalysts. This Account presents recent computational studies on cinchona alkaloid catalyzed organic reactions and the theoretical rationalizations behind their effectiveness and ability to induce selectivity. Valuable efforts to investigate the mechanisms of reactions catalyzed by cinchona alkaloids and the key aspects of the catalytic activity of cinchona alkaloids in reactions ranging from pharmaceutical to industrial applications are summarized. Quantum mechanics, particularly density functional theory (DFT), and molecular mechanics, including ONIOM, were used to rationalize experimental findings by providing mechanistic insights into reaction mechanisms. B3LYP with modest basis sets has been used in most of the studies; nonetheless, the energetics have been corrected with higher basis sets as well as functionals parametrized to include dispersion M05-2X, M06-2X, and M06-L and functionals with dispersion corrections. Since cinchona alkaloids catalyze reactions by forming complexes with substrates via hydrogen bonds and long

  19. Cytotoxic and antimalarial bisbenzylisoquinoline alkaloids from Cyclea barbata.

    PubMed

    Lin, L Z; Shieh, H L; Angerhofer, C K; Pezzuto, J M; Cordell, G A; Xue, L; Johnson, M E; Ruangrungsi, N

    1993-01-01

    An alkaloid extract derived from the roots of Cyclea barbata demonstrated cytotoxic and antimalarial activities, and five bisbenzylisoquinoline alkaloids, (+)-tetrandrine [1], (-)-limacine [2], (+)-thalrugosine [3], (+)-homoaromoline [4], and (-)-cycleapeltine [5], were isolated as the active principles. The complete and unambiguous assignments of the 1H- and 13C-nmr data of these substances were made by 1D and 2D nmr techniques (COSY, phase-sensitive ROESY, HETCOR, and FLOCK). PMID:8450318

  20. Alkaloids from roots of Stemona sessilifolia and their antitussive activities.

    PubMed

    Yang, Xin-Zhou; Zhu, Jian-Yu; Tang, Chun-Ping; Ke, Chang-Qiang; Lin, Ge; Cheng, Tin-Yan; Rudd, John A; Ye, Yang

    2009-02-01

    Protostemonamide ( 1), a new protostemonine-type alkaloid, and 12 known compounds were isolated from the roots of Stemona sessilifolia. Their structures were elucidated by 1 D and 2 D NMR spectral and other spectroscopic studies. The main alkaloidal constituents, protostemonine ( 2), stemospironine ( 4), and maistemonine ( 7), showed significant antitussive activity in a citric acid-induced guinea pig cough model following peripheral administration; stemonamine ( 11) had antitussive activity following i. c. v. administration.

  1. Synthesis of the Common Core Structure of the Stemofoline Alkaloids.

    PubMed

    Ideue, Eiji; Shimokawa, Jun; Fukuyama, Tohru

    2015-10-16

    A novel synthetic route to the common core structural motif of the stemofoline alkaloids has been developed. The key transformations include (1) an intramolecular 1,3-dipolar cycloaddition reaction of a highly functionalized nitrone, (2) the subsequent formation of a caged structure via lithiated allylic sulfoxide, and (3) the concomitant sila-Pummerer reaction of α-silylalkenyl sulfoxide to prepare a thioester precursor. A series of stereochemistries on the highly caged core structure characteristic of the stemofoline alkaloids was successfully assembled.

  2. Carbazole and amide alkaloids from the stems of Clausena lansium.

    PubMed

    Du, Yi-Qian; Liu, Hang; Li, Chuang-Jun; Yang, Jing-Zhi; Ma, Jie; Zhang, Dan; Sun, Hua; Zhang, Dong-Ming

    2015-01-01

    Two new carbazole alkaloids, claulansine S (1) and claulansine T (2), and one new amide alkaloid, clauamide A (3), together with four known analogues (4-7) were isolated from the stems of Clausena lansium. Their structures were elucidated on the basis of spectroscopic analyses, including UV, IR, and NMR experiments (HSQC, HMBC, and NOE experiments). Compounds 4 and 6 showed moderate hepatoprotective activities. PMID:26095884

  3. Genetics, Genomics and Evolution of Ergot Alkaloid Diversity

    PubMed Central

    Young, Carolyn A.; Schardl, Christopher L.; Panaccione, Daniel G.; Florea, Simona; Takach, Johanna E.; Charlton, Nikki D.; Moore, Neil; Webb, Jennifer S.; Jaromczyk, Jolanta

    2015-01-01

    The ergot alkaloid biosynthesis system has become an excellent model to study evolutionary diversification of specialized (secondary) metabolites. This is a very diverse class of alkaloids with various neurotropic activities, produced by fungi in several orders of the phylum Ascomycota, including plant pathogens and protective plant symbionts in the family Clavicipitaceae. Results of comparative genomics and phylogenomic analyses reveal multiple examples of three evolutionary processes that have generated ergot-alkaloid diversity: gene gains, gene losses, and gene sequence changes that have led to altered substrates or product specificities of the enzymes that they encode (neofunctionalization). The chromosome ends appear to be particularly effective engines for gene gains, losses and rearrangements, but not necessarily for neofunctionalization. Changes in gene expression could lead to accumulation of various pathway intermediates and affect levels of different ergot alkaloids. Genetic alterations associated with interspecific hybrids of Epichloë species suggest that such variation is also selectively favored. The huge structural diversity of ergot alkaloids probably represents adaptations to a wide variety of ecological situations by affecting the biological spectra and mechanisms of defense against herbivores, as evidenced by the diverse pharmacological effects of ergot alkaloids used in medicine. PMID:25875294

  4. [ALKALOIDS OF PEGANUM HARMALA L. AND THEIR BIOLOGICAL ACTIVITY].

    PubMed

    Vachnadze, V; Suladze, T; Vachnadze, N; Kintsurashvili, L; Novikova, J

    2015-06-01

    Peganum Harmala L., Peganасеае widely distributed in Georgia. On the basis of chemical analysis of the composition of alkaloids it was found out that the plant contains quinazoline derivatives, among which dominats alkaloid d, 1 peganine: С11Н12NО2, m.p. 198-99ºC (СН3ОН). UV, λmax 275 (lgε 3,95). In IR-spectrum (KBr) 1625 cm- (-N=C) 3200-370 (OH)cm-1 . Mass- spectrum: М+ 171(100%). It was studied the dynamics of accumulation for total alkaloids and d, l - peganine: in the budding phase the amount of alkaloids was - 3,71%, d, l - peganine 0,07÷0,09%; in the phase of mass flowering the sum of alkaloids - 4,51% ,d, l - peganine - 0,1÷0,13%; in the phase of ripeness total alkaloids - 3.92%; d,l - peganine - 0,08÷0,1. The study of specific pharmacological activity showed that the d,l - peganine similar to peganine at a dose of 30 mg/kg causes a decrease in heart rate by 30÷40 beats/min, which is characteristic for anticholinesterases, in parallel with this, a decrease in cholinesterase activity in blood serum has been observed.

  5. Tropane alkaloids and calystegines as chemotaxonomic markers in the Solanaceae.

    PubMed

    Pigatto, Aline G S; Blanco, Carolina C; Mentz, Lilian A; Soares, Geraldo L G

    2015-01-01

    This study assessed the occurrence and distribution of tropane alkaloids and calystegines in genera of the family Solanaceae to identify patterns of distribution and make evolutionary inferences. A database of tropane alkaloids and calystegines occurrences was constructed from the results of a search of scientific websites and a hand search of periodicals. The terms "Solanaceae", "tropane alkaloids", and "calystegines" were used as index terms for a full-text article search unrestricted by date of publications. The number of occurrence and chemical diversity indices were calculated and cluster analysis and principal components analysis were performed. Overall, 996 occurrences were reported, 879 of tropane alkaloids (88.3%) and 117 of calystegines (11.7%). The calystegines were significantly more relevant than tropane alkaloids for characterization of distinct groups of genera on both analyses performed here. This corroborates the trend toward a chemical dichotomy observed on database analysis and somewhat reinforces the correlation between geographic distribution and occurrence of secondary metabolites, as the presence of calystegines alone (without tropane alkaloids) was only reported in genera that have South America as their center of diversity.

  6. Evaluation of Aconitum diterpenoid alkaloids as antiproliferative agents.

    PubMed

    Wada, Koji; Ohkoshi, Emika; Zhao, Yu; Goto, Masuo; Morris-Natschke, Susan L; Lee, Kuo-Hsiung

    2015-04-01

    Little information has been reported on the antitumor effects of the diterpenoid alkaloid constituents of Aconitum plants, used in the herbal drug 'bushi'. This study was aimed at determining the antitumor activities of Aconitum C19-and C20-diterpenoid alkaloids and synthetic derivatives against lung (A549), prostate (DU145), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines. Newly synthesized C20-diterpenoid alkaloid derivatives showed substantial suppressive effects against all human tumor cell lines tested. In contrast, natural and derivatized C19-diterpenoid alkaloids showed only a slight or no effect. Most of the active compounds were hetisine-type C20-diterpenoid alkaloids, specifically kobusine and pseudokobusine analogs with two different substitution patterns, C-11 and C-11,15. Notably, several C20-diterpenoid alkaloids were more potent against multidrug-resistant KB subline KB-VIN cells. Pseudokobusine 11-3'-trifluoromethylbenzoate (94) is a possible promising new lead meriting additional evaluation against multidrug-resistant tumors.

  7. Anticholinesterase inhibitory activity of quaternary alkaloids from Tinospora crispa.

    PubMed

    Yusoff, Mashitah; Hamid, Hazrulrizawati; Houghton, Peter

    2014-01-01

    Quaternary alkaloids are the major alkaloids isolated from Tinospora species. A previous study pointed to the necessary presence of quaternary nitrogens for strong acetylcholinesterase (AChE) inhibitory activity in such alkaloids. Repeated column chromatography of the vine of Tinospora crispa extract led to the isolation of one new protoberberine alkaloid, 4,13-dihydroxy-2,8,9-trimethoxydibenzo[a,g]quinolizinium (1), along with six known alkaloids-dihydrodiscretamine (2), columbamine (3), magnoflorine (4), N-formylannonaine (5), N-formylnornuciferine (6), and N-trans-feruloyltyramine (7). The seven compounds were isolated and structurally elucidated by spectroscopic analysis. Two known alkaloids, namely, dihydrodiscretamine and columbamine are reported for the first time for this plant. The compounds were tested for AChE inhibitory activity using Ellman's method. In the AChE inhibition assay, only columbamine (3) showed strong activity with IC50 48.1 µM. The structure-activity relationships derived from these results suggest that the quaternary nitrogen in the skeleton has some effect, but that a high degree of methoxylation is more important for acetylcholinesterase inhibition. PMID:24448061

  8. A comparison of the antimalarial activity of the cinchona alkaloids against Plasmodium falciparum in vitro.

    PubMed

    Wesche, D L; Black, J

    1990-06-01

    The effects of four major cinchona alkaloids: (-) quinine, (+) quinidine, (-)cinchonidine, and (+)cinchonine against Plasmodium falciparum FCQ-27/PNG were studied. The alkaloids were tested in vitro as either single alkaloids, racemic mixtures of stereoisomers, or as an equimolar combination of all four alkaloids. Results indicate (+)quinidine to be most effective and both (+)stereoisomers were more potent than the (-)stereoisomers. Inhibitory concentrations 50% (Ki) of racemic mixtures of stereoisomers were similar to those of the (+)stereoisomers alone. The Ki of four alkaloids in equimolar combination were similar to that of the (-) cinchonidine/(+)cinchonine racemic mixture. A total alkaloidal extract of Cinchona sp. was tested and compared with the pure alkaloids. HPLC analysis indicated that (+)cinchonine, (-)cinchonidine and (-)quinine were present in a ratio of approximately 1:1:2, respectively. The total alkaloid extract, with (-)stereoisomers predominating, was less effective than the four alkaloids in combination. The nature of the interaction between stereoisomers was investigated and appears to be one of addition.

  9. The human topoisomerase 1B Arg634Ala mutation results in camptothecin resistance and loss of inter-domain motion correlation.

    PubMed

    D'Annessa, Ilda; Tesauro, Cinzia; Wang, Zhenxing; Arnò, Barbara; Zuccaro, Laura; Fiorani, Paola; Desideri, Alessandro

    2013-12-01

    Human topoisomerase 1B, the unique target of the natural anticancer compound camptothecin, catalyzes the unwinding of supercoiled DNA by introducing transient single strand nicks and providing covalent protein-DNA adducts. The functional properties and the drug reactivity of the single Arg634Ala mutant have been investigated in comparison to the wild type enzyme. The mutant is characterized by an identical relaxation and cleavage rate but it displays resistance to camptothecin as indicated by a viability assay of the yeast cells transformed with the mutated protein. The mutant also displays a very fast religation rate that is only partially reduced by the presence of the drug, suggesting that this is the main reason for its resistance. A comparative analysis of the structural-dynamical properties of the native and mutant proteins by molecular dynamics simulation indicates that mutation of Arg634 brings to a loss of motion correlation between the different domains and in particular between the linker and the C-terminal domain, containing the catalytic tyrosine residue. These results indicate that the loss of motion correlation and the drug resistance are two strongly correlated events.

  10. General CPT-even dimension-five nonminimal couplings between fermions and photons yielding EDM and MDM

    NASA Astrophysics Data System (ADS)

    Araujo, Jonas B.; Casana, Rodolfo; Ferreira, Manoel M.

    2016-09-01

    In this letter, we examine a new class of CPT-even nonminimal interactions, between fermions and photons, deprived of higher order derivatives, that yields electric dipole moment (EDM) and magnetic dipole moment (MDM) in the context of the Dirac equation. The couplings are dimension-five CPT-even and Lorentz-violating nonminimal structures, composed of a rank-2 tensor, Tμν, the electromagnetic tensor, and gamma matrices, being addressed in its axial and non-axial Hermitian versions, and also comprising general possibilities. We then use the electron's anomalous magnetic dipole moment and electron electric dipole moment measurements to reach upper bounds of 1 part in 1020 and 1025 (eV) - 1.

  11. Search for CPT and lorentz violation in B0-B[over ]0 oscillations with dilepton events.

    PubMed

    Aubert, B; Bona, M; Boutigny, D; Karyotakis, Y; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Grauges, E; Lopez, L; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Osipenkov, I L; Ronan, M T; Tackmann, K; Tanabe, T; Wenzel, W A; Del Amo Sanchez, P; Hawkes, C M; Watson, A T; Koch, H; Schroeder, T; Walker, D; Asgeirsson, D J; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Barrett, M; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Gary, J W; Liu, F; Long, O; Shen, B C; Vitug, G M; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, Ch; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Watson, J E; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Panduro Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Béquilleux, J; D'Orazio, A; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, L; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Sacco, R; Cowan, G; Flaecher, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; McLachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, G; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; Losecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Sekula, S J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; Leruste, Ph; Malclès, J; Ocariz, J; Perez, A; Prendki, J; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Biesiada, J; Elmer, P; Lau, Y P; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Roethel, W; Wilson, F F; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yèche, Ch; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; White, R M; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Luth, V; Lynch, H L; Macfarlane, D B; Marsiske, H; Messner, R; Muller, D R; Nelson, S; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Ziegler, V; Burchat, P R; Edwards, A J; Majewski, S A; Miyashita, T S; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Spanier, S M; Wogsland, B J; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martinez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2008-04-01

    We report results of a search for CPT and Lorentz violation in B(0)-B[over ](0) oscillations using inclusive dilepton events from 232 x 10(6) Upsilon(4S)-->BB[over ] decays recorded by the BABAR detector at the PEP-II B Factory at SLAC. We find 2.8sigma significance, compatible with no signal, for variations in the complex CPT violation parameter z at the Earth's sidereal frequency and extract values for the quantities Deltaa(micro) in the general Lorentz-violating standard-model extension. The spectral powers for variations in z over the frequency range 0.26 yr(-1) to 2.1 solar day(-1) are also compatible with no signal. PMID:18517935

  12. Search for T, CP, and CPT violation in B0-B0 mixing with inclusive dilepton events.

    PubMed

    Aubert, B; Barate, R; Bona, M; Boutigny, D; Couderc, F; Karyotakis, Y; Lees, J P; Poireau, V; Tisserand, V; Zghiche, A; Grauges, E; Palano, A; Pappagallo, M; Chen, J C; Qi, N D; Rong, G; Wang, P; Zhu, Y S; Eigen, G; Ofte, I; Stugu, B; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Charles, E; Day, C T; Gill, M S; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lynch, G; Mir, L M; Oddone, P J; Orimoto, T J; Pripstein, M; Roe, N A; Ronan, M T; Wenzel, W A; Barrett, M; Ford, K E; Harrison, T J; Hart, A J; Hawkes, C M; Morgan, S E; Watson, A T; Goetzen, K; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Peters, K; Schroeder, T; Steinke, M; Boyd, J T; Burke, J P; Cottingham, W N; Walker, D; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Knecht, N S; Mattison, T S; McKenna, J A; Khan, A; Kyberd, P; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Best, D S; Bondioli, M; Bruinsma, M; Chao, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Mommsen, R K; Roethel, W; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Long, O; Shen, B C; Wang, K; Zhang, L; Hadavand, H K; Hill, E J; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Nesom, G; Schalk, T; Schumm, B A; Seiden, A; Spradlin, P; Williams, D C; Wilson, M G; Albert, J; Chen, E; Dvoretskii, A; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Ryd, A; Samuel, A; Andreassen, R; Mancinelli, G; Meadows, B T; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nauenberg, U; Olivas, A; Ruddick, W O; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Chen, A; Eckhart, E A; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Zeng, Q; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Spaan, B; Brandt, T; Klose, V; Lacker, H M; Mader, W F; Nogowski, R; Petzold, A; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Grenier, P; Latour, E; Thiebaux, Ch; Verderi, M; Bard, D J; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cibinetto, G; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Capra, R; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Brandenburg, G; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bhimji, W; Bowerman, D A; Dauncey, P D; Egede, U; Flack, R L; Gaillard, J R; Nash, J A; Nikolich, M B; Panduro Vazquez, W; Chai, X; Charles, M J; Mallik, U; Meyer, N T; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gritsan, A V; Fritsch, M; Schott, G; Arnaud, N; Davier, M; Grosdidier, G; Höcker, A; Le Diberder, F; Lepeltier, V; Lutz, A M; Oyanguren, A; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Stocchi, A; Wang, W F; Wormser, G; Cheng, C H; Lange, D J; Wright, D M; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; George, K A; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; Di Lodovico, F; Menges, W; Sacco, R; Brown, C L; Cowan, G; Flaecher, H U; Hopkins, D A; Jackson, P S; McMahon, T R; Ricciardi, S; Salvatore, F; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Kelly, M P; Lafferty, G D; Naisbit, M T; Williams, J C; Yi, J I; Chen, C; Hulsbergen, W D; Jawahery, A; Lae, C K; Roberts, D A; Simi, G; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Saremi, S; Staengle, H; Willocq, S Y; Cowan, R; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Kim, H; Patel, P M; Potter, C T; Robertson, S H; Lazzaro, A; Lombardo, V; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Reidy, J; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; Cavallo, N; De Nardo, G; del Re, D; Fabozzi, F; Gatto, C; Lista, L; Monorchio, D; Piccolo, D; Sciacca, C; Baak, M; Bulten, H; Raven, G; Snoek, H L; Jessop, C P; LoSecco, J M; Allmendinger, T; Benelli, G; Gan, K K; Honscheid, K; Hufnagel, D; Jackson, P D; Kagan, H; Kass, R; Pulliam, T; Rahimi, A M; Ter-Antonyan, R; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Galeazzi, F; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Benayoun, M; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; Hartfiel, B L; John, M J J; Leruste, Ph; Malclès, J; Ocariz, J; Roos, L; Therin, G; Behera, P K; Gladney, L; Panetta, J; Biasini, M; Covarelli, R; Pioppi, M; Angelini, C; Batignani, G; Bettarini, S; Bucci, F; Calderini, G; Carpinelli, M; Cenci, R; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J; Haire, M; Judd, D; Wagoner, D E; Biesiada, J; Danielson, N; Elmer, P; Lau, Y P; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Bellini, F; Cavoto, G; D'Orazio, A; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Safai Tehrani, F; Voena, C; Ebert, M; Schröder, H; Waldi, R; Adye, T; De Groot, N; Franek, B; Olaiya, E O; Wilson, F F; Emery, S; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Legendre, M; Mayer, B; Vasseur, G; Yèche, Ch; Zito, M; Park, W; Purohit, M V; Weidemann, A W; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Berger, N; Boyarski, A M; Claus, R; Coleman, J P; Convery, M R; Cristinziani, M; Dingfelder, J C; Dong, D; Dorfan, J; Dubois-Felsmann, G P; Dujmic, D; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Halyo, V; Hast, C; Hryn'ova, T; Innes, W R; Kelsey, M H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Libby, J; Luitz, S; Luth, V; Lynch, H L; MacFarlane, D B; Marsiske, H; Messner, R; Muller, D R; O'grady, C P; Ozcan, V E; Perazzo, A; Perl, M; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; van Bakel, N; Weaver, M; Weinstein, A J R; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Roat, C; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Satpathy, A; Schilling, C J; Schwitters, R F; Izen, J M; Kitayama, I; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Dittongo, S; Grancagnolo, S; Lanceri, L; Vitale, L; Azzolini, V; Martinez-Vidal, F; Banerjee, Sw; Bhuyan, B; Brown, C M; Fortin, D; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Back, J J; Harrison, P F; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Cheng, B; Dasu, S; Datta, M; Eichenbaum, A M; Flood, K T; Hollar, J J; Johnson, J R; Kutter, P E; Li, H; Liu, R; Mellado, B; Mihalyi, A; Mohapatra, A K; Pan, Y; Pierini, M; Prepost, R; Tan, P; Wu, S L; Yu, Z; Neal, H

    2006-06-30

    We report the results of a search for T, CP, CPT, and violation in B0-B0 mixing using an inclusive dilepton sample collected by the BABAR experiment at the PEP-II factory. Using a sample of 232 x 10(6) BB pairs, we measure the T and CP violation parameter |q/p| - 1 = (-0.8 +/- 2.7(stat) +/- 1.9(syst) x 10(-3), and the CPT and CP parameters Imz = (13.9 +/- 7.3(stat) +/- 3.2(syst)) x 10(-3) and Delta Gamma x Rez = (7.1 +/- 3.9(stat) +/- 2.0(stat)) x 10(-3) ps(-1). The statistical correlation between the measurements of Imz and Delta Gamma x Rez is 76%.

  13. Search for T, CP and CPT Violation in B0-B0bar Mixingwith Inclusive Dilepton Events

    SciTech Connect

    Aubert, B.

    2006-03-31

    The authors report the results of a search for T, CP and CPT violation in B{sup 0}-{bar B}{sup 0} mixing using an inclusive dilepton sample collected by the BABAR experiment at the PEP-II B Factory. Using a sample of 232 million B{bar B} pairs, with a simultaneous likelihood fit of the same-sign and opposite-sign dileptons, they measure the T and Cp violation parameter |q/p|-1 = (-0.8 {+-} 2.7(stat.) {+-} 1.9(syst.)) x 10{sup -3}, and the CPT and CP parameters Im z = (-13.9 {+-} 7.3(stat.) {+-} 3.2(syst.)) x 10{sup -3} and {Delta}{Lambda} x Re z = (-7.1 {+-} 3.9(stat.) {+-} 2.0(syst.)) x 10{sup -3} ps{sup -1}. The statistical correlation between the measurements of Im z and {Delta}{Lambda} x Re z is 76%.

  14. Entropic information for travelling solitons in Lorentz and CPT breaking systems

    SciTech Connect

    Correa, R.A.C.; Rocha, Roldão da; Souza Dutra, A. de

    2015-08-15

    In this work we group four research topics apparently disconnected, namely solitons, Lorentz symmetry breaking, supersymmetry, and entropy. Following a recent work (Gleiser and Stamatopoulos, 2012), we show that it is possible to construct in the context of travelling wave solutions a configurational entropy measure in functional space, from the field configurations. Thus, we investigate the existence and properties of travelling solitons in Lorentz and CPT breaking scenarios for a class of models with two interacting scalar fields. Here, we obtain a complete set of exact solutions for the model studied which display both double and single-kink configurations. In fact, such models are very important in applications that include Bloch branes, Skyrmions, Yang–Mills, Q-balls, oscillons and various superstring-motivated theories. We find that the so-called Configurational Entropy (CE) for travelling solitons shows that the best value of parameter responsible to break the Lorentz symmetry is one where the energy density is distributed equally around the origin. In this way, the information-theoretical measure of travelling solitons in Lorentz symmetry violation scenarios opens a new window to probe situations where the parameters responsible for breaking the symmetries are arbitrary. In this case, the CE selects the best value of the parameter in the model.

  15. Simulating pile load-settlement behavior from CPT data using intelligent computing

    NASA Astrophysics Data System (ADS)

    Alkroosh, I.; Nikraz, H.

    2011-09-01

    Analysis of pile load-settlement behavior is a complex problem due to the participation of many factors involved. This paper presents a new procedure based on artificial neural networks (ANNs) for simulating the load-settlement behavior of pile foundations embedded in sand and mixed soils (subjected to axial loads). Three ANN models have been developed, a model for bored piles and two other models for driven piles (a model for each of concrete and steel piles). The data used for development of the ANN models is collected from the literature and comprise a series of in-situ piles load tests as well as cone penetration test (CPT) results. The data of each model is divided into two subsets: Training set for model calibration and independent validation set for model verification. Predictions from the ANN models are compared with the results of experimental data and with predictions of number of currently adopted load-transfer methods. Statistical analysis is used to verify the performance of the models. The results indicate that the ANN model performs very well and able to predict the pile load-settlement behaviour accurately.

  16. CPT Profiling and Laboratory Data Correlations for Deriving of Selected Geotechnical Parameter

    NASA Astrophysics Data System (ADS)

    Bulko, Roman; Drusa, Marián; Vlček, Jozef; Mečár, Martin

    2015-12-01

    Currently, can be seen a new trend in engineering geological survey, where laboratory analysis are replaced by in situ testing methods, which are more efficient and cost effective, and time saving too. A regular engineering geological survey cannot be provided by simple core drillings, macroscopic description (sometimes very subjective), and then geotechnical parameters are established based on indicative standardized values or archive values from previous geotechnical standards. The engineering geological survey is trustworthy if is composed of laboratory and in-situ testing supplemented by indirect methods of testing, [1]. The prevalence of rotary core drilling for obtaining laboratory soil samples from various depths (every 1 to 3 m), cannot be a more enhanced as continues evaluation of strata and properties e.g. by CPT Piezocone (every 1 cm). Core drillings survey generally uses small amounts of soil samples, but this is resulting to a lower representation of the subsoil and underestimation of parameters. Higher amounts of soil samples make laboratory testing time-consuming and results from this testing can be influenced by the storage and processing of the soil samples. Preference for geotechnical surveys with in situ testing is therefore a more suitable option. In situ testing using static and dynamic penetration tests can be used as a supplement or as a replacement for the (traditional) methods of surveying.

  17. Studies of neutron-rich nuclei using the CPT mass spectrometer at CARIBU

    NASA Astrophysics Data System (ADS)

    Chaudhuri, A.; Bertone, P. F.; Buchinger, F.; Caldwell, S.; Clark, J. A.; Crawford, J. E.; Deibel, C. M.; Gulick, S.; Lascar, D.; Levand, A. F.; Li, G.; Savard, G.; Segel, R. E.; Sharma, K. S.; Sternberg, M. G.; Sun, T.; Van Schelt, J.

    2011-09-01

    The nucleosynthetic path of the astrophysical r-process and the resulting elemental abundances depend on neutron-separation energies which can be determined from the masses of the nuclei along the r-process reaction path. Due to the current lack of experimental data, mass models are often used. The mass values provided by the mass models are often too imprecise or disagree with each other. Therefore, direct high-precision mass measurements of neutron-rich nuclei are necessary to provide input parameters to the calculations and help refine the mass models. The Californium Rare Isotope Breeder Upgrade (CARIBU) facility of Argonne National Laboratory will provide experiments with beams of short-lived neutron-rich nuclei. The Canadian Penning Trap (CPT) mass spectrometer has been relocated to the CARIBU low-energy beam line to extend measurements of the neutron-rich nuclei into the mostly unexplored region along the r-process path. This will allow precise mass measurements (~ 10 keV/c2) of more than a hundred very neutron-rich isotopes that have not previously been measured.

  18. Genetic evaluation of AMPD1, CPT2, and PGYM metabolic enzymes in patients with chronic fatigue syndrome.

    PubMed

    Maltese, P E; Venturini, L; Poplavskaya, E; Bertelli, M; Cecchin, S; Granato, M; Nikulina, S Y; Salmina, A; Aksyutina, N; Capelli, E; Ricevuti, G; Lorusso, L

    2016-01-01

    Chronic fatigue syndrome (CFS) is a disease that can seriously impair one's quality of life; patients complain of excessive fatigue and myalgia following physical exertion. This disease may be associated with abnormalities in genes affecting exercise tolerance and physical performance. Adenosine monophosphate deaminase (AMPD1), carnitine palmitoyltransferase II (CPT2), and the muscle isoform of glycogen phosphorylase (PYGM) genes provide instructions for producing enzymes that play major roles in energy production during work. The aim of this study was to look for evidence of genotype-associated excessive muscle fatigue. Three metabolic genes (AMPD1, CPT2, and PYGM) were therefore fully sequenced in 17 Italian patients with CFS. We examined polymorphisms known to alter the function of these metabolic genes, and compared their genotypic distributions in CFS patients and 50 healthy controls using chi-square tests and odds ratios. One-way analysis of variance with F-ratio was carried out to determine the associations between genotypes and disease severity using CF scores. No major genetic variations between patients and controls were found in the three genes studied, and we did not find any association between these genes and CFS. In conclusion, variations in AMPD1, CPT2, and PGYM genes are not associated with the onset, susceptibility, or severity of CFS. PMID:27525900

  19. Accumulation of ergot alkaloids during conidiophore development in Aspergillus fumigatus.

    PubMed

    Mulinti, Prashanthi; Allen, Natalie A; Coyle, Christine M; Gravelat, Fabrice N; Sheppard, Donald C; Panaccione, Daniel G

    2014-01-01

    Production of ergot alkaloids in the opportunistic fungal pathogen Aspergillus fumigatus is restricted to conidiating cultures. These cultures typically accumulate several pathway intermediates at concentrations comparable to that of the pathway end product. We investigated the contribution of different cell types that constitute the multicellular conidiophore of A. fumigatus to the production of ergot alkaloid pathway intermediates versus the pathway end product, fumigaclavine C. A relatively minor share (11 %) of the ergot alkaloid yield on a molar basis was secreted into the medium, whereas the remainder was associated with the conidiating colonies. Entire conidiating cultures (containing hyphae, vesicle of conidiophore, phialides of conidiophore, and conidia) accumulated higher levels of the pathway intermediate festuclavine and lower levels of the pathway end product fumigaclavine C than did isolated, abscised conidia, indicating that conidiophores and/or hyphae have a quantitatively different ergot alkaloid profile compared to that of conidia. Differences in alkaloid accumulation among cell types also were indicated by studies with conidiophore development mutants. A ∆medA mutant, in which conidiophores are numerous but develop poorly, accumulated higher levels of pathway intermediates than did the wildtype or a complemented ∆medA mutant. A ∆stuA mutant, which grows mainly as hyphae and produces very few, abnormal conidiophores, produced no detectable ergot alkaloids. The data indicated heterogeneous spatial distribution of ergot alkaloid pathway intermediates versus pathway end product in conidiating cultures of A. fumigatus. This skewed distribution may reflect differences in abundance or activity of pathway enzymes among cell types of those conidiating cultures. PMID:23925951

  20. Synthesis of Morphinan Alkaloids in Saccharomyces cerevisiae

    PubMed Central

    Fossati, Elena; Narcross, Lauren; Ekins, Andrew; Falgueyret, Jean-Pierre; Martin, Vincent J. J.

    2015-01-01

    Morphinan alkaloids are the most powerful narcotic analgesics currently used to treat moderate to severe and chronic pain. The feasibility of morphinan synthesis in recombinant Saccharomyces cerevisiae starting from the precursor (R,S)-norlaudanosoline was investigated. Chiral analysis of the reticuline produced by the expression of opium poppy methyltransferases showed strict enantioselectivity for (S)-reticuline starting from (R,S)-norlaudanosoline. In addition, the P. somniferum enzymes salutaridine synthase (PsSAS), salutaridine reductase (PsSAR) and salutaridinol acetyltransferase (PsSAT) were functionally co-expressed in S. cerevisiae and optimization of the pH conditions allowed for productive spontaneous rearrangement of salutaridinol-7-O-acetate and synthesis of thebaine from (R)-reticuline. Finally, we reconstituted a 7-gene pathway for the production of codeine and morphine from (R)-reticuline. Yeast cell feeding assays using (R)-reticuline, salutaridine or codeine as substrates showed that all enzymes were functionally co-expressed in yeast and that activity of salutaridine reductase and codeine-O-demethylase likely limit flux to morphine synthesis. The results of this study describe a significant advance for the synthesis of morphinans in S. cerevisiae and pave the way for their complete synthesis in recombinant microbes. PMID:25905794

  1. Synthesis of Morphinan Alkaloids in Saccharomyces cerevisiae.

    PubMed

    Fossati, Elena; Narcross, Lauren; Ekins, Andrew; Falgueyret, Jean-Pierre; Martin, Vincent J J

    2015-01-01

    Morphinan alkaloids are the most powerful narcotic analgesics currently used to treat moderate to severe and chronic pain. The feasibility of morphinan synthesis in recombinant Saccharomyces cerevisiae starting from the precursor (R,S)-norlaudanosoline was investigated. Chiral analysis of the reticuline produced by the expression of opium poppy methyltransferases showed strict enantioselectivity for (S)-reticuline starting from (R,S)-norlaudanosoline. In addition, the P. somniferum enzymes salutaridine synthase (PsSAS), salutaridine reductase (PsSAR) and salutaridinol acetyltransferase (PsSAT) were functionally co-expressed in S. cerevisiae and optimization of the pH conditions allowed for productive spontaneous rearrangement of salutaridinol-7-O-acetate and synthesis of thebaine from (R)-reticuline. Finally, we reconstituted a 7-gene pathway for the production of codeine and morphine from (R)-reticuline. Yeast cell feeding assays using (R)-reticuline, salutaridine or codeine as substrates showed that all enzymes were functionally co-expressed in yeast and that activity of salutaridine reductase and codeine-O-demethylase likely limit flux to morphine synthesis. The results of this study describe a significant advance for the synthesis of morphinans in S. cerevisiae and pave the way for their complete synthesis in recombinant microbes. PMID:25905794

  2. Alkaloids and athlete immune function: caffeine, theophylline, gingerol, ephedrine, and their congeners.

    PubMed

    Senchina, David S; Hallam, Justus E; Kohut, Marian L; Nguyen, Norah A; Perera, M Ann d N

    2014-01-01

    Plant alkaloids are found in foods, beverages, and supplements consumed by athletes for daily nutrition, performance enhancement, and immune function improvement. This paper examined possible immunomodulatory roles of alkaloids in exercise contexts, with a focus on human studies. Four representative groups were scrutinized: (a) caffeine (guaranine, mateine); (b) theophylline and its isomers, theobromine and paraxanthine; (c) ginger alkaloids including gingerols and shogaol; and (d) ephedra alkaloids such as ephedrine and pseudoephedrine. Emerging or prospective alkaloid sources (Goji berry, Noni berry, and bloodroot) were also considered. Human in vitro and in vivo studies on alkaloids and immune function were often conflicting. Caffeine may be immunomodulatory in vivo depending on subject characteristics, exercise characteristics, and immune parameters measured. Caffeine may exhibit antioxidant capacities. Ginger may exert in vivo anti-inflammatory effects in certain populations, but it is unclear whether these effects are due to alkaloids or other biochemicals. Evidence for an immunomodulatory role of alkaloids in energy drinks, cocoa, or ephedra products in vivo is weak to nonexistent. For alkaloid sources derived from plants, variability in the reviewed studies may be due to the presence of unrecognized alkaloids or non-alkaloid compounds (which may themselves be immunomodulatory), and pre-experimental factors such as agricultural or manufacturing differences. Athletes should not look to alkaloids or alkaloid-rich sources as a means of improving immune function given their inconsistent activities, safety concerns, and lack of commercial regulation.

  3. Alkaloids and athlete immune function: caffeine, theophylline, gingerol, ephedrine, and their congeners.

    PubMed

    Senchina, David S; Hallam, Justus E; Kohut, Marian L; Nguyen, Norah A; Perera, M Ann d N

    2014-01-01

    Plant alkaloids are found in foods, beverages, and supplements consumed by athletes for daily nutrition, performance enhancement, and immune function improvement. This paper examined possible immunomodulatory roles of alkaloids in exercise contexts, with a focus on human studies. Four representative groups were scrutinized: (a) caffeine (guaranine, mateine); (b) theophylline and its isomers, theobromine and paraxanthine; (c) ginger alkaloids including gingerols and shogaol; and (d) ephedra alkaloids such as ephedrine and pseudoephedrine. Emerging or prospective alkaloid sources (Goji berry, Noni berry, and bloodroot) were also considered. Human in vitro and in vivo studies on alkaloids and immune function were often conflicting. Caffeine may be immunomodulatory in vivo depending on subject characteristics, exercise characteristics, and immune parameters measured. Caffeine may exhibit antioxidant capacities. Ginger may exert in vivo anti-inflammatory effects in certain populations, but it is unclear whether these effects are due to alkaloids or other biochemicals. Evidence for an immunomodulatory role of alkaloids in energy drinks, cocoa, or ephedra products in vivo is weak to nonexistent. For alkaloid sources derived from plants, variability in the reviewed studies may be due to the presence of unrecognized alkaloids or non-alkaloid compounds (which may themselves be immunomodulatory), and pre-experimental factors such as agricultural or manufacturing differences. Athletes should not look to alkaloids or alkaloid-rich sources as a means of improving immune function given their inconsistent activities, safety concerns, and lack of commercial regulation. PMID:24974722

  4. Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity.

    PubMed

    Maples, Jill M; Brault, Jeffrey J; Witczak, Carol A; Park, Sanghee; Hubal, Monica J; Weber, Todd M; Houmard, Joseph A; Shewchuk, Brian M

    2015-08-15

    The ability to increase fatty acid oxidation (FAO) in response to dietary lipid is impaired in the skeletal muscle of obese individuals, which is associated with a failure to coordinately upregulate genes involved with FAO. While the molecular mechanisms contributing to this metabolic inflexibility are not evident, a possible candidate is carnitine palmitoyltransferase-1B (CPT1B), which is a rate-limiting step in FAO. The present study was undertaken to determine if the differential response of skeletal muscle CPT1B gene transcription to lipid between lean and severely obese subjects is linked to epigenetic modifications (DNA methylation and histone acetylation) that impact transcriptional activation. In primary human skeletal muscle cultures the expression of CPT1B was blunted in severely obese women compared with their lean counterparts in response to lipid, which was accompanied by changes in CpG methylation, H3/H4 histone acetylation, and peroxisome proliferator-activated receptor-δ and hepatocyte nuclear factor 4α transcription factor occupancy at the CPT1B promoter. Methylation of specific CpG sites in the CPT1B promoter that correlated with CPT1B transcript level blocked the binding of the transcription factor upstream stimulatory factor, suggesting a potential causal mechanism. These findings indicate that epigenetic modifications may play important roles in the regulation of CPT1B in response to a physiologically relevant lipid mixture in human skeletal muscle, a major site of fatty acid catabolism, and that differential DNA methylation may underlie the depressed expression of CPT1B in response to lipid, contributing to the metabolic inflexibility associated with severe obesity. PMID:26058865

  5. Micelle assisted structural conversion with fluorescence modulation of benzophenanthridine alkaloids.

    PubMed

    Pradhan, Ankur Bikash; Bhuiya, Sutanwi; Haque, Lucy; Tiwari, Richa; Das, Suman

    2017-01-01

    In this study we have reported the anionic surfactant (Sodium dodecyl sulfate, SDS) driven structural conversion of two benzophenanthridine plant alkaloids namely Chelerythrine (herein after CHL) and Sanguinarine (herein after SANG). Both the alkaloids exist in two forms: the charged iminium and the neutral alkanolamine form. The iminium form is stable at low pH (<6.5) and the alkanolamine form exists at higher pH (>10.1). The fluorescence intensity of the alkanolamine form is much stronger than the iminium form. The iminium form of both the alkaloids remains stable whereas the alkanolamine form gets converted to the iminium form in the SDS micelle environment. The iminium form possesses positive charge and it seems that electrostatic interaction between the positively charged iminium and negatively charged surfactant leads to the stabilization of the iminium form in the Stern layer of the anionic micelle. Whereas the conversion of the alkanolamine form into the iminium form takes place and that can be monitored in naked eye since the iminium form is orange in colour and the alkanolamine form has blue violet emission. Such a detail insight about the photophysical properties of the benzophenanthridine alkaloids would be a valuable addition in the field of alkaloid-surfactant interaction. PMID:27419642

  6. Post-genome research on the biosynthesis of ergot alkaloids.

    PubMed

    Li, Shu-Ming; Unsöld, Inge A

    2006-10-01

    Genome sequencing provides new opportunities and challenges for identifying genes for the biosynthesis of secondary metabolites. A putative biosynthetic gene cluster of fumigaclavine C, an ergot alkaloid of the clavine type, was identified in the genome sequence of ASPERGILLUS FUMIGATUS by a bioinformatic approach. This cluster spans 22 kb of genomic DNA and comprises at least 11 open reading frames (ORFs). Seven of them are orthologous to genes from the biosynthetic gene cluster of ergot alkaloids in CLAVICEPS PURPUREA. Experimental evidence of the identified cluster was provided by heterologous expression and biochemical characterization of two ORFs, FgaPT1 and FgaPT2, in the cluster of A. FUMIGATUS, which show remarkable similarities to dimethylallyltryptophan synthase from C. PURPUREA and function as prenyltransferases. FgaPT2 converts L-tryptophan to dimethylallyltryptophan and thereby catalyzes the first step of ergot alkaloid biosynthesis, whilst FgaPT1 catalyzes the last step of the fumigaclavine C biosynthesis, i. e., the prenylation of fumigaclavine A at C-2 position of the indole nucleus. In addition to information obtained from the gene cluster of ergot alkaloids from C. PURPUREA, the identification of the biosynthetic gene cluster of fumigaclavine C in A. FUMIGATUS opens an alternative way to study the biosynthesis of ergot alkaloids in fungi. PMID:16902860

  7. Ornithine Decarboxylase, Polyamines, and Pyrrolizidine Alkaloids in Senecio and Crotalaria

    PubMed Central

    Birecka, Helena; Birecki, Mieczyslaw; Cohen, Eric J.; Bitonti, Alan J.; McCann, Peter P.

    1988-01-01

    When tested for ornithine and arginine decarboxylases, pyrrolizidine alkaloid-bearing Senecio riddellii, S. longilobus (Compositae), and Crotalaria retusa (Leguminosae) plants exhibited only ornithine decarboxylase activity. This contrasts with previous studies of four species of pyrrolizidine alkaloid-bearing Heliotropium (Boraginaceae) in which arginine decarboxylase activity was very high relative to that of ornithine decarboxylase. Unlike Heliotropium angiospermum and Heliotropium indicum, in which endogenous arginine was the only detectable precursor of putrescine channeled into pyrrolizidines, in the species studied here—using difluoromethylornithine and difluoromethylarginine as the enzyme inhibitors—endogenous ornithine was the main if not the only precursor of putrescine converted into the alkaloid aminoalcohol moiety. In S. riddellii and C. retusa at flowering, ornithine decarboxylase activity was present mainly in leaves, especially the young ones. However, other very young organs such as inflorescence and growing roots exhibited much lower or very low activities; the enzyme activity in stems was negligible. There was no correlation between the enzyme activity and polyamine or alkaloid content in either species. In both species only free polyamines were detected except for C. retusa roots and inflorescence—with relatively very high levels of these compounds—in which conjugated putrescine, spermidine, and spermine were also found; agmatine was not identified by HPLC in any plant organ except for C. retusa roots with rhizobial nodules. Organ- or age-dependent differences in the polyamine levels were small or insignificant. The highest alkaloid contents were found in young leaves and inflorescence. PMID:16665870

  8. Geographic distribution of three alkaloid chemotypes of Croton lechleri.

    PubMed

    Milanowski, Dennis J; Winter, Rudolph E K; Elvin-Lewis, Memory P F; Lewis, Walter H

    2002-06-01

    Three known alkaloids, isoboldine (2), norisoboldine (1), and magnoflorine (8), have been isolated for the first time from Croton lechleri, a source of the wound healing latex "sangre de grado". An HPLC system was developed, and a large number of latex and leaf samples of C. lechleri from 22 sites in northern Peru and Ecuador were analyzed to gain an understanding of the natural variation in alkaloid content for the species. Up to six alkaloids were found to occur in the leaves including, in addition to those listed above, thaliporphine (3), glaucine (4), and taspine (9), whereas the latex contained only 9. Taspine (9) is the component that has been previously found to be responsible for the wound healing activity of C. lechleri latex, and its mean concentration throughout the range examined was found to be 9% of the latex by dry weight. In addition, three chemotypes are defined based on the alkaloid content of the leaves, and the geographic distribution of these chemotypes is discussed along with a quantitative analysis of the alkaloid content as a function of chemotype.

  9. Bovine lateral saphenous veins exposed to ergopeptine alkaloids do not relax

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ergot alkaloid, ergovaline has demonstrated a persistent binding and sustained contractile response in several vascular models. It was hypothesized that different alkaloids isolated from tall fescue (Lolium arundinaceum) will contribute to this response differently. The objective was to compare ...

  10. Bovine lateral saphenous veins exposed to ergopeptine alkaloids do not relax

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ergot alkaloid ergovaline has demonstrated a persistent and sustained contractile response in several different vascular models. It was hypothesized that different alkaloids isolated from tall fescue (Lolium arundinaceum) will contribute to this contractile response differently. The objective wa...

  11. Alkaloids of the Annonaceae: occurrence and a compilation of their biological activities.

    PubMed

    Lúcio, Ana Silvia Suassuna Carneiro; Almeida, Jackson Roberto Guedes da Silva; Da-Cunha, Emídio Vasconcelos Leitão; Tavares, Josean Fechine; Barbosa Filho, Jos Maria

    2015-01-01

    This chapter presents an overview of the chemistry and pharmacology of the alkaloids found in species of the Annonaceae family. The occurrence of alkaloids from Annonaceae species, as well as their chemical structures and pharmacological activities are summarized in informative and easy-to-understand tables. Within the Annonaceae family, the genera Annona, Duguetia, and Guatteria have led to many important publications. Valuable and comprehensive information about the structure of these alkaloids is provided. The alkaloids of the aporphine type represent the predominant group in this family. Many of the isolated alkaloids exhibit unique structures. In addition to the chemical structures, the pharmacological activities of some alkaloids are also presented in this chapter. Thus, the leishmanicidal, antimicrobial, antitumor, cytotoxic, and antimalarial activities observed for these alkaloids are highlighted. The chapter is presented as a contribution for the scientific community, mainly to enable the search for alkaloids in species belonging to the Annonaceae family.

  12. Testing CPT conservation using the NuMI neutrino beam with the MINOS experiment

    SciTech Connect

    Auty, David John

    2010-03-01

    The MINOS experiment was designed to measure neutrino oscillation parameters with muon neutrinos. It achieves this by measuring the neutrino energy spectrum and flavor composition of the man-made NuMI neutrino beam 1km after the beam is formed and again after 735 km. By comparing the two spectra it is possible to measure the oscillation parameters. The NuMI beam is made up of 7.0%$\\bar{v}$μ, which can be separated from the vμ because the MINOS detectors are magnetized. This makes it possible to study $\\bar{v}$μ oscillations separately from those of muon neutrinos, and thereby test CPT invariance in the neutrino sector by determining the $\\bar{v}$μ oscillation parameters and comparing them with those for vμ, although any unknown physics of the antineutrino would appear as a difference in oscillation parameters. Such a test has not been performed with beam $\\bar{v}$μ before. It is also possible to produce an almost pure $\\bar{v}$μ beam by reversing the current through the magnetic focusing horns of the NuMI beamline, thereby focusing negatively, instead of positively charged particles. This thesis describes the analysis of the 7% $\\bar{v}$μ component of the forward horn current NuMI beam. The $\\bar{v}$μ of a data sample of 3.2 x 10{sup 20} protons on target analysis found 42 events, compared to a CPT conserving prediction of 58.3-7.6+7.6(stat.)-3.6+3.6(syst.) events. This corresponds to a 1.9 σ deficit, and a best fit value of Δ$\\bar{m}$322 = 18 x 10-3 eV2 and sin2 2$\\bar{θ}$23 = 0.55. This thesis focuses particularly on the selection of $\\bar{v}$μ events, and investigates possible improvements of the selection algorithm. From this a different selector was chosen, which corroborated the findings of the original selector. The

  13. Diterpene alkaloids with an aza-ent-kaurane skeleton from Isodon rubescens.

    PubMed

    Liu, Xu; Yang, Jing; Wang, Wei-Guang; Li, Yan; Wu, Ji-Zhou; Pu, Jian-Xin; Sun, Han-Dong

    2015-02-27

    Two compounds belonging to a new group of diterpene alkaloids, kaurines A and B (1 and 2), and an alkaloid bearing a succinimide moiety (3) were obtained from Isodon rubescens. Their structures and absolute configurations were determined by spectroscopy and quantum-chemical computational (13)C NMR and ECD data analysis. These alkaloids differ from known diterpene alkaloids and diterpenoids and are presumably biosynthesized from ent-kaurane diterpenoids. PMID:25590529

  14. Comparative qualitative and quantitative determination of alkaloids in narcotic and condiment Papaver somniferum cultivars.

    PubMed

    Frick, Susanne; Kramell, Robert; Schmidt, Jürgen; Fist, Anthony J; Kutchan, Toni M

    2005-05-01

    In the present study morphinan, tetrahydrobenzylisoquinoline, benzo[c]phenanthridine, and phthalideisoquinoline alkaloids were determined qualitatively and quantitatively by HPLC and LC-MS analysis in tissues of the Tasmanian Papaver somniferum L. elite cultivar C048-6-14-64. The data were compared with the results from the low-morphine cultivar "Marianne". In the elite cultivar, 91.2% of the latex alkaloids consist of the three pharmaceutically most valuable alkaloids: morphine, codeine, and thebaine. In the root system, the major alkaloids are sanguinarine/10-hydroxysanguinarine and dihydrosanguinarine/10-hydroxydihydrosanguinarine. In the stems and leaves of C048-6-14-64, the same alkaloids were measured as in the latex. In the stems, a gradient in relative total alkaloid content from the top downward toward the roots was observed. The concentration of morphine was decreasing toward the roots, whereas an increasing gradient from the upper to the lower stem parts was detected for codeine. The relative total alkaloid concentration in leaves remained constant; no gradient was observed. The cultivar "Marianne" displayed a shifted pattern of alkaloid accumulation and reduced levels of total alkaloid. In the condiment cultivar, 80.5% of the alkaloids of the latex consisted of the two phthalideisoquinoline alkaloids narcotoline and noscapine. Only 18.8% of the relative total alkaloid content were morphinan alkaloids. In contrast to the narcotic cultivar, in which the benzo[c]phenanthridines in roots dominated over the morphinan and tetrahydrobenzylisoquinoline alkaloids, the concentration of benzo[c]phenanthridines in "Marianne" was similar to that of morphinan and tetrahydrobenzylisoquinoline alkaloids. These data suggest a differential alkaloid regulation in each cultivar of P. somniferum.

  15. (+)-Chenabinol (Revised NMR Data) and Two New Alkaloids from Berberis vulgaris and their Biological Activity.

    PubMed

    Novák, Zdenĕk; Hošt'álková, Anna; Opletal, Lubomír; Nováková, Lucie; Hrabinová, Martina; Kuneš, Jiří; Cahlíková, Lucie

    2015-10-01

    A known alkaloid (+)-chenabinol (1) and two new secobisbenzylisoquinoline alkaloids were isolated by standard chromatographic methods from the root bark of Berberis vulgaris L. The structures of the new alkaloids, named berkristine (2) and verfilline (3), were established by spectroscopic (including 2D NMR), and HRMS (ESI) methods. The alkaloids were tested for their inhibition activity of human cholinesterases and prolyl oligopeptidase. Compound 1 inhibited human butyrylcholinesterase with an IC50 value of 44.8 ± 5.4 μM.

  16. Hydrofocusing Bioreactor Produces Anti-Cancer Alkaloids

    NASA Technical Reports Server (NTRS)

    Gonda, Steve R.; Valluri, Jagan V.

    2011-01-01

    microgravitation of an HFB do not need to maintain the same surface forces as in normal Earth gravitation, they can divert more energy sources to growth and differentiation and, perhaps, to biosynthesis of greater quantities of desired medicinal compounds. Because one can adjust the HFB to vary effective gravitation, one can also test the effects of intermediate levels of gravitation on biosynthesis of various products. The potential utility of this methodology for producing drugs was demonstrated in experiments in which sandalwood and Madagascar periwinkle cells were grown in an HFB. The conditions in the HFB were chosen to induce the cells to form into aggregate cultures that produced anti-cancer indole alkaloids in amounts greater than do comparable numbers of cells of the same species cultured according to previously known methodologies. The observations made in these experiments were interpreted as suggesting that the aggregation of the cells might be responsible for the enhancement of production of alkaloids.

  17. The role of biocatalysis in the asymmetric synthesis of alkaloids

    PubMed Central

    2013-01-01

    Alkaloids are not only one of the most intensively studied classes of natural products, their wide spectrum of pharmacological activities also makes them indispensable drug ingredients in both traditional and modern medicine. Among the methods for their production, biotechnological approaches are gaining importance, and biocatalysis has emerged as an essential tool in this context. A number of chemo-enzymatic strategies for alkaloid synthesis have been developed over the years, in which the biotransformations nowadays take an increasingly ‘central’ role. This review summarises different applications of biocatalysis in the asymmetric synthesis of alkaloids and discusses how recent developments and novel enzymes render innovative and efficient chemo-enzymatic production routes possible. PMID:25580241

  18. [Occurrence of indole alkaloids among secondary metabolites of soil Aspergillus].

    PubMed

    Vinokurova, N G; Khmel'nitskaia, I I; Baskunov, B P; Arinbasarov, M U

    2003-01-01

    The occurrence of indole alkaloids among secondary fungal metabolites was studied in species of the genus Aspergillus, isolated from soils that were sampled in various regions of Russia (a total of 102 isolates of the species A. niger, A. phoenicis, A. fumigatus, A. flavus, A. versicolor, A. ustus, A. clavatus, and A. ochraceus). Clavine alkaloids were represented by fumigaclavine, which was formed by A. fumigatus. alpha-Cyclopiazonic acid was formed by isolates of A. fumigatus, A. flavus, A. versicolor, A. phoenicis, and A. clavatus. The occurrence of indole-containing diketopiperazine alkaloids was documented for isolates of A. flavus, A. fumigatus, A. clavatus, and A. ochraceus. No indole-containing metabolites were found among the metabolites of A. ustus or A. niger. PMID:12722658

  19. In vitro production of alkaloids: Factors, approaches, challenges and prospects

    PubMed Central

    Ahmad, Sayeed; Garg, Madhukar; Tamboli, Ennus Tajuddin; Abdin, M. Z.; Ansari, S. H.

    2013-01-01

    The wide diversity of plant secondary metabolites is largely used for the production of various pharmaceutical compounds. In vitro cell tissue or organ culture has been employed as a possible alternative to produce such industrial compounds. Tissue culture techniques provide continuous, reliable, and renewable source of valuable plant pharmaceuticals and might be used for the large-scale culture of the plant cells from which these secondary metabolites can be extracted. Alkaloids are one of the most important secondary metabolites known to play a vital role in various pharmaceutical applications leading to an increased commercial importance in recent years. The tissue culture techniques may be utilized to improve their production of alkaloids via somaclonal variations and genetic transformations. The focus of this review is toward the application of different tissue culture methods/techniques employed for the in vitro production of alkaloids with a systematic approach to improve their production. PMID:23922453

  20. HPTLC and GC/MS Study of Amaryllidaceae Alkaloids of Two Narcissus Species.

    PubMed

    Shawky, Eman; Abou-Donia, Amina H; Darwish, Fikria A; Toaima, Soad M; Takla, Sarah S; Pigni, Natalia B; Bastida, Jaume

    2015-08-01

    In this article, we report on the alkaloid profile and dynamic of alkaloid content and diversity in two Narcissus plants at different stages of development. The alkaloid profile of the two Narcissus species was investigated by GC/MS and HPTLC. Fifty eight Amaryllidaceae alkaloids were detected, and 25 of them were identified in the different organs of N. tazetta and N. papyraceus. The alkaloid 3-O-methyl-9-O-demethylmaritidine is tentatively identified here for the first time from the Amaryllidaceae family, and four alkaloids (tazettamide, sternbergine, 1-O-acetyllycorine, 2,11-didehydro-2-dehydroxylycorine) are tentatively identified for the first time in the genus Narcissus. The different organs of the two species analyzed showed remarkable differences in their alkaloid pattern, type of biosynthesis, main alkaloid and number of alkaloids. Lycorine-type alkaloids dominated the alkaloid, metabolism in N. papyraceus, while alkaloids of narciclasine-, galanthamine- and homolycorine-types were found only in the species N. tazetta L.

  1. [Clavine alkaloid biosynthesis by the fungus Penicillium palitans westling 1911 isolated from ancient permafrost deposits].

    PubMed

    Kozlovskiĭ, A G; Zhelifonova, V P; Antipova, T V

    2009-01-01

    The relic strain of Penicillium palitans isolated from the ancient permafrost deposits produces clavine alkaloids such as festuclavine, fumigaclavine A, and fumigaclavine B. Alkaloid biosynthesis is concurrent with the growth. Tryptophan and zinc ion additives to the culture medium stimulate the synthesis of alkaloids. PMID:19382708

  2. Cytotoxicity of Naturally Occurring Isoquinoline Alkaloids of Different Structural Types.

    PubMed

    Chlebek, Jakub; Doskocil, Ivo; Hulcová, Daniela; Breiterová, Katerina; Šafratová, Marcela; Havelek, Radim; Habartová, Klára; Hošt'álková, Anna; Volštátová, Tereza; Cahlíková, Lucie

    2016-06-01

    Forty-six isoquinoline alkaloids, of eleven structural types isolated in our laboratory, have been evaluated for their cytotoxicity against two cancer cell lines (Caco-2 and Hep-G2 cancer cells), as well as against normal human lung fibroblast cells. Only scoulerine, aromoline, berbamine and parfumidine showed significant cytotoxic effects, but only scoulerine was active against both Caco-2 and Hep-G2 cells (IC50 values 6.44 ± 0.87 and 4.57 ± 0.42, respectively). Unfortunately, except for parfumidine, the other active alkaloids were also cytotoxic to the normal human lung fibroblast cells.

  3. Antitussive stemoninine alkaloids from the roots of Stemona tuberosa.

    PubMed

    Lin, Li-Gen; Li, Kan Man; Tang, Chun-Ping; Ke, Chang-Qiang; Rudd, John A; Lin, Ge; Ye, Yang

    2008-06-01

    Investigation of the roots of Stemona tuberosa afforded five minor constituents, stemoenonine (1), 9a- O-methylstemoenonine (2), oxystemoenonine (3), 1,9a- seco-stemoenonine (4), and oxystemoninine (5), along with the known compound stemoninoamide (6). Their structures were elucidated by 1D and 2D NMR spectra and other spectroscopic studies. Alkaloids 1, 2, and 6, as well as the representative stemoninine-type alkaloid, stemoninine (7), were screened for antitussive activity in the citric acid-induced guinea pig cough model. Compounds 6 and 7 exhibited strong antitussive activity after oral and intraperitoneal administrations.

  4. Cytotoxicity of Naturally Occurring Isoquinoline Alkaloids of Different Structural Types.

    PubMed

    Chlebek, Jakub; Doskocil, Ivo; Hulcová, Daniela; Breiterová, Katerina; Šafratová, Marcela; Havelek, Radim; Habartová, Klára; Hošt'álková, Anna; Volštátová, Tereza; Cahlíková, Lucie

    2016-06-01

    Forty-six isoquinoline alkaloids, of eleven structural types isolated in our laboratory, have been evaluated for their cytotoxicity against two cancer cell lines (Caco-2 and Hep-G2 cancer cells), as well as against normal human lung fibroblast cells. Only scoulerine, aromoline, berbamine and parfumidine showed significant cytotoxic effects, but only scoulerine was active against both Caco-2 and Hep-G2 cells (IC50 values 6.44 ± 0.87 and 4.57 ± 0.42, respectively). Unfortunately, except for parfumidine, the other active alkaloids were also cytotoxic to the normal human lung fibroblast cells. PMID:27534109

  5. Chemiluminescence detection of opium poppy (Papaver somniferum) alkaloids.

    PubMed

    Francis, Paul S; Adcock, Jacqui L; Costin, Jason W; Purcell, Stuart D; Pfeffer, Frederick M; Barnett, Neil W

    2008-11-01

    A review with 98 references. The determination of the opium poppy (Papaver somniferum) alkaloids and their semi-synthetic derivatives has important applications in industrial process monitoring, clinical analysis and forensic science. Liquid-phase chemiluminescence reagents such as tris(2,2'-bipyridyl)ruthenium(II) and acidic potassium permanganate exhibit remarkable sensitivity and complementary selectivity for many P. somniferum alkaloids, which has been exploited in the development of a range of analytical procedures using flow analysis, high-performance liquid chromatography, capillary electrophoresis and microfluidic instrumentation.

  6. Alkaloid-derived molecules in low rank Argonne premium coals.

    SciTech Connect

    Winans, R. E.; Tomczyk, N. A.; Hunt, J. E.

    2000-11-30

    Molecules that are probably derived from alkaloids have been found in the extracts of the subbituminous and lignite Argonne Premium Coals. High resolution mass spectrometry (HRMS) and liquid chromatography mass spectrometry (LCMS) have been used to characterize pyridine and supercritical extracts. The supercritical extraction used an approach that has been successful for extracting alkaloids from natural products. The first indication that there might be these natural products in coals was the large number of molecules found containing multiple nitrogen and oxygen heteroatoms. These molecules are much less abundant in bituminous coals and absent in the higher rank coals.

  7. Recent Advances in the Synthesis of Morphine and Related Alkaloids

    NASA Astrophysics Data System (ADS)

    Chida, Noritaka

    Morphine, an alkaloid isolated from the opium poppy, has been widely used as an analgesic, and has been a fascinating synthetic target of organic chemists. After the first total synthesis reported in 1952, a number of synthetic studies toward morphine have been reported, and findings obtained in such studies have greatly contributed to the progress of synthetic organic chemistry as well as medicinal chemistry. This review provides an overview of recent studies toward the total synthesis of morphine and related alkaloids. Work reported in the literature since 2004 will be reviewed.

  8. The cell and developmental biology of alkaloid biosynthesis.

    PubMed

    De Luca, V; St Pierre, B

    2000-04-01

    Plants produce unique natural products as a result of gene mutation and subsequent adaptation of metabolic pathways to create new secondary metabolites. However, their biosynthesis and accumulation remains remarkably under the control of the biotic and abiotic environments. Alkaloid biosynthesis, which requires the adaptation of cellular activities to perform specialized metabolism without compromising general homeostasis, is accomplished by restricting product biosynthesis and accumulation to particular cells and to defined times of plant development. The cell and developmental biology of alkaloid biosynthesis, which is remarkably complex, evolved in part by recruiting pre-existing enzymes to perform new functions.

  9. 3-Methoxysampangine, a novel antifungal copyrine alkaloid from Cleistopholis patens.

    PubMed Central

    Liu, S C; Oguntimein, B; Hufford, C D; Clark, A M

    1990-01-01

    Further examination of the active ethanolic extract of the root bark of Cleistopholis patens by using bioassay-directed fractionation resulted in the isolation of a new alkaloid, 3-methoxysampangine (compound I), together with three known alkaloids, eupolauridine (compound II), liriodenine (compound III), and eupolauridine N-oxide (compound IV). The proposed structure of compound I was based on its physicochemical properties and spectral data. 3-Methoxysampangine exhibited significant antifungal activity against Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans. This is the first report of the isolation of liriodenine (compound III) from the root bark of C. patens. PMID:2188584

  10. Antifouling indole alkaloids from two marine derived fungi.

    PubMed

    He, Fei; Han, Zhuang; Peng, Jiang; Qian, Pei-Yuan; Qi, Shu-Hua

    2013-03-01

    In order to find non-toxic antifouling natural products from marine microorganisms, the chemical constituents of two marine derived fungi Penicillium sp. and Aspergillus sydowii have been investigated under bio-guided fractionation. A new indolyl diketopiperazine compound, penilloid A (1), together with 15 known ones were isolated from these two strains. The structure of 1 was elucidated on the basis of NMR and mass spectra. Some alkaloids showed significant antifouling and antibacterial activities. The results indicate that indole alkaloids could be a potential antifouling agent resource.

  11. Alkaloids from the South China Sea Black Coral Antipathes dichotoma.

    PubMed

    Qi, Shu-Hua; Su, Guo-Chen; Wang, Yi-Fei; Liu, Qiu-Ying; Gao, Cheng-Hai

    2009-01-01

    A new carbazole alkaloid, antipathine A (1), together with three known zoanthoxanthin alkaloids (2--4) was isolated from the EtOH/CH2Cl2 extracts of the South China Sea black coral Antipathes dichotoma. The structure of 1 was determined on the bases of extensive spectroscopic analysis, including 1D and 2D NMR data. Compounds 1 and 2 showed moderate cytotoxicity against human stomach carcinoma SGC-7901 cell line with IC50 of 67.38 and 86.40 microg/ml, respectively, and 1 and 2 also showed weak cytotoxicity toward human liver carcinoma Hep_G2 cell line.

  12. Dopamine D1 receptor activation improves PCP-induced performance disruption in the 5C-CPT by reducing inappropriate responding.

    PubMed

    Barnes, S A; Young, J W; Bate, S T; Neill, J C

    2016-03-01

    Attentional deficits contribute significantly to the functional disability of schizophrenia patients. The 5-choice continuous performance test (5C-CPT) measures attention in mice, rats, and humans, requiring the discrimination of trial types that either require a response or the inhibition of a response. The 5C-CPT, one version of human continuous performance tests (CPT), enables attentional testing in rodents in a manner consistent with humans. Augmenting the prefrontal cortical dopaminergic system has been proposed as a therapeutic target to attenuate the cognitive disturbances associated with schizophrenia. Using translational behavioural tasks in conjunction with inducing conditions relevant to schizophrenia pathophysiology enable the assessment of pro-attentive properties of compounds that augment dopaminergic activity. Here, using a repeated phencyclidine (PCP) treatment regimen and the 5C-CPT paradigm, we assess the pro-attentive properties of SKF 38393, a dopamine D1 receptor agonist, in rats. We show that repeated PCP treatment induces robust deficits in 5C-CPT performance indicative of impaired attention. Pre-treatment with SKF 38393 partially attenuates the PCP-induced deficits in 5C-CPT performance by reducing false alarm responding and increasing response accuracy. Impaired target detection was still evident in SKF 38393-treated rats however. Thus, augmentation of the dopamine D1 system improves PCP-induces deficits in 5C-CPT performance by selectively reducing aspects of inappropriate responding. These findings provide evidence to support the hypothesis that novel therapies targeting the dopamine D1 receptor system could improve aspects of attentional deficits in schizophrenia patients. PMID:26658514

  13. A multicenter, open-label phase II study of recombinant CPT (Circularly Permuted TRAIL) plus thalidomide in patients with relapsed and refractory multiple myeloma.

    PubMed

    Geng, Chuanying; Hou, Jian; Zhao, Yaozhong; Ke, Xiaoyan; Wang, Zhao; Qiu, Lugui; Xi, Hao; Wang, Fuxu; Wei, Na; Liu, Yan; Yang, Shifang; Wei, Peng; Zheng, Xiangjun; Huang, Zhongxia; Zhu, Bing; Chen, Wen-Ming

    2014-11-01

    Circularly permuted TRAIL (CPT), a recombinant mutant of human Apo2L/TRAIL, is a novel antitumor candidate for multiple myeloma (MM) and other hematologic malignancies. In this phase II study, the safety and efficacy of CPT plus thalidomide was investigated in thalidomide-resistant MM patients. A total of 43 patients were recruited into three CPT plus thalidomide cohorts based on CPT dosage in sequence: 5 mg/kg (n = 11), 8 mg/kg (n = 17), and 10 mg/kg (n = 15). CPT was administered via intravenous infusion on days 1-5, and thalidomide was given orally at 100 mg once daily in each 21-day cycle. The overall response rate (ORR) of 41 efficacy-evaluable patients was 22.0% (2 complete response, 3 near complete response, and 4 partial response). No significant difference in the ORR was observed among the three dose cohorts; however, the ORR tended to be higher with the higher-dose regimen. Median progression-free survival and median duration of response were 6.6 months and 6.1 months, respectively. The most common treatment-related adverse events (TRAEs) were neutropenia (46.5%), leukopenia (41.9%), fever (37.2%), elevated AST (32.6%), and elevated ALT (20.9%). TRAEs of Grade 3-4 were mainly neutropenia (18.6%), anemia (9.3%), elevated AST (7.0%), and leukopenia (4.7%). No significant differences were found in the incidence and severity of TRAEs among the three cohorts. In conclusion, CPT plus thalidomide was well tolerated with no occurrence of dose-limiting toxicities and demonstrated promising antitumor activity in RRMM patients. CPT at 10 mg/kg for 5 days in combination with thalidomide and dexamethason will be studied in the next clinical trial.

  14. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts.

    PubMed

    Prewett, Marie C; Hooper, Andrea T; Bassi, Rajiv; Ellis, Lee M; Waksal, Harlan W; Hicklin, Daniel J

    2002-05-01

    Colon carcinomas frequently express the epidermal growth factor receptor (EGFR), and this expression correlates with more aggressive disease and poor prognosis. Previous studies have shown that EGFR blockade by monoclonal antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these tumors in athymic mice. In this report, we have studied the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice. IMC-C225 was tested at a dose of 1 or 0.5 mg administered q3d. CPT-11 was administered at a dose of 100 mg/kg/week or a maximum tolerated dose of 150 mg/kg/week. Treatment with the combination of IMC-C225 (1 and 0.5 mg) and CPT-11 (100 mg/kg) significantly inhibited the growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (P < 0.05). Combination therapy with IMC-C225 (1 mg) and the MTD of CPT-11 (150 mg/kg) resulted in a regression rate of 100 and 60% of established DLD-1 and HT-29 tumors, respectively. In a refractory tumor model, combined treatment with IMC-C225 and CPT-11 significantly inhibited the growth of CPT-11 refractory DLD-1 and HT-29 tumors, whereas either agent alone did not control tumor growth. Histological examination of treated tumors showed extensive tumor necrosis, decreased tumor cell proliferation, increased tumor cell apoptosis, and a marked decrease in tumor vasculature. These results suggest that EGFR blockade by IMC-C225 combined with topoisomerase I inhibitors may be an effective therapy against chemorefractory colorectal carcinoma tumors.

  15. Topoisomerase I-mediated DNA cleavage as a guide to the development of antitumor agents derived from the marine alkaloid lamellarin D: triester derivatives incorporating amino acid residues.

    PubMed

    Tardy, Christelle; Facompré, Michaël; Laine, William; Baldeyrou, Brigitte; García-Gravalos, Dolores; Francesch, Andrés; Mateo, Cristina; Pastor, Alfredo; Jiménez, José A; Manzanares, Ignacio; Cuevas, Carmen; Bailly, Christian

    2004-04-01

    The marine alkaloid lamellarin D (LAM-D) has been recently characterized as a potent poison of human topoisomerase I endowed with remarkable cytotoxic activities against tumor cells. We report here the first structure-activity relationship study in the LAM-D series. Two groups of triester compounds incorporating various substituents on the three phenolic OH at positions 8, 14 and 20 of 6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one pentacyclic planar chromophore typical of the parent alkaloid were tested as topoisomerase I inhibitors. The non-amino compounds in group A showed no activity against topoisomerase I and were essentially non cytotoxic. In sharp contrast, compounds in group B incorporating amino acid residues strongly promoted DNA cleavage by human topoisomerase I. LAM-D derivatives tri-substituted with leucine, valine, proline, phenylalanine or alanine residues, or a related amino side chain, stabilize topoisomerase I-DNA complexes. The DNA cleavage sites detected at T downward arrow G or C downward arrow G dinucleotides with these molecules were identical to that of LAM-D but slightly different from those seen with camptothecin which stimulates topoisomerase I-mediated cleavage at T downward arrow G only. In the DNA relaxation and cleavage assays, the corresponding Boc-protected compounds and the analogues of the non-planar LAM-501 derivative lacking the 5-6 double bond in the quinoline B-ring showed no effect on topoisomerase I and were considerably less cytotoxic than the corresponding cationic compounds in the LAM-D series. The presence of positive charges on the molecules enhances DNA interaction but melting temperature studies indicate that DNA binding is not correlated with topoisomerase I inhibition or cytotoxicity. Cell growth inhibition by the 41 lamellarin derivatives was evaluated with a panel of tumor cells lines. With prostate (DU-145 and LN-CaP), ovarian (IGROV and IGROV-ET resistant to ecteinascidin-743) and colon (LoVo and

  16. Search for CPT and Lorentz Violation in B0-B0bar Oscillations with Inclusive Dilepton Events

    SciTech Connect

    Aubert, B.

    2006-09-26

    We report preliminary results of a search for CPT and Lorentz violation in B{sup 0}-{bar B}{sup 0} oscillations using an inclusive dilepton sample collected by the BABAR experiment at the PEP-II B Factory. Using a sample of 232 million B{bar B} pairs, we search for time-dependent variations in the complex CPT parameter z = z{sub 0} +z{sub 1} cos ({Omega}{cflx t} + {phi}) where {Omega} is the Earth's sidereal frequency and {cflx t} is sidereal time. We measure Imz{sub 0} = (-14.1 {+-} 7.3(stat.) {+-} 2.4(syst.)) x 10{sup -3}, {Delta}{Lambda} x Rez{sub 0} = (-7.2 {+-} 4.1(stat.) {+-} 2.1(syst.)) x 10{sup -3} ps{sup -1}, Im z{sub 1} = (-24.0 {+-} 10.7(stat.) {+-} 5.9(syst.)) x 10{sup -3}, and {Delta}{Lambda} x Re z{sub 1} = (-18.8 {+-} 5.5(stat.) {+-} 4.0(syst.)) x 10{sup -3} ps{sup -1}, where {Delta}{Lambda} is the difference between the decay rates of the neutral B mass eigenstates. The statistical correlation between the measurements of Imz{sub 0} and {Delta}{Lambda} x Rez{sub 0} is 76%; between Imz{sub 1} and {Delta}{Lambda} x Rez{sub 1} it is 79%. These results are used to evaluate expressions involving coefficients for Lorentz and CPT violation in the general Lorentz-violating standard-model extension. In a complementary approach, we examine the spectral power of periodic variations in z over a wide range of frequencies and find no significant signal.

  17. Indole alkaloids from Vinca major and V. minor growing in Turkey.

    PubMed

    Bahadori, Fatemeh; Topçu, Gülaçti; Boğa, Mehmet; Türkekul, Ayla; Kolak, Ufuk; Kartal, Murat

    2012-06-01

    A new indole alkaloid, 11-hydroxypolyneuridine, was isolated from Vinca major subsp. major L. and the known indole alkaloids vallesiachotamine and isovallesiachotamine from Vinca minor L. This is the first report on the alkaloids of both Vinca species growing in Turkey; vallesiachotamine and isovallesiachotamine were isolated from a Vinca species for the first time. V. minor may be considered as a new source for these two alkaloids due to their occurrence in high amount in the aerial parts of the plant. The alkaloid extracts of the two Vinca species were found to have high lipid peroxidation inhibitory and DPPH radical scavenging activities. Anticholinesterase activity of the extracts was also very strong.

  18. Mobilization of the Vibrio pathogenicity island between Vibrio cholerae isolates mediated by CP-T1 generalized transduction.

    PubMed

    O'Shea, Yvonne A; Boyd, E Fidelma

    2002-09-10

    Pathogenicity islands are large chromosomal regions encoding virulence genes that were acquired by horizontal gene transfer and are found in a wide range of pathogenic bacteria. In toxigenic Vibrio cholerae isolates the receptor for the cholera toxin encoding filamentous phage CTXphi, the toxin-coregulated pilus, is part of the Vibrio pathogenicity island (VPI). In this paper, we show that the VPI can be transferred between O1 serogroup strains, the predominant cause of epidemic cholera, via a generalized transducing phage CP-T1.

  19. In situ pore-pressure evolution during dynamic CPT measurements in soft sediments of the western Baltic Sea

    NASA Astrophysics Data System (ADS)

    Seifert, Annedore; Stegmann, Sylvia; Mörz, Tobias; Lange, Matthias; Wever, Thomas; Kopf, Achim

    2008-08-01

    We present in situ strength and pore-pressure measurements from 57 dynamic cone penetration tests in sediments of Mecklenburg ( n = 51), Eckernförde ( n = 2) and Gelting ( n = 4) bays, western Baltic Sea, characterised by thick mud layers and partially free microbial gas resulting from the degradation of organic material. In Mecklenburg and Eckernförde bays, sediment sampling by nine gravity cores served sedimentological characterisation, analyses of geotechnical properties, and laboratory shear tests. At selected localities, high-resolution echo-sounder profiles were acquired. Our aim was to deploy a dynamic cone penetrometer (CPT) to infer sediment shear strength and cohesion of the sea bottom as a function of fluid saturation. The results show very variable changes in pore pressure and sediment strength during the CPT deployments. The majority of the CPT measurements ( n = 54) show initially negative pore-pressure values during penetration, and a delayed response towards positive pressures thereafter. This so-called type B pore-pressure signal was recorded in all three bays, and is typically found in soft muds with high water contents and undrained shear strengths of 1.6-6.4 kPa. The type B signal is further affected by displacement of sediment and fluid upon penetration of the lance, skin effects during dynamic profiling, enhanced consolidation and strength of individual horizons, the presence of free gas, and a dilatory response of the sediment. In Mecklenburg Bay, the remaining small number of CPT measurements ( n = 3) show a well-defined peak in both pore pressure and cone resistance during penetration, i.e. an initial marked increase which is followed by exponential pore-pressure decay during dissipation. This so-called type A pore-pressure signal is associated with normally consolidated mud, with indurated clay layers showing significantly higher undrained shear strength (up to 19 kPa). In Eckernförde and Gelting bays pore-pressure response type B is

  20. Exact Foldy-Wouthuysen transformation for a Dirac spinor in torsion and other CPT and Lorentz violating backgrounds

    SciTech Connect

    Goncalves, Bruno; Shapiro, Ilya L.; Obukhov, Yuri N.

    2009-12-15

    We discuss the possibility to perform and use the exact Foldy-Wouthuysen transformation (EFWT) for the Dirac spinor coupled to different CPT and Lorentz violating terms. The classification of such terms is performed, selecting those of them which admit EFWT. For the particular example of an axial vector field, which can be associated with the completely antisymmetric torsion, we construct an explicit EFWT in the case when only a timelike component of this axial vector is present. In the cases when EFWT is not possible, one can still use the corresponding technique for deriving the perturbative Foldy-Wouthuysen transformation, as is illustrated in a particular example in the Appendix.

  1. [Effects of steaming and baking on content of alkaloids in Aconite Lateralis Radix (Fuzi)].

    PubMed

    Yang, Chang-lin; Huang, Zhi-fang; Zhang, Yi-han; Liu, Yu-hong; Liu, Yun-huan; Chen, Yan; Yi, Jin-hai

    2014-12-01

    To study the effect of steaming and baking process on contents of alkaloids in Aconite Lateralis Radix (Fuzi), 13 alkaloids were analyzed by UPLC-MS/MS equipped with ESI ion source in MRM mode. In steaming process, the contents of diester-diterpenoid alkaloids decreased rapidly, the contents of monoester-diterpenoid alkaloids firstly increased, reached the peak at 40 min, and then deceased gradually. The contents of aconine alkaloids (mesaconine, aconine and hypaconine) increased all the time during processing, while the contents of fuziline, songorine, karacoline, salsolionl were stable or slightly decreased. In baking process, dynamic variations of alkaloids were different from that in the steaming process. Diester-diterpenoid alkaloids were degraded slightly slower than in steaming process. Monoester-diterpenoid alkaloids, aconine alkaloids and the total alkaloids had been destroyed at different degrees, their contents were significantly lower than the ones in steaming Fuzi at the same processing time. This experiment revealed the dynamic variations of alkaloids in the course of steaming and baking. Two processing methods which can both effectively remove the toxic ingredients and retain the active ingredients are simple and controllable, and are valuable for popularization and application.

  2. Alkaloids in the human food chain--natural occurrence and possible adverse effects.

    PubMed

    Koleva, Irina I; van Beek, Teris A; Soffers, Ans E M F; Dusemund, Birgit; Rietjens, Ivonne M C M

    2012-01-01

    Alkaloid-containing plants are an intrinsic part of the regular Western diet. The present paper summarizes the occurrence of alkaloids in the food chain, their mode of action and possible adverse effects including a safety assessment. Pyrrolizidine alkaloids are a reason for concern because of their bioactivation to reactive alkylating intermediates. Several quinolizidine alkaloids, β-carboline alkaloids, ergot alkaloids and steroid alkaloids are active without bioactivation and mostly act as neurotoxins. Regulatory agencies are aware of the risks and have taken or are considering appropriate regulatory actions for most alkaloids. These vary from setting limits for the presence of a compound in feed, foods and beverages, trying to define safe upper limits, advising on a strategy aiming at restrictions in use, informing the public to be cautious or taking specific plant varieties from the market. For some alkaloids known to be present in the modern food chain, e.g., piperine, nicotine, theobromine, theophylline and tropane alkaloids risks coming from the human food chain are considered to be low if not negligible. Remarkably, for many alkaloids that are known constituents of the modern food chain and of possible concern, tolerable daily intake values have so far not been defined.

  3. Alkaloids from single skins of the Argentinian toad Melanophryniscus rubriventris (ANURA, BUFONIDAE): An unexpected variability in alkaloid profiles and a profusion of new structures.

    PubMed

    Garraffo, H Martin; Andriamaharavo, Nirina R; Vaira, Marcos; Quiroga, María F; Heit, Cecilia; Spande, Thomas F

    2012-12-01

    GC-MS analysis of single-skins of ten Melanophryniscus rubriventris toads (five collections of two toads each) captured during their breeding season in NW Argentina has revealed a total of 127 alkaloids of which 56 had not been previously detected in any frog or toad. Included among these new alkaloids are 23 new diastereomers of previously reported alkaloids. What is particularly distinguishing about the alkaloid profiles of these ten collections is the occurrence of many of the alkaloids, whether known or new to us, in only one of the ten skins sampled, despite two skins being obtained from each breeding site of the five populations. Many of the alkaloids are of classes known to have structures with branched-chains (e.g. pumiliotoxins and tricyclic structures) that are considered to derive from dietary mites. A large number of previously reported and new alkaloids are also of unclassified structures. Only a very few 3,5-disubstituted-indolizidine or -pyrrolizidine alkaloids are observed that have a straight-chain carbon skeleton and are likely derived from ant prey. The possible relationship of these collections made during the toad's brief breeding episodes to sequestration of dietary arthropods and individual alkaloid profiles is discussed.

  4. Pyrrolizidine alkaloids from Symphytum officinale L. and their percutaneous absorption in rats.

    PubMed

    Brauchli, J; Lüthy, J; Zweifel, U; Schlatter, C

    1982-09-15

    An analysis of a commercial sample of Symphyti radix originating from Poland with a total alkaloid content of 0.07% revealed the presence of 7 pyrrolizidine alkaloid-N-oxides: 7-acetyl intermedine, 7-acetyl lycopsamine as the main constituents and lycopsamine, intermedine, symphytine and traces of 2 further not yet identified alkaloids. The percutaneous absorption of these alkaloids was investigated in rats, using a crude alcoholic extract of the plant corresponding to a dose of 194 mg alkaloid-N-oxides/kg b.wt. The excretion of N-oxides in the urine during 2 days was in the range of 0.1-0.4% of the dose. The dermally absorbed N-oxides are not or only to a small extent converted to the free alkaloids in the organism. The oral application led to a 20-50 times higher excretion of N-oxides and free alkaloids in the urine. PMID:7128756

  5. Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale).

    PubMed

    Couet, C E; Crews, C; Hanley, A B

    1996-01-01

    Pyrrolizidine alkaloids have been linked to liver and lung cancers and a range of other deleterious effects. As with many natural toxicants, major problems arise in determining the effects of the different members of the class and the importance of various forms of ingestion. In this study we have investigated the levels of pyrrolizidine alkaloids in comfrey (Symphytum officinale), determined the levels in different parts of the plant and in herbal remedies, separated the alkaloids into two main groups--the principal parent alkaloids and the corresponding N-oxides--and, finally, carried out a simple bioassay based upon the mutagenic capability of the separated compounds in a human cell line. We conclude that the part of the plant ingested is important in terms of alkaloid challenge and that the effect of two of the major groups of alkaloids individually is different from that of alkaloids in the whole plant extract. PMID:8887946

  6. Histochemical Investigation and Kinds of Alkaloids in Leaves of Different Developmental Stages in Thymus quinquecostatus

    PubMed Central

    Jing, Haiting; Liu, Jing; Liu, Hanzhu; Xin, Hua

    2014-01-01

    Thymus quinquecostatus, with more medical value, is a kind of wild plants. In order to exploit and utilize this plant, we studied the species and locations of alkaloids in its leaves. In this paper, histochemical study of leaves at different developing stages was taken to localize the alkaloids. Meanwhile, the kinds and content of alkaloids in leaves were identified using GC-MS technique. It was found that there were two kinds of glandular trichomes, namely, peltate trichomes and capitate trichomes, on the surface of leaves, and their secretory cells could secrete alkaloids. Results showed that trichomes could secrete alkaloids as soon as the first pair of leaves formed, and there were altogether 18 kinds of alkaloids identified by GC-MS. Nearly all of these alkaloids of leaves at different developing stages were distinct from each other, except one, 3-methoxy-a-methyl-benzeneethanamine, persists at different developing stages with high concentration. PMID:25101324

  7. Diversification of Ergot Alkaloids in Natural and Modified Fungi

    PubMed Central

    Robinson, Sarah L.; Panaccione, Daniel G.

    2015-01-01

    Several fungi in two different families––the Clavicipitaceae and the Trichocomaceae––produce different profiles of ergot alkaloids, many of which are important in agriculture and medicine. All ergot alkaloid producers share early steps before their pathways diverge to produce different end products. EasA, an oxidoreductase of the old yellow enzyme class, has alternate activities in different fungi resulting in branching of the pathway. Enzymes beyond the branch point differ among lineages. In the Clavicipitaceae, diversity is generated by the presence or absence and activities of lysergyl peptide synthetases, which interact to make lysergic acid amides and ergopeptines. The range of ergopeptines in a fungus may be controlled by the presence of multiple peptide synthetases as well as by the specificity of individual peptide synthetase domains. In the Trichocomaceae, diversity is generated by the presence or absence of the prenyl transferase encoded by easL (also called fgaPT1). Moreover, relaxed specificity of EasL appears to contribute to ergot alkaloid diversification. The profile of ergot alkaloids observed within a fungus also is affected by a delayed flux of intermediates through the pathway, which results in an accumulation of intermediates or early pathway byproducts to concentrations comparable to that of the pathway end product. PMID:25609183

  8. Ergovaline, an endophytic alkaloid. 1. Animal physiology and metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ergovaline is an ergot alkaloid found in some endophyte-infected ryegrasses and has been implicated in the expression of ergotism-like symptoms of grazing livestock, as well as in the protection of the plant against invertebrate predation and abiotic stresses. These selection pressures have resulted...

  9. The alkaloid profiles of Sophora nuttalliana and Sophora stenophylla

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sophora is a diverse genus in the family Fabaceae, comprised of herbs, shrubs, and trees that occurs throughout the world, primarily in the northern hemisphere. Species of Sophora are known to contain quinolizidine alkaloids that are toxic and potentially teratogenic. Two perennial herbaceous spec...

  10. Two new Lycopodium alkaloids from Phlegmariurus phlegmaria (L.) Holub.

    PubMed

    Wang, Zhichong; Wu, Jichun; Zhao, Ningdong; Yang, Yiyu; Chen, Yegao

    2016-01-01

    Two new Lycopodium alkaloids, 4β-hydroxynankakurine B (1) and Δ(13,N),N(α)-methylphlegmarine-N(β)-oxide (2), together with three known analogues, lycoposerramine E (3), nankakurine B (4) and lobscurinol (5), were isolated from Phlegmariurus phlegmaria. Their structures were established by mass spectrometry and 1D and 2D NMR techniques.

  11. Two new C19-diterpenoid alkaloids from Aconitum straminiflorum.

    PubMed

    Qi, Yan; Zhao, Da-Ke; Zi, Shu-Hui; Zhang, Li-Mei; Guo, Cheng-Xing; Li, Gui-Qiong; Xun, Jun-Ju; Shen, Yong

    2016-01-01

    Two new C19-diterpenoid alkaloids, straconitines A (1) and B (2), were isolated from the roots of Aconitum straminiflorum. Their structures were elucidated as 14-benzoylducloudine D (1) and 6-hydroxy-14-benzoylducloudine D (2) based on spectroscopic analysis, including IR, ESI-MS, HR-ESI-MS, 1D, and 2D NMR.

  12. Effect of Ergot Alkaloids on Bovine Foregut Vasculature

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ergot alkaloids induce vasoconstriction of bovine foregut vasculature. Ergovaline induced the greatest response in ruminal artery while ergovaline and ergotamine induced the greatest response in ruminal vein. Lysergic acid did not stimulate a contractile response in either the ruminal artery or vein...

  13. Alkaloid profiling and anticholinesterase activity of South American Lycopodiaceae species.

    PubMed

    Konrath, Eduardo Luis; Ortega, María Gabriela; de Loreto Bordignon, Sérgio; Apel, Miriam Anders; Henriques, Amélia Teresinha; Cabrera, José Luis

    2013-02-01

    The alkaloid extracts of four Huperzia and one Lycopodiella species, from Brazilian habitats, were tested for their in vitro anticholinesterase activities. IC(50) values showed a potent acetylcholinesterase inhibition for H. reflexa (0.11 ± 0.05 μg/mL), followed by H. quadrifariata (2.0 ± 0.3 μg/mL), H. acerosa (5.5 ± 0.9 μg/mL), H. heterocarpon (25.6 ± 2.7 μg/mL) and L. cernua (42.6 ± 1.5 μg/mL). A lower inhibition of butyrylcholinesterase was observed for all species with the exception of H. heterocarpon (8.3 ± 0.9 μg/mL), whose alkaloid extract presented a selectivity for pseudocholinesterase. Moreover, the chemical study of the bioactive extracts performed by GC-MS, revealed the presence of a number of Lycopodium alkaloids belonging to the lycopodane, flabellidane and cernuane groups. Surprisingly, the potent acetylcholinesterase inhibitors huperzines A and B were not detected in the extracts, suggesting that other alkaloids may be responsible for such an effect. PMID:22117191

  14. The Raputindoles: Novel Cyclopentyl Bisindole Alkaloids from Raputia simulans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A novel class of bisindole alkaloids is established by the isolation and structural determination of Raputindoles A-D (1-4) from the Amazonian plant Raputia simulans Kallunki (Rutaceae). Complete spectroscopic characterization was accomplished by means of NMR spectroscopy and APCI (+) HRMS. Raputind...

  15. Pyrrolizidine alkaloids in food: A spectrum of potential health consequences

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Contamination of grain with 1,2-dehydropyrrolizidine ester alkaloids (dehydroPAs) and their N-oxides is responsible for large incidents of acute and subacute food poisoning, with high morbidity and mortality, in Africa and in central and south Asia. Herbal medicines and teas containing dehydroPAs ha...

  16. Revised NMR data for incartine: an alkaloid from Galanthus elwesii.

    PubMed

    Berkov, Strahil; Reyes-Chilpa, Ricardo; Codina, Carles; Viladomat, Francesc; Bastida, Jaume

    2007-07-12

    Phytochemical studies on Galanthus elwesii resulted in the isolation of five alkaloids: incartine, hordenine, hippeastrine, 8-O-demethylhomolycorine and lycorine. The NMR data given previously for incartine were revised and completed by two-dimensional 1H-1H and 1H-13C chemical shift correlation experiments. In vitro studies on the bioactivity of incartine were carried out.

  17. Biosynthesis of the defensive alkaloid cicindeloine in Stenus solutus beetles

    NASA Astrophysics Data System (ADS)

    Schierling, Andreas; Dettner, Konrad; Schmidt, Jürgen; Seifert, Karlheinz

    2012-08-01

    To protect themselves from predation and microorganismic infestation, rove beetles of the genus Stenus produce and store bioactive alkaloids like stenusine, 3-(2-methyl-1-butenyl)pyridine, and cicindeloine in their pygidial glands. The biosynthesis of stenusine and 3-(2-methyl-1-butenyl)pyridine was previously investigated in Stenus bimaculatus and Stenus similis, respectively. Both molecules follow the same biosynthetic pathway, where the N-heterocyclic ring is derived from l-lysine and the side chain from l-isoleucine. The different alkaloids are finally obtained by slight modifications of shared precursor molecules. The piperideine alkaloid cicindeloine occurs as a main compound additionally to ( E)-3-(2-methyl-1-butenyl)pyridine and traces of stenusine in the pygidial gland secretion of Stenus cicindeloides and Stenus solutus. Feeding of S. solutus beetles with [D,15N]-labeled amino acids followed by GC/MS analysis techniques showed that cicindeloine is synthesized via the identical pathway and precursor molecules as the other two defensive alkaloids.

  18. Two new antifungal alkaloids produced by Streptoverticillium morookaense.

    PubMed

    Feng, Na; Ye, Wanhui; Wu, Ping; Huang, Yicun; Xie, Haihui; Wei, Xiaoyi

    2007-03-01

    A new carbazole alkaloid, streptoverticillin, and a new 2-azetidinone, streptoverticillinone, along with three known cyclodipeptides were isolated from the mycelial solid culture of Streptoverticillium morookaense. Their structures were elucidated by analysis of 1D and 2D NMR, mass spectra and optical rotation data. Two new compounds exhibited antifungal activity against Peronophythora litchii. PMID:17446689

  19. In vitro cytotoxicity of various dehydropyrrolizidine ester alkaloids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dehydropyrrolizidine alkaloids (DHPAs) are plant-derived hepato-, pneumo- and geno-toxins that are carcinogenic in several species. Because of the difficulty in isolating sufficient DHPA for toxicological studies, there are few direct comparisons of toxicity. The objectives of this study was to de...

  20. Genetic variation of piperidine alkaloids in Pinus ponderosa: a common garden study

    PubMed Central

    Gerson, Elizabeth A.; Kelsey, Rick G.; St Clair, J. Bradley

    2009-01-01

    Background and Aims Previous measurements of conifer alkaloids have revealed significant variation attributable to many sources, environmental and genetic. The present study takes a complementary and intensive, common garden approach to examine genetic variation in Pinus ponderosa var. ponderosa alkaloid production. Additionally, this study investigates the potential trade-off between seedling growth and alkaloid production, and associations between topographic/climatic variables and alkaloid production. Methods Piperidine alkaloids were quantified in foliage of 501 nursery seedlings grown from seed sources in west-central Washington, Oregon and California, roughly covering the western half of the native range of ponderosa pine. A nested mixed model was used to test differences among broad-scale regions and among families within regions. Alkaloid concentrations were regressed on seedling growth measurements to test metabolite allocation theory. Likewise, climate characteristics at the seed sources were also considered as explanatory variables. Key Results Quantitative variation from seedling to seedling was high, and regional variation exceeded variation among families. Regions along the western margin of the species range exhibited the highest alkaloid concentrations, while those further east had relatively low alkaloid levels. Qualitative variation in alkaloid profiles was low. All measures of seedling growth related negatively to alkaloid concentrations on a natural log scale; however, coefficients of determination were low. At best, annual height increment explained 19·4 % of the variation in ln(total alkaloids). Among the climate variables, temperature range showed a negative, linear association that explained 41·8 % of the variation. Conclusions Given the wide geographic scope of the seed sources and the uniformity of resources in the seedlings' environment, observed differences in alkaloid concentrations are evidence for genetic regulation of alkaloid

  1. High fructose consumption induces DNA methylation at PPARα and CPT1A promoter regions in the rat liver.

    PubMed

    Ohashi, Koji; Munetsuna, Eiji; Yamada, Hiroya; Ando, Yoshitaka; Yamazaki, Mirai; Taromaru, Nao; Nagura, Ayuri; Ishikawa, Hiroaki; Suzuki, Koji; Teradaira, Ryoji; Hashimoto, Shuji

    DNA methylation status is affected by environmental factors, including nutrition. Fructose consumption is considered a risk factor for the conditions that make up metabolic syndrome such as dyslipidemia. However, the pathogenetic mechanism by which fructose consumption leads to metabolic syndrome is unclear. Based on observations that epigenetic modifications are closely related to induction of metabolic syndrome, we hypothesized that fructose-induced metabolic syndrome is caused by epigenetic alterations. Male SD rats were designated to receive water or 20% fructose solution for 14 weeks. mRNA levels for peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) was analyzed using Real-time PCR. Restriction digestion and real-time PCR (qAMP) was used for the analysis of DNA methylation status. Hepatic lipid accumulation was also observed by fructose intake. Fructose feeding also significantly decreased mRNA levels for PPARα and CPT1A. qAMP analysis demonstrated the hypermethylation of promoter regions of PPARα and CTP1A genes. Fructose-mediated attenuated gene expression may be mediated by alterations of DNA methylation status, and pathogenesis of metabolic syndrome induced by fructose relates to DNA methylation status.

  2. High fructose consumption induces DNA methylation at PPARα and CPT1A promoter regions in the rat liver.

    PubMed

    Ohashi, Koji; Munetsuna, Eiji; Yamada, Hiroya; Ando, Yoshitaka; Yamazaki, Mirai; Taromaru, Nao; Nagura, Ayuri; Ishikawa, Hiroaki; Suzuki, Koji; Teradaira, Ryoji; Hashimoto, Shuji

    DNA methylation status is affected by environmental factors, including nutrition. Fructose consumption is considered a risk factor for the conditions that make up metabolic syndrome such as dyslipidemia. However, the pathogenetic mechanism by which fructose consumption leads to metabolic syndrome is unclear. Based on observations that epigenetic modifications are closely related to induction of metabolic syndrome, we hypothesized that fructose-induced metabolic syndrome is caused by epigenetic alterations. Male SD rats were designated to receive water or 20% fructose solution for 14 weeks. mRNA levels for peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) was analyzed using Real-time PCR. Restriction digestion and real-time PCR (qAMP) was used for the analysis of DNA methylation status. Hepatic lipid accumulation was also observed by fructose intake. Fructose feeding also significantly decreased mRNA levels for PPARα and CPT1A. qAMP analysis demonstrated the hypermethylation of promoter regions of PPARα and CTP1A genes. Fructose-mediated attenuated gene expression may be mediated by alterations of DNA methylation status, and pathogenesis of metabolic syndrome induced by fructose relates to DNA methylation status. PMID:26519879

  3. A CPT-based Cs vapor cell atomic clock with a short-term fractional frequency stability of 3 x 10-13 τ-1/2

    NASA Astrophysics Data System (ADS)

    Abdel Hafiz, Moustafa; Liu, Xiaochi; Guérandel, Stéphane; De Clercq, Emeric; Boudot, Rodolphe

    2016-06-01

    This article reports on the development and short-term fractional frequency stability of a continuous-regime (CW) Cs vapor cell atomic clock based on coherent population trapping (CPT). The push-pull optical pumping technique is used to increase the number of atoms that participate to the clock transition, yielding a typical CPT resonance contrast of 25% for a CPT linewidth of about 450 Hz. The clock short-term fractional frequency stability is measured to be 3 x 10-13 τ-1/2 up to 100 seconds averaging time, in correct agreement with the signal-to-noise ratio limit. The mid-term frequency stability results are currently mainly limited by laser power effects. The detection of high-contrast narrow Raman-Ramsey fringes is demonstrated with this setup by making the atoms interact with a light pulse sequence.

  4. Ergot Alkaloids Produced by Endophytic Fungi of the Genus Epichloë

    PubMed Central

    Guerre, Philippe

    2015-01-01

    The development of fungal endophytes of the genus Epichloë in grasses results in the production of different groups of alkaloids, whose mechanism and biological spectrum of toxicity can differ considerably. Ergot alkaloids, when present in endophyte-infected tall fescue, are responsible for “fescue toxicosis” in livestock, whereas indole-diterpene alkaloids, when present in endophyte-infected ryegrass, are responsible for “ryegrass staggers”. In contrast, peramine and loline alkaloids are deterrent and/or toxic to insects. Other toxic effects in livestock associated with the consumption of endophyte-infected grass that contain ergot alkaloids include the “sleepy grass” and “drunken horse grass” diseases. Although ergovaline is the main ergopeptine alkaloid produced in endophyte-infected tall fescue and is recognized as responsible for fescue toxicosis, a number of questions still exist concerning the profile of alkaloid production in tall fescue and the worldwide distribution of tall fescue toxicosis. The purpose of this review is to present ergot alkaloids produced in endophyte-infected grass, the factors of variation of their level in plants, and the diseases observed in the mammalian species as relate to the profiles of alkaloid production. In the final section, interactions between ergot alkaloids and drug-metabolizing enzymes are presented as mechanisms that could contribute to toxicity. PMID:25756954

  5. Ergot alkaloids produced by endophytic fungi of the genus Epichloë.

    PubMed

    Guerre, Philippe

    2015-03-01

    The development of fungal endophytes of the genus Epichloë in grasses results in the production of different groups of alkaloids, whose mechanism and biological spectrum of toxicity can differ considerably. Ergot alkaloids, when present in endophyte-infected tall fescue, are responsible for "fescue toxicosis" in livestock, whereas indole-diterpene alkaloids, when present in endophyte-infected ryegrass, are responsible for "ryegrass staggers". In contrast, peramine and loline alkaloids are deterrent and/or toxic to insects. Other toxic effects in livestock associated with the consumption of endophyte-infected grass that contain ergot alkaloids include the "sleepy grass" and "drunken horse grass" diseases. Although ergovaline is the main ergopeptine alkaloid produced in endophyte-infected tall fescue and is recognized as responsible for fescue toxicosis, a number of questions still exist concerning the profile of alkaloid production in tall fescue and the worldwide distribution of tall fescue toxicosis. The purpose of this review is to present ergot alkaloids produced in endophyte-infected grass, the factors of variation of their level in plants, and the diseases observed in the mammalian species as relate to the profiles of alkaloid production. In the final section, interactions between ergot alkaloids and drug-metabolizing enzymes are presented as mechanisms that could contribute to toxicity.

  6. Ergot alkaloids--biology and molecular biology.

    PubMed

    Schardl, Christopher L; Panaccione, Daniel G; Tudzynski, Paul

    2006-01-01

    EA have been a major benefit, and a major detriment, to humans since early in recorded history. Their medicinal properties have been used, and continue to be used, to aid in childbirth, with new uses being found in the treatment of neurological and cardiovascular disorders. The surprisingly broad range of pharmaceutical uses for EA stems from their affinities for multiple receptors for three distinct neurotransmitters (serotonin, dopamine, and adrenaline), from the great structural diversity of natural EA, and from the application of chemical techniques that further expand that structural diversity. The dangers posed by EA to humans and their livestock stem from the ubiquity of ergot fungi (Claviceps species) as parasites of cereals, and of related grass endophytes (Epichloë, Neotyphodium, and Balansia species) that may inhabit pasture grasses and produce toxic levels of EA. Further concerns stem from saprophytic EA producers in the genera Aspergillus and Penicillium, especially A. fumigatus, an opportunistic pathogen of humans. Numerous fungal species produce EA with a wide variety of structures and properties. These alkaloids are associated with plants in the families Poaceae, Cyperaceae, and Convolvulaceae, apparently because these plants can have symbiotic fungi that produce EA. Pharmacological activities of EA relate to their specific structures. Known as potent vasoconstrictors, the ergopeptines include a lysergic acid substituent with an amide linkage to a complex cyclol-lactam ring structure generated from three amino acids. Simpler lysergyl amides and clavines are more apt to have oxytonic or psychotropic activities. One of the lysergyl amides is LSD (5), the most potent hallucinogen known. The EA biosynthetic pathway in Claviceps species has been studied extensively for many decades, and recent studies have also employed epichloës and A. fumigatus. The early pathway, shared among these fungi, begins with the action of an aromatic prenyl transferase

  7. Comparison of Liquefaction Potential Index Values Obtained from Using SPT and CPT Data, A Case Study Tepebasi-Eskisehir

    NASA Astrophysics Data System (ADS)

    Mutlu, Sunay; Pekkan, Emrah; Tün, Muammer; Güney, Yücel

    2015-04-01

    Turkey is inside an area which is very active regarding earthquakes, it is merely related to Turkey's geological and tectonic location on Earth. Therefore, it is very important for studies to be conducted to prevent and maximize the reduction of the risk of earthquake damage may occur. Especially, determination of the dynamic properties of the soil and the local soil conditions is the most crucial study can be done for residential areas. Water saturated sand is a soil condition, which is most negatively affected by earthquakes. This type of soil becomes liquefied during the earthquakes, loses its strength and causes significant damage. Therefore, liquefaction analysis must be done before the earthquake happens and areas at risk should be determined. Then, rehabilitation works should be applied to those areas and thus it can prevent the damage due to liquefaction. The aim of this study is to determine and compare Eskişehir/Tepebaşı in regard of liquefaction potential of new alluvial units in the district by using Cone Penetration Test (CPT) and the SPT-N data. LPI values calculated by using 42 different CPT data and 53 different SPT-N data from boreholes. While liquefaction analysis is being processed, the SPT-N data was used in the method presented by Seed and Idriss (1971) and developed by Youd et al. (2001), the CPT data was used in the method developed by Wride Robertson (1998). Also, Eskişehir Fault Zone which may affect the study area have assumed that constitute the maximum horizontal ground acceleration of 0.3 g and this value was used on calculations. As earthquake magnitude in calculations, 02.20.1956 earthquake with 6.4 magnitude has been used. In result of this study both methods have been used for given area and liquefaction analysis has been done. Results of the analysis have been used to generate liquefaction risk maps in GIS environment. In addition, since groundwater levels are directly related to liquefaction, groundwater level models have been

  8. Complement-mediated antiinflammatory effect of bisbenzylisoquinoline alkaloid fangchinoline.

    PubMed

    Hristova, M; Istatkova, R

    1999-11-01

    Complement-mediated mode of action of bisbenzylisoquinoline alkaloid fangchinoline was investigated in vivo and in vitro. The application of fangchinoline intraperitoneally (i.p.) to complement normal mice, strain ICR, inhibited the complement activity in serum and peritoneal exudate. The substance activated serum complement of C5-deficient DBA/2 mice. Fangchinoline was able to provoke local inflammatory reaction in both strains after subcutaneous (s.c.) injection. The alkaloid suppressed paw swelling induced by live Candida albicans in ICR and DBA/2 mice. Its effect depended on the dose and time of injection prior to inflammatory reaction. The in vitro experiments proved the interference of fangchinoline action with post-C5 reactions. The substance augmented C5-convertase formation and functional activity. These results are in correspondence with our previous investigations, proving the complement-mediated action of fangchinoline. The antiinflammatory effect could be a consequence of the caused complement exhaustion. PMID:11962544

  9. Antimalarial benzylisoquinoline alkaloid from the rainforest tree Doryphora sassafras.

    PubMed

    Buchanan, Malcolm S; Davis, Rohan A; Duffy, Sandra; Avery, Vicky M; Quinn, Ronald J

    2009-08-01

    Mass-directed isolation of the CH(2)Cl(2)/MeOH extract of Doryphora sassafras resulted in the purification of a new benzylisoquinoline alkaloid, 1-(4-hydroxybenzyl)-6,7-methylenedioxy-2-methylisoquinolinium trifluoroacetate (1), and the known aporphine alkaloid (S)-isocorydine (2). The structures of 1 and 2 were determined by 1D and 2D NMR and MS data analyses. The compounds were isolated during a drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library. When tested against two different strains of the parasite Plasmodium falciparum (3D7 and Dd2), 1 displayed IC(50) values of 3.0 and 4.4 microM, respectively. Compound 1 was tested for cytotoxicity toward a human embryonic kidney cell line (HEK293) and displayed no activity at 120 microM.

  10. A submarine journey: the pyrrole-imidazole alkaloids.

    PubMed

    Forte, Barbara; Malgesini, Beatrice; Piutti, Claudia; Quartieri, Francesca; Scolaro, Alessandra; Papeo, Gianluca

    2009-11-27

    In his most celebrated tale "The Picture of Dorian Gray", Oscar Wilde stated that "those who go beneath the surface do so at their peril". This sentence could be a prophetical warning for the practitioner who voluntarily challenges himself with trying to synthesize marine sponge-deriving pyrrole-imidazole alkaloids. This now nearly triple-digit membered community has been growing exponentially in the last 20 years, both in terms of new representatives and topological complexity--from simple, achiral oroidin to the breathtaking 12-ring stylissadines A and B, each possessing 16 stereocenters. While the biosynthesis and the role in the sponge economy of most of these alkaloids still lies in the realm of speculations, significant biological activities for some of them have clearly emerged. This review will account for the progress in achieving the total synthesis of the more biologically enticing members of this class of natural products.

  11. A Submarine Journey: The Pyrrole-Imidazole Alkaloids

    PubMed Central

    Forte, Barbara; Malgesini, Beatrice; Piutti, Claudia; Quartieri, Francesca; Scolaro, Alessandra; Papeo, Gianluca

    2009-01-01

    In his most celebrated tale “The Picture of Dorian Gray”, Oscar Wilde stated that “those who go beneath the surface do so at their peril”. This sentence could be a prophetical warning for the practitioner who voluntarily challenges himself with trying to synthesize marine sponge-deriving pyrrole-imidazole alkaloids. This now nearly triple-digit membered community has been growing exponentially in the last 20 years, both in terms of new representatives and topological complexity – from simple, achiral oroidin to the breathtaking 12-ring stylissadines A and B, each possessing 16 stereocenters. While the biosynthesis and the role in the sponge economy of most of these alkaloids still lies in the realm of speculations, significant biological activities for some of them have clearly emerged. This review will account for the progress in achieving the total synthesis of the more biologically enticing members of this class of natural products. PMID:20098608

  12. Stereoselective interaction of cinchona alkaloid isomers with bovine serum albumin.

    PubMed

    Liu, Yan; Chen, Mingmao; Jiang, Longguang; Song, Ling

    2015-08-15

    The dependence of the interaction between bovine serum albumin (BSA) and two cinchona alkaloids, quinine (QN) and quinidine (QD), on the absolute configuration of these stereoisomers has been comprehensively studied. The FTIR spectra showed that QN and QD interacted with both CO and C-N groups of BSA, resulting in changes to the secondary structure of the protein. Fluorescence quenching of BSA by the stereoisomers revealed lower efficiency for QD in quenching the Trp emission of BSA when compared to QN. Further analysis accurately described the different binding behaviors and recognition discrepancies of QN and QD towards BSA, which was reflected through binding affinities, driving forces, energy changes and conformational changes during the ligand-protein interactions. Synchronous fluorescence further proved that QD was farther from Trp and Tyr than that of QN. This work could provide basic data for clarifying the binding interaction, metabolism and distribution of cinchona alkaloid stereoisomers in vivo.

  13. Synthesis and Antimicrobial Characterization of Half-Calycanthaceous Alkaloid Derivatives.

    PubMed

    Zheng, Shaojun; Zhou, Xinping; Xu, Shixun; Zhu, Rui; Bai, Hongjin; Zhang, Jiwen

    2016-01-01

    A total of 29 novel tetrahydropyrroloindol-based calycanthaceous alkaloid derivatives were synthesized from indole-3-acetonitrile in good yields. The synthesized compounds were evaluated against nine strains of bacteria and a wide range of plant pathogen fungi. Bioassay results revealed that majority of the compounds displayed similar or higher in vitro antimicrobial activities than the positive control. The biological activities also indicated that substituents at R₄ and R₅ significantly affect the activities. Notably, compound c4 was found to be most active among the tested calycanthaceous analogues and might be a novel potential leading compound for further development as an antifungal agent. The results could pave the way for further design and structural modification of calycanthaceous alkaloids as antimicrobial agents. PMID:27618003

  14. Biogenetically inspired synthesis and skeletal diversification of indole alkaloids

    NASA Astrophysics Data System (ADS)

    Mizoguchi, Haruki; Oikawa, Hideaki; Oguri, Hiroki

    2014-01-01

    To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [4+2] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (±)-vincadifformine, (±)-andranginine and (-)-catharanthine.

  15. Synthesis and Antimicrobial Characterization of Half-Calycanthaceous Alkaloid Derivatives.

    PubMed

    Zheng, Shaojun; Zhou, Xinping; Xu, Shixun; Zhu, Rui; Bai, Hongjin; Zhang, Jiwen

    2016-09-09

    A total of 29 novel tetrahydropyrroloindol-based calycanthaceous alkaloid derivatives were synthesized from indole-3-acetonitrile in good yields. The synthesized compounds were evaluated against nine strains of bacteria and a wide range of plant pathogen fungi. Bioassay results revealed that majority of the compounds displayed similar or higher in vitro antimicrobial activities than the positive control. The biological activities also indicated that substituents at R₄ and R₅ significantly affect the activities. Notably, compound c4 was found to be most active among the tested calycanthaceous analogues and might be a novel potential leading compound for further development as an antifungal agent. The results could pave the way for further design and structural modification of calycanthaceous alkaloids as antimicrobial agents.

  16. Biogenetically inspired synthesis and skeletal diversification of indole alkaloids.

    PubMed

    Mizoguchi, Haruki; Oikawa, Hideaki; Oguri, Hiroki

    2014-01-01

    To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [4+2] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (±)-vincadifformine, (±)-andranginine and (-)-catharanthine.

  17. Alkaloids from the stem bark of Micromelum falcatum.

    PubMed

    Luo, Xiong Ming; Qi, Shu Hua; Yin, Hao; Gao, Cheng Hai; Zhang, Si

    2009-06-01

    Two new quinoldione alkaloids, methyl 2-(3-hydroxy-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (1) and 3-hydroxy-1-methyl-3-(2-oxopropyl)quinoline-2,4(1H,3H)-dione (2), and two quinolinone alkaloids previously synthesized but first isolated as natural products, N-methylflindersine (3) and 4-hydroxy-3-methoxy-1-methyl-2(1H)-quinolinone (4), were isolated from the stem bark of Micromelum falcatum, together with the known N-methylswietenidine-B (5). Their structures were established mainly on the basis of 1D- and 2D-NMR techniques. All compounds were evaluated for toxicity towards brine shrimp larvae, and 3 showed strong toxicity with an LD(50) value of 1.39 microg/ml.

  18. Procedure for isolating the endophyte from tall fescue and screening isolates for ergot alkaloids.

    PubMed

    Bacon, C W

    1988-11-01

    A procedure was developed to isolate and determine ergot alkaloid production by Acremonium coenophialum, the endophytic fungus of tall fescue. The procedure established that macerated leaf sheath or pith from inflorescence stem placed either in a liquid medium or on a corn meal-malt extract agar medium produced isolated mycelium and characteristic conidia within a 3- to 3.5-week period. Once isolated, each fungus was placed in another liquid medium, M104T, where competent strains produced total ergot alkaloids ranging from 38 to 797 mg/liter. Several isolates were negative for ergot alkaloid synthesis. The production of ergot alkaloids by individual isolates was unstable; isolates rapidly degenerated in their ability to produce ergot alkaloids during subculture. However, the procedure as presented allows the assessment of an isolate for ergot alkaloid synthesis during its initial isolation.

  19. Antimalarial diterpene alkaloids from the seeds of Caesalpinia minax.

    PubMed

    Ma, Guoxu; Sun, Zhaocui; Sun, Zhonghao; Yuan, Jingquan; Wei, Hua; Yang, Junshan; Wu, Haifeng; Xu, Xudong

    2014-06-01

    Two new diterpene alkaloids, caesalminines A (1) and B (2), possessing a tetracyclic cassane-type furanoditerpenoid skeleton with γ-lactam ring, were isolated from the seeds of Caesalpinia minax. Their structures were determined by different spectroscopic methods and ECD calculation. The plausible biosynthetic pathway of caesalminines A and B was proposed. The anti-malarial activity of compounds 1 and 2 is presented with IC50 values of 0.42 and 0.79 μM, respectively.

  20. Ultrasonic extraction of steroidal alkaloids from potato peel waste.

    PubMed

    Hossain, Mohammad B; Tiwari, Brijesh K; Gangopadhyay, Nirupama; O'Donnell, Colm P; Brunton, Nigel P; Rai, Dilip K

    2014-07-01

    Potato processors produce large volumes of waste in the form of potato peel which is either discarded or sold at a low price. Potato peel waste is a potential source of steroidal alkaloids which are biologically active secondary metabolites which could serve as precursors to agents with apoptotic, chemopreventive and anti-inflammatory properties. The present study investigated the relative efficacy of ultrasound assisted extraction (UAE) and solid liquid extraction (SLE) both using methanol, to extract steroidal alkaloids from potato peel waste and identified optimal conditions for UAE of α-solanine, α-chaconine, solanidine and demissidine. Using response surface methodology optimal UAE conditions were identified as an amplitude of 61 μm and an extraction time of 17 min which resulted the recovery of 1102 μg steroidal alkaloids/g dried potato peel (DPP). In contrast, SLE yielded 710.51 glycoalkaloid μg/g DPP. Recoveries of individual glycoalkoids using UAE yielded 273, 542.7, 231 and 55.3 μg/g DPP for α-solanine, α-chaconine, solanidine and demissidine respectively. Whereas for SLE yields were 180.3, 337.6, 160.2 and 32.4 μg/g DPP for α-solanine, α-chaconine, solanidine and demissidine respectively. The predicted values from the developed second order quadratic polynomial equation were in close agreement with the experimental values with low average mean deviation (E<5%) values. Predicted models were highly significant (p<0.05) for all parameters studied. This study indicates that UAE has strong potential as an extraction method for steroidal alkaloids from potato peel waste.

  1. The Daphniphyllum Alkaloids: Total Synthesis of (−)-Calyciphylline N

    PubMed Central

    2016-01-01

    Presented here is a full account on the development of a strategy culminating in the first total synthesis of the architecturally complex daphniphyllum alkaloid, (−)-calyciphylline N. Highlights of the approach include a highly diastereoselective, intramolecular Diels–Alder reaction of a silicon-tethered acrylate; an efficient Stille carbonylation of a sterically encumbered vinyl triflate; a one-pot Nazarov cyclization/proto-desilylation sequence; and the chemoselective hydrogenation of a fully substituted diene ester. PMID:25756504

  2. Prenatal exposure to arecoline (areca nut alkaloid) and birth outcomes.

    PubMed

    García-Algar, O; Vall, O; Alameda, F; Puig, C; Pellegrini, M; Pacifici, R; Pichini, S

    2005-05-01

    The betel nut is commonly used as a drug by Asian populations. A high prevalence of adverse pregnancy outcomes has been reported in women who chewed betel quid during gestation. The hypothesis that chronic exposure of the fetus to arecoline (the principal alkaloid of the areca nut) is the cause was investigated in a clinical observational study on six newborns from Asian mothers who chewed betel nut during pregnancy.

  3. Amaryllidaceae Isocarbostyril Alkaloids and Their Derivatives as Promising Antitumor Agents

    PubMed Central

    Ingrassia, Laurent; Lefranc, Florence; Mathieu, Véronique; Darro, Francis; Kiss, Robert

    2008-01-01

    This review covers the isolation, total synthesis, biologic activity, and more particularly the in vitro and in vivo antitumor activities of naturally occurring isocarbostyril alkaloids from the Amaryllidaceae family. Starting from these natural products, new derivatives have been synthesized to explore structure-activity relationships within the chemical class and to obtain potential candidates for preclinical development. This approach appears to be capable of providing novel promising anticancer agents. PMID:18607503

  4. Widespread Chemical Detoxification of Alkaloid Venom by Formicine Ants.

    PubMed

    LeBrun, Edward G; Diebold, Peter J; Orr, Matthew R; Gilbert, Lawrence E

    2015-10-01

    The ability to detoxify defensive compounds of competitors provides key ecological advantages that can influence community-level processes. Although common in plants and bacteria, this type of detoxification interaction is extremely rare in animals. Here, using laboratory behavioral assays and analyses of videotaped interactions in South America, we report widespread venom detoxification among ants in the subfamily Formicinae. Across both data sets, nine formicine species, representing all major clades, used a stereotyped grooming behavior to self-apply formic acid (acidopore grooming) in response to fire ant (Solenopsis invicta and S. saevissima) venom exposure. In laboratory assays, this behavior increased the survivorship of species following exposure to S. invicta venom. Species expressed the behavior when exposed to additional alkaloid venoms, including both compositionally similar piperidine venom of an additional fire ant species and the pyrrolidine/pyrroline alkaloid venom of a Monomorium species. In addition, species expressed the behavior following exposure to the uncharacterized venom of a Crematogaster species. However, species did not express acidopore grooming when confronted with protein-based ant venoms or when exposed to monoterpenoid-based venom. This pattern, combined with the specific chemistry of the reaction of formic acid with venom alkaloids, indicates that alkaloid venoms are targets of detoxification grooming. Solenopsis thief ants, and Monomorium species stand out as brood-predators of formicine ants that produce piperidine, pyrrolidine, and pyrroline venom, providing an important ecological context for the use of detoxification behavior. Detoxification behavior also represents a mechanism that can influence the order of assemblage dominance hierarchies surrounding food competition. Thus, this behavior likely influences ant-assemblages through a variety of ecological pathways.

  5. Enantioselective Nazarov Cyclization Catalyzed by a Cinchona Alkaloid Derivative

    PubMed Central

    Huang, Yu-Wen; Frontier, Alison J.

    2015-01-01

    Nucleophilic catalysts for a 1,6 addition/Nazarov cyclization/elimination sequence were evaluated for their ability to induce enantioselectivity in the electrocyclization step. Of the tertiary amines examined, it was found that a cinchona alkaloid derivative was able to generate substituted 5-hydroxy γ-methylene cyclopentenones with excellent enantioselectivity. The study results suggest that successful cyclization depends upon the ability of the dienyl diketone substrate to readily adopt an s-cis conformation. PMID:26085696

  6. Photoassisted Synthesis of Enantiopure Alkaloid Mimics Possessing Unprecedented Polyheterocyclic Cores

    PubMed Central

    Bhuvan Kumar, N.N.; Mukhina, Olga A.; Kutateladze, Andrei G.

    2013-01-01

    Enantiopure alkaloid mimics are synthesized via high yielding intramolecular cycloadditions of photogenerated azaxylylenes tethered to pyrroles, with further growth of molecular complexity via post-photochemical transformations of primary photoproducts. This expeditious access to structurally unprecedented polyheterocyclic cores is being developed in the context of diversity-oriented synthesis, as the modular design allows for rapid “pre-assembly” of diverse photoprecursors from simple building blocks/diversity inputs. PMID:23789841

  7. An improved synthesis of 10,11-didehydro Cinchona alkaloids.

    PubMed

    Kacprzak, Karol M; Lindner, Wolfgang; Maier, Norbert M

    2008-03-01

    A revised procedure for the conversion of the four major Cinchona alkaloids (quinine, quinidine, cinchonidine, and cinchonine) into their respective 10,11-didehydro derivatives is described. The reported protocol offers several advantages over a recently published synthetic route. These include (i) enhanced robustness (ii) ready scalability (iii) reduced operational complexity and number of steps (iv) chromatography-free work-up. In addition, toxic solvents were replaced by environmentally less problematic alternatives.

  8. Bioactive carbazole alkaloids from the stems of Clausena lansium.

    PubMed

    Du, Yi-Qian; Liu, Hang; Li, Chuang-Jun; Ma, Jie; Zhang, Dan; Li, Li; Sun, Hua; Bao, Xiu-Qi; Zhang, Dong-Ming

    2015-06-01

    Seven new carbazole alkaloids, claulansines L-R (1-7), and six known analogues (8-13) were isolated from the stems of Clausena lansium. Their structures were elucidated on the basis of spectroscopic analyses, including UV, IR, and NMR experiments (HSQC, HMBC, and NOE experiment). Compound 7 showed moderate anti-inflammatory activities. Compounds 3, 5, 6, 8, and 12 exhibited moderate hepatoprotective activities. PMID:25804252

  9. Lodopyridone, a Structurally Unprecedented Alkaloid from a Marine Actinomycete

    PubMed Central

    Maloney, Katherine N.; MacMillan, John B.; Kauffman, Christopher A.; Jensen, Paul R.; DiPasquale, Antonio G.; Rheingold, Arnold L.; Fenical, William

    2010-01-01

    Chemical examination of the secondary metabolites of a marine Saccharomonospora sp., isolated from marine sediments collected at the mouth of the La Jolla Submarine Canyon, yielded the unprecedented alkaloid lodopyridone (1). The low proton-to-carbon ratio of 1 precluded structure elucidation by NMR spectroscopic methods, thus the structure was defined by X-ray crystallography. Lodopyridone is cytotoxic to HCT-116 human colon cancer cells with IC50 = 3.6 μM. PMID:19883103

  10. Distribution of opiate alkaloids in brain tissue of experimental animals

    PubMed Central

    Pilija, Vladimir; Mimica-Dukic, Neda; Budakov, Branislav; Cvjeticanin, Stanko

    2012-01-01

    The present study examined regional distribution of opiate alkaloids from seized heroin in brain regions of experimental animals in order to select parts with the highest content of opiates. Their analysis should contribute to resolve causes of death due to heroin intake. The tests were performed at different time periods (5, 15, 45 and 120 min) after male and female Wistar rats were treated with seized heroin. Opiate alkaloids (codeine, morphine, acetylcodeine, 6-acetylmorphine and 3,6-diacetylmorphine) were quantitatively determined in brain regions known for their high concentration of µ-opiate receptors: cortex, brainstem, amygdala and basal ganglia, by using gas chromatography–mass spectrometry (GC–MS). The highest content of opiate alkaloids in the brain tissue of female animals was found 15 min and in male animals 45 min after treatment. The highest content of opiates was determined in the basal ganglia of the animals of both genders, indicating that this part of brain tissue presents a reliable sample for identifying and assessing contents of opiates after heroin intake. PMID:23554560

  11. Cactus alkaloids. XXXVI. Mescaline and related compounds from Trichocereus peruvianus.

    PubMed

    Pardanani, J H; McLaughlin, J L; Kondrat, R W; Cooks, R G

    1977-01-01

    Agurell has previously detected (tlc, glc-ms) tyramine, 3-methoxytyramine, and two unknown alkaloids in the Peruvian cactus, Trichocereus peruvianus Br. and R. The presence of mescaline in other similar Trichocereus species prompted us to reinvestigate this species, which is commercially available in the United States. The nonphenolic alkaloid extracts yielded an abundance of crystalline mescaline hydrochloride (0.82% yield) and a trace of 3,4-dimethoxyphenethylamine (tlc-ms). Crystalline tyramine hydrochloride, 3-methoxytyramine hydrochloride, and 3,5 dimethoxy-4-hydroxphenethylamine hydrochloride were isolated from the phenolic alkaloid extracts; the last compound has not been previously crystallized from nature, although it is the immediate biosynthetic precursor of mescaline. Crystalline 2-chloromescaline hydrochloride was isolated drom the nonphenolic extracts; but, as determined by mass-analyzed ion kinetic energy spectrometry, this new compound is an extraction artifact. Both 2-chloromescaline and 2.6-dichloromescaline hydrochlorides were prepared synthetically from mescaline. This cactus species has a mescaline content equal or superior to peyote and should be legally controlled as an item of drug abuse.

  12. Determination of alkaloids in onion nectar by micellar electrokinetic chromatography.

    PubMed

    Carolina Soto, Verónica; Jofré, Viviana Patricia; Galmarini, Claudio Romulo; Silva, María Fernanda

    2016-07-01

    Nectar is the most important floral reward offered by plants to insects. Minor components such as alkaloid compounds in nectar affect bee foraging, with great influence in seed production. CE is an advantageous tool for the analysis of unexplored samples such as onion nectar due to the limited amounts of samples. Considering the importance of these compounds, a simultaneous determination of nicotine, theophylline, theobromine, caffeine, harmaline, piperine in onion nectar by MEKC-UV is herein reported. The extraction of alkaloid compounds in nectar was performed by SPE using a homemade miniaturized column (C18 ). Effects of several important factors affecting extraction efficiency as well as electrophoretic performance were investigated to acquire optimum conditions. Under the proposed conditions, the analytes can be separated within 15 min in a 50 cm effective length capillary (75 μm id) at a separation voltage of 20 kV in 20 mmol/L sodium tretraborate, 100 mmol/L SDS. The amount of sample requirement was reduced up to 2000 times, when compared to traditional methods, reaching limits of detection as low as 0.0153 ng/L. For the first time, this study demonstrates that there are marked qualitative and quantitative differences in nectar alkaloids between open pollinated and male sterile lines (MSLs) and also within MSLs.

  13. Determination of alkaloids in onion nectar by micellar electrokinetic chromatography.

    PubMed

    Carolina Soto, Verónica; Jofré, Viviana Patricia; Galmarini, Claudio Romulo; Silva, María Fernanda

    2016-07-01

    Nectar is the most important floral reward offered by plants to insects. Minor components such as alkaloid compounds in nectar affect bee foraging, with great influence in seed production. CE is an advantageous tool for the analysis of unexplored samples such as onion nectar due to the limited amounts of samples. Considering the importance of these compounds, a simultaneous determination of nicotine, theophylline, theobromine, caffeine, harmaline, piperine in onion nectar by MEKC-UV is herein reported. The extraction of alkaloid compounds in nectar was performed by SPE using a homemade miniaturized column (C18 ). Effects of several important factors affecting extraction efficiency as well as electrophoretic performance were investigated to acquire optimum conditions. Under the proposed conditions, the analytes can be separated within 15 min in a 50 cm effective length capillary (75 μm id) at a separation voltage of 20 kV in 20 mmol/L sodium tretraborate, 100 mmol/L SDS. The amount of sample requirement was reduced up to 2000 times, when compared to traditional methods, reaching limits of detection as low as 0.0153 ng/L. For the first time, this study demonstrates that there are marked qualitative and quantitative differences in nectar alkaloids between open pollinated and male sterile lines (MSLs) and also within MSLs. PMID:27005835

  14. Metabolic engineering for the production of plant isoquinoline alkaloids.

    PubMed

    Diamond, Andrew; Desgagné-Penix, Isabel

    2016-06-01

    Several plant isoquinoline alkaloids (PIAs) possess powerful pharmaceutical and biotechnological properties. Thus, PIA metabolism and its fascinating molecules, including morphine, colchicine and galanthamine, have attracted the attention of both the industry and researchers involved in plant science, biochemistry, chemical bioengineering and medicine. Currently, access and availability of high-value PIAs [commercialized (e.g. galanthamine) or not (e.g. narciclasine)] is limited by low concentration in nature, lack of cultivation or geographic access, seasonal production and risk of overharvesting wild plant species. Nevertheless, most commercial PIAs are still extracted from plant sources. Efforts to improve the production of PIA have largely been impaired by the lack of knowledge on PIA metabolism. With the development and integration of next-generation sequencing technologies, high-throughput proteomics and metabolomics analyses and bioinformatics, systems biology was used to unravel metabolic pathways allowing the use of metabolic engineering and synthetic biology approaches to increase production of valuable PIAs. Metabolic engineering provides opportunity to overcome issues related to restricted availability, diversification and productivity of plant alkaloids. Engineered plant, plant cells and microbial cell cultures can act as biofactories by offering their metabolic machinery for the purpose of optimizing the conditions and increasing the productivity of a specific alkaloid. In this article, is presented an update on the production of PIA in engineered plant, plant cell cultures and heterologous micro-organisms.

  15. Ergot Alkaloids (Re)generate New Leads as Antiparasitics

    PubMed Central

    Chan, John D.; Agbedanu, Prince N.; Grab, Thomas; Zamanian, Mostafa; Dosa, Peter I.; Day, Timothy A.; Marchant, Jonathan S.

    2015-01-01

    Abstract Praziquantel (PZQ) is a key therapy for treatment of parasitic flatworm infections of humans and livestock, but the mechanism of action of this drug is unresolved. Resolving PZQ-engaged targets and effectors is important for identifying new druggable pathways that may yield novel antiparasitic agents. Here we use functional, genetic and pharmacological approaches to reveal that serotonergic signals antagonize PZQ action in vivo. Exogenous 5-hydroxytryptamine (5-HT) rescued PZQ-evoked polarity and mobility defects in free-living planarian flatworms. In contrast, knockdown of a prevalently expressed planarian 5-HT receptor potentiated or phenocopied PZQ action in different functional assays. Subsequent screening of serotonergic ligands revealed that several ergot alkaloids possessed broad efficacy at modulating regenerative outcomes and the mobility of both free living and parasitic flatworms. Ergot alkaloids that phenocopied PZQ in regenerative assays to cause bipolar regeneration exhibited structural modifications consistent with serotonergic blockade. These data suggest that serotonergic activation blocks PZQ action in vivo, while serotonergic antagonists phenocopy PZQ action. Importantly these studies identify the ergot alkaloid scaffold as a promising structural framework for designing potent agents targeting parasitic bioaminergic G protein coupled receptors. PMID:26367744

  16. Monoterpene indole alkaloids from the twigs of Kopsia arborea.

    PubMed

    Cheenpracha, Sarot; Raksat, Achara; Ritthiwigrom, Thunwadee; Laphookhieo, Surat

    2014-10-01

    The phytochemistry of Kopsia arborea Blume has received considerable attention, which has resulted in the isolation of a number of new unusual indole alkaloids with intriguing structures. In this study, a new eburnane-type alkaloid, phutdonginin (1), together with eight known alkaloids: 19-OH-(-)- eburnamonine (2), melodinine E (3), kopsinine (4), kopsilongine (5), kopsamine (6), (-)-methylenedioxy-1 1,12-kopsinaline (7), decarbomethoxykopsiline (8), and vincadifformine (9), were isolated from the twigs of K. arborea. Their structures were characterized extensively by 1D and 2D NMR spectroscopy and HR-ESI-MS. All compounds were submitted to TLC screening for acetylcholinesterase inhibitory activities. Only kopsamine and decarbomethoxykopsiline showed AChE inhibition with MIR values of 12.5 and 6.25 μg, respectively, compared with galanthamine (positive control, 0.004 μg). In addition, compounds 1 and 2 inhibited moderate antibacterial activity against E. coli TISTR 780 with the MIC value of 32 .g/mL. PMID:25522533

  17. Isoquinoline alkaloids from Tinospora cordifolia inhibit rat lens aldose reductase.

    PubMed

    Patel, Mayurkumar B; Mishra, Shrihari

    2012-09-01

    The inhibitory activity of Tinospora cordifolia stem-derived alkaloids was evaluated against lens aldose reductase (AR) isolated from male Wistar rats. Anticataract potential of the alkaloids of T. cordifolia was evaluated in vitro in rat lenses, considering the activity of normal rat lenses as 100%. The biologically active constituents of T. cordifolia extract were characterized as the isoquinoline alkaloids, jatrorrhizine, palmatine and magnoflorine, by spectral analysis. The inhibitory effects varied with all chemicals and concentrations used. The inhibitory concentration (IC₅₀) values of jatrorrhizine, palmatine and magnoflorine are 3.23, 3.45 and 1.25 µg/mL respectively. The concentration of maximum activity was selected for its effect on galactose-induced polyol accumulation in vitro. The percentage inhibition of galactose-induced polyol accumulation was 62.6, 58.8 and 27.7% in the presence of jatrorrhizine, palmatine and magnoflorine, respectively. Magnoflorine may be useful as lead compounds and new agents for AR inhibition. PMID:22294283

  18. Short-term toxicity studies of loline alkaloids in mice.

    PubMed

    Finch, S C; Munday, J S; Munday, R; Kerby, J W F

    2016-08-01

    Epichloë endophytes have been used successfully in pastoral systems to reduce the impact of insect pests through the expression of secondary metabolites. The use of endophytes could be extended to other plant species, such as cereal crops, where the production of bioactive secondary metabolites would reduce the reliance on pesticides for insect control. The success of this approach is dependent on the selection of an appropriate secondary metabolite target which must not only be effective against insect pests but also be safe for grazing and monogastric animals. The loline alkaloids have been identified as possible target metabolites as they are associated with potent effects on insects and low toxicity to grazing animals. The purpose of the current study was to generate toxicological data on the loline alkaloids in a monogastric system using mice. Male and female mice were fed 415 mg/kg/day total lolines for a 3-week period. The loline treatment caused no statistically significant effect on gross pathology, histology, haematology, blood chemistry, heart rate, blood pressure or motor coordination. Reduced weight gain and food consumption were noted in the loline groups during the initial stages of the experiment. This experiment raises no food safety concerns for the loline alkaloids. PMID:27276360

  19. Taxonomic distribution of defensive alkaloids in Nearctic oribatid mites (Acari, Oribatida).

    PubMed

    Saporito, Ralph A; Norton, Roy A; Garraffo, Martin H; Spande, Thomas F

    2015-11-01

    The opisthonotal (oil) glands of oribatid mites are the source of a wide diversity of taxon-specific defensive chemicals, and are likely the location for the more than 90 alkaloids recently identified in oribatids. Although originally recognized in temperate oribatid species, alkaloids have also been detected in related lineages of tropical oribatids. Many of these alkaloids are also present in a worldwide radiation of poison frogs, which are known to sequester these defensive chemicals from dietary arthropods, including oribatid mites. To date, most alkaloid records involve members of the superfamily Oripodoidea (Brachypylina), although few species have been examined and sampling of other taxonomic groups has been highly limited. Herein, we examined adults of more than 60 species of Nearctic oribatid mites, representing 46 genera and 33 families, for the presence of alkaloids. GC-MS analyses of whole body extracts led to the detection of 15 alkaloids, but collectively they occur only in members of the genera Scheloribates (Scheloribatidae) and Protokalumma (Parakalummidae). Most of these alkaloids have also been detected previously in the skin of poison frogs. All examined members of the oripodoid families Haplozetidae and Oribatulidae were alkaloid-free, and no mites outside the Oripodoidea contained alkaloids. Including previous studies, all sampled species of the cosmopolitan oripodoid families Scheloribatidae and Parakalummidae, and the related, mostly tropical families Mochlozetidae and Drymobatidae contain alkaloids. Our findings are consistent with a generalization that alkaloid presence is widespread, but not universal in Oripodoidea. Alkaloid presence in tropical, but not temperate members of some non-oripodoid taxa (in particular Galumnidae) deserves further study. PMID:26264156

  20. β-Carboline alkaloids from Galianthe ramosa inhibit malate synthase from Paracoccidioides spp.

    PubMed

    de Freitas, Carla S; Kato, Lucilia; de Oliveira, Cecília M A; Queiroz, Luiz H K; Santana, Mábio J; Schuquel, Ivânia T; Delprete, Piero G; da Silva, Roosevelt A; Quintino, Guilherme O; da Silva Neto, Benedito R; Soares, Célia M A; Pereira, Maristela

    2014-12-01

    As part of our continuing chemical and biological analyses of Rubiaceae species from Cerrado, we isolated novel alkaloids 1 and 2, along with known compounds epicatechin, ursolic acid, and oleanolic acid, from Galianthe ramosa. Alkaloid 2 inhibited malate synthase from the pathogenic fungus Paracoccidioides spp. This enzyme is considered an important molecular target because it is not found in humans. Molecular docking simulations were used to describe the interactions between the alkaloids and malate synthase.

  1. Taxonomic distribution of defensive alkaloids in Nearctic oribatid mites (Acari, Oribatida).

    PubMed

    Saporito, Ralph A; Norton, Roy A; Garraffo, Martin H; Spande, Thomas F

    2015-11-01

    The opisthonotal (oil) glands of oribatid mites are the source of a wide diversity of taxon-specific defensive chemicals, and are likely the location for the more than 90 alkaloids recently identified in oribatids. Although originally recognized in temperate oribatid species, alkaloids have also been detected in related lineages of tropical oribatids. Many of these alkaloids are also present in a worldwide radiation of poison frogs, which are known to sequester these defensive chemicals from dietary arthropods, including oribatid mites. To date, most alkaloid records involve members of the superfamily Oripodoidea (Brachypylina), although few species have been examined and sampling of other taxonomic groups has been highly limited. Herein, we examined adults of more than 60 species of Nearctic oribatid mites, representing 46 genera and 33 families, for the presence of alkaloids. GC-MS analyses of whole body extracts led to the detection of 15 alkaloids, but collectively they occur only in members of the genera Scheloribates (Scheloribatidae) and Protokalumma (Parakalummidae). Most of these alkaloids have also been detected previously in the skin of poison frogs. All examined members of the oripodoid families Haplozetidae and Oribatulidae were alkaloid-free, and no mites outside the Oripodoidea contained alkaloids. Including previous studies, all sampled species of the cosmopolitan oripodoid families Scheloribatidae and Parakalummidae, and the related, mostly tropical families Mochlozetidae and Drymobatidae contain alkaloids. Our findings are consistent with a generalization that alkaloid presence is widespread, but not universal in Oripodoidea. Alkaloid presence in tropical, but not temperate members of some non-oripodoid taxa (in particular Galumnidae) deserves further study.

  2. Flueggether A and Virosinine A, Anti-HIV Alkaloids from Flueggea virosa.

    PubMed

    Zhang, Hua; Zhu, Kong-Kai; Han, Ying-Shan; Luo, Cheng; Wainberg, Mark A; Yue, Jian-Min

    2015-12-18

    Two new alkaloids, flueggether A (1) and virosinine A (2), were isolated from a Chinese medicinal plant, Flueggea virosa. Their structures were assigned via spectroscopic methods with the absolute configurations of 1 and 2 being established by X-ray diffraction analysis and calculated electronic circular dichroism data, respectively. Compound 1 represents the first example with an ether bridge of Securinega alkaloid oligomers, and 2 bears a new heterocyclic backbone. Both alkaloids showed mild in vitro anti-HIV activity.

  3. Localization of the Enzymes of Quinolizidine Alkaloid Biosynthesis in Leaf Chloroplasts of Lupinus polyphyllus1

    PubMed Central

    Wink, Michael; Hartmann, Thomas

    1982-01-01

    Studies with purified chloroplasts of Lupinus polyphyllus LINDL. leaflets indicate that the first two enzymes of quinolizidine alkaloid biosynthesis, lysine decarboxylase and 17-oxosparteine synthase, are localized in the chloroplast stroma. Thus, both enzymes share the same subcellular compartment as the biosynthetic pathway of lysine, the precursor of quinolizidine alkaloids. The activity of diaminopimelate decarboxylase, the final enzyme in lysine biosynthesis, is about two to three orders of magnitude higher than that of the enzymes of alkaloid formation. PMID:16662483

  4. Alkaloids from the deep-sea-derived fungus Aspergillus westerdijkiae DFFSCS013.

    PubMed

    Peng, Jiang; Zhang, Xiao-Yong; Tu, Zheng-Chao; Xu, Xin-Ya; Qi, Shu-Hua

    2013-05-24

    Two new benzodiazepine alkaloids, circumdatins K and L (1, 2), two new prenylated indole alkaloids, 5-chlorosclerotiamide (3) and 10-epi-sclerotiamide (4), and one novel amide, aspergilliamide B (5), together with six known alkaloids were isolated from the deep-sea-derived fungus Aspergillus westerdijkiae DFFSCS013. Their structures were elucidated by extensive spectroscopic analysis. All of the compounds were tested for cytotoxicity toward human carcinoma A549, HL-60, K562, and MCF-7 cell lines.

  5. Optimization of FM spectroscopy parameters for a frequency locking loop in small scale CPT based atomic clocks.

    PubMed

    Ben-Aroya, I; Kahanov, M; Eisenstein, G

    2007-11-12

    We describe the optimization of a Frequency Locked Loop (FLL) in an atomic clock which is based on Coherent Population Trapping (CPT) in (87)Rb vapor using the D(2) transition. The FLL uses frequency modulation (FM) spectroscopy and we study the effect of FM parameters (modulation frequency and index) on the sensitivity and the signal to noise ratio of the feedback signal in the FLL. The clock which employs a small spherical glass cell containing (87)Rb atoms and a buffer gas, exhibits a short term stability of 3x10(-11)/ radicaltau. The long term relative frequency stability of the 10 MHz output is better than 10(-10) with a drift of 10(-11) per day.

  6. A New Limit on Lorentz- and CPT-Violating Neutron Spin Interactions Using a Potassium-Helium Comagnetometer

    NASA Astrophysics Data System (ADS)

    Brown, Justin Matthew

    Gravity and quantum mechanics are expected to unify at the Planck scale described by an exceedingly large energy of 1019 GeV. This regime is far from the reach of the highest energy colliders, but tests of fundamental symmetries provide an avenue to explore physics at this scale from the low energy world. Proposed theories of quantum gravity suggest possible spontaneous breaking of Lorentz and CPT symmetry that have so far been unobserved. This thesis presents a test of a Lorentz- and CPT-violating background field constant across the solar system coupling to the neutron spin. A comagnetometer with polarized atomic vapors K and 3He suppresses magnetic fields but remains sensitive to non-magnetic spin couplings. In a tabletop setup, the comagnetometer measures the equatorial components to be b~nX = (0.1 +/- 1.6) x 10-33 GeV and b~nY = (2.5 +/- 1.6) x 10-33 GeV, improving the previous neutron coupling limit by a factor of 30. This work utilizes the CPT-II apparatus, a second generation comagnetometer installation which features a compact design and evacuated bell jar enclosing all optics for improved long term stability. A rotating platform provides frequent reversals of the apparatus orientation and represents a significant improvement in a Lorentz violation search. The comagnetometer is also a sensitive gyroscope, so reorientation with respect to Earth's rotation contributes significantly to the signal. Reversals along both the north-south and east-west directions provide a separation of systematic effects from maximal and minimal gyroscope backgrounds. Systematic background effects associated with reversals of the apparatus are also identified and removed. Several novel features of comagnetometer behavior are also explored including the response to an ac magnetic field and magnetic field gradients. Furthermore, a compact, nuclear spin source containing 9 x 10 21 hyper-polarized 3He spins is designed and constructed. The spin source is used in conjunction with

  7. Secretome profile analysis of hypervirulent Mycobacterium tuberculosis CPT31 reveals increased production of EsxB and proteins involved in adaptation to intracellular lifestyle.

    PubMed

    Vargas-Romero, Fernado; Guitierrez-Najera, Nora; Mendoza-Hernández, Guillermo; Ortega-Bernal, Daniel; Hernández-Pando, Rogelio; Castañón-Arreola, Mauricio

    2016-03-01

    Epidemiological information and animal models have shown various Mycobacterium tuberculosis phenotypes ranging from hyper- to hypovirulent forms. Recent genomic and proteomic studies suggest that the outcome of infection depends on the M. tuberculosis fitness, which is a direct consequence of its phenotype. However, little is known about the molecular and cellular mechanisms used by mycobacteria to survive, replicate and persist during infection. The aim of this study was to perform a comprehensive proteomic analysis of culture filtrate from hypo- (CPT23) and hypervirulent (CPT31) M. tuberculosis isolates. Using two-dimensional electrophoresis we observed that 70 proteins were unique, or more abundant in culture filtrate of CPT31, and 15 of these were identified by mass spectrometry. Our analysis of protein expression showed that most of the proteins identified are involved in lipid metabolism (FadA3, FbpB and EchA3), detoxification and adaptation (GroEL2, SodB and HspX) and cell wall processes (LprA, Tig and EsxB). These results suggest that overrepresented proteins in M. tuberculosis CPT31 secretome could facilitate mycobacterial infection and persistence.

  8. Novel Mutations in the CPT1A Gene Identified in the Patient Presenting Jaundice as the First Manifestation of Carnitine Palmitoyltransferase 1A Deficiency.

    PubMed

    Choi, Jong Sub; Yoo, Hyeoh Won; Lee, Kyung Jae; Ko, Jung Min; Moon, Jin Soo; Ko, Jae Sung

    2016-03-01

    Carnitine palmitoyltransferase 1A (CPT1A) is an enzyme functioning in mitochondrial fatty acid oxidation (FAO) of the liver. Patients with CPT1A deficiency have impaired mitochondrial FAO and display hypoketotic hypoglycemia and hepatic encephalopathy as typical manifestations. In this report, we present a case of CPT1A deficiency presenting jaundice as the first manifestation. A 1.9 years old boy showed jaundice and elevated levels of free and total carnitine were observed. From direct sequencing analysis of CPT1A, two novel mutations, c.1163+1G>A and c.1393G>A (p.Gly465Arg), were identified. At the age of 2.2 years, hypoglycemia, tachycardia, and altered mental status developed just after cranioplasty for craniosynostosis. High glucose infusion rate was required for recovery of his vital signs and mentality. Diet rich in high carbohydrate, low fat and inclusion of medium chain triglyceride oil resulted in improvement in cholestatic hepatitis and since then the boy has shown normal growth velocity and developmental milestones to date. PMID:27066452

  9. Secretome profile analysis of hypervirulent Mycobacterium tuberculosis CPT31 reveals increased production of EsxB and proteins involved in adaptation to intracellular lifestyle.

    PubMed

    Vargas-Romero, Fernado; Guitierrez-Najera, Nora; Mendoza-Hernández, Guillermo; Ortega-Bernal, Daniel; Hernández-Pando, Rogelio; Castañón-Arreola, Mauricio

    2016-03-01

    Epidemiological information and animal models have shown various Mycobacterium tuberculosis phenotypes ranging from hyper- to hypovirulent forms. Recent genomic and proteomic studies suggest that the outcome of infection depends on the M. tuberculosis fitness, which is a direct consequence of its phenotype. However, little is known about the molecular and cellular mechanisms used by mycobacteria to survive, replicate and persist during infection. The aim of this study was to perform a comprehensive proteomic analysis of culture filtrate from hypo- (CPT23) and hypervirulent (CPT31) M. tuberculosis isolates. Using two-dimensional electrophoresis we observed that 70 proteins were unique, or more abundant in culture filtrate of CPT31, and 15 of these were identified by mass spectrometry. Our analysis of protein expression showed that most of the proteins identified are involved in lipid metabolism (FadA3, FbpB and EchA3), detoxification and adaptation (GroEL2, SodB and HspX) and cell wall processes (LprA, Tig and EsxB). These results suggest that overrepresented proteins in M. tuberculosis CPT31 secretome could facilitate mycobacterial infection and persistence. PMID:26733498

  10. [Studies on the effect of an alkaloid extract of Symphytum officinale on human lymphocyte cultures].

    PubMed

    Behninger, C; Abel, G; Röder, E; Neuberger, V; Göggelmann, W

    1989-12-01

    An alkaloid extract of Symphytum officinale was investigated for its chromosome-damaging effect in human lymphocytes in vitro. In concentrations of 1.4 micrograms/ml and 14 micrograms/ml the alkaloids had no effect, in concentrations of 140 micrograms/ml and 1400 micrograms/ml the alkaloids induced sister chromatid exchanges (SCE) as well as chromosome aberrations. Additionally, the influence of rat liver enzymes (S9) was tested. The SCE-inducing capacity and the clastogenic effect of Symphytum alkaloids was increased by simultaneous application of S9-Mix. PMID:2616671

  11. Selective uptake of pyrrolizidine N-oxides by cell suspension cultures from pyrrolizidine alkaloid producing plants.

    PubMed

    von Borstel, K; Hartmann, T

    1986-02-01

    The N-oxides of pyrrolizidine alkaloids such as senecionine or monocrotaline are rapidly taken up and accumulated by cell suspension cultures obtained from plants known to produce pyrrolizidines, i.e. Senecio vernalis, vulgaris, viscosus (Asteraceae) and Symphytum officinale (Boraginaceae). The transport of the N-oxides into the cells is a specific and selective process. Other alkaloid N-oxides such as sparteine N-oxide are not taken up. Cell cultures from plant species which do not synthesize pyrrolizidine alkaloids are unable to accumulate pyrrolizidine N-oxides. The suitability of the pyrrolizidine N-oxides in alkaloid storage and accumulation is emphasized. PMID:24247963

  12. Identification and developmental expression profiling of putative alkaloid biosynthetic genes in Corydalis yanhusuo bulbs

    PubMed Central

    Liao, Dengqun; Wang, Pengfei; Jia, Chan; Sun, Peng; Qi, Jianjun; Zhou, Lili; Li, Xian’en

    2016-01-01

    Alkaloids in bulbs of Corydalis (C.) yanhusuo are the major pharmacologically active compounds in treatment of blood vessel diseases, tumors and various pains. However, due to the absence of gene sequences in C. yanhusuo, the genes involved in alkaloid biosynthesis and their expression during bulb development remain unknown. We therefore established the first transcriptome database of C. yanhusuo via Illumina mRNA-Sequencing of a RNA composite sample collected at Bulb initiation (Day 0), early enlargement (Day 10) and maturation (Day 30). 25,013,630 clean 90 bp paired-end reads were de novo assembled into 47,081 unigenes with an average length of 489 bp, among which 30,868 unigenes (65.56%) were annotated in four protein databases. Of 526 putative unigenes involved in biosynthesis o f various alkaloids, 187 were identified as the candidate genes involved in the biosynthesis of benzylisoquinoline alkaloids (BIAs), the only alkaloid type reported in C. yanhusuo untill now. BIAs biosynthetic genes were highly upregulated in the overall pathway during bulb development. Identification of alkaloid biosynthetic genes in C. yanhusuo provide insights on pathways and molecular regulation of alkaloid biosynthesis, to initiate metabolic engineering in order to improve the yield of interesting alkaloids and to identify potentially new alkaloids predicted from the transcriptomic information. PMID:26777987

  13. Naturally occurring bioactive Cyclobutane-containing (CBC) alkaloids in fungi, fungal endophytes, and plants.

    PubMed

    Dembitsky, Valery M

    2014-10-15

    This article focuses on the occurrence and biological activities of cyclobutane-containing (CBC) alkaloids obtained from fungi, fungal endophytes, and plants. Naturally occurring CBC alkaloids are of particular interest because many of these compounds display important biological activities and possess antitumour, antibacterial, antimicrobial, antifungal, and immunosuppressive properties. Therefore, these compounds are of great interest in the fields of medicine, pharmacology, medicinal chemistry, and the pharmaceutical industry. Fermentation and production of CBC alkaloids by fungi and/or fungal endophytes is also discussed. This review presents the structures and describes the activities of 98 CBC alkaloids.

  14. Elemental step thermodynamics of various analogues of indazolium alkaloids to obtaining hydride in acetonitrile.

    PubMed

    Lei, Nan-Ping; Fu, Yan-Hua; Zhu, Xiao-Qing

    2015-12-21

    A series of analogues of indazolium alkaloids were designed and synthesized. The thermodynamic driving forces of the 6 elemental steps for the analogues of indazolium alkaloids to obtain hydride in acetonitrile were determined using an isothermal titration calorimeter (ITC) and electrochemical methods, respectively. The effects of molecular structure and substituents on the thermodynamic driving forces of the 6 steps were examined. Meanwhile, the oxidation mechanism of NADH coenzyme by indazolium alkaloids was examined using the chemical mimic method. The result shows that the oxidation of NADH coenzyme by indazolium alkaloids in vivo takes place by one-step concerted hydride transfer mechanism.

  15. Environmental and genotypic influences on isoquinoline alkaloid content in Sanguinaria canadensis.

    PubMed

    Salmore, A K; Hunter, M D

    2001-09-01

    In a common garden, we investigated genetic and environmental influences on alkaloid production using Sanguinaria canadensis as a model. Nutrient and shade regimes were applied to replicated clones over one growing season, and induction of alkaloid production in bloodroot was tested on a whole-plant basis using jasmonic acid as an elicitor. Alkaloid concentrations increased with decreasing light intensity and fertilizer levels. Induction was not achieved by foliar application of jasmonic acid. Genetic influences represented by clone effects may be indicated by variation in alkaloid concentration by clone, but this experimental design did not allow us to distinguish genetic from pre-experiment environmental influences on the rhizomes.

  16. Structural Diversity and Biological Activities of Indole Diketopiperazine Alkaloids from Fungi.

    PubMed

    Ma, Yang-Min; Liang, Xi-Ai; Kong, Yang; Jia, Bin

    2016-09-01

    Indole diketopiperazine alkaloids are secondary metabolites of microorganisms that are widely distributed in filamentous fungi, especially in the genera Aspergillus and Penicillium of the phylum Ascomycota or sac fungi. These alkaloids represent a group of natural products characterized by diversity in both chemical structures and biological activities. This review aims to summarize 166 indole diketopiperazine alkaloids from fungi published from 1944 to mid-2015. The emphasis is on diverse chemical structures within these alkaloids and their relevant biological activities. The aim is to assess which of these compounds merit further study for purposes of drug development. PMID:27538469

  17. Recent Advances on the Total Syntheses of Communesin Alkaloids and Perophoramidine.

    PubMed

    Trost, Barry M; Osipov, Maksim

    2015-11-01

    The communesin alkaloids are a diverse family of Penicillium-derived alkaloids. Their caged-polycyclic structure and intriguing biological profiles have made these natural products attractive targets for total synthesis. Similarly, the ascidian-derived alkaloid, perophoramidine, is structurally related to the communesins and has also become a popular target for total synthesis. This review serves to summarize the many elegant approaches that have been developed to access the communesin alkaloids and perophoramidine. Likewise, strategies to access the communesin ring system are reviewed.

  18. Recent Advances on the Total Syntheses of Communesin Alkaloids and Perophoramidine.

    PubMed

    Trost, Barry M; Osipov, Maksim

    2015-11-01

    The communesin alkaloids are a diverse family of Penicillium-derived alkaloids. Their caged-polycyclic structure and intriguing biological profiles have made these natural products attractive targets for total synthesis. Similarly, the ascidian-derived alkaloid, perophoramidine, is structurally related to the communesins and has also become a popular target for total synthesis. This review serves to summarize the many elegant approaches that have been developed to access the communesin alkaloids and perophoramidine. Likewise, strategies to access the communesin ring system are reviewed. PMID:26353936

  19. A new isoquinoline alkaloid with anti-microbial properties from Berberis jaeschkeana Schneid. var. jaeschkeana.

    PubMed

    Alamzeb, Muhammad; Khan, M Rafiullah; Mamoon-Ur-Rashid; Ali, Saqib; Khan, Ashfaq Ahmad

    2015-01-01

    One new isoquinoline alkaloid named berberidione (1) along with four new source alkaloids berberine (2), palmatine (3), jatrorrhizine (4) and chondrofoline (5) and three new source non-alkaloids syringic acid (6), β-sitosterol (7) and stigmasterol (8) was isolated and characterised from different fractions of Berberis jaeschkeana Schneid var. jaeschkeana. All the structures were determined from 1D and 2D spectroscopic data. Crude extract, sub-fractions and isolated compounds showed excellent anti-microbial properties. The toxicity level for the alkaloids was found to be very low on THP-1 cells.

  20. Alkaloid variation in New Zealand kōwhai, Sophora species.

    PubMed

    McDougal, Owen M; Heenan, Peter B; Jaksons, Peter; Sansom, Catherine E; Smallfield, Bruce M; Perry, Nigel B; van Klink, John W

    2015-10-01

    Alkaloid contents of leaf and seed samples of eight species of Sophora native to New Zealand, plus Sophora cassioides from Chile are reported. Fifty-six leaf and forty-two seed samples were analysed for alkaloid content by proton nuclear magnetic resonance spectroscopy, which showed major alkaloids as cytisine, N-methyl cytisine and matrine. GC analyses quantified these and identified further alkaloid components. The alkaloids identified were cytisine, sparteine, and matrine-types common to Sophora from other regions of the world. Cytisine, N-methyl cytisine, and matrine were generally the most abundant alkaloids across all species with seeds containing the highest concentrations of alkaloids. However, there was no clear taxonomic grouping based on alkaloid composition. A quantitative analysis of various parts of two Sophora microphylla trees showed that the seeds were the richest source of alkaloids (total 0.4-0.5% DM), followed by leaf and twig (0.1-0.3%) and then bark (0.04-0.06%), with only low amounts (<0.02%) found in the roots. This study represents the most comprehensive phytochemical investigation of New Zealand Sophora species to date and presents data for three species of Sophora for which no prior chemistry has been reported.